The resulting cascade of reactions greatly magnifies melatonin's efficacy in reducing oxidative stress and apoptosis even in the presence of mitochondrial electron transport inhibitors. The actions of melatonin at the mitochondrial level are a consequence of melatonin and/or any of its metabolites. Thus, the molecular terrorism meted out by reactive oxygen and nitrogen species is held in check by melatonin and its derivatives.The intracellular environmental is a hostile one. Free radicals and related oxygen and nitrogen-based oxidizing agents persistently pulverize and damage molecules in the vicinity of where they are formed. The mitochondria especially are subjected to frequent and abundant oxidative abuse. The carnage that is left in the wake of these oxygen and nitrogen-related reactants is referred to as oxidative damage or oxidative stress. When mitochondrial electron transport complex inhibitors are used, e.g., rotenone, 1-methyl-1-phenyl-1,2,3,6-tetrahydropyridine, 3-nitropropionic acid or cyanide, pandemonium breaks loose within mitochondria as electron leakage leads to the generation of massive amounts of free radicals and related toxicants. The resulting oxidative stress initiates a series of events that leads to cellular apoptosis. To alleviate mitochondrial destruction and the associated cellular implosion, the cell has at its disposal a variety of free radical scavengers and antioxidants. Among these are melatonin and its metabolites. While melatonin stimulates several antioxidative enzymes it, as well as its metabolites (cyclic 3-hydroxymelatonin, N N-acetyl-5-methoxytryptamine) is an endogenously-produced molecule found throughout the animal kingdom from unicells to humans  which is coupled to oxidative phosphorylation provides cells with their major means of generation of its energy requirements  inhaled and eventually taken up by cells is processed in the mitochondrial ETC where it is converted to water following its four electron reduction. However, during this reductive process, partially reduced species of O2 are also produced including reactants that are reduced by one, two or three electrons, i.e., the superoxide anion (O2·–) and hydroxyl radical (·OH) and one non-radical product, hydrogen peroxide (H2O2). Collectively, these agents are referred to as reactive oxygen species (ROS).The majority of molecular oxygen , respectively. Since H2O2 is the immediate precursor of the highly damaging ·OH, it is imperative that H2O2 be removed from the intramitochondrial environment as quickly as possible. The major enzyme that accomplishes this is glutathione peroxidase (GPx), which metabolizes H2O2 to water and O2; in this process GPx also converts reduced glutathione (GSH) to its oxidized metabolite (GSSG). Given the major importance of GSH in mitochondrial physiology, it is essential that GSSG be reduced back to GSH; this is accomplished by glutathione reductase (GRd) . O2O2 from the mitochondrial environment is never complete and, via the Fenton reaction, some damaging ·OH are always formed. Cellular organelles have no enzymatic means to remove ·OH so it must either be neutralized by a free radical scavenger or it mutilates a bystander molecule. This carnage occurs in the immediate vicinity of where the ·OH is formed because of its extremely rapid reaction rate; the damage is referred to as being site specific.The removal of H–). Mitochondrial NO functions as a reversible antagonist of complex IV of the ETC by competing with O2 for its binding site. Usually tissue concentrations of NO and O2 are, respectively, in the ranges of 100–500 nM and 10–30 µM. In these concentration ranges, NO causes roughly half maximal inhibition of mitochondrial respiration. Thus, NO is a physiological regulator of respiration and also of the rate of ATP synthesis ; two of these are nitric oxide (NO) and the peroxynitrite anion  has been proposed to exist in mitochondria (mtNOS) . This latter product was identified by mass spectral analysis and carbon and proton-nuclear magnetic resonance (Tan 1-acetyl-N2-formyl-5-methoxykynuramine (AFMK)   , GPx and GRd. The SOD isoforms dismutate Oet al., et al., et al., et al., It has been known for more than a decade that the activities of the antioxidative enzymes mentioned above are heightened in the presence of exogenously administered, pharmacological doses of melatonin , in the production of this tripeptide antioxidant. Often, under elevated oxidative stress conditions, melatonin preserves intracellular GSH levels. This is not necessarily related to the ability of melatonin to stimulate γ-GCS since the indoleamine could preferentially scavenger free radicals and thereby preserve basal intracellular GSH concentrations. The stimulation of γ-GCS, as originally described by Urata  et al., .One final aspect should be considered when melatonin's ability to attenuate molecular impairment due to ROS/RNS is discussed. It is what Hardeland  refers tThis section briefly summarizes the multiple processes by which melatonin may restrict the destruction of molecules and organelles normally inflicted by ROS/RNS. Whereas these processes have all been documented in vivo, the significance of each in forestalling oxidative damage may be cell specific.Several drugs have been identified which are classified as mitochondrial poisons, i.e., they interfere with the transfer of electrons through the ETC. These drugs greatly exaggerate the escape of electrons into the mitochondrial intramembraneous space leading to a reduction of molecular oxygen and formation of radicals. Additionally, reduced oxidative phosphorylation precipitates a depletion of ATP Beal, . These cet al., et al., Rotenone, a specific inhibitor of complex I of the mitochondrial ETC, causes the generation of an excessive number of free radicals. The damage inflicted by this drug is believed to be a consequence of the ·OH , strongly potentiated rotenone-mediated death of pheochromocytoma (PC12) cells, a response attenuated by melatonin. Furthermore, in the presence of melatonin, free radicals were not detected to be released from PC12 cells co-exposed to rotenone plus the Ca2+ ionophore. Since melatonin did not change the concentration of Ca2+ nor did it prevent the inhibitory effect of rotenone on mitochondrial complex I, the authors concluded that the beneficial effects of melatonin on the mitochondria were primarily related to the antioxidative and free radical scavenging capacity of the indoleamine . It was immediately suspected that the drug caused damage to the dopaminergic cells of the substantia nigra which are the major neurons lost in individuals with idiopathic PD. When these individuals died and the brain was examined there was, in fact, a selective destruction of the mesencephalic dopamine-containing neurons. As tragic as these instances were, the identification of this destructive drug provided experimentalists with an agent that causes parkinson-like signs in animals. Use of MPTP has now become a model of examine the processes of PD as well as to investigate drugs that may modify the course of the disease.+). The latter molecule is then released from the glial cells and is taken into dopaminergic nerves via the dopamine transporter. MPP+ interferes with complex I of the mitochondrial ETC; this leads to cellular energy depletion and eventually to the death of dopaminergic cells.When administered to animals, MPTP is taken up by astrocytes surrounding dopaminergic neurons and terminals where it is metabolized to 1-methyl-4-phenylpyridinium  was increased by melatonin treatment. The reduction in cyanide-mediated neural toxicity by melatonin was assumed to be related to the free radical scavenging activity of the indoleamine.Yamamoto and Tang  performeWhen cultured rat cortical neurons were exposed to potassium cyanide over a range of concentrations (0.01–1.0 mM) lactate dehydrogenase efflux, indicative of cellular damage, into the culture medium was observed. Melatonin significantly reduced escape of the enzyme from the neurons and preserved their morphology  opening, cytochrome c release, positive YOPRO-1 staining of the early apoptotic nuclei and DNA laddering. Besides inhibiting the apoptotic events initiated in astrocytes by H2O2, melatonin also reduced free radical formation and other degenerative cellular processes that resulted from the exposure of cells to either tert-butyl hydroperoxide or cumene hydroperoxide. Additionally, the protective effect of melatonin against these damaging agents was better than that provided by vitamin E (Jou et al., In a second, more complete study, this group examined in detail many aspects of apoptosis and showed that melatonin also prevented death of cells caused by the oxidizing agent, Het al., et al., et al., The greater efficacy of melatonin in reducing observable free radical generation and apoptotic processes than vitamin E is a common observation. A number of studies have compared melatonin with classic antioxidants, e.g., glutathione, mannitol, vitamin C, vitamin E, etc., and invariably melatonin performs in a superior manner (Sofic et al., According to Jou and colleagues  the openet al. (Besides reducing free radical-mediated, mitochondrial-dependent apoptosis, a process that does not require an interaction of melatonin with a receptor, melatonin may also have a receptor-mediated means of reducing the likelihood of apoptosis. Kilic et al.  examinedet al.  concludeet al., et al., et al., et al., et al. (L and the reduction in cytochrome c release from mitochondria by melatonin in the damaged newborn rat brain.A follow-up study by the same group that melatonin acts to preserve the function of the PI-3 K/Akt pathway (Kilic , et al.  who repoMitochondria are the site of a large percentage of free radicals and related toxicants that are generated in cells. These reactive products cause damage to essential mitochondrial molecules which result in opening of the mitochondrial transition pore, release of cytochrome c and activation of the down stream events that culminate in free radical-mediated, mitochondrial-dependent apoptosis.Since melatonin was discovered to be an indirect antioxidant and direct efficient free radical scavenger, its ability to reduce oxidative stress and to curtail cellular apoptosis has been repeatedly documented. It has also been shown that part of melatonin's ability to quell the oxidation of key molecules stems from its conversion to metabolites, i.e., cyclic 3-OHMEL, AFMK and AMK when it incapacitates free radicals and their related products.The ability of melatonin to protect against oxygen- and nitrogen-based reactants is obvious in situations where toxins that inhibit the mitochondrial electron transport complexes are used. The mitochondrial poisons cause electron leakage with the resultant formation of large numbers of free radicals and consequentially molecular damage. This mutilation is inhibited by melatonin and its metabolites.et al., et al., et al., et al., et al., et al., et al., et al., et al., While melatonin readily resists mitochondrial oxidative damage and cellular apoptosis, there are many unanswered questions remaining. Some of the most noteworthy relate to the intramitochondrial concentrations of melatonin, the precise location of the indoleamine in relation to the complexes of the ETC, is it melatonin or a melatonin derivative that is the active agent in mitochondria and a definitive explanation for its high efficacy in preventing mitochondrial and cellular free radical-mediated destruction. Melatonin's very low toxicity combined with its high efficacy, however, portends its use in clinical medicine to treat conditions that are associated with elevated free radical damage, e.g., septic shock (Gitto


Human Mutation by Gottlieb et al. [BAK1 genotype among abdominal aortic anerurysm (AAA) patients and some controls. In particular, sequencing revealed a statistically significant number of instances in which single nucleotide polymorphisms (SNPs) present in tissue samples from patient abdominal aorta (AA) were absent from matching blood samples. The authors proposed a novel hypothesis “postulating that multiple variants of genes may preexist in ‘minority’ forms within specific non-diseased tissues and be selected for, when intra- and/or extra-cellular conditions change” [Gottlieb et al., An article published in b et al.  receivedThe implications of this unusual finding are of potential significance as regards the role somatic mutation and intraorganismal selection might play in genetic disease, not to mention the suitability of using blood-derived genomic DNA to evaluate patient mutational status of genetic diseases that affect various tissues. The work was challenged in a Letter to the Editors by Hatchwell , who argIn the current issue, Küry et al.  discuss Human Mutation, we feel that discussion of the original article by Gottlieb et al. [These four letters were all carefully peer reviewed and evaluated editorially, but within the limitations of the rather constrained “Letter to the Editors” format. As the Managing Editor and Co-Editors of b et al.  and its


Phantom breast syndrome is a type of condition in which patients have a sensation of residual breast tissue and can include both non-painful sensations as well as phantom breast pain. The incidence varies in different studies, ranging from approximately 30% to as high as 80% of patients after mastectomy. It seriously affects quality of life through the combined impact of physical disability and emotional distress. The breast cancer incidence rate in India as well as Western countries has risen in recent years while survival rates have improved; this has effectively increased the number of women for whom post-treatment quality of life is important. In this context, chronic pain following treatment for breast cancer surgery is a significantly under-recognized and under-treated problem. Various types of chronic neuropathic pain may arise following breast cancer surgery due to surgical trauma. The cause of these syndromes is damage to various nerves during surgery. There are a number of assumed factors causing or perpetuating persistent neuropathic pain after breast cancer surgery. Most well-established risk factors for developing phantom breast pain and other related neuropathic pain syndromes are severe acute postoperative pain and greater postoperative use of analgesics. Based upon current evidence, the goals of prophylactic strategies could first target optimal peri-operative pain control and minimizing damage to nerves during surgery. There is some evidence that chronic pain and sensory abnormalities do decrease over time. The main group of oral medications studied includes anti-depressants, anticonvulsants, opioids, N-methyl-D-asparate receptor antagonists, mexilitine, topical lidocaine, cannabinoids, topical capsaicin and glysine antagonists. Neuromodulation techniques such as motor cortex stimulation, spinal cord stimulation, and intrathecal drug therapies have been used to treat various neuropathic pain syndromes. One in eight women will develop breast cancer of which approximately 60% are treated surgically for axillary node staging and primary breast tumor resection. It is estimated that over 50% of women suffer chronic pain following treatment for breast cancer surgery. “Phantom Breast Syndrome” (PBS) is a type of condition in which patients have a sensation of residual breast tissue and can include both non-painful sensations as well as phantom breast pain. Patient may have pain and discomfort, itching, pins and needles sensations, tingling, pressure, burning, and throbbing. The syndrome can start even after more than one year of surgery. The incidence varies across different studies, ranging from approximately 30% to as high as 80% of patients after mastectomy. PBS can et al.,[et al.,[et al.,[et al.,[et al.'s review, there were 21 studies with follow-up periods from 1-96 months (one study of 210 months), which revealed the following widely varying ranges of prevalence estimates: Phantom breast pain 3-44%, intercostobrachial neuralgia (ICN) 16-39% for all breast cancer surgery, ICN in breast-conserving surgery 14-61% and neuroma pain 23-49%.[et al.,[et al.,[In a recent review, Jung et al., found th,[et al., suggeste,[et al., distingu,[et al., revealed,[et al.,6 Inciden,[et al., Neuroma ,[et al., Other ne,[et al., found thThere are a number of assumed factors causing or perpetuating persistent neuropathic pain after breast cancer surgery. There is, however, a lack of large-scale multiple risk factor studies identifying the variables as independent risk factors or evaluating their relationships with other variables, which are known to affect the development of chronic pain. From the literature currently available, the most well-established risk factors for developing phantom breast pain and other related neuropathic pain syndromes are severe acute postoperative pain and greater postoperative use of analgesics.9 These aUnderlying each of the four classifications of pain after breast cancer surgery is damage to various nerves during surgery. Nerve preservation approaches have shown reduced incidence of sensory deficits (53% vs 84% of women) but nerve-sparing is only successful in 65% of the cases where it was attempted. EvidencePhantom breast pain and other pain syndromes severely affect the quality of life of patients. The negative impact on a patient's physical and psychosocial functioning is consistent with many chronic and cancer pain syndromes. It has been reported that up to half of patients report negative impact of pain on their activities and up to one-quarter report moderate to high impact on their daily activities at home and work. Not surprisingly, studies have also found that breast cancer surgery patients with chronic pain have a greater psychological stress and psychiatric morbidity than the general population.12Based upon current incomplete evidence, the goals of prophylactic strategies could first target optimal perioperative pain control and minimizing damage to nerves during surgery. Peri-operative Pain Control: Medications traditionally used for persistent neuropathic pain such as topical EMLA, gabapent16et al.,[There is some evidence that chronic pain and sensory abnormalities do decrease over time. Unfortunet al., found thet al.,[Well-established PBS needs treatment. In 2005, Finnerup et al., reviewedFor persistent post-breast cancer surgery neuropathic pain, there exist very few randomized, double-blind, placebo-controlled trials. The use of topical capsaicin23 or amiHowever, many unanswered questions remain about the optimal doses, timing and coordination of therapy with ongoing adjuvant treatment for breast cancer. There are also a number of medications and multidisciplinary approaches showing benefit for other types of neuropathic pain that have yet to be trialed. In women with early-onset or established post-breast cancer surgery neuropathic pain, neuromodulation techniques such as motor cortex stimulation,26 spinalThe small scale of existing studies in persistent pain after breast cancer surgery creates considerable uncertainty regarding the generalizability of their findings, and also regarding the identification of potentially modifiable risk factors. Recent improvements in neuropathic pain screening tools now make early identification and syndrome classification of neuropathic pain more achievable. Many imp


Recent evidences prove that, release of potent lysosomal enzymes e.g. β-Glucuronidase by degranulation of polymorponuclear leukocytes in host gingiva may contribute significantly to tissue destruction and the pathogenesis of periodontal disease. The purpose of the present study was to compare and correlate GCF β-Glucuronidase with periodontal status among diabetic and non-diabetic patients with chronic periodontitis. A total number of 75 patients were equally divided into Group I (control group), Group II (non diabetic with chronic periodontitis) and Group III (diabetic with chronic periodontitis). Clinical parameters like Plaque index, Gingival index, Probing Pocket Depth and RBS were recorded. The β-Glucuronidase level in GCF of all three groups was determined by spectrophotometric analysis. It was observed that the periodontitis patients irrespective of their diabetic status, showed increased periodontal destruction with elevated level of β-Glucuronidase than the controls. Also, the diabetic patients showed increased severity of periodontal destruction and the elevated level of β-Glucuronidase, thus indicating diabetics at a higher risk for progressive periodontal destruction. Much effort has been made in recent years to identify risk factors responsible for initiation and progression of periodontal diseases. Mounting evidences indicate that, gingivitis and periodontitis are caused by various host responses which are associated with the continuous presence of microorganisms in the gingival crevice. They mayGingival Crevicular Fluid (GCF) provides a non invasive means of studying the host response factor by change of constituents in the fluid. The inflammatory exudates from gingival microcirculation crosses inflamed periodontal tissue and en route collects molecules of potential interest from the local inflammatory reaction. Therefore, the fluid offers a great potential source of factors like enzymes that may be associated with tissue destruction.β-Glucuronidase is a neutrophil derived lysosomal acid hydrolase enzyme which is stored in the neutrophil primary (azurophil) granules and is released in response to inflammation during periodontal destruction. This enzyme is active in degradation of proteoglycans and the ground substance and is an indicator of neutrophil (PMN) influx into the crevicular environment. Lamster in a recPeriodontal disease has been shown to be more severe in diabetics as compared to non-diabetics. SignificAlthough, a positive relationship of β-Glucuronidase level and traditional clinical parameters for diagnosis of periodontal disease has been widely studied, but there are inadequate number of studies for comparing β-Glucuronidase level as a potential marker for disease activity in diabetic and non diabetic patients suffering form chronic periodontitis. Hence, the present study was conducted with the following aims and objectives:To compare GCF β-glucuronidase activity with periodontal status among diabetic and non-diabetic patients.To correlate GCF β-glucuronidase activity with periodontal status among diabetic and non-diabetic patients.The patients for this study were selected from the Department of Periodontology and Implantology, Bapuji Dental College and Hospital, Davangere, Karnataka State.Patients with good oral hygiene and clinically healthy periodontium (Group I).Non-diabetic patients having probing pocket depth of 5-9 mm with a radiographic evidence of bone loss on at least 2 teeth, in minimum of two quadrants (Group II).Diabetic patients having probing pocket depth of 5-9 mm with a radiographic evidence of bone loss (Group III) on at least 2 teeth, in minimum of two quadrants.Patients with history of intake of any antibiotics and regular use of anti-inflammatory medication or the use of other drugs known to affect the periodontium, in past 6 months.Patients who had professional teeth cleaning or any other periodontal treatment within last 6 months.Patients who were unable to perform routine oral hygiene procedures.A total number of 75 patients,  in the age group of 30-60 years were selected for this study. The selected patients were divided into three groups as follows:Group I: (Control Group) consists of 25 patients with clinically healthy periodontium and good gingival status .Group II: Consists of 25 non-diabetic patients with chronic periodontitis having 5-9 mm probing pocket depth and radiographic evidence of bone loss.Group III: Consists of 25 diabetic patients with chronic periodontitis having 5-9 mm probing pocket depth and radiographic evidence of bone loss.The following clinical parameters were recorded after the selection of test sites.Plaque Index (PI) (Silness and Loe 1964)Gingival Index (GI) (Loe and Silness 1963)Probing Pocket Depth (PD) was measured by using William's graduated periodontal probe, held parallel to the long axis of tooth from free gingival margin to base of pocket.Random blood sugar (RBS) level was recorded for Group II and Group III patients.The rate of hydrolysis of phenolphthalein glucuronidase serves to assay the activity of β-Glucuronidase.The phenolphthalein liberated is estimated by the red colour which it gives, at alkaline pH. Phenolphthalein glucuronide has hardly any absorption at the same pH.A single test site was selected from each patient of Group I, II and III. After light supragingival scaling, a standard volume of 0.5 µl GCF was collected extrasulcularly from isolated test site . Collectet al.[The β-Glucuronidase level in GCF was estimated by using the reagent kit supplied by Sigma Diagnostics  and specet al.Between the study groups, a significant increase in PI, GI, PD, RBS and β-Glucuronidase level was observed . On compPeriodontal disease process is site specific and has multifactorial origin where periodontal pathogens, host response, genetic, systemic and behavioral risk factors interplay to develop the disease process. Hence, various measures have been taken to include microbial, immunologic, systemic, genetic and behavioral factors, in addition to traditional clinical and radiographic parameters, for assessing patient's periodontal status.The activity of β-Glucuronidase is associated with severity of inflammation and also with the presence of putative pathogenic flora. This enzyme has been detected in GCF of patients with active site of periodontal disease, thus making β-Glucuronidase as an important biochemical marker for disease activity and for predicting future attachment loss.Diabetes mellitus encompasses a heterogenous group of disorders with common characteristics of altered glucose tolerance and impaired lipid and carbohydrate metabolism. Diabetes develops from either deficiency in insulin production or an impaired utilization of insulin.Diabetes is linked to severe periodontal destruction. Uncontrolled diabetic frequently show a combination of inflammatory and degenerative changes ranging from a mild gingivitis to advanced chronic periodontitis with a widened periodontal ligament, exudation from periodontal pockets, and/or multiple lateral periodontal abscesses. Although it may be more severe in nature, the periodontal disease of the diabetic seems to be clinically similar to that found in non-diabetic individuals. This suggests that the diabetic state serves as a predisposing factor which can accelerate periodontal destruction originated by microbial agents.In the present study, we have attempted to test the hypothesis that ‘diabetics with chronic periodontitis have higher levels of disease activity markers in GCF as compared to non-diabetics with chronic periodontitis’. The probing pocket depth in chronic periodontitis patients with or without diabetes was standardized, so that these parameters did not have any bearing on the level of activity of GCF β-glucuronidase, thus allowing comparisons to be made between β-glucuronidase activity of diabetic and non-diabetic patients. Also, this study was aimed to determine β-glucuronidase activity in host tissues and not from the bacterial origin hence acidic pH was used to detect activity of enzyme.et al.[In this study, plaque index, gingival index and probing pocket depth values were significantly lower in Group I, as compared to Group II and Group III patients. Though there was statistically non-significant difference in plaque index and gingival index in between Group II and Group III patients, the average probing pocket depth was significantly higher in Group III as compared to Group II. These findings are consistent with that of Oliver and Tervonen and Lamset al.The relationship between oral hygiene to periodontal disease has long been well established in the dental literature. In this study, with respect to oral hygiene (Plaque Index) and gingival status , the values in diabetic and non-diabetic patients with chronic periodontitis (Group III and II) were statistically not significant. However, when compared with Group I patients, these values were significantly higher.et al.[In Group I , low levels of β-glucuronidase activity could be demonstrated, similar to the findings of Lamster et al. In theirP < 0.001), as compared to healthy individuals, showing highly significant correlation between GCF β-glucuronidase level and probing pocket depth. These results are consistent with the findings of Bang et al.[et al.[This study demonstrates that there is an increase in GCF β-glucuronidase level in Group II patients i.e. non diabetic with chronic periodontitis . This finding is in accordance with study by Bacic et al.,[The present study also demonstrates that there is higher level of GCF β-glucuronidase activity in patients of diabetes with chronic periodontitis as compared to non-diabetic with chronic periodontitis (t=2.09, c et al., who showc et al., demonstret al,[et al,[Shlossman et al, stated tl,[et al, claimed et al,[et al,[It is also observed that there was a significant positive correlation between GCF β-Glucuronidase and RBS levels, in diabetics with chronic periodontitis. This observation is comparable to the findings of Oliver et al, who demol,[et al, did not Another important observation made in the present study was that even with difference in clinical parameters between study groups, periodontitis patients irrespective of their diabetic status, showed an increased periodontal destruction with elevated β-Glucurondiase level than control. This suggests that β-Glucuronidase level can be used as a biochemical marker for chairside diagnostic kit, which can diagnose early phases of disease with reasonable confidence.Following conclusions were drawn from the present study:Periodontitis patients irrespective of their diabetic status, showed increased periodontal destruction with elevated levels of β-Glucuronidase, than in the control group.Diabetic patients had highest level of β-Glucuronidase level and increased severity of periodontal destruction. This confirms the fact that diabetes is a risk factor for periodontal disease.The presence of β-Glucuronidase level in GCF can be used as a biochemical marker for diagnosing the chronic periodontitis cases.


Sir,et al based upon our recent report  as the fourth-line therapy. After 8 weeks, a 24% reduction in tumour size per RECIST criteria was observed. The pre-treatment (A) and post-treatment (B) computed tomography images are shown in accompanying figure. The subsequent treatment course was complicated by cholangitis and radiographic progression occurred after 20 weeks.In the commentary by Santini et al that further prospective studies are needed to determine the role of anti-EGFR therapy in SBA. In an attempt to build upon our previous work with the combination of capecitabine and oxaliplatin, CAPOX (We agree with Santini


In striated muscle, the actin cytoskeleton is differentiated into myofibrils. Actin and myosin filaments are organized in sarcomeres and specialized for producing contractile forces. Regular arrangement of actin filaments with uniform length and polarity is critical for the contractile function. However, the mechanisms of assembly and maintenance of sarcomeric actin filaments in striated muscle are not completely understood. Live imaging of actin in striated muscle has revealed that actin subunits within sarcomeric actin filaments are dynamically exchanged without altering overall sarcomeric structures. A number of regulators for actin dynamics have been identified, and malfunction of these regulators often result in disorganization of myofibril structures or muscle diseases. Therefore, proper regulation of actin dynamics in striated muscle is critical for assembly and maintenance of functional myofibrils. Recent studies have suggested that both enhancers of actin dynamics and stabilizers of actin filaments are important for sarcomeric actin organization. Further investigation of the regulatory mechanism of actin dynamics in striated muscle should be a key to understanding how myofibrils develop and operate. © 2010 Wiley-Liss, Inc. Actin is one of the major cytoskeletal proteins in eukaryotic cells and plays essential roles in a number of cellular processes including cell migration, cytokinesis, vesicle transport, and contractile force generation . However, the function of CAS-1 is currently unknown.Proteins that bind to G-actin influence actin dynamics by altering polymerization/depolymerization kinetics and exchange rates of actin-bound ATP or ADP [Paavilainen et al., C. elegans striated muscle, tropomyosin functions antagonistically to ADF/cofilin and AIP1 to stabilize sarcomeric actin organization [Ono and Ono, TPM1 cause hypertrophic and dilated cardiomyopathies [Thierfelder et al., TPM2 cause nemaline myopathy [Donner et al., TPM3 cause nemaline myopathy [Laing et al., TPM3 causes nemaline myopathy and reduces affinity of tropomyosin with tropomodulin, a pointed-end capping protein, thereby potentially influencing the actin dynamics at the pointed ends [Akkari et al., Proteins that bind to the side of actin filaments are integral components of sarcomeric thin filaments and commonly stabilize actin filaments. Tropomyosin is perhaps the best characterized side-binding protein that regulates muscle contraction as well as actin filament stability [Gunning et al., NEB) cause nemaline myopathy [Pelin et al., Nebulin is a large protein (600–800 kDa) that has been proposed to be a ruler that determines lengths of sarcomeric thin filaments [McElhinny et al., MYOT) cause myotilinopathy that includes three known types of skeletal muscle diseases: limb girdle muscular dystrophy type 1A, myofibrillar myopathy, and spheroid body myopathy. Myotilinopathy patients commonly exhibit progressive disorganization of sarcomeres with disarrayed Z-bands [Olive et al., Several actin-binding proteins with multiple immunoglobulin-like (Ig) repeats are expressed in striated muscle and associated with myofibrillar actin filaments. The palladin/myopalladin/myotilin family of Ig-repeat proteins localize to the Z-band and play important roles in sarcomeric organization [Otey et al., Drosophila and C. elegans. Kettin is associated with actin filaments during early myofibrillogenesis in Drosophila muscle [Ayme-Southgate et al., sallimus (sls) gene that also encodes zormin and connectin/titin by complex alternative splicing [Machado and Andrew, sls mutant phenotypes is complicated due to defects in multiple sarcomeric proteins. By contrast, C. elegans kettin is encoded by ketn-1 that is a separate gene from other connectin/titin-related genes in C. elegans [Ono et al., C. elegans kettin by RNAi causes disorganization of sarcomeric actin filaments when muscle is subjected to chemically induced hypercontraction, suggesting that kettin is important for stability of sarcomeric actin during contraction. C. elegans kettin cooperates functionally with α-actinin and ALP-enigma [Ono et al., Kettin is a large protein of 500–700 kDa with 30-35 Ig-repeats that is specifically present in invertebrate striated muscle. Kettin directly binds to actin filaments and localizes to the I-band and Z-band [Lakey et al., Xin is a muscle-specific protein in vertebrates that stabilizes actin filaments. Xin contains 15–28 repeats of 16-amino-acid sequence, called Xin repeats. Xin repeats directly bind to actin filaments in vitro and stabilize actin filaments in stress fibers when Xin repeats are expressed in cultured smooth muscle cells [Pacholsky et al., C. elegans cause disorganization of sarcomeric actin filaments in body wall muscle, but this phenotype is suppressed when muscle contraction is reduced, suggesting that UNC-87 stabilizes actin filaments during actomyosin contraction [Goetinck and Waterston, C. elegans does not have nebulin or Xin, UNC-87 might be a functional homologue of these actin stabilizing proteins in striated muscle.UNC-87 is a calponin-like protein that stabilizes actin filaments and is found only in nematode muscle [Goetinck and Waterston, Both pointed and barbed ends of sarcomeric actin filaments are capped by capping proteins. However, as described above, sarcomeric actin filaments are capable of exchanging actin monomers at both ends, indicating that the filaments have dynamic caps rather than permanent caps. The barbed ends of sarcomeric actin filaments are capped by CapZ  and aligned in register at the Z-band [Casella et al., Drosophila [Bai et al., C. elegans [Stevenson et al., Tmod1 null cardiac myocytes develop fewer and thinner myofibrils than wild-type cells but with sarcomeric organization of uniformly aligned actin filaments [Ono et al., The pointed ends of sarcomeric actin filaments are capped by tropomodulin (Tmod) [Fowler et al., TPM3 causes nemaline myopathy and reduces the affinity of tropomyosin for Tmod [Akkari et al., C. elegans muscle, TMD-1 (C. elegans Tmod) appears to cooperate with ADF/cofilin and AIP1 in sarcomeric organization of actin filaments [Yamashiro et al., Drosophila sarcomere length short (SALS) functions to enhance elongation of thin filaments by antagonizing the activity of Tmod [Bai et al., Drosophila striated muscle, knockdown of SALS shortens the length of thin filaments, while overexpression of SALS elongates thin filaments from their pointed ends. The sals gene encodes two SALS isoforms that have one or two WASP homology 2 (WH2) domains. However, in vitro, a SALS fragment containing two WH2 domains binds to the actin pointed ends and inhibits elongation rather than promoting elongation as expected from the in vivo observations. Therefore, the precise mechanism of SALS-mediated thin filament elongation remains unclear. An ortholog of SALS appears to be absent in vertebrates and nematodes, and it remains to be determined whether a functional homolog of SALS exists in other organisms.Tmod cooperates with other actin-regulatory proteins and regulates length or stability of thin filaments. Tropomyosin binds to Tmod and enhances its capping activity [Fischer and Fowler, Drosophila SALS.Leiomodin (Lmod) is a Tmod-related protein with a unique C-terminal extension containing a poly-proline sequence and a WH2 domain [Conley et al., C. elegans, FHOD-1 is the only formin of the FHOD subfamily, and it is predominantly expressed in several types of muscle cells. FHOD-1-null mutant worms exhibit some thinner striated muscle cells than wild-type worms but show no major abnormalities in sarcomeric actin organization [Pruyne et al., As mentioned above, an actin nucleator for initial assembly of thin filaments in muscle cells has not been identified. The Arp2/3 complex nucleates branched actin networks [Goley and Welch, Drosophila embryonic muscle, nonmuscle myosin II (zipper) is required for formation of striated sarcomeres [Bloor and Kiehart, Myosin II is the force-generating enzyme in sarcomeres. It is also an important regulator of myofibril assembly. Pharmacological perturbation of myosin motor activity disrupts organized assembly of sarcomeric actin filaments [Soeno et al., Studies in live muscle cells have demonstrated that actin in sarcomeres is dynamic during assembly and even in mature myofibrils. A number of regulators of sarcomeric actin dynamics have been identified, and functional studies have revealed their important roles in myofibril assembly, sarcomere organization, and maintenance of myofibrils . Regulat


Sir,et al. on the usage of silicone gel for the treatment of hypertrophic scars.[et al. mentioned that “The results of the self-drying silicone gel have been satisfactory.[et al. reported that “silicone gel is able to reduce the formation of keloid and hypertrophic scars and the signs/symptoms associated with the healing process (paraesthesia, pulling sensation, alterations in colour.[et al. recently performed a comparative study among silicone gel, silicone gel sheeting and topical onion extract, including heparin and allantoin, for the treatment of postburn hypertrophic scars and concluded that “Silicone products, either in gel or sheet, are superior to Contractubex in the treatment of the hypertrophic scar.[et al. also mentioned that “The therapist should select the most appropriate agent according to the patient’s need and guidelines of these signs.[I read with great interest the report by Puri ic scars. Puri et sfactory.” Indeed,n colour.” Howeverhic scar.” Karagozse signs.” Further


A century after Robert Koch linkedindividual cultured microbes to specific diseases (Koch's postulates), it hasbecome increasingly apparent that the complex community of microorganisms associated with the human body plays a key role in health and disease. The NationalInstitutes of Health recently announced the Human Microbiome Project as part ofthe NIH Roadmap for medical research, with a primary goal of advancing ourunderstanding of the relationships among host-associated microbial communities,health, and disease. Many physicians and researchers, however, have onlypassing familiarity with the concepts involved in the study and therapeuticmanipulation of complex microbial communities.This special issue was conceived toaccomplish several goals. We wanted to provide readily accessible overviews ofthe concepts and methods used in the study of complex microbial communities,and demonstrate how changes in indigenous microbial communities can play a rolein diseases such as antibiotic-associated diarrhea and bacterial vaginosis. Wealso set out to find examples of how probiotics can be used for the therapeuticmanipulation of the indigenous microbiota.Clostridium difficile infection through the lens of microbial ecology,” by S. Walk and V. Young, discusses the role of thegut microbiota in antibiotic-associated diarrhea and Clostridium difficile infection while Y. Sanz et al., in the seventh article “Insightsinto the roles of gut microbes in obesity,” review the evidence for therole of gut microbes in obesity. In the eighth article “The human vaginal bacterial biota and bacterialvaginosis,” by S. Srinivasan and D. Fredericks review the human vaginalbacterial microbiota and theninth article “Temporal shifts in microbial communities in non-pregnantafrican-american women with and without bacterial vaginosis,” by J. Wertzet al., examines this microbial community in the setting of bacterialvaginosis. The tenth article “Vaginal microbiota and the use of probiotics,” by S. Cribby et al. discusses the use of probiotics toalter the vaginal microbiota. Finally, the eleventh article “Probiotics and gastrointestinalinfections,” by R. Britton and J. Versalovic, and the twelveth article“Probiotic bacteria influence the composition and function of the intestinal microbiota,” byP. O’Toole and J. Cooney, summarize the potential role of probiotics toinfluence gastrointestinal health.We were fortunate to receive a strong collection of reviewarticles and primary research manuscripts to meet the goals of this specialissue. In the firstarticle “Conceptualizing the human microbiota: from multicelled organ toecological community,” B. Foxman et al. present a novelconceptualization of the human microbiome that blends perspectives of epidemiologists,classical ecologists and infectious diseases physicians. The second article “Application ofecological network theory to the human microbiome,” by J. Foster et al.,outlines how ecological network theory can be applied to studies of the humanmicrobiome, while the third article “Interactions of the intestinal epithelium with the pathogen andthe indigenous microbiota: a three way crosstalk,” by C. V. Srikanth and B. McCormick, review the interactions between epithelial pathogens and theindigenous microbiota in the mammalian gut. In the fourth article “Application of sequence-dependentelectrophoresis fingerprinting in exploring biodiversity and populationdynamics of human intestinal microbiota: what can be revealed?” G. Huyset al. review the use of sequence-dependent fingerprinting methods for studyingthe structure and dynamics of complex microbial systems using the humanintestinal microbiota as an example. The fifth article “Ecological characterization of thecolonic microbiota of normal and diarrheic dogs,” by J. Bell, employssuch a fingerprinting method to study the canine colonic microbiota. The sixth article “Emerginginsights into antibiotic-associated diarrhea and


Helicobacter pylori (HP)-independent growing tumors. However a few cases of regression of high-grade gastric lymphomas after the cure of Helicobacter pylori infection had been described.Treatment of primary gastric diffuse large B-cell lymphoma is still controversial. The treatment of localized disease was based on surgery alone, or followed by chemotherapy and/or radiotherapy. High-grade gastric lymphomas are generally believed to be We report here a case with primary diffuse large B-cell lymphoma that showed a complete pathologic remission after HP eradication and we reviewed the literature. A computerized literature reach through Medline, Cancerlit and Embase were performed, applying the words: high grade gastric lymphoma, or diffuse large B cell, MALT gastric lymphoma, DLBCLL (MALT) lymphoma and Helicobacter. Articles and abstracts were also identified by back-referencing from original and relevant papers. Selected for the present review were papers published in English before January 2007.Helicobacter pylori as first line therapy in high grade gastric lymphoma: 22 of a total of 38 enrolled patients obtained complete remission. Depth of gastric wall infiltration and clinical stage were important factors to predict the response to antibiotic therapy. Our case and the review of the literature show that high-grade transformation is not necessarily associated with the loss HP dependence. In early stage, for high-grade B-cell HP-positive gastric lymphomas, given the limited toxicity of anti-HP therapy, this treatment may be considered as one of the first line treatment options.Forty two cases of primary high grade gastric lymphoma that regressed with anti HP treatment were found. There were anedoctal cases reported and patients belonging to prospective studies; four trials studied the effect of eradication of  Helicobacter pylori (HP) infection plays an important role in the development and growth of gastric mucosa-associated lymphoid tissue (MALT) lymphomas [ymphomas ,2. Eradiymphomas .in vitro study by Hussell et al [It has been demonstrated by laboratory and clinical studies that primary gastric large B cell MALT lymphomas are transformed, antigen independent, autonomously growing tumors that are unlikely to respond to eradication therapy of the HP infection. An ll et al  showed tll et al ,6.et al [However anedoctal cases of primary gastric large B-cell lymphoma that responded to antibiotic therapy had been described and, more recently, Chen et al  reportedWe report here a patient with diffuse large B cell lymphoma of the stomach, that achieved a complete pathologic remission after anti HP therapy and a detailed review of literature is also presented.In May 2003, a 43-year-old man was admitted for epigastric pain of two months duration and weight loss (more than 10% of the body weight). Clinical examination was unremarkable and laboratory data were within normal values; only a mild hypochromic anemia was disclosed (Hb 12.4 g/dl).Helicobacter pylori was identified in the mucosa. The previously reported diagnostic criteria for gastric diffuse large B-cell lymphoma were used [A gastroscopy was performed and revealed an ulcerative lesion in the gastric antrum ranging 3 cm in diameter. Biopsies established the diagnosis of diffuse large B cell lymphoma (DLBCL) of the stomach and ere used ,8  showed a hemicircumferencial thickness of the anterior gastric wall, which was infiltrated until to the serosa. Staging was completed with neck, chest and abdominal computed tomography and with bone marrow biopsy. There were not other lymphoma-deposits outside the stomach, and a clinical stage E IThe patient refused chemotherapy and a surgical treatment was then planned. Waiting this treatment, the patient underwent an HP eradication therapy. He received a triple therapy with omeprazole (20 mg twice a day), amoxicillin (1 g twice a day) and clarithromycin (500 mg twice a day) for seven days, and after that omeprazole (20 mg every day) for other 21 days.Prior to surgery, the patient underwent repeat gastroscopy (a month later) that showed a clear improvement of the ulcerative lesion of the gastric antrum and biopsies showed a complete disappearance of the lymphoma Figure .The patient was informed of the good results from anti HP therapy but he preferred to undergo to subtotal gastric resection. The histological examination revealed complete remission of the lymphoma and absence of Helicobacter pylori. He did not receive additional treatment and is in continuous complete remission after 42 months.We selected all cases reported with primary gastric large B-cell lymphoma treated with anti HP treatment and all cases of primary gastric large B-cell lymphoma treated in prospective studies with anti HP-therapy. According to the WHO classification, low grade MALT lymphoma with focal high grade component constituted by "solid or sheet-like proliferations of transformed cells" were included as diffuse large B-cell lymphoma .Tumors were staged clinically according to the modified by Musshoff  and  Schmidt-Vollmer, Ann Arbor Classification  for extrHelicobacter pylori as first line therapy in gastric high grade gastric lymphoma: 22 of a total of 38 (57.9%) enrolled patients obtained complete remission. Data of the 42 responsive patients are reported in Table A total of 61 patients, including the present case, with primary gastric large B-cell lymphoma were treated with anti HP treatment ,10-25 anHelicobacter pylori in one patient) with remaining nodal disease. In one patient, large B cells disappeared, but areas of MALT lymphoma and nodal disease persisted. The patient with Burkitt-like lymphoma, obtained a complete remission.Different schedules of eradication treatment were used and were based on a proton pump inhibitor  together with a combination of antibiotics . Forty-two of 61 patients obtained a complete remission of the lymphoma. In two patients there was gastric complete remission  in the majority of patients; only in one patient, there was a progression of disease after an initial partial response .Four patients including present case underwent subtotal or total gastrectomy, after endoscopic confirmation that Helicobacter pylori infection was cured and lymphoma regressed ,22.Other patients in complete remission didn't undergo further treatment, except one patient with AIDS who relapsed after 6 months and needed chemotherapy. This is the only one relapse described. Two patients, in partial remission after eradication treatment, gained complete regression of lymphoma after chemotherapy ,22. Becaet al., [The median period of follow-up was 22 months. The longer period of follow-up was reported in the series of Chen et al., : all theInformation about genetics of large B cells didn't express bcl-6 and p53; in the patient with Burkitt-like lymphoma, malignant cells expressed bcl-6 and p53; in the with Burkitt-like lymphoma, malignant cells expressed bcl-6 and not bcl-2; in two patients there were not alterations of p53 and k-ras genes and microsatellite instability .et al., [et al., [et al., [et al., [In 20 patients, tumor response was unexpected, but in 22 cases it was obtained in prospective trials. Chen et al.,  reported[et al.,  5 cases,[et al.,  2 cases In the present case, eradication of HP infection obtained with a short course of antibiotic therapy resulted in a complete pathologic remission of a diffuse large B cell lymphoma of the stomach. This complete regression of the disease was confirmed not only by gastroscopy and biopsies but also by gastrectomy.Helicobacter pylori stimulation. This assertion was supported by in vitro and in vivo results.This finding confirms one more time that large B cell HP-positive gastric lymphomas are not necessarily associated with loss of HP dependence. Until few years ago, large B cell gastric lymphoma was considered independent of et al., [in vitro in response to Helicobacter pylori, as MALT lymphoma cells did.A study by Hussell et al.,  showed tIn vivo confirmation came from the fact that a number of cases of antibiotic-resistant MALT lymphoma contained large B cells in deep layers of the stomach and these cells were thought responsible for absent response of these tumors [et al., [Helicobacter pylori eradication could play a part in optimum treatment of an accompanying low grade component.e tumors ,6. Boot [et al.,  concludeet al., [et al., [Helicobacter pylori associated chronic active gastritis; she refused chemotherapy and received only eradication treatment with an unexpected tumor remission. These two cases were the first published cases of regression of large B cell lymphoma after eradication therapy. Afterwards analogous surprising situations were reported.In 1997, Rudolph et al.,  describe[et al.,  reportedet al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [Morgner et al., , collect[et al., , in 50% [et al.,  and in 5[et al., . Alpen e[et al.,  started [et al.,  and Hiya[et al.,  are a we[et al., . Alpen e[et al.,  in theiret al., [et al., [et al., [These authors paid attention to different prognostic factors. Hiyama et al.,  focused [et al., ; for Nak[et al., , 93% of In this review of the literature, age, sex, location of tumor and the presence or absence of areas of MALT lymphoma don't seem to influence the response of anti Helicobacter therapy. Clinical stage and depth of tumor invasion are the most important predictive factors of complete remission . HoweverHelicobacter pylori infection, to MALT lymphoma and large B cell lymphoma. There is consistent evidence for the clonal link between the small cell tumor and the large cell tumor [de novo [de novo. The absence of the low grade component could be due to sampling bias or to overgrowth by large cells [Helicobacter pylori eradication have a common genetic pattern and if cases without areas of MALT lymphoma are transformed lymphomas or de novo lymphomas.Very little is reported about genetics of these tumors ,29. Accoll tumor . This evll tumor . t disease was based on surgery alone, or followed by chemotherapy and/or radiotherapy, however recent studies showed that clinical outcome of localized gastric lymphoma treated by systemic chemotherapy alone was similar to that treated by surgery followed by chemotherapy in terms of tumor response, disease-free survival and overall survival suggesting that surgery be reserved for those with residual lymphoma after chemotherapy -38.According to this review, among patients with complete remission obtained after eradication therapy, only one patient, who was affected by HIV infection, relapsed. These data suggest that after a complete remission, no other treatment including gastrectomy might be necessary, even if full thickness of gastric wall is infiltrated at presentation.Helicobacter pylori eradication, but a late response of up to 45 months has been described [et al., [et al., [In most cases of gastric MALT lymphoma remission is achieved within 12 months after escribed . Among tescribed ,10,22. A[et al.,  extendedIn all cases that responded to eradication therapy, initial or complete regression of lymphoma was evident at the first endoscopic and histologic examination. Only in one case, there was a disease progression, after an initial response, at the second examination .Our case reported here and the review of the literature allow us to conclude that:1. Complete remission was obtained after HP eradication treatment in 42 of 61 patients with primary gastric HP related DLBCL.2. There is no marker that can predict if the tumor will regress after antimicrobial therapy. However, depth of gastric wall infiltration and clinical stage can strongly predict the probability of a complete remission, it must be emphasized that complete remission was reached in anecdotal cases independently of these factors after anti HP eradication.Helicobacter pylori infection a complete staging with endoscopic ultrasonography, computed tomographic imaging and bone marrow biopsy should be carried out and the patients should first be treated by anti HP treatment. An endoscopic revaluation 4–6 weeks after the eradication treatment should be performed. These evolutions of lymphoma can happen:From a practical point of view we suggest that all patients with primary gastric DLBCL associated with - No response or progression: patient must undergo to surgery or other conventional treatment.- Partial remission: lymphoma is probably responsive and could obtain a complete remission; patient must be strictly monitored to detect signs of progression or a complete remission.- Complete remission: patient must be strictly monitored but may not require further treatments.The author(s) declare that they have no competing interests.LC diagnosed and treated the patient, revised and finally approved the manuscript for been published, RP performed bibliographic research and participated in manuscript revision process, PS performed bibliographic research and participated in manuscript revision process, AZ and CP performed pathological diagnosis and histological pictures. All authors read and approved the final manuscript.


Recent advances in understanding the characteristics of renal cell carcinoma (RCC) have brought to our attention many prognostic markers that affect and predict the survival outcome of patients with the disease. For the moment, however, patients with RCC have not received any benefit from such markers. If a patient is diagnosed as “high risk” by using such prognostic markers, there is no promising systemic therapy available. In this review we mainly focus on biomarkers of RCC that can be applied for therapeutic use reported in recent publications. Several issues and limitations in the reported studies are also highlighted and discussed. Developing biomarkers from the viewpoint of therapeutic application will lead to improvement of the prognosis of RCC patients. Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. It accounts for 3% of all adult malignancies and for approximately 95,000 deaths per year worldwide. More tha2Somatic and epigenetic mutations of the von Hippel-Lindau (VHL) disease tumor suppressor gene are observed in 42-57% and 5-19% of sporadic clear cell RCCs, respectively. Under hyet al.,[et al.,[Lidgren et al., demonstret al., Therefor,[et al., who demoet al.,[et al., showed that CAIX expression was a significant predictor in univariate and multivariate analyses and proposed accurate systems for predicting survival for patients with localized or metastatic RCC.[et al.,[et al.,[Carbonic anhydrase IX is one of the most validated prognostic biomarkers of RCC. Bui et al., performeatic RCC.13 They c.[et al., reported,[et al., detected,[et al., Carbonicet al.,[et al.,[et al.,[+ target cells and production of IFN-γ on stimulation with such cells in all patients. However, liver enzyme disturbances reached National Cancer Institute Common Toxicity Criteria Grades 2 to 4 in all three patients. They performed liver biopsy, which suggested that the liver toxicity was caused by a specific attack of the scFv(G250)+ T-cells against CAIX+ bile duct epithelial cells. Therefore, CAIX may not be an appropriate target for specific therapy.Recently CAIX-targeted therapies were reported in several studies. Uemura et al., discusse,[et al., investig,[et al., transducUpregulation of VEGF, the most potent growth factor for tumor vasculature, is significantly associated with upregulation of HIF-α. Renal cec in the cytoplasm.[c, released by tBID (truncated BH3-interacting-domain death agonist) from the mitochondria, binds and activates apoptotic protease activating factor-1 (Apaf-1). It forms a multiprotein caspase-activating complex (apoptosome) and leads to activation of caspase-9, undergoing autoactivation to promote recruitment and cleavage of caspase 3. Caspase 3 cleaves its target substrates to affect the changes associated with apoptosis.[Apoptosis is essential to sculpt the developing organism by removing outdated or unneeded structures and also central to the homeostasis of adult tissues by maintaining the balance between cell production and cell elimination. Since caytoplasm. Cytochropoptosis.c release by inhibiting the terminal effector caspase-3 and caspase-7 and interfering with caspase-9 activity and processing. It has also been reported to affect cell division, cell cycle progression, signal transduction pathways and protein degradation.[Inhibitor of apoptosis protein can inhibit apoptosis by binding to prevent a common step downstream of mitochondrial cytochrome radation. Eight huin vitro.[et al.,[et al.,[Although the expression of c-IAP1 and c-IAP2 is not tumor-specific, their overexpression can suppress chemotherapy-induced apoptosis in vitro. Kempkens.[et al., performe,[et al., reportedet al.,[et al.,[Survivin is overexpressed in various human malignancies and its expression is associated with features of biologically aggressive disease, resistance to therapy and poor clinical outcome in patients with various malignancies. Parker et al., demonstr,[et al., evaluate,[et al., However,et al.,[Smac (second mitochondria-derived activator of caspase)/DIABLO (direct inhibitor of apoptosis-binding protein with low PI) is a proapoptotic protein that in healthy cells resides in the intermembrane space in the mitochondria, but is released into the cytosol during apoptosis, where it interacts with IAPs and disrupts their ability to bind caspases . The balet al., evaluateIt is well known that RCC frequently harbors numerous tumor-infiltrating lymphocytes (TILs), suggesting that a host antitumoral immune response is stimulated by the malignant transformation of cells. However, there is a paradoxical relation between increased levels of TILs and diminished cancer-specific survival. Tumor-inet al.,[+ cells. Moreover, significantly fewer NK cells in peripheral blood, a lower proportion of CCR5/CXCR3/CD4+ cells and a higher proportion of CCR4/CD4+ cells were observed in patients with metastatic RCC in the study. These results indicate a change in helper T responses during the progression of RCCs. Donskov and von der Maase[+ cells  were significant prognostic factors of poor survival both in univariate and multivariate analyses, whereas intratumoral macrophages, CD4+, CD8+, CD20+ and CD56+ cells were not significant ones. However, it is not yet clear why “low” CD57+ NK cells can be a prognostic factor for IL-2-based immunotherapy. Furthermore, there seems to be a discrepancy between the results of the two studies. Thus, the question remains: “Is infiltration of NK cells into tumors a positive prognostic factor or a negative one?”Cózar et al., evaluateder Maase analyzedNatural killer cells mainly kill tumor cells that have reduced major histocompatibility complex (MHC) Class I expression and can escape killing by cytotoxic T lymphocytes (CTLs). If the tumor cells have acquired escape mechanisms from CTLs, NK cell-infiltration can be a positive finding for suppressing the tumor. Therefore, it is important to evaluate the expression of MHC Class I molecules on RCC cells. We recently demonstrated that MHC Class I was down-regulated in 38% of conventional RCCs and the down-regulation was an independent prognostic factor. Unfortun+ T cells that coexpress CD25, the IL-2 receptor α-chain. In search of more specific markers for Treg, the transcription factor forkhead box P3 (FOXP3) has been identified. Forkhead box P3 is not only a key intracellular marker but also a crucial developmental and functional factor for Tregs. Siddiqui et al.,[+ CD25+ FOXP3− (but not CD4+ CD25+ FOXP3+) T cells was significantly associated with higher TNM stage, larger tumor size, the presence of coagulative tumor necrosis and poorer cancer-specific survival. Interestingly, they also showed that CD4+ CD25+ FOXP3− TILs expressed more IL-10 (cytokine synthesis inhibitory factor) than CD4+ CD25+ FOXP3+ cells, suggesting that FOXP3− Tregs have a powerful inhibitory function. Moreover, Dannuli et al.,[389 IL-2, acting like a CD25-specific antibody, reduced the number of Tregs present in the peripheral blood of metastatic RCC patients without severe side-effects and abrogated Treg-mediated immunosuppressive activity in vivo. They also demonstrated that the antitumor effects of DAB389 IL-2 followed by vaccination with RNA-transfected DCs significantly improved the tumor-specific T cell responses. Thus, depletion of Tregs is one of the strategies to suppress the progression of RCCs.Another topic of TIL is the regulatory T cell (Treg) that regulates the activation of other T cells and may be necessary to maintain peripheral tolerance to self antigens. One mechanism by which cancers evade immune destruction is by recruiting regulatory cells into the tumor microenvironment. Treg is i et al., demonstri et al., demonstret al.,[et al.,[The B7 family of molecules on antigen-presenting cells (APCs) is one of the best-defined costimulators for T cells. These molecules bind to the CD28 molecule on T cells and provide signals required for the activation of naive T cells. B7-H1, a member of the B7 family, can be induced on T lymphocytes, but aberrant expression on tumor cells has been described in various human malignancies. The expression of B7-H1 on tumor cells is considered to enhance apoptosis of activated tumor-specific T cells. Thompson et al., demonstret al., Furtherm,[et al., indicateet al.,[Here we will introduce two papers with high impacts on biomarker studies. Jiang et al., assessedet al.,[During the past decade, a large number of markers have been studied for their prognostic value in RCC. For example, molecular tumor proliferation markers, including Ki-67 (MIB-1), proliferation cell nuclear antigen (PCNA), topoisomerases and p100, have been investigated in many studies, but their value as prognostic markers is still controversial. Furthermore, urologists cannot apply most such results to improve the survival of RCC patients. Therefore, it is important to identify novel RCC-specific antigens. Recently, bioinformatical approaches have been used to search for such antigens. Yao et al., examinedDuring the past decade, a large number of proteins that are putatively important in carcinogenesis and cancer biology have been studied for their prognostic value in RCC, but their clinical use remains controversial. Recently, however, novel biomarkers have been identified by various methods and some of them have been verified as clinical predictors of prognosis of RCC patients . It is i


Dear Editor,et al.,[I read the article by Dhingra et al., which deAutofluorescence in Inflammatory CNVMMany reports showed the utility of AF as a marker for early disease and in predicting the outcome of treatment in CNVM due to age-related macular degeneration. There are very few reports on AF findings in inflammatory CNVM.Inflammatory CNVM, which is usually of the classic type (type 2), is seen on AF photography as a precise hyper-autofluorescent area due to the hyperplastic retinal pigment epithelium (RPE). Following treatment, CNVM may contract and leave a zone of absent RPE causing a hypo-autofluorescence.Secondary choroidal neovascularization in multifocal choroiditis and panuveitis (MCP) is readily visible as a hyper-autofluorescencent area originating from a hypo-autofluorescent spot (scar). With increasing follow-up time, the hyper-autofluorescence associated with CNV decreases. AF imaging provides a method to image the appearance of new or enlarging spots that appear, which is more sensitive than using ophthalmoscopically visible signs.More studies are required to understand the role of AF in inflammatory diseases. AF imaging could be an important noninvasive tool to reduce the need for angiography and to help in early diagnosis, as also in the follow-up of inflammatory CNVM patients.Use of Anti Vegf0 in Inflammatory CNVMThere are potential disadvantages of treating inflammatory CNV with photodynamic therapy (PDT). PDT can cause localized inflammation and increase VEGF production. Local release of VEGF, after PDT, may be associated with a higher incidence of recurrent choroidal neovascularization (CNV).et al, studied 10 patients with CNV, who were refractory to previous immunosuppression and PDT or intravitreal triamcinolone (IVTA). They reported that intravitreal bevacizumab improved the best corrected visual acuity (BCVA) and reduced the central macular thickness in the eyes with 2.5 injections (mean), and this was seen at 7.5 months of follow up. In this study they included a patient who recurred three months after pegaptanib injection and responded well.[et al reported successful treatment of inflammatory CNVM with ranibizumab in a patient with multifocal choroiditis and pan uveitis (MCP), who did not responded to bevacizumab or the PDT and IVTA therapy.[Tran ded well. Fine et  therapy.et al reported significant improvement of 2.2 lines in BCVA at 24 months, with a significant decrease in foveal thickness (265 microns), with only 1.3 injections (mean). This study confers the long-term benefits of intravitreal bevacizumab.[The recent and largest case series by Monsour ckness 26 microns,Serious side effects and chances of recurrence make PDT an obsolete treatment option. Recent promising results favor intravitreal bevacizumab as a primary / mono therapy in inflammatory CNVM.


The conference venue included two locations: the Lindy Boggs Conference facility at the University of New Orleans (UNO); and Dinner/Speaker venues in the French Quarter – Broussard's of New Orleans and The House of Blues. The conference featured three days of technical presentations, with the third day partly devoted to a satellite Conference on Nanopore Cheminformatics with an on-site demo presentation of a nanopore detector (from the Research Institute for Children and UNO Nanopore Cheminformatics/Biophysics Labs). The theme of this year's conference was "Computational Frontiers in Biomedicine".The Fourth Annual MidSouth Computational Biology and Bioinformatics Society (MCBIOS-IV) conference was held in New Orleans, Louisiana on February 1st place went to 1st: Mutlu Mete of UALR, 2nd place to William Sanders of MSU and 3rd place to Stephanie Byrum of the UALR. In Poster Session II, 1st place went to Matthew Landry of UNO, 2nd place to Terra Colvin, Jr. of UALR, and 3rd place to Iftekhar Amin of UNO.  1st place for outstanding oral presentation went to Vijayaraj Nagarajan of USM.At MCBIOS 2007, awards for outstanding poster presentations were given to the following students: In Poster Session I, 1This year, 24 out of 31 submitted papers were accepted for inclusion in the proceedings (77%), similar to the number published in last year's Proceedings . Each ofet al [One of the most important challenges of current miRNA research is to decipher the "code" of miRNA regulation – to find the connection between miRNA expression and phenotypic changes. Gusev et al  report tet al study is that there is a large body of microarray data that is becoming available for analysis. As such, methods to begin inferring regulatory networks from this data are important. In another paper, Peng Li et al compare probabilistic Boolean Network (PBNs) and Dynamic Bayesian Network (DBNs) approaches to correctly inferring regulatory networks [One of the things evident from the Gusev networks . They fiet al [Enterococcus bacteria. A complex response was mapped out involving cytoskeletal rearrangement, immune response, modulation of growth and cellular metabolism, and Wnt signaling, as well as responses heretofore unrecognized because they involve poorly annotated genes.While microarray technology is steadily improving, it still suffers from noise; hence experiments are repeated several times to reduce error. To reduce the amount of replication necessary, Dozmorov et al  used F-tet al [Biological analysis spans several different areas from the genome/proteome to the metabolome, collectively referred to as "omics" for the study of different biological bodies. In one study, Schnackenberg et al  study agS. aureus. Their combination of methods suggests that Msa is membrane-bound with sites for phosphorylation and protein-binding, suggesting it plays a role in signal transduction, which is consistent with its known activity as a modulator of the protein SarA.Nagarajan and Elasri  use bioiet al. [Not all peptide fragments are represented equally in mass spectrometry (MS) experiments. To help predict which peptides might be lost or underrepresented, Sanders et al.  use artiBridges et al  develop DNA-protein binding interactions: (1) TBP – TATA receptor binding, and (2) HIV Integrase – HIV DNA Terminus binding. The method is also effective at detecting DNA-DNA binding interactions that occur with annealing of DNA single-strand overhangs [protein-protein binding interactions for the medically important case of antibody-antigen interactions [Four papers explore a new transduction-based nanopore detector mechanism. The first  introducverhangs  as well ractions .clustering (unsupervised learning) – a marked departure from the standard supervised-learning approach to SVMs. The author's objective was to have a powerful, non-parametric, method for phase tracking on nanopore transduction signals, a key requirement for extracting binding kinetics from channel current signals. They also describe a new form of Hidden Markov Model (HMM) that has the strengths of the much more complex HMM-with-Duration (HMMwD) models, but at a computational cost approximating the simpler HMM [Pattern recognition is a critical part of making sense of the high-throughput data gathered in modern biomedical experiments. Four papers explore the development of machine learning based pattern recognition methods and their application to resolving complex nanopore-transduction detector signals. The first  describepler HMM . The goapler HMM , examinepler HMM , exploreet al [Rather than focus on refinement of methods, several authors report the effectiveness and utility of existing bioinformatics approaches to better understand a biological system. For example, Nan Mei et al  studied et al. [Guo et al.  used micCircadian rhythms are generally associated with the sleep/wake cycle, but also regulate many activities and affect the expression pattern of practically all genes. Time-course microarrays can potentially detect this baseline oscillation, which Ptitsyn and Gimble  use in aIdentification of DNA binding sites for transcription factors (motifs) is important for a complete understanding of co-regulation of gene expression, but has proven to be quite challenging. Das and Dai  review pet al [Loganantharaj et al  have proet al [Eisenia fetida, which is often used in toxicology studies. They describe the sequencing and analysis of 3,144 new ESTs.Pirooznia et al  report tet al [The insertion of new or altered genes into genomes is a key step in many functional analysis studies, and it is important to determine how many copies of each of these transgenes are present. Yuan et al  report tet al [k-median, but which uses statistical spatial depth to identify the "center" of a cluster. A new subcluster selection rule, Relative Average Depth, is also introduced. In data sets that are noisy or have high dimension and low sample size, which is common in gene expression data sets, the bisecting k-spatial median algorithm does well compared to the component-wise bisecting k-median algorithm.Ding et al  propose et al [Cancer diagnosis usually begins with histopathological examinations of tissue biopsies. These evaluations are usually somewhat subjective and the growing number of such images has provides an opportunity to test automated approaches to tissue sample categorization. Mete et al  report ard and 24th, 2008. Our web site, , contains further information on the society and future meetings. MCBIOS is a regional affiliate of the International Society for Computational Biology .The fifth annual MCBIOS Conference will be held in Oklahoma City, Oklahoma in the Cox Convention Center in downtown Oklahoma City on February 23The authors declare that they have no competing interests.All authors served as co-editors for these proceedings, with JDW serving as Senior Editor. All authors helped write this editorial.


In May 1998, three large outbreaks of salmonellosis, affecting 91 persons, were identified in the Republic of Georgia. Eighteen Salmonella Typhimurium strains were characterized by arbitrary primed polymerase chain reaction and pulsed-field gel electrophoresis; the results suggested that all cases were part of a single outbreak caused by a distinct clonal strain.


Molecular Neurodegeneration and Institute for Biomedical Research, Xiamen University co-organized the 2009 International Conference on Molecular Neurodegeneration in Xiamen, China on May 18-20, 2009. The objectives of this meeting were to (1) promote cutting-edge neurodegeneration research in China and in neighboring Asian countries; (2) facilitate the exchange of information relevant to neurodegenerative research; (3) provide education opportunity for students, postdocs and physicians; and (4) provide a platform for investigators at different career levels to interact and network, and to foster collaborations at the international levels. About 100 investigators presented their recent discoveries with a wide range of scopes of neurodegeneration research, including new genes, molecular pathways, animal models, and potential therapeutics.Age-related neurodegenerative diseases are great challenges as the aging population grows. To promote neurodegeneration research and to share recent progress in understanding molecular mechanisms underlying these devastating diseases, the journal  As life expectancy continues to increase and a growing number of people enter the aged population, neurodegenerative diseases have increasingly become a major problem for which treatments are critically needed. Although much progress has been made in the past 20 years on understanding the mechanisms of neurodegenerative diseases and on developing novel therapeutic strategies, most of these achievements are from the United Stated and European countries. Neurodegeneration research in Asian countries, most of which are very populated and also suffered severely with the spread of neurodegenerative diseases, is lagged far behind. The 2009 International Conference on Molecular Neurodegeneration is designed to bridge this gap. The major aim of this meeting is to provide a unique platform for Asian researchers and scientists from Western countries to exchange information and ideas, to share their most recent research advances, and to establish future collaborations in neurodegeneration studies.Molecular Neurodegeneration , an open access, peer-reviewed online journal that publishes all aspects of neurodegeneration research, and Institute for Biomedical Research, Xiamen University , which is dedicated to revealing the fundamental molecular causes of diseases and devising the innovative therapies of tomorrow. Finacial supports of this meeting come from both foundations and pharmaceutical companies including Alzheimer's Association, Ellison Medical Foundation, National Natural Science Foundation of China, Science and Technology Bureau of Xiamen City, Raptor Pharmaceutical, GlaxoSmithKline, Beckman Coulter, Zeiss, Perkin Elmer, Millipore, Applied Biosystems, and Genetimes Techonolgoy, Inc. Drs. Guojun Bu from Washington University School of Medicine and Huaxi Xu from Burnham Institute for Medical Research, Editors-in-Chief of Molecular Neurodegeneration, are co-chairs of this conference.This conference is jointly sponsored by More than 20 world-renowned scientists, including Dr. Aaron Ciechanover, a 2004 Nobel Laureate in Chemistry for his discovery of the ubiquitin system, and Dr. Steven Heinemann, a member of the US National Academy of Sciences, presented their research progress in the meeting. In addition, researchers from Asian countries, including China , Japan, and South Korea, also presented their work in short talk and poster sessions.See figure • Keynote Speaker: Aaron Ciechanover : "The ubiquitin proteolytic system: from basic mechansisms through human diseases and onto drug targeting"Session I: ApoE and apoE receptors in AD• Guojun Bu (Washington University School of Medicine): "ApoE receptors in apoE and Aβ metabolism"• Mary Jo LaDu (University of Illinois at Chicago): "Aβ42 and apoE structure/function interactions: implications for Alzheimer's disease"Session II: APP processing: β- and γ-secretases• Robert Vassar (Northwestern University): "Regulation of BACE1 in Alzheimer's disease"• Takeshi Iwatsubo (University of Tokyo): "Alzheimer's disease: unraveling the structure-function relationship of gamma-secretase"• Gopal Thinakaran (University of Chicago): "Function and dysfunction of presenilins"Session III: Presenilin and amyloid beta• Sam Sisodia (University of Chicago): "Presenilin function in adult neurogenesis"Short Talk Session I• Taisuke Tomita (The University of Tokyo): "Identification and analysis of a substrate-specific genetic modulator for the γ-secretase activity"• Yingying Le : "Activation of β-adrenergic receptor on microglia promotes uptake and clearance of Alzheimer's disease-associated amyloid β peptide"• Wandong Zhang : "ABCG2 is up-regulated in Alzheimer's brain with cerebral amyloid angiopathy and acts as a gatekeeper at the blood-brain barrier for Aβ peptides"Keynote Address- Steve Heinemann : "New approaches to understanding Alzheimer's disease"Session IV: Functions of APP and its processing products• Hui Zheng (Baylor College of Medicine): "APP function in neurons and synapses"• Frederic Checler : "Regulatory functions of APP intracellular domain"Session V: Parkinson and trinucleotide repeat disorders• Jie Shen : "Impaired neurotransmitter release in Alzheimer's and Parkinson's diseases"• Xiaojiang Li (Emory University): "Synaptic toxicity of mutant huntingtin"Short Talk Session II• Hongyu Hu : "Mechanism of α-synulcein aggregation associated with Parkinson's disease"• Hua Gao (Key Laboratory for Neurodegenerative Disease of the Ministry of Education): "DJ-1 decrease rotenone-mediated dopaminergic cell death via ERK signaling"• Cristine Alves da Costa (Institut de Pharmacologie Moleculaire et Cellulaire): "DJ-1-mediated cell death control by p53 is regulated by caspase proteolysis"• Lingqiang Zhu : "Activation of glycogen synthase kinase-3 inhibits long term potentiation with synapse-associated impariments"Session VI: BDNF and novel genes in neurodegeneration• Eric Tzeng (Beckman Coulter): "The latest total solution characterizes neurodisorder diseases"Yunwu Zhang (Xiamen University): "A novel gene that inhibits Alzheimer's β-amyloid generation and tau phosphorylation"Short Talk Session III• Jin Tae Hong : "Mutant presenilin 2 (N141I) increases beta-secretase activity through increase of ERK pathway dependent hydrogen peroxide generation"• Ling Li (University of Alabama at Birmingham):"Simvastatin prevents cognitive and hippocampal synaptic deficits in APP/PS1 double transgenic mice"• Wangxia Wang (University of Kentucky): "MicroRNA miR-107 targets genes related to neurodegenerative disease"• Qingyan Liu : "A novel transmembrane protein down regulated in Alzheimer's brains and interacts with a DnaJ-like heat shock protein (DNAJB4)"• Xiuqi Bao : "Establishment of gonadectomy-accelerated brain aging model in mice"Session VII: Metal, cell cycle and signaling in neurodegeneration• Ashley Bush (University of Melbourne): "The metal theory of Alzheimer's disease: from bench to clinic"• Karl Herrup (Rutgers University): "Cell cycle events as risks for neurodegeneration: a look into mechanism"• Yong Shen : "Tumor necrosis factor and Alzheimer's disease"Session VIII: AD genetics and therapy• George Martin (University of Washington): "Classes of gene action with the potential to modulate the times of onset and the rates of progression of neurodegenerative disorders"• Edward Koo : "Gamma secretase modulators, nonsteroidal anti-inflammatory drugs, and Alzheimer's disease"• Colin Masters : "Aβ oligomers as tractable targets for Alzheimer's disease: diagnostics and therapeutics"The authors declare that they have no competing interests.GB supervised plans for the meeting and made final decisions regarding meeting and planning.YZ helped prepare and set up for the meeting and wrote this article and cover letter.LO helped prepare program and agenda for meeting, cooresponded with all involved and served as administrative contact.


To the Editor: Gupta et al. raise important issues regarding molecular profiling as an epidemiologic tool (Gupta et al. interpret their experience as indicating that, with geographically dispersed isolates, a higher degree of genomic similarity than is reliably provided by single-enzyme PFGE is necessary to improve specificity, thereby avoiding fruitless investigative efforts (


Sir,et al for their interest in our recent study and for their remarks concerning the safety of using involved-field irradiation in treating limited-stage small-cell lung cancer (SCLC). We have updated our analysis of failure patterns in patients with limited-stage SCLC who were treated in our phase II study of involved-field irradiation during the second and third cycles of carboplatin, paclitaxel and etoposide (We thank Dr Chun-Ru Chien Recently, A phase III trial of concurrent chemoradiotherapy without elective nodal irradiation in limited-stage SCLC, where patients will be randomised to either once daily irradiation to a dose of 66 Gy or twice daily irradiation to a dose of 45 Gy will shortly commence . Such a


Sulfur mustard (SM), also known as mustard gas, has been the most widely used chemical weapon. The toxicity of SM as an incapacitating agent is of much greater importance than its ability to cause lethality. Acute toxicity of SM is related to reactive oxygen and nitrogen species, DNA damage, poly(ADP-ribose) polymerase activation and energy depletion within the affected cell. Therefore melatonin shows beneficial effects against acute SM toxicity in a variety of manner. It scavenges most of the oxygen- and nitrogen-based reactants, inhibits inducible nitric oxide synthase, repairs DNA damage and restores cellular energy depletion. The delayed toxicity of SM however, currently has no mechanistic explanation. We propose that epigenetic aberrations may be responsible for delayed detrimental effects of mustard poisoning. Epigenetic refers to the study of changes that influence the phenotype without causing alteration of the genotype. It involves changes in the properties of a cell that are inherited but do not involve a change in DNA sequence. It is now known that in addition to genetic mutations, epimutations can also involve in the pathogenesis of a variety of human diseases. Several actions of melatonin are now delineated by epigenetic actions including modulation of histone acetylation and DNA methylation. Future studies are warranted to clarify whether epigenetic mechanisms are involved in pathogenesis of delayed sulfur mustard toxicity and melatonin alleviates delayed toxicity of this warfare agent. Among the available chemical warfare agents, sulfur mustard (SM), also known as mustard gas, has been a widely used chemical weapon. Because of its devastating toxicity, its use during the World War I earned it the sobriquet “king of the battle gases”. Other compounds such as nitrogen mustard (HN2) were developed during World War II, but found to be unsuitable as a munition. Soon after discovering HN2, it became the first non-hormonal agent used in cancer chemotherapy. A number of HN2 derivatives including cyclophosphamide (CP), ifosfamide, mechlorethamine, melphalan and chlorambucil are valuable cytotoxic and radiomimetic agents for the treatment of cancer    and triggers the expression of selectins and cellular adhesion molecules, via enhancing nuclear factor (NF)-κB and activator protein (AP)-1 activation, thereby promoting pro-inflammatory responses including most importantly tumor necrosis factor (TNF)-α and interleukin (IL)-1β.ONOO– also induces apoptosis and necrosis in cells depending on the exposure concentration. In case of higher concentration, a DNA repair enzyme poly (ADP ribose) polymerase-1 (PARP-1), mediates ONOO–-induced necrosis  to various nuclear proteins. In case of severe DNA injury, overactivation of PARP-1 depletes the cellular stores of NAD+, an essential cofactor in the glycolytic pathway, the tricarboxylic acid cycle, and the mitochondrial electron transport chain. As a result, the loss of NAD+ leads to a marked reduction in the cellular pools of ATP, resulting in cellular dysfunction and cell death via the necrotic pathway. Experimental evidence has established that the PARP-1 pathway of cell death plays a pivotal role in tissue injury and organ dysfunction in mustard-induced acute toxicity , histone acetyl transferases (HATs) and DNA methyltransferases (DNMTs)  is glucocorticoid resistance. Although inhaled glucocorticoids are highly effective in asthma, they provide relatively little therapeutic benefit in COPD, despite the fact that active airway and lung inflammation is present. This may reflect that the inflammation in COPD is not suppressed by glucocorticoids, with no reduction in inflammatory cells, cytokines or proteases in induced sputum even with high doses of inhaled and oral glucocorticoids  that have been activated during the chronic inflammatory process. The increased expression of most of these inflammatory proteins is regulated at the level of gene transcription through the activation of pro-inflammatory transcription factors, such as nuclear NF-κB and AP-1. The molecular pathways involved in regulating inflammatory gene expression are now being delineated and it is now clear that chromatin remodeling and a variety of epigenetic mechanisms play a critical role in the transcriptional control of genes. Stimuli that switch on inflammatory genes do so by changing the chromatin structure of the inflammatory gene, whereas glucocorticoids reverse this process.et al., et al., et al., Glucocorticoids produce their effect on responsive cells by activating the glucocorticoid receptor (GR) to directly or indirectly regulate the transcription of target genes. Most of the anti-inflammatory actions of glucocorticoids are due to suppression of the actions of AP-1 and NF-κB Barnes, . The actet al., et al., et al., et al., et al., –  are similar to those that have been observed previously in patients with asthma and chronic bronchitis from other common causes (Emad and Rezaian, – scavenging agent in both in vivo and in vitro (Sourdeval et al., et al., et al., et al., et al., et al., et al., et al., et al., Melatonin shows beneficial effects against SM-induced acute toxicity as a multifunctional antioxidant and ONOOet al., Despite 75 years of research, there is still no antidote for mustard. This fact is especially crucial when we consider that probably at least a dozen countries have mustard in their arsenals today. Melatonin has been administered in both physiological and pharmacological amounts to humans and animals, and there is widespread agreement that it is a non-toxic molecule. In pregnant rats, maternal lowest no observed effect level has been found to be 200mg/kg/day and developmental no observed adverse effect level is ≥ 200 mg/kg/day (Jahnke


Frequent ventricular premature complexes  (VPC) can result in left ventricular dysfunction. Several case reports have found this association and reversal with radiofrequency ablation -4. OtherThe relation between the burden of ventricular ectopy and left ventricular function was evaluated by Baman TS et al . VPC burImprovement in left ventricular end systolic and end diastolic dimensions as well as ejection fraction has been documented after VPC ablation . In spitDarrieux FC, et al  noted anLelakowski J et al  reportedTwo articles in this issue of the journal focus on the ablation of VPCs. While Sheldon SH et al  discusse


GABAergic inhibitory neurotransmission contributes to diverse aspects of brain development and adult plasticity, including the expression of complex cognitive processes. This is afforded for in part by the dynamic adaptations occurring at inhibitory synapses, which show great heterogeneity both in terms of upstream signaling and downstream effector mechanisms. Single-particle tracking and live imaging have revealed that complex receptor-scaffold interactions critically determine adaptations at GABAergic synapses. Super-resolution imaging studies have shown that protein interactions at synaptic sites contribute to nano-scale scaffold re-arrangements through post-translational modifications (PTMs), facilitating receptor and scaffold recruitment to synaptic sites. Additionally, plasticity mechanisms may be affected by the protein composition at individual synapses and the type of pre-synaptic input. This mini-review article examines recent discoveries of plasticity mechanisms that are operational within GABAergic synapses and discusses their contribution towards functional heterogeneity in inhibitory neurotransmission. The plasticity of individual synapses occurs downstream of activity or neuro-modulatory signaling and must be reconciled with homeostatic mechanisms to maintain overall network function  receptors. These CB1 receptors are pre-synaptically enriched at CCK+ synapses and participate in the depolarization-induced suppression of inhibition , post-synaptic scaffolding and signaling proteins, and trans-synaptic adhesion molecules which facilitate effective communication between the pre- and post-synapse for efficient neurotransmission. GABAARs are composed of pentamers from a family of subunits encoded by 19 distinct genes . Although it has been recently shown that many receptor subunits can access the synaptic space (Hannan et al., ARs composed of the combination of α1–3 subunits along with β1–3 and γ2 subunits, whereas those containing the subunits α4–6 and δ tend to be extra-synaptic (Fritschy and Panzanelli, ARs are trafficked to the plasma membrane from cytoplasmic pools, or diffuse laterally within the membrane in and out of synapses to alter the local concentration of receptors and therefore synaptic strength (Flores and Méndez, ARs is an important mechanism by which inhibitory plasticity is achieved (Petrini and Barberis, ARs scales with the size of gephyrin clusters (Specht et al., via decreased confinement of GABAARs (Jacob, AR clustering. For example, activity induction in hippocampal slices leads to inhibitory potentiation that is correlated to increases in gephyrin cluster size concordant with mIPSC amplitude (Flores et al., AR synaptic organization can be used to understand mechanistic bases for synapse alterations.The GABAergic post-synapse contains GABAs Jacob, . SimilarAR synaptic accumulation through CaMKII signaling (Flores et al., ARs at synapses, large increases in calcium leads to reduced retention of GABAARs (Petrini and Barberis, While plasticity occurs at all synapses, basal synapse characteristics such as size, strength, and composition are variable, and therefore the extent of induced synaptic plasticity is also variable. For example, spinal cord synapses contain over four times as many gephyrin molecules per synapse and at a higher density than cortical synapses (Specht et al., ARs, the interaction between GABAARs and post-synaptic scaffolds, or the dynamics of the post-synaptic scaffolds themselves could all contribute to modulating synaptic receptor retention and therefore the function of inhibitory synapses (Choquet and Triller, via altered receptor-scaffold interactions. Of these, modification of GABAARs (Comenencia-Ortiz et al., ARs and gephyrin result in enhanced surface localization (Matt et al., ARs controls both surface trafficking and removal (Comenencia-Ortiz et al., via gephyrin-dependent (Mukherjee et al., Direct modification of GABAARs as well as those of pre-synaptic vesicle release sites clearly demonstrating that synaptic gephyrin nano-domains represent functional organizational units (Crosby et al., ARs has been shown by perturbing gephyrin clustering via overexpression of dominant-negative gephyrin, which causes a reduction in the number and size of GABAAR nano-domains (Crosby et al., ARs at synaptic sites (Battaglia et al., Recent efforts towards describing post-synaptic dynamics have employed live-imaging and super-resolution microscopy to determine real-time and nano-scale re-organization of the post-synapse (Specht et al., AR retention at synapses. A recent study has found that phosphorylation of gephyrin at serine 268 (regulated by ERK1/2; Tyagarajan et al., AR synaptic dwell time (Battaglia et al., AR dynamics outside of synaptic sites, suggesting that gephyrin is involved in extra-synaptic receptor scaffolding regulated by phosphorylation of distinct serine residues (Battaglia et al., via receptor-scaffold interactions. Phospho-proteomic analyses of synaptic proteins indicate that more than just gephyrin and GABAARs are dynamically phosphorylated, and that altered brain states such as sleep deprivation (Wang et al., ARs and gephyrin (Šmidák et al., PTMs have now been shown to control gephyrin nano-domain structure and GABAARs dynamics and inhibitory synapse function have been identified (Fritschy et al., Models for receptor-scaffold interactions propose that modifying the number of scaffolds or the affinity of receptor-scaffold binding will define the equilibrium governing immobilization of receptors at the synapse (Choquet and Triller, ARs and adaptor proteins (Cajigas et al., AR subunit is disrupted in a loss-of-function mouse model null for the RNA binding protein NONO, leading to a reduction in synaptic GABAARs and gephyrin clustering (Mircsof et al., Recent data suggests that local translation of mRNA coding for synaptic proteins could offer a way to acutely modify synaptic composition in a synapse-specific manner (Rangaraju et al., The findings highlighted in this mini-review article (summarized in BC and ST contributed to the organization and writing of this 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.