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.

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.

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.

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.

Analysis of the additivity of in vitro inhibition of cholinesterase by mixtures of chlorpyrifos-oxon and azinphos-methyl-oxon.

Organophosphorus (OP) insecticides or their active metabolites act through a common mechanism of toxicity, the inhibition of cholinesterase (ChE). The effects of in vitro exposure of brain (target) and serum (biomarker) ChE to chlorpyrifos-oxon (C horizontal lineO) and azinphos-methyl-oxon (AZM horizontal lineO), the active metabolites of the insecticides chlorpyrifos and azinphos-methyl, respectively, were investigated to determine if simultaneous or sequential exposure to these two OP compounds results in purely additive effects. Additive was defined by the theoretical calculated percent inhibition (dose additivity), which takes into account the fraction of ChE molecules assumed to be available for inhibition by the second compound following inhibition by the first compound, not simple mathematical summation of percent inhibition (response additivity). Brain ChE simultaneously exposed to the two compounds resulted in additive effects, which were less than the simple mathematical summation of percent inhibition. However, serum ChE simultaneously exposed to the two compounds resulted in a nonlinear response, presumably due in part to the presence of detoxifying enzymes in the serum. Sequential exposure of both brain and serum ChE to the two compounds resulted in greater than additive effects at the higher concentrations of each compound. There was no departure from additivity at the lower concentrations of the two compounds. These data suggest that simple mathematical summation of percent inhibitions, i.e., response additivity, is not the appropriate method for describing the combined effects of C horizontal lineO and AZM horizontal lineO on ChE in vitro. In addition, there are other mechanisms involved, such as the presence of detoxication enzymes, that must be taken into account when analyzing the effects of combined exposure of ChE to these two compounds.

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.

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.

Non-invasive assessment of cardiac output in children.

BACKGROUND: Stroke distance, the systolic velocity integral of aortic blood flow, is a linear analogue of stroke volume; its product with heart rate is minute distance, analogous to cardiac output. OBJECTIVE: To investigate the feasibility of assessing cardiac output in children with a simple non-invasive Doppler ultrasound technique, and to determine the normal range of values. METHODS: Peak aortic blood velocity, stroke distance, and minute distance were measured through the suprasternal window in 166 children (mean age 9.6 years, range 2-14) using a portable non-imaging Doppler ultrasound instrument. RESULTS: The technique was well tolerated by all the children participating. Mean peak aortic blood velocity was 138 cm/s and was independent of age. Mean stroke distance was 31.8 cm and showed a small but significant increase with age; mean minute distance was 2490 cm and fell with age, as did heart rate. CONCLUSIONS: Suprasternal Doppler ultrasound measurement of stroke distance is a convenient, well tolerated, non-invasive technique for the assessment of cardiac output in children. The normal range of values during childhood has been established. The technique has great potential for assessing hypovolaemia in children.

Deflation techniques for faulty Foley catheter balloons: presentation of a cystoscopic technique.

The Foley catheter is used for drainage of the urinary bladder in < or = 15% of hospitalized patients and is self-retained by an inflatable balloon mechanism. Faulty balloon deflation, which leads to a retained catheter, is a condition treated by the urologist. In this article we describe a cystoscopic approach to deflation, evaluation, and recovery of retained fragments; review the techniques for deflation; and provide an algorithm to approach the retained Foley catheter.

Fatal genitourinary mucormycosis in a patient with undiagnosed diabetes.

We present what we believe is the first report in the world literature of penile necrosis due to mucormycosis, a rare and often fatal fungal infection. This case of rhizopus mucormycosis began with a penile lesion in a 27-year-old patient with undiagnosed diabetes; it led to necrosis of the phallus, lower urinary tract, rectum, and pelvic musculature and finally to death. Despite repeated aggressive surgical debridement in conjunction with medical therapy, we were unable to halt the progression of the fungal and synergistic bacterial infections.

Paraphimosis in elderly men.

Paraphimosis occurs when the foreskin of the penis is retracted over the glans and cannot be replaced in its normal position. The tight ring of preputial skin constricts the distal penis causing vascular occlusion, much like a tourniquet. The condition is painful and, if not dealt with quickly, can lead to necrosis of the glans. Simple reduction of the prepuce can be achieved by compressing the edematous fluid out of the glans and repositioning the foreskin. Irreducible paraphimosis is treated by dorsal slit procedure and subsequent circumcision. We present two cases illustrating the treatment techniques and possible complications of paraphimosis in men.

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.

Continuous infusion of intrathecal morphine to control acquired immunodeficiency syndrome-associated bladder pain.

A 36-year-old man with acquired immunodeficiency syndrome had incapacitating dysuria and vesical pain secondary to interstitial cystitis. When medical management and suprapubic urinary diversion failed to control the symptoms the patient was started on subarachnoid morphine sulfate. Bupivacaine was added 1 year later via an implanted Therex M-3000 implantable continuous infusion pump, which has continued successfully for more than 18 months. We believe that subarachnoid narcotics and other analgesic agents, such as clonidine, bupivacaine hydrochloride and baclofen, may prove equally valuable in the treatment of bladder spasm and pain. Furthermore, implanted intrathecal ports and pumps may have less associated risk of infection than the percutaneous vascular access catheters presently used for the continuous delivery of medications in immunosuppressed patients.

Angiographic management of retroperitoneal hemorrhage from renal angiomyolipoma in polycystic kidney disease.

Angiographic management of bilateral angiomyolipomas complicated by hemorrhage in autosomal dominant polycystic kidney disease is presented. The patient had mild stigmata of tuberous sclerosis, and a family history of tuberous sclerosis and autosomal dominant polycystic kidney disease. The radiographic features at diagnosis, and those present during and after embolization are described. Radiological criteria for diagnosis and successful control of bleeding with intra-arterial selective embolization are discussed. Radiographic features before, during and after embolization are exhibited.