Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic neuropeptide, first isolated from hypothalamic extracts, but later shown in peripheral organs, such as endocrine glands, gastrointestinal system, cardiovascular system, and reproductive organs. PACAP plays a role in fertility and reproduction. Numerous studies report on the gonadal regulatory effects of PACAP at hypothalamo-hypophyseal levels. However, the local effects of PACAP at gonadal levels are also important. The present review summarizes the effects of PACAP in the ovary. PACAP and its receptors are present in the ovary, and PACAP plays a role in germ cell migration, meiotic division, follicular development, and atresia. The autocrine-paracrine hormonal effects seem to play a regulatory role in ovulation, luteinization, and follicular atrophy. Altogether, PACAP belongs to the ovarian regulatory peptides. Pituitary adenylate cyclase activating polypeptide (PACAP) was originally isolated from the hypothalamus, and named after its cAMP increasing effect in pituitary cells  migrate from the wall of the yolk sac to the ovaries during early mammalian development. Ovarian germ cells then undergo mitosis and develop further into primary oocytes. Developing oocytes are surrounded by epithelial cells, which build the ovarian follicles. At first, follicular epithelial cells are flattened and surround the primary oocytes entering the first meiotic division. They subsequently are arrested during fetal development until the female reaches sexual maturity. The first meiotic division is only completed during the follicular development before ovulation in each cycle, and the second meiotic division is completed only at the time of fertilization, resulting in the haploid gamete Sadler, .A cohort of primordial follicles is activated at the beginning of the maturation process in cyclic manner. Follicular maturation involves changes in the oocyte, the follicular epithelial cells, and the surrounding ovarian stroma. Although significant inter-species differences exist in the follicular growth and its regulation, the major steps show basic similarities in mammalian species, and in most mammals, the vast majority of follicles undergo apoptosis similarly to humans (Matsuda et al., There is evidence for the involvement of PACAP in the proliferation of primordial germ cells (Pesce et al., In rat ovarian cells, PACAP positive cells were found in the preovulatory and ovulatory periods (Gras et al., Pituitary adenylate cyclase activating polypeptide expression in the corpus luteum of the rat was subsequently shown by Kotani et al. , 1998. PTransient expression of PACAP has also been observed in the mouse ovary within granulosa cells of preovulatory follicles after hCG treatment (Barberi et al., In situ hybridization has revealed that PACAP receptor mRNA is present mainly in the granulosa cells of the large preantral follicles, while atretic follicles and mural granulosa cells are devoid of the receptor. The authors have also demonstrated that the dominant splice variant of the PAC1 receptor was the short variant in the ovary (Park et al., Earlier studies examining binding sites for PACAP have already identified specific binding sites in the ovary (Gottschall et al., in vivo. Gras et al. (A more detailed analysis of the rat ovarian PACAP receptor expression has confirmed the expression of PAC1 receptors in the granulosa cells and, furthermore, the presence of VPAC2 receptors in these cells (Vaccari et al., s et al.  also dess et al. .All three receptors have also been identified in the mouse (Barberi et al., In all mammalian species, the early stages of folliculogenesis, including the initiation of primordial follicle growth, are independent from gonadotropins (Latini et al., Studies on the endocrine effects of PACAP revealed that PACAP can stimulate cAMP accumulation and steroidogenesis in the rat ovary (Zhong and Kasson, Interestingly, one intracerebroventricular PACAP treatment was shown to inhibit ovulation in adult animals (Koves et al., The effects of PACAP on ovarian steroidogenesis have been confirmed in human studies as well (Apa et al., PLC was activated by PACAP in granulosa but not theca cells (Vaccari et al., In addition to gonadotropins, factors secreted from granulosa cells, including steroids, growth factors, and cytokines, are essential for granulosa cell survival and follicular growth (Matsuda et al., One of the main effects of PACAP is its cell survival-promoting effects, which was first described in neuronal cells, and thus, PACAP was designated as an important neuroprotective peptide (Vaudry et al., Based on these data, it is expected that PACAP can also exert antiapoptotic effects in ovarian cells. Indeed, several studies have shown this in granulosa cells. In isolated granulosa cells, apoptosis can be induced by serum-free culturing. In accordance with the generally known antiapoptotic role of PACAP, the peptide could reduce the granulosa cell apoptosis in a dose-dependent manner, an effect that could be blocked by the PACAP antagonist PACAP6-38 (Vaccari et al., Expression of PACAP in both benign and malignant ovarian tumors has been shown (Odum and Fahrenkrug, Fully developed oocytes express PAC1 receptor and the addition of nanomolar concentrations of PACAP induces calcium release. However, this answer could not be observed in Met-I and II phase oocytes, supporting that finding that receptors are expressed stage-specifically (Vaccari et al., Xenopus oocytes, PACAP has been described to modulate membrane potential by eliciting hyperpolarization-activated chloride current, thereby affecting oocyte physiology (Kato et al., In Very interesting results have been described by Apa et al.  supportiRecently, mass spectrometric and radioimmunoassay analysis have shown that PACAP is present in human follicular fluid obtained from patients undergoing hyperstimulation treatment (Brubel et al., Recent reports point to the important roles of PACAP in fish reproduction, pointing to the fact that the effects of PACAP on the hypothalamo-pituitary axis, as well as in the gonads, are conserved and biologically ancient functions (Levy and Degani, Given the important functions of PACAP in reproduction outlined above, it would be expected that the lack of endogenous PACAP have major effects on fertility and reproduction. Indeed, PACAP deficient mice have been shown to have lower reproductive rates in several studies (Shintani et al., The present review summarized findings on the presence and effects of PACAP in the ovary. It has to be emphasized that this is only one role in the plethora of actions that PACAP plays in fertility and reproduction and that the detailed discussion of these is beyond the scope of the present review. Briefly, PACAP, at the hypothalamic level, influences receptive behavior in female rodents, in association with GnRH and steroids (Apostolakis et al., Pituitary adenylate cyclase activating polypeptide also plays a role in the muscle contraction of the vaginal wall as well as that of the uterus and uterine tube (Steenstrup et al., Effects of PACAP have also been shown in the placenta where PACAP and its receptors are present (Scaldaferri et al., In summary, PACAP is one of the peptides regulating germ cell development in the ovary and it has several other regulatory functions in reproduction. PACAP influences ovarian hormone production, affects meiosis, and is an important local regulator of follicular development. The exact physiological role and its possible clinical importance still awaits further investigation, but the current evidence points to a possible clinical diagnostic or therapeutic use of the peptide in both human and veterinary fertility.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We apologize if our article  was unclContrary to the claims by Gochfeld et al., the Avon Longitudinal Study of Parents and Children (ALSPAC) study was designed to investigate the effects of various prenatal measures of the environment ; the initial aim was to determine the relationship of these measures to a variety of different outcomes.Gochfeld et al. state that “< 2% of the ALSPAC subsample” were women who ate fish frequently (> 3 portions a week). However, when consumers of both oily and white fish are combined, the frequent fish-eaters actually comprised 647 (18%) of our pregnant population.In our article , we repoIn their letter, Gochfeld et al. cite two references  to suppoThe categorical nature of our food frequency questionnaire successfully characterizes fish consumption in the study population; people do not eat the same type of fish regularly but typically consume different types of seafood. Internal validation of our fish exposure estimates shows that they are correlated with biological markers of fish consumption, such as omega-3 fatty acids . The meaIn response to the statement of Gochfeld et al. that our study “did not address the risk for the frequent fish-eater who has elevated blood mercury,” we analyzed separately the group of frequent fish consumers (> 3 portions/week). We found that members of this group had a similar or lower contribution of blood mercury from seafood than the less-frequent consumers.Gochfeld et al. suggest that published benefits of fish consumption may generally be a result of healthy lifestyles in general. In a previous study , we perfAs we note in our paper , detaileWe were surprised that Gochfeld et al. did not highlight the important finding of contributions to mercury levels from foods that have no obvious nutrient value, such as herbal drinks, which we found to have an important association with blood mercury levels. Warning against such drinks may have greater net benefits to pregnant women than reduced fish consumption.Finally, we agree with Gochfeld et al. that pregnant women might benefit slightly by substituting fish species containing very high methylmercury with those having lower levels, but we do not recommend that women cut down their overall fish consumption.


Non-communicable causes of death and disability will dominate global health agenda for the foreseeable future. The progress in addressing their burden and achieving measurable reduction in low– and middle–income countries (LMICs) will likely require similar steps that were effective in reducing maternal and child mortality globally: (i) defining the size of the burden and the main causes responsible for the majority of the burden; (ii) understanding the most important risk factors and their importance in different contexts; (iii) systematically assessing the effectiveness and cost of the interventions that are feasible and available in LMICs; and (iv) formulating evidence–based health policies that will define appropriate health care and health research priorities to tackle the burden in the most cost–effective way.Over the past year the pandemic of non–communicable diseases (NCDs) has become a key focus of global political agenda. At the United Nations' high–level meeting on the prevention and control of NCDs in September 2011, a general consensus has been reached that NCDs were already the leading causes of death in all world regions and that their burden is increasing rapidly . In LMICThe release of the new global burden of disease (GBD) estimates for the year 2010, by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington in Seattle, is anticipated with great interest . The newThe first step in this process is to measure the burden of NCDs in LMICs. This is a challenging task given the scarcity of available data, inconsistency in case definitions of the measured diseases, differences in reporting of results  used by different investigators, lack of funding, research infrastructure and capacity for community–based studies in LMICs, changing definitions of diseases over time, low transcultural adaptability of screening instruments, and many others -8. MethoJournal of Global Health, we are publishing several studies that attempt to summarise information on the burden of non–communicable diseases and provide estimates for a region that has traditionally been considered “information gaps”: the African continent. The papers by George-Carey et al. [In the current issue of the y et al. , Paul ety et al. , Graham y et al.  and Dowmy et al.  provide y et al. , Moten ey et al. , Kolcic y et al. , while My et al. . In the


We show that this claim is not supported by the data and analysis reported in Allen et al.’s paper.There has been much recent debate in Australia over whether lethal control of dingoes incurs environmental costs, particularly by allowing increase of populations of mesopredators such as red foxes and feral cats. Allen  Canis dingo Meyer 1793). The usual approach to this problem is to attempt to suppress dingo populations by distributing meat baits laced with poison [Vulpes vulpes) and feral cat (Felis catus) [One of the most vexed issues in the management of Australian wildlife is how to protect livestock from predation by dingoes  ,6, whichet al.[Varanus sp.) was measured on each area . Then, they applied a differential poison-baiting regime in which the treatment area was baited twice per year for two to three years, and the control area was left unbaited.In a recent paper, Allen et al. report tet al. make two claims from the results of this experiment: (i) as a result of poison-baiting, activity of dingoes was “demonstrably less” in baited areas; and (ii) increase of mesopredators did not occur in response to these reductions because those smaller predators were also suppressed by baiting, with the result that mesopredators were in “similar or greater abundance in unbaited areas relative to baited areas”. Allen et al. conclude that poison baiting of dingoes does not lead to mesopredator release. The purpose of this comment is to make it clear that this conclusion is not supported by Allen et al.’s data.Allen et al. tested for an effect of their baiting programs on dingo activity by averaging all estimates of activity through time and contrasting mean values on their treatment and control areas. They found significantly higher dingo activity in unbaited areas at four of the six experimental sites. On the face of it, this suggests that baiting tended to produce sustained reductions in dingo activity. However, at two of these sites (Mt Owen and Quinyambie), the activity of dingoes was already higher on the ‘unbaited’ areas before the differential baiting treatment was applied . These differences did not obviously change thereafter, and so cannot be attributed to baiting. Presumably, they were caused by other differences between those areas that were not considered in the analysis. These two sites happened to be the ones with the highest measures of dingo activity on the sites that were allocated to the ‘unbaited’ treatment, so they make a large contribution to the difference in mean activity on ‘baited’ versus ‘unbaited’ sites.Allen et al.’s analysis of their data. Their experimental design should have allowed them to compare the difference in dingo activity on paired study areas before and after the imposition of the differential baiting treatment, and so attribute changes in mean activity to the effect of their baiting programs. But they did not make this before/after comparison: they compared activity on baited and unbaited sites after taking means of all measurements of activity, pooling samples from before and after application of their treatment. It remains unclear whether baiting did cause sustained reductions in dingo activity on their sites. We requested Allen et al.’s raw data so that we could check for such an effect, but they were unwilling to provide it. Inspection of Allen et al.’s plotted data  suggests that the effect of their baiting programs on mean dingo activity was in fact weak or absent in most cases.This observation points to a serious problem in Allen et al. tested whether individual episodes of bating caused short-term reductions in dingo activity. They did this by comparing activity of dingoes before and soon after individual episodes of baiting, and making the same comparison on paired unbaited areas surveyed at the same times. They conclude that baiting produced rapid reductions in dingo activity, but that dingo activity then recovered towards pre-baiting levels, presumably due to immigration. However, their own analysis of their data refutes this. A short-term effect of baiting would be revealed by a significant time-by-treatment interaction in the ANOVA that Allen et al. used to analyse these data. The interaction term in their ANOVA was weak and non-significant, showing that knockdowns due to baiting were either too small or too transient to be distinguished from background variation in activity.In a separate analysis, Allen et al.’s analysis. Their data on activity of dingoes and other predators are highly skewed and contain many zero values. Data with such skewed distributions ought not be analysed by conventional parametric methods such as ANOVA unless normalised by appropriate data transformations. This was evidently not done. For this reason alone, all inferences that Allen et al. draw from their results should be regarded as unreliable.We note in passing a third problem with Allen et al. have little support for their inference that baiting affected dingo activity. There is even less support for their conclusion that smaller predators were affected by baiting, such that they showed higher activity on unbaited areas relative to baited areas. The problems here are similar to those detailed above. At only two of the six experimental sites (Cordillo and Quinyambie) was average fox activity significantly higher on unbaited than baited areas, but these differences were present before the differential baiting treatment was applied and so cannot be attributed to the effects of baiting. There are no indications of differences in activity with respect to baiting for feral cats and goannas at any of the study sites. The analysis testing for short-term responses also found no effects for foxes, cats or goannas.So, Allen et al. Foxes readily take poison baits laid for dingoes and, other things being equal, should have increased their activity in the absence of baiting. Instead, one of the strongest patterns in Allen et al.’s data is that fox activity was consistently low at all of their sites, and at almost all times. Activity indices for foxes were typically about 5-10 % of those measured for dingoes, and many surveys returned zero values for fox activity. Other research using similar methods in the same region has shown that measures of fox activity varied over a similar range to that of dingoes . Why Allen et al. recorded such low fox activity is puzzling. One explanation could be that availability of prey for foxes was low at the times and in the places where Allen et al. worked, so foxes were unable to increase when released from the effects of baiting; alternatively, dingo activity might have remained sufficiently high to prevent foxes  from increasing in unbaited areas. Supporting this latter interpretation, Letnic et al.’s (2009) surveys found that fox activity was greatest at levels of dingo activity lower than those recorded at any of the sites sampled by Allen et al.The lack of evidence for increased fox activity in unbaited areas should have been surprising to Allen et al. – sand-plot tracking – is relatively insensitive to changes in activity of cats and goannas [For feral cats and goannas, a direct impact of baiting on activity would be more surprising. Feral cats are much less likely than foxes to take meat baits, because they have a strong preference for hunting of live prey ,10. Goan goannas .et al. had produced large and sustained reductions in dingo activity? This question is an important one, because while baiting seems to have had little effect in this study, there is evidence that it can be effective in reducing dingo activity [et al.’s results are not relevant to areas where broad-scale aerial baiting is employed, or where ground baiting is coordinated over large areas, or conducted in conjunction with exclusion fencing. These measures are likely to increase the efficacy of baiting in reducing dingo populations.The question this study cannot answer is: what would have happened if the poisoning programs implemented by Allen activity ,5. Otheractivity  or, if bactivity ,15. In aet al. for taking an experimental approach to this problem. Unfortunately, they have not conducted a rigorous analysis of their data. Especially, we find little or no support for their inference that the poison baiting programs reported in their paper had any effect on activity of wild predators, contrary to their view that baiting suppressed activity of all medium-sized and large vertebrate predators. We conclude that their study does not provide useful evidence on the environmental costs of lethal control of dingoes.The management of dingoes is a highly conflicted and frequently emotional issue in rural Australia. There is an urgent need to find approaches that can balance the needs of agricultural production with environmental conservation. Achieving this balance requires rigorous evaluation of evidence on the effectiveness of alternative strategies of dingo management and their environmental consequences. We commend Allen The authors declare that they have no competing interests.All authors contributed equally to the content of the paper; CNJ led the writing. All authors read and approved the final manuscript.CNJ is Professor of Wildlife Conservation at the School of Zoology, University of Tasmania; MSC is Senior Lecturer at the School of Biological Sciences, University of Sydney; CRD is Professor in Terrestrial Ecology at the School of Biological Sciences, University of Sydney; MIL is ARC Future Fellow at the Centre for Ecosystem Science, School of Biological Earth and Environmental Sciences, University of New South Wales; TMN is Postdoctoral Scholar at the Department of Forest Ecosystems and Society, Oregon State University; DGN is Postdoctoral Scholar at the Centre for Integrative Ecology and School of Life and Environmental Sciences, Deakin University; EGR is Senior Lecturer at the Centre for Integrative Ecology and School of Life and Environmental Sciences, Deakin University; ADW is Adjunct Lecturer at the School of Marine and Tropical Biology, James Cook University.


Obesity remains a prominent public health concern in the United States as well as many other countries, with 33% of adults worldwide overweight or obese in 2005 and an estimated 60% by 2030  (Davis et al.,


A number of cellular stresses and cytotoxic agents trigger mitochondrial permeability transition (mPT), considered as a final common pathway of cell death  ratio warrants further analysis, particularly in view of the fact that the number of copies of subunit c is constant and appears to be independent of the metabolic state within all vertebrate animals and most invertebrate species  was able to almost completely block TNF/emetine-induced cell death, aurovertin B  had no effect on mPT in this cell death modality (Shchepina et al., Finally, these findings recall an old question about the pharmacology of mPT. Oligomycin, a potent inhibitor of the F1F0 ATP-synthase in mPT and cell death will soon follow.Altogether, as shown by the above list of outstanding questions, we anticipate that the findings by Bonora et al.  are only


Publication of papers related to psycho-social interventions in general and Behavior Therapy, in particular, in Indian Journal of Psychiatry has been limited. Though the first paper related to Behavior Therapy was published in 1952, a manual search of all available issues of the journal from 1949 showed that only 42 papers related to Behavior Therapy have been published till 2009. Among them 10 are case reports. Methodological limitations abound even in the papers on larger groups of patients. Studies using operant conditioning have been very few. Aversion therapy and progressive muscle relaxation have been very frequently used. The published articles are reviewed under the various diagnostic categories. Publications in the recent years have been mostly on Cognitive Behavior Therapy. Even after 57 years of co-existence, the relationship between Behavior Therapy and Indian Psychiatry remains a tenuous one. One of the characteristics of psychiatry, as practised in India, is the extremely limited use of psycho-social methods of treatment. In 1973, when Varma and Ghosh[The above observation on psychological methods of treatment in general is also true with regard to Behavior Therapy (BT) or any of its variants. Most psychiatrists in India, I feel, will admit that these psychological methods are useful or even essential in some psychiatric disorders, but many of them do not have either the time or inclination to practice them. Often such patients are referred to psychologists or social workers who are interested in psycho-social methods of treatment. So it is likely that publications like Indian Journal of Clinical Psychology may have many more papers on BT than Indian Journal of Psychiatry. However, the present article is not an attempt to review the state of BT in India, but is a more restricted attempt to review articles published in Indian Journal of Psychiatry since it will more accurately reflect the Indian psychiatrists’ attitude towards BT.Using the key words ‘Behavior Therapy’ on the IJP web site yielded a list of 42 articles related to the topic. However, when one went through the list only nine articles were found to have anything to do with BT and the rest were on totally unrelated topics ranging from ‘ECT and clozapine’ to ‘psychotic symptoms in acromegaly’!So a manual search was done through the contents of all available issues of Indian Journal of Neurology and Psychiatry (1949 to 1953) and Indian Journal of Psychiatry (1958 to 2008) in the DVD published by Indian Psychiatric Society. Contents of the three issues of the Journal published in 2009 were also searched. Articles which contain words like - Behavior therapy, behavior modification, behavioral intervention, cognitive therapy, and cognitive behavior therapy, biofeedback, relaxation training, which are related to BT, were searched. In addition, if the title of the articles suggested the possibility of BT use, for example ‘Treatment of Trichotillomania,’ then the articles were given a detailed look to see whether the authors have in fact used BT and those papers were also selected.The article which could be considered the first on this topic was authored by Ganguly in IndiaIt may come as a surprise to many readers, especially of the older generation, that Satyanand who has Skepticism about the newly emerging treatment method is evident in Neki’s review oIn the early 1970s BT was still a new entrant in to the field of psychiatry in India. This is evident from the two articles by Chopra.6 In the All 11 patients improved (six markedly improved) with the treatment. On follow-up varying from one month to two years only one patient was found to have relapsed. Though published in IJP, the papers were based on the author’s work in Australia. It is interesting to note that Chopra as well as other authors at that time, while talking about outcome on follow-up usually added “there was no symptom substitution,” perhaps to counter the criticism of psychoanalytically oriented therapists who held that BT is only removing symptoms at a superficial level and since the deep seated conflicts are not dealt with, the patient will invariably present with some other symptoms at a later date.BT was the first psychological method of treatment which showed that its therapeutic efficacy can be established by rigorous scientific methods of evaluation like randomized, placebo-controlled, double blind studies, instead of merely relying on the subjective opinions of patients and therapists. It has shown that methodological issues like sample size, randomization, use of controls, masking of the assessor, valid outcome measures, determination of statistical as well as clinical significance of outcome etc. are important and feasible in evaluating efficacy of psychotherapeutic methods also. But when we go through the published studies in India it becomes obvious that we have not paid attention to such methodological issues.Out of the 42 articles related to BT till 2009, 10 are single case reports. In a newly emerging model of treatment single case reports have a place. BT papers by western workers have shown that efficacy of treatment technique can be more convincingly demonstrated, even in a single case by following an A-B-A-B design. But none of our case reports have included such a step.Main model of BT as practiced in India seems to be classical conditioning. Operant conditioning which has emerged as a more versatile and effective approach and has a greater degree of acceptance by patients, has few adherents here.Excessive reliance on aversive techniques is seen in many of the studies in a wide variety of disorders-hysteria, homosexuality, tremors, titubation etc. It is interesting to note that even in the 1970s, in the ‘Instructions to Authors” in the well known BT journal, ‘Behavior Therapy and Experimental Psychiatry’ (edited by Joseph Wolpe), it was stated that reports using aversion therapy techniques will not be accepted, unless no other proven method of treatment exists for that condition.Jacobson’s Progressive Muscle Relaxation (JPMR) is used as a part of BT in almost all conditions ranging from nail-biting to schizophrenia! Justification for its use is not given in many of the papers, so much so, even in some of our academic institutions JPMR is considered to be synonymous with BT, even to the extent of postgraduate trainees in psychiatry who are posted in Behavior Therapy units getting trained only in JPMR.Many of the reports show that every behavioral technique described in a standard text book on the subject is used for every disorder, often without justifying such a multipronged approach, which reduces the cost effectiveness of the therapy and its application in settings with limited time and trained personnel.et al.[et al.[Agarwal’s paper inet al. treated l.[et al. treated In an attempt to help unmarried men who present with ED, but were unable to go through the classical Masters and Johnson sex therapy, because of the lack of a partner, Kuruvilla introducThe above reviewed studies highlight some of the modifications introduced by Indian therapists to deal with certain special difficulties encountered in our country, in the treatment of sexual dysfunctions.et al.[et al.[et al.[In the 1970s and 80s, men with ego-dystonic homosexuality often came to Indian psychiatrists for help and behavioral techniques were used in treating such persons. Sakthivel et al. treated l.[et al. with elel.[et al. treated et al.[in-vivo for eliminating the avoidance behavior to social situations which produced anxiety in him because of frotteurism. Frotteurism itself was treated with exposure to situations of bodily contact with males in imagery and in-vivo and also aversion therapy. Symptoms were eliminated in 10 sessions. This patient was followed up for one year when he was found to have no anxiety in social situations and no indulgence in frotteurism. BT consisting of relaxation training, aversion therapy with aversion relief, modeling, orgasmic reconditioning, behavioral counseling and sex education, was used by Andrade et al.[A case of frotteurism was treated by Kuruvilla et al. with sysde et al. for a paet al.[et al.[et al.[Nammalvar et al. treated et al. suggest l.[et al. treated l.[et al. describeet al.[et al.[et al.[et al.[Fernandez reportedet al. paper pul.[et al. brought l.[et al. also repl.[et al. reportedet al.[Biofeedback, which is often considered a BT technique, was used in the treatment of anxiety neurosis by Sargunraj et al. Thirty set al.[et al.[Sahasi et al. comparedl.[et al. but thiset al.[Sethi et al. comparedFive executives with tension headache were treated by Mehta with JPMGada comparedet al.[Trivedi et al. reportedet al.[In a more recent paper, Kaur et al. reportedet al.[Seven females diagnosed with ‘hysterical vomiting’ were treated by Bhattacharya et al. with eleet al.[Vyas et al. reportedet al.[Nasirabadi et al. reportedet al.[Forty eight alcoholics were treated by Bagadia et al. with eleTen patients diagnosed to have ‘neurotic depression’ were given multi-modal BT by Kumariah. TreatmenThe earliest case report on the use of BT, published in IJP was by Ratan Singh who treaet al.[Nammalvar et al. treated et al.[A four-and-a-half year old child with an I.Q of 110, with encopresis for two and a half years, unable to even attend nursery school, was treated by Behre et al. Basal raReevar reportedThe emergence of Cognitive Therapy (CT) as an effective treatment approach for many conditions like depression and anxiety disorders and its subsequent merger with BT to form Cognitive Behavior Therapy (CBT) has had its impact on the Indian scene also. There are a few psychiatrists and many psychologists practicing it, but publications in this field in IJP have been few. An early paper by Kuruvilla on 17 paThe few original reports on the use of CBT which have appeared in IJP are reviewed below.et al.[in vitro, exposure and response prevention, stress inoculation, skills training and cognitive restructuring. Treatment led to improved adjustment scores in Bell’s Adjustment Inventory, decrease in intensity of perceived symptoms and automatic thoughts. During follow-up, gradual decline in improvement with CBT happened, but at nine months the patients were still better than they were before CBT. The paper does not give information on concomitant anti-psychotic medication which also could have had an influence on the outcome. Description of the symptoms the patients in this study had suggest that at the time of CBT most of them were in a state of post psychotic depression and were not actively psychotic. It is also not clear how many patients have had each of the various interventions listed and their effect on specific problems. Clinical significance of the improvement seen on rating scales is not given either.Shriharsh et al. treated et al.[In a case report on a 31-year-old man with paranoid schizophrenia, who had the delusion of being controlled, being made to laugh, cry etc. through the internet, Dugal et al. report tet al.[in vivo exposure. The second group was treated by what the authors call ‘behavioral intervention’ (BI), which included only psycho-education and applied relaxation. BT group had 15 to 20 sessions in five weeks while the BI group had eight to 10 sessions in two weeks. Although both the groups showed improvement, the CBT group was superior in the reduction of panic symptoms, avoidance behavior, safety behaviors and negative cognitions. In a large percentage of CBT patients the magnitude of change was clinically significant. The therapist herself being the assessor of improvement, inequality in the time of contact with the therapist as well as total duration of treatment are some the methodological problems that could have influenced the outcome. The BI group had only psycho-education and applied relaxation as its components whereas standard BT of panic disorder also include interoceptive exposure and in vivo exposure while in this study they are part of CBT only.Thirty patients with panic disorder were treated by Manjula et al. in two gIn a survey of the current scene on the use of CBT, Kuruvilla evaluate


BMC Medicine, several aspects of autoimmunity have been addressed, suggesting that we are now at the forefront of autoimmunity science. Within the environmental factors generating autoimmunity are now included unsuspected molecules such as vitamin D and aluminum. Some adjuvants such as aluminum are recognized as causal factors in the development of the autoimmune response. An entirely new syndrome, the autoimmune/inflammatory syndrome induced by adjuvants (ASIA), has been recently described. This is the new wind blowing within the branches of autoimmunity, adding knowledge to physicians for helping patients with autoimmune disease.Almost 25 years ago, the concept of the ‘mosaic of autoimmunity’ was introduced to the scientific community, and since then this concept has continuously evolved, with new pebbles being added regularly. We are now looking at an era in which the players of autoimmunity have changed names and roles. In this issue of  BMC Medicine, several aspects of autoimmunity have been addressed suggesting that we are now at the forefront of autoimmunity science.Almost 25 years ago the concept of the ‘mosaic of autoimmunity’ was intret al.[One of the mainstays of the mosaic concept is that autoimmune diseases (ADs) occur in genetically predisposed individuals. This coet al.. Physiciet al.[highFoxP3+ T-regulatory cells, is very characteristic in elderly people. It is possible that during aging, an imbalance between thymic and peripheral regulatory T-cell output occurs, with the ratio favoring the peripheral component, which possibly allows a pro-inflammatory response and increases the susceptibility to autoimmunity. Furthermore, in addition to this disruption of adaptive immunity, it has been shown that disruption of the autoimmune response also occurs in the innate immune system[et al.[Strengthening the theory of a genetic basis is the evidence that ADs occur more often in young people. Howeveret al. suggestee system. Pollard[et al. suggeste[et al.. By recr[et al.. By cont[et al..Nonetheless, environmental factors are still central to autoimmunity. Indeed,et al.[per se, or a result of the background therapy, or if it represents another causative factor of ADs[Ramagopalan et al. analyzedr of ADs.et al.[et al.[It has been shown that a link exists between the mycobacterium, ADs, and, surprisingly, another component of the puzzle, namely, vitamin D. Vitaminet al.. Moreove[et al., in thei[et al.,24. The [et al.. Finally[et al..Thus, it is evident that every day, people are exposed to several triggering factors for ADs. People can be exposed to such elements through diet , and other sources. For instance, another defendant, aluminum , is used as an adjuvant in vaccines, and its association with autoimmunity has recently been highlighted. Alum caet al.[Alum has a number of mechanisms by which it works as an adjuvant Table . Moreoveet al. showed tThese various lines of evidence reinforce the idea that alum is neurotoxic, and that continuously escalating doses of this poorly biodegradable adjuvant in the population may become insidiously unsafe, especially in cases of over-immunization or immature/altered blood–brain barrier or high constitutive CCL-2 production.It is possible that this is part of the explanation for the real new wave in autoimmunity, that of autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This syet al.[et al.[Neuropsychiatric (NP)SLE is triggered by multiple mechanisms, including several autoantibodies. One of the leading pathogenic autoantibodies in NPSLE is anti-ribosomal P protein. Carmona-Fernandes et al. found thet al.,32. Like[et al. identifi[et al.. This po[et al., who higet al.[One of the autoimmune conditions more clearly associated with CNS involvement is anti-phospholipid syndrome (APS). Katzav et al. have shoet al.[The thrombophilic network is also involved in another autoimmune disorder, celiac disease. Lerner et al. showed tA further component in the mosaic of autoimmunity is the question of what stays in the renal pyramids. Renal involvement represents a major issue in autoimmune connective tissue diseases (CTDs). The main question is whether renal damage is caused by the underlying disease or by interventions, particularly by drug reactions as described by Kronbichler and Mayer. ConsequPhosphodiesterase-targeted therapies 4 are also a promising tool for treating patients with a variety of autoimmune diseases. Intriguingly, these inhibitors have been used to treat both diseases of the CNS (such as Parkinson’s disease) and of the lung (such as chronic obstructive pulmonary disease), suggesting a common soil between the lung and the CNS.et al.[Finally, the revolutionary roads traced by biologic therapies continue to provide benefits for patients with ADs. Rosman et al., in theiIn conclusion, a new wind is blowing within the branches of autoimmunity, from the unexplored continent of ASIA syndrome, which iThe authors declare that they have no competing interests.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/11/101/prepub


In this research topic, Herzallah et al.  have conThe findings reported in this paper (Herzallah et al., Several paradigms have been used to explore the processing capabilities of depressed patients in contexts of reward and/or punishment. Findings have not been entirely consistent, possibly due to heterogeneity of patient samples and differences in testing protocols, with different authors suggesting that patients with MDD have more significant deficits in reward learning (Henriques and Davidson, Others have compared neural responses to stimuli with positive and negative valence between depressed and non-depressed volunteers. McCabe et al.  comparedemotional blunting described by some patients during SSRI treatment (Price et al., per se and the effects of recovery from depression. Future work, with a longitudinal study design and/or including groups at different phases of treatment or treated with non-SSRI drugs or non-pharmacological alternatives, should address these questions.The findings now reported by Herzallah et al.  highligh


Long non-coding RNAs are attracting the attention of researchers in many fields. These RNAs are longer than 200 nucleotides and do not encode any protein. A subset of them is reported to be strongly correlated with poor patient prognosis, suggesting a potential role in cancer progression , and Array Express Databases to analyze the expression level of most recent cited and noted lncRNAs in studies on cancer progression  between gastric cancer and normal tissues are brought in Table Student's MALAT-1 is not significantly different between gastric cancer and normal tissues in the datasets. MALAT-1 was originally identified to be up-regulated in patients at the high risk of metastasis of non-small cell lung tumors (NSCLC). It seems that MALAT-1 functions in the regulation of alternate splicing by modulating the activity of SR proteins (Ji et al., We found that the expression level of ANRIL plays an important role in the repression of P14ARF, P15INK4b, and P16INK4a. The proposed mechanism of ANRIL is an interaction with Polycomb complexes and silencing target genes. Although some relationships between the ANRIL gene and cancer progression have been reported (Yu et al., There are some reports indicating that CRNDE has been identified as an lncRNA whose expression is highly elevated in some tumors. It seems that CRNDE is associated with a “stemness” signature in some cancer types (Ellis et al., HOTAIR is an lncRNA that binds to the PRC2 complex and targets it at some genes involved in tumor suppression. Its up-regulation is reported in different cancer types (Gupta et al., The datasets show that this lncRNA is up-regulated in gastric adenocarcinoma compared with normal tissues. H19 is an lncRNA which is implicated as having both oncogenic and tumor suppression properties. These two controversial roles of H19 may be attributed to the nature of H19 function or context in different tissues. Our results may support its oncogenic role in gastric carcinogenesis.There is a significant up-regulation in gastric adenocarcinoma tissues compared with normal ones in our results drawn from databases Table . H19 is MEG3 is an lncRNA which is identified as having an inhibitory role in tumor growth. This lncRNA is the first one proposed to have a tumor suppressor role (Zhang et al., MEG3 is down-regulated in gastric adenocarcinoma compared with normal tissues.HOTAIR, H19, and MEG3 may potentially be suitable candidates for study in order to find some biomarkers or therapeutic targets. Hajjari et al. found a significant up-regulation of HOTAIR lncRNA in gastric adenocarcinoma tissues compared with normal ones by Real-time PCR (Hajjari et al., H19 levels were increased in gastric cancer cells and tissues compared with normal controls (Yang et al., Altogether, based on the results, it seems that some lncRNAs such as HOTAIR and H19 on cell proliferation and metastasis (Yang et al., The different expression of certain cancer type-specific lncRNAs can be exploited for the development of novel biomarkers as lncRNA expression (Gibb et al., HOTAIR and H19 as potential biomarkers or therapeutic targets in this type of cancer.Our results, drawn from microarray databases, may help researchers to investigate the role of lncRNAs in gastric cancer progression. Large scale and follow-up studies are necessary to consider lncRNAs such as


Decision-Making Experiments under a Philosophical Analysis: Human Choice as a Challenge for Neuroscience.” As the first editor of the issue I want to briefly comment on each of the articles highlighting its achievements and prospects for the future.This is an opinion article on the special research topic now turned into an e-book called “To what extent a decision to deceive someone is conditioned by social pressure of being caught in a lie and suffering the consequences of it? This socially relevant question is addressed in Sip et al. . DeceptiDeneve  presentsOsman  empiricaReviews' section we have a very innovative article by Nakao et al. (In the o et al. . This meHeinzelmann et al.  discusseTaking as a standpoint Stephens and Anderson's  already Lucci  proposesSmaldino and Richerson  approachVolz and Gigerenzer  differenper se, it contends that compatibilism of responsibility and mechanism is possible. Their arguments function in hypothetical manner: if agents can be accountable for policies that in some sense determine decisions, they can be held responsible for those decisions, even if they do not have conscious access to the reasons for those decisions.Shadlen and Roskies  argue fo


Dear Editor,I read with interest the recently published article by Imani et al., in your


Was it a vision, or a waking dream? .Reminiscent of Wilder Penfield's famous experiments, Neurologists in France have reported a remarkable case in which intraoperative electrical stimulations of the posterior cingulate cortex (PCC) in a conscious patient induced transient dreamlike states with vivid visual imagery  in an epilepsy patient by Herbet et al. . The PCCUpon reading Herbet et al.'s report, we were struck by similarities between the subjective reports given post-PCC stimulation and those we observed after controlled administration of the classic hallucinogen, psilocybin  sleep relative to waking (Braun et al., So, how might disrupting DMN activity be the cause of dreamlike visions? One way to address this question is to look for clues from studies on REM-sleep and other dreamlike states. Firstly, it is worth noting that the MTLs are major subcortical nodes of the DMN (Supekar et al., quality of consciousness (Carhart-Harris et al., In summary, we were struck by similarities between Herbet et al.'s findings with direct electrical stimulation of the PCC and those of our own with psilocybin and neuroimaging. Their case provides some causative support for the notion that the PCC is centrally involved in mediating the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Neurotrophins are important proteins that regulate survival, development and function of neurons. They are produced by a variety of cells and exert their effects upon binding to specific tyrosine kinase receptors. The first neurotrophin to be identified was Nerve Growth Factor (NGF). From the pioneer studies performed by Rita-Levi Montalcini, awarded with the Nobel Prize, other neurotrophins have been identified and this family of neurotrophic factors now includes Brain Derived Neurotrophic Factor (BDNF), Neurotrophin 3 and Neurotrophin 4. Their function as pro-survival proteins has been consolidated but subsequent studies have demonstrated that neurotrophins may also play a role in some pathological conditions. This is the focus of this special issue of Current Neuropharmacology. et al., addresses the involvement of neurotrophins, NGF and BDNF in particular, in Alzheimer’s disease and the possibility of using neurotrophin-based therapies.The paper by Allen et al., summarize studies that support the involvement of neurotrophins in the lower urinary tract (LUT) dysfunction and suggest the use of urinary neurotrophins as biomarkers of LUT pathologies.Frias et al., addresses the involvement of neurotrophins in depression, a poorly understood pathology with an increasing prevalence in Western countries.The paper by Neto et al., addresses the involvement of neurotrophins in neuropathic pain, a complex pathology difficult to tackle with, and its importance as targets for neuropathic pain treatment. The paper by Siniscalco et al., summarize the clinical uses of stem cell-based administration of neurotrophins for the treatment of spinal cord injury.Teng This issue is published in memory of David Dawbarn, who passed away unexpectedly in January 2010. David dedicated most of his work at the Bristol University to understanding the importance of neurotrophic factors in Alzheimer’s disease, unraveling the molecular interactions between neurotrophins and their high-affinity receptors. His research was a key factor to the design of new therapies for the treatment of Alzheimer’s disease, pain and asthma. He is greatly missed by the scientific community, friends and family.


The objective of this paper is to provide a review on the psychiatric comorbidity research in India based on the data published in the last six decades. The comorbidity data world over reflects that it is a much more common phenomenon than observed in routine clinical practice. In India, research into this domain of psychiatry has been limited, with comorbidity reported to be as high as 60%. In the few publications in this area, most of the authors have looked into substance related comorbidity. Small numbers of studies have looked into comorbid conditions in child psychiatry, especially mental retardation and very few studies have looked at other comorbidities. The landmarks in the studies in the area of psychiatric comorbidity have been highlighted in this review article. The term comorbidity was first introduced by Feinstein in 1970 to denote those cases in which a ‘distinct additional clinical entity’ occurred during the clinical course of a patient having an index disease. economic36Similar results have been obtained from the Australian National survey of Mental Health and wellbeing. Comorbidet al.[To compare substance use in mentally ill and the normal population Dube et al. conducteet al.[Cannabis has been socially accepted substance in India and has been used in traditional Indian medicine. The psychological consequences of chronic cannabis use have been studied by many Indian researchers. In India it was Dhunjbhoy, who firset al. analyzedet al.[Trivedi et al. screenedet al.[Kishore et al. assessedet al.[Goswami et al. examinedet al.[In a group of 70 patients with schizophrenia, Aich et al. found thet al.[In another study on 30 subjects with alcohol dependence, by Vohra et al. 23 (76.6et al.[In a study examining the comorbidity in alcohol dependence by Singh H.N. et al. the prevet al.[Hundred subjects who met the criteria for current manic episode were recruited from a psychiatric hospital and were evaluated for substance abuse by Suresh et al. 50% of tMendhekar and Mehta publisheS.S. Raju studied et al.[A study conducted in the child psychiatry unit of a tertiary psychiatric hospital by Khess R.J. et al. evaluateet al.[In a cross sectional study, Bhattacharyya et al. found thGreydanus and Pratt in a revet al.[Karande et al. documentet al. evaluateet al.et al.[Girimaji SR et al. at NIMHAEvaluation and diagnosis of comorbid disorder is of paramount importance in order to modify treatment schedules and improve patient outcomes. In the present times, comorbid diagnosis should be an expectation and not an exception. Studies have consistently shown in the past that appropriate psychopharmacology of a known psychiatric disorder ensures better outcome for both the index mental illness and comorbid diagnosis with special reference to substance use. At the same time we now have some literature bringing out the fact that the treatment of both index and comorbid conditions is necessary, for example, integrated mental health and substance abuse treatment is the best treatment practice. Treatment of patients with comorbid diagnosis should be individually matched and based on assessment of diagnoses, level of disability, stage of change, treatment, rehabilitative goals or strengths, and level of care. Treatment should also be stage specific including individual and family interventions, community reinforcement and contingency management. Each of these areas need further research in relation to specific comorbidity combinations. It can be seen that the research so far has started to address some of the above issues but many of them remain unexplored.


As animals navigate through the environment, they use internal and external sensory cues to update their movements and successfully locate food or nest sites. The rich repertoire of spatial behaviors characteristic of many species has spurred intense research into the neural basis for representing external space. For many years, the mammalian hippocampus has been considered a structure crucial for supporting the creation or storage of spatial information (O’Keefe and Dostrovsky, Since the discovery of grid cells, computational modeling has been a key tool in generating hypotheses and theories to explain the origin of periodic and hexagonal firing patterns (For a review see Giocomo et al., in vitro studies described a myriad of biophysical properties which also showed a strong dorsal-ventral organization in mEC (Giocomo et al., in vitro finding that theta band oscillations measured in single mEC neurons decrease in frequency along the dorsal-ventral axis (Giocomo et al., in vitro slice recordings showing a decrease in the frequency of the theta band resonance after the application of cholinergic agonists (Heys et al., A prominent feature of grid cells is their spatial scale, which is organized topographically, increasing progressively from dorsal to ventral medial entorhinal cortex (mEC; Hafting et al., Spatial representations are thought to depend not only on grid cells but also on a multitude of other functionally specialized neurons in the parahippocampus. One of these specialized neuronal classes is head direction cells, which respond strongest when an animal faces a particular direction in the environment, irrespective of their behavior or location at the time (Taube et al., The apparent flexibility in grid scale under conditions of novelty, experience, or fragmentation of the spatial environment may be reflected by hippocampal place cell signals, which have been proposed as downstream targets for the grid cell output (Solstad et al., One way to gain a deeper understanding of how these different spatial signals interact in the parahippocampal circuit is to study and compare their developmental time course. Work in very young animals has already demonstrated that specific features of place cells reach adult levels at an earlier age than grid cells (Langston et al., This Research Topic provides a unique collection of new data and discussion covering a broad scope of questions aimed at understanding the neural representation of external space. We encourage the reader to sample the full range of articles.


Uterine contractions during labor are discretely regulated by rhythmic action potentials (AP) of varying duration and form that serve to determine calcium-dependent force production. We have employed a computational biology approach to develop a fuller understanding of the complexity of excitation-contraction (E-C) coupling of uterine smooth muscle cells (USMC). Our overall aim is to establish a mathematical platform of sufficient biophysical detail to quantitatively describe known uterine E-C coupling parameters and thereby inform future empirical investigations of physiological and pathophysiological mechanisms governing normal and dysfunctional labors. From published and unpublished data we construct mathematical models for fourteen ionic currents of USMCs:  For over 50 years it has been known that uterine smooth muscle (myometrium) generates spontaneous action potentials (APs) Modifications of myometrial cell electrophysiological characteristics during pregnancy are evident. The resting membrane potential of myometrial cells becomes progressively more positive towards term There is increasing awareness of the benefits of developing mathematical descriptions of uterine function The general mathematical formulae used for parameter modeling are given in the Mathematical descriptions of the biophysical characteristics of this current are given in et al., et al., et al., et al., Properties of et al., et al., et al., et al., i.e. prior to peak current at each voltage step being reached, from Jones et al., et al., There is little information available for voltage-dependent activation time constants of myometrial et al., et al., Simulated time tracings of oto  of  .et al., et al., Peak With in vitro experimental conditions: It is possible that the reported Mathematical descriptions of the biophysical characteristics of this current are given in Modeling of The equation for Mathematical description of the biophysical characteristics of this current are given in et al., et al., et al., et al., et al., et al., et al., et al., et al., The equation for Mathematical description of the biophysical characteristics of this current are given in We have considered the electrophysiological data of several major types of potassium currents described from myometrial cells of rat and human myometrium: (two) voltage-gated potassium currents  and TEA. As such, we developed mathematical models predominantly based upon the more abundant information of electrophysiological characteristics of human myometrial C1 and C2 of Wang et al., et al., et al., The equations of et al., et al., et al., et al., et al., et al., Activation time constants of  et al., . We ther5 cells,  or   and via the via PMCA when the cell was stimulated by ten short depolarization pulses between In myometrial cells from near-term pregnant rats, intracellular et al., et al., et al., et al., bringing in extracellular calcium at resting membrane potentials of et al., et al., et al., extrude intracellular We modified a myometrial intracellular calcium model We have modeled three major plasmalemmal calcium fluxes: the voltage-dependent membrane channels permeable to et al., The parameters for The There are three et al., et al., viaWe used an electrogenic PMCA activity in rat myometrial cells has been characterized in fractionated plasma membranous vesicles with a reported ATP-dependent uptake with half saturation at Our ability to integrate the information obtained from the above biophysically detailed models of individual ionic fluxes into simulations of APs and the ensuring changes in Myometrial cells can produce different forms of APs including those consisting of a single spike, a burst of spikes or a plateau-type. A first task of validation was to assess if integration of our individual ionic current models and et al., We began to assemble a model of AP configuration that incorporated all of the currents and ion fluxes described above. However, under physiological conditions of ionic concentrations The USMC model is excitable and responds to a brief stimulus with an all-or-none AP. The voltage threshold is The range of AP shapes reported for the pregnant rat myometrium at The cell model is validated with voltage-clamp and current-clamp experimental data from pregnant rat myometrial cells at ance by  .The extraction of the mathematical descriptions for modeling calcium-dependent force changes is denoted in  (equations 3 and 8–9) and et al., A final step in our validation of the model was to establish if it was able to accommodate the integration of uterine smooth muscle electrical, The model could also reproduce several additional published E-C coupling datasets of V(t), Our approach has resulted in a number of advances for our understanding of uterine smooth muscle E-C coupling. The model encompasses the most comprehensive biophysical description of ion channel and exchanger electric currents applied to the myometrium with 14 separate electrogenic components, summarized in in vitro solutions and at different temperatures. Although this neglects any species-specific quantitative differences in uterine electrogenicity and E-C coupling, it presently is unavoidable. It is also common in biophysical modeling approaches when it is rare that all information is available for one cell type from one species. However, an advantage of the comprehensive assembly of this mathematical model is that it enables identification of gaps in our knowledge of myometrial electrogenesis. This will inform future empirical work in several ways.As with any mathematical model of biological phenomena there are limitations. The 14 electrogenic currents are likely to be an underestimate of the number of ion channel contributors to myometrial AP form. This highlights a lack of sufficient biophysical detail on other currents. In biophysical modeling of cells and tissues, it is often the case that some published electrophysiological information on particular currents is of insufficient detail to furnish biophysical modeling of all its steady-state and dynamic characteristics. Therefore, data from different resources with close cell types, or the same type of cells from different species, are used. This is the same case for the present model. The model is a hybrid containing information primarily from rat myometrium but also from human myometrium and cells expressing smooth muscle ion channel subunits, and this data has been obtained from experiments using different e.g. there are many putative pharmacological blockers/openers First, the putative contribution of many ion channel subtypes to myometrial function has often been extrapolated from molecular data (mRNA or protein) which is incomplete  or pharmacological data utilizing compounds of weak specificity  function at late pregnancy was developed from the integration of data of individual ionic currents, calcium dynamics and contraction. A glossary of symbols used in the equations is given in e.g., from human USMC, or clonal cells expressing rat-derived proteins, then this has been mentioned.The individual membrane current components that were modeled were (i) four inward currents: L-type and T-type y) describes the time-dependent activation or inactivation profile of the channel conductance where et al., Most of the membrane currents were modeled with Hodgkin-Huxley type formulation in the following form:et al., i.e., time-independent. Herein we have included the temporal dynamics of membrane calcium currents in et al., Bursztyn The geometry of a uterine smooth muscle cell is assumed to be two cone shapes joined end-to-end at their bases Force development during uterine contraction was modeled with a simple first-order ordinary differential equation:Action potentials were induced in the whole cell model by applying an external stimulus current Click here for additional data file.Figure S2Different inactivation kinetics of myometrial (PDF)Click here for additional data file.Figure S3Divalent ion concentration versus (PDF)Click here for additional data file.Figure S4Experimental current tracings of (PDF)Click here for additional data file.Figure S5Experimental current tracings of (PDF)Click here for additional data file.Figure S6Modeling the dynamics of (PDF)Click here for additional data file.Figure S7Modeling simultaneous changes in V and (PDF)Click here for additional data file.Figure S8Modeling force output consequent to spike APs or plateau-like APs.(PDF)Click here for additional data file.Table S1Definitions of the equation symbols.(PDF)Click here for additional data file.Table S2Definition of gating variables for individual currents and force, and the corresponding experimental temperature and species.(PDF)Click here for additional data file.Table S3Initial values of the dynamics variables used in model simulations.(PDF)Click here for additional data file.Table S4Constant parameter values used in model simulations.(PDF)Click here for additional data file.Appendix S1Equations used in the model simulations.(PDF)Click here for additional data file.Appendix S2Model source code.(BZ2)Click here for additional data file.


We clarify that our view does in fact place motivation and emotion center-stage in the anxiety-ERN relationship.We reiterate that there is currently little compelling evidence that an enlarged ERN in anxious individuals reflects “the disposition to respond more strongly to uncertain threat”  that worry-related anxiety was associated with an enlarged ERN in the presence of unaltered behavioral performance, (2) that loading working memory with non-valenced information  also enlarged the ERN, and (3) that worriers with an enlarged ERN performed better in school than worriers with relatively smaller ERNs, but similarly to non-worriers. These results strongly suggest that an enlarged ERN among individuals high in worry serves a compensatory function.The findings in support of our CEMH are not well explained by Proudfit et al.'s perspective that an enlarged ERN in anxiety reflects a heightened threat response. Principally, their perspective does not account for the meta-analytic finding that worry demonstrates the most robust link with the enlarged ERN. In fact, their view is that worry is not necessary for enhanced ERN in anxiety. It is likewise unclear how their position would explain the other findings we reported in support of our CEMH (listed above). Thus, our first concern with Proudfit et al.'s conceptualization is that their threat sensitivity proposal does not capture a number of anxiety-ERN findings.r = −0.07 vs. r = −0.38 with the outlier included; See Appendix for details of this reanalysis). The ERN is also unrelated to perfectionistic concerns about mistakes  measures of threat sensitivity are interrelated. To date, little compelling evidence exists for this multivariate relationship. Specifically, the ERN is uncorrelated with other physiological markers of defensive responding to errors, including error-related skin conductance, heart rate changes (Hajcak et al., To provide evidence for their threat sensitivity hypothesis Proudfit et al. cite a study wherein undergraduates scoring high on negative affect showed increased ERN and increased error-related skin conductance (Hajcak et al., Perhaps most problematic for their view are the data showing that obsessive compulsive patients fail to demonstrate an especially large ERN to errors that are punished with monetary loss (Endrass et al., per se. For example, behavioral indicators from Bartholow et al. suggest that individuals in the alcohol group were well aware of their mistakes and even made appropriate adjustments to their mistakes compared to the no-substance control group. It also seems important to point out that, in fact, Bartholow et al.'s results may be supportive of our CEMH in that alcohol may have reduced worry and therefore reduced the ERN. The same may also be true of other studies showing that anxiolytic agents reduce the amplitude of the ERN (e.g., Johannes et al., Flipping this “integral affect” notion on its head, Proudfit et al. cite Bartholow et al.  who showFinally, the interesting developmental considerations outlined by Proudfit et al. do not rule out the possibility that enhanced ERN in anxiety reflects compensatory processes. Proudfit et al. have shown that the ERN is unchanged (Meyer et al., We emphasize that developmental considerations are important for both theoretical and practical reasons. Likewise, we agree with Proudfit et al. that intensive longitudinal studies across significant periods of development will help clarify whether the ERN is a cause or a consequence of anxiety. On this point, if the ERN emerges as an endophenotype for anxiety it could certainly reflect compensatory processes. Nonetheless, we simply believe the existing developmental literature is too sparse and inconsistent to serve as a strong basis for drawing inferences about the functional relationship between anxiety and ERN.To reiterate, the motivation in developing the CEMH was to understand the functional significance of the elevated ERN characteristic of many individuals with heightened anxiety. We do not attempt to provide an overarching account of the much broader and thornier relation between anxiety and threat. This is a critical distinction between our view and that of Proudfit et al. Our central claim, one that we believe is better supported by the existing data, is that the enlarged ERN characteristic of some anxious individuals and patients reflects compensatory cognitive control.Finally, although we have outlined our disagreements with Proudfit et al.'s position, there is clearly benefit for this line of research—and for science in general—to having opposing views on the same findings. Future work in this area ideally should attempt to directly adjudicate between our view and that of Proudfit et al., as well as develop alternatives that may ultimately prove more accurate. Our view and that of Proudfit et al. also leverage somewhat different literatures—cognitive science/neuroscience versus affective-motivational science/ neuroscience, respectively—and so clearly a union of such synergistic perspectives will eventually be needed. At the heart of the anxiety-ERN relationship is likely an interplay of cognition and emotion/motivation, to the extent that the two are meaningfully separable (Shackman et al.,


Psychological research uses multifarious assessment strategies to describe and to explain emotional and cognitive processes accompanying behavior in order to predict future behavior. However, laboratory assessments and questionnaire approaches dominate psychology, which has been criticized lately  will deliver valid and reliable information.Society for Ambulatory Assessment—Understanding Behavior in Context defines AA as any use of “… infield methods to assess ongoing behavior, physiology, experience, and environmental aspects of humans …” .Another methodological question is raised if research seeks to gain data out of subjects' real life. If the ecological validity should be convincing research has to go into everyday life using a suitable approach to get valid and reliable data. Ambulatory Assessment (AA) or ecological momentary assessment is an appropriate and promising approach for infield real time investigations. The European Psychologist edited by Ebner-Priemer et al. ;moods, affective reactions, symptoms like aches, commentaries;psychological tests infield;behaviors ;environmental conditions ;bio-markers .Although electronic diaries have gained increasing interest in psychology to assess variables of interest in real time, and although accelerometers are quite popular in sports and exercise science to objectively assess physical activity and movement pattern in everyday life, the combination of both methods is still alarmingly rare. To give researchers, in the context of physical activity and exercise psychology, guidance in the advantages and benefits of combining e-dairies with accelerometers, we invited experts to report their original studies. It resulted in a reader giving an impression of the fruitfulness of AA in this special field.The reader starts with a position statement done by the editors themselves (Kanning et al., This statement is followed by an article written by Bossmann et al.  looking Bussmann , the nexThe same author, together with his co-author (Bussmann and van den Berg-Emons, theory article. They tested the feasibility and validity of an EMA self-report protocol using electronic surveys on mobile phones. It is feasible and data are valid, but the volume of physical activity is underestimated, especially for those persons underweight or normal weight.An original research article done by Dunton et al.  follows Ebner-Priemer et al.  highlighKanning  uses objFrom work and leisure time the next text goes to pupils in elementary schools. Kühnhausen et al.  asked ifMurphy et al.  originalSchwerdtfeger et al.  report aTwo articles in which von Haaren is a contributor (von Haaren et al., Given the combination of texts the reader has a colorful bouquet of different inquiries in his hands and we hope this launches more studies in the natural environment assessing behavior in real settings.


Sir,TGFBR1 and colorectal cancer risk in Caucasian and Ashkenazi populations’ .We appreciate the data and comments provided by et al criticise the lack of a detailed description of the subjects studied by In their letter, Abadie et al point out that the significant discrepancies observed among studies, mostly between the first , very different from the average ASE value 1.07  obtained by Abadie et al in CRC cases, also using the SNaPshot technology . This observation suggests that the difference in the study population is not the cause of discrepancies between the original and subsequent reports.Abadie et al indirectly support that SNaPshot is especially sensitive to RNA quality. et al ensured very high RNA quality, probably explaining why SNaPshot provided consistent values among SNPs and low s.d.'s between independent replicates, even for rs7871490, a SNP located in a complex repetitive stretch.The results shown by Abadie et al clarifies the role of ASE of TGFBR1 in CRC susceptibility. Current evidence suggests that differences observed among studies are not directly attributable to study population or technique, provided high-quality RNA is used for allele expression experiments, and that allele-specific expression of TGFBR1 is not a strong risk factor for CRC.The letter by Abadie


However, we have some concerns regarding the rigour of assessment of elements of the evidence base and the authors’ accuracy in presentation of this evidence. The largest randomised controlled trial referenced  is that of Mathur et al.et al states that Mathur et al showed CHO supplements reduced length of hospital stay. This is at odds with Mathur’s own conclusion: ‘Preoperative CHO treatment did not improve postoperative fatigue or length of hospital stay after major abdominal surgery.’We read with interest the review of Jones et alet al investigated whole-body protein kinetics via a stable isotope labelled amino acid technique and not whole-body protein. This protein kinetic study looked at changes in protein balance before and after colorectal surgery. Whole-body protein balance was shown to be negative at a set point in time during the preoperative fast and again at a set point during the early postoperative period. The rate of loss of protein mass at this instant was faster in the group receiving low dose preoperative CHO than in the high dose group. To interpret this as meaning whole-body protein did not change in the perioperative period in the group receiving high dose CHO is erroneous.Furthermore, the work of Svanfeldt et al have shown a reduced loss of muscle mass postoperatively in patients receiving CHO,et aldo measure total body protein in lower GI surgery but have not as yet demonstrated that CHO can significantly attenuate the perioperative loss of total body protein.While Yuill We agree that measures to minimise the stress response to surgery will benefit our patients. Evidence exists that supports the implementation of ERAS programmes,


Without blood vessels, tumors cannot grow beyond a critical size. Angiogenesis is regulated by a balance of pro- and anti-angiogenic molecules  still remains controversial . No significant correlation for CD31 between mRNA and protein levels by immunohistochemistry implies that in the typical slow growth of PC, the angiogenesis dynamics are also quite low (Steiner et al., Despite its importance as a prognostic indicator in untreated tumors, MVD has not been shown to be a valid measure to guide or evaluate anti-angiogenic treatment (Hlatky et al., A non-invasive imaging technique that could reflect MVD would hold great promise in tumor detection and characterization (Jain et al., status of neovascularity, but there are still several open questions, including whether angiogenesis is a canonic hallmark of PC, and the absence of a powerful method of quantifying the reversal of neovascularity.Scientific knowledge develops through the evolution of new concepts, and this process is usually driven by new methodologies that provide previously unavailable observation. The potential broad applicability of the Fractal geometry makes it possible to explore the range of the morphological variability of neovasculature that can be produced in nature, thus increasing its diagnostic importance in cancer research (Taverna et al.,


Dear Editor,I read with interest the published article by Bayani et al.  in your Bayani et al.  reportedFinally I would like to mention that adding to educational approach for health care workers and more attending to health precautions during work, vaccination of non-immune individuals against HAV infection in this high risk group is wisdom strategy now , 9. Vacc


International Journal of Environmental Research and Public Health by Chari et al. [et al. for analysis do not provide comparable information on regression coefficients for the blood lead level-IQ relationship. The coefficients differ from one another more on the basis of unequal blood lead metrics, ages of blood lead measurement, and differences in covariate adjustments and standardization, than the difference postulated by Chari et al. to correspond to low vs. high SES populations.A recent publication in i et al.  provides Although it has long been observed that there is an inverse association between SES and blood lead levels, the authors go beyond this observation to hypothesize that differences in the dose-response relationship between blood lead and IQ exist depending on the SES status of the population. As a result, they conclude that EPA’s decision framework for development of the National Ambient Air Quality Standard (NAAQS) for lead should result in a lower NAAQS in order to protect these susceptible populations. However, Chari et al.’s analysis is not adequate for this purpose.In , Chari eet al. rely on four publications that examine the blood lead-IQ relationship as a function of SES status: Dietrich et al. [et al. [et al. [et al. [et al. and McMichael et al. employed the Mental Development Index (MDI) of the Bayley Scales of Infant Development, administered at 6 months by Dietrich et al. and at 2 years by McMichael et al. Harvey employed the British Ability Scales, administered at 2 years, and Tong et al. employed the Wechsler Intelligence Scale for Children (WISC-R), administered at 11–13 years. IQ testing at these various ages obviously takes different forms, and after control for confounders, there is little correlation between the MDI and IQ administered at later ages  to 11–13 years , while the blood lead metric includes a measure of early childhood , lifetime average , and age 2.5 years, approximately peak blood lead . Further, the McMichael et al. and Tong et al. studies are of the same Port Pirie children, but at different ages. Blood lead levels are a function of age, peaking at approximately age 2–3 years, and declining into adolescence. Regression coefficients describing the relationship between blood lead level and IQ vary as a function of the age of blood lead measurement and the blood lead metric. This can be seen in Lanphear et al. [et al.). The difference in coefficients in the McMichael et al. and Tong et al. studies may result in part from the age difference. Comparisons of different SES groups must be based on regression coefficients for the same blood lead metric and approximately the same age, or adjusted in some way for the impact of variable blood lead metrics and ages at time of measurement. Although Chari et al. note that the variable blood lead metrics are a limitation of their analysis, they don’t indicate the direction of bias associated with this limitation and the subsequent impact on their conclusions. The difference in coefficients proposed by Chari et al. for high and low SES populations is similar to the difference seen between studies of children at different ages, suggesting if this bias were considered that there might be no difference in dose-response relationships at different SES levels.Children’s ages at the time of blood lead measurement range from 10 days (Dietrich r et al.  where foet al. study are hematocrit-adjusted. This adjustment would also have an impact on the magnitude of the regression coefficient, and complicate the comparison of this result to those of other studies.Blood lead levels reported in the Dietrich et al. analysis comes from the authors’ extrapolation of the log-linear regression coefficients to a blood lead level of 2 µg/dL, well below the average blood lead levels in each of the studies. Although extrapolation of linear coefficients to lower blood lead levels may produce a bias towards underestimating effects, extrapolation of log-linear coefficients may produce a bias in either direction. As an example of the impact on the dose-response slope resulting from this extrapolation, Chari et al. extrapolate and linearize the regression coefficient from Dietrich et al. at 2 µg/dL to be −2.35. However, a later publication on the same data set by Dietrich et al. [et al. for high vs. low SES children, suggesting again that there might be no difference in dose-response relationships at different SES levels.Additional uncertainty in the Chari h et al.  reports et al. should have indicated the direction of this bias. Further, Harvey et al. reported a standardized regression coefficient. The value of a standardized coefficient, which can vary from negative to positive one, is not comparable to an unstandardized coefficient. Although Chari et al. acknowledge that some coefficients are adjusted and others are not, they neither note the direction of bias associated with this limitation, nor note the lack of comparability with the Harvey et al. standardized regression coefficient.Complicating the comparison of coefficients among these four studies further, some of the coefficients are adjusted for covariates while others are not, and some are standardized while others are not. The regression coefficients from the McMichael study are unadjusted, while those from the other three studies are adjusted. This difference matters: Bellinger  notes thet al. cite two studies that give this comparison: McMichael et al. and Tong et al. As noted above, these two studies are of the same children, and it is perhaps not surprising that a similar result is found. However, in neither study did the authors find a statistically significant impact of SES on the blood lead-IQ relationship.Although the comparison across studies is complicated by the various types of regression coefficients, and the mixed ages, blood lead metrics and cognitive tests, it remains worth reviewing the results found within a study between the high and low SES categories. Chari et al. also did not find statistical significance. Before adjustment for covariates, Harvey et al. reported a correlation between blood lead and IQ that was larger and negative for the manual labor class. Harvey et al. [et al. [et al. [et al. included the younger children from the first study where the father is engaged in manual labor as low SES in their analysis, but did not include the older children from the second study where the result was the opposite.The study by Harvey y et al.  present  [et al.  report t [et al.  found thet al. found statistical significance, in an analysis of the Cincinnati cohort based on blood lead levels at age of ten days. However Dietrich et al. [et al. also note that an SES effect was not seen in the Cincinnati cohort in later years.Only the study by Dietrich h et al.  also exaet al. are similar to or less than the differences between regression coefficients expected as a result of mixing blood lead metrics, children’s ages, adjusting or not adjusting for covariates, and comparing standardized and non-standardized regression coefficients. Further, the studies selected by Chari et al. show little or no statistical significance of an SES effect on the relationship between blood lead and IQ. As a result, the Chari et al. analysis does not support a need to modify the Pb NAAQS for protection of low-SES populations. At this time, the methods by which to consider non-chemical stressors in risk assessment are an active area of investigation and debate within the scientific community and among policy makers. The Chari et al. analysis does not inform this debate for the impact of SES on the relationship between blood lead and cognitive impacts. An appropriate analysis would need to focus, at a minimum, on a data set for the same blood lead metric, in children with blood lead measures and cognitive testing at approximately the same age.In summary, the differences in regression coefficients describing the blood lead-IQ relationship between low and high SES populations as put forward by Chari


The eukaryotic cell possesses specialized pathways to turn over and degrade redundant proteins and organelles. Each pathway is unique and responsible for degradation of distinctive cytosolic material. The ubiquitin-proteasome system and autophagy  act synergistically to maintain proteostasis. Defects in this equilibrium can be deleterious at cellular and organism level, giving rise to various disease states. Dysfunction of quality control pathways are implicated in neurodegenerative diseases and appear particularly important in Parkinson's disease and the lysosomal storage disorders. Neurodegeneration resulting from impaired degradation of ubiquitinated proteins and α-synuclein is often accompanied by mitochondrial dysfunction. Mitochondria have evolved to control a diverse number of processes, including cellular energy production, calcium signalling and apoptosis, and like every other organelle within the cell, they must be ‘recycled.’ Failure to do so is potentially lethal as these once indispensible organelles become destructive, leaking reactive oxygen species and activating the intrinsic cell death pathway. This process is paramount in neurons which have an absolute dependence on mitochondrial oxidative phosphorylation as they cannot up-regulate glycolysis. As such, mitochondrial bioenergetic failure can underpin neural death and neurodegenerative disease. In this review, we discuss the links between cellular quality control and neurodegenerative diseases associated with mitochondrial dysfunction, with particular attention to the emerging links between Parkinson's and Gaucher diseases in which defective quality control is a defining factor.http://dx.doi.org/10.1111/bph.2014.171.issue-8This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit  They aret al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Neurons have an absolute dependence on mitochondrial oxidative phosphorylation for their ATP supply, with very limited capacity for glycolysis  gene and is associated with PD as it appears that similar underlying defects in autophagy and mitochondrial dysfunction may link the neurodegenerative aspect of these two disorders  as the most prevalent of the group  and the autophagic pathways: chaperone-mediated (CMA), macro, micro as well as organelle specific , or more recently reported, the mitochondria . The process of mitophagy is remarkably specific; by uncoupling a single mitochondrion via photo-irradiation, this and only this mitochondrion will be degraded  and PARK2 encoding the E3 ubiquitin ligase Parkin -dependent manner , PINK1 fails to import and accumulates on the OMM where it remains trapped at the TOM complex, recruiting Parkin to the OMM where it exerts its E3 ligase activity  is not clear.Although a complex multi-step process, regulation of mitophagy under the PINK1/Parkin (Mfn2?) system does seem logical. However some doubts remain as to the physiological relevance of this pathway. Although well characterized, experimental demonstration of this model pathway relies on complete depolarization of the ΔΨet al., et al., et al., et al., et al., CMA is one of the lysosomal pathways of proteolysis. It is markedly different to conventional autophagy as no vesicular transport is involved; instead, cytosolic proteins are recognized and delivered to the lysosome by chaperones in a molecule-by-molecule-dependent manner Dice, . In thiset al., et al., Under normal circumstances CMA is induced under starvation conditions with heat shock protein 40 (Hsp40) stimulating Hsc70 activity, which then binds substrate proteins in an ATP-dependent manner. Hsc70  transport the cytosolic protein to the membrane of the lysosome where they bind to lysosome-associated membrane protein 2A , a small 76 amino acid polypeptide with poly-ubiquitin marking the substrate for transportation to the proteasome  and soma (body)  were fragmented with a reduced ability to buffer Caet al., GM1-gangliosidosis is a rare inherited disorder that is generally characterized by progressive neurodegeneration  was observed in astrocytes as well as abnormal mitochondrial morphology and a decrease in ΔΨm  or BD are recessively inherited neurodegenerative disorders, characterized by lysosomal accumulation of subunit c of the ATP synthase within neurons   and is responsible for the conversion of its substrate glucocerebroside to glucose and ceramide  suggesting that damage is mediated by ROS generation from CI . In this system, knockout (KO) of GCase in primary neurons and astrocytes caused defects in the autophagy pathway with reductions in LC3-I/II and Atg5/12 levels, suggesting the presence of a negative feedback loop upstream of lysosomal involvement (Osellame et al., et al., et al., et al., et al., et al., in vivo (Spencer et al., et al., et al., et al., There appears to be a strong clinical association between these two classes of disease. As the lysosome is central to the autophagy process, it is not unreasonable to assume this pathway is integral in protecting against neurodegeneration (Xilouri and Stefanis,


We aget al. In consequence, as shown in et al. [et al. [et al. [et al. to engender uncertainty and affect mortality estimates. We regard them as minor compared with the ‘safety margin’ factor of 8 × 10−7 by which Perry et al. inflated the estimated mortality through deliberate choice of a small value of the logit slope, designed to give worst-case mortality.Regarding sensitivity analysis, it is important to allow for the fact that depositions of pollen in the field occur at far lesser concentrations than the LC50s for the three species considered by Perry n et al.  is vanis [et al. ,4 slope  [et al.  would reet al. model is that it provides a transparent, structured and simple approach to exposure analysis that may be followed for other species and taxa in other settings, if sufficient data become available. Further, in its derivation of an integrated mortality–distance relationship, it offers the opportunity for relatively accurate laboratory-based estimation of mortality–dose relationships to supplement relatively inaccurate determinations of mortality in the field. We agree with Lang et al. that species' sensitivity to particular GM events that express different forms of Cry1 proteins is an important determinant of mortality; also that further data would be welcome on the mortality–dose relationships (particularly regarding the slopes) for a range of species, especially those of conservation concern. However, we disagree that we have been incautious regarding the implications of our results for conclusions regarding regulatory policy. We therefore reaffirm the robustness of our conclusion from our model that, after accounting for large-scale exposure effects, the ‘estimated environmental impact of MON810 pollen on non-target Lepidoptera is low’.The value of the Perry


The biological basis of psychiatric disorders has been the focus of research in various studies across the world including India. In this selective overview we summarize findings of various EEG, neuro-imaging and blood related studies that have been reported in the Indian Journal of Psychiatry. The biological basis for psychiatric disorders has been increasingly becoming a major research focus over the past many decades in various countries. Similar trends have been observed in Indian psychiatry too. In this selective overview, we have attempted to summarize various biological investigations that have been reported in the Indian J Psychiatry over the past many decadeset al.[et al.[Studies involving schizophrenia subjects have primarily looked at blood levels of various chemicals. In addition, EEG studies have observed REM sleep defects and neuro-imaging studies have looked at perfusion defects in relevant brain regions. Rao et al. examinedl.[et al. assessedet al.[Prakash and Sethi assessedet al. studied et al.[Kuruvilla et al. studied et al. studied et al.[There was a two fold increase in prolactin level but no correlation between baseline serum prolactin level and severity of baseline psychopathology. Authors concluded that baseline prolactin may not be a reliable indicator of psychopathology and prognosis. Singh et al. studied et al.[Tiwari et al. assessedet al.[Das et al. in theirGong and colleagues studied Studies examining for brain abnormalities in schizophrenia using neuroimaging techniques have reported Significant hypo-perfusion in frontal as well as temporal areas in childhood onset patients.FDG-PET study revealed that participants With negative symptoms of schizophrenia had significantly decreased metabolism in all regions of the brain as compared to the positive type. The positive syndrome of schizophrenia was associated with significantly increased glucose metabolism in the medial temporal regions, basal ganglia and left thalamic regions. Hypo metabolism was also noted in the cerebellum.et al.[Studies in bipolar affective disorder have mainly focused on clinical correlates of serum lithium levels. Srinivasan et al. assessedet al.[Kuruvilla et al. reportedet al.[Prakash and Sethi examinedet al. examinedet al.[Khandelwal et al. studied et al.[Shukla et al. studied et al.[et al.[Geetha et al. studied l.[et al. examinedet al.[Solanki et al. assessedet al.[Mishra et al. studied Verma and colleagues studied 2-relaxometry technique .[Tharyan and colleagues studied l. 2007).et al.[Shah and colleagues comparedet al. studied In conclusion, review of research studies focusing on biological investigations in psychiatry suggest varied parameters that have been examined with mixed findings. It is possible that uncertainties of these observations are mainly implicated upon the heterogeneity of these disorders. This emphasizes the need for ‘endophenotype-based’ research approaches that might help us to advance our understanding of various psychiatric disorders.


Sir,et al . The median time to progression .Previous work has also shown treatment response to metronomic cyclophosphamide and dexamethasone in castration refractory prostate cancer; Glode et al  publisheet al (et al (It is possible that response to metronomic chemotherapy is, in part, influenced by the histology of the primary tumour. The study by Khan et al  containel (et al  shows beThe use of dexamethasone concurrently with cyclophosphamide could have contributed to the response demonstrated in our patients. However, as stated above, virtually all of our patients had been treated previously with corticosteroids, and so we believe the use of cyclophosphamide was responsible for most of the clinical benefit seen.In conclusion, we believe that metronomic treatment with cyclophosphamide is a well tolerated and useful treatment in heavily pre-treated patients with metastatic castration refractory carcinoma of the prostate, and warrants further investigation.


Radiofrequency catheter ablation is a well established modality of treatment for ventricular tachycardia (VT). But it may not be successful in certain cases when the re-entrant circuit is situated deep within the myocardium and inaccessible to both endocardial and epicardial ablation. One of the earliest reports on transcoronary ethanol ablation of refractory ventricular tachycardia was by Inoue H et al in 1987 . BrugadaQi XQ et al  also repVerna E et al  describeRecent reports by  Sacher F et al  and Toku