Changes in expression in these genes have been observed in recognition, working and fear related memories across the brain. Despite the enormous amount of data supporting changes in their expression during learning and memory and the importance of those cognitive processes in psychiatric conditions, there are very few studies analyzing the direct implication of the IEGs in mental illnesses. In this review, we discuss the role of some of the most relevant IEGs in relation with memory processes affected in psychiatric conditions.Many psychiatric disorders, despite their specific characteristics, share deficits in the cognitive domain including executive functions, emotional control and memory. However, memory deficits have been in many cases undervalued compared with other characteristics. The expression of Immediate Early Genes (IEGs) such as,  The diagnoses of psychiatric disorders are based on a cluster of specific symptoms. The genetic, clinical and neuroimaging evidence suggests that they share important features including common affected functions  were used as an indirect marker to measure neuronal activity and, although many of them are routinely measured in thousands of labs around the world, their role in many biological processes is still unknown. The IEGs most commonly used to map neuronal activity, c-fos, Egr1 and arc are related in literature to learning and memory. Changes in their expression observed in a limited number of cells in regions associated with learning and memory lead to widespread use as readout of plastic changes subserving long-term memory formation and maintenance in specific neuronal populations , duration (short-term and long-term) and to the type of information that it is stored (explicit and implicit), which are reviewed somewhere else Eysenck, . We now extinction or reconsolidation. The reactivated memory trace becomes labile and is susceptible to being modified or disrupted in the process called reconsolidation. If there is a reinforcement of the original trace during retrieval, the reconsolidation—a protein synthesis-dependent process—re-stabilizes the original memory trace  in rats in which the infusion of the ASO produce deficits in spatial long-term memory  protein also known as Arg3.1, is one of the most characterized molecules involved in the consolidation of different types of memories. In contrast to Arc gene has specific sequences normally found in retroviruses such as HIV  together with changes in long-term plasticity  is a mood disorder with prominent disturbances in cognitive functions such as certain types of memory, executive function, and attention  mainly in nucleus accumbens neurons  and a physiological defect in response to that component. Anxiety disorders include simple phobia, social phobia—which involves fear and avoidance of social situations—, and panic disorder; they all share abnormal fear responses associated with different environmental stimuli but also differ in important and specific symptoms. For example, PTSD is a chronic neuropsychiatric disorder that results from a very strong traumatic event and it is characterized by intrusive and persistence fear related memories. The etiology of PTSD remains largely unknown but different neurobiological systems have been identified as participants in the disorder (Parsons and Ressler, The first opportunity to apply treatments designed to modify the formation and persistence of fear memories is around the aversive experience, mainly through pharmacological manipulations (Monfils et al., arc expression was observed along the septo-temporal axis of the hippocampus of PTSD susceptible rats (Nalloor et al., arc expression in the hippocampus is also involved in the perpetuation of fear related memories (Nakayama et al., Few studies have analyzed the role of IEG in PTSD related animal models, though they reported interesting results. Changes in Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex. The brains of patients with schizophrenia show atrophy in the dendrites of the pyramidal cells, particularly from dorsolateral prefrontal cortex (Weinberger et al., Egr1 expression is decreased in the dorsolateral prefrontal cortex of schizophrenic patients. This down-regulation correlates with the levels of gad1 mRNA, which is also down-regulated in schizophrenia (Yamada et al., Egr1 and related IEGs in frontal and striatal regions (de Bartolomeis et al., It has been shown that Egr1 (Kurian et al., Egr1 and other IEGs are also associated with response to antipsychotic drugs (MacGibbon et al., Searching for biological markers of schizophrenia in peripheral tissues, it was found that whole blood samples of patients suffering this disease have an increased expression of c-fos expression have been reported in schizophrenia related animal models. Acute treatment with the NMDA antagonist MK-801 produced deficits in novel object recognition, conditioned test aversion and a moderate increase in locomotion. Interestingly, animals treated with this drug showed increased levels of c-Fos expression in cortical regions associated with cognitive processing (Vishnoi et al., c-fos expression (Castañé et al., c-fos expression in the mPFC does not correlate with glutamic acid decarboxylase 67 expression as does Egr1 (Kimoto et al., c-fos regulation (Michaluk and Kaczmarek, Changes in arc was deleted in the whole brain, Managò et al. (The interaction between Arc and dopamine appears to be bidirectional. Using a genetic model in which ò et al.  found a ò et al. .c-fos and Egr1 expression in the striatum and nucleus accumbens (MacGibbon et al., c-fos expression in the medial prefrontal cortex (Robertson and Fibiger, Egr1 and an upregulation of FOS-like expression in the same structures (Verma et al., IEGs have not only been associated directly with particular psychiatric disorders but they have also been used as markers of the specific action of different psychiatric drugs that are related. Haloperidol, a typical antipsychotic drug induces changes in c-fos in the anterior insular cortex, the septum and the amygdala using different antidepressants. In the case of Egr1 a consistent change was found only in the amygdala (Slattery et al., c-fos in the frontal cortex following an acute stress experience (Beck and Fibiger, Antidepressants’ activity has also been analyzed in relation to their effect on IEG expression. Acute administration of fluoxetine, imipramine, LiCl, or mirtazapine produced changes in IEG expression in different regions. There were changes found for Although these studies show changes in the expression of IEGs in apparent response to different drugs, they are correlational studies and do not address any role of these proteins in their mechanism of action. Despite this caveat, even these studies provide important information regarding circuits involved in learning and memory that can be affected in psychiatric disorders.Although the prolific use of IEGs in neuroscience, our understanding of their role in neurobiological processes remains insufficient. This is due at least to the large number of IEGs that are currently under study, but also because of the difficulty in fully comprehending their roles and their downstream effectors. Independently of this, IEGs are used as markers of synaptic activity and as that, are useful. Even more, when combined with modern techniques, like optogenetic or chemogenetics (Reijmers et al., FTG, CK, JFM, JHM and NVW conceived the content, wrote and organized the manuscript.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.


Whilst a formal statistical analysis of any experimental data is always preferable in principle, in the case of Pilling et al. (PLoS ONE 8:e77193,  The focus of Schick et al.’s 2017 [Schick et al.  criticisIn their analysis, Schick et al. categorise the mortality data into ‘before’, ‘during’ and ‘after’ exposure. However, the Pilling et al.’s  trials wdf) for experimental error for oilseed rape and only ever two df for experimental error for maize. In both cases, it can be argued that this number of df is simply too few to generate a reliable estimate of experimental error. Also, with so few data points in any given analysis (i.e. four for oilseed rape and six for maize), it is difficult to see how it can be verified that the data meet the underlying assumptions upon which the validity of the analyses depend. Moreover, with so few data points it is difficult to see how Schick et al. could justify their choice of error distribution and link function ahead of other viable alternatives; this is important because alternative but equally justifiable choices could lead to very different results, particularly with regard to the whereabouts of the upper confidence limits. Thus, the Schick et al.’s [With regard to the data analysis carried out by Schick et al., they are in danger of confusing two separate issues. The first is whether an approach based on estimated effect sizes and 95% confidence intervals is more informative than the one based solely on tests of significance. The second is whether either approach can generate reliable results given the limitations of the experimental design. Regardless of which approach is chosen, there is only ever one degree of freedom (et al.’s  analyseset al.’s  to not set al.’s  results Ecotoxicological field testing and risk assessment for pesticides is a continually evolving area, as shown by the regular review of guidelines for regulatory testing. It is for this reason that Syngenta co-sponsored with Bayer a bespoke landscape-level honeybee neonicotinoid field effect study with UK Centre for Ecology and Hydrology . This beSchick et al.  criticisIn addition, since the publication of Pilling et al. , there hSchick et al.  focus on


Recently published study of Ma et al. evaluates two relatively novel measures of fluid responsiveness, carotid blood flow and corrected carotid flow time (ccFT). Both measures have been recently quoted as possibly useful, technically simple, and noninvasive dynamic tools in predicting fluid responsiveness. Recently, more research interest has been focused on ccFT and, intrigued by the data presented in this study, we discuss here the impact of the data presented in the paper of Ma et al. to the significance of this metric as a potential tool in the assessment of fluid responsiveness. Dear Editor,It was a great pleasure to read about the study of Ma et al.  which evThe study of Ma et al. sheds a new light on the role of ccFT and is the first prospective clinical study to compare ccFT with the gold standard of cardiac output measurement, right heart catheterization (RHC). This study evaluated patients undergoing diagnostic RHC who were subjected to a passive leg raise maneuver (PLR) which mimics a fluid bolus and has been used to assess fluid responsiveness in shock . Unfortuchanges in this measures that may correlate better. Several studies have looked at the change of ccFT (∆ccFT) as a potential tool in the process of evaluation of fluid responsiveness and found that change in duration of ccFT in dehydrated patients receiving intravenous fluid resuscitation [In this study, ccFT did not correlate well with cardiac output which is not surprising. Flow time is a proxy for left ventricular ejection time, which has classically been considered to represent a static hemodynamic measure, along with other “static” preload indices , 7, and citation , 8, 9 orcitation  may be hcitation . Practiccitation .There are several methodological concerns worth bringing up in order to separate a moderate correlation of average ccFT and cardiac output presented in the study of Ma et al. and possible usefulness of the change in ccFT in fluid resuscitation of patients in shock. Patients undergoing RHC who were evaluated in the study of Ma et al. may have very little in common with the population of fluid under-resuscitated patients in shock who are usually evaluated with PLR and where the role of ccFT has been recently discussed as possibly relevant . The cohFrom the technical perspective, an interesting idea presented in the study of Ma et al. is an attempt to avoid the selection bias by averaging ccFT values of multiple (three) heart beats instead of taking a single value. Understanding the impact of breathing on cardiac rhythm, this concept is valid and important but the method may require further optimization as averaging should probably be taken in the context of respiratory cycle rather than randomly selecting three beats.There is a common agreement that the dynamic parameters have become a gold standard in fluid responsiveness assessment , but the


The 18th and 19th centuries in England were characterised by a period of increasing industrialisation of its urban centres. It was also one of widening social and health inequalities between the rich and the poor. Childhood is well‐documented as being a stage in the life course during which the body is particularly sensitive to adverse socio‐economic environments. This study therefore aims to examine the relationship between health and wealth through a comprehensive skeletal analysis of a sample of 403 children (0–17 years), of varying socio‐economic status, from four cemetery sites in London (c.1712–1854).Measurements of long bone diaphyseal length, cortical thickness, vertebral neural canal size, and the prevalence of a range of pathological indicators of health stress were recorded from the Chelsea Old Church (high status), St Benet Sherehog (middle status), Bow Baptist (middle status), and Cross Bones (low status) skeletal collections.Children from the low status Cross Bones site demonstrated deficient growth values, as expected. However, those from the high status site of Chelsea Old Church also demonstrated poor growth values during infancy. Fashionable child‐care practices  may have contributed to poor infant health amongst high status groups. However, differing health risks in the lower status group revealed the existence of substantial health inequality in London at this time. © 2016 The Authors International Journal of Osteoarchaeology Published by John Wiley & Sons Ltd. The industrial cities of the 18th and 19th centuries in England were notorious for their unhealthy living conditions. Urban districts increasingly experienced severe overcrowding, poor sanitation and ventilation, and high levels of air pollution Kay, . During et al.,The expanding cities posed significant health risks, particularly for the youngest members of society. Children are vulnerable to adverse environments, because of their under‐developed immune system and the physiological demands of growth Lewis, . Under cThis study assesses growth and skeletal indicators of stress in the skeletal remains of non‐adults (0–17 years) excavated from cemeteries known to comprise different social status groups from London (c.1712–1856). The aim is to discern whether health stress was experienced in children throughout all levels of the social strata, or whether children of middle to high status groups were buffered through social privilege from the detrimental effects of urban life.London was a highly stratified society during the 18th and 19th centuries: the rich and the poor lived in relatively close proximity Booth, , but wouet al.,et al.,Social inequality is known to have a profound effect on the overall well‐being of a population, producing a social gradient in health that deteriorates as income lessens  were also reassessed in line with recent publications (see below) to construct crude prevalence rates of pathology.et al.,Dental age was assessed using standards for dental calcification Smith,  of both et al.,et al.,Tibial lengths for individuals within each sample were plotted against dental age to assess longitudinal growth (a proxy for growth in height in non‐adults). The tibia was selected because it is considered to be more sensitive than the other long bones to growth disruption  was assessed through measurement of cortical thickness. Cortical thickness (CT) is considered to be a more sensitive indicator of stress than longitudinal growth  size is an effective indicator of stress in early life Watts, , 2013b. et al.  providedet al.,et al.,Scatterplots were constructed for tibial length, femoral CT, and TR diameter to determine the homogeneity of the regression slopes Field, . Once itThe presence or absence of four pathological categories was determined using data collected from the WORD database , and on the mandible and maxillae , arising because of the disturbance of enamel formation in the developing teeth Hillson, , was recThe overall sample sizes for pathological analysis, longitudinal growth, appositional growth, and vertebral growth are provided in Table Figure Tibial lengths were plotted against dental age, with each data point representing one individual Figurea. All siFigure Measurements of transverse diameter for each individual were plotted against dental age Figure d. All ofAll four groups have a high rate of rickets, between approximately 12% and 17% Figure . The oveKay stated in 1832 that ‘…more than one‐half of the offspring of the poor…die before they have completed their fifth year’ p.42–43), and around 42% of total deaths in London between 1837 and 1838 were in those aged 5 years and under . Poor maternal health may lead to intrauterine growth restriction, resulting in infants that are born small‐for‐gestational age (SGA) (Eveleth & Tanner, et al.,et al.,et al.,et al.,Overall, Cross Bones demonstrates the highest prevalence of pathology. Peaks in metabolic disease occurred from the perinatal stage, to 1–5 years of age Table . ParticuCheadle, . In ordeStudies by Barker , 1994 anet al.,Inequalities in health are thus often rooted in early life and can continue to impact on health throughout the life course (Elgar All of the samples in this study were affected by high infant mortality and morbidity, but the lower status Cross Bones sample was most severely affected. While it is true that Chelsea Old Church also demonstrated some of the lowest growth values alongside Cross Bones, it must be considered that these deficiencies developed for very different reasons. Children of wealthier families were more likely to succumb to poor health because of fashionable child care practices, whereas mothers born and raised in poverty could pass on their health deficits to their children. This, combined with the detrimental external environment and disadvantageous family economy, meant that life chances at birth for the children of the poor were limited to a high risk of premature death, or a lifetime of poor health and hard labour Gowland, .While interesting patterns related to child health and social status in the 18th/19th centuries have been identified, it is important to consider the limitations that accompany studies such as these. The current issues surrounding the identification of sex in non‐adult individuals creates a limiting factor in the study of growth within adolescents, because of sex‐related differences in the pubertal growth spurt. Without knowing the proportion of males and females within an adolescent sample, it is not known whether the data is skewed towards higher or lower growth values for a particular age. Sample size is also an inherent issue in bioarchaeology. The requirement for well‐preserved skeletal elements for measurement often means that sample sizes are small. Additionally, differential preservation of skeletal elements between populations means that, as seen in this study, sample sizes of collections may be imbalanced. The use of modern data as a comparative sample to infer whether past skeletal populations were ‘unhealthy’ by present standards is also problematic, as this involves comparing those who did not survive childhood, and were thus inherently ‘weaker’, to healthy living children.et al. (Life in the city came with some significant health risks to all of its members. While undoubtedly the lower classes experienced a much higher risk of mortality and morbidity, this study revealed that some of these risks were also often felt by the upper classes, supporting recent research by DeWitte et al. , Hughes‐et al. , and Watet al. . Poor in


The article by Zhang et al. (We evaluated the PCR primers/probes used by Zhang et al. . OverallAs proposed by Ngounga et al. (In metagenomics approaches, the number of reads detected and the distribution along the whole viral genome are essential parameters for viral detection. In practice, the search for mimivirus is complicated by the great genetic variability of the virus and the restricted availability of mimivirus culture systems to a few research laboratories (


Reason for Corrigendum:In the original article, there was an error. A correction has been made to the Introduction, section ‘Imaging Methods and Imaging Postures’, first paragraph.superficial brain regions (Goldenholz et al., The sentence “MEG outperforms EEG in terms of signal-to-noise ratio when accessing deeper brain regions (Goldenholz et al., The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.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.


Diffuse scattering provides evidence that variations are correlated across molecular boundaries in macromolecular crystals. In this case, the diffuse intensity is derived from the squared crystal transform, which is sharply peaked. In a modified version of the model, correlations terminate at the molecular boundary . In this case, the diffuse intensity is derived from the squared molecular transform of the asymmetric unit , which is continuous in reciprocal space. In both cases, the transform is blurred; shorter correlation lengths correspond to a larger scale blurring of the transform. Both models are optimized to maximize the agreement with the data, enabling a well controlled comparison.In this issue, Peck and co-workers (Peck ry Fig. 1b. In thet al., 2017et al., 2017et al., 2016et al., 2011et al., 2009et al., 2007et al., 2010To be consistent with the state of the art (Meisburger et al., 2018As illustrated in this issue (Peck


Hemoptysis is a very common symptom in the practice of pulmonary physicians of India. We present a case of uncontrolled hemoptysis managed with bronchial artery embolization. Bronchial artery embolization is an effective treatment for patients with hemoptysis. Serious complications are rare, but may occur if the arterial supply to other structures is compromised. Massive hemoptysis usually originates from the systemic arterial supply to the lung. Episodes of hemoptysis may be managed by several approaches, depending on the urgency of the situation, ranging from medical management and bronchial artery embolization (BAE) to surgery. Bronchial artery embolization is a well-accepted and effective form of treatment for massive and recurrent hemoptysis. Bronchial arteries are small vessels that arise directly from the descending thoracic aorta and supply blood to the airways of the lung, esophagus, and lymph nodes.‐3 BronchA 69-year-old male patient came with complaints of cough and hemoptysis from last one year. The symptoms were not relieved by conservative medications. There was no contact history with any case of pulmonary tuberculosis in the family or neighbourhood. Patient gave no history of any chronic illness, surgery or hospital admission in the past. The patient was a chronic smoker for the past 30 years. The patient was given a trial of anti tubercular treatment for six months but with no relief. Other than crepitations in right inframammary area, rest of the physical examination and routine laboratory work up was inconclusive. Repeated sputa examination for AFB were negative.Chest X-ray revealed unfolding of aorta, hazy right parahilar and para cardiac area . USG whoSources of pulmonary bleeding include the low pressure pulmonary circulation  and the high pressure bronchial circulation (at systemic blood pressure). Bronchial circulation arises from the aorta and therefore has systemic arterial pressure. The bronchial arteries are the main supply of the airways and the supporting structures of the lung while pulmonary arteries supply the lung parenchyma and respiratory bronchioles. Bronchial circulation is the source of massive hemoptysis in 90% of cases.et al.[10et al. and 97%.et al. The probet al.et al 2005[Bronchial artery embolization might be the only treatment option available to patients who are not fit to undergo surgery. Bronchia14et al 2008[et al 2005[et al 1999[et al 2004[µm Embosphere particles. The authors suggested that the Embosphere particles had crossed the bronchiopulmonary shunt into the systemic circulation. Severe but rare complications are neurological deficiencies and pulmonary necrosis.[5BAE is an alternative safe and effective nonsurgical treatment for patients with massive hemoptysis which can be done simultaneously on both sides. Success rate is about 88%. Intervent al 2008 reportedt al 1999 concludet al 1999 There hat al 1999, posterit al 1999 and Acutt al 1999 Vinaya et al 2004 reportednecrosis. Neurolognecrosis. Recurrenecrosis.515 ProximThis case has been presented with the view that in cases of hemoptysis, bronchial biopsy should not be jumped to and the possibility of vascular nature of the tumor should be kept in mind and thoroughly discussed so that if required bronchial artery embolization could be done to control hemoptysis and to avoid massive bleeding during bronchial biopsy.


Sir,et al's Letter to the Editor.We would like to clarify the results in ‘Excessive annual BMI increase after chemotherapy among young survivors of testicular cancer’ as a reply to Huddart et al's results, our study showed no influence of chemotherapy or any other treatment type on BMI compared to our healthy control material (Controls). Our results from the multivariate regression analysis indicated that in survivors of testicular cancer (TCSs), chemotherapy had an impact on the annual BMI increase independent of age and that the surgery group displayed no significant annual BMI increase , but our results do not show any impact on BMI, measured once in a cross-sectional study.We still conclude that young TCSs, especially after chemotherapy, are at risk of excessive annual BMI increase as compared to the normal population (


We consider the problem of identifiability in the recently developed carcinogenesis models of Little and Wright (Math Biosci 2003 183 111–134) and Little et al. (J Theoret Biol 2008 254 229–238). These models, which incorporate genomic instability, generalize a large number of other quasi-biological cancer models, in particular those of Armitage and Doll (Br J Cancer 1954 8 1–12), the two-mutation model , the generalized multistage model of Little (Biometrics 1995 51 1278–1291), and a recently developed cancer model of Nowak et al. (PNAS 2002 99 16226–16231).Heidenreich Math Biosci 2003 183 111–134) the number of identifiable combinations of parameters is at most two less than the number of biological parameters, thereby generalizing previous results of Heidenreich et al.  for the two-mutation model. For the more general model of Little et al. (J Theoret Biol 2008 254 229–238) the number of identifiable combinations of parameters is at most We show that in the simpler model proposed by Little and Wright (We have shown that the previous results on parameter identifiability can be generalized to much larger classes of quasi-biological carcinogenesis model, and also identify particular combinations of identifiable parameters. These results are of theoretical interest, but also of practical significance to anyone attempting to estimate parameters for this large class of cancer models. In principle it may well be that some of these parameters may not be observed, or be possible to be derived from observed data via regression techniques. Such parameters are said to be redundant if the likelihood can be written using a strictly smaller parameter vector; otherwise they are irredundant. Rothenberg local identifiability, to mean that within a neighbourhood of each set of parameter values the likelihood differs for at least some data points. This notion has been extended by Little et al.gradient weak local identifiability and weak local identifiability. Little et al.weakly locally identifiable if the maxima of the likelihood are isolated; they defined parameters to be gradient weakly locally identifiable if the turning points (those for which the likelihood derivative with respect to the parameters is zero) are isolated. The results obtained by Little et al.There is a substantial literature on identifiability in stochastic models in various contexts et al.Heidenreich et al.et al.et al.et al.In this paper we consider the problem of identifiability in recently developed carcinogenesis models of Little and Wright et al.et al.et al.We consider the problem of parameter identifiability in a particular class of stochastic cancer models, those of Little and Wright et al.k cancer-stage mutations have occurred, no matter how many destabilizing mutations there have been. Once a cell has acquired a destabilizing mutation of type multiplicity of destabilization mutation types. It is to be expected that the more destabilizing mutations cells acquire of each type, the higher the cancer stage mutation rate is, but this is not intrinsic to the model. We write signature of the destabilizing mutation types. We habitually describe this model as of type The model of Little et al.Cells at different stages of the process are labelled by et al.et al.et al.In , where  . Assuminrameters , at mostet albsstep routine, Press et al.F02FAFThat there are likely to be exactly this number of estimable parameters is supported by numerical evaluation of the Hessian matrix of the hazard function. We make use of the solution of the system of ordinary differential equations defining the Hessian, outlined in −3 year−1, destabilizing mutation rates of 3.0×10−3 year−1, intermediate cell proliferation rates of 1.0×10−1 year−1, and intermediate cell death rates of 5.0×10−1 year−1. For each of 1000 random sets of parameters we evaluated the Hessian by numerical integration, as outlined in F02FAFWe evaluated the Hessian matrix for a model with three cancer-stage mutations and one destabilizing mutation, and a model with two cancer-stage mutations and one destabilizing mutation; log-normal perturbations of all parameters were performed, assuming a geometric standard deviation (GSD) of 4, centred on models with cancer-stage mutation rates of 4.0×10et al.et al.et al.We have shown that in the class of stochastic cancer models incorporating genomic instability developed by Little and Wright A weakness of the paper is that one cannot be absolutely sure  that the bound demonstrated by the mathematics of section 3 and et al.These results have obvious implications for the large number of other quasi-biological cancer models that are special cases of these models, in particular those of Armitage and Doll Our results imply that for the general class of cancer models considered here, only certain specific parameter combinations should be estimated in principle, and this is the case whatever the size of the dataset being considered. Whether for complex models for even this theoretically available number of parameters there is useful information is of course uncertain, and may well depend on the particular dataset and on the likely size of the parameters to be estimated. However, fits to a large population-based registry of colon cancer, as recently analysed by Little and Li Text S1Text S1(0.42 MB DOC)Click here for additional data file.


BMC Women's Health from the Estonian Postmenopausal Hormone Therapy trial has concluded that quality of life is not related to hormonal therapy use. The commentary article discusses this finding and considers other factors related to symptoms and quality of life during menopause. Important factors known to affect hot flushes and quality of life are smoking and high body weight. Since both these factors are modifiable, menopause is a suitable area for health promotion. However, evidence concerning lifestyle changes in symptom relief or increase of quality of life is weak. More trials in this area are needed before women may consider non-pharmacological treatment of symptoms as a reliable option for menopausal symptom cure.Menopausal health is important since this stage of life is not to be avoided. A recent article in  BMC Women's Health by Veerus et al [Menopause is not avoided by any woman but frequency and severity of menopausal symptoms vary. A recent article published in us et al  reportedus et al -4 and slus et al . The prous et al ,7. Crossus et al ,8. Aboutus et al . Howeverus et al ,8-11 andet al's Veerus study [et al [et al study [During recent years hormonal therapy (HT) has been introduced as a solution to menopausal symptoms. The Women's Health Initiative's (WHI) study results  showed t's study  was basey [et al  but in ty [et al . Both HEy [et al . A cruciy [et al . The resal study  was impoEarly onset of menopause  as well et al [et al [The quality of life of smokers and persons with high BMI is known to be low and an increase in hot flushes does not alleviate their situation, quite the opposite. There is a clear need for general health promotion and obesity prevention during the menopausal age in order to increase quality of life. Lifestyle changes, such as increasing physical activity, is one alternative to HT. Evidence on reducing cardiovascular disease by physical activity exists especially among postmenopausal women ,26. Howeet al  concludel [et al  study shet al [Menopausal transition may make women more aware of future health risks due to increased symptomatology and help-seeking behaviour. Motivation for health promotion may be further strengthened if women perceive life-style modifications as an alternative, non-pharmacological, way of managing menopausal symptoms. However, more evidence on effectiveness and efficacy of lifestyle changes, especially exercise, on decreasing hot flushes and increasing quality of life is urgently needed. In the future, menopause may act as a window of opportunity for health promotion and life-modifications. Studies from randomized trials such as Veerus et al  are neceRL originated the idea for the commentary article and is in charge of the article.The pre-publication history for this paper can be accessed here:


Wandering spleen is a rare condition defined as a mobile spleen only attached with its pedicle. It can be complicated by a volvulus, which is a surgical abdominal emergency. Preventing infarction is the aim of a prompt surgery that can preserve the spleen and then proceed to splenopexy. We report a rare case of torsion of a wandering spleen associated with a dolichosigmoïd. Wandering spleen is a rare condition characterized by the absence or underdevelopment of one or all of the ligaments that hold the spleen in its normal position in the left upper quadrant of the abdomen. It is an® 0 prepared on the upper and lower borders of the pedicle before the spleen replacement in its quadrant, which were knotted at the end; sigmoidectomy and colorectal anastomosis were performed. The patient recovery was uneventful. She was discharged on the sixth day.A 27-year-old woman presented to the emergency department after three days of abdominal pain, vomiting and constipation without fever. She had a recurrent constipation but no history of recurrent abdominal pain, abdominal mass, or trauma. On physical examination, abdominal distension was noted. There was a moderate diffuse abdominal tenderness more pronounced on the left side. Abdominal radiography showed an important colon distention especially at the upper left quadrant without air fluid levels . An abdoWandering spleen is defined as mobile spleen that is attached only by an elongated vascular pedicle, allowing it to migrate to any part of the abdomen or pelvis. It is a result of congenital anomalies in the development of the dorsal mesogastrium and the absence or malformation of normal splenic suspensory ligaments.3 The splHowever, acquired anomalies have been described and are attributed to laxity of the ligaments due to weakness of the abdominal wall, multiple pregnancies, hormonal changes or increase in size in the spleen. Both conPatients with a wandering spleen may be asymptomatic, present with a movable mass in the abdomen, or have chronic or intermittent abdominal pain because of partial torsion and spontaneous detorsion of the spleen.6 Torsion76Sonography showed the characteristic comma-shaped spleen in an ectopic position and the lack of splenic tissue in the left upper quadrant. Duplex Doppler color flow evaluation, provided optimal visualization of the organ and assessment of vascular supply. However,1Computed tomography is the preferred study for diagnosing a wandering spleen when torsion is suspected clinically or on other imaging studies. The CT manifestations included: (I) absence of the spleen anterior to the left kidney and posterior to the stomach, (II) a lower abdominal or pelvic mass with homogenous or heterogenous splenic parenchyma and an attenuation value less than that of normal splenic tissue, (III) whorled appearance of splenic vessels and surrounding fat only, and (IV) secondary findings such as ascites and necrosis of the pancreatic tail.797et al.[et al.[et al.[et al.[et al.[However, it is the whorled appearance of the splenic vessels and surrounding fat at the splenic hilum that is considered as specific of torsion of a wandering spleen. This sig11et al. fixed thl.[et al. fixed itl.[et al. and Peitl.[et al. used tral.[et al. sutured l.[et al. van der l.[et al. and Steil.[et al. dissectel.[et al.20 have ul.[et al.In the present case, the spleen was fixed by its pedicle using a technique inspired by the one described by stringel. In the sThe splenic torsion is sometimes associated with other manifestations like gastric or pancreatic tail volvulus.23 The on24The torsion of a wandering spleen is a rare abdominal emergency. Its diagnosis should be made in prompt time to prevent infarction of the spleen. Splenopexy by means of the extraperitoneal pocket creation appears to allow anatomic placement of the spleen along with the protection of the rib cage without the employment of biomaterials. Splenectomy should be performed only in patients with splenic torsion in whom massive infarction and thrombosis of the splenic vessels has occurred.


Dear Sir,et al.,[I have read with interest the article by Das et al., in whichet al., Morquio et al.,3The author has not mentioned the status of mental development or the results of echocardiography.In my opinion, this may be a patient with Morquio syndrome in view of the presence of hepatomegaly, cardiac valvular lesion, swollen alveolar ridges and gums with misaligned teeth, cloudy corneas, skeletal dysplasia, normal auditory functions, and normal intelligence.


Reported by Danovaro  Although there are only 22 described species, they have been recorded from a broad range of depths and settings ranging from shallow, coastal waters to methane seeps and hydrothermal vents, to the Izu-Ogasawara trench off Japan ,8. Loricet al., using aet al.[Why is this finding important? These metazoans have had to cope with multiple physiological stresses - extreme salinity, toxic sulfide levels and the absence of oxygen. Evolving adaptations to any one of these would be a challenge. Clues to the success of the Loricifera found by Danovaro et al. may lie et al. and appaet al., which tet al.. If suchet al.[et al.[The findings by Danovaro et al. may at fet al.. The thrl.[et al., represeet al.[What does it mean to have metazoans inhabiting anoxic environments? As exploration of low-oxygen settings has intensified, it has become apparent that metazoan life can persist at very low oxygen levels of only a few micromolar per kg. In such settings metazoans can play important functional roles in the recycling, bioturbation and burial of carbon and nitrogen ,14,5. Ofet al. it appeaet al.[Are there more metazoan taxa out there that can live without oxygen? Almost certainly. The finding by Danovaro et al. offers tet al. or in otet al. points tAre there metazoans on other planets with atmospheres different from our own? Our ability to answer this question would be strengthened considerably by more intensive studies of animal - microbe interactions in extreme settings of our own inner space - the deep ocean.


TB) difficult in countries with high prevalence of TB, and vice versa, but TB has also been linked to causation of sarcoidosis. All those who deal with such conditions would remember the cases, when TB, after successful treatment (or during it), is followed by a diagnosis of sarcoidosis and more commonly when patient being treated with steroids following with a diagnosis of sarcoidosis, land up with TB. In both of the clinical scenarios, the authenticity of the primary diagnosis has to be confirmed, before one can say that either of the conditions has lead to the other one.Relationship of tuberculosis (TB) with sarcoidosis has baffled physicians and researchers ever since the description of sarcoidosis. Not only sarcoidosis is a close clinical mimic of TB, which makes the diagnosis of sarcoidosis (et al. present an interesting viewpoint regarding an entity called ‘tuberculous sarcoidosis’. Further, the authors have even laid down the criteria for the diagnosis of tuberculous sarcoidosis.[In this issue of the journal, Shah coidosis. Tuberculcoidosis. However,et al. [originally by Wong et al.,[et al. [For example, in the illustrative case 1 described by Shah g et al., represeng et al., could beg et al., followedg et al., The illu,[et al.  are highSince sarcoidosis was first described, there has always been a belief that the disease is in some way related to TB. Sarcoido210Tropheryma whippelli as a causative agent for Whipple's disease[Of late, nucleic acid amplification of the genetic material of putative agents serves as an alternative method for isolating fastidious organisms. This method has been used successfully in identifying s disease and coros disease as an ags disease These res diseaseet al. are neither evidence-based nor play any role in day-to-day clinical practice.Based on the current understanding, we believe that there is no merit in the term “tuberculous sarcoidosis”; and the criteria laid down by Shah


Most of the total body virus is located in lymphoid tissues, typically in association with follicular dendritic cells (FDCs) Viral clearance rates have been estimated in the blood, and different techniques have yielded a variety of estimates Virus production rates have also been estimated by several techniques. Because in other lentivirus infections, most notably visna virus, intracellular viral DNA levels increase approximately exponentially and then virus appears to be released rapidly in situ hybridization to estimate burst size. Assuming that the maximal HIV RNA count in a cell corresponds to the burst size, Haase et al.et al.et al.et al.Recent studies have combined image analysis with et al.et al.One can also attempt to measure burst size by directly imaging the extracellular viral particles surrounding an infected cell tion see , and theFinally, the most direct estimates for the total amount of virus produced per infected cell was achieved using single-cycle SIV to infect PBMC which were placed back in uninfected rhesus macaques. By measuring the total amount of virus produced and accounting for clearance, this experiment yielded a total production of approximately et al. and Chen et al. depend on the viral clearance rate, et al.et al.Summarizing, the latest production rate estimates converge on a few thousand to approximately per virion clearance rate of In one earlier modeling study a production rate of several thousand particles per cell was shown to be consistent with a viral half-life of 3–4 hours in the lymphoid tissue In this paper we attempt to reconcile the various estimates for the viral clearance rate, the viral production rate, and the amount of long-lived virus trapped on FDCs within one modeling framework in order to test whether there is a consistent interpretation explaining all observations. To do so we introduce compartmental models to analyze recent experimental data on viral clearance in various organs, and estimate the rates at which virus is exchanged between them.et al.A simple and direct approach to estimate the clearance rate of virus from the blood is to infuse virus particles into the blood, and monitor their disappearance by taking frequent blood samples. Zhang If most of the viral degradation indeed takes place in organs such as the liver If et al.et al.Using the estimated clearance rate from the blood of 0.2 minr organs . The estOnly 40.5% of the total radioactivity was recovered in the monkey 2 hr after injection. This could be due to a loss of radioactivity by viral degradation and removal of labeled molecules, or to accumulation of SIV in other body compartments, such as the gastrointestinal tract, that were not examined s organs .et al.et al.HIV-1 clearance rates from plasma have been estimated in chronically infected patients by plasma apheresis over a period of two hours. Plasma was removed at a rate of 39 mL per min, and was replaced by an equivalent volume of isotonic saline containing 5% albumin. On average, this procedure removed a total of approximately d et al., suggestet al.It is worth noting that the estimate for the efflux rate in humans of HIV-1 from plasma is more than 10-fold slower than the estimated plasma efflux rate of SIV in rhesus monkeys Since most virus production takes place in the lymphoid tissue, we modify a previously published compartmental model ex vivoIn this model we make a distinction between clearance and efflux. We speak of efflux when the number of virus particles is conserved, and speak of viral clearance in an organ only if the virus is being degraded there. Thus, these equations assume that there is no viral clearance from the blood; there only is efflux to the lymphoid tissue and to other organs that have viral clearance rates, The parameter in situ hybridization suggested that most of the virus in the lymphoid tissue is associated with the FDC network In a typical patient the FDC pool seems saturated, i.e., To consider the total virus load we add Eqs. (6)–(9) yielding,et al.We can use the relationships between per capita clearance rate in LT, et al.For the more “realistic” example, of virus . The rec per day . When Chith FDCs , we find, i.e.,  . In thisAnalysis of the plasma apheresis experiments in humans provided estimates for the influx of virus from the LT into the blood . This caeriments . FinallyTo test whether the full model (Eqs. 6–9) is consistent with the plasma apheresis experiments, we make reasonable guesses for the other parameters of the model. Allowing rapid filling of the pool of virus bound to FDCs we set the number of FDC binding sites he blood , reducinaffected . Very siChoosing the efflux rates estimated in monkeys per capita viral clearance rates in lymphoid tissues. The larger the viral production rate per productively infected cell, and the more virus that is bound to FDCs (see per capita clearance rate of free virus in lymphoid tissue must be to balance viral production. Recent estimates of a burst size up to We have shown that the balance between viral production and viral clearance implies rapid FDCs see , the lary  to  d .et al.In our modeling work the rate of virion clearance, et al.The efflux and/or clearance rate of SIV from the blood of uninfected monkeys and of infected monkeys with a low viral load Finally, it may seem that the notion of a large FDC store of bound virus is incompatible with the rapid viral clearance rates seen in spleen and lymphoid tissues of uninfected macaques Rapid viral clearance in lymphoid tissue is not surprising. The lymphoid tissue contains more than In a previous paper we showed that the rate of viral clearance in lymphoid tissue would markedly affect the estimated life span, Summarizing, we have provided new estimates of viral efflux and clearance rates in various organs, including blood and lymphoid tissue. We have confirmed that the exchange rate from lymphoid tissue to the blood should be slow et al.in situ hybridization in lymphoid tissue, including measurements of the number SIV RNA copies on the surface of and in the vicinity of activated and resting CD4Reilly et al.To estimate viral production rates per virus producing cell from this data, one has to integrate the virus production function over the life span of the cells. Reilly Note that the estimates obtained in


In response to the case report of Brugada-type Electrocardiographic Pattern Induced by Electrocution by R Rangaraj et al  , the ele


Sir,et al.We read with great interest the article by Omoti et al.et al.et al.et al.However, we do not completely agree with the authors’ contention that most reports of ocular involvement in lymphoma involve few patients. Cassoux et al.6The authors have comprehensively documented the ocular and adnexal involvement in a series of patients with systemic lymphomas. It would also be of interest to the ophthalmologists to look at it from the other point of view. Shields et al.Omoti The article also presents three cases of presumed lymphoma-associated retinopathy based only on features of hemorrhages and vasculitis. Although possible, we believe that angiocentric lymphomas are extremely rare and the classic presentation would be in the form of confluent, round, or geographic greasy-yellow subretinal pigment epithelium infiltrates. 8


Sir,Br J Cancer  on the prognostic significance of molecular detection of melanoma cells in melanoma patients under adjuvant interferon . In our work, in 27 patients tested, one was already positive before operation becoming negative some time following operation. No data on that point are given on the 418 cases studied by Gogas et al. This type of information may permit further confirmation of a theory claiming that surgery manipulations may cause forced release of melanocytes to blood circulation (Gogas et al claim that no evidence for an interference of the so-called ‘illegitimate transcription’ (Gogas


Although we know from Hodson's water hammer theory that Scars could occur in sterile reflux, Edwards and Smellie in theiret al, involvinl,[et al, wherein


Sir,et al.[et al.[Chavan et al. sought tl.[et al. suggesteet al.[et al.[Is this scoring valid? I think not. No study has systematically examined long-term memory loss after ECT for us to assume that such memory loss does not exist. In fact, the available data suggests that at least some patients may experience extensive, protracted and possibly permanent memory disturbance after ECT. For example, Lisanby et al. describel.[et al. observedl.[et al. describel.[et al. suggesteAnd does ECT cause pain? It certainly might. Patients may reasonably be expected to consider the injection of the ECT premedication noxious and many patients do experience headache or bodyache for several hours after an ECT treatment.Items 3 and 12 therefore elicit attitudes more than knowledge; this is even more true for item 2, which states that ECT is an inhuman treatment. To some, it is; to others, it is not. There cannot be a correct position for an attitude; for example, there are proponents for and against the death sentence and who has the right to say which stance is correct? It is therefore necessary to separate items reflecting knowledge from those reflecting attitudes and, to view attitudes as positive and negative (rather than right or wrong), much as we did in a study which has now become a landmark reference in the field. Other me


Sir,We read the article of Shukla and Barreto with interest. This sysThe basis of surgical strategy in solid cancer like gallbladder carcinoma must be the knowledge of local and disiminated spread of the cancer. Because of this, the background for actual recommendations of some authors of routine resection of the extrahepatic bile duct in gallbladder cancer appears completely unclear, particularly based on the well-known early and late complications of resection, anastomosis and reconstructions of the extrahepatic bile duct.et al.[Miyazaki et al. were theet al. In advanet al. This is The cited studies which advocate radical resection including resection of the extrahepatic bile duct mostly include even extended liver resection and an extended lymphadenectomy. For thiset al. and Wakai et al.[The importance of liver resection in surgical treatment of gallbladder carcinoma was recently – among many other authors – emphasized and proved by Araida ai et al.5 Oncologai et al.4et al.[Yamaguchi et al. found ouet al. If this The cited authors who advocate aggressive resection including resection of the extrahepatic bile duct are extraordinary experienced hepatobiliary surgeons. The results, especially the risks of these extended procedures cannot be compared and are not conferrable on a broad medical surgical supply level, and can therefore not be recommended generally.The paper of Shukla and Barreto makes an important contribution to a differentiated and censorious consideration of the resection of the extrahepatic bile duct as part of the surgical strategy in operative treatment of gallbladder carcinoma. The final eight conclusions of Shukla and Barreto cover up exactly with our concept and our attitude to this subject.


Biosensors are analytical devices being approachable for multiple analytes assay. Here, biosensors with intercepted acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) are presented as tool for assay of anticholinergic compounds such as pesticides, nerve agents and some natural toxins. Principle of assay is based on evaluation of cholinesterase activity and its pertinent decrease in presence of analyte. Nerve agents, pesticides, anticholinergic drugs useable for treatment of Alzheimer′s disease as well as myasthenia gravis and aflatoxins are enlisted as compounds simply analyzable by cholinesterase biosensors. Nerve agents, insecticides such as organophosphates as well as carbamates and some drugs may be named , malaoxon, malathion, chlorpyrifos and dichlorvos may be listed as typical examples Marrs, . Toxicitet al., et al., Amperometric biosensors are a good alternative to the potentiometric ones. Amperometric biosensors provide linear output signal dependence on concentration of analyte in comparison with the logarithmic relationship typical for potentiometric sensors  and charge z; total mass of substances, which either precipitated or dissolved on the electrode, is expressed as m. An indifferent ion should be added to solution for polarization suppression.The meaning of symbols is common; et al., et al., et al., Biosensors are analytical devices consisting from biorecognition element and a proper sensor element  and oxygen or hydrogen peroxide amperometric transducer (Campanella et al., et al., et al., et al., et al., The second way being frequently performed for amperometric evaluation of AChE activity is based on replacement of native substrate acetylcholine by an alternative acetylthiocholine. The mechanism is lucidly depicted in Amperometric biosensors with intercepted cholinesterases are promising tools for evaluation of many anticholinergic compounds. Assay of pesticides, nerve agents and aflatoxins are typical analytes. The second way of biosensor performance is evaluation of drugs administered to patients suffering from Alzheimer′s disease and myasthenia gravis.


Acute perinatal asphyxia is a major cause of death and neurological injury in newborn infants. Severe asphyxia can occur in infants around the time of birth for several reasons. The aim of our study was to find the most sensitive, easily obtainable and fast assessable parameter of the presence and quantification of asphyxia.In our study 39 term newborns , from vaginal deliveries admitted within 24 hours of life were monitored and parameters of blood count from venous blood were assessed. Laboratory findings of blood count parameters revealed significant differences between term asphyxial and healthy newborns in erythrocyte count and hemoglobin and hematocrit values.Hematological changes observed early after delivery can determine the duration of hypoxemia (acute vs. chronic) and asphyxia of short duration may be accompanied without occurrence of polyglobulia. Birth itself is a strong oxidative stress. Oxidative stress, excess of free radicals and their reactive metabolites in the organism, plays an important role in the pathogenesis of so called free-radical diseases, not only in adults but also in newborns  were determined.The study involved 39 term newborns , from vaginal deliveries admitted within 24 hours of life. In both groups of newborns, blood samples of venous blood were taken on the 1Blood count was determined by an automatic analyzer ADVIA 120  using an optical system for measurement. The number of erythrocytes, leukocytes and thrombocytes was assessed by the analyzer using a laser beam which registered the flow of cells in certain time intervals. Hemoglobin was measured colorimetrically. Using a laser beam, the size of erythrocytes was determined and further the value of hematocrit was calculated.p ≤ 0.05 was considered significant. The presence of asphyxia was the first factor  and the time of blood sampling was the second factor (1st and 5th day of life).For statistical analysis ANOVA followed by Fisher's post hoc test was used, This study complies with the guidelines for human studies and animal welfare regulations and subjects have given their informed consent. The study protocol has been approved by the Committee on Human Research in Medical School, Comenius University, Bratislava, Slovakia.Laboratory findings of blood count parameters revealed significant differences between term asphyxial and healthy newborns in erythrocyte count and hemoglobin and hematocrit values . We did et al., et al., Several changes in structure, function and amount of certain blood elements have been observed in asphyxia .In our study blood count variables were found to be affected differently than observed by other authors. In the blood samples obtained on the 1et al., et al. (In asphyxia, in the first 96h of life increased peripheral leukocyte counts may contribute to abnormal neurodevelopmental outcome (Morkos , et al. .th day of life a normal number of thrombocytes is established.Thrombocytes take part in hemostasis, influence coagulation cascade and are the main source of many biologically active substances. Thrombocytopenia can be observed during the first 2 days of life, on the 10st and 5th day of life. We agree with the finding of Phelan et al. (In either groups studied we did not confirm a statistically significant thrombocytopenia, though in the group of asphyxial newborns the levels of thrombocytes were slightly decreased on 1n et al. , that thIn spite of the recent decrease of perinatal morbidity and mortality, the risk of pre/postnatal CNS damage as a consequence of asphyxia did not decrease. The aim of current perinatology research is finding and determining the most sensitive, easily obtainable and fast assessable parameter of the presence and quantification of asphyxia.et al., et al., et al., The newborns have inadequate antioxidant protection and oxidative stress is a major cause of irreversible CNS damage in term asphyxial newborns. Studies have confirmed the helpful effects of antioxidant supplementation during hypoxemia (Pecháň et al., et al., In combination with other biochemical blood parameters (Brucknerová


Dear Sir,et al.[et al. have concluded that "Simultaneous laparoscopic procedures can be done for urological diseases in selected patients, with the advantages of single anaesthesia and hospital admission without increasing the morbidity".[With great interest, I read the recent publication on 'using concomitant laparoscopic procedures for urological diseases' by Maurya et al. Maurya erbidity". Indeed, rbidity".


International Journal of Environmental Research and Public Health’. I was invited to be the guest editor, and to oversee the refereeing process and subsequent selection of timely, relevant and high quality papers highlighting particularly novel aspects concerned with sustainability issues in environmental studies.This special issue ‘Sustainability: Environmental Studies and Public Health’ is part of the internationally leading ‘Contributions that have a significant impact on solving public health problems were particularly encouraged. It follows that major public health issues, sustainable water management and environmental risk were topics of particular interest to the editorial team and reviewers. Ten papers comprising various scientific contributions including technical and critical review papers relevant for a world-wide audience were selected.et al. [et al. [Three comprehensive critical review papers were published. Remoundou and Koundouri  reviewedet al.  explored [et al.  reviewedet al. [et al. [Seven original papers were published in this special issue. Saarloos et al.  linked t [et al.  discusseThe human health theme features also strongly in this special issue. For example, Markandya and Chiabai  valued cet al. [Other papers had a clear international dimension. For example, Cross et al.  studied et al.  presenteet al.  assessedThe high diversity of excellent environmental and public health studies with a strong sustainability theme is likely to be of interest to a broad audience for decades to come. This special issue is not just a timely reference source for academics, but should particularly be of practical use for medical doctors, environmental scientists and engineers, and civil engineers concerned with public health engineering, environmental protection and sustainability.It is a pleasure to thank the members of the Editorial Board, all authors and co-authors and all referees for their valuable contributions to this special issue. Moreover, this most interesting publication would not have been possible without the efficient support from the Journal Office.


Sir,et al. published in December 2009 issue of IJA.[I read with interest the article titled “Comparison of Midazolam and Propofol for BIS-Guided Sedation during Regional Anaesthesia” by Khurana e of IJA. I congraet al.[et al.[et al.[50 (BIS at which 50% of patients were unresponsive) of 65 for propofol alone but 76 for propofol with nitrous oxide. Iselin-Chaves et al.[50 of 64 for propofol alone and 72 for propofol with alfentanil.Several reports have suggested that BIS measurements may not be independent of the drug used. There is evidence that BIS is influenced by the choice of anaesthetic agent. In a study conducted by Ibrahim et al. wherein l.[et al. found BIl.[et al. found a As per the study protocol, the initial BIS targeted in both the midazolam and propofol groups was 75, with infusions manipulated intra-operatively to maintain BIS values in the 65–85 range. The incidence of awareness has been stated to be 20% in the midazolam group and 16.7% in the propofol group.et al.[However, in view of the above evidence, identical BIS values may not necessarily indicate identical levels of sedation for both midazolam and propofol as understood in clinical parlance. The authors’ concern that assessment of depth of sedation by clinical means may itself alter such a depth is no doubt valid. Despite such concerns, however, it would have been interesting to note the levels of sedation at identical BIS levels for both groups and infer there from. Furthermore, the methods by which awareness during sedation, as defined by recall of intraoperative events, in the study under discussion were assessed, probably required greater elaboration. In this regard, specific memory tests for immediate and delayed recall as utilized by Ibrahim et al. might ha


We appreciate the comments by Rylance et al. stimulated by our analysis of the global burden of disease due to outdoor air pollution . We acknIn the 2004 World Health Organization (WHO) comparative risk assessment, We agree with Rylance et al. that the approach used by


We report two cases of plunging ranula, which had recurred after marsupialization. Both were successfully treated by removal of the ipsilateral sublingual gland. A brief review of the literature regarding the treatment options is presented. Ranula is an extravasation cyst found in the floor of the mouth. They develop from extravasation of mucus after trauma to the sublingual gland or obstruction of the ducts.–3 PlungiAn 8-month-old girl baby was referred with an intraoral swelling with extension into the submandibular and submental space. Marsupialization had been done at 2 months of age. A provisional diagnosis of plunging ranula was made. Magnetic resonance imaging (MRI) showed a thin walled cystic lesion on the left side involving the floor of the mouth in the sublingual region and extending inferiorly into the submental region, laterally into the submandibular region, superiorly into the left parapharyngeal region up to the pharynx . IntraorA 10-year-old girl presented with a recurrent intraoral swelling. She had undergone marsupialization for an intraoral swelling 2 months earlier at a local hospital. The clinical examination revealed a large cystic swelling of 3 × 4 cm with extension into the submental space with cross-fluctuation . The intRanula develops from extravasation of mucus after trauma to the sublingual gland or obstruction of the ducts.3 Ranula The pathophysiology involved in extravasation is hypertension in the duct due to obstruction leading to acinar rupture in the salivary gland and then extravasation of the mucus. The initial stage is a traumatic rupture of the excretory duct and the second stage is the extravasation and subsequent accumulation of saliva within the tissue, as shown by experimental studies.7 Ranula When these extravasation cysts extend into the submandibular or submental space, they are called plunging ranula. Its true incidence is unknown. The cause of plunging ranula is not known, but anomalies or obstruction of the salivary gland duct and naturally occurring defects in the mylohyoid muscle have been shown to be prerequisites for the extravasation. These cysts commonly extend into the submandibular triangle, occasionally they may extend superiorly into the parapharyngeal space as far as the base of the skull. They may extend inferiorly to the supraclavicular area and upper mediastinum or posteriorly into the retropharyngeal space.898Ranula is a clinical diagnosis, and imaging studies are done mainly to know the extension of swelling prior to surgery or when the diagnosis is unclear. Computed tomography and specifically the presence of “tail sign” is pathognomonic for the plunging ranula.–12 This et al[et al[et al[et al[et al[Surgery is the main stay for the management of ranulas. These include incision and drainage, excision of ranula, marsupialization, and marsupialization with packing or complete excision of the sublingual gland. Simple marsupialization has fallen into disfavor primarily because of the failure rate, which has been anywhere from 61% to 89%.[et al have tre al[et al suggeste al[et al had two  al[et al Mahadeva al[et al did not et al[et al[Other treatment modalities have also been utilized. Sclerotherapy with OK-432 is a good substitute for surgery. Recurrenet al used a h al[et al have perIn conclusion, removal of the ipsilateral salivary gland is the management of choice in ranulas. Intralesional sclerotherapy with OK-432 is a good option but may not be feasible due to nonavailability of the product universally.


We thank Guzzi et al. for their interest in our study on the association of environmental cadmium exposure and periodontal disease . There aThat dental amalgams are the major source of Cd body burden has been questioned , and fur


Sir,et al., a diagnosis of Netherton's syndrome was made.et al. in his review of 43 patients described a male patient[Netherton's syndrome is characterized by the triad of ichthyosis linearis circumflexa, trichorrhexis invaginata (bamboo hair) and an atopic diathesis. Our case37e patient In our ce patient our patiWe report this case for its rarity and classical presentation.


It causes profound hemodynamic effects, especially when the rupture is acute. Like most other left-to-right shunts, it was only a matter of time before this rare defect also became amenable to transcatheter closure (TCC). Since the first report of TCC of RSOV by Cullen . in 1994 it was o94[et al. In this l.[et al. we too hl.[et al. Traditiol.[et al. Before oet al. have performed TCC for RSOV rupturing into the right atrium and the right ventricle using two Amplatzer duct occluders (ADOs).[Sen and coworkers attemptes (ADOs). Because s (ADOs).10 as wels (ADOs). have beeet al.[The technique is very similar to TCC of perimembranous VSD, given that the defect is just above the aortic valve instead of below. It entails crossing the defect from the left side, establishing the standard arteriovenous wire loop and deploying the device from the venous side under fluoroscopic and transesophageal echocardiographic (TEE) guidance. Although Arora et al. have useet al. Balloon et al. We have et al.[Residual shunting causing hemolysis in this high-flow defect and procedure-related AR are the potential complications of TCC of RSOV. Although Sen et al. have hadet al. We have et al. AlthoughIn summary, RSOV is yet another hole that can be successfully plugged by the interventional cardiologist. TCC can be considered a safe and effective alternative to traditional surgical correction in selected cases. However, a longer follow-up is necessary. Given the rarity of this defect, it would be essential to maintain a registry of such procedures.


Dear Editor,et al.[First, we appreciate the details with which Chalisgaonkar et al. have reaet al. and searet al.,[In the case report by Biswas et al., on the cIn all case reports of retinoblastoma in adults, retinocytoma was diagnosed as benign appearing areas in malignant tumor tissue and not as pre-existing lesions that turned malignant on follow-up. In our cet al.,[may have an effect on retinoblastoma due to circulating mutagens and immunosuppression.[Ours is the only case reported in literature where retinoblastoma was found in pregnancy. There is one case reported by Takahashi et al., six montpression.


Sir,et al. recommended that “a precautionary approach when dealing with radio and microwave frequency radiation is recommended for the individual and the general population.”[The cellular phone is a widely used tool at present. The interesting question is whether cellular phone has any effects on germ cell. Basically, the effect of cellular phone on health is believed to due to microwave emitted from the phone. The effect of microwave from cellular phone on germ cell is a controversial issue.2 The topulation.” In this et al.[Focusing on the effect of cellular phone on ovary, according to the literature search, there is only one experimental report on this topic published by Gul et al. They reaet al. There aret al. reported on null correlation between exposure to cellular phone and testicular cancer in their case control study.[in vitro studies pointing to the possible effect of cellular phone on human spermatozoa.[et al. reported that radiation from cellular phone might induce reactive oxygen species production and DNA damage in human spermatozoa in vitro.[et al. also observed similar findings in their in vitro study and proposed that “keeping the cell phone in a trouser pocket in talk mode may negatively affect spermatozoa and impair male fertility.”[et al.[in vitro studies usually depend on small number of tested samples. This makes the limited implication of the results.Focusing on the effect of cellular phone on testes, there are many reports on the effect of cellular phone on testicular cell. Effect of cellular phone on mammalian cells and sperm DNA as well as its effect on apoptosis is still controversial. In an exol study. However,rmatozoa.–10 De Iuin vitro. Agarwal rtility.” A decrea.”[et al. However,In conclusion, effect of cellular phone on the germ cell is still a myth. The previous reports usually pose some problems implying the need for further well-controlled studies for clarification on this topic.


Acute appendicitis is a common surgical problem however the diagnosis is often overlooked when it presents as a small bowel obstruction. In this report we present two cases of elderly patients who presented with small bowel obstruction and raised inflammatory markers. Both patients were successfully treated with a laparotomy, adhesiolysis and appendicectomy and went on to make a good recovery. Acute appendicitis may rarely present as small bowel obstruction . The sma9/L and 362 mg/L respectively. Her renal function was deranged with a creatinine of 251 μmol/L and a urea of 14.8 mmol/L. An abdominal film  fet al [Bose et al  reportedet al [Assenza et al  reportedet al [et al [However, variations of the above mechanisms have been reported. Zissin et al  report al [et al  presenteet al [et al [Appendicitis can be caused by an appendiceal mucocele and Mourad et al  report sl [et al  report aThe presentation of acute appendicitis in the elderly can be atypical which can result in a delayed diagnosis with potential for increased morbidity and mortality . PresentAcute appendicitis should be considered in the differential diagnosis of patients with small bowel obstruction presenting with raised inflammatory markers to avoid delays in management.CT: computerised tomography.Written consent was obtained from both patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.SH collected the data on both patients and contributed to the literature search and writing of the manuscript. KM conceived the idea and helped with the draft of the case report. DB interpreted the radiological images and contributed to the draft of the manuscript. LB was consultant in charge of patient 1 and contributed to the draft of the manuscript. PKS was the consultant in charge of patient 2 and contributed to the draft of the manuscript. All authors read and approved the final manuscript.


Dear Editor,et al.[We read with interest the article "Amyloidosis of lacrimal gland" by Prabhakaran et al. We wouldet al.,[et al.[The authors report that approximately 24 cases of primary localized amyloidosis of orbit have been reported. However, we believe that this number is likely to be higher. In a review article by Taban .,[et al.et al.,[et al.,[The authors mention that one bilateral case of isolated lacrimal gland amyloidosis has been reported. We wish to draw attention to one of the cases reported by Cheng et al., who had ,[et al., have desHertel's exophthalmometer is designed to measure axial proptosis and is unable to measure ocular displacement. We would value being educated as to how the authors were able to measure the displacement with the help of a Hertel's exophthalmometer. Perhaps the authors are merely implying that apart from having 2 mm of axial proptosis, the patient also had 2 mm of displacement.Lastly, was any reoccurrence noted? Recurrence has been said to occur in approximately one-third of cases as total excision is usually not possible in these patients.


The mixed epithelial stromal tumour is morphologically characterised by a mixture of solid and cystic areas consisting of a biphasic proliferation of glands admixed with solid areas of spindle cells with variable cellularity and growth patterns. In previous reports the seminal vesicle cystoadenoma was either considered a synonym of or misdiagnosed as mixed epithelial stromal tumour. The recent World Health Organisation Classification of Tumours considered the two lesions as two distinct neoplasms. This work is aimed to present the low-grade epithelial stromal tumour case and the review of the literature to the extent of establishing the true frequency of the neoplasm.We describe a low-grade epithelial stromal tumour of the seminal vesicle in a 50-year-old man. Computed tomography showed a 9 × 4.5 cm pelvic mass in the side of the seminal vesicle displacing the prostate and the urinary bladder. Magnetic resonance was able to define tissue planes between the lesion and the adjacent structures and provided useful information for an accurate conservative laparotomic surgical approach. The histology revealed biphasic proliferation of benign glands admixed with stromal cellularity, with focal atypia. After 26 months after the excision the patient is still alive with no evidence of disease.Cystoadenoma and mixed epithelial stromal tumour of seminal vesicle are two distinct pathological entities with different histological features and clinical outcome. Due to the unavailability of accurate prognostic parameters, the prediction of the potential biological evolution of mixed epithelial stromal tumour is still difficult. In our case magnetic resonance imaging was able to avoid an exploratory laparotomy and to establish an accurate conservative surgical treatment of the tumour. The mixed epithelial and stromal tumour (MEST) is morphologically characterised by a mixture of solid and cystic areas with a biphasic proliferation of glands admixed with solid areas of spindle cells, with variable cellularity and growth patterns. We report a low grade MEST of the seminal vesicle and we emphasize the diagnostic criteria and the different diagnosis as cystoadenoma.A 50-year-old man was admitted in November 2005 to our hospital with disuria, fever and gradual decrease in urinary stream for several months. On ultrasound (US) a hynomogeneous, hypoechoic pelvic mass of the posterior side of the bladder was demonstrated. Abdominal computed tomography (CT) revealed a 9 × 4.5 cm pelvic mass in the side of the seminal vesicles displacing the prostate and urinary bladder. On precontrast CT, the mass showed fluid heterogeneous content, well-defined margins, and irregular thin enhanced internal septa after intravenous contrast material administration. On axial spin-echo T1-weighted and axial and sagittal T2-weighted Fig.  magneticIn our case the low-grade MEST diagnosis was made in accordance with the World Health Organization (WHO) classification criteria . The leset al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., may be not accepted as conclusive because only three cases were considered. In our case US was only useful to detect the lesion, but both its site and relations with adjacent organs were not established. CT confirmed the presence, size, location, internal consistency, extension of the primary tumour, and the absence of distant metastases. MRI was useful in establishing the tumour origin from the seminal vesicles and its relations with the adjacent organs (Fig. These tumours have been considered to represent morphological variants of the same neoplasm, which may reveal local recurrence but not malignant transformation ,10. In tet al.,  and Son [et al.,  reported[et al., , Bullock[et al., , Damjano[et al., , Lundhus[et al., , should [et al.,  or becau[et al., , Baschin[et al., , Mazzucc[et al., , Gil et [et al., , the mes[et al., , the ben[et al., , should [et al.,  and Hosh[et al.,  the clas[et al.,  in low, [et al., . In the [et al.,  examined[et al.,  and Soul[et al., : obviousSVC and MEST are two distinct pathological entities with different histological features and clinical outcome. Predicting the potential biological behaviour of MEST remains difficult because accurate prognostic parameters are not available. In our case MRI was able to avoid an exploratory laparotomy and to establish an accurate conservative surgical treatment of the tumour.MEST: mixed epithelial and stromal tumour; US: ultrasound; WHO: World Health Organization; CT: Computed tomography; MRI: magnetic resonance imaging; CEA: carcinoembryonic antigen; PAP: prostate acid phosphatase; PSA: prostate specific antigen.Written informed consent was obtained from the patient for publication of this case report.The authors declare that they have no competing interests.IF collected the tissue specimen, made the histological diagnosis and images, revised the manuscript. IP made the radiological diagnosis, prepared radiological images. BM conceived the study and revised the manuscript.  ML, FF, GP: collected clinical records and wrote the manuscript. All authors read and approved the final manuscript.


Sir,et al[et al[I read with much interest the article of Creado et al which de al[et al concludeThis conclusion, though intuitively appealing, is not necessarily correct. An equally credible argument is that patients who are more severely ill increase the caregiver burden of illness and provoke maladaptative methods of coping, such as escape avoidance, fatalism and passivity, whereas patients who are less severely ill decrease the burden of illness and allow the unfolding of more adaptative methods of coping, such as expressive action and problem-solving.et al[Causality can never be proven from statistical associations. If variables A and B are significantly correlated, A may cause B, B may cause A or A and B may both be influenced by a third, measured or unmeasured, variable. In the last-mentioned instance, the third variable is known as a confounding variable. Creado et al opted toSeveral criteria have been outlined to help researchers interpret causality. These include the temporal sequence of the variables, the strength, consistency and specificity of the association, the presence of a dose-response type of relationship, and the existence of a credible explanation. However, the most definitive method of determining causality would stem from research that is based on randomized, controlled designs.et al[So, do the findings of Creado et al reflect A backward, stepwise, multiple regression analysis which examines the effects of measures of illness severity and measures of coping on burden of illness. This anaA path analysis which examines chains of influence among variables, and whether the data are consistent with the specified model of causality. Several It is hoped that these digressions on statistical and research methods guide these and future authors in their approach to hypothesis-setting and data analysis.


Bmal1 knockout mice and rescued by restoration of Bmal1 expression selectively in the dorsomedial hypothalamus was published in 2008 by Fuller et al and critiqued in 2009 by Mistlberger et al. Fuller et al have responded to the critique with new information. Here we update our critique in the light of this new information. We also identify and correct factual and conceptual errors in the Fuller et al response. We conclude that the original results of Fuller et al remain inconclusive and fail to clarify the role of Bmal1 or the dorsomedial hypothalamus in the generation of food-entrainable rhythms in mice.Evidence that circadian food-anticipatory activity and temperature rhythms are absent in  Bmal1 deficient mice fail to anticipate a daily mealtime, and that restoration of Bmal1 by adenoassociated viral vector restricted to the dorsomedial hypothalamus (DMH) rescues food-anticipatory circadian rhythms. The authors concluded that the clock gene Bmal1 and the DMH are both required for this circadian function. However, two other labs have found that Bmal1 null mice do anticipate a daily meal under the same conditions as those used by Fuller et al [Bmal1 in the entrainment of circadian anticipatory rhythms by food ['each of these points [is]incorrect'. Our objectives in this reply are to briefly revisit each point in the critique and to update our analysis in view of what little new information Fuller et al have provided. We also identify and correct factual errors and misconceptions in the Fuller et al response. Fuller et al conclude that 'in no case does [the new information] change our results or their import'. We agree: the results of Fuller et al substantially increased by food restriction and the other is dramatically decreased'. This statement is again not evidence-based. We 'deliberately' did not report absolute values in that paper because it is irrelevant, but provide them here  = 1.31, p = .21). During a subsequent 50 h food deprivation test, telemetry and motion sensor counts increased but remained below baseline levels .Fuller et al  in theirere Fig. . When fonot sufficient if food anticipation is weak or absent. Food-anticipation is clock-controlled foraging, and more sophisticated behavioral assays  should be employed to properly phenotype this circadian function.It bears emphasizing, the criterion for selecting a measure of food anticipatory activity (or physiology) should not be whether mean daily levels of this measure go up or down during food restriction. Rats and mice reduce total daily energy expenditure when calories are restricted, and this will be reflected in reduced activity at times of day when food is not expected. They are able to do this by utilizing a circadian clock to concentrate food seeking at the expected mealtime. General measures of activity, such as provided by telemetry or IR motion sensors, are adequate to detect food anticipation in neurologically intact, wildtype rats and mice, but such measures sometimes fail to detect circadian clock-controlled food anticipation revealed by foraging-related measures . The us4b. Fuller et al [consistently misrepresent what we [have shown and how we frame it". This is a puzzling complaint. To remind the reader, the Saper laboratory [critical' for food entrainment. That is in the title of their paper. Fuller et al [Bmal1 expression in the DMH is sufficient to restore food anticipatory rhythms. Taken together, the two studies claim to have demonstrated that the DMH is both necessary and sufficient for food entrainment, and that his how we have summarized their findings. Fuller et al [This is not correct'. Yet, in the final paragraph of their response , they state that 'we stand by our findings that the DMH is necessary for organizing food entrained circadian rhythms, and that ...robust activation of ... clock genes in the DMH is sufficient to restore food-entrained rhythms'. There are many other food-entrainable circadian oscillators in brain and body, but if the DMH meet criteria for necessity and sufficiency, as claimed, then these other oscillators cannot also be both necessary and sufficient for food anticipatory activity rhythms.er et al  state th what we ,21have ser et al  say thatthe food entrainable oscillator uses the same output mechanisms through the DMH as does the SCN'. However, lesion data cannot establish whether the DMH is input, oscillator or output, only whether it is or is not 'critical'.Fuller et al  state thEuropean Journal of Neuroscience [learn cognitively' by 'classical conditioning' that food is delivered each day in the middle of the light period (either 5 or 6 h after lights-on). They attempt to support this argument by stating that in the Moriya et al DMH lesion study , food aya et al  are corrnot generate a conditioned response  if there is a 5–6 h gap between the CS onset and the US . Furthermore, if the CS (light) is omitted, then the CR (anticipation) should be absent. If food anticipatory activity were a CR to an association between light and feeding, then it would begin at light onset and would be completely absent in DD, not attenuated 25%. Food anticipation in Moriya et al [First, for classical conditioning to occur, the conditioned stimulus  and the unconditioned stimulus  need to be closely spaced in time if not contiguous. Classical conditioning does ya et al  exhibiteSecond, as is clearly stated in the figure legend, the waveforms in Fig. 8C in Moriya et al  illustrasic, radiofrequency) DMH lesions in Landry et al [not distorted, and major landmarks (fiber tracts and other nuclei) are clearly evident, permiting an accurate assessment of what structures are damaged or absent. Electrolytic and radiofrequency lesions are the only way to unambiguously remove the entire DMH. The neurotoxin used by the Saper group makes only partial lesions, and requires cell counting to estimate lesion size. Cell counting sounds rigorous but it is problematic if the cells are not phenotyped and the boundaries between areas are normally unclear or have become obscured by loss of cells. The rational approach to assessing whether a structure is necessary for a particular circadian behavior is to ablate the entire structure and surrounding area. If there is a loss of function, then cell-specific lesion techniques can be used to assess a role for fibers of passage or specific cell phenotypes. We and others find no loss of food anticipatory activity rhythms despite complete removal of the DMH and fibers of passage . As noted already [Although the Saper laboratory has claimed that the DMH is critical for the expression of food anticipatory activity rhythms , others s  in the LD or DD ,3, direcer et al  observed already ,23,25,26Science for many examples). Our critique is unusual only in its length. The response by Fuller et al [Two months prior to writing the critique  of Fulleer et al  only serThe authors declare that they have no competing interests.The manuscript was drafted by RM and the final version read, edited and approved by RB, EC, CE, GL, AK, PP and SS.