The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD) characterized by steatosis, inflammation, and fibrosis often associated with metabolic syndrome. Fibroblast growth factor 15 (FGF15), an endocrine factor mainly produced in the distal part of small intestine, has emerged to be a critical factor in regulating bile acid homeostasis, energy metabolism, and liver regeneration. We hypothesized that FGF15 alters the development of each of the listed features of NASH. To test this hypothesis, four-week old male Fgf15-/- and their corresponding wild-type (WT) mice were fed either a high fat diet (HFD) or a control chow diet for six months. The results confirmed that HFD feeding for six months in WT mice recapitulated human NASH phenotype, including macrovesicular steatosis, inflammation, and fibrosis. Whereas FGF15 deficiency had no effect on the severity of liver steatosis or inflammation, it was associated with decreased liver fibrosis. Furthermore, FGF15 deficiency resulted in abnormal bile acid homeostasis, increased insulin resistance, increased HFD-induced serum triglycerides, decreased inductions of hepatic cholesterol content by HFD, and altered gene expression of lipid metabolic enzymes. These data suggest that FGF15 improves lipid homeostasis and reduces bile acid synthesis, but promotes fibrosis during the development of NASH.

Laparoscopic radical 'no-touch' left pancreatosplenectomy for pancreatic ductal adenocarcinoma: technique and results.

BACKGROUND: Laparoscopic left pancreatectomy has been well described for benign pancreatic lesions, but its role in pancreatic adenocarcinoma remains open to debate. We report our results adopting a laparoscopic technique that obeys established oncologic principles of open distal pancreatosplenectomy. METHODS: This is a post hoc analysis of a prospectively kept database of 135 consecutive patients undergoing laparoscopic left pancreatectomy, performed across two sites in the UK and the Netherlands (07/2007-07/2015 Southampton and 10/2013-07/2015 Amsterdam). Primary outcomes were resection margin and lymph node retrieval. Secondary endpoints were other perioperative outcomes, including post-operative pancreatic fistula. Definition of radical resection was distance tumour to resection margin >1 mm. All patients underwent 'laparoscopic radical left pancreatosplenectomy' (LRLP) which involves 'hanging' the pancreas including Gerota's fascia, followed by clockwise dissection, including formal lymphadenectomy. RESULTS: LRLP for pancreatic adenocarcinoma was performed in 25 patients. Seven of the 25 patients (28 %) had extended resections, including the adrenal gland (n = 3), duodenojejunal flexure (n = 2) or transverse mesocolon (n = 3). Mean age was 68 years (54-81). Conversion rate was 0 %, mean operative time 240 min and mean blood loss 340 ml. Median intensive/high care and hospital stay were 1 and 5 days, respectively. Clavien-Dindo score 3+ complication rate was 12 % and ISGPF grade B/C pancreatic fistula rate 28 %; 90-day (or in-hospital) mortality was 0 %. The pancreatic resection margin was clear in all patients, and the posterior margin was involved (<1 mm) in 6 patients, meaning an overall R0 resection rate of 76 %. No resection margin was microscopically involved. Median nodal sample was 15 nodes (3-26). With an average follow-up of 17.2 months, 1-year survival was 88 %. CONCLUSIONS: A standardised laparoscopic approach to pancreatic adenocarcinoma in the left pancreas can be adopted safely. Our study shows that these results can be reproduced across multiple sites using the same technique.

Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and l-DOPA reversible motor deficits.

The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite-to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with l-DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and l-DOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson's disease.

Convergence of HbA1c values towards target in 272 primary care patients following nine years of target-driven care.

BACKGROUND: We wished to determine the effect of a target-driven incentivised programme on haemoglobin A1c (HbA1c ) values in a UK diabetic population. METHODS: An audit was carried out in 1999-2000, which included an estimation of glycaemic control in a randomly selected diabetic cohort from ten primary care practices in Sutton Coldfield, serving a population of 90 000 patients. Each practice was given a randomised list of patients and asked to complete detailed questionnaires on patients with confirmed diabetes. We collected data on 516 patients, 425 of whom had their HbA1c measured in 1999-2000 (Audit 2000). A re-audit of HbA1c was carried out in 2007-08 (Audit 2008) determining the changes in HbA1c since the original audit. Of the original cohort, 272 patients had an audit of HbA1c carried out in Audit 2008. RESULTS: Overall, a small increase in median and mean HbA1c values was observed. We estimated that the proportion of patients with HbA1c achieving the lower Quality and Outcomes Framework HbA1c target of < 7.5%; 173 of the 272 patients met this target in Audit 2000, whereas the number was 162 in Audit 2008. To understand the changes observed, patients were stratified as quintiles based on the HbA1c in Audit 2000 and changes in HbA1c after 8 years for each quintile were estimated. The mean changes for the different quintiles are: quintile 1 (HbA1c < 6.1%), +1.49%; quintile 2 (HbA1c 6.1- 6.6%), +0.8%; quintile 3 (HbA1c 6.7-7.3%), +0.3%; quintile 4 (HbA1c 7.4-8.5%), -0.18%; and quintile 5 (HbA1c > 8.5%), -1.55%. CONCLUSION: Our results suggest that, eight years on, patients with poor glycaemic control in 2000 saw an overall decrease in HbA1c by 2008, with the reverse seen in patients with good control.

Effect of stomaching on numbers of bacteria recovered from chicken skin.

Stomaching of skin samples releases only slightly more bacteria than a single rinse. Successive rinses, however, continue to remove almost as many bacteria as the first rinse. One hypothesis to explain this observation is that relatively violent treatment of skin generates smaller pieces of skin, thus increasing the net surface area and effectively sequestering bacteria in a water film on the skin pieces so that numbers of bacteria suspended in the rinsate do not increase. An experiment was conducted to determine whether inoculated marker bacteria are removed from the rinse liquid as skin pieces are stomached and naturally occurring bacteria are released. In each of 4 replications, 5 prechill broiler carcasses were collected from a commercial processing plant. Two 5-g pieces (n = 40) of breast skin were removed from each carcass and placed in a stomacher bag. An inoculum of 30 mL of 0.85% saline solution containing approximately 10(4) of nalidixic acid-resistant Salmonella enterica serovar Typhimurium per milliliter was added to each sample. Skin samples were hand-massaged for 30 s to mix the inoculum, after which a 1-mL aliquot was removed for enumeration of bacteria. A similar sample was taken after 4 min of vigorous stomaching of the skin sample. Bacterial counts recovered from the 30-s hand-massage were 4.3, 2.7, 2.6, and 3.7 log(10) cfu/mL of rinsate for aerobic bacteria, coliforms, Escherichia coli, and Salmonella, respectively. After stomaching, counts were 4.3, 2.9, 2.8, and 3.8, respectively. There was no difference in aerobic plate counts, but mean coliform and E. coli counts were significantly higher (P < 0.05) after stomaching. Numbers of inoculated Salmonella did not decrease. Breaking up the skin into smaller pieces by stomaching did not reduce the number of inoculated bacteria suspended in the rinsate.

Brachiopods in mud: resolution of a dilemma.

Assumptions made from studies of sparse living faunas of brachiopods, namely, that they are intolerant of mud, that the free-lying habit is confined to species without pedicles, and that the pedicle of articulate brachiopods is uniform in structure and function, do not withstand critical examination. Studies in New Zealand show that some species in the same area occur in both attached and free-lying populations. Individuals cannot always be differentiated morphologically, but the structure of populations from hard and soft substrates is distinctive. Attachment to a substrate appears to be a larval rather than an adult requirement in most species.

Locomotory adaptations in a free-lying brachiopod.

Magadina cumingi inhabits an environment of high current energy and mobile sediments by using its pedicle in Pogo-stick fashion as an elevating device. This type of progression is associated with pedicle musculature different from that of attached and other free-lying forms, and some diagnostic differences in muscle attachment areas are evident in preservable hard parts.

PACAP38 increases vesicular monoamine transporter 2 (VMAT2) expression and attenuates methamphetamine toxicity.

Pituitary adenylyl cyclase activating polypeptide, 38 amino acids (PACAP38) is a brain-gut peptide with diverse physiological functions and is neuroprotective in several models of neurological disease. In this study, we show that systemic administration of PACAP38, which is transported across the blood-brain barrier, greatly reduces the neurotoxicity of methamphetamine (METH). Mice treated with PACAP38 exhibited an attenuation of striatal dopamine loss after METH exposure as well as greatly reduced markers of oxidative stress. PACAP38 treatment also prevented striatal neuroinflammation after METH administration as measured by overexpression of glial fibrillary acidic protein (GFAP), an indicator of astrogliosis, and glucose transporter 5 (GLUT5), a marker of microgliosis. In PACAP38 treated mice, the observed protective effects were not due to an altered thermal response to METH. Since the mice were not challenged with METH until 28 days after PACAP38 treatment, this suggests the neuroprotective effects are mediated by regulation of gene expression. At the time of METH administration, PACAP38 treated animals exhibited a preferential increase in the expression and function of the vesicular monoamine transporter (VMAT2). Genetic reduction of VMAT2 has been shown to increase the neurotoxicity of METH, thus we propose that the increased expression of VMAT2 may underlie the protective actions of PACAP38 against METH. The ability of PACAP38 to increase VMAT2 expression suggests that PACAP38 signaling pathways may constitute a novel therapeutic approach to treat and prevent disorders of dopamine storage.

Herpes simplex neuropathy.

Atypical facial pain and permanent sensory loss in the second and third divisions of the trigeminal nerve developed in a patient who had had multiple attacks of herpes simplex neuralgia over a period of 8 years. Intravenous cytosine arabinoside failed to prevent a recurrence of the vasicular eruption, but carbamazepine produced symtomatic pain relief. This case demonstrates that herpes simplex can closely mimic herpes zoster as a cause of postherpetic neuralgia and suggests a possible etiology of atypical facial pain and/or trigeminal sensory neuropaty in some patients.

Effects of repeated oral postnatal exposure to chlorpyrifos on open-field behavior in juvenile rats.

Organophosphorus (OP) insecticides have the potential to cause behavioral effects in children. This study was designed to determine if repeated oral exposure of preweanling rats to chlorpyrifos would produce behavioral changes at both pre- and postweanling ages. Treatment occurred every second day beginning on post-natal day (PND) 1, and continued through PND 21. The rats received one of the following regimens: a low-dosage (3 mg/kg) from PND 1-21; a medium dosage (mg/kg from PND 1-5, and then 6 mg/kg from PND 7-21; or a high-dosage schedule of 3 mg/kg on PND 1-5, then 6 mg/kg from PND 7-13, and 12 mg/kg from PND 15-21. There were no differences in body weights among the control-, low-, and medium-dosage groups but the high-dosage group had significantly lower body weights on PND 13-21. An open field was used to measure locomotor activity on PND 10, 12, 14, 16, 18, 20, 25, and 30. There were no differences in locomotor activity levels or treatment effects between males and females. On PND 10, 12, 14, 16, 18, and 20 there was no effect on locomotor activity with any dosage. On days 25 and 30, locomotor activity was significantly decreased with the medium- and high-dosage groups. Brain cholinesterase (ChE) inhibition was about 25-38% on PND 25 and 14-34% on PND 30. On PND 25 but not 30, lung and diaphragm ChE and serum butyrylcholinesterase (BChE), with the high-dosage animals, and heart ChE with the medium- and high-dosage groups were significantly inhibited. There was no significant inhibition of skeletal muscle ChE or serum acetylcholinesterase (AChE) on PND 25 and 30. These data suggest that early postnatal chlorpyrifos exposures will depress locomotor activity in juvenile rats, with the effects most pronounced after brain ChE activity has substantially recovered.

Adenocarcinoma of kidney in a child. Tumor rupture following trauma.

A ten-year-old white girl with Stage I clear cell adenocarcinoma of the kidney was seen after local trauma had produced a renal laceration with rupture of the tumor. She was treated with nephrectomy followed by a second exploration several months later. No adjunctive therapy was used.

Unsuspected intraperitoneal rupture of bladder presenting with abdominal free air.

We present a case of intraperitoneal rupture of the bladder discovered during exploratory laparotomy for abdominal free air associated with an indwelling Foley catheter found in the peritoneal cavity. This report emphasizes the need for systematic and thorough evaluation of the genitourinary tract in the patient with multiple trauma.

Diuretic renal scan: is it always reliable?

The differentiation between significant mechanical obstruction and nonobstructive dilation of the kidneys and ureters is fundamental to patient management. The diuretic renal scan is a useful test in this situation because it usually is reliable and reproducible and is noninvasive and objective, providing information about the function of each kidney. However, this study has given variable results in a small number of patients. We report our experience with five such patients and recommend an algorithm for evaluating patients with equivocal scan results. This report emphasizes the importance of continued follow-up and the need for periodic reevaluation of patients with unexplained urinary symptoms or persistent flank pain, even when the initial diuretic renal scan is normal.

Dietary protein and beef consumption predict for markers of muscle mass and nutrition status in older adults.

OBJECTIVE: To determine the relationship of beef and protein intake to nutrition status, body composition, strength, and biochemical measures of vitamin and mineral status, inflammation and blood lipids in older adults. DESIGN: Cross-sectional observational study. SETTING: State of Ohio, U.S.A. PARTICIPANTS: 142 adults ages 60-88. MEASUREMENTS: Subjects completed a Diet History Questionnaire, and questionnaires related to nutrition status and activity. Subjects also underwent measurements of body composition and strength, and a subset took part in a blood draw for biochemical measurements. RESULTS: Beef intake (g/d) was positively correlated to muscle mass measured by mid-arm muscle area (R=0.128, p=0.030). From multiple linear regression analysis, a 1oz/d (~28g/d) increase in beef consumption predicts for a 2.3cm(2) increase in mid-arm muscle area. Beef intake was negatively correlated to total (R=-0.179, p=0.035) and HDL (R=-0.247, p=0.004) cholesterol, and there was no association between beef and LDL-cholesterol, triglycerides, liver enzymes, or inflammatory markers. Protein intake (% of total energy) was positively correlated to nutrition status measured by the Mini Nutrition Assessment (R=0.196, p=0.020), and calf circumference (R=0.190, p=0.024), and these correlations remained when potential confounders were accounted for in multiple linear regression models. Protein intake was also positively correlated with BMI when analyzed with multiple linear regression. CONCLUSIONS: Beef intake was positively associated with mid-arm muscle area, and protein intake was positively associated with nutrition status, calf circumference, and BMI in older adults. Consuming lean cuts of beef in moderation may be a healthy way in which older adults can increase protein intake, preserve muscle mass and improve nutrition status.

Leydig cell tumor and metachronous Leydig cell hyperplasia: a case associated with gynecomastia and elevated urinary estrogens.

We report a case of unilateral Leydig cell tumor associated with gynecomastia and elevated urinary estrogens. Nine years after orchiectomy urinary estrogens became elevated and Leydig cell hyperplasia but no distinct tumor was identified in the remaining contralateral testicle.

Coronary angiography and coronary artery revascularisation rates in public and private hospital patients after acute myocardial infarction.

OBJECTIVE: To determine the rates of coronary angiography or coronary artery revascularisation procedures in patients with acute myocardial infarction (AMI) managed in private versus public hospitals. DESIGN: Case record linkage analysis of data from the Victorian Inpatient Minimum Dataset for admissions for AMI in the 12 months after the index admission. SETTING: Victorian acute care hospitals from July 1995 to December 1997. PATIENTS: Victorian residents aged 15-85 years admitted to hospital with AMI. MAIN OUTCOME MEASURES: Rates of coronary angiography or coronary artery revascularisation procedures after AMI. RESULTS: Compared with public patients in public hospitals, patients with AMI managed in private hospitals were more likely to undergo coronary angiography (rate ratio [RR], 2.17; P< 0.001; 95% CI, 2.06-2.29), coronary angioplasty or stenting (RR, 3.05; P<0.001; 95% CI, 2.82-3.31), and coronary artery bypass grafting (RR, 1.95; P<0.001; 95% CI, 1.79-2.14). Once coronary angiography had been performed, patients in private hospitals were more likely to undergo angioplasty or stenting (RR, 1.94; P<0.001; 95% CI, 1.79-2.11), but were only marginally more likely to undergo coronary artery bypass grafting (RR, 1.17; P<0.001; 95% CI, 1.07-1.28). CONCLUSIONS: In Victoria, management of patients with acute myocardial infarction is influenced by the public or private status of the patient, and by whether management occurs in private or public hospitals. Patients are more likely to undergo coronary angiography and coronary artery revascularisation procedures in private hospitals.