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.

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.

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.

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.

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.

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.

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%.

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.

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.

Stereocontrol of intramolecular Diels-Alder reactions: synthetic studies and transition structure modeling with c5-substituted 1,3,8-nonatrienes and nonadienynes.

An investigation into the endo/exo selectivity and pi-diastereofacial selectivity of ester-tethered intramolecular Diels-Alder reactions is reported. High levels of exo selectivity are realized with terminally substituted dienophiles, and high lk pi-diastereofacial selectivities are induced by the presence of a bulky dioxolanyl substituent at the allylic position of the tether. Precursors 19S, 20S, and 21S, readily prepared from glucose, provide densely functionalized bicyclic lactones of predictable stereochemistry in high yields in enantiomerically pure form upon thermolysis at 110 degrees C. B3LYP/6-31G(d) theory provides good descriptions of transition structures for these reactions and allows an understanding of the formation of the major cycloadducts.

Evidence for overlapping substrate specificity between large neutral amino acid (LNAA) and dipeptide (hPEPT1) transporters for PD 158473, an NMDA antagonist.

PURPOSE: The objective of this research was to investigate the substrate specificity of large neutral amino acid carrier (LNAA) and di/tripeptide (hPEPT1) transporters with respect to PD 158473, an NMDA antagonist. METHODS: Cellular uptake studies were carried out using two types of Chinese Hamster Ovary (CHO). CHO-K1 cells represent the wild type with inherent large neutral amino acid (LNAA) activity. CHO-PEPT1 cells were generated by stable transfection of hPEPT1 gene into CHO cells. Therefore, these cells possess both LNAA activity and di/tripeptide transporter activities as a result of the transfection. Cellular uptake of PD 158473 was quantified using a HPLC method previously developed in our laboratory. RESULTS: The utility of the CHO-PEPT1 cell model was demonstrated by determining the uptake kinetics of Gly-Sar, a prototypical dipeptide transporter substrate. Uptake kinetics of PD 158473 displayed two carrier-mediated transport components in CHO-PEPT1 cells, while in CHO-K1 cells the relationship was consistent with classic one component Michaelis-Menten kinetics. These results confirmed the affinity of PD 158473 for both LNAA and di/tripeptide transporters. Further, results from inhibition experiments using these two cell types indicate that the high affinity-low capacity system was the LNAA carrier and the low affinity-high capacity carrier was the di/tripeptide transporter. CONCLUSIONS: This study demonstrates overlapping substrate specificity between LNAA carrier and di/tripeptide transporter (hPEPT1) for PD 158473, an amino acid analog. Establishing Structure Transport Relationship (STR) for this overlap will aid in a design strategy for increasing oral absorption or targeting specific drugs to selected tissues.

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.

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.