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The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.

Summary Isolated Growth Hormone Deficiency (IGHD) is a rare cause of short stature, treated with the standard regimen of subcutaneous synthetic growth hormone (GH). Patients typically achieve a maximum height velocity in the first year of treatment, which then tapers shortly after treatment is stopped. We report a case of a 9-year-old male who presented with short stature (95th percentile for age and race. In conclusion, this is a case of primary hypopituitarism with differential diagnosis of IGHD vs Idiopathic Short Stature vs Constitutional Growth Delay. This case supports two objectives: Firstly, it highlights the importance of confirmatory genetic testing in patients with suspected, though diagnostically uncertain, IGHD. Secondly, it demonstrates a novel secondary growth pattern with implications for better understanding the tremendous variability of GH treatment response. Learning points: GHD is a common cause of growth retardation, and IGHD is a specific subtype of GHD in which patients present solely with short stature. The standard treatment for IGHD is subcutaneous synthetic GH until mid-parental height is reached, with peak height velocity attained in the 1st year of treatment in the vast majority of patients. Genetic testing should be strongly considered in cases of diagnostic uncertainty prior to initiating treatment. Future investigations of GH treatment response that stratify by gene and specific mutation will help guide treatment decisions. Response to treatment in patients with IGHD is variable, with some patients demonstrating little to no response, while others are ‘super-responders.’

Background: Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.Methods: FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.Findings: Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months.Interpretation: Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.Funding: UK Stroke Association and NIHR Health Technology Assessment Programme.

Purpose To determine the clinical outcomes of patients who underwent image-guided drainage of peripancreatic fluid collections after simultaneous pancreas-kidney (SPK) transplantation. Materials and Methods A retrospective review of all patients who underwent peripancreatic fluid collection drainage after SPK, from January 2000 to August 2017, at a single institution was performed. Patient characteristics, surgical technique, medication regimen, microbial analysis, and clinical outcomes were reviewed. Thirty-one patients requiring a total of 41 drainages were included in this study. The median age was 44 years (range 30–58 years), and median time between SPK and drainage was 28 days (range 8 to 3,401 days). Fisher’s exact test, unpaired Student t -tests, and Pearson correlations were used for statistical analysis. Results Fever (51%) and abdominal pain (31%) were the most common presenting symptoms. The average amount of fluid drained at the time of drain placement was 97 mL (SD 240 mL). The average time spent with a drain in place was 33 days (SD 31 days). Microorganisms were isolated in the fluid of 22 of 41 drainages (54%), with mixed gastrointestinal flora being the most common. No further intervention was needed in 34 of 41 drainages (82%). However, drainage failed in 5 of 31 patients (16%), requiring surgical intervention with removal of the pancreas transplant. Conclusions Percutaneous drainage of peripancreatic fluid collections after SPK transplantation is a safe and effective treatment option.

Background. The Neuromuscular Recovery Scale (NRS) was developed by researchers and clinicians to functionally classify people with spinal cord injury (SCI) by measuring functionally relevant motor tasks without compensation. Previous studies established strong interrater and test-retest reliability and validity of the scale. Objective. To determine responsiveness of the NRS, a version including newly added upper-extremity items, in an outpatient rehabilitation setting. Methods. Assessments using the NRS and 6 other instruments were conducted at enrollment and discharge from a locomotor training program for 72 outpatients with SCI classified as American Spinal Injury Association Impairment Scale grades A to D (International Standards for Neurological Classification of Spinal Cord Injury). Mixed-model t statistics for instruments were calculated and adjusted for confounding factors (eg, sample size, demographic variables) for all patients and subgroups stratified by injury level and/or severity. The resulting adjusted response means (ARMs) and 95% confidence intervals (CIs) were used to determine responsiveness, and significant differences between instruments were identified with pairwise comparisons. Results. The NRS was significantly responsive for SCI outpatients (ARM = 1.05; CI = 0.75-1.35). Changes in motor function were detected across heterogeneous groups. Regardless of injury level or severity, the responsiveness of the NRS was equal to, and often significantly exceeded, the responsiveness of other instruments. Conclusions. The NRS is a responsive measure that detects change in motor function during outpatient neurorehabilitation for SCI. There is potential utility for its application in randomized controlled trials and as a measure of clinical recovery across diverse SCI populations.

Retinoic acid signaling is required for maintaining a range of cellular processes, including cell differentiation, proliferation, and apoptosis. We investigated the actions of all-trans-retinoic acid (atRA) signaling in pancreatic β-cells of adult mice. atRA signaling was ablated in β-cells by overexpressing a dominant-negative retinoic acid receptor (RAR)-α mutant (RARdn) using an inducible Cre-Lox system under the control of the pancreas duodenal homeobox gene promoter. Our studies establish that hypomorphism for RAR in β-cells leads to an age-dependent decrease in plasma insulin in the fed state and in response to a glucose challenge. Glucose-stimulated insulin secretion was also impaired in islets isolated from mice expressing RARdn. Among genes that are atRA responsive, Glut2 and Gck mRNA levels were decreased in isolated islets from RARdn-expressing mice. Histologic analyses of RARdn-expressing pancreata revealed a decrease in β-cell mass and insulin per β-cell 1 mo after induction of the RARdn. Our results indicate that atRA signaling mediated by RARs is required in the adult pancreas for maintaining both β-cell function and mass, and provide insights into molecular mechanisms underlying these actions.—Brun, P.-J., Grijalva, A., Rausch, R., Watson, E., Yuen, J. J., Das, B. C., Shudo, K., Kagechika, H., Leibel, R. L., Blaner, W. S. Retinoic acid receptor signaling is required to maintain glucose-stimulated insulin secretion and β-cell mass.

Identifying practice patterns for therapy interventions following distal radius fractures (DRFs) is necessary to define the most frequently used examination and intervention techniques. The purpose of this study was to identify preferred practice patterns and physical and functional outcome measures used during DRF management. Two hundred forty-two therapists (PTs, OTs, and CHTs) were surveyed by questionnaire at an annual hand therapy meeting. A descriptive analysis of data was performed. Preferred practice patterns during the immobilization and the post-immobilization periods were identified. More than 75% of the surveyed therapists used upper extremity range-of-motion exercises and compressive wrap with retrograde massage during the immobilization phase. More than 90% of therapists included range-of-motion exercises and heat/cold modalities in the post-immobilization treatment plans. Physical impairment measures of outcome were used much more frequently than functional outcome questionnaires in assessing progress during treatment. This study advances the evidence-based practice of therapy by establishing a foundation for future research.

Ildr2, a modifier of diabetes susceptibility in obese mice, is expressed in most organs, including islets and hypothalamus, with reduced levels in livers of diabetes-susceptible B6.DBA mice congenic for a 1.8 Mb interval of Chromosome 1. In hepatoma and neuronal cells, ILDR2 is primarily located in the endoplasmic reticulum membrane. We used adenovirus vectors that express shRNA or are driven by the CMV promoter, respectively, to knockdown or overexpress Ildr2 in livers of wild type and ob/ob mice. Livers in knockdown mice were steatotic, with increased hepatic and circulating triglycerides and total cholesterol. Increased circulating VLDL, without reduction in triglyceride clearance suggests an effect of reduced hepatic ILDR2 on hepatic cholesterol clearance. In animals that overexpress Ildr2, hepatic triglyceride and total cholesterol levels were reduced, and strikingly so in ob/ob mice. There were no significant changes in body weight, energy expenditure or glucose/insulin homeostasis in knockdown or overexpressing mice. Knockdown mice showed reduced expression of genes mediating synthesis and oxidation of hepatic lipids, suggesting secondary suppression in response to increased hepatic lipid content. In Ildr2-overexpressing ob/ob mice, in association with reduced liver fat content, levels of transcripts related to neutral lipid synthesis and cholesterol were increased, suggesting “relief” of the secondary suppression imposed by lipid accumulation. Considering the fixed location of ILDR2 in the endoplasmic reticulum, we investigated the possible participation of ILDR2 in ER stress responses. In general, Ildr2 overexpression was associated with increases, and knockdown with decreases in levels of expression of molecular components of canonical ER stress pathways. We conclude that manipulation of Ildr2 expression in liver affects both lipid homeostasis and ER stress pathways. Given these reciprocal interactions, and the relatively extended time-course over which these studies were conducted, we cannot assign causal primacy to either the effects on hepatic lipid homeostasis or ER stress responses.

Background Previous studies of mixed background mice have demonstrated that targeted deletion of Vgf produces a lean, hypermetabolic mouse that is resistant to diet-, lesion-, and genetically-induced obesity. To investigate potential mechanism(s) and site(s) of action of VGF, a neuronal and endocrine secreted protein and neuropeptide precursor, we further analyzed the metabolic phenotypes of two independent VGF knockout lines on C57Bl6 backgrounds. Results Unlike hyperactive VGF knockout mice on a mixed C57Bl6-129/SvJ background, homozygous mutant mice on a C57Bl6 background were hypermetabolic with similar locomotor activity levels to Vgf+/Vgf+ mice, during day and night cycles, indicating that mechanism(s) other than hyperactivity were responsible for their increased energy expenditure. In Vgf-/Vgf- knockout mice, morphological analysis of brown and white adipose tissues (BAT and WAT) indicated decreased fat storage in both tissues, and decreased adipocyte perimeter and area in WAT. Changes in gene expression measured by real-time RT-PCR were consistent with increased fatty acid oxidation and uptake in BAT, and increased lipolysis, decreased lipogenesis, and brown adipocyte differentiation in WAT, suggesting that increased sympathetic nervous system activity in Vgf-/Vgf- mice may be associated with or responsible for alterations in energy expenditure and fat storage. In addition, uncoupling protein 1 (UCP1) and UCP2 protein levels, mitochondrial number, and mitochondrial cristae density were upregulated in Vgf-/Vgf- BAT. Using immunohistochemical and histochemical techniques, we detected VGF in nerve fibers innervating BAT and Vgf promoter-driven reporter expression in cervical and thoracic spinal ganglia that project to and innervate the chest wall and tissues including BAT. Moreover, VGF peptide levels were quantified by radioimmunoassay in BAT, and were found to be down-regulated by a high fat diet. Lastly, despite being hypermetabolic, VGF knockout mice were cold intolerant. Conclusion We propose that VGF and/or VGF-derived peptides modulate sympathetic outflow pathways to regulate fat storage and energy expenditure.

OBJECTIVES In patients with suspected sarcoidosis requiring pathologic confirmation of the presence of noncaseating granulomatous inflammation and the exclusion of alternative disorders, bronchoscopic transbronchial lung biopsy and more recently transbronchial needle aspiration of mediastinal lymph nodes have been the standard biopsy procedures in most cases. We describe our experience with computed tomography-guided transthoracic needle biopsy (CT-TNB) of mediastinal lymph nodes for the diagnosis of sarcoidosis. MATERIALS AND METHODS We retrospectively reviewed our single institution experience with coaxial CT-TNB of enlarged mediastinal lymph nodes in the diagnosis of sarcoidosis. Forty-one biopsies were performed in 40 patients over a 10-year period from 1997 to 2007. Final pathologic diagnosis was obtained from record review. The type of biopsy performed (aspiration cytology, core needle biopsy for histology, or both) was recorded. The method of needle approach used was obtained from review of images obtained during biopsy and the radiology report. Complications including pneumothorax, bleeding, and need for chest tube insertion for pneumothorax drainage were recorded. Yield of cytologic versus histologic diagnosis of sarcoidosis was compared using a Fisher exact test. RESULTS Overall diagnostic yield was 93%, with core needle biopsy having a significantly higher yield as compared with fine needle aspiration cytology (96% vs. 78%, P

Two recent, large whole-genome association studies (GWAS) in European populations have associated a ∼47-kb region that contains part of the FTO gene with high body mass index (BMI). The functions of FTO and adjacent FTM in human biology are not clear. We examined expression of these genes in organs of mice segregating for monogenic obesity mutations, exposed to underfeeding/overfeeding, and to 4°C. Fto/ Ftm expression was reduced in mesenteric adipose tissue of mice segregating for the Ay, Lepob, Leprdb, Cpefat, or tub mutations, and there was a similar trend in other tissues. These effects were not due to adiposity per se. Hypothalamic Fto and Ftm expression were decreased by fasting in lean and obese animals and by cold exposure in lean mice. The fact that responses of Fto and Ftm expression to these manipulations were almost indistinguishable suggested that the genes might be coregulated. The putative overlapping regulatory region contains at least two canonical CUTL1 binding sites. One of these nominal CUTL1 sites includes rs8050136, a SNP associated with high body mass. The A allele of rs8050136 associated with lower body mass than the C allele preferentially bound CUTL1 in human fibroblast DNA. 70% knockdown of CUTL1 expression in human fibroblasts decreased FTO and FTM expression by 90 and 65%, respectively. Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed “ciliopathy.” FTM has recently been shown to be a ciliary basal body protein.

1. The vgf gene encodes a neuropeptide precursor with a restricted pattern of expression that is limited to a subset of neurons in the central and peripheral nervous systems and to specific populations of endocrine cells in the adenohypophysis, adrenal medulla, gastrointestinal tract, and pancreas. In responsive neurons, vgf transcription is upregulated by neurotrophins. the basis for the original identification of VGF as nerve growth factor- (NGF) inducible in PC12 cells (A. Levi, J. D. Eldridge, and B. M. Paterson, Science 229:393-395, 1985). 2. In this review, we shall summarize data concerning the transcriptional regulation of vgf in vitro, the structural organization of the vgf promoter as well as the transcription factors which regulate its activity. 3. On the basis of in situ hybridization and immunohistochemical studies, the in vivo tissue-specific expression of VGF during differentiation and in the adult will be summarized. 4. Parallel biochemical data will be reviewed, addressing the proteolytical processing of the pro-VGF precursor within the secretory compartment of neuroendocrine cells. 5. Finally, analysis of the phenotype of VGF knockout mice will be discussed, implying a nonredundant role of VGF products in the regulation of energy storage and expenditure.

The incidence and causative agents of discospondylitis in cats are unknown. This report describes a cat with radiologic changes consistent with discospondylitis and concurrent urinary tract infection. As in dogs, discospondylitis should be the primary rule out for vertebral end plate lysis in cats.

There has been no large scale study of the effects of bereavement on parents who have experienced an unexpected infant death (cot death). Three hundred and eight such families were studied in nine area health authorities in Great Britain. Each family was visited by two suitably qualified members of the Community Health Services to assess the effect of the bereavement on the family and to identify their sources of support. Results of this study indicate the profoundly disruptive effect of the tragedy on the majority of these families. It has highlighted the importance of skilled interviewing to help parents verbalize their fears and assuage guilt feelings. Guidance and training in counselling is recommended for all health care professionals likely to have contact with such families.

Three groups of subjects were administered a redefinition strategy which asked them to focus on sensations during noxious stimulation. Those in one group were informed that the strategy would reduce pain (positive expectancy), those in a second were informed that it would augment pain (negative expectancy), and those in a third were given no information on expectancy. Subjects in a fourth group received neither redefinition nor instructions on expectancy. The four groups did not differ either in expectancy of pain reduction or in reduction of reported pain. Subjects in all groups expected more pain than they reported, and expectations for pain reduction showed only a small correlation with degree of reported pain reduction. In all groups, men reported less pain than women.

Similar histories of illness were recorded in the three weeks prior to death for children who died unexpectedly in infancy and for live controls in the three weeks prior to interview. Symptom analysis showed that the main difference between the two groups of children was the non-specific behavioural changes manifested in the case infants shortly before death. Underestimation of the severity of symptoms by parents or medical attendants was indicated in a proportion of the cases in all areas. Use of medical services was shown to vary widely between areas with a marked tendency to use hospital rather than general practitioner services in the inner city. The investigation into sudden infant death in one area included periodic progress meetings where possible preventable causes of the deaths were examined and future child health service planning decided in the light of the knowledge gained. Since the study began, the number of sudden infant deaths in this area has dropped significantly. It is suggested that such an enquiry into the circumstances at each death would be a simple method of undertaking a study of sudden death in a locality and possibly lowering the incidence.

This paper shows that a modified form of scoring would be useful in identifying infants at risk in these areas. It is predicted that a useful reduction in unexpected infant deaths would follow increasing the care given to high risk infants. To evaluate such a programme and to update the scoring system, an ongoing survey of all cases of unexpected death would be required. Case conferences based on this information would also improve the level of care so that the overall effect of the whole package might be substantially larger than predicted from theory.

An epidemiological survey of unexpected deaths in infancy covering nine areas of southern England is reported. The areas include specially deprived inner city areas of London, inner and outer suburbs of London, rapidly developing and new towns and their surrounding country districts and a coastal resort. The report is based on 308 cases and 236 controls.Theepidemiological patterns found in respect of time of death, age, sex and season are similar to those reported by previous studies. The characteristic ‘cot death’ age distribution cannot be explained by the inclusion of older infants whose respiratory passages are obstructed by bedding or infection. Possible explanations for a substantial outbreak in one area are considered. Well recognized differences between cases and controls in respect of age of parents, parity, prematurity, twinning, hospital admission and clinic attendance were found to persist and to be essentially similar in all areas despite there being significant differences between the populations. Sociological differences between cases and controls were largest in the most socially deprived areas, illustrated by an illegitimacy rate of 27 per cent in inner north London.Bottle feeding was only significantly associated with unexpected death when the standard of the home was excellent. Where the homes were poor more cases than controls were breast fed.

As one of the components of a longitudinal study of the use made of child health services by mothers resident in Tower Hamlets an attempt was made to assess psychiatric morbidity across cultures using three measures, Goldberg's General Health Questionnaire, the interviewer's assessment of distress and the mother's own opinion; and secondly to see whether mothers from varying cultures differ from the indigenous population in the psychological symptoms they experienced in the year following their infants' birth. There was a reasonable agreement between the three measures suggesting that it is possible to compare psychiatric morbidity across cultures; in addition there seemed to be little difference in the psychological symptoms experienced in the year following their infants' birth by mothers in the varying cultures.

An investigation into sudden death in infancy is described, which demonstrates the feasibility and value of using NHS personnel for interviewing bereaved parents in cases of sudden death in infancy both for the support and reassurance it provides for the parents and for the assistance it gives the Community Services in planning future provision of services in the areas concerned. Preliminary data are presented on the comparative pattern of sudden infant death in metropolitan and non-urban areas.

Two cases of sudden infant death (cot death) are described, occurring within 5 days of each other, in the same house, with identical pulmonary pathology but in unrelated families. The cases illustrate the interrelationship of infection and unfavourable social factors peculiar to many cases of sudden infant death. They also point to the importance of environmental rather than genetic factors as a cause of ‘clusters’ of cot deaths in families.