Circulating Metabolomic and Lipidomic Signatures Identify a Type 2 Diabetes Risk Profile in Low-Birth-Weight Men with Non-Alcoholic Fatty Liver Disease.

The extent to which increased liver fat content influences differences in circulating metabolites and/or lipids between low-birth-weight (LBW) individuals, at increased risk of type 2 diabetes (T2D), and normal-birth-weight (NBW) controls is unknown. The objective of the study was to perform untargeted serum metabolomics and lipidomics analyses in 26 healthy, non-obese early-middle-aged LBW men, including five men with screen-detected and previously unrecognized non-alcoholic fatty liver disease (NAFLD), compared with 22 age- and BMI-matched NBW men (controls). While four metabolites (out of 65) and fifteen lipids (out of 279) differentiated the 26 LBW men from the 22 NBW controls (p ≤ 0.05), subgroup analyses of the LBW men with and without NAFLD revealed more pronounced differences, with 11 metabolites and 56 lipids differentiating (p ≤ 0.05) the groups. The differences in the LBW men with NAFLD included increased levels of ornithine and tyrosine (PFDR ≤ 0.1), as well as of triglycerides and phosphatidylcholines with shorter carbon-chain lengths and fewer double bonds. Pathway and network analyses demonstrated downregulation of transfer RNA (tRNA) charging, altered urea cycling, insulin resistance, and an increased risk of T2D in the LBW men with NAFLD. Our findings highlight the importance of increased liver fat in the pathogenesis of T2D in LBW individuals.

The effects of intranasal esketamine on on-road driving performance in patients with major depressive disorder or persistent depressive disorder.

BACKGROUND: Intranasal esketamine demonstrates rapid improvement of depressive symptoms. However, transient adverse effects (dissociation, sedation and dizziness) may occur, which could impact driving performance. AIMS: To evaluate the effects of 84 mg intranasal esketamine on driving performance in unipolar major depressive disorder (MDD) or persistent depressive disorder (PDD) patients. METHODS: The study consisted of two parts. Part A was a single-blind, double-dummy, randomized three-period, cross-over study to compare effects of esketamine versus placebo on next morning driving, 18 ± 2 h post-treatment. Alcohol was administered to demonstrate assay sensitivity. In Part B, same-day driving, 6 ± 0.5 hours post-treatment, was assessed during twice weekly esketamine administration for 3 weeks. Twenty-seven patients with mild-to-moderate MDD or PDD without psychotic features completed a 100 km on-the-road driving test on a public highway in normal traffic. The primary outcome was standard deviation of lateral position (SDLP; cm; weaving of car). RESULTS: In Part A, alcohol impaired driving performance compared to placebo: Least-square means (95% CI), p-value for delta SDLP (cm) compared with placebo: (ΔSDLP = + 1.83 (1.03; 2.62), p < 0.001), whereas esketamine did not: (ΔSDLP = -0.23 (-1.04; 0.58), p = 0.572). In Part B, weekly driving tests showed no differences between placebo baseline SDLP and after esketamine administration over 3 weeks: Day 11: (ΔSDLP = -0.96 (-3.72; 1.81), p = 0.493), Day 18: (ΔSDLP = -0.56 (-3.33; 2.20), p = 0.686) and Day 25: (ΔSDLP = -1.05 (-3.82; 1.71), p = 0.451). CONCLUSIONS: In this study, esketamine did not impair on-road driving performance the next morning following a single dose, or on same day after repeated administration.

Immune Responses after Heavy Alcohol Consumption: Cytokine Concentrations in Hangover-Sensitive and Hangover-Resistant Drinkers.

This study investigated immunological changes during an alcohol hangover, and the possible difference between hangover-resistant and hangover-sensitive drinkers in terms of immune reactivity. Using a semi-naturalistic design, N = 36 healthy social drinkers (18 to 30 years old) provided saliva samples on a control day (after drinking no alcohol) and on a post-alcohol day. Hangover severity was rated directly after saliva collection. Cytokine concentrations, interleukin (IL)-1ß, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α, and hangover severity were compared between both test days and between hangover-sensitive and -resistant drinkers. Data from N = 35 drinkers (17 hangover-sensitive and 18 hangover-resistant) were included in the statistical analyses. Relative to the control day, there were significant increases in saliva IL-6 and IL-10 concentrations on the post-alcohol day. No significant differences in cytokine concentrations were found between hangover-sensitive and hangover-resistant drinkers, nor did any change in cytokine concentration correlate significantly with hangover severity. In line with previous controlled studies assessing cytokines in blood, the current naturalistic study using saliva samples also demonstrated that the immune system responds to high-level alcohol intake. However, further research is warranted, as, in contrast to previous findings in blood samples, changes in saliva cytokine concentrations did not differ significantly between hangover-sensitive and hangover-resistant drinkers, nor did they correlate significantly with hangover severity.

Blood pressure and brain injury in cardiac surgery: a secondary analysis of a randomized trial.

OBJECTIVES: Brain dysfunction is a serious complication after cardiac surgery. In the Perfusion Pressure Cerebral Infarcts trial, we allocated cardiac surgery patients to a mean arterial pressure of either 70-80 or 40-50 mmHg during cardiopulmonary bypass (CPB). In this secondary analysis, we compared selected cerebral metabolites using magnetic resonance spectroscopy hypothesizing that a postoperative decrease in occipital grey matter (GM) N-acetylaspartate-to-total-creatine ratio, indicative of ischaemic injury, would be found in the high-target group. METHODS: Of the 197 patients randomized in the Perfusion Pressure Cerebral Infarcts trial, 55 and 42 patients had complete and useful data from GM and white matter (WM), respectively. Spectroscopies were done preoperatively and on postoperative days 3-6. Cognitive function was assessed prior to surgery, at discharge and at 3 months. We predefined the statistical significance level to be 0.01. RESULTS: A postoperative decrease was found in GM N-acetylaspartate-to-total-creatine ratio in the high-target group [mean difference -0.09 (95% confidence interval -0.14 to -0.04), P = 0.014]. No significant differences were found in other metabolite ratios investigated in GM or WM. No significant association was found between changes in metabolite ratios and new cerebral infarcts, WM lesion score or cognitive dysfunction. CONCLUSIONS: A higher mean arterial pressure during CPB was associated with signs of impaired cerebral metabolism, though not at the predefined significance level of 0.01. No significant association was found between metabolite ratio changes and neuroradiological pathology or change in cognitive function. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT02185885.

Evaluation of inflammatory lesions over 2 years in facioscapulohumeral muscular dystrophy.

OBJECTIVE: We followed up patients with facioscapulohumeral muscular dystrophy (FSHD) with sequential examinations over 2 years to investigate whether inflammatory lesions always precede fat replacement, if inflammation can be resolved without muscle degeneration, and if inflammatory lesions in muscle are always followed by fat replacement. METHODS: In this longitudinal study of 10 sequential MRI assessments over 2.5 years, we included 10 patients with FSHD. We used MRI with short TI inversion recovery to identify regions of interest (ROIs) with hyperintensities indicating muscle inflammation. Muscle T2 relaxation time mapping was used as a quantitative marker of muscle inflammation. Dixon sequences quantified muscle fat replacement. Ten healthy controls were examined with a magnetic resonance scan once for determination of normal values of T2 relaxation time. RESULTS: We identified 68 ROIs with T2 elevation in the patients with FSHD. New ROIs with T2 elevation arising during the study had muscle fat content of 6.4% to 33.0% (n = 8) and 47.0% to 78.0% lesions that resolved (n = 6). ROIs with T2 elevation had a higher increase in muscle fat content from visits 1 to 10 (7.9 ± 7.9%) compared to ROIs with normal muscle T2 relaxation times (1.7 ± 2.6%; p < 0.0001). Severe T2 elevations were always followed by an accelerated replacement of muscle by fat. CONCLUSIONS: Our results suggest that muscle inflammation starts in mildly affected muscles in FSHD, is related to a faster muscle degradation, and continues until the muscles are completely fat replaced. CLINICALTRIALSGOV IDENTIFIER: NCT02159612.

5-year outcome after complete mesocolic excision for right-sided colon cancer: a population-based cohort study.

BACKGROUND: The benefits of extensive lymph node dissection as performed in complete mesocolic excision are still debated, although recent studies have shown an association with improved long-term outcomes. However, none of these studies had an intention-to-treat design or aimed to show a causal effect; therefore in this study, we aimed to estimate the causal oncological treatment effects of complete mesocolic excision on right-sided colon cancer. METHODS: We did a population-based cohort study involving prospective data collected from four hospitals in Denmark. We compared the oncological outcome data of patients at one centre performing central lymph node dissection and vascular division after almost complete exposure of the proximal part of the superior mesenteric vein (ie, the complete mesocolic excision group) with three other centres performing conventional resections with unstandardised and limited lymph node dissection (ie, non-complete mesocolic excision; control group). We included data for all patients in the Capital Region of Denmark undergoing elective curative-intent right-sided colon resections for stages I-III colon cancer, as categorised by the Union for International Cancer Control (UICC; 5th edition), from June 1, 2008, to Dec 31, 2013. Patients were followed-up for 5·2 years after surgery. The primary outcome was the cumulative incidence of recurrence after 5·2 years of surgery. Inverse probability of treatment weighting and competing risk analyses were used to estimate the possible causal effects of complete mesocolic excision. This study is registered with ClinicalTrials.gov, number NCT03754075. FINDINGS: 1069 patients (813 in the control group and 256 in the complete mesocolic excision group) underwent curative-intent elective surgery for right-sided colon cancer during the study period. None of the patients were lost to follow-up regarding survival or recurrence status, and consequently no patient was censored in the analyses. The 5·2-year cumulative incidence of recurrence was 9·7% (95% CI 6·3-13·1) in the complete mesocolic excision group compared with 17·9% (15·3-20·5) in the control group, and the absolute risk reduction of complete mesocolic excision after 5·2 years was 8·2% (95% CI 4·0-12·4; p=0·00015). In the control group, 145 (18%) of 813 patients were diagnosed with a recurrence and 281 (35%) died during follow-up, whereas in the complete mesocolic excision group 25 (10%) of 256 patients were diagnosed with a recurrence and 75 (29%) died during follow-up. INTERPRETATION: This study shows a causal treatment effect of central mesocolic lymph node excision on risk of recurrence after resection for right-sided colon adenocarcinoma. Complete mesocolic excision has the potential to reduce the risk of recurrence and improve long-term outcome after resection for all UICC stages I-III of right-sided colon adenocarcinomas. FUNDING: The Tvergaard Fund, Helen Rude Fund, Krista and Viggo Petersen Fund, Olga Bryde Nielsen Fund, and Else and Mogens Wedell-Wedellsborg Fund.

Good outcome after posterior reversible encephalopathy syndrome (PRES) despite elevated cerebral lactate: a case report.

Posterior reversible encephalopathy syndrome (PRES) may cause irreversible brain damage. The diagnosis is confirmed by magnetic resonance imaging (MRI), where vasogenic edema may be seen especially in the posterior parts of the brain. MR spectroscopy (MRS) may be included to help predict the outcome by measuring selected metabolites for instance lactate. Usually lactate is immeasurable in brain tissue, but elevates in cases of hypoxia, and it has been associated with poor outcome. We report a case of a patient with eclampsia and PRES, who had elevated lactate initially, but complete remission clinically and on MRI.

Aberrant subcellular immunolocalization of NOTCH-1 activated intracellular domain in feline mammary tumours.

NOTCH-1 is a transmembrane receptor protein. Ligand proteins expressed on the surface of neighbouring cells bind to the NOTCH-1 extracellular domain by juxtacrine signalling and release the NOTCH intracellular domain (NICD) to alter gene expression. Forty feline mammary lesions (34 malignant and six hyperplastic) were submitted for immunohistochemical analysis of NICD expression using an anti-feline NICD monoclonal antibody. Associations between NICD expression in carcinomas and morphological parameters, as well as overall survival (OS), were investigated. NICD nuclear expression was observed in hyperplastic lesions (100%) while cytoplasmic localization was evident in carcinomas (0% nuclear positive; 87.5% cytoplasmic positive; 12.5% negative). Cytoplasmic NICD localization was statistically associated with carcinomas, while nuclear labelling was associated with hyperplasia. No significant correlation between positive or negative NICD expression and OS or morphological parameters was detected. NOTCH-1 activation, immunohistochemically identified by the NICD active form, appears to play a role in feline mammary carcinoma biology as the majority of tumours express this protein. Nuclear localization is consistent with the established NICD metabolic intranuclear pathway while cytoplasmic accumulation suggests aberrant NOTCH-1 signalling typical of malignant tumour progression.

Cerebral Magnetic Resonance Spectroscopy Demonstrates Long-Term Effect of Bone Marrow Transplantation in α-Mannosidosis.

α-Mannosidosis, OMIM #248500, is an autosomal recessive lysosomal storage disease caused by acidic α-mannosidase deficiency. Treatment options include bone marrow transplantation (BMT) and, possibly in the future, enzyme replacement therapy. Brain magnetic resonance spectroscopy (MRS) enables non-invasive monitoring of cerebral treatment effect. Accumulated cerebral mannose-containing oligosaccharides were demonstrated by MRS in a patient who at age 2 years and 11 months received a BMT from a haploidentical non-carrier sibling. The cerebral mannose-containing oligosaccharides had disappeared as early as 9½ months after BMT. MRS furthermore demonstrated the persistent treatment effect at regular intervals up to 5½ years after BMT. MRS is a non-invasive tool that can demonstrate the effect of BMT treatment. Likewise, MRS may be used to demonstrate the cerebral effect of other potential treatments such as enzyme replacement therapy.

Feline mammary carcinoma stem cells are tumorigenic, radioresistant, chemoresistant and defective in activation of the ATM/p53 DNA damage pathway.

Cancer stem cells were identified in a feline mammary carcinoma cell line by demonstrating expression of CD133 and utilising the tumour sphere assay. A population of cells was identified that had an invasive, mesenchymal phenotype, expressed markers of pluripotency and enhanced tumour formation in the NOD-SCID mouse and chick embryo models. This population of feline mammary carcinoma stem cells was resistant to chemotherapy and radiation, possibly due to aberrant activation of the ATM/p53 DNA damage pathway. Epithelial-mesenchymal transition was a feature of the invasive phenotype. These data demonstrate that cancer stem cells are a feature of mammary cancer in cats.

Outcome of accidental hypothermia with or without circulatory arrest: experience from the Danish Præstø Fjord boating accident.

BACKGROUND: Resuscitation guidelines for the treatment of accidental hypothermia are based primarily on isolated cases. Mortality rates are high despite aggressive treatment aimed at restoring spontaneous circulation and normothermia. METHODS: The present report is based on a boating accident where 15 healthy subjects (median age 16 (range 15-45) years) were immersed in 2 °C salt water. Seven victims were recovered in circulatory arrest with a median temperature of 18.4 °C (range 15.5-20.2 °C). They were all rewarmed with extracorporeal membrane oxygenation (ECMO) and were subsequently evaluated with advanced neuroradiological and functional testing. The remaining 7 had established spontaneous circulation without the use of ECMO. One victim drowned in the accident. RESULTS: The victims that survived the accident without circulatory arrest were predominantly females with a higher body mass index. Victims with circulatory arrest pH on arrival was a median of 6.61 (range 6.43-6.94), with ECMO being established a median of 226 (178-241)min after the accident. Magnetic resonance spectroscopy showed neuronal dysfunction in five. In five victims initial normal white matter spectra progressed to show evidence of abnormal axonal membranes. Based on the seven-level Functional Independence Measure test functional outcome was good in six circulatory arrest victims and in all without circulatory arrest. Mild to moderate cognitive dysfunction was seen in six and severe dysfunction in one circulatory arrest victim. CONCLUSION: Seven patients with profound accidental hypothermic circulatory arrest were successfully resuscitated using a management approach that included extracorporeal rewarming, followed by successive periods of therapeutic hypothermia and sedated normothermia and intensive neurorehabilitation. Seven other hypothermic victims (core temperature as low as 23 °C) that did not suffer circulatory arrest also survived the accident.

Breed, age and gender distribution of dogs with chronic hepatitis in the United Kingdom.

Standardised histological criteria are now available for the diagnosis of canine chronic hepatitis (CH). CH is common in dogs, but no studies have reported breed, age and gender distributions in the United Kingdom (UK). The objective of this study was to determine which breeds had an increased risk for developing CH in the UK and to report the age and gender distribution for those breeds. The databases of six veterinary histopathology laboratories were searched for cases with a histological diagnosis of CH according to standardised criteria. The breed, age and gender of dogs was recorded and compared to a control population to calculate the odds ratio and 95% confidence intervals for developing CH. A total of 551 cases of CH were identified, consisting of 61 breeds. Nineteen breeds were represented by five or more cases. Breeds with an increased risk for developing CH included the American cocker spaniel, Cairn terrier, Dalmatian, Dobermann pinscher, English cocker spaniel, English springer spaniel, Great Dane, Labrador retriever and Samoyed. The median age at diagnosis for all breeds with CH was 8 years (range 7 months to 16 years). Dalmatians, Dobermann pinschers and English springer spaniels with CH were significantly younger than Cairn terriers, English cocker spaniels and Labrador retrievers with CH. Females were over-represented when all cases were examined together. In conclusion, several breeds in the UK have an increased risk of CH, some of which have not been previously reported.

Clinical and molecular characterization of limb-girdle muscular dystrophy due to LAMA2 mutations.

INTRODUCTION: In this study we describe the clinical and molecular characteristics of limb-girdle muscular dystrophy (LGMD) due to LAMA2 mutations. METHODS: Five patients clinically diagnosed with LGMD and showing brain white matter hyperintensities on MRI were evaluated using laminin α2 genetic and protein testing. RESULTS: The patients had slowly progressive, mild muscular dystrophy with various degrees of CNS involvement. Epilepsy was observed in 2, and subtle symptoms of CNS involvement (mild deficit in executive functions and low IQ scores) were noted in 3 patients. Novel LAMA2 mutations were identified in all patients. The amount of laminin α2 protein in the muscle biopsies ranged from trace to about 50% compared with controls. CONCLUSIONS: This study represents the largest series of LGMD laminin α2-deficient patients and expands the clinical phenotype associated with LAMA2 mutations. The findings suggest that brain MRI could be included in the diagnostic work-up of patients with undiagnosed LGMD.

Hypovitaminosis D in dogs with inflammatory bowel disease and hypoalbuminaemia.

OBJECTIVES: To compare serum vitamin D metabolites and plasma parathyroid hormone concentrations in dogs with inflammatory bowel disease and normal albumin concentration, dogs with inflammatory bowel disease and hypoalbuminaemia, healthy dogs and hospitalised ill dogs with non-gastrointestinal illness. METHODS: Serum 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D concentrations were measured in 36 healthy dogs, 49 hospitalised ill dogs with non-gastrointestinal illnesses, 21 dogs with inflammatory bowel disease and normoalbuminaemia and 12 dogs with inflammatory bowel disease and hypoalbuminaemia. Plasma parathyroid hormone and ionised calcium concentrations were measured in a subset of these dogs. RESULTS: Concentrations of serum 25 hydroxyvitamin D were lower in hypoalbuminaemic dogs with inflammatory bowel disease than in the healthy dogs (P<0·001), hospitalised ill dogs (P<0·001) and normoalbuminaemic dogs with inflammatory bowel disease (P<0·001). Dogs with inflammatory bowel disease and hypoalbuminaemia had a higher plasma concentration of parathyroid hormone (P<0·01) and lower plasma concentration of ionised calcium (P<0·001) than hospitalised ill dogs. Dogs with inflammatory bowel disease had a positive correlation between serum 25 hydroxyvitamin D concentrations and serum albumin (P<0·0001), serum calcium (P<0·0001) and plasma ionised calcium (P<0·0005) concentrations. CLINICAL SIGNIFICANCE: Dogs with inflammatory bowel disease and hypoalbuminaemia frequently have ionised hypocalcaemia, high parathyroid hormone and low serum 25 hydroxyvitamin D concentrations. Further studies are indicated to establish the pathogenesis of this disease complication as well as therapeutic strategies to reverse this state.

Severe necrotizing myocarditis caused by serratia marcescens infection in an axolotl (Ambystoma mexicanum).

This report provides the first account of the pathological changes associated with infection by Serratia marcescens in an adult male axolotl. The infection resulted in septicaemia with severe multifocal necrotizing myocarditis. The latter lesion evolved to cardiac rupture, haemopericardium and death resulting from cardiac tamponade. This animal was exposed to higher than usual temperatures (24-25 °C) 2 weeks before the onset of disease and this may have resulted in immunocompromise and opportunistic bacterial infection. S. marcescens was isolated from the coelomic and pericardial cavity. Both isolates were identical and were resistant to ß-lactam antibiotics, but not to aminoglycosides or fluoroquinolones. The production of red prodigiosin pigment by the bacterium suggested an environmental origin. Overall, the clinical and histopathological presentation suggests that S. marcescens should be included in the list of aetiological agents of the 'red-leg'/bacterial dermatosepticaemia syndrome of amphibians.

Arrhythmogenic right ventricular cardiomyopathy as a cause of unexpected cardiac death in two horses.

Postmortem and histological examination of the hearts from two horses, a five-year-old Clydesdale gelding and a 15-year-old cob gelding, revealed changes characteristic of arrhythmogenic right ventricular cardiomyopathy. In both cases, on gross examination, the right ventricular endocardium and interventricular septum were almost entirely replaced with a gelatinous yellow fibroareolar tissue. This tissue was histologically a combination of fibrous and adipose tissue that had replaced the normal myofibres and disrupted the Purkinje fibres.

Evaluation of suicide awareness programmes delivered to veterinary undergraduates and academic staff.

In an effort to increase suicide awareness skills among veterinary undergraduates, a three-hour suicide awareness workshop (safeTALK) was delivered to third-year Royal (Dick) School of Veterinary Studies undergraduates as part of their professional development curriculum. Students were able to opt out of the session by contacting the course organisers. A total of 26 of 151 (17 per cent) third-year students attended the workshop, and 17 completed a feedback questionnaire. The vast majority of the students reported that after completing the workshop they were more likely or much more likely to recognise the signs of a person at risk of suicide, approach a person at risk of suicide, ask a person about suicide, and connect a person at risk of suicide with help. Five veterinary academics attended a two-day Applied Suicide Intervention Skills Training (ASIST) course, and all reported that the course was effective in improving suicide awareness and intervention skills.

Hereditary spastic paraplegia caused by the PLP1 'rumpshaker mutation'.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterised by progressive spasticity and weakness in the lower limbs. Mutations in PLP1 on the X chromosome cause spastic paraplegia type 2 (SPG2) or the allelic Pelizaeus-Merzbacher Disease (PMD). The PLP1 protein is a major myelin protein involved in stabilisation and maintenance of the myelin sheath. The function of the protein has been studied in the rumpshaker mouse, which is a model of SPG2/PMD. OBJECTIVE: To characterise the phenotype of patients with the 'rumpshaker mutation.' PATIENTS: A family with HSP caused by the 'rumpshaker mutation.' RESULTS: The patients showed nystagmus during infancy and had early onset of HSP. They had normal cognition, and cerebral MRI showed relatively unspecific white matter abnormalities on T2 sequences without clear progression. Urinary urgency was reported among the female carriers. MRS of both patients showed increased myo-inositol in the white matter, while decreased N-acetylaspartate was found exclusively in the oldest patient. All evoked potential examinations were compatible with severe central demyelination, while no signs of peripheral demyelination or axonal degeneration were found. (18)F-FDG-PET scans were normal. CONCLUSION: The phenotypes of the patients reported here are the mildest described to be caused by the rumpshaker mutation and represent the mildest form among the spectrum of PLP1 related disorders. No definite symptoms in the female carriers could be ascribed to the mutation. These data suggest the pathology to be an underlying dysmyelinating disorder in combination with a central axonal degeneration.