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Supplemental Digital Content is available in the text.Mechanical circulatory support for children under 6 years of age remains a challenge. This article describes the preclinical status and the results of recent animal testing with the Penn State Infant Left Ventricular Assist Device (VAD). The objectives have been to 1) demonstrate acceptably low thromboembolic risk to support Food and Drug Administration approval, 2) challenge the device by using minimal to no anticoagulation in order to identify any design or manufacturing weaknesses, and 3) improve our understanding of device thrombogenicity in the ovine animal model, using multicomponent measurements of the coagulation system and renal ischemia quantification, in order to better correlate animal results with human results.The Infant VAD was implanted as a left VAD (LVAD) in 18–29 kg lambs. Twelve LVAD and five surgical sham animals were electively terminated after approximately 30 or 60 days. Anticoagulation was by unfractionated heparin targeting thromboelastography R times of 2x normal (n= 6) or 1x normal (n= 6) resulting in negligible heparin activity as measured by anti-Xa assay (<0.1 IU/ml). Platelet inhibitors were not used.There were no clinically evident strokes or evidence of end organ dysfunction in any of the 12 electively terminated LVAD studies. The degree of renal ischemic lesions in device animals was not significantly different than that found in five surgical sham studies, demonstrating minimal device thromboembolism.In summary, these results in a challenging animal test protocol support the conclusion that the Penn State Infant VAD has a low thromboembolic risk and may allow lower levels of anticoagulation.

Supplemental Digital Content is available in the text

Diabetes is the leading cause of end-stage renal disease, resulting in a significant health care burden and loss of economic productivity by affected individuals. Because current therapies for progression of diabetic nephropathy (DN) are only moderately successful, identification of underlying mechanisms of disease is essential to develop more effective therapies. We showed previously that inhibition of arginase using S-(2-boronoethyl)-l-cysteine (BEC) or genetic deficiency of the arginase-2 isozyme was protective against key features of nephropathy in diabetic mouse models. However, those studies did not determine whether all markers of DN were dependent only on arginase-2 expression. The objective of this study was to identify features of DN that are associated specifically with expression of arginase-1 or −2. Elevated urinary albumin excretion rate and plasma urea levels, increases in renal fibronectin mRNA levels, and decreased renal medullary blood flow were associated almost completely and specifically with arginase-2 expression, indicating that arginase-2 selectively mediates major aspects of diabetic renal injury. However, increases in renal macrophage infiltration and renal TNF-α mRNA levels occurred independent of arginase-2 expression but were almost entirely abolished by treatment with BEC, indicating a distinct role for arginase-1. We therefore generated mice with a macrophage-specific deletion of arginase-1 (CD11bCre/Arg1fl/fl). CD11bCre/Arg1fl/flmice had significantly reduced macrophage infiltration but had no effect on albuminuria compared with Arg1fl/flmice after 12 wk of streptozotocin-induced diabetes. These results indicate that selective inhibition of arginase-2 would be effective in preventing or ameliorating major features of diabetic renal injury.

Novel therapeutic interventions for preventing or attenuating kidney injury following ischemia-reperfusion injury (IRI) remain a focus of significant interest. Currently, there are no definitive therapeutic or preventive approaches available for ischemic acute kidney injury (AKI). Our objective is to determine 1) whether renal arginase activity or expression is increased in renal IRI, and 2) whether arginase plays a role in development of renal IRI. The impact of arginase activity and expression on renal damage was evaluated in male C57BL/6J (wild type) and arginase-2 (ARG2)-deficient (Arg2−/−) mice subjected to bilateral renal ischemia for 28 min, followed by reperfusion for 24 h. ARG2 expression and arginase activity significantly increased following renal IRI, paralleling the increase in kidney injury. Pharmacological blockade or genetic deficiency of Arg2conferred kidney protection in renal IRI. Arg2−/−mice had significantly attenuated kidney injury and lower plasma creatinine and blood urea nitrogen levels after renal IRI. Blocking arginases using S-(2-boronoethyl)-l-cysteine (BEC) 18 h before ischemia mimicked arginase deficiency by reducing kidney injury, histopathological changes and kidney injury marker-1 expression, renal apoptosis, kidney inflammatory cell recruitment and inflammatory cytokines, and kidney oxidative stress; increasing kidney nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation, kidney peroxisome proliferator-activated receptor-γ coactivator-1α expression, and mitochondrial ATP; and preserving kidney mitochondrial ultrastructure compared with vehicle-treated IRI mice. Importantly, BEC-treated eNOS-knockout mice failed to reduce blood urea nitrogen and creatinine following renal IRI. These findings indicate that ARG2 plays a major role in renal IRI, via an eNOS-dependent mechanism, and that blocking ARG2 activity or expression could be a novel therapeutic approach for prevention of AKI.

Inflammation is a central pathophysiologic mechanism that contributes to diabetes mellitus and diabetic nephropathy. Recently, we showed that macrophages directly contribute to diabetic renal injury and that pharmacological blockade or genetic deficiency of chemokine (C-C motif) receptor 2 (CCR2) confers kidney protection in diabetic nephropathy. However, the direct role of CCR2 in kidney-derived cells such as podocytes in diabetic nephropathy remains unclear. To study this, we developed a transgenic mouse model expressing CCR2 specifically in podocytes (Tg[NPHS2-Ccr2]) on a nephropathy-prone (DBA/2J) and CCR2-deficient (Ccr2-/-) background with heterozygous Ccr2+/-littermate controls. Diabetes was induced by streptozotocin. As expected, absence of CCR2 conferred kidney protection after nine weeks of diabetes. In contrast, transgenic CCR2 overexpression in the podocytes of Ccr2-/-mice resulted in significantly increased albuminuria, blood urea nitrogen, histopathologic changes, kidney fibronectin and type 1 collagen expression, podocyte loss, and glomerular apoptosis after nine weeks of streptozotocin-induced diabetes. Interestingly, there was no concurrent increase in kidney macrophage recruitment or inflammatory cytokine levels in the mice. These findings support a direct role for CCR2 expression in podocytes to mediate diabetic renal injury, independent of monocyte/macrophage recruitment. Thus, targeting the CCR2 signaling cascade in podocytes could be a novel therapeutic approach for treatment of diabetic nephropathy.

This interview with Guddu Khan of Guddu’s Film Archive was conducted in October 2015, concurrent with the first major public exhibition of Guddu Khan’s memorabilia collection in Karachi, and was translated from Urdu by Abeera Arif-Bashir. An introductory essay prefaces this interview and explores some of the methodological implications of the ways in which Guddu re-contextualizes both the objects he collects and the audience-consumer for which they were initially produced. Despite a rich and vibrant “golden-age” of film production that flourished from the 1960s to the early 1980s, the circulation and dissemination of cinema in contemporary Pakistan is defined by a socio-cultural climate that is hostile to filmmaking as a system of production and film as an object of mass consumption. In spite of this, Guddu Khan shares his small apartment in Karachi with an unparalleled collection of artifacts relating to the Pakistani film industry, a collection he has amassed in parallel with the deterioration of the industry that has become interwoven with his own personal biography.

The article focuses on the work "Material Speculation: ISIS" by Iranian-American artist Morehshin Allahyari in which he used three-dimensional printing technology.

The article offers information on UTOPIA 2016, a celebration of the 500th anniversary of the publication of author Thomas More's political philosophical fiction, that will be held across London, England, in 2016.

Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell–intrinsic IFN-γ receptor (IFN-γR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development. We further demonstrate that IFN-γR and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-γ production by B cells. Global or B cell–specific IFN-γR deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG2c and IgG2b auto-Ab titers compared with B6.Sle1b mice. Additionally, we observed that the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell–intrinsic IFN-γR signaling, suggesting that IFN-γR signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-γR deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell–dependent foreign antigens, indicating that IFN-γR signaling regulates autoimmune, but not the foreign antigen–driven, GC and Tfh cell responses. Together, our data define a novel B cell–intrinsic IFN-γR signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus.

The article looks at the protected status earned by audiocassettes in United Nations Educational, Scientific and Cultural Organization's (UNESCO) Intangible Cultural Heritage (ICH). Topics covered include the social habits and practices surrounding the uses of audiocassettes, symbol of low-cost production, distribution, and duplication, cassette use and consumption in Pakistan, cassette cultures in Afghanistan and South Asia, cassette-dramas, audio letters, and capacious media.

The management of patients with advanced stages of head and neck cancer requires a multidisciplinary and multimodality treatment approach which includes a combination of surgery, radiation, and chemotherapy. These toxic treatment protocols have significantly improved survival outcomes in a distinct population of human papillomavirus (HPV) associated oropharyngeal cancer. HPV negative head and neck squamous cell carcinoma (HNSCC) remains a challenge to treat because there is only a modest improvement in survival with the present treatment regimens, requiring innovative and new treatment approaches. Oncolytic viruses used as low toxicity adjunct cancer therapies are novel, potentially effective treatments for HNSCC. One such oncolytic virus is Respiratory Orphan Enteric virus or reovirus. Susceptibility of HNSCC cells towards reovirus infection and reovirus-induced cell death has been previously demonstrated but has not been compared in HPV positive and negative HNSCC cell lines. To compare the infectivity and oncolytic activity of reovirus in HPV positive and negative HNSCC cell lines. Seven HNSCC cell lines were infected with serial dilutions of reovirus. Two cell lines (UM-SCC-47 and UM-SCC-104) were positive for type 16 HPV. Infectivity was measured using a cell-based ELISA assay 18 h after infection. Oncolytic activity was determined using an alamar blue viability assay 96 h after infection. Non-linear regression models were used to calculate the amounts of virus required to infect and to cause cell death in 50% of a given cell line (EC50). EC50values were compared. HPV negative cells were more susceptible to viral infection and oncolysis compared to HPV positive cell lines. EC50for infectivity at 18 h ranged from multiplicity of infection (MOI) values (PFU/cell) of 18.6 (SCC-9) to 3133 (UM-SCC 104). EC50for cell death at 96 h ranged from a MOI (PFU/cell) of 1.02×102(UM-SCC-14A) to 3.19×108(UM-SCC-47). There was a 3×106fold difference between the least susceptible cell line (UM-SCC-47) and the most susceptible line (UM-SCC 14A) EC50for cell death at 96 h. HPV negative HNSCC cell lines appear to demonstrate greater reovirus infectivity and virus-mediated oncolysis compared to HPV positive HNSCC. Reovirus shows promise as a novel therapy in HNSCC, and may be of particular benefit in HPV negative patients.

Our previous publication showed that inhibition of arginase prevents the development of diabetic nephropathy (DN). However, identification of targets that retard the progression of established DN–which is more clinically relevant–is lacking. Therefore, we tested the hypothesis that arginase inhibition would prevent the progression of established DN. Effects of arginase inhibition were compared with treatment with the angiotensin-converting enzyme inhibitor captopril, a current standard of care in DN. Experiments were conducted in Ins2Akitamice treated with the arginase inhibitor S-(2-boronoethyl)-l-cysteine (BEC) or captopril starting at 6 wk of age for 12 wk (early treatment) or starting at 12 wk of age for 6 wk (late treatment). Early and late treatment with BEC resulted in protection from DN as indicated by reduced albuminuria, histological changes, kidney macrophage infiltration, urinary thiobarbituric acid-reactive substances, and restored nephrin expression, kidney nitrate/nitrite, kidney endothelial nitric oxide synthase phosphorylation, and renal medullary blood flow compared with vehicle-treated Ins2Akitamice at 18 wk of age. Interestingly, early treatment with captopril reduced albuminuria, histological changes, and kidney macrophage infiltration without affecting the other parameters, but late treatment with captopril was ineffective. These findings highlight the importance of arginase inhibition as a new potential therapeutic intervention in both early and late stages of diabetic renal injury.

IMPORTANCE: Keratinization is a histologic feature on hematoxylin-eosin staining associated with adverse outcomes in head and neck cancer, particularly oral cavity squamous cell carcinoma. However, the prognostic value of keratinization has not been demonstrated in oropharyngeal squamous cell carcinoma (OPSCC) in a large cohort of patients. OBJECTIVE: To quantify the prognostic value of keratinization in a large cohort of patients with OPSCC with subgroup analysis based on p16 status, basaloid differentiation, and smoking status. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cross-sectional study using a prospectively collected database that identified 208 patients with OPSCC diagnosed and treated at a single tertiary cancer center from 2002 to 2009. Tissue microarrays (TMAs) were generated from 208 patient specimens stained with hematoxylin-eosin and immunohistochemical markers. Digital images from stained TMAs were scored for the presence of keratinization and/or basaloid differentiation and for p16 status. INTERVENTIONS: Patients were treated with curative intent with surgery, radiation, and/or chemotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome measure was 5-year disease-specific survival (DSS) in OPSCC according to keratinization. Univariate and multivariate survival analyses were performed to estimate survival according to histopathologic profile and smoking status. RESULTS: In the 208 samples, 96 were keratinizing and 112 were nonkeratinizing. Patients with keratinizing tumors were more likely to have advanced-stage disease and be p16 negative. Keratinization was independently associated with adverse outcomes. The 5-year DSS was significantly higher for nonkeratinizing tumors (63.3%) compared with keratinizing tumors (44.8%; P = .007). In subgroup analysis, nonkeratinization was associated with improved DSS in those with nonbasaloid and p16-negative tumors and in patients who were smokers. When stratifying patients based on keratinization, p16-status, and smoking status, patients with p16-negative keratinizing tumors who were smokers had the lowest 5-year DSS (26.7%). CONCLUSIONS AND RELEVANCE: Patients with nonkeratinized OPSCC have improved survival compared with those with keratinizing tumors. Information on keratinization is most useful prognostically in those who have p16-negative and nonbasaloid tumors and in patients who are smokers. Survival can be stratified using keratinization, p16 status, and smoking status.

The article examines various issues relating to torrent websites, which allow users to upload and download large files on the Internet to and from other users. Particular focus is given to how this relates to the art and culture of Pakistan. Additional topics discussed include art and artifacts looted under colonial rule, Pakistani filmmaking and the work of the artist and essayist Hito Steyerl.

Our recent publication showed that pharmacological blockade of arginases confers kidney protection in diabetic nephropathy via a nitric oxide (NO) synthase (NOS)3-dependent mechanism. Arginase competes with endothelial NOS (eNOS) for the common substrate l-arginine. Lack of l-arginine results in reduced NO production and eNOS uncoupling, which lead to endothelial dysfunction. Therefore, we hypothesized that l-arginine or l-citrulline supplementation would ameliorate diabetic nephropathy. DBA mice injected with multiple low doses of vehicle or streptozotocin (50 mg/kg ip for 5 days) were provided drinking water with or without l-arginine (1.5%, 6.05 g·kg−1·day−1) or l-citrulline (1.66%, 5.73 g·kg−1·day−1) for 9 wk. Nonsupplemented diabetic mice showed significant increases in albuminuria, blood urea nitrogen, glomerular histopathological changes, kidney macrophage recruitment, kidney TNF-α and fibronectin mRNA expression, kidney arginase activity, kidney arginase-2 protein expression, and urinary oxidative stress along with a significant reduction of nephrin and eNOS protein expression and kidney nitrite + nitrate compared with normal mice after 9 wk of diabetes. Surprisingly, l-arginine or l-citrulline supplementation in diabetic mice did not affect any of these parameters despite greatly increasing kidney and plasma arginine levels. These findings demonstrate that chronic l-arginine or l-citrulline supplementation does not prevent or reduce renal injury in a model of type 1 diabetes.

IMPORTANCE: The classic presentation of laryngomalacia (LM) is stridor, but alternate presentations include snoring and/or sleep-disordered breathing (S-SDB) and swallowing dysfunction (SWD). Several classification schemes have been developed for LM, but to our knowledge, none have been successfully investigated as to the ability to predict parameters of patients with LM or surgical outcomes. OBJECTIVE: To compare parameters of patients with different types of LM and determine whether the type has prognostic value for surgical outcomes and to explore if any variable predicts or correlates with the type of LM. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series from a single tertiary pediatric otolaryngology practice. Patients with LM treated with supraglottoplasty (SGP) were eligible. We included patients with confirmed diagnosis of LM who underwent a cold steel SGP and had complete resolution of symptoms or at least 3 months of follow-up, with complete data. INTERVENTIONS: Investigations and treatment of the patients were followed as per routine practice for the senior author (H.E.). MAIN OUTCOMES AND MEASURES: Demographics, type of LM, secondary airway lesions, secondary diagnosis, primary presentation (stridor, S-SDB, SWD), and outcome of SGP were collected. Correlation and multiple regression analysis were performed. RESULTS: A total of 125 children with LM who underwent SGP for LM were identified. Of these procedures, 119 were cold steel technique, and 8 were repeated procedures. Ninety patients met criteria and were included (mean [SD] age, 1.46 [2.34] years [range, &lt;6 months to 15 years]; male to female ratio, 1.9:1). The primary presentation was stridor in 66 children, S-SDB in 14, and SWD in 10. The type of LM correlated significantly with age (−0.9), and presentation (0.49). Sex and presence of neurological diagnosis (correlation coefficient [SE], −0.317 [0.136], P = .02; and −0.968 [0.361], P &lt;.01, respectively) were associated with outcome. Presentation and obesity were associated with type of LM (−0.251 [0.071], P &lt;.001; and 0.593 [0.296], P = .048, respectively). CONCLUSIONS AND RELEVANCE: Type of LM varies by age and primary presentation. Outcome of management is poorer for males and in the presence of a neurological diagnosis. The findings of the present study may help in counseling parents on the risks and benefits of SGP surgery as well as on expected outcomes postoperatively. Further work is required in validating an existing classification scheme for LM or developing a new, validated classification system with may be used for future outcomes research.

Exogenous administration of cholecystokinin (CCK) induces hypertrophy and hyperplasia of the pancreas with an increase in DNA content. We hypothesized that endogenous CCK is involved in the malignant progression of pancreatic intraepithelial neoplasia (PanIN) lesions and the fibrosis associated with pancreatic cancer.

IMPORTANCE: Laryngomalacia (LM) classically presents with stridor in early infancy but can present atypically with snoring and/or sleep-disordered breathing (S-SDB) or swallowing dysfunction (SwD). The epidemiology of these atypical presentations has not been established in the literature. OBJECTIVE: To document the primary modes of presentation for LM in a consecutive series of children and to compare the characteristics of each subgroup. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series in a single tertiary pediatric otolaryngology practice. Outpatient and surgical records were searched for patients diagnosed as having LM from 2002 to 2009. We included all children with endoscopically confirmed LM without prior documentation of the diagnosis (n = 88). INTERVENTIONS: Patients were investigated and managed according to the routine practice pattern of the senior author. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the proportion of the various primary presentations of LM. Age, sex, type of LM, management, and secondary diagnoses were also collected. Subgroup analysis was performed. RESULTS: Of 117 potentially eligible patients identified, 88 children had a confirmed diagnosis of LM and were thus included (1.9:1 male to female sex ratio; mean [SD] age, 14.5 [23.0] months; age range, 0.2-96.0 months). Fifty-six children (64%) presented primarily with awake stridor and variable respiratory distress; 22 (25%) with S-SDB; and 10 (11%) with SWD. The difference in mean (SD) age for each group was statistically significant by analysis of variance: stridor, 3.5 (2.8) months; S-SDB, 46.0 (27.2) months; and SwD, 4.8 (4.6) months (P &lt; .001). By χ2 analysis, sex distribution was not significantly different between subgroups (P = .29), nor was the proportion of children who underwent supraglottoplasty (P = .07). The difference in proportion of types of LM between the stridor and atypical presentations was statistically significant (χ2P &lt; .05), with type 1 LM predominating in children presenting with S-SDB. CONCLUSIONS AND RELEVANCE: Because LM may present primarily with S-SDB and SwD in a significant proportion of children, the diagnosis must be considered in patients presenting with these upper airway complaints. The morphologic type of LM may vary by presentation.

Monocyte/macrophage recruitment correlates strongly with the progression of renal impairment in diabetic nephropathy (DN), yet their direct role is not clear. We hypothesized that macrophages contribute to direct podocyte injury and/or an abnormal podocyte niche leading to DN. Experiments were conducted in CD11b-DTR mice treated with diphtheria toxin (DT) to deplete macrophages after streptozotocin-induced diabetes. Additional experiments were conducted in bone marrow chimeric (CD11b-DTR→ C57BL6/J) mice. Diabetes was associated with an increase in the M1-to-M2 ratio by 6 wk after the induction of diabetes. Macrophage depletion in diabetic CD11b-DTR mice significantly attenuated albuminuria, kidney macrophage recruitment, and glomerular histological changes and preserved kidney nephrin and podocin expression compared with diabetic CD11b-DTR mice treated with mutant DT. These data were confirmed in chimeric mice indicating a direct role of bone marrow-derived macrophages in DN. In vitro, podocytes grown in high-glucose media significantly increased macrophage migration compared with podocytes grown in normal glucose media. In addition, classically activated M1 macrophages, but not M2 macrophages, induced podocyte permeability. These findings provide evidence showing that macrophages directly contribute to kidney injury in DN, perhaps by altering podocyte integrity through the proinflammatory M1 subset of macrophages. Attenuating the deleterious effects of macrophages on podocytes could provide a new therapeutic approach to the treatment of DN.

Pigment epithelium-derived factor (PEDF) is a multifunctional protein with antiangiogenic, antioxidative, and anti-inflammatory properties. PEDF is involved in the pathogenesis of diabetic retinopathy, but its direct role in the kidneys remains unclear. We hypothesize that a PEDF fragment (P78-PEDF) confers kidney protection in diabetic nephropathy (DN). The localization of the full-length PEDF protein were determined in DBA mice following multiple low doses of streptozotocin. Using immunohistochemistry, PEDF was localized in the kidney vasculature, interstitial space, glomeruli, tubules, and renal medulla. Kidney PEDF protein and mRNA expression were significantly reduced in diabetic mice. Continuous infusion of P78-PEDF for 6 wk resulted in protection from diabetic neuropathy as indicated by reduced albuminuria and blood urea nitrogen, increased nephrin expression, decreased kidney macrophage recruitment and inflammatory cytokines, and reduced histological changes compared with vehicle-treated diabetic mice. In vitro, P78-PEDF blocked the increase in podocyte permeability to albumin and disruption of the actin cytoskeleton induced by puromycin aminonucleoside treatment. These findings highlight the importance of P78-PEDF peptide as a potential therapeutic modality in early phase diabetic renal injury.

Poly Implant Prothèse implants were recalled in Australia in April of 2010 following concerns of higher than expected rupture rates and the use of unauthorized industrial grade silicone as a filler material. Although subsequent investigations found that the gel filler material does not pose a threat to human health, the important question of what caused a relatively modern breast implant to have such a poor outcome compared with contemporary silicone breast implants is yet to be addressed.

Malignant transformation by oncogenes requires additional genetic/epigenetic changes to overcome enhanced susceptibility to apoptosis. In the present study, we report that Bif-1 (Sh3glb1), a gene encoding a membrane curvature–driving endophilin protein, is a haploinsufficient tumor suppressor that plays a key role in the prevention of chromosomal instability and suppresses the acquisition of apoptosis resistance during Myc-driven lymphomagenesis. Although a large portion of Bif-1–deficient mice harboring an Eμ-Myc transgene displayed embryonic lethality, allelic loss of Bif-1 dramatically accelerated the onset of Myc-induced lymphoma. At the premalignant stage, hemizygous deletion of Bif-1 resulted in an increase in mitochondrial mass, accumulation of DNA damage, and up-regulation of the antiapoptotic protein Mcl-1. Consistently, allelic loss of Bif-1 suppressed the activation of caspase-3 in Myc-induced lymphoma cells. Moreover, we found that Bif-1 is indispensable for the autophagy-dependent clearance of damaged mitochondria (mitophagy), because loss of Bif-1 resulted in the accumulation of endoplasmic reticulum–associated immature autophagosomes and suppressed the maturation of autophagosomes. The results of the present study indicate that Bif-1 haploinsufficiency attenuates mitophagy and results in the promotion of chromosomal instability, which enables tumor cells to efficiently bypass the oncogenic/metabolic pressures for apoptosis.

Malignant transformation by oncogenes requires additional genetic/epigenetic changes to overcome enhanced susceptibility to apoptosis. In the present study, we report that Bif-1(Sh3glb1), a gene encoding a membrane curvature–driving endophilin protein, is a haploinsufficient tumor suppressor that plays a key role in the prevention of chromosomal instability and suppresses the acquisition of apoptosis resistance during Myc-driven lymphomagenesis. Although a large portion of Bif-1–deficient mice harboring an Eμ-Myctransgene displayed embryonic lethality, allelic loss of Bif-1dramatically accelerated the onset of Myc-induced lymphoma. At the premalignant stage, hemizygous deletion of Bif-1resulted in an increase in mitochondrial mass, accumulation of DNA damage, and up-regulation of the antiapoptotic protein Mcl-1. Consistently, allelic loss of Bif-1suppressed the activation of caspase-3 in Myc-induced lymphoma cells. Moreover, we found that Bif-1 is indispensable for the autophagy-dependent clearance of damaged mitochondria (mitophagy), because loss of Bif-1resulted in the accumulation of endoplasmic reticulum–associated immature autophagosomes and suppressed the maturation of autophagosomes. The results of the present study indicate that Bif-1haploinsufficiency attenuates mitophagy and results in the promotion of chromosomal instability, which enables tumor cells to efficiently bypass the oncogenic/metabolic pressures for apoptosis.

The Penn State Infant Ventricular Assist Device (VAD) is a 12–14 ml stroke volume pneumatically actuated pump, with custom Björk-Shiley monostrut valves, developed under the National Heart, Lung, and Blood Institute Pediatric Circulatory Support program. In this report, we describe the seven most recent chronic animal studies of the Infant VAD in the juvenile ovine model, with a mean body weight of 23.5 ± 4.1 kg. The goal of 4–6 weeks survival was achieved in five of seven studies, with support duration ranging from 5 to 41 days; mean 26.1 days. Anticoagulation was accomplished using unfractionated heparin, and study animals were divided into two protocol groups: the first based on a target activated partial thromboplastin time of 1.5–2 times normal, and a second group using a target thromboelastography R-time of two times normal. The second group required significantly less heparin, which was verified by barely detectable heparin activity (anti-Xa). In both groups, there was no evidence of thromboembolism except in one animal with a chronic infection and fever. Device thrombi were minimal and were further reduced by introduction of the custom valve. These results are consistent with results of adult VAD testing in animals and are encouraging given the extremely low levels of anticoagulation in the second group.

The vascular form of Ehlers-Danlos syndrome (vEDS), a rare disease with grave complications resulting from rupture of major arteries, is caused by mutations of collagen type III [α1 chain of collagen type III (COL3A1)]. The only, recently proven, preventive strategy consists of the reduction of arterial wall stress by β-adrenergic blockers. The heterozygous (HT) Col3a1 knockout mouse has reduced expression of collagen III and recapitulates features of a mild presentation of the disease. The objective of this study was to determine whether changing the balance between synthesis and degradation of collagen by chronic treatment with doxycycline, a nonspecific matrix metalloproteinase (MMP) inhibitor, could prevent the development of vascular pathology in HT mice. After 3 months of treatment with doxycycline or placebo, 9-month-old HT or wild-type (WT) mice were subjected to surgical stressing of the aorta. A 3-fold increase in stress-induced aortic lesions found in untreated HT mice 1 week after intervention (cumulative score 4.5 ± 0.87 versus 1.3 ± 0.34 in WT, p < 0.001) was fully prevented in the doxycycline-treated group (1.1 ± 0.56, p < 0.001). Untreated HT mice showed increased MMP-9 activity in the carotid artery and decreased collagen content in the aorta; however, in doxycycline-treated animals there was normalization to the levels observed in WT mice. Doxycycline treatment inhibits the activity of tissue MMP and attenuates the decrease in the collagen content in aortas of mice haploinsufficient for collagen III, as well as prevents the development of stress-induced vessel pathology. The results suggest that doxycycline merits clinical testing as a treatment for vEDS.

The computer-generation of the crystal structures of the α-amino acid valine is used as a challenging test of lattice energy modeling methods for crystal structure prediction of flexible polar organic molecules and, specifically, to examine the importance of molecular polarization on calculated relative energies. Total calculated crystal energies, which combine atom-atom model potential calculations of intermolecular interactions with density functional theory intramolecular energies, do not effectively distinguish the real (known) crystal structures from the rest of the low energy computer-generated alternatives when the molecular electrostatic models are derived from isolated molecule calculations. However, we find that introducing a simple model for the bulk crystalline environment when calculating the molecular energy and electron density distribution leads to important changes in relative total crystal energies and correctly distinguishes the observed crystal structures from the set of computer-generated possibilities. This study highlights the importance of polarization of the molecular charge distribution in crystal structure prediction calculations, especially for polar flexible molecules, and suggests a computationally inexpensive approach to include its effect in lattice energy calculations.

Calnexin is an endoplasmic reticulum (ER) lectin that mediates protein folding on the rough ER. Calnexin also interacts with ER calcium pumps that localize to the mitochondria-associated membrane (MAM). Depending on ER homeostasis, varying amounts of calnexin target to the plasma membrane. However, no regulated sorting mechanism is so far known for calnexin. Our results now describe how the interaction of calnexin with the cytosolic sorting protein PACS-2 distributes calnexin between the rough ER, the MAM, and the plasma membrane. Under control conditions, more than 80% of calnexin localizes to the ER, with the majority on the MAM. PACS-2 knockdown disrupts the calnexin distribution within the ER and increases its levels on the cell surface. Phosphorylation by protein kinase CK2 of two calnexin cytosolic serines (Ser554/564) reduces calnexin binding to PACS-2. Consistent with this, a Ser554/564 Asp phosphomimic mutation partially reproduces PACS-2 knockdown by increasing the calnexin signal on the cell surface and reducing it on the MAM. PACS-2 knockdown does not reduce retention of other ER markers. Therefore, our results suggest that the phosphorylation state of the calnexin cytosolic domain and its interaction with PACS-2 sort this chaperone between domains of the ER and the plasma membrane.

Because of their close phylogenic relationship with humans, the use of non‐human primates (NHP) as experimental subjects has a long history in biomedical research. Although research topics have shifted focus and species used have changed, NHP remain vital as models in basic and applied research. While there is a wealth of information available on the spontaneous lesions of NHP, most of this information is fragmented, dated, or narrow in focus, often limited to single case reports. This review attempts to integrate this information to illustrate and enumerate the spectrum of spontaneous pathology of the reproductive tract and mammary gland of NHP. Although not the focus of this review, steroid‐related changes are inextricably linked to these tissues, and brief consideration is given to this subject as well. Birth Defects Res (Part B), 2007. © 2007 Wiley‐Liss, Inc.

Atomistic computer simulation techniques were employed to investigate the interaction of a selection of organic surfactant molecules with different surface features of the calcium fluoride 111 surface. The adsorbates coordinate mainly to the surface through interaction between their oxygen or nitrogen atoms to surface calcium ions, followed by hydrogen-bonded interactions to surface fluoride ions. Bridging between two surface calcium ions is the preferred mode of adsorption, but a bidentate interaction by two adsorbate oxygen ions to the same surface calcium ion is also a stable configuration and multiple interactions between surfaces and adsorbate molecules lead to the largest adsorption energies. All adsorbates containing carbonyl and hydroxy groups interact strongly with the surfaces, releasing energies between approximately 60 and 190 kJ mol−1, but methylamine containing only the –NH2functional group adsorbs to the surfaces to a much lesser extent 60–80 kJ mol−1. Both hydroxy methanamide and hydroxy ethanal adsorb to some surfaces in an eclipsed conformation, which is a requisite for these functional groups. Sorption of the organic material by replacement of pre-adsorbed water at different surface features is calculated to be mainly exothermic for the O and –OH functional groups, but less so for the –NH2group. Alkyl hydroxamates are judged to be more suitable than carboxylic acids for use in flotation reagents, as the hydroxy amide functional group adsorbs most strongly to the predominant terrace sites. The efficacy of the surfactant molecules is hence calculated to be alkyl hydroxamates > carboxylic acids > hydroxy aldehydes > alkyl amines. The results from this study suggest that computer simulations may provide a route to the identification or even design of particular organic surfactants for use in mineral separation processes.

Density functional theory calculations of the calcium tungstate material scheelite CaWO₄ have shown that water introduced into the bulk material remains undissociated and leads to swelling and layering of the structure, a behaviour which may resemble silicate clays more than three-dimensional poly-anionic materials, but which results in a structure that is even more similar to a rare hydrous calcium carbonate phase—a finding which suggests the existence of semi-crystalline hydrous precursor phases to the dehydrated scheelite material.

Electronic structure calculations based on the density functional theory (DFT) are employed to investigate the electronic structure of fluorite (CaF2) and the mode and energies of adsorption of water at the main {111} cleavage plane. Electron density plots show the crystal to be strongly ionic with negligible ionic relaxation of the unhydrated surface. We find associative adsorption of water at the surface with hydration energies between 41 and 53 kJ mol−1, depending on coverage. We next employ atomistic simulation techniques to investigate the competitive adsorption of water and methanoic acid at the planar and stepped {111}, {011} and {310} surfaces. The hydration energies and geometries of adsorbed water molecules on the planar {111} surface agree well with those found by the DFT calculations, validating the interatomic potential parameters. Methanoic acid adsorbs in completely different configurations on the three surfaces, but always by one or both oxygen atoms to one or more surface calcium atoms. Molecular Dynamics simulations at 300 K show that the effect of temperature is to increase the difference in adsorption energy between methanoic acid and water at the planar {111} surface. The methanoic acid remains bound to the surface whereas the water molecules prefer to form a droplet of water between the two surface planes. We show in a series of calculations of the co-adsorption of water and methanoic acid that the presence of solvent makes a significant contribution to the final adsorption energies and that the explicit inclusion of solvent in the calculations is necessary to correctly predict relative reactivities of different surface sites, a finding which is important in the modelling of mineral separation processes such as flotation.

Electronic structure calculations based on the density functional theory (DFT) are employed to investigate the electronic structure of fluorite (CaF₂) and the mode and energies of adsorption of water at the main {111} cleavage plane. Electron density plots show the crystal to be strongly ionic with negligible ionic relaxation of the unhydrated surface. We find associative adsorption of water at the surface with hydration energies between 41 and 53 kJ mol−1, depending on coverage. We next employ atomistic simulation techniques to investigate the competitive adsorption of water and methanoic acid at the planar and stepped {111}, {011} and {310} surfaces. The hydration energies and geometries of adsorbed water molecules on the planar {111} surface agree well with those found by the DFT calculations, validating the interatomic potential parameters. Methanoic acid adsorbs in completely different configurations on the three surfaces, but always by one or both oxygen atoms to one or more surface calcium atoms. Molecular Dynamics simulations at 300 K show that the effect of temperature is to increase the difference in adsorption energy between methanoic acid and water at the planar {111} surface. The methanoic acid remains bound to the surface whereas the water molecules prefer to form a droplet of water between the two surface planes. We show in a series of calculations of the co-adsorption of water and methanoic acid that the presence of solvent makes a significant contribution to the final adsorption energies and that the explicit inclusion of solvent in the calculations is necessary to correctly predict relative reactivities of different surface sites, a finding which is important in the modelling of mineral separation processes such as flotation.

Male sexual behavior is mediated in part by androgens, but in several species, mating is also influenced by estradiol formed locally in the brain by the aromatization of testosterone. The role of testosterone aromatization in the copulatory behavior of male Syrian hamsters is unclear because prior studies are equivocal. Therefore, the present study tested whether blocking the conversion of testosterone to estradiol would inhibit male hamster sexual behavior. Chronic systemic administration of the nonsteroidal aromatase inhibitor Fadrozole (2.0 mg/kg/day) for 5 or 8 weeks did not significantly increase mount latency or reduce mount frequency, intromission frequency, ejaculation frequency, or anogenital investigation relative to levels shown by surgical controls. However, Fadrozole effectively inhibited aromatase activity, as evidenced by the suppression of estrogen-dependent progesterone receptor immunoreactivity in the male hamster brain. The JZB39 anti-progesterone receptor antibody labeled significantly more neurons in brains of sham-treated hamsters than in brains of Fadrozole-treated hamsters. These data suggest that aromatization of testosterone to estradiol is not necessary for normal mating behavior in Syrian hamsters.

The article reviews the art exhibition "My East Is Your West," which was held at the 56th Venice Biennale art exhibition in Venice, Italy, from May 9th through November 22, 2015 and featured works by contemporary artists including Shilpa Gupta and Rashid Rana.

Reported herein are 130 consecutive cases of free groin flap transfer performed by one surgeon over a 19year period. Transplantation was performed for softtissue cover or augmentation of contour defects involving the head and neck 68 cases, trunk 4 cases, upper limb 14 cases, and lower limb 44 cases. Indications for flap coverageaugmentation were classified broadly into tumor, trauma, radiation induced, and miscellaneous. Specific reconstructive problems included augmentation for Romberg's hemifacial atrophy, external ear canal reconstruction after tumor ablation, and coverage of lower limb defects. There were nine failures total flap loss, seven cases of partial flap loss, and two cases were abandoned intraoperatively. Of 15 cases that were urgently reexplored, 9 flaps were salvaged. The failure rate for the groin flap series 130 cases was 8.5 percent compared with the failure rate of 4.2 percent for the other 517 cases of microvascular transfer performed over the same period by the same surgeon. Donorsite complications occurred in 24 cases and included hematoma or seroma formation, hypertrophic scars, nerve paresthesiae, infection, and dehiscence. Secondary debulking procedures were performed in 26 cases. The free groin flap, contrary to some reports, is a reliable flap that provides relatively thin pliable softtissue cover or augmentation, with minimal donorsite morbidity. The specific indications for its use have undergone an evolution since first described in 1973. Plast. Reconstr. Surg.103 918, 1999.

One hundred forty-seven flaps in 135 consecutive patients undergoing microvascular transplantation were monitored using a miniature Doppler ultrasonic probe. Using a modification of a technique described previously by Swartz, the probes were secured to the outflow vein of the flap with Vicryl mesh. Twenty instances of thrombosis or spasm were detected in 16 patients, and all flaps were salvaged (100 percent). There were four false positive and no false negative results. This probe allows for safe, continuous monitoring of flap blood flow, which permits the rapid detection and hence rapid treatment of postoperative complications. Our experience suggests that a significant improvement in the salvage rate of microvascular transplants may be attainable with the use of this device.