Transplantation therapy for diabetes is limited by unavailability of donor organs and outcomes complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy to overcome supply problems. Implantation of tissue obtained early during embryogenesis is a way to reduce transplant immunogenicity. Insulin-producing cells originating from embryonic pig pancreas obtained very early following pancreatic primordium formation (embryonic day 28 (E28)) engraft long-term in non-immune, suppressed diabetic rats or rhesus macaques. Morphologically, similar cells originating from adult porcine islets of Langerhans (islets) engraft in non-immune-suppressed rats or rhesus macaques previously transplanted with E28 pig pancreatic primordia. Our data are consistent with induction of tolerance to an endocrine cell component of porcine islets induced by previous transplantation of embryonic pig pancreas, a novel finding we designate organogenetic tolerance. The potential exists for its use to enable the use of pigs as islet cell donors for humans with no immune suppression requirement. J. Transplantation, why transplantation of embryonic pancreatic primordia to replace endocrine pancreas function is advantageous relative to transplantation of either pluripotent embryonic stem (ES) cells, or of terminally differentiated (adult) organs [We have reviewed previously, for ) organs : (1) unlTransplantation of human embryonic pancreas in human hosts has been contemplated . HoweverCells originating from E28 pig pancreatic primordia transplanted in mesentery engraft similarly in non-immune-suppressed STZ-diabetic rhesus macaques , 8. GlucIn lieu of increasing the numbers of transplanted primordia or transplant surgeries in diabetic rhesus macaques, we embarked on a series of experiments to determine whether porcine islets, a more easily obtainable and possibly more robust source of insulin-producing cells, could be substituted for animals in which embryonic pig pancreas already had been engrafted. To this end, we implanted adult porcine islets beneath the capsule of one kidney of rats or macaques, that several weeks earlier had been transplanted with E28 pig pancreatic primordia in mesentery. We employed the renal subcapsular site for islet implantation so that we could differentiate engrafted porcine tissue originating from the islets from tissue originating from prior mesenteric E28 pig pancreatic transplants, that never engraft in host kidney , 8. In t Figures Neither cells that stain for insulin nor cells to which the probe for porcine proinsulin mRNA binds are present in contralateral (nonimplanted) kidneys of STZ diabetic rats  or macaqTo provide additional evidence that cells in the kidneys of islet-implanted rats or macaques previously transplanted with E28 pig pancreatic primordia in mesentery are of porcine origin, we demonstrated using fluorescent in situ hybridization, that the cells contain pig X chromosomes , 8. ShowMultiple organs were excised from a STZ-diabetic macaque transplanted with E28 pig pancreatic primordia in mesentery and subsequently with porcine islets in the renal subcapsular space of one kidney. Tissues were homogenized individually and total RNA was purified. RT-PCR was performed using primers specific for pig or monkey proinsulin mRNA. Products were separated by electrophoresis on 3% agarose gels and their identities confirmed by sequencing in the Washington University Core Protein and Nucleic Acid Chemistry Laboratory [To ascertain whether cells originating from kidney-implanted porcine islets function in rats or rhesus macaques, we determined whether the glucose tolerance of STZ-diabetic animals normalized partially by prior transplantation of E28 pig pancreatic primordia in mesentery was rendered normal by subsequent islet implantation, and measured glucose-stimulated insulin release from islet-implanted kidneys in vitro. Rats were rendered fully glucose tolerant by subsequent implantation of porcine islets in one kidney . The gluAs illustrated in a representative of 3 experiments using weight-matched tissue, no insulin could be detected at time 0 in supernatants from the implanted macaque kidney . HoweverCells containing endocrine granules in an expanded renal subcapsular space were identified in electron micrographs of kidneys from rats implanted with porcine islets following transplantation of E28 pig pancreatic primordia in mesentery .  FigureThe shortage of human pancreas donor organs imposes severe restrictions on the use of allotransplantation to treat diabetes mellitus –22. WhenThe severity of humoral rejection effectively precludes the use of pigs as whole pancreas organ donors for humans. However, because they are vascularized by the host posttransplantation, islets like other cell transplants are not subject to humoral rejection. Porcine islets are rejected within two weeks of transplantation in non-immune suppressed non-human primates , 16–18. Xenotransplantation of embryonic pig pancreatic primordia in lieu of mature pig organs or porcine islets couples the wide availability of pig organs with the immunological advantages inherent in transplanting cellular embryonic tissue, circumventing humoral rejection and obviating the need for host immune suppression . HoweverCells from porcine islets do not survive afterimplantation in rat or macaque kidneys without prior transplantation of E28 pig pancreatic primordia transplantation in mesentery , 8. WholSchroeder et al.  define tEngraftment of pancreatic progenitors transplanted across a xenogeneic barrier to non-immune-suppressed immune-sufficient hosts has been reported twice previously. Eloy et al. described normalization of glucose posttransplantation of E15, but not E18 embryonic chick pancreas into liver of non-immune-suppressed STZ-diabetic rats . AbrahamHost immune suppression is required for successful engraftment of embryonic pig pancreas in rodents  or non-hInterestingly, GALT may have served similarly to prevent an immune response to insulin-producing cells scattered originally in the gut epithelium of primitive vertebrates , 32 and Harada et al. have proposed a similar coopting of oral tolerance to explain the muted immune response in vivo and by cells from mesenteric lymph nodes in vitro to a colon carcinoma of BALB/c origin or a human CD80-transfected DBA/2 mastocytoma injected into the subserosal space of cecum in BALB/c mice relative to tumors injected subcutaneously . One way to confirm a causative link between gut immunity and our ability to transplant E28 pig pancreatic primordia and porcine islets in non-immune-suppressed hosts would be to “break” the established oral tolerance , using gIn any case, we have demonstrated in two species , 8, a no


Natural Killer (NK) cells contribute to the control of cancer through immunosurveillance and may influence phenotypic sculpting of cancer through immunoediting. NK cells may also contribute to the control of hematological malignancies such as acute myeloid leukemia (AML) following allogeneic stem cell transplantation. However, no studies have shown direct clinical evidence that supports immunoediting by NK cells in AML at presentation, or whether activating ligand expression at diagnosis serves as a prognostic indicator of survival. We now show that at diagnosis, expression of NK cell ligands on AML blast populations is heterogeneous. Furthermore, expression of multiple activating ligands is associated with favorable cytogenetics and improved leukemia-free survival. In analyses of paired diagnostic and relapse samples, AML blasts exhibiting lower expression of activating ligands were selectively increased at relapse, indicating that NK cell-mediated blast immunoediting occurred prior to AML escape. Therapeutically, NK cell activating ligands could be upregulated on AML by in vitro treatment with bortezomib that enhanced NK cell-mediated cytotoxicity. Thus, diagnostic analyses of the expression of NK cell activating ligands in AML could be used to design therapeutic approaches for specific patients, and agents that stimulate NK cell function by restoring NK cell ligand expression may be appropriate to eliminate minimal residual disease and reduce risk of relapse.


Disseminated metastatic breast cancer needs aggressive treatment due to its reduced response to anticancer treatment and hence low survival and quality of life. Although in theory a combination drug therapy has advantages over single-agent therapy, no appreciable survival enhancement is generally reported whereas increased toxicity is frequently seen in combination treatment especially in chemotherapy. Currently used combination treatments in metastatic breast cancer will be discussed with their challenges leading to the introduction of novel combination anticancer drug delivery systems that aim to overcome these challenges. Widely studied drug delivery systems such as liposomes, dendrimers, polymeric nanoparticles, and water-soluble polymers can concurrently carry multiple anticancer drugs in one platform. These carriers can provide improved target specificity achieved by passive and/or active targeting mechanisms. Breast cancer is the most common cancer in females and the second most common cause of death in women in the United States . MetastaFor better therapeutic effectiveness combination anticancer treatment has long been adopted in clinics. The general rationale for employing combination therapy is twofold. First, when multiple drugs with different molecular targets are applied, the cancer adaptation process such as cancer cell mutations can be delayed. Second, when multiple drugs target the same cellular pathway they could function synergistically for higher therapeutic efficacy and higher target selectivity. Currently available combination regimens for metastatic breast cancer in clinics are limited to administrating a physical mixture of two or more anticancer agents. The clinically used combination regimens in the US can be broadly classified based on their mechanisms of action Figures  includinSmall molecule chemotherapeutic agents can be given singly or in combination . ToxicitStreptomyces bacteria, are a class of drugs widely used and studied in cancer chemotherapy. Mechanisms of action of anthracyclines are (1) to inhibit DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells, (2) to inhibit topoisomerase II, preventing the relaxing of supercoiled DNA, and thus blocking DNA transcription and replication, and (3) to create iron-mediated free oxygen radicals that damage the DNA and cell membranes. Anthracyclines-based combination chemotherapy has shown improved anticancer activity than anthracyclines alone. For example, doxorubicin has achieved response rate of 40–50% as single agent while 60–70% in combination [With response rates of up to 60% in previously untreated patients with metastatic breast cancer anthracycline-based regimens are one of the most widely used first-line chemotherapies. Because of this advantage patients relapsing more than 12 months after anthracycline-based treatment may be reinduced with anthracycline-based combination chemotherapy . Anthracbination . These rbination . The combination . These rbination , 24. JoeTaxanes are another class of chemotherapy agents originally derived from natural sources then synthetically derivatized including paclitaxel (Taxol) and docetaxel (Taxotere). The mechanism of action of taxanes is to disrupt microtubule function. Microtubules are essential to cell division, and taxanes stabilize GDP-bound tubulin in the microtubule, thereby inhibiting the process of cell division. Therefore taxanes also can be classified as mitotic inhibitors. However due to their poor water-solubility, taxanes encounter difficulties in pharmaceutical formulation and this often results in reduced bioavailability.Different mechanisms of action of anthracyclines and taxanes provide the rationale of combination therapy of these two classes of drugs. Taxanes and anthracyclines typically do not produce overlapping toxicities with existing therapies. Bria et al. reported improved time to progression and overall survival from doxorubicin with paclitaxel (or docetaxel) therapy compared to anthracycline-based combination therapy (FAC or AC). Although greater hematologic toxicity (such as neutropenia) occurs from taxane containing regimen (74%) than the anthracycline regimen (63%)  the overTaxane with nonanthracycline combinations is another highly effective regimen and is particularly useful in patients with rapidly progressive visceral metastases, who were previously treated with an anthracycline. In this regimen, capecitabine and gemcitabine are drugs of choices as nonanthracycline drugs for combination with taxanes (docetaxel or paclitaxel). Albain et al. reported the combination of gemcitabine and paclitaxel regimen to be superior to paclitaxel alone with longer time to progression (6 versus 4 months) and better response rate (41% versus 26%). However toxicity of this combination was higher with increased neutropenia (61% versus 22%), fatigue (19% versus 13%), and neuropathy (24% versus 22%) .Increased use of anthracyclines and taxanes in adjuvant (given in addition to main treatment) and neoadjuvant (given before the main treatment) settings limits the treatment options for patients upon relapse. Multidrug resistance (MDR) is a major limitation of conventional chemotherapy . This isAs discussed above most combination therapies with small molecule chemotherapeutic agents present improved clinical benefits including enhanced response rate and prolonged overall survival, progression-free survival, relapse-free survival, and/or time to progression. However, with additive efficacy the adverse effects from each agent are compounded resulting in patients' suffering from more treatment-related toxicity. The nonspecific nature of small molecule chemotherapeutics accounts for much of the toxicity due to nonselective biodistribution in healthy tissues concurrently with tumor accumulation. Additionally exposure to multiple conventional chemotherapeutic agents reduces response rate due to increased efflux of these drugs out of the cells mediated by the overexpression of MDR related efflux pumps or transporters . TherefoSmall molecule chemotherapeutic agents lack cancer cell-specific targeting ability and also affect the fast-dividing normal cells of the body . Therefore, the major adverse effects from these chemotherapeutic agents are nonspecific toxicities including anemia, nausea, vomiting, and hair loss. Biologic agents are advantageous to chemotherapy in their ability to actively target-specific receptors. Conventional chemotherapy does not discriminate effectively between tumor cells and rapidly dividing normal cells thus leading to nonspecific adverse effects. In contrast, target-specific anticancer therapies interfere with molecular targets that have an important role in tumor growth or progression distinct from normal cells. Also some of these agents act as inhibitors to MDR-related proteins thereby increasing the response rate . OverallMonoclonal antibodies are monospecific antibodies made by identical immune cells as clones of a unique parent cell. Due to their nature monoclonal antibodies can be designed to bind to specific substances hence they are widely used for target specific detection or purification . ApproxiBevacizumab, a monoclonal antibody against VEGFR, acts as an inhibitor of angiogenesis. VEGF is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from preexisting vasculature). Since angiogenesis is the essential way of providing nutrition to tumors and a fundamental step in the transition of tumors from a dormant state to a malignant one, it serves as important target for anticancer therapy. As monotherapy in metastatic breast cancer, it has only modest activity (response rate of 9%) . HoweverCetuximab is a monoclonal antibody that targets overexpressed EGFR in various cancers . EGFR isMonoclonal antibodies as biologic anticancer agents have shown reduced toxicity while having modest activities. The low response rates due to drug resistance can explain such modest activities. TRZ resistance is developed in about 70% of TRZ-treated breast cancer patients in early treatment period  and onlyLapatinib is a small molecule dual tyrosine kinase receptor inhibitor of EGFR and HER2 that, like TRZ, has demonstrated a significant improvement in overall survival when added to the treatment of HER2-positive metastatic breast cancer . The benAnother strategy for targeting VEGF and tumor angiogenesis is the use of small molecule tyrosine kinase receptor inhibitors that target the VEGF receptor (VEGFR), including sunitinib, sorafenib, axitinib, and pazopanib. Gianni et al. reported improved response rate of 72% with the docetaxel plus sunitinib combination compared to 11% with sunitinib monotherapy. Most common side effects of sunitinib are anorexia, fatigue, mucositis, diarrhea, and nausea. However, the combination was well tolerated and did not significantly worsen the toxicity associated with the chemotherapy alone . Although these agents, alone or in combination with chemotherapy and/or other biologics, hold great promise, to date they have failed to demonstrate significant activity in metastatic breast cancer , 55. MosP = 0.02) of patients receiving olaparib, gemcitabine, and carboplatin compared to that of placebo and chemotherapy groups [Poly(adenosine diphosphate-ribose) polymerase (PARP) is a DNA-binding protein involved in detection and repair of DNA strand breaks . PARP iny groups .Although not many of the regimens are clinically approved, the concept of combination of two or more target-specific biologic agents is promising . The ratCmax were not significantly different in comparing the combination with lapatinib alone. AUC24 and Cmax of TRZ were not significantly different when comparing the combination to trastuzumab alone [Beneficial therapeutic effectiveness from combination treatment is promising when considering theoretically nonoverlapping mechanisms of action of each anticancer agent. However, current combination treatments in metastatic breast cancer are far from perfect with moderate enhanced efficacy but additive toxicity as described above. Commonly these anticancer agents are administered together as a physical mixture of each agent without pharmacokinetic modification. These agents (free drugs) therefore distribute are eliminated independently of each other. As a result the additive effects are seen not only in anticancer activity but concurrently in adverse effects. Combining molecularly targeted agents is an improved strategy, but brings added complications including patient compliance issue. For example, in HER2 targeted combination therapy with TRZ and lapatinib, these two agents have two different routes of administration. TRZ is given intravenously weekly while lapatinib is administered daily as an oral formulation. Due to two different ways of administration with different schedules it is challenging to manage proper pharmacokinetic and pharmacodynamic profiles and virtually impossible to achieve uniform temporal and spatial codelivery. Storniolo et al. reported the results of a pharmacokinetic study of coadministration of TRZ and lapatinib to 27 patients. Serial blood samples were collected over a 24-hour period after ingestion of the lapatinib dose and/or the initiation of the 0.5-hour TRZ infusion. They reported that lapatinib area under the plasma drug concentration versus time curve within a 24-hour period after dosing and ab alone . HoweverThe challenges discussed above have driven researchers to investigate novel approaches by incorporating nanotechnology with combination anticancer treatment. The promising hypothesis is that by delivering two of more drugs simultaneously using a carrier-mediated drug delivery system the combination system can generate synergistic anticancer effects and reduce individual drug related toxicity. However this area of delivering multiple drugs with a single vehicle remains largely unexplored while most research efforts focus on single agent delivery systems. Therefore, here we will review carrier-mediated drug delivery systems containing multiple anticancer agents for cancer treatment in general not limited to metastatic breast cancer. Carrier-mediated drug delivery systems can offer many advantages over delivery of physical mixture of multiple drugs. The advantages include (1) prolonged drug circulation half-life mediated by the carrier, (2) reduced nonspecific uptake, (3) increased accumulation at the tumor site through passive enhanced permeation and retention (EPR) effect and/or active targeting by incorporation of targeting ligands , (4) preLiposomes are spherical vesicles composed of one or more lipid bilayers with a drug containing aqueous core . LiposomAnother unique liposomal system is a polymer-caged nanobin PCN,  developeAttaching targeting ligands such as antibodies and peptides to a drug carrier is a widely applied strategy drastically increasing carrier accumulation in the desired cells, tissues, and organs. Several such targeted liposomes have been developed for combination drug delivery applications . Wu et aAs with any carrier-mediated codelivery system, determination of the optimal dose as the relative ratio of multiple drugs is a complex aspect in liposome-based combination drug delivery system. Mayer et al. reported precise control over combinatorial drug dosing in liposomes . The comDendrimers are well-established three-dimensional, branched polymers that have been thoroughly investigated as controlled and targeted drug delivery systems. The structure of dendrimers can be defined by an initiator core and layers of branched repeating units  with functional end groups on the outmost layer . DendrimPolymeric nanoparticles are submicron-sized aggregate structures (3–200 nm) that are prepared using random or block copolymers. Polymeric nanoparticles are widely used as drug delivery carriers where the active drug may be physically encapsulated or covalently bound to the polymer matrix depending upon the method of preparation. Several polymeric nanoparticle systems have been explored specifically for combination drug delivery in cancer using both passive and active targeting strategies . For exaIn general it has been shown that polymeric nanoparticles, compared to liposomes, have greater stability, controlled size distribution, more tunable physicochemical properties, sustained and more controllable drug-release profiles, and higher loading capacity for poorly water-soluble drugs. While majority of the nanoparticle systems described above have demonstrated synergistic therapeutic efficacy in both in vitro and in vivo models some of these studies specifically illustrate that synergistic therapeutic effect is primarily due to the ability to administer two drugs in a tunable mass ratio with predictable spatial and temporal drug release profiles. For example Sengupta et al. developed a hybrid polymeric micelle  comprisiPolymer-drug conjugates are drug delivery systems in which a drug is covalently bound to a water-soluble polymeric carrier, normally via a biodegradable linker. Such nanoconstructs were first proposed in the 1970s , develop N-(2-hydroxypropyl)methacrylamide (HPMA) is one example of biocompatible, non-immunogenic, non-toxic water-soluble copolymers that can be tailor-made for specific combination drug delivery needs . The uniOthers have explored modifications of the PEG backbone to conjugate a combination of chemotherapeutic agents. While unmodified PEG can only conjugate two drug molecules per chain (one on each end), Pasut et al. developed a PEG with a dendritic structure on one end that allowed coupling of upto 8 nitric oxide (NO) and one epirubicin (EPI) molecule per chain , 100. InOur research group has recently proposed a novel carrier-mediated combination drug delivery system for HER2 overexpressing metastatic breast cancer . We synthttp://www.celator.ca/) has developed a methodical approach to assess different drug ratios within their liposomal technology resulting in the development of different liposomal formulations that are now being assessed in phase II clinical trials, namely, CPX-1 (irinotecan: floxuridine) and CPX-351 (cytarabine: daunorubicin). Such an approach needs to be extended to other combination delivery systems such as dendrimers or polymer-drug conjugates. Determination of the kinetics of release of each drug in a multidrug combination system will be also necessary to determine the optimum ratio as one drug may affect the release profile of the other drug and thereby affect activity. Finally clinical development of these combination products is extremely challenging, due to developmental costs of designing such complex systems. However, these combination drug delivery system-based therapeutics are likely to be perceived by pharmaceutical companies as novel opportunities to extend the patent lives compared to current blockbuster drugs.The presence of two or more therapeutic agents on a single carrier platform offers new therapeutic possibilities but at the same time poses many new challenges. In order to identify an appropriate drug combination, it is necessary to perform thorough biological evaluation which must be supported by a profound understanding of the molecular mechanisms involved. Another critical aspect is the determination of the optimal mass ratio of each component within a combination drug delivery system. This requires systematic research investigating the impact of different drug ratios on the biological activity of the combination delivery systems. Recently a Canadian pharmaceutical company Celator (


Tension-type headache (TTH) is the most prevalent headache among adults and is associated with impaired functional and psychosocial quality of life. Further analysis of eventual pathophysiology and comorbidities is needed. Temporomandibular Disorders (TMD) and TTH are frequently coexisting disorders and both characterized by increased pericranial tenderness. In a specialised tertiary headache centre more than half of the patients were also diagnosed with TMD but their eventual causality is yet unknown. Likewise is the relationship between tenderness, sleep quality and oral health in TTH patients also unknown. Our aim was to characterize the relationship between pericranial tenderness, sleep quality and oral health in TTH patients in comparison with healthy controls.The survey included 58 consecutive patients with frequent, episodic TTH or chronic TTH from a tertiary Headache Center and 58 healthy controls. Questionnaires regarding The Research Diagnostic Criteria for Temporomandibular Disorders (RDC), Oral Health Impact profile and Sleep/tiredness/snoring were completed.TTH-patients were significantly more affected in the RDC-Screening by increased characteristic pain intensity (CPI) regarding self reported temporomandibular pain (TMP) (p<0.001), decreased quality of life , and the total sleep score (p<0.001) compared to healthy controls).TTH patients are severely affected by TMP; demonstrate impaired sleep quality and oral health function and may reflect common underlying pathophysiological mechanisms.


Complex patients present with numerous risk factors and disease states. Clinical uses of biomarkers include diagnosis , risk stratification (assessing future risk of adverse outcomes or monitoring risk of adverse events), screening, and guiding therapy. Plasma natriuretic peptide are released from the heart in response to volume overload, as well as serving as markers of elevated filling pressures, a finding that in many cases would otherwise only be detectable with invasive testing. Therefore, the use of natriuretic peptides is an important adjunct to echocardiography in many circumstances. Just as BNP levels can be considered the arbitrator of CHF, cardiac troponins (TnI/TnT) are decisive for myocardial necrosis. The introduction of novel assays with even higher clinical sensitivity, detecting troponin levels at nanogram quantities, suggest even earlier diagnosis of acute myocardial infarction and identification of patients at substantial risk post-infarction. NGAL is one of the earliest and most robustly induced genes and proteins in the kidney after ischemic or nephrotoxic injury. Elevations are detectable within hours of acute kidney injury (AKI); whereas corresponding creatinine elevations lag 1 to 3 days behind.


This manuscript describes the NIH Human Microbiome Project, including a brief review of human microbiome research, a history of the project, and a comprehensive overview of the consortium's recent collection of publications analyzing the human microbiome. The Human Microbiome Project (HMP) Pioneering medical microbiologists applied these approaches, finding far more microbial diversity than expected even in well-studied body site habitats http://commonfund.nih.gov/hmp/) To coordinate these efforts relating the microbiome to human health, the NIH Common Fund launched the HMP as a community resource program  unique to the study of the microbiome Any study of human populations must put both subject protection and study design first, and the HMP was no exception. Power calculations for microbiome studies in human cohorts are particularly challenging, as they must simultaneously address assay types , depth of sequencing, taxon detection, and fold abundance changes in clades, genes, or pathways of interest http://hmpdacc.org) hosts all available HMP data and many tools, focusing the tremendous quantity of raw data through lenses such as SitePainter Finally, quality data generation from appropriately designed microbiome studies enables a variety of subsequent computational analyses . While wThe HMP was designed in part to address a key question about our microbial selves: do all humans have an identifiable “core" microbiome of shared components comparable to our shared genome A potentially more universal “core" human microbiome emerged during the consideration of microbial genes and pathways carried throughout communities' metagenomes. While microbial organisms varied among subjects as described above, metabolic pathways necessary for human-associated microbial life were consistently present, forming a functional “core" to the microbiome at all body sites Data from individuals without overt signs of disease serve as an excellent reference for disease-associated microbiome studies, while also providing a comprehensive baseline for comparison of Western populations with disparate geographic, ethnic, and genetic cohorts The HMP has thus greatly advanced our knowledge of the microbes in a healthy adult reference population, and provided much-needed infrastructure in terms of reference genomes, laboratory protocols, computational methods, and ELSI considerations


Although very late stent thrombosis (VLST) after drug-eluting stent (DES) implantation remains a major concern, the precise mechanisms have not been clarified. An association between late acquired incomplete stent apposition (ISA) and VLST of DES has been suggested by several intravascular ultrasound studies demonstrating very high prevalence of ISA in the setting of VLST. To clarify the pathological mechanisms of VLST, we investigated vascular responses of coronary arteries of VLST cases after DES implantation. Drug-eluting stents (DESs) have dramatically reduced angiographic restenosis and clinical need for repeat revascularization procedures , 2. Howe The pathological findings from patients who died of late DES thrombosis have demonstrated that delayed arterial healing characterized by incomplete reendothelialization is an important underlying factor . The patAlthough a correlation has been observed between uncovered DES struts and LST, in our pathological studies of Japanese patients, considerable number of cases showed neointimal coverage with reendothelialization of a great deal of the DES struts, especially in simple lesions beyond 1 year . Thus, e Late ISA has been observed on follow-up intravascular ultrasound (IVUS) in patients who received sirolimus-eluting stents (SESs) . Althoug Thus, late ISA by focal positive vessel remodeling caused by medial necrosis may be responsible for LST and/or VLST after DES implantation. Peri-stent contrast staining (PSS) was defined as contrast staining outside the stent contour extending to ≥20% of stent diameter measured by quantitative coronary angiography. PSS found within 12 months after SES implantation appeared to be associated with subsequent VLST . PSS couRecent studies have identified immune cells and mediators at work in atheroma, implicating inflammatory mechanisms in disease development . As prevThus, DES can induce atherosclerotic and thrombogenic lesions with a significantly higher incidence and earlier than with BMS.  LST may be more frequently related to incomplete healing and/or inadequate neointimal coverage with poor re-endothelialization. However, in the cases of VLST, several pathological studies have suggested a causal relationship between the inflammatory responses to the durable polymer and VLST, provoking late ISA and accelerated atherosclerosis followed by neointimal disruption. Histopathologic differences  among DES platforms have been observed; this may reflect unique responses to the specific polymer/drug. Thus, until novel DES using superbly biocompatible and/or biodegradable polymers becomes available, we still need to be cautious and carefully keep surveying these devices.


Isolated granulomatous noncaseating pancreatitis is a rare condition exceptionally described in human population. We demonstrate a case of the a 71-years-old female patient suffering from recent diabetes mellitus, generalized atherosclerosis and hypertension who died due to pulmonary embolism and terminal bronchopneumonia. Lipomatosis of pancreatic tissue was observed during the postmortem examination. Histological examination of pancreatic tissue discovered multiple small noncaseating epithelioid cell and giant cell granulomas, partly replacing the islets of Langerhans. To our knowledge, our case represents the first description of noninfectious granulomatous pancreatitis associated with acute manifested insulin-dependent diabetes mellitus. Noncaseating granulomatous inflammation confined to the pancreas has been only exceptionally described in human patients. Infections like tuberculosis and syphilis, exogenous noxes, autoimmunity, and systemic granulomatous diseases are the most frequent causes of granuloma formation within the pancreatic tissue . AbdominA 71-year-old obese woman was admitted with the recent onset of diabetes mellitus manifested as hyperglycaemic ketoacidotic precoma. The past medical history was unremarkable. Recently, arterial hypertension was discovered. Her body weight was 110 kg, BMI 38. The plasma glucose level ranged from 3.1 to 15.1 mmol/L. The patient was treated with intensified insulin regime. The status of the patient was complicated by intermittent fever and several antibiotics were repeatedly administered. Terminally, clinical signs of septic shock and multiorgan failure appeared and the patient died. Postmortem examination performed 11 hours after death discovered signs of septic shock with activation of spleen pulp and terminal bronchopneumonia. Thromboemboli were found in several peripheral branches of the pulmonary artery. Hypertrophy of the heart (545 g), predominantly of the left ventricle, was also observed. The pancreas showed a macroscopically lobular arrangement and lipomatosis; other macroscopic changes were not visible. Lungs, thoracic lymph nodes, and other organs did not show any changes corresponding with tuberculous process or sarcoidosis.μm-thick sections were stained with haematoxylin and eosin and by immunohistochemical methods using N-Histofine Immunohistochemical staining reagent  and 3-3′diaminobenzidine as a chromogen to visualize the reaction. The list of antibodies, including manufacturers and the dilutions used, is introduced in Five representative tissue samples of pancreatic tissue taken from head, body, and tail were fixed with 10% formalin and routinely embedded in paraffin. Five-Microscopic examination of pancreatic tissue discovered an increased amount of lipomatous tissue within the pancreatic lobules. Irregular inflammatory infiltrates of a variable density composed predominantly of small lymphocytes and sparse neutrophilic and eosinophilic granulocytes were also observed (μm) noncaseating epithelioid granulomas with giant cells, without Schaumann bodies, were present within the pancreatic lobules  and pancreatic hormones  verified the original microscopic finding of absence of islets of Langerhans . The majority of patients were presented by the obstructive jaundice, weight loss, and abdominal pain. Other autoimmune disorders, like sclerosing cholangitis or interstitial pneumonia, can appear in patients with AP. Histologically, AP is characterized by dense lymphoplasmacytic infiltrates and secondary fibrosis within the pancreatic tissue. Inflammation frequently displays a patchy collar arrangement around both small and large interlobular ducts and periphlebitis and obliterative phlebitis is invariably observed . It seemDiabetes mellitus in adults is predominantly of type 2. Much less frequently, type 1 diabetes and latent autoimmune diabetes (LADA) can appear in adult patients . DiabeteOur recent finding suggests that granulomatous pancreatitis is a possible underlying cause of diabetes mellitus and urges the microscopic examination of pancreatic tissue obtained during the post mortem examination of patients who died with signs and symptoms of recently manifested diabetes mellitus.


Burden of obesity has increased significantly in the United States over last few decades. Association of obesity with insulin resistance and related cardiometabolic problems is well established. Traditionally, adipose tissue in visceral fat depot has been considered a major culprit in development of insulin resistance. However, growing body of the literature has suggested that adipose tissue in subcutaneous fat depot, not only due to larger volume but also due to inherent functional characteristics, can have significant impact on development of insulin resistance. There are significant differences in functional characteristics of subcutaneous abdominal/truncal versus gluteofemoral depots. Decreased capacity for adipocyte differentiation and angiogenesis along with adipocyte hypertrophy can trigger vicious cycle of inflammation in subcutaneous adipose tissue and subsequent ectopic fat deposition. It is important to shift focus from fat content to functional heterogeneity in adipose tissue depots to better understand the relative role of subcutaneous adipose tissue in metabolic complications of obesity. Therapeutic lifestyle change continues to be the most important intervention in clinical practice at any level of increased adiposity. Future pharmaceutical interventions aimed at improving adipose tissue function in various subcutaneous depots have potential to help maintain adequate insulin sensitivity and reduce risk for development of insulin resistance complications. Prevalence of obesity has been increasing in the US. In 1960s, prevalence of obesity was approximately 13% , 3. ObesHowever, we have to consider clinical paradoxes along the spectrum of obesity, insulin resistance and metabolic complications. Metabolically healthy but obese (MHO) phenotype exhibits higher insulin sensitivity, absence of hypertension, and favorable lipid, inflammation, hormonal and liver enzyme profile. On the basis of epidemiological and clinical studies, prevalence of MHO phenotype varies from 10%–40% . The extExcessive insulin resistance and related metabolic abnormalities can be due to differential distribution of adipose tissue and/or adipose tissue dysfunction. Anatomically adipose tissues can be divided into truncal region or peripheral region. Truncal adipose tissue includes subcutaneous fat in thoracic and abdominal region and also intrathoracic and intraabdominal fat depots . PeripheVague in 1947 described two patterns of adipose tissue distribution—android (upper body) and gynoid (lower body)—and suggested that android obesity was associated with diabetes, coronary artery disease, gout, and uric acid renal stones . Later oVisceral fat has increased metabolic activity, both lipogenesis and lipolysis, compared to other fat depots. Free fatty acids, product of lipolysis, can directly enter liver via portal circulation and lead to increased lipid synthesis, gluconeogenesis, and insulin resistance resulting in hyperlipidemia, glucose intolerance, hypertension, and ultimately atherosclerosis . Excess We have examined the relationships between generalized and regional adiposity and insulin sensitivity in a group of nondiabetic men with varying degree of obesity . We concSimple explanation for stronger relationship between subcutaneous adipose tissue and insulin sensitivity comes from larger volume of subcutaneous adipose tissue mass. The subcutaneous abdominal fat mass is approximately twice more than intraperitoneal fat mass and total subcutaneous truncal fat mass can be 4-5 times larger than intraperitoneal fat mass , 23, 26.κB stress pathway were upregulated suggesting stimulation of inflammatory mediators. Lundgren et al. [Inflammation in adipose tissue has been identified as a mediator of systemic insulin resistance. This has been suggested by presence of macrophage in the form of crown-like structures (CLSs) in adipose tissue. Apovian et al.  examinedn et al.  examinedn et al. . This isn et al.  reportedn et al. , 35. Recent work on angiogenesis in adipose tissue has provided important insights into potential mechanisms of heterogeneity in the systemic metabolic impact of specific adipose tissue compartments. Gealekman et al.  reportedIn contrast to abdominal subcutaneous adipose tissue, larger subcutaneous thigh fat mass has a protective effect. The Health, Aging, and Body Composition Study  reportedκB pathway. The resultant effects are downregulation of cellular insulin signaling, recruitment of additional macrophages through monocyte chemoattractant protein 1, propagation of inflammation by interleukins and tumor necrosis factor alpha, and tissue matrix remodeling through matrix metalloproteinase-9 [Finally, it is worth putting truncal/abdominal subcutaneous adipose tissue characteristics all together to explain their emerging role in insulin resistance . Increaseinase-9 . These iConclusion. There is enough evidence in the literature for association between obesity and insulin resistance. Many investigators have proposed that visceral adipose tissue is a major contributor to insulin resistance. Our previous studies, in concordance with those of other investigators, suggest that subcutaneous truncal adipose tissue has significant impact on development of insulin resistance. Thus, adipose tissue distribution and function in different body compartments can be heterogeneous and can differentially contribute to insulin resistance. Changing focus from visceral adipose tissue mass as a sole contributor to insulin resistance to functional heterogeneity in adipose tissue depots can help better understand relationship of adiposity and insulin resistance. Therapeutic lifestyle change, including physical activity and weight loss, continues to be the most important intervention at any level of adiposity. One can envision that better understanding of adipose tissue function in various depots will help identify much needed additional and more effective therapeutic modalities to improve adipose tissue function and maintain adequate systemic glucose and lipid metabolism to reduce risk for morbidity and mortality associated with insulin resistance.


Since the introduction of recombinant human growth hormone (GH) in in the mid-1980s, supplies are almost limitless and predictably GH usage has escalated dramatically. There have been more than 150,000 children treated with GH worldwide with a wide variety of growth disorders.Adverse events (AE) with all forms of drug therapy are markedly under-reported, considerably underestimating the incidence of the AE. This under-reporting occurs even when the AE is serious and has a possible or probable association with GH therapy. Careful audit of the frequency of reporting of severe AE to other drugs with a possible or probable association with treatment is only 14%. Furthermore missing data is very common and adds to the difficulty in interpreting AE.Important conditions (adverse events) possibly linked to GH treatment are fortunately rare. There are several major limitations to accurately assessing the prevalence and risk of rare adverse events. Firstly, extremely large datasets are required found in large databases such KIGS and NCGS each with >50,000 enrolled patients. Secondly, accurate risk assessment of the possible adverse event in an untreated population that matches the GH treated population has rarely been determined.Important potential adverse events that have received considerable attention will be addressed. These include; tumour recurrence, new malignancies including leukaemia, diabetes mellitus, benign intracranial hypertension and slipped upper femoral epiphyses. The physiological rationale and the risk of these conditions during GH treatment will be addressed.Serum IGF-I monitoring to prevent elevated levels that may further increase the risk of adverse events is recommended. The potential adverse consequences of sustained elevated serum IGF-I levels will be discussed. In addition, monitoring IGF-I helps to monitor compliance of GH therapy in children with GH deficiency.


Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory pathological left ventricle (LV) hypertrophy due to sarcomere dysfunction. In an important proportion of patients with HCM, the site and extent of cardiac hypertrophy results in severe obstruction to LV outflow tract (LVOT), contributing to disabling symptoms and increasing the risk of sudden cardiac death (SCD). In patients with progressive and/or refractory symptoms despite optimal pharmacological treatment, invasive therapies that diminish or abolish LVOT obstruction relieve heart failure-related symptoms, improve quality of life and could be associated with long-term survival similar to that observed in the general population. The gold standard in this respect is surgical septal myectomy, which might be supplementary associated with a reduction in SCD. Percutaneous techniques, particularly alcohol septal ablation (ASA) and more recently radiofrequency (RF) septal ablation, can achieve LVOT gradient reduction and symptomatic benefit in a large proportion of HOCM patients at the cost of a supposedly limited septal myocardial necrosis and a 10-20% risk of chronic atrioventricular block. After an initial period of enthusiasm, standard DDD pacing failed to show in randomized trials significant LVOT gradient reductions and objective improvement in exercise capacity. However, case reports and recent small pilot studies suggested that atrial synchronous LV or biventricular (biV) pacing significantly reduce LVOT obstruction and improve symptoms (acutely as well as long-term) in a large proportion of severely symptomatic HOCM patients not suitable to other gradient reduction therapies. Moreover, biV/LV pacing in HOCM seems to be associated with significant LV reverse remodelling. Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory LV hypertrophy mainly due to sarcomere dysfunction. Prevalence of the disorder in the general population is estimated to be 0.2% . A subseMedical therapy is at least partially effective in the majority of HOCM patients  and consIn severely symptomatic HOCM patients despite optimal medical treatment and with significant resting or provocable LVOT obstruction (with gradient ≥30 mm Hg at rest or ≥50 mm Hg during exercise) non-pharmacologic treatment is indicated  even in less symptomatic HOCM patients , with a  even in In the overwhelming majority of HOCM patients LV/biV pacing is acutely more effective for gradient reduction than standard RVA pacing: eight out of nine in one study  and all In contrast to studies with DDD RVA pacing, LV/biV pacing showed that the reduction in LVOT gradient induced a progressive and significant reduction in LV mass (reverse remodelling) . The thiDuring long term LV/biV pacing in HOCM there was no SCD/syncope in patients with CRT-P ,38. In tThe small number of patients included in studies with LV/biV pacing in HOCM as well as the fact that all of them are observational and uncontrolled  requires caution in interpreting the results. However, the differences observed in comparison with standard DDD RVA pacing warrants further research. Considering the relatively large number of HOCM patients submitted to cardioverter-defibrillator implantation for primary or secondary prevention, data for such analysis should be readily available.In selected patients with HOCM, LV/biV pacing is feasible and usually the best configuration for gradient reduction. Overall, LV/biV pacing in patients with HOCM significantly and progressively improves functional capacity and quality of life. It may also induce LV reverse remodelling.


Microbial cells are highly complex and heterogeneous systems. In general, cell populations contain subgroups of cells which exhibit differences in growth rate as well as resistance to stress and drug treatment In the past 20 years a new form of microscopy, atomic force microscopy (AFM), has revolutionized the way researchers probe the microbial cell surface. Instead of using an incident beam, AFM measures the minute forces acting between a sharp tip and the sample AFM is much more than a surface-imaging tool in that it also measures the localization and mechanical properties of the individual cell surface molecules. In this modality, known as single-molecule force spectroscopy, the cantilever deflection is recorded as a function of the vertical displacement of the scanner (as the sample is pushed towards the tip and it retracts) Lactobacillus rhamnosus GG, Lactococcus lactis, and Lactobacillus plantarumL. rhamnosus GG had a rough surface morphology decorated with 15 nanometer–high wave-like structures, attributed to the production of extracellular polysaccharides involved in host adhesion L. lactis showed 25 nanometer–wide striations documenting peptidoglycan cables running parallel to the short cell axis, thus supporting the classical model for peptidoglycan organization Bacillus subtilisL. plantarum documented a highly polarized surface morphology  that was correlated with a heterogeneous distribution of teichoic acids There has been rapid progress in recent years using AFM for imaging microbial surfaces under physiological conditions. In structural biology, AFM has provided fascinating insights into the supramolecular architecture of membrane proteins, thereby complementing data obtained by electron and X-ray crystallography Bacillus thuringiensis flagella involved in cell motility Aspergillus fumigatusCorynebacterium glutamicumStaphylococcus aureus was observed during growth, revealing ring-like and honeycomb structures at 20 nanometers resolution Bacillus atrophaeus spores revealed germination-induced alterations in spore coat architecture and disassembly of rodlet structures Candida albicans and macrophages Remarkably, high-resolution imaging has allowed researchers to observe cell surface structures to a resolution of a few nanometers. Observed structures include Escherichia coli cells AFM imaging thus opens up unprecedented possibilities for studying the structural details of the surface of microbial pathogens without drying, staining, or fixation. As conventional AFM imaging is limited by a rather poor temporal resolution, an important challenge is to increase the speed of AFM to study fast dynamic biological processes Shewanella oneidensis bacteria C. albicans with AFM tips terminated with specific antibodies triggered the formation and propagation of adhesion nanodomains on the cell surface While AFM imaging lacks biochemical specificity, single-molecule force spectroscopy with functionalized AFM tips makes it possible to map the distribution of specific molecules on living cells. The method involves scanning the cell surface with a tip bearing cognate ligands while measuring specific receptor-ligand forces E. coli fimbrial adhesive protein FimH which strengthen under external mechanical force C. albicans revealed sawtooth patterns with multiple force peaks, corresponding to the force-induced unfolding of hydrophobic tandem repeats engaged in cell adhesion  and respond to force . Knowing these molecular properties is critical to our understanding of cell surface functions.Many challenges remain to be addressed. As we have already discussed, further developments in high-speed AFMs


There is no consensus on optimal use of radiotherapy following radical prostatectomy. The purpose of this study was to describe opinions of urologists and radiation oncologists regarding adjuvant and salvage radiotherapy following radical prostatectomy.Urologists and genitourinary radiation oncologists were solicited to participate in an online survey. Respondent characteristics included demographics, training, practice setting, patient volume/experience, and access to radiotherapy. Participant practice patterns and attitudes towards use of adjuvant and salvage radiotherapy in standardized clinical scenarios were assessed.One hundred and forty-six staff physicians participated in the survey (104 urologists and 42 genitourinary radiation oncologists). Overall, high Gleason score , positive surgical margin , and extraprostatic tumour extension  conferred an increased probability of recommending adjuvant radiotherapy. Radiation oncologists were more likely to recommend adjuvant radiotherapy across all clinical scenarios . Major differences were found for patients with Gleason 6 and isolated positive surgical margin (radiotherapy selected by 21% of urologists vs. 70% of radiation oncologists), and patients with extraprostatic extension and negative surgical margins (radiotherapy selected by 18% of urologist vs. 57% of radiation oncologists).Urologists and radiation oncologists frequently disagree about recommendation for post-prostatectomy adjuvant radiotherapy. Since clinical equipoise exists between adjuvant versus early salvage post-operative radiotherapy, support of clinical trials comparing these approaches is strongly encouraged. Approximately 40% of patients diagnosed with prostate cancer will be treated with radical prostatectomy and approximately 15-35% will develop a detectible serum prostate-specific antigen (PSA) following surgery . A positTraditionally, clinicians may have been more likely to treat patients with androgen deprivation if clinicopathologic features were associated with high risk of systemic disease  and more likely to treat patients with adjuvant or salvage radiotherapy if features were associated with high risk of isolated localized disease  . HoweverWhile indications for pelvic radiotherapy may have changed, questions remain about the timing of treatment. Adjuvant radiotherapy is offered to patients prior to PSA recurrence while salvage radiotherapy reserves treatment, and its associated side effects, for men with proven biochemical recurrence. Randomized trials of adjuvant radiotherapy versus observation reveal a reduction in biochemical recurrence  and prolonged survival (SWOG 8794) while observational studies suggest salvage radiotherapy versus observation reduces progression and prolongs survival ,20. The th, 2011. Institutional ethics approval was obtained for this survey from the Ottawa Hospital Research Ethics Board prior to study commencement.In October 2011, Canadian Urological Association (CUA) members and genitourinary radiation oncologists from the Canadian Association of Radiation Oncology (CARO) were invited to participate in an online survey. CUA members were contacted through the CUA listserv and radiation oncologist emails were available through the CARO member directory. A second request was made one month following the original invitation. E-mail recipients were provided with a hyperlink to an online survey that populated a secure database. The survey was closed on November 7Participants were asked to provide demographic information including age, geographic location of practice, specialty (urology or radiation oncology), practice type (academic or community), years in practice, sub-specialty training, number of prostate cancer patients assessed per year, and access to radiotherapy.Respondents were asked to rate how various clinical and pathologic variables independently influenced their recommendation for adjuvant and salvage radiotherapy via Likert items. Clinical variables included patient age, urinary continence, and erectile function. Pathologic variables included extraprostatic tumour extension, seminal vesicle tumour invasion, lymph node metastases, pre- and post-operative PSA concentrations, Gleason score, pathologic stage, and surgical margin status. Respondents were provided with a standardized case scenario of a healthy 60 year old male 3-months post radical prostatectomy with an undetectable PSA. They were asked to recommend for or against adjuvant radiotherapy for this patient given varied Gleason score, pathologic stage, and surgical margin status.adjuvant radiotherapy after radical prostatectomy in the provided clinical scenario. A-priori independent variables for the clinical scenario model were Gleason grade, tumour stage, surgical margin status, and medical specialty. P-values < 0.05 were considered statistically significant.Survey responses were summarized with frequencies and percentages. Associations between clinician/patient characteristics and choice of adjuvant radiotherapy were calculated using logistic regression. Log binomial regression was used to calculate relative risks (RR) using the proc genmod procedure in SAS. RR are presented with 95% confidence intervals (CI). Candidate predictor variables included clinician characteristics  and pathologic factors . Each predictor variable was assessed as a categorical variable. The primary outcome was the respondent’s decision to recommend From 586 listed emails, 146 (25%) staff physicians participated in the survey and were included in the analysis. 104 (22%) of solicited urologists and 42 (40%) of solicited genitourinary radiation oncologists completed the survey. The majority of radiation oncologists  and approximately half of urologists  indicated they practiced in an academic institution. Sub-specialty training in genitourinary oncology was reported in 51 (35%) respondents. The mean number of years in practice was 14 years (SD 10.3). Full demographic characteristics are presented in A majority of urologists  and radiation oncologists  reported that recent randomized trials have changed the way they manage patients after radical prostatectomy. When asked their opinion regarding the value of adding androgen deprivation therapy (ADT) to adjuvant or salvage radiotherapy, 29 (35%) urologists and 13 (32%) radiation oncologists reported believing it is likely beneficial and 44 (52%) urologists and 22 (55%) radiation oncologist would recommend it to high risk patients. A large proportion of urologists  and radiation oncologists  believed more research is required to evaluate the benefit and harm of ADT when used in conjunction with radiotherapy following prostatectomy. The influence of clinical and pathologic factors on the recommendation for adjuvant or salvage radiotherapy is presented in Large differences were identified in the opinions of radiation oncologists and urologists regarding recommendations for adjuvant radiotherapy when pathologic variables were placed in the context of a standardized clinical scenario . SeventyOverall, radiation oncologists were 48% more likely to recommend adjuvant radiotherapy compared to urologists . Of the remaining clinical factors evaluated, only physician age had a significant impact on the recommendation for adjuvant radiotherapy with older physicians being less likely to recommend radiotherapy . Practice setting, access to radiotherapy, and genitourinary oncology fellowship training did not strongly influence the probability of recommending radiotherapy .Pathologic variables  were associated with the recommendation for adjuvant radiotherapy . A GleasTo adjust for potential confounders, multivariable analysis was performed to determine the independent associations between each predictor variable and the recommendation for adjuvant radiotherapy . PatholoThis survey explored the practice patterns and opinions of two different specialty groups involved in the management of patients with prostate cancer, urologists and radiation oncologists, and identified factors that influence recommendations for post-operative radiotherapy. For every pathological variable examined, radiation oncologists were more likely to recommend adjuvant radiotherapy than were urologists with a mean absolute difference of 27% and relative difference of 48%. There were clinical scenarios where urologists and radiation oncologists agreed; specifically, both commonly recommended adjuvant radiotherapy in patients with extraprostatic tumour extension and a positive surgical margin, high Gleason score and a positive surgical margin, or seminal vesicle invasion. Conversely, there was lack of consensus for patients with low Gleason score and an isolated positive surgical margin, and for patients with extraprostatic extension and negative surgical margin. The influence of medical specialty on treatment recommendations was striking and is a trend that has been previously observed amongst urologists and radiation oncologists when selecting primary treatment of prostate cancer .Standardized scenarios in the survey represented patients that would have met inclusion criteria for entry into SWOG 8794 . The SWOExamining each variable independently, a large proportion of physicians surveyed were more likely to recommend adjuvant post-operative radiotherapy in patients with extraprostatic disease, high Gleason score, seminal vesicle invasion, and positive surgical margins. It is interesting to note that surgical margin status appeared to influence urologists much more than radiation oncologists (RR 1.6 vs. 1.08). Taken as a whole, these results indicate a departure from the dogmatic approach of avoiding radiotherapy in patients with high risk of metastases  . FactorsAmong post-operative patients who develop a detectable serum PSA, the survey identified several factors that influence the likelihood of physicians recommending salvage radiotherapy. In addition to the pathological and clinical characteristics identified for adjuvant radiotherapy, post-operative PSA kinetics strongly influenced physician opinion. Physicians were more likely to recommend radiotherapy when there was a prolonged duration between prostatectomy and detection of post-operative PSA and when the PSA doubling time was long. This finding is somewhat surprising and illustrates a misconception amongst physicians surveyed regarding the value of salvage radiotherapy for long and short PSA doubling times (PSADT). Although observational studies have reported a better prognosis for men with PSADT > 10 months, the absolute benefit of salvage radiotherapy is in fact greater in men with rapid PSADT ,20. TherA limitation of the current literature is a lack of randomized comparison of adjuvant and salvage radiotherapy. Adjuvant radiotherapy (prior to PSA recurrence) may be better than salvage radiotherapy (when PSA becomes detectible) for several reasons. Firstly, recurrences are predominantly local in the absence of seminal vesicle invasion or lymph node metastases, therefore early local treatment may prevent metastases . FurtherIdentification of patients likely to benefit from post-operative radiotherapy is important since this intervention is associated with harm . ComplicThis survey has limitations. We are unable to determine the true response rate since email lists were used and the activity of the email accounts could not be determined. While a wide distribution of clinician age, practice setting, and sub-specialty training was observed in the respondents, information about non-respondents was not available to assess potential biases. This survey included primarily Canadian physicians, and practice patterns may be different in other health care settings. Finally, this survey draws data from responses to realistic but fictional patient scenarios and thus cannot control for variations in respondent interpretation.The results of this survey reveal some consensus and some salient differences in the opinions of physicians regarding post-radical prostatectomy radiotherapy. Most notably, there was a large difference in the proportion of urologists and radiation oncologists who recommended radiotherapy for patients with low Gleason scores and isolated positive margins or extraprostatic extension. Since clinical equipoise exists between adjuvant and early salvage post-operative radiotherapy, support of clinical trials comparing these two approaches is strongly encouraged.


Cuculus canorus) is a generalist brood parasite that lays its eggs in the nest of many different passerine birds, but each female tends to specialize on one particular host species giving rise to highly specialized host races. The different host species show large variation in their ability to invest in the parasitic offspring, presenting an opportunity for female cuckoos to bias offspring sex ratio in relation to host species quality. Here, we investigate host-race specific sex allocation controlling for maternal identity in the common cuckoo. We found no evidence of any significant relationship between host race and sex ratio in one sympatric population harbouring three different host races, or in a total of five geographically separated populations. There was also no significant association between host quality, as determined by species-specific female host body mass, and cuckoo sex ratio. Finally, we found no significant relationship between individual cuckoo maternal quality, as determined by her egg volume, and sex ratio within each host race. We conclude that the generalist brood-parasitic common cuckoo show no significant sex-ratio bias in relation to host race and discuss this finding in light of gene flow and host adaptations.Sex allocation theory and empirical evidence both suggest that natural selection should favour maternal control of offspring sex ratio in relation to their ability to invest in the offspring. Generalist parasites constitute a particularly interesting group to test this theory as different females commonly utilize different host species showing large variation in provisioning ability. The common cuckoo ( Fisher In birds, females are the heterogametic sex and the sex determining division in avian meiosis occurs prior to ovulation and fertilization, providing the females with an unusual direct opportunity to modify offspring sex ratio Cuculus canorus) therefore constitutes a particular interesting species for investigating sex allocation. The common cuckoo is highly polygynous with ca. half of all males siring offspring with more than one female and is sexually size dimorphic The avian brood-parasitic common cuckoo (Molothrus ater) A few previous studies have not revealed any significant relationship between host species and sex ratio in the common cuckoo or the brood-parasitic brown-headed cowbird  was drawn by puncturing either the brachical or femoral vein. Permits for working with cuckoos and their hosts and collect DNA samples was received in each country; permits were issued by the Ministry of Environment and Water in Bulgaria; the Municipal Office in Hodonin (3C2KA/2003) in the Czech Republic; the Southeast Finland Regional Environment Centre in Finland; the Middle-Danube-Valley Inspectorate for Environmental Protection (31873), Nature Conservation and Water in Hungary; and the Regional Ethical Committee in Wrocław and the Faculty of Biology (KWB.0118.1-2003), University of Wrocław in Poland.Milaria calandra), great reed warblers  and marsh warblers  was collected in the surroundings of Zlatia, north-western Bulgaria A. scirpaceus) in Luzice, Czech Republic where also great reed warblers, marsh warblers and sedge warblers (A. schoenobaenus) are parsitized Phoenicurus phoenicurus) Data on three sympatrically breeding cuckoo host races parasitizing corn buntings . All loci were amplified by polymerase chain reaction (PCR) on a GeneAmp PCR System 9700  and run on a 3130XL Genetic Analyser . The sex marker and microsatellites were scored in Genemapper v. 3.7 , and the mitochondrial sequence data were assembled and manually checked in Geneious v. 4.7.6 We used the CHD1-M5 primer in combination with P8 for molecular sex determination Many cuckoo nestlings were collected within the same geographic area and could be either full- or halfsiblings, and hence potentially represent a problem of pseudoreplication. We therefore analysed a genetic dataset on 13 microsatellite markers . Furthermore, there were no significant differences in sex ratio between any pair of the five host races pooled across the different geographic localities , or between sympatric and allopatric populations, including host species as a random effect to control for host race identity .In order to analyze the effect of host species quality we included species-specific host female body mass In this study, we investigated host-specific sex ratio in the generalist brood-parasitic common cuckoo. We hypothesized that sex ratio of cuckoo offspring should vary in relation to host species quality in accordance with predictions from sex allocation theory. However, we found no evidence of any significant relationship between host race and sex ratio in one sympatric population harbouring three different host races, or in a total of five different geographically separated populations. Hence, our results corroborate the few previous studies on avian brood parasites According to theory, female cuckoos have both the ability and opportunity to increase their own fitness by selectively producing the rarer sex. Firstly, avian females have an unusual direct opportunity to modify offspring sex ratio because the sex determining division in avian meiosis occurs prior to ovulation and fertilization The traditional Trivers-Willard hypothesis rests on three assumptions. Firstly, parental condition must be associated with offspring condition; secondly, any difference in offspring condition must persist into adulthood; and thirdly, condition must differentially affect the mating success of one sex more than the other sensu Trivers and Willard The occurrence of genetic differentiation and assortative mating may explain why females show no evidence of sex ratio bias in relation to host quality. If males commonly mate within their own host race, males from large host races will not compete directly with males from smaller host races, and therefore not achieve a higher reproductive success than their sisters. Hence, natural selection will not select for a male-biased sex ratio sensu Trivers-Willard may be counteracted by the selection for smaller females in cuckoos. This could also explain the lack of any relationship between sex ratio and female quality, as determined by cuckoo egg volume, within each host race. It is also possible that egg volume does not capture maternal quality in the way we expect, and that other measures like investment in hormones and anti-oxidants in the oocyte would be more suitable A comparative study on the family Cuculidae suggests that sexual size dimorphism has more likely evolved via coevolution than sexual selection in this taxa We conclude that the generalist brood-parasitic common cuckoo show no evidence of sex-ratio bias in relation to host race, host race quality or individual maternal quality.


Aging is accompanied by substantial changes in brain function, including functional reorganization of large-scale brain networks. Such differences in network architecture have been reported both at rest and during cognitive task performance, but an open question is whether these age-related differences show task-dependent effects or represent only task-independent changes attributable to a common factor . To address this question, we used graph theoretic analysis to construct weighted cortical functional networks from hemodynamic  responses in 12 younger and 12 older adults during a speech perception task performed in both quiet and noisy listening conditions. Functional networks were constructed for each subject and listening condition based on inter-regional correlations of the fMRI signal among 66 cortical regions, and network measures of global and local efficiency were computed. Across listening conditions, older adult networks showed significantly decreased global  efficiency relative to younger adults after normalizing measures to surrogate random networks. Although listening condition produced no main effects on whole-cortex network organization, a significant age group x listening condition interaction was observed. Additionally, an exploratory analysis of regional effects uncovered age-related declines in both global and local efficiency concentrated exclusively in auditory areas , further suggestive of specificity to the speech perception tasks. Global efficiency also correlated positively with mean cortical thickness across all subjects, establishing gross cortical atrophy as a task-independent contributor to age-related differences in functional organization. Together, our findings provide evidence of age-related disruptions in cortical functional network organization during speech perception tasks, and suggest that although task-independent effects such as cortical atrophy clearly underlie age-related changes in cortical functional organization, age-related differences also demonstrate sensitivity to task domains. Aging is characterized by marked declines in sensory and cognitive functions In recent years, graph theoretic analysis has offered a powerful data-driven framework to explore the topological organization of brain networks These functional differences are underlain by neuroanatomical changes across the lifespan. Such changes include widespread atrophy of both subcortical and cortical grey matter structures Given these pervasive, co-occurring functional and neuroanatomial changes, the question also arises whether age-related effects on brain functional organization are independent of cognitive domains , or show task specificity. Recently, Wang et al. examined changes in functional networks of younger and older adults obtained via fMRI during memory encoding and retrieval tasks involving visually presented words and pictures To address these questions, we employed functional MRI to investigate age-related differences in large-scale cortical networks associated with speech perception tasks. In the scanner experiment, we tested 12 younger and 12 older adults' abilities to recognize spoken word stimuli and match them to objects on a screen  in both a quiet listening condition and in loud multi-talker background noise regional measures) and also averaged across all nodes in each network  to describe the overall network topology. We compared both regional and whole-cortex measures across age groups and task conditions, after normalizing the graph measures to values in surrogate random networks. Additionally, to test for a relationship between age-related changes in functional network properties and neuroanatomical characteristics, we examined the relationship between whole-cortex network measures and mean cortical thickness.In the present analysis, we applied graph theoretic analysis to construct weighted cortical functional networks for each subject and listening condition based upon interregional correlations of the fMRI signal among 66 cortical regions. Graph measures describing the efficiency of global and local information transfer were computed within each individual network node  of older adults coupled with age-related increases in cognitive areas in prefrontal and posterior parietal cortex, changes believed to underlie a compensatory mechanism for reduced sensory abilities in aging To foreshadow the results, we found significant age-related decreases in global  network efficiency, agreeing with previous studies of age effects on large-scale brain networks globE) and local (locE) efficiency were computed and averaged across all cortical regions to quantify the efficiency of global and local information transfer within the networks.  by assigning connections based on the inter-regional correlation of fMRI responses between 66 cortical regions specified in the Desikan-Killiany atlas . Both younger and older adults possessed small-world network topologies characterized by es e.g., . RelativTo test these differences statistically, summary measures of osts see . HencefoConceivably, observed differences in brain functional connectivity could be related to head motion in the scanner Next, we tested for effects of subject group and listening condition on network measures within individual cortical regions. We applied a single p-value cutoff of 0.05 (uncorrected for multiple comparisons) to establish significance for regional effects; thus, our results at the regional level must be regarded as exploratory. Additionally, we found several areas that showed main effects of listening condition on the network measures see . The noiWe also observed regions showing an interaction effect between subject group and task condition see . For , ssubjects .As anticipated, older adults had significantly reduced mean cortical thickness relative to younger adults  despite normal peripheral hearing abilities Interestingly, we observed a different pattern of results in these residual data relative to the original results see , S2. ForThe performance effect analysis also revealed a different pattern of results for the regional network measures . As in tyrus see . ListeniIn this study, we applied a weighted graph theoretic analysis to assess cortical functional organization in younger and older adults during performance of a speech perception task in both quiet and noisy listening conditions. We found that older adult cortical networks possessed significantly reduced global  efficiency relative to younger adults after normalizing graph measures to values in randomized networks. Most importantly, a significant group x listening condition interaction effect for This report adds to a body of research linking cognitive aging to disrupted organization of communication pathways encompassing the entire cerebral cortex Importantly, the age-related disruptions observed for whole-cortex network properties were underlain by regional changes concentrated in auditory areas of the lateral temporal cortex. Older adults possessed decreased global and local efficiency within bilateral superior and middle temporal cortex. The superior temporal cortices constitute key auditory regions responsible for low-level acoustic analysis; thus, declines in efficient information transfer involving these regions could affect mapping of inputs from the peripheral auditory system onto acoustical representations Additionally, we observed regions that exhibited main effects of listening condition (quiet vs. noisy) on either global or local efficiency. Several of these regions overlapped the default-mode network, including bilateral posterior parietal and right parahippocampal cortex We also found several cortical areas showing significant group x listening condition interaction effects on the regional network measures. Group x condition interaction effects were observed in left primary auditory cortex, right middle temporal cortex, and in default-mode areas within posterior parietal cortex. Thus, in addition to task-dependent age-related differences on whole-cortex network structure, the two listening conditions evoked differential effects on network organization between younger and older adults at the regional level.In addition, group x condition interaction effects on Based on findings of consistent age-related differences in activation patterns and functional network topology across memory encoding and recognition tasks, Grady et al. and Wang et al. argued that age-related changes in brain network organization derive from a common, domain-general factor Declining cognitive performance is a central aspect of aging. Even though the older participants in our study possessed normal peripheral hearing abilities, their speech perception performance  was significantly worse than that of younger adults under the increased sensory/cognitive demands of the noisy listening environment Ultimately, the effects of reduced cognitive performance on cortical functional organization in aging remains an area for further investigation. However, the significant age-related effects at both the whole-cortex and regional levels in this residual analysis suggest that task performance is not the only important factor driving the results observed in this study. These types of complementary analyses may prove useful in future studies to help disentangle the various behavioral, anatomical, and physiological factors influencing functional organization of the cortex in both aging research and comparative neuroimaging studies in general.Looking across all subjects, we found a significant positive correlation between mean cortical thickness and It is also worth noting some important limitations of our study. First, similar to previous studies This study provides evidence of age-related disruptions in large-scale cortical functional organization during performance of a speech perception task. Although the observed age-related differences in whole-cortex network topology partly corroborated previous studies of resting-state connectivity All subjects in this experiment gave informed written consent prior to inclusion in the study and were compensated monetarily for their participation. All research was conducted under the approval of the Northwestern University Institutional Review Board, and thus adhered to the ethical standards outlined in the 1964 Declaration of Helsinki.In this study, we employed functional magnetic resonance imaging (fMRI) to examine characteristics of cortical functional networks related to speech perception in noise (SPIN) performance in younger (19–27 years) and older (63–75 years) adults We recruited twelve younger ; 8 females) and twelve older ; 6 females) adults with no reported neurological deficits for participation in the study.Speech stimuli consisted of a set of twenty target words obtained from In the scanner experiment, subjects were presented with one-word speech stimuli via headphones . During each stimulus presentation, subjects were shown three images on a screen, including an image matching the target word and two distracters, and used a response box to select the image corresponding to the target word. For instance, in one trial, subjects heard the word “witch” in the presence of background noise, and had to select between images of a witch and two other objects from the list of stimuli. Stimuli were presented in 12-second blocks consisting of three individual stimuli (each corresponding to the same listening condition), limiting response times to four seconds per stimulus. In total, the fMRI experiment consisted of 60 stimulus blocks per condition as well as 30 null blocks during which no stimuli were presented, with all blocks presented in pseudorandomized order.*-weighted functional images were acquired using a susceptibility-weighted EPI pulse sequence , with 24 slices acquired per scan in an interleaved measurement . Functional image acquisition occurred directly after each 12-second stimulus block and lasted two seconds in duration, resulting in a 14-second repetition time (TR). The sparse functional image acquisition (long TR) ensured there was no scanner noise during stimulus presentation MR imaging data were acquired on a Siemens 3T Trio machine at the Center for Advanced MRI at Northwestern University. T1-weighted, high-resolution anatomical images were acquired axially . During the speech perception experiment, T2We pre-processed MRI data using AFNI V) were extracted containing the functional data from the stimulus blocks corresponding to the listening condition of interest, and pair-wise, zero time-lag Pearson's correlations were calculated between nodes such thati and j, where R) containing the pair-wise correlations of the fMRI responses between each pair of cortical regions for each listening condition.Next, using FreeSurfer's automated cortical parcellation G by assigning undirected, weighted connections (edges) between nodes whose absolute pair-wise correlation exceeded a pre-specified cost threshold, cr. This resulted in a weighted adjacency matrix (W), such that ij = W|ijR| if ij|≥rc|R or ij = 0W if ij|<rc|R. The cost thresholds (cr) were specified separately for each subject in order to generate networks with fixed costs . This approach facilitated comparison of network properties by ensuring that each individual network contained the same number of nodes and edges. To ensure that results were not dependent on any particular network cost, we constructed networks over a cost range from 0.10 to 0.40 at increments of 0.02.Subsequently, we defined weighted cortical graphs netL) and cluster coefficient (netC) to quantify small-world network properties i, the global efficiency (glob(i)E) quantifies the efficiency of parallel information transfer between that node and the network at large:N is the total number of nodes in the network and ijL is the shortest weighted path linking nodes i and j. Shortest paths are calculated as Watts & Strogatz originally proposed the characteristic path length (i (loc(i)E) defines the efficiency of information transfer within the subgraph iG of nodes directly connected to node i:ik equals the number of nodes directly neighboring node i. This measure represents the speed of processing within the immediate functional vicinity of a node, with high local efficiency indicating efficient local functional organization globE and locE) may then be obtained by averaging the values across all individual nodes. Small-world networks possess globE approaching (but slightly less than) that of comparable random networks .The local efficiency of an individual node We compared the cost-averaged network measures  and local (locE) efficiency for cortical networks after regressing out performance (task accuracy) effects. Error bars indicate the standard error of the mean. (JPG)Click here for additional data file.Figure S2Aging and listening condition effects on whole-cortex network measures after regressing out performance (task accuracy) effects. Summary values of (JPG)Click here for additional data file.Methods S1(DOC)Click here for additional data file.Table S1(DOC)Click here for additional data file.Table S2(DOC)Click here for additional data file.


Caenorhabditis elegans (C. elegans) to high-throughput genomic, proteomic and drug screening approaches make this organism an attractive choice for identifying new therapeutic compounds for these disorders and for understanding their mechanism of action. Indeed, a diverse set of informative C. elegans ND models have been developed manifesting abnormal behavioural or pathological phenotypes that partially recapitulate the salient cellular, molecular and pathological aspects of several distinct human NDs processes. Recent studies have identified dnajc5 encoding cysteine-string protein α (CSPα) as the disease-causing gene of a rare autosomal dominant human ND known as adult-onset neuronal ceroid lipofuscinosis (ANCL). The null animal models of CSP are characterised by impaired neurotransmission, pre-synaptic neurodegeneration and premature mortality. Simple model organisms may therefore shed light on potential therapeutic approaches for ANCL and other NDs.Debilitating neurodegenerative disorders (NDs) including Alzheimer’s disease, Parkinson’s disease, and polyglutamine diseases are a major public health challenge in increasingly aging societies. Currently approved therapeutics are successful in slowing the progression of NDs but not in reversing or preventing the symptoms of NDs. The simplicity and amenability of the nematode C. elegans ND models to uncover potential therapeutic interventions that target shared pathogenic pathways. We tested parameters such as locomotion and lifespan which act as a measure of neurological and neuromuscular function, and viability upon drug treatment in C. elegans.In this study, we are integrating multiple well-defined C. elegans null mutant model of ANCL, but also ameliorates the mobility defect and short lifespan of a distinct worm tauopathy model based on transgenic expression of mutant human tau. We are currently investigating how ethosuximide might exert its neuroprotective properties. We found that ethosuximide has no obvious aggregation-suppressing effect and suppression of proteotoxicity by ethosuximide is independent of the low voltage activated T-type calcium channel, the principal therapeutic target of ethosuximide in controlling generalised absence epilepsy.Using locomotion behaviour and lifespan as phenotypic readouts, we uncovered the anticonvulsant ethosuximide as a promising candidate drug that not only rescues the short lifespan of a Overall, our data provide good evidence that anti-epileptic ethosuximide is efficacious in several worm ND models. Further investigation of its precise mode of action and validation in vertebrate systems is required to gauge the effectiveness of this compound as early leads for drug discovery. These findings should encourage further screening and characterisation of other neuroprotective compounds, and ultimately may assist in accelerating the clinical evaluation and development of drugs to combat protein conformational disorders in general.


Analysis of MZvangl2 mutants revealed that PCP is not required for cilia formation but is required for the posterior tilting and posterior positioning of motile cilia. To determine whether cilia were required to establish cell polarity, we generated MZift88 mutants where ciliogenesis is completely abolished. MZift88 mutants have normal C&E movements, suggesting that cilia are not directly required for PCP mediated morphogenetic movements. However, we have observed defects in PCP-controlled OCD occurring during gastrulation. Remarkably, these divisions occur prior to cilia formation, suggesting a cilia-independent role for IFT proteins in cell divisions. We are currently determining whether IFT88 regulates all OCD or just those that are PCP-controlled.Polycystic kidney disease (PKD) is characterized by dilated collecting tubules causing fluid filled cysts and enlarged kidneys. Dilated tubules can result from disrupted convergence and extension (C&E) movements and defects in oriented cell divisions (OCD). Planar cell polarity (PCP) signalling has been implicated in PKD since defects in C&E and OCD are both characteristic of disrupted PCP. Surprisingly, genetic studies of mutations causing PKD predominantly affect proteins that localize near cilia and basal bodies. The functional relationship between cilia and PCP signalling in the context of PKD is still poorly understood. Previous studies of PCP effector proteins suggested that PCP signalling was required for cilia formation. However, these proteins are not specific to PCP signalling and are shared with other Wnt pathways. To determine the role of a core and specific PCP regulator on ciliogenesis, we examined maternal-zygotic (MZ)


Tonight at a classical dance recitalsymbolizing the eternal quest of the soul-force for GodI too raised for myself some questionsAs I saw the dancer adopt body twistedbeautifully gymnastic postureslike a question mark put before me- who am I?Am I the inquisitive streetwalker listening at pavementsto snake charmers’ aphrodisiac calls,watching indolently as the fast cycling roguewhirling past knocks her off, squeezes her breasts,makes offand leaves me to pacify her smothered adolescence.Or am I the automatonThat hangs on to footboards and breezes past in fast trainsevery morning and eveningthe only sensation left in me being in my handsholding on for dear life, and in my lipswolf whistling as I swirl past platforms.Or just the nimble fingerstyping away at jet-speed,taking down bosses’ notes, thumbing across wads of money,hand shakingwith prospective customers.Or just tongues, tongues and more tongueswith mounds and mounds of sugar and ghee and adulterated oilspouring it all into unknowing earsfurthering business prospectsfeeding everyone around in slow poison dosesand fattening on pure ghee, purity of expression, conscience.So that I can decorate my drawing room with costly paintings andupholsterywatch expensive dance recitalsand answer question marks once in a while.Ajai R. Singh


ATRX are clinically characterised by severe cognitive disabilities and muscular hypotonia, thus dramatically compromising their independent locomotory ability.The growth of muscle tissue and its regeneration from injury is crucially dependent on a self-renewing population of muscle progenitor cells called satellite cells. Activated satellite cells give rise to a rapidly expanding population of myoblasts that increase muscle mass by differentiating into new or adding into pre-existing muscle fibers. Patients with mutations in the chromatin remodeling gene Myf5-Cre mice with mice harbouring the Atrx floxed conditional knockout allele (herein referred to as Atrx cKO). Body mass of Atrx cKO and control littermates were measured along with general morphometric analysis of select hindlimb muscles at 3-weeks, 5-weeks, and greater than 8-weeks of age. Methods of analysis included single muscle fiber preparations from the extensor digitorum longus (EDL) and soleus muscles as well as RNA expression analysis from the EDL and soleus muscles. Primary myoblasts were also cultured from dissociated muscle tissue from the hindlimbs and analyzed via immuno-fluorescent microscopy. Neuromuscular acuity and endurance was assessed in Atrx cKO and control littermates by the roto-rod apparatus. Muscle strength was assessed by utilizing a digital grip strength measuring apparatus.We generated a skeletal muscle specific knockout mouse model by interbreeding Atrx cKO mice presented with telltale characteristics of weaker musculature, exemplified by spinal kyphosis and reduced body mass at 3-weeks of age. Satellite cell derived myoblasts from Atrx cKO mice were incapable of rapid expansion in culture but were fully capable of terminally differentiating. Atrx cKO myoblasts displayed delayed cell cycle progression through mid-late S-phase and rampant signs of genomic instability characterised by fragmented nuclei, γ-H2AX foci, and telomeric aberrations. Despite inefficient myoblast proliferative capacity, Atrx cKO animals were able to re-establish normal body mass by adulthood. Muscular fitness and function in Atrx cKO mice was also age dependent, as younger 3-week old Atrx cKO mice had a reduced capacity to stay on the roto-rod and poorer gripping strength. However, differences in grip strength of adult Atrx cKO mice were almost indistinguishable from their control littermates. Data regarding pathways mediating the hypertrophic compensatory adaptation in Atrx cKO mice will also be presented.Inefficient expansion of activated satellite cells in Atrx cKO mice results in delayed muscle development up to 3-weeks of age, when myonuclear accretion reaches its plateau. Reduced muscle mass at 3-weeks of age also correlated with poorer performance in physical tasks that require muscular force, endurance, and coordination. Compensatory mechanisms are triggered after 3-weeks of age in Atrx cKO mice that allow for the eventual recovery of body mass and muscle functionality in adults.