Placement of a percutaneous nephrostomy tube for drainage has been an integral part of the standard percutaneous nephrolithotomy (PCNL) procedure. However, in recent years, the procedure has been modified to what has been called ‘tubeless’ PCNL, in which nephrostomy tube is replaced with internal drainage provided by a double-J stent or a ureteral catheter. The objective of this article is to review the evidence-based literature on ‘nephrostomy-free’ or ‘tubeless’ PCNL to compare the safety, effectiveness, feasibility, and advantages of tubeless PCNL over standard PCNL. We performed a MEDLINE database search to retrieve all published articles relating to ‘tubeless’ PCNL. Cross-references from retrieved articles as well as articles from urology journals not indexed in MEDLINE, were also retrieved. The majority of the studies have shown ‘tubeless’ PCNL to be a safe and economical procedure, with reduced postoperative pain and morbidity and shorter hospital stay. tubeless PCNL has been found to be safe and effective even in patients with multiple stones, complex staghorn stones, concurrent ureteropelvic junction obstruction, and various degrees of hydronephrosis. The technique has been successful in obese patients, children, and in patients with recurrent stones after open surgery. Tubeless PCNL can be used with a favorable outcome in selected patients , with the potential advantages of decreased postoperative pain, analgesia requirement, and hospital stay. However, for extended indications, like supine PCNL, multiple, complex and staghorn stones, and concurrent PUJ obstruction, the evidence is insufficient and should come from prospective randomized trials. The important milestones in the history of percutaneous renal surgery include Goodwin's description of percutaneous nephrostomy in 1955 Wickham 3With the expanding experience of both the radiologists and the surgeons, the success rate of this procedure increased dramatically.7 In 1984et al. described ‘mini-PCNL’ with a 13F nephroscope followed by the placement of an 8F nephrostomy tube with a 7F double pigtail ureteric stent.[et al.[Chan ic stent. Maheshwat.[et al. reportedt.[et al.–19 HowevPreviously it was thought that nephrostomy tubes provide hemostasis along the tract, avoid urinary extravasation, and maintain adequate drainage of the kidney. However,et al.[It may be interesting to note that the idea of ‘tubeless’ existed even in the early years of evolution of PCNL. In 1984, Wickham[et al. reportedIn 1997, Bellman and associates challenget al.[Candela et al. showed tet al.–26 In moet al..To the best of our knowledge, there are only few studies in the literature comparing tubeless PCNL with standard nephrostomy drainage in randomized fashion .In the largest prospective randomized trial published yet, in 202 patients treated at our center, tubelesset al.[et al.,[et al.,[et al.[Desai et al. showed d.[et al., Tefekli ,[et al., and Sing.,[et al. have alset al.[Shah et al. comparedIn contrast, a randomized study by Marcovich and coworkers showed net al.,[et al.[Additional variations of the tubeless procedures have been described. Goh and Wolf, Lojanapet al., and Mour.,[et al. reported.,[et al.. Compareet al.[et al.[et al.[Karami et al. reportedl.[et al. in 128 pl.[et al. in a stul.[et al..et al.[Gonen et al. prospectet al.[One major disadvantage of tubeless PCNL with double-J stent is the need for postoperative cystoscopy to remove the stent. Bellman et al. suggesteet al..et al.[The use of tether was further modified by Bellman et al. by placiThe principle of maintaining the tether exiting from the flank may have several applications beyond routine stent placement after tubeless PCNL. In a standard PCNL, nephrostomy tube is left in when a second-look procedure is anticipated. However, it may be possible to leave only a stent with a tether in these cases as well. At the time of the second-look procedure, the tether could be used to pull the end of the stent to the level of the skin, and a guide wire could be passed antegrade into the bladder, thus reestablishing the access tract.et al.[® Loop stent to facilitate tubeless PCNL and minimize pain and narcotic use. The Polaris stent has two fine loops distally to minimize bladder irritation. Following PCNL, Polaris stent was placed antegradely in reverse orientation. The pigtail rested in the bladder and the loops in the nephrostomy tract with the string tether secured at the skin for simple, atraumatic removal. Authors reported that tubeless PCNL with the Polaris stent decreased postoperative pain and narcotic use, and allowed earlier discharge from the hospital.Berkman et al. presenteTotally tubeless approach was first reported by Wickham and coworkers. They staet al.[In a randomized study of 60 patients, Aghamir et al. assessedThese studies favor the suggestion that the best available drainage of the kidney is the normal peristalting ureter. According to this school of thought, the only indication for the placement of a ureteral stent is in the situation when the ureteropelvic junction (UPJ) or upper ureter is inflamed and edematous, or where there is UPJ obstruction, managed or unmanaged. However, this approach has not formed universal acceptability due to the concerns relating to the obstruction of ureter due to clots or stone fragments. Most authors seem to favor some kind of internal drainage in tubeless procedures.The traditional prone position used in PCNL is difficult and risky for patients with cardiopulmonary ailments and compromised respiratory functions, and in markedly obese patients. Sometimes it is impossible for the patient to lie prone because of problems with body habitus such as ankylosing spondylitis, severe lordosis or kyphosis, or hip or lower limb contractures.Supine PCNL, in addition to saving operating room time, has several benefits. Because the tract is inclined downward and more dependent in relation to the renal pelvis, the pressure within the pelvicaliceal system is low, and stone fragments tend to fall out spontaneously. The possibility of a stone falling into the renal pelvis and the ureter is also minimized. It also permits the patient to remain in the lithotomy position for simultaneous ureteral instrumentation if necessary.52On the other hand, PCNL in the supine position has limitations in upper caliceal puncture as the upper pole is more medial and posterior, and concealed deeply in the rib cage. Classical prone position provides a larger surface area for the choice of puncture site and a wider space for instrument manipulation.et al.,[Rana et al., in a stuFor reasons of safety, most investigators have focused on using tubeless PCNL only in selected patients with uncomplicated stones. The selection criteria for tubeless PCNL include stone burden <3 cm, a single access tract, no significant residual stones, no significant perforations, minimal bleeding, and no requirement for a secondary percutaneous procedure.However, in recent years, the tubeless technique has been applied for the treatment of multiple stones, branching and complex stones, staghorn stones, concurrent UPJ obstruction, and collecting systems with various degrees of hydronephrosis. The technique has been successful in obese patients, children, and patients with recurrent stones after open surgery.et al.[Shah et al. reportedRana and Mithani reportedet al.[Sofer et al. reportedet al.[Malcolm et al. publisheet al.[Jou et al. performeet al.[Falahatkar et al. achievedet al.[Salem et al. assessedet al.[Shah et al. reportedSeveral centers have reported their experience with bilateral tubeless PCNL.63 Shah aSingh and co-workers performeTubeless PCNL also has been performed in patients with ectopic kidneys. Matlaga and associates reportedet al.[Yang et al. reportedet al.[Tubeless PCNL using supracostal access was done for 72 patients by Shah et al. The outcet al.,[In a study by Sofikerim et al., 48 patieTwo hemostatic agents have been commonly used in PCNL: Gelatin matrix hemostatic sealant (GMHS) and fibrin glue . Gelatin70et al.[et al.[Nagele and Schilling et al.74 reportl.[et al. were thel.[et al.–78®) to seal the working tract and concluded that such sealing of the nephrostomy tract after totally tubeless PCNL did not decrease bleeding or urinary extravasation. In a prospective study of 50 patients, Singh et al. [®) in tubeless PCNL. They observed lower wound soakage/discomfort in the gelatin-assisted tubeless PCNL group as compared to controls.Aghamir and colleagues  used oxih et al.  evaluateet al.[et al.[et al.,[In 51 patients, Jou et al. reportedl.[et al. also rep.[et al., in theirPatients who undergo tubeless PCNL have significantly less pain postoperatively and require less analgesia dosage.Tubeless PCNL minimizes the hospital stay, allowing many patients to be discharged from hospital in less than 24 h.A tubeless procedure offers the advantage of passive dilation of the ureter caused by the indwelling double-J stent to facilitate passage of any unrecognized small stone fragments.The omission of a nephrostomy tube with the placement of an indwelling double-J stent is associated with rapid healing and minimal urine leakage.The general consensus is that the tubeless approach is feasible only in a selected population that generally excludes cases requiring two or more accesses, significant intraoperative bleeding, or situations with a likelihood of residual stone fragments.The other limitations to tubeless PCNL are the possibility of missed residual stone fragment  that become apparent later, as a tubeless operation precludes a ‘second-look’ procedure.The need for an additional procedure, that is, cystoscopy, to remove the double-J stent.‘Stent dysuria’, which can be troublesome in some patients, and may even warrant the need of early double-J removal.One of the criticisms of this approach is that the ureteral stent does not necessarily provide drainage of the kidney. It is well established in animal models that stents cause a degree of obstruction and raise intrapelvic pressure.Tubeless PCNL can be used with a favorable outcome in selected patients , with the potential advantages of decreased postoperative pain, analgesia requirement, and hospital stay.Several retrospective studies have shown that its application can be extended even in patients with multiple, complex and staghorn stones, concurrent UPJ obstruction, solitary kidney, previous ipsilateral open surgery, raised serum creatinine level, with multiple or supracostal tracts, and in patients undergoing bilateral synchronous PCNL. The technique has been successful in obese patients, children, and patients with recurrent stones after open surgery. However, for all these extended indications, the available evidence is insufficient, and needs to be substantiated by prospective randomized trials.


Since publication of our article, "An unusual and difficult diagnosis of intestinal obstruction: The abdominal cocoon. Case report and review of the literature." World J Emerg Surg. 2006, 1: 8 we believe that the case mentioned should have been described as a 'peritoneal encapsulation' rather than 'abdominal cocoon' as concluded in the original publication. Since publication of our article  we belieThe abdominal cocoon is a condition in which a variable length of healthy small bowel is enveloped in a fibrocollagenous membrane, giving the appearance of a cocoon. It is an unusual cause of intestinal obstruction in children and adolescents. It was first described and named in 1978 by Foo et al. .Peritoneal encapsulation was first described by Cleland in 1868 . PeritonIn our article  the pathThere are other case reports that have confused these two entities by mistake. For example Sayfan et al.  describe


Ever since the development of Hybridoma Technology in 1975 by Kohler and Milstein, our vision for antibodies as tools for research for prevention, detection and treatment of diseases, vaccine production, antigenic characterization of pathogens and in the study of genetic regulation of immune responses and disease susceptibility has been revolutionized. The monoclonal antibodies being directed against single epitopes are homogeneous, highly specific and can be produced in unlimited quantities. In animal disease diagnosis, they are very useful for identification and antigenic characterization of pathogens. Monoclonal antibodies have tremendous applications in the field of diagnostics, therapeutics and targeted drug delivery systems, not only for infectious diseases caused by bacteria, viruses and protozoa but also for cancer, metabolic and hormonal disorders. They are also used in the diagnosis of lymphoid and myeloid malignancies, tissue typing, enzyme linked immunosorbent assay, radio immunoassay, serotyping of microorganisms, immunological intervention with passive antibody, antiidiotype inhibition, or magic bullet therapy with cytotoxic agents coupled with anti mouse specific antibody. Recombinant deoxyribonucleic acid technology through genetic engineering has successfully led to the possibility of reconstruction of monoclonal antibodies viz. chimeric antibodies, humanized antibodies and complementarily determining region grafted antibodies and their enormous therapeutic use. Antibodies are a mixture of closely related immune system proteins, with subtle but important differences. Conventional techniques for preparation of antibodies in antiserum against a particular antigen always result in the production of antibodies having different classes, specificities and affinities. The development of Hybridoma Technology by Kohler and Milstein2 has proThe development of hybridoma technology offered a number of advantages over the original art of polyclonal antibodies viz. (i) the generation of MAbs is now a standard and increasingly routine procedure, (ii) the use of impure antigen is tolerated since the detection of MAb of interest is largely dictated by the selection strategy, (iii) antibodies with selected properties or reactivities for specific structures could be selected and (iv) since the hybridoma cells line is immortal, there is an unlimited source of the MAb.in vitro and secrete a single monoclonal antibody[In hybridoma technology, a myeloma cell rendered drug sensitive through mutation in a growth essential gene hypoxanthine guanine phosphoribosyl transferase (HGPRT) is chemically fused with immune cells from a host immunized with the antigen of interest and the resulting cells are grown in medium containing the selective drug. Since the immune cells have a short life span in tissue culture and the myeloma cells are drug sensitive, the only cell that will survive are those myeloma cells which obtained a normal HGPRT gene from the immune cells. Such cells also have a high likelihood of carrying the immune cell's antibody gene resulting in the generation of a hybridoma that can grow continuously  antibody.Selection of hybridomas secreting desired antibodies is quite tedious. Screening assay should be rapid, reliable, versatile, sensitive and easily performed with a large number of samples. The most commonly used system fulfilling these criteria is the enzyme linked immunosorbent assay (ELISA). However, antibodies can also be detected by radio immunoassay (RIA), immune fluorescence and haemolytic plaque assays. In ELISA, an antigen is passively adsorbed to a plastic surface (polystyrene). The sample (serum/culture supernatant) is applied to the immobilized antigen. The monoclonal antispecies antibody enzyme conjugate is then added, followed by addition of substrate and spectroscopy. Selected hybridomas after screening are expanded to be frozen and cloned to generate monoclonal by limiting dilution method. The selected and desired MAbs can be purified by affinity chromatography, being more efficient and less tiresome. They are characterized by isotyping to determine the class/sub class of immunoglobulins by ELISA and western blot to test their ability to bind different antigen preparations.in vivo production in mice by ascites induction has been preferred for its cost effectiveness and high concentration of MAbs produced. But the growing ethical concern about mice and the improved cell culture techniques, led to an increased emphasis on in vitro methods being parallel to the in vivo methods both in capacity and cost effectiveness[in vitro production of MAbs which are released in culture medium at concentrations between 1 to 100 μg/ml[et al.[Since the inception of hybridoma technology, various approaches and technologies have been developed for large scale production of MAbs. For a long time, the ctiveness. Convent100 μg/ml. In the 100 μg/ml. But Treml[et al. have demDuring the past decades MAbs have found tremendous applications in therapeutics, drug targeting and had a profound impact on diagnostics. The diagnosis of any infectious disease often needs the demonstration of the causative organism or a specific antibody. In some infectious diseases such as reproductive or respiratory infections, the causative organism can be demonstrated throughout the course of infection. Specific antibody based tests identify the pathogens associated with the disease. MAbs recognizing unique antigenic determinants on pathogens can be developed. MAb can read with a single antigenic determinant (epitope) and this restricted reactivity allows for precise identification of the organism of interest which is the major advantage of MAbs over polyclonal antisera. In case of a pathogen occurring as sub type defined by unique antigenic differences, specific MAbs can be used whereas conventional antisera needs laborious absorption to remove cross reactive antibodies. Because of the specificity, homogeneity and unlimited availability of the MAbs, vast amount of work has been carried out on the production/development of MAbs diagnostic reagent tests against various pathogenic agents of veterinary importance.et al.[et al.[et al.[et al.[et al. in 1982[et al. in 1983[Production of monoclonal antibodies against mouse lymphocyte surface glycoprotein has been reported by Trowbridge, againstet al., againstl.[et al. and for l.[et al.. Falmandl.[et al. have usel.[et al. for anti. in 1982 and Weis. in 1983 have repTrichomonas vaginalis[Leishmania donovani[Trypanosoma congolense[Babesia bovis[P. carinii pneumonia have been reported by Kudryk et al.[et al.[et al[et al[The immuno diagnosis of protozoal and parasitic diseases has significantly been improved by MAb technology because the tests involving MAb as diagnostic reagents overcome the limitations of polyclonal antibodies. MAbs were found extremely useful in the rapid outbreak of East Coast Fever (ECF). MAbs ofvaginalis, Leishma donovani, Trypanoongolense, Babesiasia bovis. With imsia bovis–21. The sia bovis and theisia bovis. Productyk et al. and Natol.[et al., respectal.[et al and Hilg al[et al, respectet al.[Taylor et al. have comet al..et al.[et al[Candida albicans ATCC 26555 as an immunoglobulin G1 used for the recognition of high molecular mass proteins present in the cell wall of Candida albicans has been reported by Marcilla et al[Use of MAbs with magnetic particles to separate cell sub populations by negative selection as well as by positive selection has been reported by Vaccaro and Markenacin 199531. Quiliet al. have comal.[et al have stalla et al.Two easy-to-use commercial diagnostic assays, a dipstick ELISA and an immuno chromatographic card assay were evaluated for detection of IgM antibody to dengue virus with an in house IgM antibody capture microplate ELISA as a reference assay. Both commercial assays provide sensitive and specific detection of anti dengue virus IgM antibody and would prove useful in settings where the microplate ELISA is impractical.Monoclonal and recombinant antibodies provide a never ending source of molecules and can produce endless possibilities for novel genetic constructs. Antibodies are still very much in vogue and are now also being used in micro array analysis of the proteome using protein chips.et al.[et al[Skin derived anti leukoproteinase (SKALP), also known as elafin, is an epithelial proteinase inhibitor with antimicrobial properties that is not normally expressed in human epidermis, but is induced under inflammatory conditions and in some types of skin cancer. SKALP iet al. have deval.[et al.Y. pseudotuberculosis has been developed by Fedorova et al[et al.[et al[Monoclonal antibodies based competitive immunoassay for the detection of specific antibodies to ova et al. Peknicoal[et al. have deval.[et al.in vitro affinity maturation, large scale production of antibodies in transgenic animals and plants, chimeric and humanized antibodies, human MAbs from transgenic mice using conventional hybridoma techniques, intrabodies and so many. These and similar constructs will provide the basis of an incredible number of new therapeutic antibody based products, besides being a transition to less costly and smaller synthetic molecules like bioactive peptides etc. The time and cost of travelling from the laboratory to the clinic are shorter for MAbs than for many conventional drugs. Antibodies are relatively easy to detect, manipulate and test. The FDA now regards MAbs as biotechnology derived pharmaceuticals with relatively few reports of serious side effects. The public health possibilities of MAbs are fabulous. Additional MAbs are being investigated in treatment of a variety of cancers including B-cell lymphomas, multiple myeloma and colorectal cancer besides rheumatoid arthritis, allergic asthama and others characterized by chronic inflammation[et al[et al[et al[The diversity of antibody engineering technologies is amazing; synthetic combinatorial libraries, cell free libraries, lammation43. Sincelammation. The phaion[et al. Using a al[et al. Very re al[et al.The basic mechanism of a MAb is the same as an antibody produced by the body. However, when MAbs are used in the diagnosis and treatment of diseases, certain substances are often added to them to give them their therapeutic and diagnostic characteristics. They can also be used on their own to block or encourage certain responses from the immune system. In diagnosis, radioactive markers are attached to them to locate a certain kind of cell within the body. They are used in diagnostic imaging of internal organs and tumors.While the utility of MAbs as drugs that can specifically target a disease associated antigen is enormous, it has taken a quarter century for these molecules to be adopted as bonafide diagnostics. Despite their slow pace in drug development during the pioneering years, it is now estimated that there are nearly 500 MAb based therapies in the field. Major factors that have influenced the acceptance of MAbs as diagnostics include their drug safety profiles, technological advancements for facilitating MAb's discovery, their development and market success.Monoclonal antibodies generally exhibit exquisite specificity for the target antigen. The binding site on the antigen called the epitope, can be linear or conformational, and may comprise continuous or discontinuous amino acid sequences. The epitope is the primary determinant of the antibody's modulatory functions and depending on the epitope, the antibody may exert antagonist or agonist effect, or it may be non modulatory. The epitope may also influence the antibody's ability to induce antibody dependent cell mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). MAbs exert their pharmacological effects via multiple mechanisms that include direct modulation of the target antigen, CDC, ADCC, and delivery of a radio nucleotide or immuno toxins to target cells.The monoclonal antibody production technology has revolutionized the world of Biotechnology. Advances in genetic engineering over the years have provided numerous ways to design MAbs that are more robust and efficacious compared with their original murine version. MAbs have not only been used as diagnostics, therapeutics, research reagents, drug targettor for various infectious diseases but also cancerous, metabolic and hormonal disorders. MAb technology in conjunction with recombinant DNA technology has successfully led to the reconstruction of chimeric antibodies, humanized antibodies and CDR grafted antibodies and has enormous potentials for therapeutic uses.


We thank Schaider et al. for their interest in our research on possible environmental causes of breast cancer in upper Cape Cod, Massachusetts . Our stuIn our study , we applFortunately, groundwater sources of drinking water in this area are subject to more protections today, and we agree that ongoing monitoring of known and emerging contaminants is important to maintain water quality.


Research in the medical field is a dynamic process without which science will be dead. It has more significance now as we are in the era of evidence-based medicine.et al.[The path of research is not without obstacles. Research needs proper infrastructure and sufficient funds apart from a dedicated group of workers. It demands honesty, commitment and time. In our country, the institution of healthcare gets priority over research for obvious reasons. Research is not preferred as a career by the majority. There are many challenges in the development of research in Asian countries which have been well described by Wong et al. Firstly,et al.‐5 These Investigators have to overcome many challenges while conducting research in India. Inadequaet al.,[In spite of the limitations discussed earlier, there is a silver lining. In future, up to 65% of food and drug administration (FDA)-regulated trials are expected to be outsourced from the US. India and China have been projected as the favorite destinations for these clinical trials.[et al., It is adet al.,[et al.,[et al.,[Indian Journal of Ophthalmology (IJO). Their conclusion shows a heartening trend of nearly doubling of publications from 284 in 2001 to 460 in 2006 by Indian researchers. However, 50% of the publications came from only nine major eye hospitals in India. A Pubmed search of publications by Indian authors and institutions in 2008 yielded 16290 results as against 11307 in 2005. Hopefully, the 2009 amendment of the regulations of the Medical Council of India (MCI) for appointment of teachers will provide enough incentive for researchers to publish their completed research.[Completion of research has no meaning unless it is published in peer-reviewed journals. Dhaliwal et al., have rep,[et al., it was c,[et al., must be The scope for research in India is tremendous simply because India is a vast country with a rapidly improving economy. There are many organizations, such as the Indian Council of Medical Research (ICMR), Department of Biotechnology (DBT), Department of Science and Technology (DST) and others who are prepared to fund the appropriate research. ICMR has identified the scope of research in ophthalmology and has appointed coordinators for the various sub-specialties.There is a need to understand the nuances of research. Researchers should realize the importance of taking IRB/ethics committee approval before starting the study. It is now mandatory to take IRB/ethical clearance for the dissertation done during the Diplomate of the National Board (DNB) course. Many jouTo conclude, India is fast becoming a new destination for multicentric trials. It is time to wake up and educate ourselves with the nitty-gritty of research to reap the entire benefit from this favorable trend. We have a huge potential and we must explore it to its full capacity.


One of the objectives of extirpative oncological surgery is negative surgical margins. The gold standard of treatment of high-grade recurrent superficial bladder carcinoma and muscle-invasive organ-confined bladder carcinoma is radical cystectomy. Transitional cell carcinoma has always been associated with a pan urothelial malignant field change. Frozen section analysis (FSA) to assess negative ureteral margins has been reported from as early as the late 1960s and early 1970s. Based onin situ (CIS) of the urinary bladder.[in situ or solid tumors undergoing radical cystectomy for TCC with coexisting CIS in the bladder.[in situ of the ureteral margin has been discovered in up to 8.5% of patients undergoing radical cystectomy. Positive ureteral margin CIS has been associated with a high risk of upper tract recurrence, with CIS of the ureteral margins having a risk of 17% and negative histology of the ureteral margin having a 3% upper tract recurrence risk.[et al suggested that FSA of ureteral margins enables a more thorough removal of malignant urothelium. Frozen section analysis of the ureteral margins has been recommended by the European Association of Urology and the National Comprehensive Cancer Network for patients undergoing radical cystectomy with extensive CIS of the bladder. Ureteral CIS has most commonly been observed in patients with multifocal, high-stage, high-grade tumors and tumors involving the prostatic urethra.[The distal ureter has the highest incidence of urothelial malignancy in patients with carcinoma  bladder. The rang bladder.4 Local r bladder. Carcinom urethra.et al [et al[et al[With the above evidence it would seem justifiable to perform an FSA of all ureteral margins. However, evidence to the contrary is just as extensive and impressive. Sharma et al  discoveret al  suggesteal [et al in theiral [et al Upper tr al[et al found ur al[et al looked a al[et al making set al[It would seem reasonable to do FSA on palpable induration or frank tumor infiltration of the distal ureter discovered unexpectedly at the time of the operation. Similarly, in those with diffuse CIS the risk of ureteral involvement may be greater than average necessitating the need for an FSA. But should one do an FSA on patients with prostatic TCC with the increased risk of metastatic disease? In this subset the mainstay of treatment is effective chemotherapy which provides a greater survival benefit than the absolute eradication of distal ureteral atypia. An FSA iet al found 13The presence of positive CIS at the ureteral margin predicts risk of upper tract recurrence and not necessarily anastomotic recurrence. Routine FSA of the ureteral margins is probably unnecessary in the majority of patients undergoing radical cystectomy. In patients with high risk of upper tract recurrence, such as diffuse CIS or induration at the margins a frozen section analysis of the ureteral margins may be helpful in tailoring the operation. However, the practice of resecting the ureter to achieve a negative margin does not seem to prevent upper tract recurrence.


We read with great interest the article on human norovirus (hNoV) by Straub et al. (Straub et al. demonstrate through fluorescent in situ hybridization the presence of viral RNA through 5 passages in his system. This phenomenon could be similar to the findings of Duizer et al. ( Cryptosporidium parvum that supplement approved fluorescent microscopy assays do not result in amplification of the environmentally resistant hard-walled oocysts (We appreciate the comments provided by Chan et al., in response to our recently published article (Nonetheless, Leung et al.’s assertion regarding the suitability of our method for the in vitro propagation of high titers of hNoV is valid for the medical research community. In this case, well-characterized challenge pools of virus would be useful for developing and testing diagnostics, therapeutics, and vaccines. As further validation of our published findings, we have now optimized RT quantitative PCR to assess the level of viral production in cell culture, where we are finding increases in viral titer. The magnitude and time course of these increases is dependent on both virus strain and multiplicity of infection. We are currently preparing a manuscript that will discuss these findings in greater detail, and the implications this may have for creating viral challenge pools.


Sir,Pemphigus is a collective term for a group of chronic bullous dermatoses characterized by an intraepidermal cleft and circulating antibodies against epithelial cell surface. To date, there are no objective criteria to map the disease activity and severity. Various studies have given different and confusing definitions for remission and control of the disease. Also, there are no universally accepted treatment regimens.2The study of activity and inactivity of the disease is important. Pemphigus is a chronic disorder with remission and exacerbation, even when patients are on treatment. Systemic steroids alone or in combination with other immunosuppressive drugs are the main stay of treatment. These drugs have to be given on long-term basis with considerable side effects, for example, osteoporosis, avascular necrosis, HPA-axis suppression, cataract, cushingoid features, myopathy, mood changes, and immunosuppression. Therefore, a system is required to monitor disease activity and inactivity so as to lower the dosage of the drug(s) and eventually withdraw and reintroduce when there is a relapse or activity reappear. Though no system is available to date that allows the withdrawal of drugs various clinical and laboratory monitoring may allow the lowering of dosage. In recent years dexamethsone cyclophosphamide in pulse doses is the treatment of choice for pemphigus. The therapy has claimed to induce remission for more than 10 years in many patients. This article is aimed at discussing the currently available clinical and laboratory systems for monitoring of pemphigus disease activity and inactivity.et al., describe a microscopic Nikolsky's sign in which tangential pressure given to an area before a biopsy produces changes in epidermis that are diagnostic of pemphigus vulgaris if in suprabasal level and pemphigus foliaceous if in intraepidermal. This is a useful sign in patients with old/infected blisters, no fresh/intact blisters, or when no facility of immunofluorescence is available in the hospital.[The formation of new blisters indicates active stage of the disease. The considerable clinical activity usually correlates with circulating antibodies titer and antibodies in skin. Presence of new blisters in patients on treatment call for increase in dose of steroid.–5 After hospital.et al.,[Oral lesions, despite presenting early, may last to clear.10 In addet al., noted whet al.,[et al.,[et al.,[et al.[How to grade severity of the disease? Frenandes et al., noted th,[et al., suggest ,[et al., report t.,[et al.IIF17 may beIn patients of clinical remission the decision about further reduction in dose of drug can be very difficult. Clinical criteria and IIF which are not sensitive enough to detect low levels of circulating antibody so cannot be used.12 In staet al.,[Desmoglein ELISA22 is a s23et al., demonstrBeta-glucuronidase: This lyActivity in pemphigus can be defined by: 1) presence of new blisters, 2) spontaneous peripheral extension of existing blisters, 3) positive Nikolsky's sign on lesion, perilesional, or normal appearing skin, 4) demonstration of circulating antibodies against cell adhesion molecules and/or non-desmoglein protein antigen, e.g., keratinocytes cholinergic receptors, 5) presence of IgG antibodies in epidermis demonstrated by DIF, even in clinically normal appearing skin.


Severe leptospirosis requires critical care and has a high mortality. We reviewed the literature to identify factors predicting mortality, and such predictors were classified according to the predisposition, infection, response, organ dysfunction (PIRO) concept, which is a risk stratification model used in severe sepsis.PUBMED was searched for all articles (English), with the key word leptospirosis in any field, within the last 20 years. Data were collected from 45 relevant papers and grouped into each component of the PIRO model.The following correlated with increased mortality: predisposition – increasing age and chronic alcoholism; infection - leptospiraemic burden; response - hemodynamic disturbances, leukocytosis; organ dysfunction – multiple organ dysfunction syndrome, pulmonary involvement and acute renal failure.Further research is needed to identify the role of infecting serovars, clinical signs, inflammatory markers, cytokines and evidence of hepatic dysfunction as prognostic indicators. It is hoped that this paper will be an initiative to create a staging system for severity of leptospirosis based on the PIRO model with an added component for treatment-related predictors. Leptospira. Initially, this genus was thought to have only two species. Currently, nine pathogenic species of Leptospira are identified, with another five being classified as “intermediate,” bringing the total number of possible pathogenic species to 14.[Leptospirosis is a zoonotic spirochaetal illness with considerable morbidity and mortality in areas of high prevalence. The causative organism is classified in the genus es to 14.An accurate assessment of the disease burden of leptospirosis is not easy due to diagnostic difficulties and under-reporting. The estimated incidence differs as to whether an endemic or a non-endemic area is considered . Such locMany infections are asymptomatic or pass off as a mild febrile episode. However, a small proportion develops a severe form of the disease with multiple organ dysfunction. The case fatality ratio in severe disease can exceed 40%.[The objectives of this review are two-fold. Firstly, it summarizes the mortality predictors for leptospirosis published by different authors. While some indicators are repeatedly cited as predictors of mortality, the significance of others is questionable. Secondly, an attempt is made to classify such predictors into a clinically relevant classification .It is our opinion that a simple detailed description of mortality indicators will not be of much use to a clinician in his practice. The clinician will be more interested in a systematic manner of application of such knowledge to predict mortality and identify the “at risk” patients early. The ideal method to integrate such information to an applicable clinical tool is to develop a valid classification and a scoring system.The PIRO model is a risk stratification system for severe sepsis. PIRO stands for predisposition (P), infection (I), response (R) and organ dysfunction (O) . This review classifies the prognostic indicators for severe leptospirosis according to the PIRO model but stops short of developing a scoring system. Available data were inadequate, and non-comparable due to differences in study methodology, to develop a valid scoring system. It is our opinion that such quantification is best handled by a well-designed, dedicated, prospective study rather than by a literature review. Still, this work serves as a concept paper to show the possibility and relevance of such a scoring system.A PUBMED search was performed for all articles with the key word “leptospirosis” in any field. The search was restricted to articles published in English within the last 20 years (1989–May 2009) as they would contain more recent data. There were 1898 abstracts in the original search with these restrictions. The software, Endnote X1, was used to filter articles. Bibliographies of cited literature were also searched. All abstracts were read through independently by the three authors and relevant papers were identified for review of the full papers. Related papers were also included. We reviewed 163 selected papers.These sources were screened for a well-described methodology, accurate statistical analysis and an adequate sample size where relevant. Identification of prognostic indicators was performed by three reviewers independently blinded to each other. Later, they were classified into each component of the PIRO model by consensus. While such a classification was possible, the development of a scoring system based on it was not possible for the reasons mentioned above (non-comparability of data). Data sources included reviews published in core clinical journals, cohort studies, interventional studies, case control studies, cross-sectional analysis and epidemiological data. Suitable data were available in 45 papers from the initially selected 163. A summary of the cited literature is shown in Tables The following four sections are titled according to the four components of the PIRO model. Mortality predictors for leptospirosis reported by various authors are discussed under each subtopic.Three mortality indicators were reported in the literature that can be classified under predisposition: age, alcohol dependence and male sex. A summary of the studies in this regard is given in et al.et al.[et al.0,[et al.,[et al.[Five studies have reported age as an indicator. Cetin al.et al. describe[et al.0, in a pro,[et al., in a ret.,[et al. showed tet al.[Only Chawla et al. reportedet al.11 failedet al.,[Chronic alcoholism was reported to be significantly associated with death in two studies.12 Martinet al., in a retet al.[per se or due to hepatic dysfunction on a background of alcoholic liver disease is not clear.On analyzing the available evidence, the strongest predictor of mortality under “predisposition” is increasing age. The evidence for poor outcome among males is limited (two large retrospective studies failed to show such an association).11 Jansenet al. suggesteWhile there are many predisposing factors for contracting leptospirosis , none of these have been reported to predict outcome after acquiring the infection.–18 Male et al.[4 leptospires/ml were associated with death. These findings were confirmed by Segura et al.[The classifiable material under this topic is minimal . Trucculet al. measuredra et al. in an inWe encountered difficulty in differentiating mortality indicators under response and organ dysfunction categories as such a division seemed arbitrary. Therefore, the items categorized under the response section are restricted to components of severe inflammatory response syndrome (SIRS) and a few other indicators such as abdominal pain and muscle tenderness .et al.[et al.[Pertuiset et al. report tl.[et al. identifil.[et al.–24 Leukol.[et al.et al.,[et al.[P = 0.03).Abdominal pain is also reported as a mortality indicator by Pertuiset et al., although.,[et al. describeet al., P = 0.02), platelet count <70,000  and high cerebrospinal fluid protein levels in patients with neuroleptospirosis .[Other indicators classifiable under this section include high tumor necrosis factor alpha (TNF α) levels (Tajiki < 0.001).26–28et al.[Of all these indicators, only hypotension was confirmed as a predictor of mortality in three independent studies with an adequate sample size.–24 Otheret al. observedThree organ systems are commonly cited as involved in severe leptospirosis: the lungs, the kidneys and the CNS .et al.[et al.[et al.,[11Although relatively uncommon, pulmonary involvement has been repeatedly and consistently incriminated as a mortality predictor in more than 10 studies. Pertuiset et al. and Dupol.[et al. reported.[et al., in a pro.[et al., dyspnoea.[et al., and the .[et al., are also.[et al.,1131–33th–6th days of disease and can progress rapidly to death within 72 h. Mortality rates from different studies vary between 30% and 60%. Different aspects of lung involvement such as clinical signs, radiographical evidence and ALI are all predictors of mortality.[While many manifestations of lung involvement are mild, pulmonary hemorrhage is associated with a high mortality. Patients also die from acute lung injury (ALI), acute respiratory distress syndrome and combined MODS. Respiratory symptoms appear on the 4ortality.35Acute renal failure (ARF) and its manifestations are also reported as mortality indicators. Oliguria and anuria are cited as independent predictors of mortality in six studies.62223253662223256212324478Bacterial infection, insults from the inflammatory process, and hemodynamic disturbances are thought to contribute to renal failure in leptospirosis. The basic pathology is an interstitial nephritis with tubular necrosis resulting in ARF. Manifestations of renal involvement vary from laboratory evidence  to clinically defined ARF with hyperkalaemia and elevated creatinine. It is es43et al.[P < 0.05). Esen et al.[P = 0.01) in deceased patients compared to survivors . According to Ko et al.,[et al.,[P < 0.037). Meningism and disorientation  are also reported as mortality indicators by Pappachan et al.[Central nervous system involvement is another predictor of severe disease and death. Covic et al. publisheen et al. also repo et al., who stud,[et al., reportinan et al.Three studies have independently associated altered mental status with death. However, many factors can cause altered mental status in severe leptospirosis, and thus this clinical feature is lacking in specificity. These studies also do not specify the criteria used to assess altered mental status and hence it is difficult to assess the uniformity of the findings.et al.[et al.,[Cardiac involvement in leptospirosis is underestimated. Describing the findings of 44 autopsies with a presumptive cause of death with leptospirosis-related complications, Charkurkar et al. reported.[et al., in his ret al.[et al.[et al. reported that a high Aspartate transaminase (AST)/alanine transaminase (ALT) ratio in late disease is associated with death.[et al.[Evidence for hepatic dysfunction is prominent during the clinical course of leptospirosis. However, many of these are not reported as predictors of mortality. Pappachan et al. reportedl.[et al. reportedth death. Bleedingh.[et al.MODS, which is the involvement of more than one organ system, has been shown to be associated with death in four studies .7304045730457304045et al.,[P = 0.01). In their study involving 35 critically ill patients with ARF, Vieira et al.[There were a few other predictors of mortality that could not be classified under the PIRO model. These were mainly treatment related. Andrade et al., in a twora et al. stated tra et al.There is a place for further research to determine the role of gender, infecting serovars, clinical signs, inflammatory markers, cytokines, biochemical parameters and markers of hepatic dysfunction as prognostic indicators. It is interesting to note that several recent studies in India have shown that clinical manifestations like pancreatitis and syndrome of inappropriate secretion of anti-diuretic hormone were more common than previously thought. In one study, the majority of patients with these presentations were anicteric. There may be many other predictors of mortality yet unidentified in relation to these presentations.Only articles published in English were included in the review. Therefore, it is possible that certain important papers were missed. Similarly, relevant information published beyond the time limits of our search have not been taken into account. Such gaps in data may affect the validity and generalizability of the conclusions.This review was synthesized as a concept paper to direct further research into mortality indicators of leptospirosis.It attempts tosummarize and discuss evidence on predictors of mortality in severe letospirosisdevelop a classification system for such factors based on the PIRO concept used for staging of severe sepsisOn analyzing the evidence on mortality indicators, some predictors  have been repeatedly and independently confirmed by different authors. Still, some other associations such as the impact of inflammatory markers and leukocytosis have not been assessed in detail. Many identified risk factors could be categorized into the four domains of the PIRO concept. However, treatment-related factors could not be incorporated into the existing model. In this regard, we propose to add a fifth domain of treatment (T) when modifying the PIRO concept for leptospirosis.While we managed to classify the mortality indicators, a scoring system to quantify the relative risk could not be developed due to differences of the methodologies and non-comparability of data. Such a scoring/staging system would be more scientifically valid if developed by a prospective study specially designed for such a purpose. It is hoped that our work will be a starting point to the development of a staging system to predict the severity of leptospirosis.


Rattus Norvegicus) and its effect on the reproductive functions in relation to the biochemical effects was studied. It was observed that the chronic dose of lead caused an elevation in the level of proteins, acid phosphatase, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase in all the soft tissues studied indicating tissue damage. It also inhibited the level of acetylcholinesterase in all the tissues. Fertility tests by pairing treated females with males showed that lead-treated female showed irregular estrous cycle and the fertility rate dropped to 40% as female pups of lead-treated mothers showed loss in weight, high mortality rate, poor growth rate, and late vaginal opening. Histological studies of ovary showed atresia in all the stages of folliculogenesis sustaining the poor fertility observations. The present study revealed that lead caused great tissue damage and affected reproductive performance of female rats at a chronic dose.Lead being a toxic cumulative poison and an environmental pollutant, experiments were conducted at an oral chronic dose of (60 mg/kg/day) for 90 days on adult female rats ( Alanineet al.[Daily oral administration of lead produced significant decrease in AChE level in liver, kidney, and ovary and nonsignificant decrease in plasma . The decet al. in calveet al. Acetylchet al. Thus decSignificant increase in the levels of proteins in liver, kidney, ovary and nonsignificant increase in proteins in plasma were observed following daily oral dosing of lead . The eleet al.[Five sets of experiments that were set up for the testing effect of lead on fertility of rats indicated that lead at a dose of 60 mg/kg caused 40% reduction in the fertility rate  as compaet al. reportedet al.[et al.[et al.[et al.[et al.[In addition to the observations made above, the treated females showed irregularity in estrous cycle. Der et al. and Ronil.[et al. have alsl.[et al., and decl.[et al.. Ronis el.[et al.12 also rl.[et al. Lead-fedl.[et al.. Lower bl.[et al. and Schwl.[et al. Furtherml.[et al.The above study concluded that lead has interaction with the vital body functions and reproductive parameters in rats. The dosage administered caused significant biochemical alterations and reduction in the weight of pups as well as the treated mothers. Lead caused high mortality rate in pups and also slows down their growth rate.


Accelerated Idioventricular Rhythm (AIVR) is a ventricular rhythm consisting of three or more consecutive monomorphic beats, with gradual onset and gradual termination. It can rarely manifest in patients with completely normal hearts or with structural heart disease. It is usually seen during acute myocardial infarction reperfusion. This manuscript aims to review the history of the main discoveries that lead to the identification and comprehension of this fascinating arrhythmia. The so called "Accelerated Idioventricular Rhythm" (AIVR) is a ventricular rhythm  consisting of three or more consecutive monomorphic beats, with gradual onset. Less commonly, AIVR is polymorphic. The discharge rate of the ectopic focus is similar to the sinus rate (isorhythmic) between 50 and 120 bpm. The ectopic focus manifests when the sinus rate slows down (below the ectopic focus) or when the ectopic focus accelerates above the intrinsic rate by 30-40 beats per minute. When both discharge rates (sinus and ectopic focus) are similar, isorhythmic dissociation, fusion and capture beats can be seen.AIVR is usually a benign and well-tolerated arrhythmia. Most of the cases will require no treatment and in rare situations such as sustained or incessant AIVR or when AV dissociation induces syncope, the risk of sudden death is higher, and the arrhythmia should be treated.Different terminology was used to describe AIVR: Non paroxysmal ventricular tachycardia (VT), isorhythmic slow VT, and the curious benevolent tachycardia.Non paroxysmal VT is currently a non accepted definition given the fact that AIVR is usually a ventricular rhythm at rate slower than 100 bpm, thus not meeting criteria to be called tachycardia.Rarely, AIVR can be detected in the youth and, in this subgroup, is usually benign  and requAIVR occurs infrequently in patients without demonstrable heart disease and, in this case, it has a good prognosis. When AIVR presents in individuals with no structural heart disease, the mechanism involved is usually an increased vagal tone and decreased sympathetic tone , as obseAIVR is frequently observed during the reperfusion phase that follows an acute myocardial infarction (AMI) . It remaA typical example of AIVR in the setting of normal structural heart can be seen in The main electrophysiological mechanism involved in AIVR is an abnormal calcium-dependent automatism (ectopic automaticity) that affect phase 4 of action potential (diastolic depolarization) . When AIThis manuscript aims to be a chronological historical review on the main findings that contributed to the understanding of this fascinating arrhythmia.Sir Thomas Lewis  a pioneer of the British cardiology showed the first ECG trace of AIVR case in his book entitled "Mechanism and graphic registration of the heartbeat"  , dedicatHarris  was the Mariot and Menendez  have intDessertene  describeAgustín Castellanos Jr  used theRothfeld et al  showed fRothfeld and Zucker , were thAgustín Castellanos Jr et al  reportedHasin and Rogel  presenteDelise et al  reportedBernard et al , describSclarovsky et al , showed Chiale et al , reporteMartini et al  describeTatu-Chitoiu , used thNakawa et al , showed Grimm et al  followedMarret et al  reportedDulac et al , reporteBonnemeier et al , determiTsai et al  reportedHsu et al , reporteThis intriguing arrhythmia could manifest in several different clinical scenarios. There are benign forms in subjects with no structural heart disease in which case, it usually requires no intervention, but sometimes it can present as a more severe arrhythmia, requiring treatment. Since its initial identification by Harris, major advances have been done in the understanding on the underlying mechanisms involved in the genesis of this arrhythmia. Abnormal calcium-dependent automatism that affects the phase 4 slope of the action potential (ectopic automaticity) has been identified as the main electrophysiological mechanism involved in AIVR. Autonomic imbalance has also been identified as a trigger of this abnormal rhythm. More recent reports showed that the presence of AIVR does not constitute a specific marker of complete reperfusion during the acute phase of a myocardial infarction, but it could indicate that the responsible vessel is open.  In this context, AIVR usually does not require specific treatment.


BMC Bioinformatics presents another ten! These papers have in common the fact that they are follow-on work to papers originally published in the proceedings of the BioNLP 2008 workshop at the annual meeting of the Association for Computational Linguistics (ACL). All have gone through a separate rigorous review process and represent an advance beyond the work originally presented at the workshop. Like the annual BioNLP workshop itself, they represent a wide cross-section of the type of work that goes on in BioNLP today.A recent posting to the BioNLP mailing list notes that the past few months of 2008 have seen the appearance of over fifty papers on biomedical natural language processing/text mining (BioNLP). This number  represents about as many papers on genomic language processing as existed in all of PubMed at the end of 2003  – just fAnnual BioNLP workshops have been held since 2002 in conjunction with the annual meeting of the ACL or its North American chapter. Whereas other venues, such as NLP sessions at biomedical informatics and computational biology meetings, provide excellent opportunities for presenting applications of NLP in the biomedical domain, the BioNLP workshop has consistently been a venue for presenting work in areas of fundamental BioNLP that is innovative and challenging from an NLP perspective.BMC Bioinformatics. Of 19 full papers and 5 posters submitted to the workshop, 10 were accepted as full papers and 18 as poster presentations. The combined expertise of the program committee allowed for providing three thorough reviews for each paper. The exceptionally high quality manuscripts accepted for presentation covered a wide area of subjects in clinical and biological areas, as well as methodological issues applicable to both sublanguages. Separately, those authors were invited to submit papers describing significant advances beyond their original papers and posters for inclusion in this supplement.Research in computational linguistics in the biomedical domain traditionally focuses on two major areas: fundamental advances in language processing; and application of language processing methods to bridge the gap between basic biomedical research, clinical research, and translation of both types of research into practice. The expanded and updated versions of the best papers in both areas presented at the BioNLP 2008 workshop have been selected by the Program Committee for publication in this supplement to In addition to the presented papers and posters, BioNLP 2008 featured two keynote talks.John Hutton, MD, Professor of Pediatrics and Director of Biomedical Informatics, Cincinnati Children's Hospital, presented a large academic medical center perspective on computational linguistics approaches to enhancing Clinical Decision Support Systems.LTC Hon Pak, MD, Chief, Advanced Information Technology Group Telemedicine and Advanced Technology Research Center (TATRC), U.S. Army Medical and Material Research Command, discussed the need for NLP in Department of Defense Military Health System (MHS).et al. [et al. [Two papers are dedicated to relation extraction. Airola et al.  present  [et al.  treat clet al. [As automatic named entity recognition (NER) significantly impacts all subsequent processes in BioNLP pipelines, it continues to be an active area of research. Corbett and Copestake  achieve et al.  combine et al. [Many NLP applications are believed to require determination of the sense of a recognized entity. For example, an automatic system that links research evidence to a patient's record needs information on the sense of discharge  in a given context to provide appropriate evidence. Wang and Matthews  demonstret al.  adapt anet al. [et al. [Creation of domain-specific resources is an important task that stimulates BioNLP research, once the resources are made available to the community. To that end, Tsuruoka et al.  present  [et al.  describeet al. [Determining authors' confidence in their findings  is another important area of research. Kilicoglu and Bergler  use lexiet al. .The authors declare that they have no competing interests.


Drosophila melanogaster has shown that two distinct axonal guidance receptors are precisely clustered in adjacent segments of the commissural axons both in vivo and in vitro, suggesting a cell‐intrinsic mechanism underlying the compartmentalized receptor localization. In Caenorhabditis elegans, a subset of interneurons exhibits calcium dynamics that are localized to specific sections of the axon and control the gait of navigation, demonstrating a regulatory role of compartmentalized neuronal activity in behaviour. These findings have led to a number of new questions, which are important for our understanding of neuronal development and function. How are these sub‐compartments established and maintained? What molecular machinery and cellular events are involved? What is their functional significance for the neuron? Here, we reflect on these and other key questions that remain to be addressed in this expanding field of biology.Neurons are highly polarized cells that consist of three main structural and functional domains: a cell body or soma, an axon, and dendrites. These domains contain smaller compartments with essential roles for proper neuronal function, such as the axonal presynaptic boutons and the dendritic postsynaptic spines. The structure and function of these compartments have now been characterized in great detail. Intriguingly, however, in the last decade additional levels of compartmentalization within the axon and the dendrites have been identified, revealing that these structures are much more complex than previously thought. Herein we examine several types of structural and functional sub‐compartmentalization found in neurons of both vertebrates and invertebrates. For example, in mammalian neurons the axonal initial segment functions as a sub‐compartment to initiate the action potential, to select molecules passing into the axon, and to maintain neuronal polarization. Moreover, work in  I.Neurons are specialized cells with a high level of polarization defined by the presence of three major compartments: the dendrites, a cell body (or soma) and an axon Fig. A. DendriSome clear and well‐studied sub‐compartments within dendrites and axons, such as the dendritic spines and the presynaptic boutons, were recognized decades ago, in part due to their distinct morphology. Dendritic spines were first observed as protrusions on the dendrites through gold staining by Ramon y Cajal, and represent the dendritic sub‐compartments that receive inputs from a single axon Gray, . More adin vitro and in vivo models provide evidence of neurites with shared axonal and dendritic properties, axonal compartmentalization of membrane proteins, such as axon guidance receptors and ion channels, and clustering of intracellular components within neurites, which include protein aggregates, organelles and ions , which play critical roles in thermotaxis, navigation and learning  neurons, which control fertility, are bipolar, with a long dendrite that extends for about 1000 μm. For many years, scientists struggled to identify the axonal structure of these neurons until it was revealed that the process of the GnRH neurons functions as both an axon and a dendrite   repulsive cue , which are located in the olfactory bulb and are involved in odour discrimination, the β3 subunit of gamma‐aminobutyric acid receptors (GABARs) is clustered in the soma and dendritic shafts but not in the spines  channels, which have also been implicated in regulating the electrical properties of these neurons et al.,et al.,et al.,Organelles such as mitochondria  and lysosomes  can adopt specific and dynamic localizations within neuronal sub‐compartments that reflect the functional needs of the cell Fig. A. Early D. melanogaster), and the outer mitochondrial membrane molecule Miro, which acts as a calcium sensor  being smaller than the non‐synaptic forms (nsMito) C. elegans AWC neurons, a pair of olfactory neurons in the head of the animal, cyclic guanosine monophosphate (cGMP) regulates both olfactory sensation  et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al.,A large body of literature has revealed that cells can compartmentalize not only proteins but also important inorganic molecules, such as calcium ions. Calcium is the most abundant signal transduction molecule controlling key physiological events, which include gene transcription, exocytosis, and cell death Clapham, , and is et al.,et al.,et al.,et al.,Neurons also exhibit additional sophisticated mechanisms of calcium compartmentalization important for complex neuronal functions. For example, detecting image motion is a fundamental function for vision that is regulated by the direction‐selective retinal ganglion cells de novo proteins in close proximity to their final functional milieu within different cellular compartments. In neurons, both coding RNAs (mRNAs) et al.,et al.,et al.,Polysomes, the ribosomal complexes for mRNA translation, are found at the base of dendritic spines of neurons in the dentate gyrus of the rat brain , with the goal of elucidating the molecular mechanisms for their axonal compartmentalization et al.,et al.,MicroRNAs (miRNAs), small non‐coding RNAs which are 21–25 nucleotides in length, play an important role in regulating gene expression. Binding of a miRNA to the 3′ UTR of a target mRNA inhibits translation and/or leads to the degradation of the mRNA et al.,et al.,Circular RNAs (circRNAs) constitute a divergent class of RNAs which are mainly produced during RNA splicing of protein‐encoding genes. Their common characteristic, the form of a full loop, confers unique properties that have only recently started to emerge et al.,The long non‐coding RNAs (lncRNAs) are RNA molecules that are longer than 200 nucleotides and do not encode any protein. Many lncRNAs are enriched in the brain tissues and approximately 40% of them are expressed selectively in the mammalian brain  Synaptic mitochondria are crucial for neuronal function and have a specific proteome that differs from that of non‐synaptic mitochondria. What mechanisms underlie the association of different proteins with synaptic versus non‐synaptic mitochondria? (4) Although the compartmentalization of intracellular components has been shown to depend on either the cytoskeleton (as for organelles) or the association with scaffolding proteins (as for the glycolytic enzymes which cluster at the synapse in response to metabolic requirements), the mechanism of calcium compartmentalization in axons and dendritic spines remains largely unknown.However, some of these processes are still not fully elucidated and important questions remain to be addressed. (1) The dendron awaits the identification of the molecular pathways and genetic factors involved in its development and maintenance. (2) For unipolar neurons that contain functionally different synaptic domains, the molecular and cellular events that regulate the specificity of these domains remain to be characterized. For example, only UNC‐101, TTX‐7, and two cyclin‐dependent kinase pathways have been identified as regulators of the polarity of RIA interneurons in VI.(1) The dendritic and axonal compartments of both invertebrate and vertebrate neurons often contain functional domains, which are characterized by distinct molecular distributions, activity patterns, and functional outputs. The formation of these sub‐compartments depends on the integration of intrinsic factors with external cues or on neuronal activity and external stressors.D. melanogaster commissural neurons, and compartmentalization of calcium at the tip of the growth cone to direct turning during navigation towards the target. Moreover, in C. elegans neurons the precise clustering of membrane receptors also plays a crucial role in the axonal compartmentalization of synapses.(2) During early development, axon guidance requires a cell‐autonomous axonal compartmentalization of receptors for guidance cues, as shown in the (3) Once neurons are fully developed, sub‐compartmentalization is still important for neuronal activity and plasticity. For example, compartmentalization of mitochondria at synapses is necessary to supply energy for synaptic transmission, while in the dendrites it is required for the activity‐dependent generation of new spines.C. elegans the level of the second messenger cGMP is locally regulated upon stimulation. The level of cytoplasmic calcium is also locally regulated in the axons of AIY or RIA interneurons of C. elegans to encode temporal neuronal activity.(4) A number of functional compartments contribute to distinct temporal properties of specific neurons. For example, glycolytic enzymes cluster at synaptic loci to support the elevated energy expenditure of high neuronal activity, through an interaction with synaptic scaffolding proteins. Moreover, in the AWC chemosensory neurons of


Livestock is a major driver in most rural landscapes and economics, but it also polarises debate over its environmental impacts, animal welfare and human health. Conversely, the various services that livestock farming systems provide to society are often overlooked and have rarely been quantified. The aim of analysing bundles of services is to chart the coexistence and interactions between the various services and impacts provided by livestock farming, and to identify sets of ecosystem services (ES) that appear together repeatedly across sites and through time. We review three types of approaches that analyse associations among impacts and services from local to global scales: (i) detecting ES associations at system or landscape scale, (ii) identifying and mapping bundles of ES and impacts and (iii) exploring potential drivers using prospective scenarios. At a local scale, farming practices interact with landscape heterogeneity in a multi-scale process to shape grassland biodiversity and ES. Production and various ES provided by grasslands to farmers, such as soil fertility, biological regulations and erosion control, benefit to some extent from the functional diversity of grassland species, and length of pasture phase in the crop rotation. Mapping ES from the landscape up to the EU-wide scale reveals a frequent trade-off between livestock production on one side and regulating and cultural services on the other. Maps allow the identification of target areas with higher ecological value or greater sensitivity to risks. Using two key factors , we identified six types of European livestock production areas characterised by contrasted bundles of services and impacts. Livestock management also appeared to be a key driver of bundles of services in prospective scenarios. These scenarios simulate a breakaway from current production, legislation (e.g. the use of food waste to fatten pigs) and consumption trends . Overall, strategies that combine a reduction of inputs, of the use of crops from arable land to feed livestock, of food waste and of meat consumption deliver a more sustainable food future. Livestock as part of this sustainable future requires further enhancement, quantification and communication of the services provided by livestock farming to society, which calls for the following: (i) a better targeting of public support, (ii) more precise quantification of bundles of services and (iii) better information to consumers and assessment of their willingness to pay for these services. In this review, we attempt to explain the trade-offs and synergies derived from livestock production and analyse their relevance or irrelevance across spatial scales in search of options for a more sustainable livestock sector in Europe. We conclude by highlighting key aspects that need to be explored to further enhance, quantify and reveal the services provided by livestock farming to society.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Livestock is a major driver of rural landscapes and economics, but it also polarises debate over animal welfare, impact of animal product consumption on human health and on the environmental footprint of livestock production, including greenhouse gas (GHG) emissions and the relative inefficiency of energy and protein conversion into animal products  detev. ES dimensions in ruminant systems. Recent reviews  synergies between livestock production and other dimensions, especially a number of studies on the production et al., et al., et al., 2 fixation by legumes increases N availability and thus decreases the inputs needed for production. Daily animal intakes of forage and digestion were also shown to be higher when fed on grass–legume mixtures  within UAA. These two criteria allow accounting for the variability of bundles of services as they are related to all main system characteristics: animal species, feeding strategy, manure management, etc. Based on Eurostat data for 2010, Hercule et al.  evaluate global options to ensure food security in a more sustainable way. These scenarios simultaneously account for production and its environmental footprint, but also for population growth, trade of livestock products and human health. They simulate a breakaway from current production, legislation (e.g. the use of food waste to fatten pigs) and consumption trends  most often in interaction with climate change. Scenarios are not forecasts or predictions but offer a dynamic view of livestock futures by exploring trajectories of change that broaden the range of plausible alternatives  and indirect (shifts in vegetation communities under elevated CO2) effects of climate change  has long aimed to support livestock farming in areas where farming systems face pedoclimatic constraints that limit their competitiveness, which is also a way to support territorial vitality and to preserve biodiversity and landscapes with strong heritage value. Beyond this, the CAP also integrated some of the environmental dimensions of livestock farming. In high livestock density areas, policies such as the EU Nitrates Directive aim to regulate the local nuisances of water and air pollution from intensive farming. For example, the Nitrates Directive led to a decrease in N cycling disruption by clustering crop and livestock production into specific areas to optimise crop fertilisation . Beyond information to consumers, the bundle of services framework highlights the entire range of regulating, cultural and rural vitality services provided by livestock farming. By doing this, it allows the implementation of policy pathways that optimise livestock contributions to the global food system while remaining within planet boundaries.Finally, it remains difficult to share the positive services provided by livestock farming  with consumers and citizens so that they can develop their own system of consumption ethics. This calls to investigate their willingness to pay for the services provided by livestock farming. Apart from organic farming and PDO products, which are usually based on strict production specifications, most product labels are indeed vague, unverified and unverifiable (Treves and Jones,


The water in the structure is believed to act as a lubricating agent in the packing of hydrates, thus facilitating slippage of molecules in the plastic bending of the crystals under external mechanical stress.Khandavilli  Such plasticity phenomena have also been studied in molecular materials, such as globular hydrocarbons with predominantly dispersive interactions, where the plastic crystal is a mesophase between the solid and liquid states (Sherwood, 1979et al., 2005The terms elasticity, plasticity and brittleness in molecular solids typically depend on their intrinsic molecular arrangements and the rate of applied load (Reddy tert-butyl, methoxy, chloro, bromo and aromatic groups among many others (Reddy et al., 2006et al., 2015et al., 2015et al., 2016et al., 2015et al., 2018et al., 2017et al., 2018Plasticity in molecular crystals can generally be obtained when the crystals are anisotropic and have facile slip planes, which weakly interact through dispersive noncovalent interactions, involving functional groups such as methyl, IUCrJ, Khandavilli et al. (2019et al., 2017et al., 2018et al., 2019et al. (2019et al., 2017Reporting in  al. 2019 have sho al. 2019, where w al. 2019 contrastet al. (2019Mechanical properties are fundamental properties, much like density, optical, thermal and electrical properties. Therefore, mechanical properties are relevant to all types of materials and their importance cannot be ignored when addressing problems in practical applications. Molecular level understanding is currently lacking for most mechanical processes, such as milling and flowability, that are important in designing flexible optoelectronics and manufacturing processes in pharmaceutical, fine chemical, agrochemical industries and so on. The solutions sought currently using empirical methods are tedious and expensive. Hence, further development of a scientific basis in this regard by systematic studies, such as Khandavilli  al. 2019, will re


Recently Pascual and colleagues have contributed a study about the identity of cells that initiate metastasis . They iIn the past decade much progress has been made in understanding the principles that control formation of metastases (McGranahan et al, 2017; Adawy, In many tumor types high expression of proliferation associated genes has been shown to lead to an increased risk of metastasis (Schmidt et al., 2008; SiggelkIn conclusion, Pascual and colleagues bring forward an interesting concept that metastasis-initiating tumor cells rely on dietary lipids in a CD36 dependent manner. It remains to be shown, whether CD36 is a promising target for anti-cancer therapy.


Information on intoxication of livestock by plants in Brazil, in terms of cause, clinical signs and pathology, is compared with information on livestock poisoning by plants in South Africa. Plant poisoning, including mycotoxicosis, is considered to be one of three major causes of death in livestock in Brazil, which is one of the top beef producing countries in the world, with a cattle population of more than 200 million. Cattle production in South Africa is on a more modest scale, but with some 600 species of plants and fungi known to cause toxicity in livestock, as opposed to some 130 species in Brazil, the risk to livestock in South Africa appears to be much greater. The comparisons discussed in this communication are largely restricted to ruminants. Plantas Tóxicas do Brasil, published in 2012  were important in cattle; the first two also affect sheep. Cardiac glycoside-containing plants occur worldwide but significant livestock poisoning has only been reported in southern Africa and, to a much lesser extent, in Australia  as well as Ateleia glazoviana (Fabaceae) may cause sudden death, with chronic heart lesions revealed at necropsy, like gousiekte, but more often the animals develop signs of congestive heart failure before death occurs. Two other syndromes, one involving abortions and the other involving neurological signs including lethargy are associated with poisoning by A. glazoviana  and poisoning, due to ingestion of Lantana spp., occur in both South Africa and Brazil. The intoxications present with the same clinical picture as in South Africa. While seneciosis is well known in Brazil, particularly in the southern states, and appears to show the same pattern as in South Africa, with cattle more often affected than small stock, Lantana poisoning appears to be less frequent, and only a single outbreak of diplodiosis has been recorded in Brazil  and geeldikkop are due to bile duct occlusion. In facial eczema, inflammatory bile duct occlusion is caused by sporidesmin. In geeldikkop the bile duct obstruction is due to accumulation of birefringent crystals that are produced as a result of steroidal saponins in the plants themselves , castor oil beans (Ricinus communis), Cestrum spp., Xanthium spp., Amaranthus spp., Solanum spp., Equisetum spp., Pteridium aquilinum (bracken fern), Leucaena leucocephala, Allium spp., Crotalaria spp., Vicia villosa, Aspergillus flavus, Aspergillus clavatus, Claviceps purpurea, Claviceps paspali and Fusarium spp.Other plant poisonings and mycotoxicoses that Brazil and South Africa have in common include those caused by cosmopolitan plants and fungi such as syringa  and is strongly suspected to be a glycoprotein storage disease based on the histopathological lesions  as well as Sida carpinifolia  are responsible for glycoprotein storage disease (Tokarnia et al. Ipomoea carnea, has also been reported to cause glycoprotein storage disease in goats in Mozambique (De Balogh et al. Solanum fastigiatum var. fastigiatum causes neurolipidosis, with clinical signs similar to those produced by S. tettense var. renschii in South Africa (Tokarnia et al. Lysosomal storage diseases that cause neurological disorders and pathology of the central nervous system have been described in both Brazil and southern Africa (Kellerman Prosopis poisoning. Cattle and goats are poisoned when large quantities of the pods of the highly invasive Prosopis glandulosa, also known as mesquite or Suidwesdoring, are ingested. It should be noted that Tokarnia et al. (Prosopis juliflora, a synonym of P. glandulosa (Nkonki et al. et al. Another peculiar neurotoxicity that has been described in both countries is a et al. , 2012 rea Nkonki . ClinicaSolanum malacoxylon and Nierembergia veitchii (Tokarnia et al. Systemic calcinosis as a result of plant poisoning has not been described in South Africa, but is associated with two plants in Brazil: et al. (An interesting poisoning that is reported by Tokarnia et al.  is a syset al. (Nolletia gariepina was confirmed by dosing trials, but in the field, the intoxication only occurred when cattle that had been penned for periods of 36–48 h without feed were released onto pastures where the plant was abundant (Du Plessis, Prozesky & Botha Although plant poisoning of livestock is reported to be important in Brazil, it appears to involve fewer plants than have been reported in South Africa. It is possible that in many parts of Brazil, plant intoxication is under-reported, as many of the poisonings described by Tokarnia et al.  occurred


In recent years, there has been growing interest in the potential of video games to improve health and cognition (Russoniello et al., Rumination, traditionally associated with poor attentional control, has been suggested to lead to difficulty disengaging from negative thoughts; thus, rumination has been implicated in depression (Hsu et al., One factor that may limit the video games' effectiveness in reducing rumination is a temporal threshold for sufficient cognitive activation. In a meta-analysis, Bediou et al.  observedAnother possibility for the lack of a positive result is perhaps explained by the impact of video game genre, as studies have suggested different video game genres have differential effects on cognitive abilities. Indeed, a meta-analysis by Powers et al.  on the eTimely action games prioritize the precise timing of an action, whereas accurate action games prioritize the precise execution of an action. Given these definitions, it seems Boson X is most accurately classified as a timely action game, since it places emphasis on the precise timing of a series of jumps. According to Mondéjar et al. (Dobrowolski et al.  discusser et al. , timely,r et al. ; this per et al. .Furthermore, Bernstein et al.  recentlyKühn et al.  did not All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Chen et al.  provide Although the cerebellum has been implicated in higher-order domains functions—from a network-based perspective (Koziol et al., AI: conception and design. AI and AG: drafting 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.


The recent work by Young et al.  demonstrRegarding the importance of removing DNA from dead cells during microbial analysis, similar conclusions have been drawn by studies of, for example, environmental samples (Carini et al., vPCR methodology is theoretically simple to use since it requires only a reagent and a light source; however, as with many techniques, a lack of practical experience with the technique led the authors to overlook some important considerations. vPCR is still relatively new, with the first paper by Nogva et al. . The sci2 for 5 min, and this percentage decreases to 3–5% after 20 min of exposure (Brusa et al., (Cuthbertson et al., In the paper by Young et al. , the autThe authors evaluated the effect of freezing the samples and concluded that freeze/thawing did not change the results for the stool samples. However, factors other than storage were not considered, so it remains unclear whether their conclusions were influenced by additional biases.The work of Young et al. is valuable, and the conclusions very clearly show the importance of overcoming bias due to DNA from dead cells in a microbial diversity analysis. We suggest that an additional warning about the importance of appropriate sample handling would be helpful to readers who may wish to conduct similar analyses.Both authors reviewed the original work and wrote this commentary.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.


Cross-modal interactions are common in sensory processing, and phenomena reach from changed perception within one modality due to input from another like in the well-known McGurk effect  is the earliest processing stage in the auditory pathway in which acoustic trauma leads to tinnitus-related changes and increased spontaneous firing rates (Kaltenbach et al., It is well-known that the DCN receives not only input from the cochlea, but also from the somatosensory system (Ryugo et al., For example, it is well-known that jaw movements lead to a modulation of tinnitus sensation in patients (Pinchoff et al., In addition, the finding that DCN responses to somatosensory stimulation are enhanced after noise-induced hearing loss (Shore et al., Finally, the finding that electro-tactile stimulation applied to the index finger significantly improves speech perception thresholds (Huang et al., In a previous paper we already discussed the possibility of superseding the internally generated neuronal noise by adding external acoustic noise, thereby suppressing the tinnitus percept (Krauss et al., Based on these observations we here speculate that stochastic resonance in one sensory modality driven by input from another modality may be a general principle, namely multisensory integration causing stochastic resonance like cross-modal enhancement. For example, it is known that the concept of stochastic resonance via internal noise applies also to visual perception (Aihara et al., In addition to the here proposed neuronal mechanism of somatosensory-driven stochastic resonance in the auditory system explaining the better hearing in the CI patients during finger tapping (Huang et al., Even though multisensory integration leading to improved perception has been reported earlier (Stein and Stanford, PK and HS wrote the manuscript. PK, HS, KT, and AS discussed possible interpretations of the cited studies and developed the hypothesis presented in this paper.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. The reviewer SV and the handling editor declared their shared affiliation.


The Revolting Self to emphasize the disgust associated with low self-esteem and poor perception of body image.Body image is a complex mystery. Contributions to low self-esteem can be sorted out, one by one, until the source of the “problem” is found. To tackle this vast concept, several professors gathered together from the United States, Europe, Italy, and other parts of the world. Their expertise focused on chronic pain, anxiety, sexual dysfunction, addiction, and mood disorders. They explored feelings of guilt, shame, disgust, and avoidance. More positive aspects of their work included research on ethics, pride, mindfulness, and decision-making abilities. These doctrines formed a thought-provoking book that emphasized the role of body image in eating disorders. This book was titled as disgust as the typical reaction to vomit, mucus, or fecal matter, which generally creates distinct facial expressions and certain avoidance behaviors (Overton et al., The book starts by defining The Revolting Self digs deeper into self-disgust and the negative emotions that follow, which include impaired moral judgment (Overton et al., Comprehensive Psychiatry conducted a research study on seventy-two participants to find that moral judgment is the same for both schizophrenics and populations without schizophrenia (McGuire et al., Alterations in moral judgment can manifest themselves into mental disorders, such as eating disorders (Overton et al., The Revolting Self states that “acts of psycho-emotional disablism contribute to the social marginalization of disabled people and their cultural representation as less than human” (Overton et al., The book goes on to explain that certain populations promote feelings of disgust. Those who feel that they are disabled are more likely to experience disgust and a low self-esteem (Overton et al., International Journal for Equality in Health agrees that individuals with a disability see themselves as “less than human,” which creates cultural and psychosocial inequalities (Agmon et al., American Journal of Public Health echoes this same thought by claiming that disabled individuals consist of over twelve percent of the population, so they should be considered a cultural group (Krahn et al., The perfect human with a small body mass, flawless skin and perhaps curves in just the right places. The book suggests that “social norms” are what society uses to define the ideal human (Overton et al., There are other cultural features of disgust as well. The media paints a pretty picture of the Yale Journal of Biology and Medicine claims that obesity is the most negative of all the stigmas (Pryor et al., The The Revolting Self suggests that women are more prone to low self-esteem because they often hide natural behaviors, such as menstruation (Overton et al., Frontiers in Psychology looked closely at the relationship between sex and culture, which showed cultural differences in emotional reactions to sex (Zhao et al., Some cultures might promote thinness, while others may prefer a larger body frame. Either way, low self-esteem occurs in many people before they engage in sexual intercourse (Overton et al., The Revolting Self suggests that disgust can take on many dimensions.All of these key points compile to form the theory that a poor sense of body image leads to inward anger or harsh criticism toward oneself (Overton et al., Approval for publication has been granted by the author, who is the sole contributor to this book review.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The use of nanomaterials for food applications is a rapidly evolving field and, given the specific properties of nanomaterials and their tremendous potential, an increased number of material innovations that contribute to improved food quality and safety are foreseen. Although the possibilities are unlimited, and nanomaterials in the food area have been applied with different purposes , the devThis special issue is devoted to compiling several papers on these fascinating topics. Specifically, five research papers and one review paper are included in the special issue “Food Packaging based on Nanomaterials”. The manuscripts by Sharif et al.  and BugaCombining inherent antimicrobial polymers (like chitosan) with antimicrobial nanoparticles (like zinc oxide) was the approach used by Al-Naamani et al. . These hA different strategy was explored by Muriel-Galet et al.  in anothThe toxicological aspects of packaging nanomaterials are also covered in this Special Issue through the work of Bott and Franz , who stuThe Special Issue is completed with a review paper from Huang et al.  which coIn summary, this Special Issue of Nanomaterials entitled “Food Packaging based on Nanomaterials” compiles a series of original research articles and a review paper providing new insight on the preparation and on the wealth of applications of hybrid nanomaterials for food-packaging applications. We are confident that this Special Issue will provide the reader with an overall view of some of the latest prospects in this fast-evolving and cross-disciplinary field.


Caenorhabditis elegans small noncoding RNAs, known as microRNAs, by Ambros, Ruvkun, and colleagues in 1993; this revolution has wrought huge changes in all fields of biology and medicine by identifying a new layer of gene regulation. The most unbiased proof of their impact is the publication of over 100 000 papers on the topic of short or long noncoding RNAs, reporting their roles in cell fate, tissue organization, organism homeostasis, and circadian rhythms, their use as biomarkers, their involvement in a plethora of disease mechanisms, and, starting recently, their potential as drugs or drug targets in several clinical trials for various disorders.Revolutions bring great changes to societies. The noncoding RNA revolution began with the seminal discovery of Molecular Oncology on the topic of noncoding RNAs is focused on specific issues that have practical significance, rather than trying to encompass the full biology of these molecules.Due to this unprecedented coverage of the role of noncoding RNAs in almost all aspects of biology and pathology, this special issue of Joanne Weidhaas and Ye Yuan review microRNA‐associated polymorphisms that have been shown to be important biomarkers of cancer risk, prognosis, and treatment outcomes. This has great translational significance, as these predictive biomarkers can be used for patient selection into treatment groups in clinical trials (Yuan and Weidhaas, et al., Anke van den Berg, Joost Kluiver, and colleagues cover the important topic of crosstalk between MYC and noncoding RNAs, and the significance for potential new therapeutic approaches in human cancers (Swier The review by Spina and Rossi gives an overview of the mutation landscape in the most frequent type of human leukemia, chronic lymphocytic leukemia, with a particular focus on noncoding lesions of the genome (Spina and Rossi, et al., Martin Pichler and colleagues review the role of a highly expressed ncRNA, NEAT1, in carcinogenesis and discuss some contradictory reports related to its potential interaction with microRNAs (Klec et al., Cristina Lo Nigro and colleagues discuss the roles of lncRNAs as regulators of cancer immunity, a particularly important topic in light of the recent success of several types of immunotherapies (Denaro et al., Manuela Ferracin and colleagues report on the involvement of certain small and long noncoding RNAs in cutaneous melanoma, and the diagnostic and prognostic potential of microRNAs for this disease (Riefolo et al., Ioana Berindan and colleagues focus on the roles of the miR‐181 family, one of the most frequently deregulated families of microRNAs in lung cancers, and their potential use as biomarkers and therapeutic targets for this deadly malignancy (Braicu In closing, we hope that this special issue will not only answer many of our readers’ questions on this topic, but also raise new ones that will open new venues of research and lead to significant discoveries in this ongoing revolution.