Identification of ALK in Thinness.

There is considerable inter-individual variability in susceptibility to weight gain despite an equally obesogenic environment in large parts of the world. Whereas many studies have focused on identifying the genetic susceptibility to obesity, we performed a GWAS on metabolically healthy thin individuals (lowest 6th percentile of the population-wide BMI spectrum) in a uniquely phenotyped Estonian cohort. We discovered anaplastic lymphoma kinase (ALK) as a candidate thinness gene. In Drosophila, RNAi mediated knockdown of Alk led to decreased triglyceride levels. In mice, genetic deletion of Alk resulted in thin animals with marked resistance to diet- and leptin-mutation-induced obesity. Mechanistically, we found that ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis. Our genetic and mechanistic experiments identify ALK as a thinness gene, which is involved in the resistance to weight gain.

Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man.

Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and the molecular determinants of "healthy" versus "unhealthy" obesity remain ill-defined. Chronic metabolic inflammation (metaflammation) is believed to be pivotal. Here, we tested a hypothesized anti-inflammatory role for heme oxygenase-1 (HO-1) in the development of metabolic disease. Surprisingly, in matched biopsies from "healthy" versus insulin-resistant obese subjects we find HO-1 to be among the strongest positive predictors of metabolic disease in humans. We find that hepatocyte and macrophage conditional HO-1 deletion in mice evokes resistance to diet-induced insulin resistance and inflammation, dramatically reducing secondary disease such as steatosis and liver toxicity. Intriguingly, cellular assays show that HO-1 defines prestimulation thresholds for inflammatory skewing and NF-κB amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease.

Stereoscopic Vision in Macular Telangiectasia Type 2.

PURPOSE: To investigate stereoscopic vision in patients with macular telangiectasia (MacTel) type 2 and correlate paracentral sensitivity loss to reduced stereoscopic function. METHODS: In a prospective single-center study, 50 patients with MacTel type 2 and 25 age-matched controls were investigated. Stereoscopic function was evaluated with Lang I, Titmus, and TNO tests. Sensitivity of the central 16° was tested using fundus-controlled perimetry (microperimetry). Functional loss was quantified as depth, size, and localization of scotomata. RESULTS: Both the Titmus and the TNO test revealed significantly reduced stereoscopic vision in patients compared to controls (p < 0.0001 for both). This applied even to patients with only relative or monocular paracentral scotoma. A strong correlation was observed for reduced stereoscopic vision with horizontal scotoma size and with the distance of scotomata from the foveal center. CONCLUSIONS: The results indicate that stereoscopic vision is impaired early in patients with MacTel type 2. A paracentral sensitivity loss, even if mild and limited to one eye, may considerably interfere with stereoscopic function despite normal visual acuity. Projection of paracentral scotomata within the patient's central visual field plays an important role in stereoscopic vision and should be considered when interpreting stereoscopic test results.

Deep Learning and Machine Vision Approaches for Posture Detection of Individual Pigs.

Posture detection targeted towards providing assessments for the monitoring of health and welfare of pigs has been of great interest to researchers from different disciplines. Existing studies applying machine vision techniques are mostly based on methods using three-dimensional imaging systems, or two-dimensional systems with the limitation of monitoring under controlled conditions. Thus, the main goal of this study was to determine whether a two-dimensional imaging system, along with deep learning approaches, could be utilized to detect the standing and lying (belly and side) postures of pigs under commercial farm conditions. Three deep learning-based detector methods, including faster regions with convolutional neural network features (Faster R-CNN), single shot multibox detector (SSD) and region-based fully convolutional network (R-FCN), combined with Inception V2, Residual Network (ResNet) and Inception ResNet V2 feature extractions of RGB images were proposed. Data from different commercial farms were used for training and validation of the proposed models. The experimental results demonstrated that the R-FCN ResNet101 method was able to detect lying and standing postures with higher average precision (AP) of 0.93, 0.95 and 0.92 for standing, lying on side and lying on belly postures, respectively and mean average precision (mAP) of more than 0.93.

SEX STEROIDS AND MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: To investigate the relationship between macular telangiectasia Type 2 and systemic levels of sex steroids or their antagonization. METHODS: In a prospective single-center study, 90 patients with macular telangiectasia Type 2 were investigated. Female patients were evaluated for previous surgical (e.g., ovariectomy) and/or pharmacological (e.g., aromatase inhibitors, tamoxifen) therapy resulting in reduced action of sex steroids. In males, free serum testosterone levels were assessed in patients and controls. RESULTS: Fourteen of 49 (29%) female patients had a history of pharmacological suppression of sex steroids and/or ovariectomy. These patients were younger at disease onset when compared with those without such medical history (mean ± SD: 47.1 ± 7.8, range: 38-59, versus 60.1 ± 7.6, range: 45-76; P < 0.0001). Male patients showed significantly lower free serum testosterone levels compared with controls at younger age (P < 0.0001 and 0.04 in the first and second age quartiles, respectively), as opposed to nonsignificant differences in older patients. In men ≤ 60 years of age, a biochemical hypogonadism (free serum testosterone < 0.05 ng/mL) was present in 53% (8/15) and 4% (2/49) of patients and controls, respectively (P < 0.0001). CONCLUSION: The results indicate that steroidal sex hormones might be involved in the presumably multifactorial pathophysiology of macular telangiectasia Type 2.

Fungaemia caused by obstructive renal candida bezoars leads to bilateral chorioretinitis: a case report.

BACKGROUND: Renal fungal bezoars are remarkably rare and mostly occur in immunodeficient patients. Only a small number of cases with immunocompetent patients have been published so far. The published treatment approaches comprised systemic antimycotic therapy and surgical or minimal invasive removal of the fungal balls. In some cases irrigation of the renal duct system with amphotericin B was performed. By obstruction of the urinary tract bezoars can lead to infected hydronephrosis and severe urosepsis with high lethality. Fungaemia can cause fungal colonization in different distant organs. Fulminant chorioretinitis and irreversible visual impairment can be the consequence of ocular fundus colonization. The following report highlights that a co-operation between urologists and ophthalmologists is absolutely indispensible in case of fungaemia. CASE PRESENTATION: Hereinafter we describe a case of an immunocompetent 56 years old woman, presenting with flank pain and shivering. The diagnosis turned out to be difficult due to initially negative urine culture. The fungaemia caused by obstructive nephropathy led to bilateral candida chorioretinitis. The patient was treated with intravenous amphotericin b and the bezoar was removed by percutaneous "nephrolitholapaxy". After two months, a follow up revealed the patient felt well, chorioretinal lesions regressed and urine culture did not show any fungal growth. CONCLUSION: To the best of our knowledge, this is the first case reporting on obstructive renal bezoars, which lead to haematogenous fungus spread and bilateral chorioretinitis. It points out that extensive ophthalmologic examination should be performed in case of fungaemia even if the patient is not suffering from any visual impairment.

The Mount Sinai clinical pathway for the management of pheochromocytoma.

OBJECTIVE: Pheochromocytomas are complex tumors that require a comprehensive and systematic management plan orchestrated by a multidisciplinary team. METHODS: To achieve these ends, The Mount Sinai Adrenal Center hosted an interdisciplinary retreat where experts in adrenal disorders assembled with the aim of developing a clinical pathway for the management of pheochromocytomas. RESULTS: The result was a consensus for the diagnosis, perioperative management, and postoperative management of pheochromocytomas, with specific recommendations from our team of adrenal experts, as well as a review of the current literature. CONCLUSION: Our clinical pathway can be applied by other institutions directly or may serve as a guide for institution-specific management.

Conditional ablation of TYK2 in immunity to viral infection and tumor surveillance.

Tyrosine kinase 2 (TYK2) has a pivotal role in immunity to infection and tumor surveillance. It is associated with several cytokine receptor chains including type I interferon (IFN) receptor 1 (IFNAR1), interleukin- (IL-) 12 receptor beta 1 (IL-12Rb1) and IL-10R2. We have generated a mouse with a conditional Tyk2 null allele and proved integrity of the conditional Tyk2 locus. TYK2 was successfully removed by the use of ubiquitous and tissue-specific Cre-expressing mouse strains. Myeloid TYK2 was found to critically contribute to the defense against murine cytomegalovirus. Ubiquitous TYK2 ablation severely impaired tumor immunosurveillance, while deletion in myeloid, dendritic or T cells alone showed no effect. The conditional Tyk2 mouse strain will be instrumental to further dissect TYK2 functions in infection, inflammation and cancer.

Patient and physician gender concordance in preventive care in university primary care settings.

OBJECTIVE: To assess the quality of preventive care according to physician and patient gender in a country with universal health care coverage. METHODS: We assessed a retrospective cohort study of 1001 randomly selected patients aged 50-80 years followed over 2 years (2005-2006) in 4 Swiss university primary care settings (Basel, Geneva, Lausanne, Zürich). We used indicators derived from RAND's Quality Assessment Tools and examined percentages of recommended preventive care. Results were adjusted using hierarchical multivariate logistic regression models. RESULTS: 1001 patients (44% women) were followed by 189 physicians (52% women). Female patients received less preventive care than male patients (65.2% vs. 72.1%, p<0.001). Female physicians provided significantly more preventive care than male physicians (p=0.01) to both female (66.7% vs. 63.6%) and male patients (73.4% vs. 70.7%). After multivariate adjustment, differences according to physician (p=0.02) and patient gender (p<0.001) remained statistically significant. Female physicians provided more recommended cancer screening than male physicians (78.4 vs. 71.9%, p=0.01). CONCLUSIONS: In Swiss university primary care settings, female patients receive less preventive care than male patients, with female physicians providing more preventive care than male physicians. Greater attention should be paid to female patients in preventive care and to why female physicians tend to provide better preventive care.

Influence of dietary amino acid level on chemical body composition and performance of growing-finishing boars of two sire lines.

There is only little information available concerning the chemical body composition of growing-finishing boars. For that reason, a total of 26 entire male pigs (boars) of two different Piétrain sire lines were fed with different levels of dietary essential amino acids (EAA) and the influence of this treatment on performance and chemical body composition was evaluated. In addition, an initial group of eight boars (n = 4 per sire line) was slaughtered at approximately 21 kg live weight (LW). The other 26 boars were fed three different diets containing 11.5, 13.2 and 14.9 g lysine/kg during the grower period and 9.0, 10.4, 11.7 g lysine/kg during the finisher period, respectively. Other EAA were added in relation to lysine (Lys: Met + Cys: Thr: Trp: Val = 1: 0.60: 0.65: 0.18: 0.75). At a LW of approximately 122 kg these 26 boars (six groups with three to seven animals each) were also slaughtered. The effects of EAA level and sire line on fattening and slaughter performance was recorded, and body and weight gain composition were analysed. There were no significant effects of EAA level on performance or on chemical body composition. Boars sired with Piétrain line 1 demonstrated increased lean meat content and protein body content (p < 0.05) as compared to Piétrain line 2-sired boars.

Trypanosomosis: a priority disease in tsetse-challenged areas of Burkina Faso.

Trypanosomosis is an important disease affecting humans as well as animals. It remains a big constraint to livestock productions in tropical areas. The objective of this study was to assess the importance of trypanosomosis among cattle diseases in Burkina Faso, mainly in tsetse-challenged areas, and to capture information on how farmers apply available methods for controlling the disease. A survey has been carried out in 29 villages of Burkina Faso in three regions (north, southwest, and west regions). One hundred and thirty-four cattle breeders were interviewed individually with a questionnaire. The results indicate that among the 16 diseases mentioned by cattle breeders, trypanosomosis is the most important one in tsetse-challenged areas. Overall, 76.12 % of the breeders mentioned it as the most important disease, while 54.55 % of the farmers in the southwest region and 70.91 % of the farmers in the west region ranked it as a priority disease. Chemoprophylaxis/chemotherapy is widely used as a control method. Isometamidium chloride and diminazene aceturate were used by 53.49 and 46.52 % of the responders, respectively. Among farmers, 85.55 % ranked diminazene aceturate as the less efficient while 14.45 % ranked isometamidium chloride as the most efficient trypanocid. Trypanocidal drug quality and drug resistance were raised as a major concern by 30.77 and 50 % of the respondents, respectively. According to them, zebu cattle are more susceptible to trypanosomosis than taurine Baoule cattle and their crosses with zebu, emphasizing that crossing susceptible breeds with trypanotolerant ones, could be used as part of an integrated control strategy.

Multicytokine-producing CD4+ T cells characterize the livers of patients with NASH.

A role of CD4+ T cells during the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) has been suggested, but which polarization state of these cells characterizes this progression and the development of fibrosis remain unclear. In addition, a gut-liver axis has been suggested to play a role in NASH, but the role of CD4+ T cells in this axis has just begun to be investigated. Combining single-cell RNA sequencing and multiple-parameter flow cytometry, we provide the first cell atlas to our knowledge focused on liver-infiltrating CD4+ T cells in patients with NAFLD and NASH, showing that NASH is characterized by a population of multicytokine-producing CD4+ T cells. Among these cells, only those with a Th17 polarization state were enriched in patients with advanced fibrosis. In parallel, we observed that Bacteroides appeared to be enriched in the intestine of NASH patients and to correlate with the frequency of multicytokine-producing CD4+ T cells. In short, we deliver a CD4+ T cell atlas of NAFLD and NASH, providing the rationale to target CD4+ T cells with a Th17 polarization state to block fibrosis development. Finally, our data offer an early indication to test whether multicytokine-producing CD4+ T cells are part of the gut-liver axis characterizing NASH.

Contrast sensitivity and visual acuity under low light conditions in macular telangiectasia type 2.

BACKGROUND/AIM: Macular pigment optical density (MPOD) is centrally depleted early on in macular telangiectasia type 2 (MacTel). Contrast sensitivity (CS) might be related to MPOD, and thus impaired in early MacTel. The effect of low luminance was assessed on both CS and best corrected visual acuity (BCVA). METHODS: This is a cross-sectional study. Pelli-Robson charts were used for CS testing at 1 m in photopic (110 lux) and mesopic (1 lux) conditions. BCVA was tested with ETDRS charts and low luminance visual acuity (LLVA) with a 2.0 log unit neutral density filter. MPOD was obtained with dual-wavelength autofluorescence. RESULTS: One hundred and three eyes of 52 patients with MacTel (mean±SD age 62.9±10.2, range 35-77) were compared with 34 healthy eyes of 17 controls (mean±SD age 65.2±7.4, range 53-78). CS was significantly lower in the eyes with MacTel. This impairment was higher in low light conditions (low light contrast sensitivity (LL-CS)). Eyes at the early stages of MacTel had significantly lower LL-CS than controls, but normal (photopic) CS. The results were similar but less pronounced for BCVA/LLVA. Decrease in CS was correlated with loss of MPOD. CONCLUSIONS: Low light conditions have a detrimental effect on visual performance in MacTel. Impaired CS might correlate with MPOD depletion as a pathognomonic finding in MacTel. Functional impairment might precede structural disintegration, indicating dysfunction at the cellular level. The applied tests might be useful as additional functional assessments in clinical routine and as outcome measures in future interventional clinical trials.

Rigid conformation of an immunoglobulin domain tandem repeat in the A-band of the elastic muscle protein titin.

Most of the structure of the giant muscle protein titin is formed by small modular domains. Many of them are predicted to be arranged in repeats with short linkers that may be key determinants of the peculiar elastic properties of titin. Here, we present the molecular structure of a tandem arrangement of two immunoglobulin-like domains, A168 and A169, located within the A-band segment of titin. The two domains are connected by a 17 residue long beta-strand and form a common interface. Based on these data, we establish general principles to estimate the amount of conformational flexibility of tandem domain motifs in titin. An unusual bulge within the second domain, A169, is directly involved into binding to a sarcomeric ligand, MURF-1, thus suggesting a dual role of this tandem for both the mechanical properties of titin and for sarcomeric signaling.

An uncommon zoonosis.

SUMMARY: In a patient with foreign-body granulomas, dog hairs were identified as the causative agent by combing history, histopathology and highly sensitive detection of species-specific canine mitochondrial DNA. Granulomas from human hair are well known in hairdressers. Animal hair granulomas have so far been only described in dog groomers, milkers, and shearers. To the best of our knowledge this patient represents the first described case of dog hair granulomas in a pet owner.

Macular Pigment Distribution as Prognostic Marker for Disease Progression in Macular Telangiectasia Type 2.

PURPOSE: To evaluate macular pigment distribution pattern as a prognostic marker for disease progression in patients with macular telangiectasia type 2 (MacTel). DESIGN: Retrospective cohort study. METHODS: In this single-center study, 90 eyes of 47 patients were analyzed. Macular pigment optical density (MPOD) was measured with dual-wavelength fundus autofluorescence. Eyes were graded into MPOD distribution classes 1 to 3 with increasing loss of macular pigment and grading was performed masked by 2 independent graders. Best-corrected visual acuity, reading acuity, total scotoma size in fundus-controlled perimetry (microperimetry), and break of the ellipsoid zone (EZ) in optical coherence tomography (en face measurement) were defined as functional and morphologic outcome parameters and evaluated at baseline and after 60 months. RESULTS: After a mean review period of 59.6 months (±standard deviation 5.2 months), no change between MPOD classes was observed compared to baseline. Morphologic and functional deficits were limited to the area of MPOD loss. At last follow-up, a significant mean decrease of visual acuity and reading acuity as well as a significant mean increase of scotoma size and EZ break were observed in eyes assigned to MPOD classes 2 and 3, while outcome parameters remained stable in eyes of class 1. CONCLUSIONS: The results indicate that MPOD and its distribution may serve as a prognostic marker for disease progression and functional impairment in patients with MacTel.

Natural history and effect of therapeutic interventions on subretinal fluid causing foveal detachment in macular telangiectasia type 2.

AIM: To report the natural history of subretinal fluid (SRF) causing foveal detachment in macular telangiectasia type 2 (MacTel) and our experience of therapeutic intervention with intravitreal steroids or antivascular endothelial growth factor inhibitor (anti-VEGF) agents in some cases. METHODS: Retrospective case series. Three of the MacTel study's largest registries were searched to identify eyes with foveal detachment. RESULTS: We identified 7 eyes from 6 exclusively female patients. The prevalence of foveal detachment was low, present in 1.4% of the assessed MacTel population. Age at presentation ranged from 50 to 66 years. Follow-up ranged from 2 to 8 years. There was late-phase leakage on fluorescein angiography from what was presumed to be ectatic capillaries. The SRF fluctuated without a rapid decline in visual acuity in cases that were not treated. When they were, intravitreal anti-VEGF and steroid therapy in general reduced SRF, at least temporarily, but did not halt the gradual long-term decrease in visual acuity. In one case, optical coherence tomography angiography showed significant reduction in the extent of the predominantly deep intraretinal vascular complex 1 month after anti-VEGF therapy. DISCUSSION AND CONCLUSIONS: As the natural history of this unusual MacTel phenotype is not characterised by rapid visual decline, intervention with intravitreal anti-VEGF or steroid therapy may not be necessary.

Crystal structure of the PB1 domain of NBR1.

The scaffold protein NBR1 is involved in signal transmission downstream of the serine/protein kinase from the giant muscle protein titin. Its N-terminal Phox and Bem1p (PB1) domain plays a critical role in mediating protein-protein interactions with both titin kinase and with another scaffold protein, p62. We have determined the crystal structure of the PB1 domain of NBR1 at 1.55A resolution. It reveals a type-A PB1 domain with two negatively charged residue clusters. We provide a structural perspective on the involvement of NBR1 in the titin kinase signalling pathway.

Preclinical safety assessment of Vasovist (Gadofosveset trisodium), a new magnetic resonance imaging contrast agent for angiography.

OBJECTIVES: Vasovist (EPIX Pharmaceuticals and Schering AG) is a newly developed blood pool contrast agent for magnetic resonance imaging with a high affinity for human albumin, making it an ideal tool for the detection of structural abnormalities such as stenosis and aneurysm. For the risk assessment of the single diagnostic use in patients, the toxicity of this compound was investigated. MATERIALS AND METHODS: Studies of acute, repeated-dose, reproductive, and developmental toxicity as well as local tolerance, immunotoxicity, and mutagenic potential were performed. RESULTS: Lethality was observed in rodents after single intravenous administration at doses of at least 2 orders of magnitude higher than the anticipated human dose of 0.03 mmol/kg. The no observed adverse effect level after repeated daily administration over the course of 4 weeks to monkeys exceeded the single diagnostic dose by a factor of 3.3. The main effect of repeated dosing in both rats and monkeys was vacuolation in kidney proximal tubules without concomitant effect on kidney function. Studies into reproduction toxicity have shown no evidence of effects on fertility or perinatal and postnatal development. Signs of embryo-fetal toxicity were observed in rabbits after repeated administration of high doses. No indications of immunotoxic and mutagenic effects were observed. In local tolerance testing, Vasovist was well tolerated after intravenous administration. CONCLUSIONS: Vasovist was well tolerated with reasonable safety margins between the single diagnostic dose of 0.03 mmol/kg in humans and the doses resulting in adverse effects in animal studies.

From Cabling the Atlantic to Wiring the World: A Review Essay on the 150th Anniversary of the Atlantic Telegraph Cable of 1866.

The year 2016 witnesses the 150th anniversary of laying the first successful transatlantic telegraph cables. This review essay offers a critical rereading of existing scholarship while simultaneously suggesting new perspectives for research. Telegraphy = globalization, the history of wiring the world commencing with the Atlantic cable of 1866 seems to suggest. At the same time, this essay argues, this equation should make scholars uneasy and cautious of a possible technological determinism retracing its steps back into the middle of scholarly debates on globalization. More attention needs to be paid to whose globalization we are talking about, what the globalization of politics, markets, and media means in connection to communication, and whether the cables really started something radically new. 150 years after laying the "first" Atlantic cable, there is still room for research. New spaces, theories, and methodologies, as well as alternate user groups including women and subalterns, offer avenues to test established scholarship on global communications.