Hepatic steatosis and non-alcoholic fatty liver disease are not associated with decline in renal function in people with Type 2 diabetes.

AIMS: We aimed to determine whether the presence of hepatic steatosis and/or non-alcoholic fatty liver disease was associated with decline in renal function or onset of microalbuminuria in a cohort of people with Type 2 diabetes, including those managed in both primary and secondary care. METHODS: Nine hundred and thirty-three patients from the Edinburgh Type 2 Diabetes Study, a cohort of Scottish men and women aged 60-74 years with Type 2 diabetes, underwent assessment for hepatic steatosis by liver ultrasonography 1 year after recruitment. Non-alcoholic fatty liver disease was defined as the presence of steatosis following exclusion of secondary causes of liver disease. Patients were followed for 4 years and decline in renal function was assessed by the change in estimated glomerular filtration rate over time. RESULTS: Of the 933 subjects, 530 had hepatic steatosis and, of those with hepatic steatosis, 388 had non-alcoholic fatty liver disease. Neither hepatic steatosis nor non-alcoholic fatty liver disease were significantly associated with rate of decline in renal function, with the mean rate of decline in estimated glomerular filtration rate being -1.55 ml min(-1) 1.73 m(-2) per year for participants with hepatic steatosis compared with -1.84 ml min(-1) 1.73 m(-2) for those without steatosis (P = 0.19). Similar results were obtained when the analysis was restricted to participants with and without non-alcoholic fatty liver disease (-1.44 vs. -1.64 ml min(-1) 1.73 m(-2) per year, respectively; P = 0.44). Additionally, neither hepatic steatosis nor non-alcoholic fatty liver disease were associated with the onset or regression of albuminuria during follow-up (all P ≥ 0.05). CONCLUSIONS: The presence of hepatic steatosis/non-alcoholic fatty liver disease was not associated with decline in renal function during a 4-year follow-up in our cohort of older people with Type 2 diabetes.

The use of ultrasound to diagnose hepatic steatosis in type 2 diabetes: intra- and interobserver variability and comparison with magnetic resonance spectroscopy.

AIM: To compare ultrasound gradings of steatosis with fat fraction (FF) on magnetic resonance spectroscopy (MRS; the non-invasive reference standard for quantification of hepatic steatosis), and evaluate inter- and intraobserver variability in the ultrasound gradings. MATERIALS AND METHODS: Triple grading of hepatic ultrasound examination was performed by three independent graders on 131 people with type 2 diabetes. The stored images of 60 of these individuals were assessed twice by each grader on separate occasions. Fifty-eight patients were pre-selected on the basis of ultrasound grading (normal, indeterminate/mild steatosis, or severe steatosis) to undergo (1)H-MRS. The sensitivity and specificity of the ultrasound gradings were determined with reference to MRS data, using two cut-offs of FF to define steatosis, ≥9% and ≥6.1%. RESULTS: Median (intraquartile range) MRS FF (%) in the participants graded on ultrasound as normal, indeterminate/mild steatosis, and severe steatosis were 4.2 (1.2-5.7), 4.1 (3.1-8.5) and 19.4 (12.9-27.5), respectively. Using a liver FF of ≥6.1% on MRS to denote hepatic steatosis, the unadjusted sensitivity and specificity of ultrasound gradings (severe versus other grades of steatosis) were 71 and 100%, respectively. Interobserver agreement within one grade was observed in 79% of cases. Exact intraobserver agreement ranged from 62 to 87%. CONCLUSION: Hepatic ultrasound provided a good measure of the presence of significant hepatic steatosis with good intra- and interobserver agreement. The grading of a mildly steatotic liver was less secure and, in particular, there was considerable overlap in hepatic FF with those who had a normal liver on ultrasound.

Rocuronium and sugammadex for rapid sequence induction of obstetric general anaesthesia.

BACKGROUND: Many anaesthetists use rocuronium in place of suxamethonium for rapid sequence induction (RSI). This is less common in obstetric anaesthesia as the duration of action of an effective dose of rocuronium exceeds most obstetric procedures. Sugammadex offers the possibility of rapidly reversing profound rocuronium neuromuscular blockade at the end of surgery. We aimed to determine whether rocuronium 1.2 mg/kg used for RSI in the obstetric population would provide good intubating conditions at 60 s and would be effectively reversed by sugammadex at the end of surgery. METHODS: We present a prospective series of 18 patients who received rocuronium 1.2 mg/kg at induction of anaesthesia, monitored with a train-of-four ratio (TOF)-Watch SX(®) , and reversed using sugammadex 4 mg/kg. RESULTS: The mean (95% CI) onset time of rocuronium was 71 (56-86) s, and the mean (95% CI) time to recovery of the TOF to ≥90%, after the administration of sugammadex 4 mg/kg at the end of surgery, was 86 (69-104) s. CONCLUSION: Rocuronium 1.2 mg/kg reversed by sugammadex appears to be effective in the obstetric population.

Availability of lipid emulsion in obstetric anaesthesia in the UK: a national questionnaire survey.

There is evidence that administration of lipid emulsion improves outcome in cardiovascular collapse secondary to local anaesthetic toxicity. We sent a questionnaire to the lead consultant anaesthetist in every consultant-led labour ward in the UK asking about local guidelines for treatment of cardiac arrest, and whether or nor lipid emulsion was available on the labour ward and included in the guideline. We received replies from 195 (86%) labour wards. One hundred and seven (55%) reported having a guideline for the treatment of cardiovascular collapse secondary to local anaesthetic toxicity. Of these guidelines, lipid emulsion was included in 78 (40%). Lipid emulsion was readily available on 95 labour wards (49%). Of the remaining units, there were plans to make lipid available in the near future in 46 (46%). Of the 95 labour wards where lipid emulsion was readily available, 80 (84%) had a recommended dose regimen for its administration. Around three-quarters of labour wards in the UK either have lipid emulsion available or plan to obtain it. This uptake should ideally be 100%.

Postoperative muscle weakness in a patient recently treated with infliximab.

We present a case of profound postoperative muscle weakness in a patient who had been treated with infliximab, and whose weakness had not manifested pre-operatively. We believe this to be the first case report of infliximab-related muscle weakness manifesting immediately after anaesthesia.

Clinically significant chronic liver disease in people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

BACKGROUND: Type 2 diabetes is an independent risk factor for chronic liver disease, however disease burden estimates and knowledge of prognostic indicators are lacking in community populations. AIMS: To describe the prevalence and incidence of clinically significant chronic liver disease amongst community-based older people with Type 2 diabetes and to determine risk factors which might assist in discriminating patients with unknown prevalent or incident disease. DESIGN: Prospective cohort study. METHODS: Nine hundred and thirty-nine participants in the Edinburgh Type 2 Diabetes Study underwent investigation including liver ultrasound and non-invasive measures of non-alcoholic steatohepatitis (NASH), hepatic fibrosis and systemic inflammation. Over 6-years, cases of cirrhosis and hepatocellular carcinoma were collated from multiple sources. RESULTS: Eight patients had known prevalent disease with 13 further unknown cases identified (prevalence 2.2%) and 15 incident cases (IR 2.9/1000 person-years). Higher levels of systemic inflammation, NASH and hepatic fibrosis markers were associated with both unknown prevalent and incident clinically significant chronic liver disease (allP < 0.001). CONCLUSIONS: Our study investigations increased the known prevalence of clinically significant chronic liver disease by over 150%, confirming the suspicion of a large burden of undiagnosed disease. The disease incidence rate was lower than anticipated but still much higher than the general population rate. The ability to identify patients both with and at risk of developing clinically significant chronic liver disease allows for early intervention and clinical monitoring strategies. Ongoing work, with longer follow-up, including analysis of rates of liver function decline, will be used to define optimal risk prediction tools.

Potent, orally active, competitive N-methyl-D-aspartate (NMDA) receptor antagonists are substrates for a neutral amino acid uptake system in Chinese hamster ovary cells.

A series of enantiomerically pure (phosphonomethyl)-substituted phenylalanine derivatives related to SDZ EAB 515 (1) were prepared as competitive N-methyl-D-aspartate (NMDA) receptor antagonists. Unlike most known competitive NMDA antagonists, analogs in this series with the S-configuration are potent NMDA antagonists whereas analogs with the unnatural R-configuration are weak NMDA antagonists, as determined by receptor binding experiments and their anticonvulsant action in mice. Examination in a previously reported competitive NMDA pharmacophore model revealed that receptor affinity can be explained partially by a cavity that accommodates the biphenyl ring of 1, while the biphenyl ring of the R-enantiomer 2 extends into a disallowed steric region. We proposed that analogs with the natural S-configuration and a large hydrophobic moiety would have an advantage in vivo over analogs with an R-configuration by being able to use a neutral amino acid uptake system to enhance both peripheral adsorption and transport into the brain. Examination in a system L neutral amino acid transport carrier assay shows that 1 competes with L-Phe for transport in an apparent competitive and stereospecific manner (estimated Ki = 50 microM). The 1- and 2-naphthyl derivatives 3a,3b were found to be among the most potent, competitive NMDA antagonists yet discovered, being ca. 15-fold more potent than 1 in vitro and in vivo, with a long duration of action. The title compound 3a had potent oral activity in MES (ED50 = 5.0 mg/kg). 3a also retains its ability to compete, albeit more weakly than 1 (estimated Ki = 200 microM), for L-Phe uptake to CHO cells. In this series, analogs with the R-configuration are not substrates for the system L neutral amino acid transport carrier. These results provide evidence that central nervous system active agents can be designed as substrates of a neutral amino acid transporter as a means to enhance penetration of the blood-brain barrier.

Ethionine-induced atrophy of rat pancreas involves apoptosis of acinar cells.

The mechanism of acinar cell loss occurring during ethionine-induced atrophy of the pancreas was investigated. Rats were given a standard diet, a protein-depletion diet (PDD), or a PDD with low- (0.04 g/kg body wt; LDE) or high- (0.4 g/kg; HDE) dose ethionine administered intraperitoneally daily for 10 days. Changes were most extensive in the animals given a PDD and HDE: After 10 days, pancreatic weight was reduced by 72%, and most of the acinar cells had disappeared. Prior to their deletion, these cells showed cytoplasmic vacuolation and enhanced autophagy. The main mechanism involved in their deletion was apoptosis, the apoptotic bodies being phagocytosed and degraded by adjacent acinar cells and intraepithelial macrophages. In contrast, necrosis of acinar cells was rare. Interstitial inflammation and apoptosis of capillary endothelial cells were also observed. In animals given a PDD and LDE, enhanced apoptosis occurred later and was more limited in extent, and additional manifestations of cell injury were not evident. As in other circumstances where glandular atrophy is effected by apoptosis, the basic tissue architecture was preserved, thus explaining the known capacity for the pancreas to regenerate after ethionine is discontinued.

Squamous cell carcinoma of the eyelids.

AIM: To review the clinical features, management, and outcomes of surgical treatment of eyelid squamous cell carcinoma (SCC). METHODS: A retrospective review of all eyelid SCCs treated between 1992 and 2001. RESULTS: 51 cases were identified in 50 patients. Patient ages ranged from 26 to 93 years, with a mean age of 65 years. 33 patients were male and 17 were female. The lesion was found on the lower lid in 31 cases, upper lid in five cases, lateral canthus in six cases, and medial canthus in nine cases. Perineural invasion was found in four patients, and orbital invasion in three patients. Recurrence occurred in one patient. Treatment was by complete excision with histological confirmation of clear margins. Exenteration was required in three patients. No patients developed lymph node or distant metastases. One patient, who declined treatment, died as a result of the tumour. Mean follow up was 31.1 months. CONCLUSIONS: Eyelid SCC is a relatively uncommon, but potentially fatal disease. However, if detected early and treated adequately, the prognosis is generally excellent. Treatment by complete excision with histological confirmation of tumour clearance is recommended. Perineural spread is an adverse prognostic sign, which may require postoperative radiotherapy. Orbital invasion is a rare complication but, if recognised early, can be treated effectively with exenteration. Because presentation varies and histological examination is required for accurate diagnosis, any suspicious lesion occurring on the eyelids should be excised or biopsied. All patients with eyelid SCC should be advised of the risk of recurrent or new tumours and encouraged to attend lifelong follow up. Prevention remains of prime importance in minimising the morbidity and mortality of these lesions.

Large intestinal lymphocytic phlebitis and venulitis in chronic ulcerative colitis.

Colonic vasculitis is seen in Crohn's disease and as a component of primary systemic vasculitis. It has rarely been described in chronic ulcerative colitis. Here we report a case of ulcerative colitis with prominent transmural lymphocytic phlebitis and venulitis. Although this is, to our knowledge, the first description of such an association, its recognition is important if confusion with other entities is to be avoided. The etiology of the vascular changes is unclear but they may be a secondary phenomenon induced by antigens, toxins or cytokines draining from the inflamed mucosa.

The distribution of Anoplocephala perfoliata in the intestine of the horse and associated pathological changes.

The intestinal tracts of 130 horses were examined for infection with Anoplocephala perfoliata at necropsy. Fifty horses (38.5%) harboured the tapeworm, and the site of attachment of each worm was recorded using predetermined anatomical landmarks. The worms were attached in four regions of the gastrointestinal tract: 17% of the worms were found at the ileocaecal junction, 81% on the caecal wall, 1.7% in the terminal ileum and 0.2% in the ventral colon. The severity of lesions produced at the sites of attachment was related to the number of worms attached. Due to the small area of the ileocaecal junction, worms at this site were attached in close proximity, resulting in more severe lesions. The major features of the lesions included ulceration, diphtheritic membranes and thickening of the mucosa, submucosa and lamina propria. There was an increase in the number of eosinophils and a decrease in the number of lymphocytes present at the sites of lesions.

Coprological methods for the diagnosis of Anoplocephala perfoliata infection of the horse.

OBJECTIVE: To compare the sensitivities of three coprological techniques for the diagnosis of Anoplocephala perfoliata infection in horses and to assess the value of the methods for diagnosis of horses at risk of clinical cestodiasis. DESIGN: Faecal samples were collected from necropsied horses with or without A perfoliata infection and examined using one sedimentation and two different flotation methods. The coprological results were compared with worm counts performed at necropsy of the horses and the degree of mucosal damage. In addition, the efficiency of recovery of A perfoliata eggs from faeces was tested. RESULTS: The overall sensitivities of the methods ranged from 22.5 to 37.5%, and the capacity of the methods to diagnose infection increased with the intensity of infection. A simple flotation method achieved a better sensitivity (37.5%) at all intensities of infection compared with the other two methods (22.5 to 25%). That method was also more sensitive in detecting eggs in 'negative' faecal samples spiked with known numbers of A perfoliata eggs. CONCLUSION: The results indicated that, despite the low sensitivities of present methods, faecal flotation is likely to be of value in detecting horses at risk of clinical disease.

Prevalence and markers of advanced liver disease in type 2 diabetes.

BACKGROUND: Type 2 diabetes is a risk factor for progression of non-alcoholic fatty liver disease (NAFLD) to fibrosis and cirrhosis. We examined the prevalence of advanced liver disease in people with type 2 diabetes and analysed the effectiveness of liver function tests (LFTs) as a screening tool. METHODS: Participants (n = 939, aged 61-76 years) from the Edinburgh Type 2 Diabetes Study, a randomly selected population of people with type 2 diabetes, underwent abdominal ultrasonography. Hyaluronic acid (HA) and platelet count/spleen diameter ratio (PSR) were used as non-invasive markers of hepatic fibrosis and portal hypertension. Subjects were screened for secondary causes of liver disease that excluded them from a diagnosis of NAFLD. The efficacy of LFTs [alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT)] in screening for liver disease was determined. RESULTS: Cirrhosis was identified by ultrasound in four participants (0.4%). Ten (1.1%) had evidence of portal hypertension (PSR < 909), and two (0.2%) had hepatocellular carcinoma. Fifty-three participants (5.7%) had evidence of hepatic fibrosis (HA > 100 ng/ml in the absence of joint disease); a further 169 had HA > 50 ng/ml. In participants with NAFLD-related fibrosis (HA > 100 ng/ml), 12.5% had an elevated ALT level and 17.5% had an elevated GGT level. CONCLUSION: The prevalence of hepatic fibrosis and cirrhosis were lower than expected. The use of LFTs to screen for liver disease missed most cases of fibrosis predicted by raised HA levels.

Anoplocephala perfoliata of horses--significant scope for further research, improved diagnosis and control.

Anoplocephala perfoliata is the commonest tapeworm parasite of horses and is incriminated as a significant cause of clinical disease (e.g., ileocaecal intussusception, caeco-caecal intussusception and/or caecal perforation), particularly in horses chronically infected with large numbers of worms. The high prevalence (approximately 20-80%) of the parasite in some countries suggests an increased risk of clinical cases. In spite of research, there is still a paucity of information regarding the pathogenesis of the disease, the epidemiology of the parasite in different geographical regions and there are significant limitations with the diagnosis of infection. The present article provides an account of the biology, epidemiology and pathogenic effects of A. perfoliata, the diagnosis of infection and treatment. It highlights some gaps in knowledge of the parasite and the disease it causes, and suggests opportunities for future research and prospects for improved diagnosis, prevention and control.

Membrane association of leucyl-tRNA synthetase during leucine starvation in Escherichia coli.

The influence of leucine starvation on the subcellular location of leucyl-tRNA synthetase in Escherichia coli was examined in a leucine auxotrophic strain by sucrose density sedimentation analysis. Analysis of the subcellular distribution of leucyl-tRNA synthetase activity revealed that during unrestricted growth, the leucine synthetase enzyme activity was found to be localized in the soluble protein fraction of the gradient. However, during restricted growth on low levels of leucine, leucyl-tRNA synthetase activity was localized in the cytoplasmic membrane fraction of the gradient. The transition from soluble to membrane-association of the enzyme also occurred following inhibition of protein synthesis by treatment of cells with chloramphenicol. These results collectively suggest that leucyl-tRNA synthetase may be recruited to the cytoplasmic membrane in response to shortages of leucine or perturbation of protein synthesis.

Information theory analysis of the relationship between primary sequence structure and ligand recognition among a class of facilitated transporters.

Determining how specificity for a given ligand occurs among sequence and structurally related transporters is a fundamental problem in elucidating facilitated transport. It is likely that the specificity of a transporter for a ligand is defined by the primary amino acid sequence, and that different ligand specificities among highly related proteins are associated with variations in the amino acid sequence. To assist studies on the potential relationships between protein structure and ligand specificity, information theory was used to assign a measure that quantitates the importance of amino acid choice at individual sites in protein sequences based upon their variability. The approach allows for the transformation of a collection of multiply aligned sequences into a profile that provides a quantitative assessment of the relative frequencies of chemically similar residues at each site. Profiles generated from particular groups of proteins can be directly compared to profiles generated for other groups. These comparisons allow unique differences in the utilization of amino acids at individual sites to be identified as differences in information distribution. The approach was applied to the problem of identifying sites of the dopamine transporter which may play a role in distinguishing its ligand specificity and function from those of a related population of transporters for amino acid and amino-acid-like ligands. Several sites were identified that appear highly likely to distinguish the dopamine transporter from related proteins. Many of the sites identified were also found to be associated with predicted variations in local secondary and tertiary structure between the two classes of proteins.