Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease.

Dopaminergic cell loss due to the accumulation of α-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown to exacerbate neurodegeneration, yet the role of central nervous system (CNS) resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating α-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response.

Evaluation of the therapeutic efficacy of praziquantel against schistosomes in seven countries with ongoing large-scale deworming programs.

The World Health Organization (WHO) recommends periodic assessment of the therapeutic efficacy of praziquantel (PZQ) to detect reduced efficacy that may arise from drug resistance in schistosomes. In this multi-country study (2014), we assessed the therapeutic efficacy of a single oral dose of PZQ (40 mg/kg) against Schistosoma mansoni (Brazil, Cameroon, Ethiopia, Mali, Madagascar and Tanzania), S. haematobium (Cameroon, Ethiopia, Mali, Tanzania and Zanzibar) and S. japonicum (the Philippines) infections in school-aged children, across a total of 12 different trials. Each trial was performed according to the standardized methodology for evaluating PZQ efficacy as described by the WHO. Overall, therapeutic efficacy, measured as the reduction in arithmetic mean of schistosome egg counts following drug administration (egg reduction rate; ERR), was high for all three schistosome species (S. mansoni: 93.4% (95%CI: 88.8-96.8); S. haematobium: 97.7% (95%CI: 96.5-98.7) and S. japonicum: 90.0% (95%CI: 68.4-99.3). At the trial level, therapeutic efficacy was satisfactory (point estimate ERR ≥90%) for all three Schistosoma species with the exception of S. mansoni in Cameroon where the ERR was 88.5% (95%CI: 79.0-95.1). Furthermore, we observed that in some trials individual drug response could vary significantly (wide 95%CI) and that few non-responsive individuals could significantly impact ERR point estimates. In conclusion, these results do not suggest any established reduced efficacy of the standard PZQ treatment to any of the three schistosome species within these countries. Nevertheless, the substantial degree of variation in individual responses to treatment in some countries underpins the need for future monitoring. The reported ERR values serve as reference values to compare with outcomes of future PZQ efficacy studies to ensure early detection of reduced efficacies that could occur as drug pressure continues increase. Finally, this study highlights that 95%CI should be considered in WHO guidelines to classify the therapeutic efficacy of PZQ.

Rural-Urban Differences in Breast Reconstruction Utilization Following Oncologic Resection.

BACKGROUND: Breast reconstruction (BR) is the reconstructive surgical technique that focuses on restoring normal form and function to the breast following oncologic resection. The goal of this study was to determine if BR disparities exist among rural female patients in Kentucky. METHODS: A retrospective (2006-2015), population-based cohort study was conducted on breast cancer patients (stages I-III) treated with mastectomy with or without BR. We used 2013 Beale codes to stratify patients according to geographic status. Chi-square tests were used to examine the association of BR along the rural-urban continuum. A multivariate logistic regression model controlling for patient, disease, and treatment factors was used to predict BR. The likelihood of BR was reported in odds ratios (OR) using a 95% confidence interval (CI). RESULTS: Overall, 10,032 patients met study criteria. Of those, 2,159 (21.5%) underwent BR. The rate of BR among urban, near-metro, and rural patients was 31.1%, 20.4%, and 13.4%, respectively (P < .001). Multivariate analysis revealed that women from near metro (OR 0.54, CI: 0.47-0.61; P < .001) and rural areas (OR 0.36, CI: 0.31-0.41; P < .001) were less likely to undergo BR than women from urban areas. CONCLUSION: Although BR benefits are well documented, women from rural Kentucky undergo BR at lower rates and are less likely to receive BR than their urban counterparts. Efforts should seek to promote equitable access to BR for all patients, including those from rural areas.

Appalachian Status Is a Negative Predictor of Breast Reconstruction Following Breast Cancer Resection.

BACKGROUND: Health care disparities in Appalachia are well documented. However, no previous studies have examined possible differences in the utilization of breast reconstruction (BR) in Appalachia. This study aims to determine if a disparity in BR utilization exists in women from Appalachia Kentucky. METHODS: A retrospective, population-based cohort study was conducted from January 1, 2006, to December 31, 2015. The Kentucky Cancer Registry was queried to identify population-level data for female patients diagnosed with breast cancer and treated with mastectomy. A multivariate logistic regression model controlling for patient, disease, and treatment characteristics was constructed to predict the likelihood of BR. RESULTS: Bivariate testing showed differences (P < 0.0001) in BR utilization between Appalachian and non-Appalachian women in Kentucky (15.0% and 26.3%, respectively). Multivariate analysis showed that women from Appalachia (odds ratio, 0.54; confidence interval (95), 0.48-0.61; P < 0.0001) were less likely to undergo BR than non-Appalachian women. Interestingly, the rate of BR increased over time in both Appalachian (r = 0.115; P < 0.0001) and non-Appalachian women (r = 0.148; P < 0.0001). CONCLUSIONS: Despite the benefits of BR, women from Appalachia undergo BR at lower rates and are less likely to receive BR than non-Appalachian Kentuckians. Although the rates of BR increased over time in both populations, access to comprehensive breast cancer care remains a challenge for women from Kentucky's Appalachian region.

Therapeutic glucocorticoids prevent bone loss but drive muscle wasting when administered in chronic polyarthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) experience extra-articular manifestations including osteoporosis and muscle wasting, which closely associate with severity of disease. Whilst therapeutic glucocorticoids (GCs) reduce inflammation in RA, their actions on muscle and bone metabolism in the context of chronic inflammation remain unclear. We utilised the TNF-tg model of chronic polyarthritis to ascertain the impact of therapeutic GCs on bone and muscle homeostasis in the context of systemic inflammation. METHODS: TNF-tg and wild-type (WT) animals received either vehicle or the GC corticosterone (100 µg/ml) in drinking water at onset of arthritis. Arthritis severity and clinical parameters were measured, serum collected for ELISA and muscle and bone biopsies collected for µCT, histology and mRNA analysis. In vivo findings were examined in primary cultures of osteoblasts, osteoclasts and myotubes. RESULTS: TNF-tg mice receiving GCs showed protection from inflammatory bone loss, characterised by a reduction in serum markers of bone resorption, osteoclast numbers and osteoclast activity. In contrast, muscle wasting was markedly increased in WT and TNF-tg animals receiving GCs, independently of inflammation. This was characterised by a reduction in muscle weight and fibre size, and an induction in anti-anabolic and catabolic signalling. CONCLUSIONS: This study demonstrates that when given in early onset chronic polyarthritis, oral GCs partially protect against inflammatory bone loss, but induce marked muscle wasting. These results suggest that in patients with inflammatory arthritis receiving GCs, the development of interventions to manage deleterious side effects in muscle should be prioritised.

Intervention-related increases in preoperative physical activity are maintained 6-months after Bariatric surgery: results from the bari-active trial.

Higher preoperative physical activity (PA) strongly predicts higher post-operative PA in bariatric surgery (BS) patients, providing rationale for preoperative PA interventions (PAIs). However, whether PAI-related increases can be maintained post-operatively has not been examined. This study compared PA changes across pre- (baseline, post-intervention) and post-operative (6-month follow up) periods in participants randomized to 6 weeks of preoperative PAI or standard care control (SC). Of 75 participants initially randomized, 36 (PAI n=22; SC n=14) underwent BS. Changes in daily bout-related (⩾10-min bouts) moderate-to-vigorous PA (MVPA) and steps were assessed via the SenseWear Armband monitor. PAI received weekly counseling to increase walking exercise. Retention (86%) at post-operative follow up was similar between groups. Intent-to-treat analyses showed that PAI vs SC had greater increases across time (baseline, post-intervention, follow up) in bout-related MVPA minutes/day (4.3±5.1, 26.3±21.3, 28.7±26.3 vs 10.4±22.9, 11.4±16.0, 18.5±28.2; P=0.013) and steps/day (5163±2901, 7950±3286, 7870±3936 vs 5163±2901, 5601±3368, 5087±2603; P<0.001). PAI differed from SC on bout-related MVPA at post-intervention (P=0.016; d=0.91), but not follow up (P=0.15; d=0.41), and steps at post-intervention (P=0.031; d=0.78) and follow up (P=0.024; d=0.84). PAI participants maintained preoperative PA increases post-operatively. Findings support preoperative PAIs and research to test whether PA changes can be sustained and influence surgical outcomes beyond the initial post-operative period.

RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury.

Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.

Adsorption of Bovine Serum Albumin (BSA) at the Oil/Water Interface: A Neutron Reflection Study.

The structure of the adsorbed protein layer at the oil/water interface is essential to the understanding of the role of proteins in emulsion stabilization, and it is important to glean the mechanistic events of protein adsorption at such buried interfaces. This article reports on a novel experimental methodology for probing protein adsorption at the buried oil/water interface. Neutron reflectivity was used with a carefully selected set of isotopic contrasts to study the adsorption of bovine serum albumin (BSA) at the hexadecane/water interface, and the results were compared to those for the air/water interface. The adsorption isotherm was determined at the isoelectric point, and the results showed that a higher degree of adsorption could be achieved at the more hydrophobic interface. The adsorbed BSA molecules formed a monolayer on the aqueous side of the interface. The molecules in this layer were partially denatured by the presence of oil, and once released from the spatial constraint by the globular framework they were free to establish more favorable interactions with the hydrophobic medium. Thus, a loose layer extending toward the oil phase was clearly observed, resulting in an overall broader interface. By analogy to the air/water interface, as the concentration of BSA increased to 1.0 mg mL(-1) a secondary layer extending toward the aqueous phase was observed, possibly resulting from the steric repulsion upon the saturation of the primary monolayer. Results clearly indicate a more compact arrangement of molecules at the oil/water interface: this must be caused by the loss of the globular structure as a consequence of the denaturing action of the hexadecane.

A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration.

NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein Wld(S) prevent this rise. These data indicate that the mechanism by which NMNAT and the related Wld(S) protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies.

Durability and complications of photoselective vaporisation of the prostate with the 120W high performance system GreenLight™ lithium triborate laser.

INTRODUCTION: The aim of this study was to examine the durability of photoselective vaporisation of the prostate (PVP) with the 120W GreenLight HPS(®) laser (American Medical Systems, Minnetonka, MN, US), and to examine the incidence, nature and factors associated with complications from the procedure. METHODS: Clinical records of PVP patients were reviewed to compare details between patients who developed complications and those who did not. Kaplan-Meier survival curves were used to assess durability. Cox regression was used to examine associations between complications and perioperative factors. RESULTS: Successful outcomes were maintained in 84% of 117 patients at the 2-year follow-up appointment. Complication rates were low and comparable with transurethral resection of the prostate (TURP). Complications were developed by 18 patients (15.4%) over a mean follow-up duration of 20.8 months. The most common complications were residual prostate requiring another surgery (5/117, 4.3%) and urethral stricture (4/117, 3.4%). Patients with complications had significantly longer catheterisation duration. Length of hospital stay, lasing energy, pre and postoperative levels of prostate specific antigen (PSA), pre and postoperative maximum flow rate (Qmax), and age at surgery were not found to influence development of complications. CONCLUSIONS: Results from PVP with an HPS(®) laser are durable. Complications are low and compare favourably with TURP. Lasing energy, PSA, Qmax, patient age and length of stay are not associated with development of complications. However, a longer postoperative catheterisation after PVP is associated with development of complications.

Ureteral replacement and onlay repair with reconfigured intestinal segments.

PURPOSE: Ureteral loss represents a surgical challenge to provide low pressure drainage while avoiding urinary stasis and reflux. The ideal replacement should optimize drainage while minimizing absorption, allowing for ureteral repair of varied lengths and locations with maximal preservation of the urinary tract. We reviewed our experience with ureteral repair, focusing on the use of reconfigured intestine. We report what is to our knowledge the novel use of reconfigured intestine as an onlay flap on the preserved ureteral segment and as a circumferential interpositioned segment. MATERIALS AND METHODS: A total of 16 ureters were repaired in 4 men and 9 women using reconfigured ileum, colon or appendix. Mean patient age was 45 years (range 26 to 66). The etiology of the ureteral defect was iatrogenic in 8 patients, retroperitoneal fibrosis in 3, trauma in 3 and ureteritis cystica in 1. Mean defect length was 10 cm (range 5 to 20) in the 10 right and 6 left ureters, and the defect was proximal in 3, mid in 4, distal in 7 and panureteral in 2. Ureteral replacement was performed using a segment of ileum in 13 cases or colon in 1. The segment was detubularized and reconfigured according to the Yang-Monti principle and used as a complete retubularized interposed segment in 7 cases or as an onlay flap on the opened ureter without resection in 7. Also, 2 ureters were reconstructed with an incised appendiceal flap onlayed over the preserved ureteral plate. At a mean followup of 44 months (range 12 to 78) all patients underwent antegrade nephrostogram, followed by renal scan and upper tract imaging. RESULTS: All patients tolerated the procedure without initial bowel or urinary tract complications. In 1 patient who had received radiation a ureteral fistula developed to a blind Hartmann pouch at 9 months, requiring repair. Ultimately, cystectomy was done for irradiation cystitis (onlay group). Another patient with bilateral obstruction at presentation lost unilateral renal function during 5 years. Urinary drainage was achieved in all 14 remaining renal units with preservation of function, as shown on renal scan. Patients reported minor mucous production without renal colic or stone formation. CONCLUSIONS: Long ureteral defects require tissue replacement when bladder flaps do not suffice. Ureteral replacement can be achieved by reconfigured intestinal segments, which are readily mobilized and secured as interposed segments or as an onlay flap on the preserved ureter. A relatively short segment can be used to repair a lengthy defect along any segment of ureter, also allowing for nonrefluxing reimplantation.

Smoking cessation in the workplace.

BACKGROUND: The workplace is an important setting for reaching potentially large numbers of smokers. AIMS: To review the evidence about smoking cessation in the workplace. METHODS: Literature review including a synthesis of findings from recent systematic reviews and meta-analyses of workplace smoking cessation programmes, a separate review of the qualitative evidence, case studies and an expert panel assessment. RESULTS: We found advantages, identified or confirmed from the mixed methods used in this work to holding smoking cessation programmes in the workplace. These included: (i) easy access to large numbers of worker populations for large workplaces, (ii) the potential improved recruitment to such programmes given this, (iii) the opportunity to access young men, traditionally difficult to achieve, (iv) access to occupational health and other staff who can assist with support and delivery and (v) ability for workers to attend relatively easily. Evidence on the importance of developing peer support at work was mixed. The simple provision or availability of programmes and interventions was unlikely to provide any beneficial behaviour change. Interventions should target workers that actively want to stop smoking, use elements that workers have identified as useful or focus on altering beliefs about smoking and the need to stop. CONCLUSIONS: Smoking cessation programmes at work can provide useful support for workers wishing to stop smoking. They are only likely to be effective if participants have moved beyond the contemplation stage regarding smoking cessation, so that stopping smoking is a personal priority.

Psychiatric disorders among individuals who drive after the recent use of alcohol and drugs / Transtornos psiquiátricos entre indivíduos que dirigem sob uso recente de álcool e drogas

INTRODUCTION: This cross-sectional study assessed the prevalence of psychiatric disorders among drivers , as well as the association between recent alcohol and drug use and psychiatric diagnoses using telephone interviews. METHODS: Drivers (n = 1,134) included in a roadside survey from 25 Brazilian state capitals were given a breathalyzer test, and their saliva was tested for psychoactive drugs. A telephone interview was conducted to perform psychiatric disorder evaluations using the MINI. This association was analyzed with a Poisson regression model. RESULTS: The prevalence of any psychiatric disorder was 40.5% among drivers with recent alcohol or drug use, compared with 12.9% among the other drivers. Alcohol/drug-positive drivers reported a higher prevalence of depression (19.4%), mania (6.5%), hypomania (5.4%), post-traumatic stress disorder (8.6%), antisocial personality (7.8%), and substance/alcohol abuse or dependence (48.1%) compared with other drivers (3.5, 2.5, 2.1, 0.5, 1.3 and 18.3% [p < 0.001], respectively). Drivers with recent alcohol or drug use were 2.5 times more likely to have a psychiatric diagnosis (CI: 1.8-3.6, p < 0.001). DISCUSSION: This is the first study in a low-/middle-income country to evaluate psychiatric disorders in drivers with recent alcohol or drug using telephone interviews. Psychiatric disorders were found to be associated with drug and alcohol use. This type of epidemiological information for curtailing related driving problems, as these psychiatric conditions are diagnosable. FINAL REMARKS: The results of this study can aid in the design of interventions, treatment programs and focused psychiatric evaluations, both in Brazil and abroad.

INTRODUÇÃO: Este estudo transversal avaliou a prevalência de transtornos psiquiátricos e a associação entre dirigir alcoolizado e transtornos psiquiátricos entre motoristas por meio de entrevistas telefônicas. MÉTODO: Motoristas (n = 1.134) selecionados a partir de um estudo realizado nas rodovias de 25 capitais brasileiras foram etilometrizados e tiveram sua saliva testada para substâncias psicoativas. Uma entrevista por telefone foi realizada para obter dados sobre transtornos psiquiátricos através do MINI. A associação entre transtornos psiquiátricos e dirigir com uso recente de substâncias foi analisada com um modelo de regressão de Poisson. RESULTADOS: A prevalência de transtornos psiquiátricos foi de 40,5% entre os motoristas que beberam/usaram drogas, em comparação com 12,9% nos demais motoristas. Motoristas que dirigiram com uso recente de substâncias relataram uma maior prevalência de depressão (19,4%), mania (6,5%), hipomania (5,4%), transtorno de estresse póstraumático (8,6%), personalidade antissocial (7,8%), e abuso ou dependência de álcool/drogas (48,1%) quando comparados com os outros motoristas (3,5%, 2,5%, 2,1%, 0,5%, 1,3% e 18,3%, p < 0,001), respectivamente). Motoristas com uso recente de substâncias apresentaram 2,5 mais chance de ter qualquer diagnóstico psiquiátrico (IC: 1,8-3,6, p < 0,001). DISCUSSÃO: Este é o primeiro estudo em países de baixa e média renda cujo objetivo é avaliar transtornos psiquiátricos em motoristas com uso recente de substâncias por meio de entrevistas telefônicas. Transtornos psiquiátricos foram associados com o comportamento de dirigir com uso recente de substâncias. Este tipo de informação epidemiológica é fundamental para estratégias de planejamento que visam enfrentar problemas relacionados com o beber e dirigir, uma vez que estas condições psiquiátricas são diagnosticáveis. OBSERVAÇÕES FINAIS: Os resultados deste estudo podem auxiliar no desenvolvimento de intervenÇÕes, programas de tratamento e avaliação psiquiátrica, tanto no Brasil quanto no exterior.

Hyperthyroidism and human chorionic gonadotrophin production in gestational trophoblastic disease.

BACKGROUND: Gestational trophoblastic disease (GTD) is a rare complication of pregnancy, ranging from molar pregnancy to choriocarcinoma. Patients with persistent disease require treatment with chemotherapy. For the vast majority, prognosis is excellent. Occasionally, GTD is complicated by hyperthyroidism, which may require treatment. This is thought to occur due to molecular mimicry between human chorionic gonadotrophin (HCG) and thyroid-stimulating hormone (TSH), and hence cross-reactivity with the TSH receptor. Hyperthyroidism usually resolves as the GTD is successfully treated and correspondingly HCG levels normalise. METHODS: This paper reviews cases of GTD treated over a 5-year period at one of the three UK centres and identifies the prevalence of hyperthyroidism in this population. Four cases with clinical hyperthyroidism are discussed. RESULTS: On review of the 196 patients with gestational trophoblastic neoplasia treated with chemotherapy in Sheffield since 2005, 14 (7%) had biochemical hyperthyroidism. Of these, four had evidence of clinical hyperthyroidism. CONCLUSION: Concomitant biochemical thyroid disease in patients with GTD is relatively common, and measurement of thyroid function in patients with persistent GTD is, therefore, important. The development of hyperthyroidism is largely influenced by the level of HCG and disease burden, and usually settles with treatment of the persistent GTD. However, rarely the thyroid stimulation can have potentially life-threatening consequences.

Proposal of a 2-tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior.

Currently, prognostic and therapeutic determinations for canine cutaneous mast cell tumors (MCTs) are primarily based on histologic grade. However, the use of different grading systems by veterinary pathologists and institutional modifications make the prognostic value of histologic grading highly questionable. To evaluate the consistency of microscopic grading among veterinary pathologists and the prognostic significance of the Patnaik grading system, 95 cutaneous MCTs from 95 dogs were graded in a blinded study by 28 veterinary pathologists from 16 institutions. Concordance among veterinary pathologists was 75% for the diagnosis of grade 3 MCTs and less than 64% for the diagnosis of grade 1 and 2 MCTs. To improve concordance among pathologists and to provide better prognostic significance, a 2-tier histologic grading system was devised. The diagnosis of high-grade MCTs is based on the presence of any one of the following criteria: at least 7 mitotic figures in 10 high-power fields (hpf); at least 3 multinucleated (3 or more nuclei) cells in 10 hpf; at least 3 bizarre nuclei in 10 hpf; karyomegaly (ie, nuclear diameters of at least 10% of neoplastic cells vary by at least two-fold). Fields with the highest mitotic activity or with the highest degree of anisokaryosis were selected to assess the different parameters. According to the novel grading system, high-grade MCTs were significantly associated with shorter time to metastasis or new tumor development, and with shorter survival time. The median survival time was less than 4 months for high-grade MCTs but more than 2 years for low-grade MCTs.

Recommended guidelines for the conduct and evaluation of prognostic studies in veterinary oncology.

There is an increasing need for more accurate prognostic and predictive markers in veterinary oncology because of an increasing number of treatment options, the increased financial costs associated with treatment, and the emotional stress experienced by owners in association with the disease and its treatment. Numerous studies have evaluated potential prognostic and predictive markers for veterinary neoplastic diseases, but there are no established guidelines or standards for the conduct and reporting of prognostic studies in veterinary medicine. This lack of standardization has made the evaluation and comparison of studies difficult. Most important, translating these results to clinical applications is problematic. To address this issue, the American College of Veterinary Pathologists' Oncology Committee organized an initiative to establish guidelines for the conduct and reporting of prognostic studies in veterinary oncology. The goal of this initiative is to increase the quality and standardization of veterinary prognostic studies to facilitate independent evaluation, validation, comparison, and implementation of study results. This article represents a consensus statement on the conduct and reporting of prognostic studies in veterinary oncology from veterinary pathologists and oncologists from around the world. These guidelines should be considered a recommendation based on the current state of knowledge in the field, and they will need to be continually reevaluated and revised as the field of veterinary oncology continues to progress. As mentioned, these guidelines were developed through an initiative of the American College of Veterinary Pathologists' Oncology Committee, and they have been reviewed and endorsed by the World Small Animal Veterinary Association.

An Electrode Array for Limiting Blood Loss During Liver Resection: Optimization via Mathematical Modeling.

Liver resection is the current standard treatment for patients with both primary and metastatic liver cancer. The principal causes of morbidity and mortality after liver resection are related to blood loss (typically between 0.5 and 1 L), especially in cases where transfusion is required. Blood transfusions have been correlated with decreased long-term survival, increased risk of perioperative mortality and complications. The goal of this study was to evaluate different designs of a radiofrequency (RF) electrode array for use during liver resection. The purpose of this electrode array is to coagulate a slice of tissue including large vessels before resecting along that plane, thereby significantly reducing blood loss. Finite Element Method models were created to evaluate monopolar and bipolar power application, needle and blade shaped electrodes, as well as different electrode distances. Electric current density, temperature distribution, and coagulation zone sizes were measured. The best performance was achieved with a design of blade shaped electrodes (5 x 0.1 mm cross section) spaced 1.5 cm apart. The electrodes have power applied in bipolar mode to two adjacent electrodes, then switched sequentially in short intervals between electrode pairs to rapidly heat the tissue slice. This device produces a ~1.5 cm wide coagulation zone, with temperatures over 97 masculineC throughout the tissue slice within 3 min, and may facilitate coagulation of large vessels.

Variable hearing impairment in a DFNB2 family with a novel MYO7A missense mutation.

Myosin VIIA mutations have been associated with non-syndromic hearing loss (DFNB2; DFNA11) and Usher syndrome type 1B (USH1B). We report clinical and genetic analyses of a consanguineous Iranian family segregating autosomal recessive non-syndromic hearing loss (ARNSHL). The hearing impairment was mapped to the DFNB2 locus using Affymetrix 50K GeneChips; direct sequencing of the MYO7A gene was completed. The Iranian family (L-1419) was shown to segregate a novel homozygous missense mutation (c.1184G>A) that results in a p.R395H amino acid substitution in the motor domain of the myosin VIIA protein. As one affected family member had significantly less severe hearing loss, we used a candidate approach to search for a genetic modifier. This novel MYO7A mutation is the first reported to cause DFNB2 in the Iranian population and this DFNB2 family is the first to be associated with a potential modifier. The absence of vestibular and retinal defects, and less severe low frequency hearing loss, is consistent with the phenotype of a recently reported Pakistani DFNB2 family. Thus, we conclude this family has non-syndromic hearing loss (DFNB2) rather than USH1B, providing further evidence that these two diseases represent discrete disorders.

Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ.

Recent advances in the study of the tumor microenvironment have revealed significant interaction between tumor cells and their surrounding stroma in model systems. We have previously shown that two distinct stromal signatures derived from a macrophage (CSF1) response and a fibroblastic (DTF-like) response are present in subsets of invasive breast cancers and show a correlation with clinical outcome. In the present study we explore whether these signatures also exist in the stroma of ductal carcinoma in situ (DCIS). We studied the signatures by both gene expression profile analysis of a publically available data set of DCIS and by immunohistochemistry (IHC) on a tissue microarray of DCIS and invasive breast cancer cases. Both the gene expression and immunohistochemical data show that the macrophage response and fibroblast expression signatures are present in the stroma of subsets of DCIS cases. The incidence of the stromal signatures in DCIS is similar to the incidence in invasive breast cancer that we have previously reported. We also find that the macrophage response signature is associated with higher grade DCIS and cases which are ER and PR negative, whereas the fibroblast signature was not associated with any clinicopathologic features in DCIS. A comparison of 115 matched cases of DCIS and invasive breast cancer found a correlation between the type of stromal response in DCIS and invasive ductal carcinoma (IDC) within the same patient for both the macrophage response and the fibroblast stromal signatures (P = 0.03 and 0.08, respectively). This study is a first characterization of these signatures in DCIS. These signatures have significant clinicopathologic associations and tend to be conserved as the tumor progresses from DCIS to invasive breast cancer.