Snoring Remediation with Oral Appliance Therapy Potentially Reverses Cognitive Impairment: An Intervention Controlled Pilot Study.

Respiration rate (RR) dynamics entrains brain neural networks. RR differences between mild cognitive impairment (MCI) and Alzheimer's disease (AD) in response to oral appliance therapy (OAT) are unknown. This pilot study investigated if RR during stable sleep shows a relationship to pathological severity in subjects with MCI and AD who snore and if RR is influenced following stabilization of the upper airway using OAT. The study cohort was as follows: cognitively normal (CN; n = 14), MCI (n = 14) and AD (n = 9); and a sub-population receiving intervention, CN (n = 5), MCI (n = 7), AD (n = 6) subjects. The intervention used was an oral appliance plus a mouth shield (Tx). RR maximum (max) rate (breaths/minute) and RR fluctuation during 2116 stable sleep periods were measured. The Montreal cognitive assessment (MoCA) was administered before and after 4 weeks with Tx. Baseline data showed significantly higher RR fluctuation in CN vs. AD (p < 0.001) but not between CN vs. MCI (p = 0.668). Linear mixed model analysis indicated Tx effect (p = 0.008) for RR max. Tx after 4 weeks lowered the RR-max in MCI (p = 0.022) and AD (p < 0.001). Compared with AD RR max, CN (p < 0.001) and MCI (p < 0.001) were higher with Tx after 4 weeks. Some MCI and AD subjects improved executive and memory function after 4 weeks of Tx.

A Curious Case of Blastomyces Osteomyelitis.

Blastomycosis is an uncommon disease caused by the dimorphic fungus, Blastomyces dermatitidis, often found in endemic regions of Midwestern America. It can be found in forested, sandy soils, decaying vegetation, rotting wood near water sources, and even in bird feces. Most commonly, blastomycosis manifests as a pulmonary infection presenting as pneumonia, or in severe cases, respiratory distress syndrome (ARDS). Dissemination to the bone is less common but osteomyelitis of the lower thoracic and lumbar spine, ribs, skull, and long bones have been most frequently reported. Disseminated infection to the genitourinary system commonly manifests as prostatitis or epididymo-orchitis in men and as an endometrial infection or tubo-ovarian abscess in women. In the nervous system, blastomycosis can manifest as meningitis or with a cranial abscess. Having a high degree of clinical suspicion and obtaining a detailed medical and social history is important for making a diagnosis. Culturing a specimen will provide a definitive diagnosis. Sputum or tissue specimens stained in 10% potassium hydroxide under microscopy will reveal the classic appearance of B. dermatitidis (broad-based budding with a double-contoured cell wall). In mild to moderate disease without dissemination, itraconazole is the treatment of choice. In severe, life-threatening cases, patients with CNS involvement or in immunocompromised individuals, amphotericin B is the preferred initial drug of choice.  We present an interesting case of a 42-year-old African-American male with no significant past medical history who was admitted initially for suspicion of cellulitis/septic arthritis and was started on broad-spectrum antibiotics. However, he was eventually found to have Blastomyces osteomyelitis.

Prevalence of adenomas and sessile serrated adenomas in Chinese compared with Caucasians.

BACKGROUND AND AIMS: Colonic adenomas and sessile serrated adenomas (SSA) are the most common premalignant polyps identified at colonoscopy. This study compares the prevalence of neoplastic polyps in Chinese and Caucasians in a general gastroenterology outpatient practice in Australia. METHODS: This study included consecutive unselected colonoscopies performed for standard clinical indications by a single endoscopist (JMH). All polyps detected were measured, resected, and sent for histopathology. The prevalence of adenomas, advanced adenomas, SSA, and cancer in the Chinese and Caucasian cohorts were compared. Advanced adenomas were defined as adenomas > 10 mm, villous histology, or high-grade dysplasia. RESULTS: The study included 346 Chinese and 654 Caucasians. There was no significant difference in the baseline characteristics including age, gender, and indications of colonoscopy, although Chinese were more likely to present with rectal bleeding (22.8% vs 15.9%, P = 0.01). The prevalence of adenomatous polyps was similar in both Caucasians (34.3%) and Chinese (35.3%). However, advanced adenomas were more significantly common in Caucasians (11.3%) compared with Chinese (4.6%) (P < 0.001). SSA was rare in Chinese (2%) but present more frequently in Caucasians (7%) (P = 0.001). Multivariate analysis showed that Caucasian ethnicity (odds ratio 2.4, 95% confidence interval 1.6-3.6) and the presence of SSA (odds ratio 4.4, 95% confidence interval 2.3-8.6) were independent predictors for the detection of an advanced adenoma. CONCLUSIONS: The prevalence of significant colorectal lesions, including advanced adenomas, large adenomas, and SSA, were lower in Chinese compared with Caucasians. These findings may influence the guidelines for colonic cancer screening in Chinese populations.

The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study.

UNLABELLED: Information on the long-term prognosis of nonalcoholic fatty liver disease (NAFLD) is limited. We sought to describe the long-term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis by prospectively studying 247 such patients from four international centers (in Australia, USA, UK and Italy). Their natural history was then compared with 264 patients with HCV infection who were either naïve or non-responders to treatment. Both cohorts were Child-Pugh class A and had advanced fibrosis (stage 3) or cirrhosis (stage 4) confirmed by liver biopsy at enrollment. In the NAFLD cohort, followed up for a mean of 85.6 months (range, 6-297), there were 48 (19.4%) liver-related complications and 33 (13.4%) deaths or liver transplants. In the HCV cohort, followed up for 74.9 months (mean; range, 6-238), there were 47 (16.7%) liver-related complications and 25 (9.4%) deaths or liver transplants. When adjusting for baseline differences in age and gender, the cumulative incidence of liver-related complications was lower in the NAFLD than the HCV cohort (P = 0.03), including incident hepatocellular cancer (6 versus 18; P = 0.03), but that of cardiovascular events (P = 0.17) and overall mortality (P = 0.6) were similar in both groups. In the NAFLD cohort, platelet count, stage 4 fibrosis, lowered platelet count, and lowered serum cholesterol and alanine aminotransferase (ALT) levels were associated with liver-related complications; an aspartate aminotransferase/ALT ratio >1 and older age were associated with overall mortality, and higher serum bilirubin levels and stage 4 fibrosis were associated with liver-related mortality. CONCLUSIONS: Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver-related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality. Some clinical and laboratory features predict liver-related complications and other outcomes in patients with NAFLD.

An anthropomorphic phantom study of visualisation of surgical clips for partial breast irradiation (PBI) setup verification.

Surgical clips were investigated for partial breast image-guided radiotherapy (IGRT). Small titanium clips were insufficiently well visualised. Medium tantalum clips were best for megavoltage IGRT and small tantalum clips were best for floor mounted kilovoltage IGRT (ExacTrac). Both small tantalum and medium titanium clips were suitable for isocentric kilovoltage IGRT.

Genotype-specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C.

UNLABELLED: The interaction between insulin resistance (IR), steatosis and genotype to fibrosis in chronic hepatitis C virus (HCV) infection has not been comprehensively assessed. We hypothesized that IR is a key mediator for the development of both steatosis and fibrosis in 346 untreated, nondiabetic patients solely infected with either genotype 1 or 3. We examined for genotype-specific interactions between IR, steatosis and fibrosis by performing subgroup analyses. Because cirrhosis is known to cause IR, we repeated the analysis in a cohort of 313 noncirrhotic HCV-infected patients. We confirmed the impact of IR on fibrosis by analysis of 153 lean subjects in whom any effect of steatosis would be minimized. In HCV genotype 3 patients, increased steatosis was linked to high viral load (P = 0.001), and was not associated with fibrosis (P = 0.1). In contrast, body mass index (P = 0.04) and homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.01) contributed directly to steatosis in HCV genotype 1. HOMA-IR rather than steatosis was independently associated with fibrosis for both HCV genotype 1 (OR, 3.22; P = 0.02) and genotype 3 (OR, 3.17; P = 0.04). Exclusion of cirrhotic subjects did not alter the findings with respect to the greater contribution of IR compared to hepatic steatosis, as a predictor of fibrosis (P = 0.02). Genotype-specific subgroup analyses did not alter this finding. The extent of HOMA-IR remained significantly associated with fibrosis in lean patients, independent of the confounding effect of body mass index on IR (OR, 8.02; P = 0.003). CONCLUSION: IR is a major independent determinant of fibrosis in chronic HCV infection, regardless of the genotype and the severity of liver damage.

Visceral fat: a key mediator of steatohepatitis in metabolic liver disease.

UNLABELLED: Visceral obesity is intimately associated with metabolic disease and adverse health outcomes. However, a direct association between increasing amounts of visceral fat and end-organ inflammation and scarring has not been demonstrated. We examined the association between visceral fat and liver inflammation in patients with nonalcoholic fatty liver disease (NAFLD) to delineate the importance of visceral fat to progressive steatohepatitis and hence the inflammatory pathogenesis of the metabolic syndrome. We undertook a cross-sectional, proof of concept study in 38 consecutive adults with NAFLD at a tertiary liver clinic. All subjects had a complete physical examination, anthropometric assessment, and fasting blood tests on the day of liver biopsy. Abdominal fat volumes were assessed by magnetic resonance imaging within 2 weeks of liver biopsy. The extent of hepatic inflammation and fibrosis augmented incrementally with increases in visceral fat (P < 0.01). For each 1% increase in visceral fat, the odds ratio for increasing liver inflammation and fibrosis was 2.4 (confidence interval [CI]: 1.3-4.2) and 3.5 (CI: 1.7-7.1), respectively. Visceral fat remained an independent predictor of advanced steatohepatitis (odds ratio [OR] 2.1, CI: 1.1-4.2, P = 0.05) and fibrosis (OR 2.9, CI: 1.4-6.3, P = 0.006) even when controlled for insulin resistance and hepatic steatosis. Interleukin-6 (IL-6) levels, which correlated with visceral fat, also independently predicted increasing liver inflammation. Visceral fat was associated with all components of the metabolic syndrome. CONCLUSION: Visceral fat is directly associated with liver inflammation and fibrosis independent of insulin resistance and hepatic steatosis. Visceral fat should therefore be a central target for future interventions in nonalcoholic steatohepatitis and indeed all metabolic disease.

Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3.

BACKGROUND/AIMS: Obesity is associated with impaired treatment responses in chronic hepatitis C. The aim of this study was to determine the relationship between the insulin resistance frequently seen in obese subjects and sustained virological response to anti-viral therapy (SVR) in patients with genotype 2 or 3 infection. METHODS: Eighty-two patients were studied; 59 received interferon/ribavirin while 23 received peg-interferon/ribavirin. RESULTS: The overall SVR was (77%). Patients with a SVR had lower mean serum insulin (10.7+/-0.8 microU/ml vs. 22.2+/-4.9; P = 0.03), fibrosis stage (1.9+/-0.1 vs. 2.7+/-0.3; P = 0.007) and insulin resistance measured by the homeostasis model (HOMA-IR) (2.5+/-0.2 vs. 6.1+/-1.5; P = 0.03). Age, gender, ethnicity, alcohol consumption, treatment regimen, viral load, portal activity and steatosis did not influence the SVR. By linear regression, body mass index (P < 0.001) and fibrosis stage (P < 0.001) were independently associated with HOMA-IR. After adjusting for fibrosis stage, patients with HOMA-IR of < 2 were 6.5 times more likely to achieve SVR than those with HOMA-IR > or = 2. CONCLUSIONS: Even in treatment-responsive genotypes 2 and 3, high HOMA-IR is associated with a reduced response. Improving insulin sensitivity may be a useful adjunct to anti-viral therapy in these individuals.

Insulin resistance and liver injury in hepatitis C is not associated with virus-specific changes in adipocytokines.

UNLABELLED: The role of tumor necrosis factor alpha, interleukin 6, leptin, and adiponectin in the pathogenesis of hepatitis C virus (HCV)-associated insulin resistance (IR) remains controversial. We tested the hypothesis that these adipocytokines contribute to chronic HCV-associated IR and liver injury by first comparing their serum levels and homeostasis model assessment of insulin resistance (HOMA-IR) in 154 untreated, non-diabetic, HCV-infected male subjects with fibrosis stage 0-2, to that in 75 healthy volunteers matched for age, body mass index (BMI), and waist-hip ratio (WHR). We next examined whether the adipocytokine levels were associated with the extent of hepatic steatosis, portal/periportal inflammation and fibrosis in our total cohort of 240 HCV-infected male subjects. Significantly higher levels of HOMA-IR (2.12 versus 1.63, P = 0.01), TNFalpha (1.28 versus 0.60 pg/ml, P < 0.001) and IL6 (2.42 versus 1.15 pg/ml, P = 0.001) were noted in the HCV cohort compared with healthy controls respectively, but there were no significant differences in leptin and adiponectin concentrations. By multiple linear regression, independent predictors of HOMA-IR included the body mass index, and the serum levels of leptin (positive correlation) and adiponectin (negative correlation), but not that of TNFalpha and IL6. Only TNFalpha levels were correlated with the extent of histological injury (portal/periportal inflammation, P = 0.02). CONCLUSION: Whereas leptin and adiponectin contribute to IR, none of the adipocytokines accounted for the elevated IR in HCV-infected subjects. The adipocytokines were not associated with histological features of chronic HCV infection except for TNFalpha which correlated with portal/periportal inflammation. HCV-associated IR is most likely an adipocytokine-independent effect of the virus to modulate insulin sensitivity.

The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD.

UNLABELLED: Patients with nonalcoholic fatty liver disease (NAFLD) and advanced liver fibrosis are at the highest risk for progressing to end-stage liver disease. We constructed and validated a scoring system consisting of routinely measured and readily available clinical and laboratory data to separate NAFLD patients with and without advanced fibrosis. A total of 733 patients with NAFLD confirmed by liver biopsy were divided into 2 groups to construct (n = 480) and validate (n = 253) a scoring system. Routine demographic, clinical, and laboratory variables were analyzed by multivariate modeling to predict presence or absence of advanced fibrosis. Age, hyperglycemia, body mass index, platelet count, albumin, and AST/ALT ratio were independent indicators of advanced liver fibrosis. A scoring system with these 6 variables had an area under the receiver operating characteristic curve of 0.88 and 0.82 in the estimation and validation groups, respectively. By applying the low cutoff score (-1.455), advanced fibrosis could be excluded with high accuracy (negative predictive value of 93% and 88% in the estimation and validation groups, respectively). By applying the high cutoff score (0.676), the presence of advanced fibrosis could be diagnosed with high accuracy (positive predictive value of 90% and 82% in the estimation and validation groups, respectively). By applying this model, a liver biopsy would have been avoided in 549 (75%) of the 733 patients, with correct prediction in 496 (90%). CONCLUSION: a simple scoring system accurately separates patients with NAFLD with and without advanced fibrosis, rendering liver biopsy for identification of advanced fibrosis unnecessary in a substantial proportion of patients.

Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data.

BACKGROUND & AIMS: Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index. METHODS: We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States. RESULTS: Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in 1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in 142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation. CONCLUSIONS: In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC.

Beyond insulin resistance in NASH: TNF-alpha or adiponectin?

Adiponectin has antilipogenic and anti-inflammatory effects, while tumor necrosis factor alpha (TNF-alpha) reduces insulin sensitivity and has proinflammatory effects. We examined (1) the extent to which hypoadiponectinemia and TNF-alpha activation are features of nonalcoholic steatohepatitis (NASH) and (2) whether serum levels of these markers correlate with the severity of histological changes in 109 subjects with nonalcoholic fatty liver disease (NAFLD), including 80 with NASH and 29 with simple steatosis. By multivariate analysis, subjects with NASH had reduced adiponectin level and increased TNF-alpha and soluble TNF receptor 2 (sTNFR2)-but not leptin levels, compared with controls matched by age, sex, and body mass index; these differences were independent of the increased insulin resistance (by homeostasis model [HOMA-IR]) in NASH. When compared with simple steatosis, NASH was associated with lower adiponectin levels and higher HOMA-IR, but there were no significant differences in the levels of TNF-alpha and sTNFR2. The majority of subjects with steatohepatitis (77%) had adiponectin levels less than 10 microg/mL and HOMA-IR greater than 3 units, but only 33% of those with pure steatosis had these findings. HOMA-IR and low serum adiponectin were also independently associated with increased grades of hepatic necroinflammation. In conclusion, hypoadiponectinemia is a feature of NASH independent of insulin resistance. Reduced adiponectin level is associated with more extensive necroinflammation and may contribute to the development of necroinflammatory forms of NAFLD.

Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index.

We sought to develop a clinically useful index comprising standard and physiologically relevant variables to predict the probability of significant hepatic fibrosis in subjects with chronic hepatitis C virus (HCV) infection. Fibrosis was graded as mild (stages F0 or F1) or significant (stages F2-F4). Thirty-five clinical and laboratory parameters were analyzed initially in 176 patients with detectable HCV RNA to derive a fibrosis probability index (FPI) to predict significant fibrosis. This index then was validated in a second group of 126 subjects. Among 18 variables associated with severe fibrosis on univariate analysis, multiple logistic regression analysis identified age, aspartate aminotransferase (AST), total cholesterol level, insulin resistance (by homeostasis model), and past alcohol intake as independent predictors of significant fibrosis. The area under the receiver operating characteristic (ROC) curves was 0.84 for the initial cohort and 0.77 for the validation cohort. In the initial cohort, the sensitivity of the FPI based on these five predictors was 96%, and the negative predictive value was 93% at a score of >/=0.2. At scores >/=0.8, the FPI was 94% specific and had a positive predictive value of 87%. In conclusion, an FPI using routinely assessed markers and incorporating a measure of insulin resistance can reliably predict the probability of significant hepatic fibrosis in most patients with chronic HCV infection. Such an index should prove useful to guide decision making regarding the need for liver biopsy, and potentially for avoiding or deferring biopsy in a large proportion of patients with mild liver disease.

Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C.

Data on the long-term outcome of nonalcoholic steatohepatitis (NASH)-associated cirrhosis are few, and most reports describe cases of cryptogenic cirrhosis associated with risk factors for NASH but without histologic definition. In this prospective cohort study, we describe the long-term morbidity and mortality of 23 patients with NASH-associated cirrhosis defined by strict clinicopathologic criteria. Outcomes were compared with 46 age- and gender-matched patients with cirrhosis from chronic hepatitis C virus (HCV) infection: 23 untreated and 23 nonresponders to antiviral therapy. During follow-up (mean, 84 months; median, 60 months; range, 5-177 months), 9 of the 23 NASH-associated cirrhosis cases developed liver-related morbidity (8 ascites and/or encephalopathy, 1 variceal bleeding). The probability of complication-free survival was 83%, 77%, and 48% at 1, 3, and 10 years, respectively, and the cumulative probability of overall survival was 95%, 90%, and 84% at 1, 3, and 10 years, respectively. Five deaths were from liver failure, 1 from a non-liver-related cause. By multivariate analysis, bilirubin (P =.02) and platelet (P =.04) were independent predictors of complication-free survival; bilirubin (P =.05) was the only predictor for overall survival. After controlling for these factors, there was no difference in complication-free or overall survival between the NASH-cirrhosis cohort and either group of HCV-cirrhosis. However, 8 cases of liver cancer occurred in the HCV-cirrhosis groups compared with none among NASH cases. In conclusion, liver failure is the main cause of morbidity and mortality in NASH-associated cirrhosis. The prognosis is either similar or less severe than HCV-cirrhosis, except that HCC appears less common.

Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected].

BACKGROUND & AIMS: Chronic hepatitis C virus infection is associated with an increased prevalence of type 2 diabetes. We hypothesized that virus-induced insulin resistance may be a mechanism for fibrogenesis in chronic hepatitis C virus infection. METHODS: In 260 hepatitis C virus-infected subjects, we examined the relationship between histological findings and anthropometric and biochemical data, including insulin resistance determined by the homeostasis model assessment (HOMA-IR). We also compared fasting serum insulin, C peptide, and HOMA-IR levels between the subset of 121 hepatitis C virus patients with stage 0 or 1 hepatic fibrosis and 137 healthy volunteers matched by sex, body mass index, and waist-hip ratio. RESULTS: Hepatitis C virus-infected subjects with stage 0 or 1 hepatic fibrosis had higher levels of insulin, C peptide, and HOMA-IR (all P < or = 0.01) compared with matched healthy controls. In the 250 hepatitis C virus patients (fibrosis stage 0 to 4), viral genotype and portal, but not lobular, inflammation were univariate predictors of HOMA-IR. By multiple linear regression analysis, independent predictors of HOMA-IR included body mass index (P < 0.001), previous failed antiviral treatment (P < 0.001), portal inflammatory grade (P < 0.001), and genotype 3 status (P = 0.01). Genotype 3 had significantly lower HOMA-IR than other genotypes (which were comparable when adjusted for effects of the remaining independent predictors). HOMA-IR was an independent predictor for the degree of fibrosis (P < 0.001) and the rate of fibrosis progression (P = 0.03). CONCLUSIONS: Hepatitis C virus may induce insulin resistance irrespective of the severity of liver disease, and this effect seems to be genotype specific. Further, our findings support the hypothesis that insulin resistance may contribute to fibrotic progression in chronic hepatitis C virus infection.