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Surveillance, treatment, and outcomes for African-American (AA) populations with hepatocellular carcinoma (HCC) remain under evaluated. This study evaluated demographics, surveillance, therapy, and outcomes for a predominately AA population.The electronic medical records of a large health-care provider were used to identify 274 patients with visits for HCC between 2010 and 2017. Tumor size at diagnosis was defined by imaging with ≤ 5 cm being defined as "small." Surveillance for HCC was defined based on ultrasound (US) assessments.Patients were primarily AA (78%) and male (76%) with an average age at diagnosis of 62 years. Hepatitis C virus (HCV) was more likely to be a risk factor for the development of HCC in AA as compared to non-AA (92% vs 67%; p0.005). Surveillance rates were low (16% for AA vs 7% for non-AA). An aspartate aminotransferase platelet ratio index (APRI) value0.7 within 2 years of tumor diagnosis was a strong predictor for the risk of the development of HCC (86% AA vs 79 % non-AA). In this study, race was not a factor in treatment or outcomes, and most patients received tumor ablative treatment.Given the low surveillance rates and the demonstrated increased survival for patients with small tumors, ways to increase surveillance must be initiated. The results of this study demonstrate the need for physician/patient education on the importance of surveillance US. Further, this study supports routine assessment of APRI in AA patients in an effort to identify patients in whom intensive surveillance will significantly improve earlier detection of tumors.

Trimethoprim/sulfamethoxazole is well known to cause intra-hepatic cholestasis which in rare instances can be prolonged and lead to vanishing bile duct syndrome. The risk regarding the potential for cross-reactivity between structurally related molecules such as dapsone and trimethoprim/sulfamethoxazole in causing hepatotoxicity is scarce. Herein, we report a case of vanishing bile duct syndrome following dapsone use in a patient with HIV infection and a recent history of trimethoprim/sulfamethoxazole-induced cholestasis. The patient had severe and protracted cholestasis during 2 years of follow-up and eventually died of liver failure.

African Americans (AA) are 4 times as likely as Caucasians to have chronic Hepatitis B (CHB) and yet are under represented in the literature especially with respect to treatment response. The objective of this study was to compare demographics, treatment decisions and outcomes of AA to Non-AA patients seen in the same GI clinic. Of the 92 patients with CHB, 60% were AA. AA patients had similar ALT and viral load at early visits as compared to Non-AA but significantly less fibrosis as defined by AST Platelet Ratio Index. Treatment rates were lower but not statistically different for AA (38%) vs. Non-AA (46%) and the majority of patients (80%) were HBeAntigen (HBeAg) negative. The patients responded well to treatment, although HBeAg positive AA were less likely to have a decline in HBV DNA than HBeAg negative AA patients. The primary conclusions of this study are that AA as compared to Non-AA patients are less likely to have fibrosis and appear to have a dissimilar response to anti-viral therapy.

Hepatitis B virus (HBV) causes both acute and chronic hepatitis and infects large numbers of individuals worldwide. Unfortunately, prediction of typical clinical outcome is problematic and there is considerable variability in the frequency, duration and severity of disease progression. The mainstay of HBV treatment is directed towards the suppression of HBV replication by nucleos(t)ide analogs (NUCs). The use of immunomodulators such as α-Interferon and thymosin α1 can, in select patients, results in elimination of both HBsAg and HBeAg. Given the observation that viral clearance is most effective in the presence of a strong immune response, this review summarizes data suggesting that the use of a combination of an immune modulator such as Tα1 with a highly effective NUC may result in a more successful therapeutic approach in patients with chronic hepatitis B (CHB). Results from small studies using combination Tα1 and NUCs are encouraging, and ongoing clinical trials combining entecavir with Tα1 are anticipated to provide important data assessing the use of a combination of Tα1 with a NUC to achieve resolution of CHB.

African Americans (AA) in the US are twice as likely to be infected with hepatitis C virus (HCV) compared to the non-Hispanic-white US population (Cau). They are also more likely to be infected with HCV genotype 1, more likely to develop hepatocellular carcinoma, and, in addition, have a lower response rate to interferon-based therapies. With the increase in response rates reported for combinations of direct-acting antivirals, the possibility that racial disparity would be eliminated by agents that directly inhibit virus replication has become a reality. The objective of this review is to evaluate the literature from clinical studies and retrospective analysis with respect to the response of AA to the most prescribed antiviral combination sofosbuvir plus ledipasvir. While few studies have focused on AA patients, sufficient information is availed from the literature and studies in our predominately AA clinic population to confirm that ledipasvir-sofosbuvir has a similar effectiveness in AA as compared to Cau.

INTRODUCTION: There is considerable uncertainty with respect to predicting the liver disease status of African American (AA) patients with Hepatitis C seen in the current era of highly effective direct acting anti-virals (DAA). This uncertainty is due to the complex interplay between the identification of patients early in their disease progression by screening, the fact that many AA patients failed earlier interferon based therapy, duration of the HCV viremia in AA patients, the possible variation In disease course in AA as compared to other races, and potential early mortality of AA patients due to liver disease. Understanding the evolution of HCV infection as defined by comparing previous and current patient populations provides information relevant to both therapeutic and health costs decisions. METHODS: We selected patients from a 24 month period between 2002 and 2003 (Epoch 1; n = 414) to compare with patients seen in the same GI clinic between 2012 and 2013 (Epoch 2; n=405). Epoch 1 was the beginning of the peg-interferon and ribavirin treatment era and Epoch 2 reflects the patient population seen when DAA therapy was first available. RESULTS: Epoch 2 patients were older (59.7 vs 50.3 years) with a similar gender distribution (55% vs 59% male). Consistent with the change in clinic demographics, more AA patients were seen in Epoch 2 (89%) as compared to Epoch 1 (77%). There was no significant difference between hepatic fibrosis as assessed by APRI (1.1 vs 0.9) or FIB-4 (2.4 vs 2.6) but there was an increase in intermediate degree of fibrosis as defined by liver biopsy. The majority of Epoch 2 patients were still naive to treatment (96% Epoch 1 vs 61% Epoch 2) and a similar proportion had cirrhosis (15% Epoch 1 vs 17% Epoch 2) at the time of first visit in the different time periods. CONCLUSIONS: The patients in Epoch 2 from this urban GI referral clinic are older and the majority of them had not been treated or had not responded to treatment. This age demographic continues to reflect patients who were likely infected during the 1960’s-1980’s which is when HCV infection became widespread. Epoch 2 patients also do not have more advanced liver disease as defined either by significant fibrosis or cirrhosis as compared to Epoch 1. Possible explanations include that Epoch 2 patients’ disease was detected earlier by surveillance, progressed very slowly to advanced liver disease, or had a high mortality that resulted in a decline in patients with advanced disease. The role of access to therapy in patients not treated remains to be determined and the increased effectiveness of DAA are predicted to increase the number of AA patients seeking and accepting treatment.

The obesity epidemic in developed societies has led to increased cardiovascular diseases including pulmonary hypertension associated with left heart disease (PH-LHD), the largest and fastest-growing class of PH. Similar to obese humans, PH and heart failure (HF) are increasingly recognized in North American fattened beef cattle. We hypothesized that PH and HF in fattened beef cattle are novel, phenotypically distinct manifestations of bovine PH arising from left ventricular (LV) dysfunction similar to obesity-related PH-LHD in humans. We conducted a semi-quantitative histopathological assessment of cardiopulmonary tissues obtained from fattened beef cattle suffering end-stage HF compared to asymptomatic cattle of equivalent age undergoing the same fattening regimens. In HF animals we observed significant LV fibrosis, abundant cardiac adipose depots, coronary artery injury, and pulmonary venous remodeling recapitulating human obesity-related PH-LHD. Additionally, striking muscularization, medial hypertrophy, adventitial fibrosis, and vasa vasorum hyperplasia in the pulmonary arterial circulation were associated with sequela of pathologic right ventricular (RV) remodeling suggesting combined pulmonary venous and arterial hypertension. The association between obesity, pathologic cardiopulmonary remodeling, and HF in fattened beef cattle appears to recapitulate the complex pathophysiology of obesity-associated PH-LHD in humans. This novel, naturally occurring, and large animal model may provide mechanistic and translational insights into human disease.

Acute retroviral syndrome (ARS) can present as a wide array of clinical manifestations. Establishing a diagnosis early in the disease course can provide an opportunity to minimize immunosuppression and limit further transmission of human immunodeficiency virus (HIV). We present a case of a previously healthy young male who presented with acute hepatitis, as a manifestation of ARS. Initial HIV antigen/antibody testing was negative; however, a high index of suspicion prompted HIV ribonucleic acid (RNA) virologic testing revealing >10 million RNA copies/mL. Anti-retroviral treatment was initiated, along with supportive measures, accomplishing resolution of the transaminitis and the restoration of CD4 counts within normal at one month. Early in the disease course, HIV screening immunoassay could still be negative; hence, confirmatory testing with HIV RNA virologic testing should be pursued when clinical suspicion is high. Prompt diagnosis and treatment can improve outcome and curtail viral transmission.

Background: Changes in metabolism have been suggested to contribute to the aberrant phenotype of vascular wall cells, including fibroblasts, in pulmonary hypertension (PH). Here, we test the hypothesis that metabolic reprogramming to aerobic glycolysis is a critical adaptation of fibroblasts in the hypertensive vessel wall that drives proliferative and proinflammatory activation through a mechanism involving increased activity of the NADH-sensitive transcriptional corepressor C-terminal binding protein 1 (CtBP1). Methods: RNA sequencing, quantitative polymerase chain reaction, 13 C–nuclear magnetic resonance, fluorescence-lifetime imaging, mass spectrometry–based metabolomics, and tracing experiments with U- 13 C-glucose were used to assess glycolytic reprogramming and to measure the NADH/NAD + ratio in bovine and human adventitial fibroblasts and mouse lung tissues. Immunohistochemistry was used to assess CtBP1 expression in the whole-lung tissues. CtBP1 siRNA and the pharmacological inhibitor 4-methylthio-2-oxobutyric acid (MTOB) were used to abrogate CtBP1 activity in cells and hypoxic mice. Results: We found that adventitial fibroblasts from calves with severe hypoxia-induced PH and humans with idiopathic pulmonary arterial hypertension (PH-Fibs) displayed aerobic glycolysis when cultured under normoxia, accompanied by increased free NADH and NADH/NAD + ratios. Expression of the NADH sensor CtBP1 was increased in vivo and in vitro in fibroblasts within the pulmonary adventitia of humans with idiopathic pulmonary arterial hypertension and animals with PH and cultured PH-Fibs, respectively. Decreasing NADH pharmacologically with MTOB or genetically blocking CtBP1 with siRNA upregulated the cyclin-dependent genes (p15 and p21) and proapoptotic regulators (NOXA and PERP), attenuated proliferation, corrected the glycolytic reprogramming phenotype of PH-Fibs, and augmented transcription of the anti-inflammatory gene HMOX1 . Chromatin immunoprecipitation analysis demonstrated that CtBP1 directly binds the HMOX1 promoter. Treatment of hypoxic mice with MTOB decreased glycolysis and expression of inflammatory genes, attenuated proliferation, and suppressed macrophage numbers and remodeling in the distal pulmonary vasculature. Conclusions: CtBP1 is a critical factor linking changes in cell metabolism to cell phenotype in hypoxic and other forms of PH and a therapeutic target.

Background: Evaluation of advanced fibrosis in patients with hepatitis C virus (HCV) infection is used to facilitate decisions on treatment strategy and to initiate additional screening measures. Unfortunately, most studies have predominately Caucasian (Cau) patients and may not be as relevant for African Americans (AA). Aims: This study specifically addresses the issue of defining minimal vs. significant fibrosis in African Americans (AA) with chronic hepatitis C (CHC) using noninvasive assays. Methods: All patients (n = 319) seen between 1 January 2008 and 30 June 2013 for whom a FibroSpect II® (FSII) assay was performed and had data for calculation of aspartate aminotransferase (AST) platelet ratio index (APRI) and Fibrosis-4 (FIB-4) were identified using the medical records. Results: When liver biopsy score and FSII assay results for the AA patients with CHC were compared, 31% of AA had advanced FSII fibrosis scores (F2-F4) despite a biopsy score of F0-F1. In contrast, 10% of Cau over-scored. The AA false positive rate was 14% for APRI and 34% for FIB-4. Combining FSII with either APRI (7% false positive) or FIB-4 (10% false positive) improved the false positive rate in AA to 7% (FSII + APRI) and 10% (FSII + FIB-4) but reduced the sensitivity for significant fibrosis. Conclusions: The FSII assay overestimates fibrosis in AA and should be used with caution since these patients may not have significant fibrosis. If the APRI or FIB-4 assay is combined with the FSII assay, minimal fibrosis in AA can be defined without subjecting the patients to a subsequent biopsy.

Defining mortality for Caucasians and African American patients with chronic hepatitis C with respect to racial diversity is critical for counselling patients on therapy options. The objective of this study was to define racial diversity influence on mortality and morbidity of 3724 consecutive hepatitis C virus (HCV)-infected patients seen in an urban clinic between 1995 and 2008. Mortality, as of 2011, was defined using the SSA National Death Index and correlated with early visit medical information. The HCV chronically infected patient population consisted of 2879 African Americans (AA), 758 Caucasians and 87 other, and the majority were not treated for their infection prior to 2011. The average time to death from first visit was 5 years, the average age at death was 55 years, and despite racial diversity, AA were just as likely to be reported dead as Caucasians (23% AA vs 22% Caucasians). Cirrhosis and fibrosis (liver biopsy, AST Platelet Ratio Index or Fibrosis-4) at first visit as well as low albumin, diabetes, renal impairment and cardiac symptoms were associated with increased mortality. Treated patients who cleared the virus (sustained viral response (SVR); AA = 59; Caucasians = 40) had lower mortality than patients who were not treated (AA: 5% vs 27%; Caucasians 5% vs 26%). Hence, we find that race is not a factor in the early mortality of patients with chronic HCV infection and achieving a SVR reduced mortality. Unexpectedly, nonresponding AA also benefited by a lower mortality. African American patients with kidney disease and low albumin were at highest risk and should be treated as soon as identified.

Altitude-induced pulmonary hypertension is a disease once thought to only occur at extremely high elevations (>1,600 m), but recently, it has been observed at moderate elevations of 1,200 to 1,600 m. Pulmonary arterial pressure (PAP) has been used as an indicator of tolerance to high altitude in mountainous beef production systems for over 30 yr. The trait is typically measured on yearling bulls and heifers with values ≤ 41 mmHg being favorable. These observations were historically only considered valid when they were recorded at elevations ≥ 1,600 m; however, if observations from lower (i.e., moderate) elevations were reliable indicators, a greater number of cattle records could be used in genetic improvement programs for high-altitude beef systems. The objectives of this study were to evaluate the relationship between PAP and elevation, as well as to determine whether PAP measures obtained at moderate elevations (ME) less than 1,600 m have a genetic relationship with PAP observations obtained at high elevations (HE) 1,600 m or greater. Elevation and PAP data from purebred Angus cattle (n = 14,665) from 349 contemporary groups were used in the analyses. Elevation and PAP averaged 1,887 ± 1.8 m and 43.0 ± 0.1 mm Hg, respectively. A univariate model containing the effects of sex, age, elevation category (HE vs. ME), elevation (continuous), and elevation category by elevation interaction along with a random direct genetic effect was utilized to determine the relationship between PAP and elevation. In this model, all main effects were found to be significant contributors of variation in PAP (P < 0.001). The interaction between elevation category and elevation was not a significant contributor to variability of PAP (P > 0.05). A bivariate animal model was then used to evaluate the relationship between PAP observations obtained between HE and ME groups. Heritability estimates for these 2 groups were 0.34 ± 0.03 and 0.29 ± 0.09, respectively, and their genetic correlation was 0.83 ± 0.15. Even though this is a strong genetic relationship, results of this study support the hypothesis that PAP observations collected at HE and ME are not perfectly, genetically related. Results suggest that PAP measures collected from 1,219 to 1,600 m may be useful as a correlated trait in a multitrait genetic evaluation to produce EPD useful for selection of animals with reduced susceptibility to pulmonary hypertension.

Background and Aims: African Americans (AA) historically have a low response rate to hepatitis C therapies, and there is limited information available for this patient population regarding the development and treatment of chronic hepatitis C (CHC). The aim of this study was to evaluate liver disease progression and hepatocellular carcinoma (HCC) development in AA with CHC. Methods: Between 1995 and 2008, 246 AA patients with CHC were identified from a database of patients and followed until 2012-2013 (average 8 years) or the development of HCC after 2008. Results: Viral clearance (intent to treat; sustained virus response (SVR)) was achieved in 15% of patients with interferon based therapies with or without ribavirin. AA patients who achieved an SVR (n=22) did not develop HCC or new onset cirrhosis, whereas the HCC incidence in untreated AA patients was 23% (51/203). Patients who achieved an SVR also had improved fibrosis, as defined by the AST Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4) score, relative to nonresponders and untreated patients. Conclusions: The severity of liver disease at the first visit (except for cirrhosis) correlated with the development of HCC, but because of the overlap in values between patients, these measurements were not useful for predicting individual risk. Since cirrhosis at the first visit was not a predictive factor, treatment with newer antiviral therapies is the best option for reducing the incidence of advanced liver disease and its harmful outcomes in the AA population.

Hepatic sinusoidal obstruction syndrome (SOS) is a life-threatening state generally occurring as a complication of conditioning regimens used for hematopoietic stem cell transplant. Hepatic SOS after a standard dose of chemotherapy in malignancies is rare, and there are only a few cases in pediatric literature. We report a 56-year-old man with multiple myeloma who experienced SOS after being initiated on chemotherapy including cyclophosphamide, dexamethasone, and bortezomib and who experienced a delay in treatment with defibrotide, because it is currently approved by the Food and Drug Administration for only patients who develop SOS after hematopoietic stem cell transplant.

The toxicity of ricin resides in the ricin A-chain (RTA) and is attributed to the inhibition of protein synthesis but inflammation and oxidative stress have also been implicated. RTA can independently enter cells producing comparable tissue injury and inflammation, although at much higher concentrations than intact ricin. Treatment for exposure to ricin or RTA is supportive.To examine the effectiveness of conventional or liposome-encapsulated N-acetylcysteine (Lipo-NAC) in ameliorating RTA-induced hepatotoxicity.Four hours after RTA administration (90 µg/kg b.wt, iv), rats were treated with conventional NAC or Lipo-NAC (25 mg/kg NAC). The hepatoprotective effects of the antioxidant formulations were assessed by measuring indexes for liver injury (alanine [ALT] and aspartate [AST] aminotransferase activities), inflammation (myeloperoxidase, tumor necrosis factor-α, chloramine levels), and oxidant response (lipid peroxidation, nitrotyrosine, glutathione levels) 24-h post-RTA exposure.Administration of RTA to animals resulted in hepatotoxicity as demonstrated by elevated plasma ALT and AST levels, increases in an inflammatory response, and increases in oxidant response. Treatment of animals with the antioxidant formulations reversed the RTA-induced hepatotoxicity, being most evident following the administration of Lipo-NAC.NAC, administered in a liposomal form, may serve as a potentially effective pharmacological agent in the treatment of RTA-induced liver injuries.

The ability to adapt to different environments is critical when livestock are moved because of drought or other management considerations. The impact of previous experience on grazing patterns and diet selection of Brangus cows in desert conditions was evaluated. Cows originating from a humid-subtropical environment (Leona, Texas) were brought to the Chihuahuan Desert (naive) and evaluated against cows that spent their life in the Chihuahuan Desert (native) and cows that were born and raised in the Chihuahuan Desert but were moved to Leona, Texas during the preceding 3 yr (tourist). In addition, native cows with recent experience in desert conditions were compared with naive cows and tourist cows that had not been in the Chihuahuan Desert for at least 3 yr. All cows were mature and had similar pedigrees (n = 21). Cows from the three groups were tracked in three extensive pastures (> 1 000 ha) for three 8–10-d periods during winter, early summer, and later summer. Cows never grazed in the experi...

Hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC) are growing health problems around the world. Oxidative stress plays a significant role in the initiation and progression of hepatocellular damage and possibly in the development of HCC in HCV infected patients. In vitro, animal and clinical studies suggest that lycopene, a nonprovitamin A carotenoid and a potent antioxidant, may attenuate the liver injury and possibly prevent the development of HCC. In this article, we discuss the relationship between HCV infection and oxidative stress and review the potential role of lycopene in the treatment of HCV and prevention of HCC.

Acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS) are frequent complications in critically ill patients and are responsible for significant morbidity and mortality. So far, experimental evidence supports the role of oxidants and oxidative injury in the pathogenesis of ALI/ARDS. In this study, the antioxidant effects of conventional N-acetylcysteine (NAC) and liposomally entrapped N-acetylcysteine (L-NAC) were evaluated in experimental animals challenged with lipopolysaccharide (LPS). Rats were pretreated with empty liposomes, NAC, or L-NAC (25mg/kg body weight, iv); 4h later were challenged with LPS (E. coli, LPS 0111:B4) and sacrificed 20h later. Challenge of saline (SAL)-pretreated animals with LPS resulted in lung injury as evidenced by increases in wet lung weight (edema), increases in lipid peroxidation (marker of oxidative stress), decreases of lung angiotensin-converting enzyme (ACE) (injury marker for pulmonary endothelial cells) and increases in the pro-inflammatory eicosanoids, thromboxane B(2) and leukotriene B(4). The LPS challenge also increased pulmonary myeloperoxidase activity and chloramine concentrations indicative of neutrophil infiltration and activation of the inflammatory response. Pretreatment of animals with L-NAC resulted in significant increases in the levels of non-protein thiols and NAC levels in lung homogenates (p0.05) and bronchoalveolar lavage fluids (p0.001), respectively. L-NAC was significantly (p0.05) more effective than NAC or empty liposomes in attenuating the LPS-induced lung injuries as indicated by the aforementioned injury markers. Our results suggested that the delivery of NAC as a liposomal formulation improved its prophylactic effectiveness against LPS-induced lung injuries.

We recently showed that acute oxidant-related lung injury (ALI) in rats after application of 2-chloroethyl ethyl sulfide (CEES) is attenuated by the airway instillation of antioxidants. We investigated whether intratracheal administration of antioxidant-containing liposomes immediately after instillation of CEES would attenuate short-term as well as long-term (fibrotic) effects of CEES-induced lung injury. In the acute injury model (4 h after injury), N-acetylcysteine (NAC)-containing liposomes were protective and reduced to baseline levels both the lung permeability index and the appearance of proinflammatory mediators in bronchoalveolar lavage fluids from CEES-exposed lungs. Similar results were obtained when rat alveolar macrophages were incubated in vitro with either CEES or lipopolysaccharide in the presence of NAC-liposomes. When lung fibrosis 3 weeks after CEES was quantitated by using hydroxyproline content, liposomes containing NAC or NAC + glutathione had no effects, but liposomes containing alpha/gamma-tocopherol alone or with NAC significantly suppressed the increase in lung hydroxyproline. The data demonstrate that delivery of antioxidants via liposomes to CEES-injured lungs is, depending on liposomal content, protective against ALI, prevents the appearance of proinflammatory mediators in bronchoalveolar fluids, and suppresses progressive fibrosis. Accordingly, the liposomal strategy may be therapeutically useful in CEES-induced lung injury in humans.

High-altitude pulmonary hypertension (HAPH) has heritable features and is a major cause of death in cattle in the Rocky Mountains, USA. Although multiple genes are likely involved in the genesis of HAPH, to date no major gene variant has been identified. Using whole-exome sequencing, we report the high association of an EPAS1 (HIF2α) double variant in the oxygen degradation domain of EPAS1 in Angus cattle with HAPH, mean pulmonary artery pressure >50 mm Hg in two independent herds. Expression analysis shows upregulation of 26 of 27 HIF2α target genes in EPAS1 carriers with HAPH. Of interest, this variant appears to be prevalent in lowland cattle, in which 41% of a herd of 32 are carriers, but the variant may only have a phenotype when the animal is hypoxemic at altitude. The EPAS1 variant will be a tool to determine the cells and signalling pathways leading to HAPH., Pulmonary hypertension and congestive right heart failure afflict some cattle living at high altitude in an autosomal dominant pattern, yet no responsible genes have been identified. Here Newman et al. use whole-exome sequencing to identify variants in the hypoxia inducible factor gene, EPAS1.

Exposure to mustard gas causes inflammatory lung diseases including acute respiratory distress syndrome (ARDS). A defect in the lung surfactant system has been implicated as a cause of ARDS. A major component of lung surfactant is dipalmitoyl phosphatidylcholine (DPPC) and the major pathway for its synthesis is the cytidine diphosphocholine (CDP-choline) pathway. It is not known whether the ARDS induced by mustard gas is mediated by its direct effects on some of the enzymes in the CDP-choline pathway. In the present study we investigated whether mustard gas exposure modulates the activity of cholinephosphotransferase (CPT) the terminal enzyme by CDP-choline pathway. Adult guinea pigs were intratracheally infused with single doses of 2-chloroethyl ethyl sulfide (CEES) (0.5 mg/kg b.wt. in ethanol). Control animals were injected with vehicles only. The animals were sacrificed at different time and the lungs were removed after perfusion with physiological saline. CPT activity increased steadily up to 4 h and then decreased at 6 h and stabilized at 7 days in both mitochondria and microsomes. To determine the dose-dependent effect of CEES on CPT activity we varied the doses of CEES (0.5-6.0 mg/kg b.wt.) and sacrificed the animals at 1 h and 4 h. CPT activity showed a dose-dependent increase of up to 2.0 mg/kg b.wt. of CEES in both mitochondria and microsomes then decreased at 4.0 mg/kg b.wt. For further studies we used a fixed single dose of CEES (2.0 mg/kg b.wt.) and fixed exposure time (7 days). Lung injury was determined by measuring the leakage of iodinated-bovine serum albumin into lung tissue and expressed as the permeability index. CEES exposure (2.0 mg/kg b.wt. for 7 days) caused a significant decrease of both CPT gene expression (approximately 1.7-fold) and activity (approximately 1.5-fold) in the lung. This decrease in CPT activity was not associated with any mutation of the CPT gene. Previously we reported that CEES infusion increased the production of ceramides which are known to modulate PC synthesis. To determine whether ceramides affect microsomal CPT activity the lung microsomal fraction was incubated with different concentrations of C(2)-ceramide prior to CPT assay. CPT activity decreased significantly with increasing dose and time. The present study indicates that CEES causes lung injury and significantly decreases CPT gene expression and activity. This decrease in CPT activity was not associated with any mutation of the CPT gene is probably mediated by accumulation of ceramides. CEES induced ceramide accumulation may thus play an important role in the development of ARDS by modulating CPT enzyme.

Mustard gas exposure causes adult respiratory distress syndrome associated with lung injury. The purpose of this study was to investigate whether an antioxidant, such as N-acetylcysteine (NAC), has any protective effect. Guinea pigs were given single exposure (0.5–6 mg/kg body weight) of 2-chloroethyl ethyl sulfide (CEES) as a mustard analogue intratracheally and maintained for various lengths of time (1 h to 21 days). Within 1 h of CEES infusion at 4 mg/kg, high levels of tumor necrosis factor α (TNF-α), ceramides, and nuclear factor κB accumulated in lung and alveolar macrophages. Both acid and neutral sphingomyelinases were activated within 4 h. These signal transduction events were associated with alteration in the oxygen defense system. Within 1 h of exposure to CEES (6 mg/kg body weight), there was 10-fold increase in the 125I-BSA leakage into lung tissue, indicating severe lung injury. Although low level of CEES exposure (0.5 mg/kg body weight) produced symptoms of chemical burn in lung as early as 1 h after exposure, the severity of edema, congestion, hemorrhage, and inflammation increased progressively with time (1 h to 21 days). Feeding of single dose of NAC (0.5 g) by gavage just before the CEES infusion was ineffective to counteract these effects. However, consumption of the antioxidant in drinking water for 3 or 30 days prior to CEES exposure significantly inhibited the induction of TNF-α, activation of neutral and acid sphingomyelinases, production of ceramides, activation of caspases, leakage of 125I-bovine serum albumin (125I-BSA) into lung tissue, and histological alterations in lung. Pretreatment with NAC for 3 and 30 days protected against 69–76% of the acute lung injury. Therefore, NAC may be an antidote for CEES-induced lung injury. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:177–184, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10076

Objective: The purpose of this case study is to describe the case of a person with agenesis of the corpus callosum (ACC), intellectual disability and features of antisocial behaviour and lying. Methods: A 26-year-old woman with a mild intellectual disability who presented with antisocial behaviour and chronic lying was found to have ACC and associated cerebral abnormalities. Results: Psychiatric, radiological and neuropsychological assessment of this patient provided convergent evidence of the importance of the corpus callosum in enabling understanding of social situations and appropriate social behaviour, particularly via its connectivity with the frontal regions of the brain. Conclusion: Antisocial behaviour and lying may be more commonly associated with callosal dysgenesis than is currently realised.

Objective To analyse the annual incidence of end-stage renal disease (ESRD) associated with lithium-induced nephropathy (LiN) in Australia. Design, setting and participants Retrospective cohort study of patients commencing renal replacement therapy (RRT) in Australia. We compared patients with LiN with all other RRT patients between 1 January 1991 and 31 December 2011, using Australia and New Zealand Dialysis and Transplant Registry data. Main outcome measures Numbers and characteristics of incident RRT patients, primary kidney disease (LiN or other, based on clinical diagnosis). Results LiN contributed to 187 people in Australia commencing RRT between 1 January 1991 and 31 December 2011. The incidence rate increased from 0.14 cases/million population/year (95% CI, 0.06-0.22) in 1992-1996 to 0.78 (95% CI, 0.67-0.90) in 2007-2011. This increase is unlikely to be attributed solely to demographic changes in Australia. LiN patients were more likely than non-LiN patients to be women, to be white, to smoke, and to have a higher body mass index, but were less likely to have undergone renal biopsy. Conclusions Rates of ESRD attributed to LiN are increasing rapidly. Currently accepted lithium dosages and duration of treatment might induce ESRD in a large cohort of patients. We encourage clinicians to exercise discretion when prescribing lithium, check renal function regularly, stop lithium if there is a deterioration in two consecutive readings, and consider substitution with other drugs.

Question: A 60-year-old man presented with anemia and black tarry stools, off and on for the last 2 months. He had metastatic non–small-cell lung cancer with metastasis to the liver and spleen. He underwent a left upper lobectomy followed by recent chemotherapy. Physical examination revealed normal vital signs and splenomegaly. Laboratory results showed a drop in hemoglobin from 9.5 to 7.8 g/dL. Esophagogastroduodenoscopy (EGD) revealed a 1.5-cm ulcer in the fundus of the stomach (Figure A). There was no sign of recent bleeding at the ulcer site. Biopsy specimen was taken from the ulcer edges (Figure B). Based on the EGD and pathology, a computed tomography (CT) was performed (Figure C). Based on the image findings, what is your diagnosis and how would you manage the condition? Look on page 288 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

African Americans as a group have a higher incidence of chronic hepatitis C (CHC) than Caucasians but are often under-represented in clinical trials used to define response rates to interferon therapy. The aim of this study was to compare African Americans with Caucasians with respect to end-of-treatment response to interferon. This retrospective study had 61 African Americans and 49 Caucasians with CHC. All patients were treated for at least 12 weeks with interferon-alpha2b (Intron A) thrice weekly. End-of-treatment response was defined as three consecutive nondetectable HCV RNA measurements at least 1 month apart. Sustained response was defined as a negative serum HCV RNA 6 months after end of treatment. Of the 110 patients, 19 achieved an end-of-treatment response (17%) but only four achieved a sustained response (4/110=4%). Of the patients achieving a sustained response, one was genotype 1 (male Caucasian), three were genotype 2/3 with four patients having no follow-up information. The end-of-treatment response was 7% for patients with genotype 1 and 71% for genotype non-1 (P < 0.005 for genotype non-1). The end-of-treatment response was significantly higher in Caucasians (14/49=31%) compared with African Americans (5/61=8%; P < 0.05). A lower response rate in African Americans with genotype 1 in contrast to Caucasians was the primary reason for the difference in end-of-treatment response (1/45=2% vs. 5/33=15%, P < 0.05). Hence, interferon treatment resulted in a poor sustained response rate in the group of patients representative of the urban populations with the highest prevalence of hepatitis C. A genotype other than type 1 was the strongest predictor of end-of-treatment response in patients treated but over 86% of patients in this urban clinic were genotype 1. Caucasians were more likely to respond than African Americans, especially in patients with genotype 1.

To study the potential association between hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC), cirrhosis and latent hepatitis B (LHB) infection, defined as the absence of detectable serum hepatitis B surface antigen (HBsAg) and the presence of hepatitis B core antibody (HBcAb).This retrospective analysis is comprised of 185 cirrhotic patients with HCC who were hepatitis C virus antibody (HCV Ab) (+) and HBsAg(-) at Wayne State University between 1999 and 2008. From these, 108 patients had HCV polymerase chain reaction confirmation of viremia while the remaining (77) were considered to have CHC on the basis of a positive HCV Ab and the absence of any other cause of liver disease. Controls were drawn from our institutional database from the same time period and consisted of 356 HBsAg(-) age, race and gender matched patients with HCV RNA-confirmed CHC and without evidence of HCC. A subgroup of controls included 118 matched patients with liver cirrhosis. χ² test and t test were used for data analysis.Seventy-seven percent of patients in all 3 groups were African Americans. Patients with HCC had a significantly higher body mass index (P = 0.03), a higher rate of co-infection with human immunodeficiency virus (HIV) (P = 0.05) and a higher prevalence of alcohol abuse (P = 0.03) than the controls. More patients with HCC had LHB than controls (78% vs 39%, P = 0.01). Sixty three percent of patients with HCC were both hepatitis B surface antigen (HBsAb)(-) and HBcAb(+) compared to 23% of controls (P0.01). When compared to cirrhotic controls, the frequency of HBcAb(+) remained higher in patients with HCC (78% vs 45%, P = 0.02). Patients with HCC were more likely to be both HBsAb(-) and HBcAb(+) than the cirrhotic controls (63% vs 28%, P = 0.01). Although not statistically significant, 100% of CHC and HIV co-infected patients with HCC (n = 11) were HBcAb(+) when compared to controls (44%; n = 9).These data suggest that LHB occurs at a significantly increased frequency in patients with CHC and HCC than in patients with CHC without HCC.

Background Glucocorticoids are widely used in medicine and are known to cause psychiatric side effects, including mania. There is anecdotal evidence that sodium valproate is effective for treating psychiatric side effects of glucocorticoids. Objective To describe a case series of 20 patients receiving corticosteroids for various medical conditions who developed manic-like symptoms. They were treated with sodium valproate while continuing on corticosteroids. Method Patients treated with corticosteroids who reported to their physician subjective distress or who were openly disruptive in the ward were assessed by a consultation-liaison psychiatrist on the same day with the Young Mania Rating Scale. Immediately afterwards, blood was taken to measure the cortisol or dexamethasone level and then started on sodium valproate 500 mg twice daily. Valproate levels were measured on day 3 to adjust the dose. Results There was a significant, rapid improvement of symptoms within 48 hours after sodium valproate was initiated. Within 72 hours all patients were euthymic and remained so over the ensuing week. The only major side effect was hyperammonemia in 1 case which resolved when valproate was stopped. Conclusions This case series shows that sodium valproate is a safe medication that rapidly reverses manic-like symptoms within a few days without needing to stop the corticosteroids, thus allowing the medical treatment to continue. The ability to continue treatment while controlling or ameliorating the psychiatric side effects of glucocorticoids with sodium valproate is an advance over previous approaches. The mechanism of this rapid action is unclear and deserves further study.

At the present time, interferon is considered the only effective therapeutic approach in the treatment of both chronic hepatitis B and chronic hepatitis C. It is clear that the disappointing response rates in both chronic hepatitis B and C place added emphasis on efforts to identify alternative forms of therapy. In addition to the development of other antiviral agents including the nucleoside analogs which might prove more effective and have fewer associated side-effects, other agents currently under investigation include thymic peptides such as thymosin alpha 1. In the future, the therapeutic approach to the treatment of chronic hepatitis B and C may consist of combination therapy using perhaps an immune modulator and an antiviral agent or, several antiviral drugs. Alternatively, there is indication that cellular targeting systems with delivery of the toxic material to the specific cell containing the virus may be more effective, while minimizing side-effects. Finally, there are agents such as ursodeoxycholic acid which perhaps, makes bile less toxic and can be used as adjunctive therapy with improvement in liver chemistry values. The treatment of chronic hepatitis B and chronic hepatitis C has shifted in emphasis form the concept of treating liver disease towards that of treating viral infections which happen to effect primarily the liver.

This study reports alleviation of the sharp, burning pains characteristic of systemic distal polyneuropathy (SDPN) patients with adult-onset (Type II) diabetes mellitus (AODM).Twenty-one patients w...

An attempt to classify the histologic lesions seen in allergic diseases is herein presented. It is shown that anatomic differences in these lesions divide them into a relatively small number of groups, each of which has not only a certain histologic identity but clinical and immunologic similarities as well. Pathognomonic significance cannot be claimed for any of the lesions described but all of them are highly characteristic and their presence suggests allergy as a possible cause. Many of the lesions can, no doubt, be caused by both allergic and non-allergic mechanisms. The position of some of the diseases in this classification is uncertain and may have to be changed. It is hoped, however, that the classification may suggest considerations which will clarify these anomalous positions and lead to a more useful classification.

2-Choloroethyl Ethyl Sulfide (CEES) exposure causes inflammatory lung diseases, including acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. This may be associated with oxidative stress, which has been implicated in the desensitization of beta-adrenergic receptors (β-ARs). The objective of this study was to investigate whether lung injury induced by intratracheal CEES exposure (2 mg/kg body weight) causes desensitization of β-ARs. The animals were sacrificed after 7 days and lungs were removed. Lung injury was established by measuring the leakage of iodinated-bovine serum albumin ([125I]-BSA) into lung tissue. Receptor-binding characteristics were determined by measuring the binding of [3H] dihydroalprenolol ([3H] DHA) (0.5–24 nM) to membrane fraction in the presence and absence of DLDL-propranolol (10 μ M). Both high- and low-affinity β-ARs were identified in the lung. Binding capacity was significantly higher in low-affinity site in both control and experimental groups. Although CEES exposure did not change KD and Bmax at the high-affinity site, it significantly decreased both KD and Bmax at low affinity sites. A 20% decrease in β2-AR mRNA level and a 60% decrease in membrane protein levels were observed in the experimental group. Furthermore, there was significantly less stimulation of adenylate cyclase activity by both cholera toxin and isoproterenol in the experimental group in comparison to the control group. Treatment of lungs with 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterase (PDE) could not abolish the difference between the control group and the experimental group on the stimulation of the adenylate cyclase activity. Thus, our study indicates that CEES-induced lung injury is associated with desensitization of β2-AR. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:59–70, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20265

Chronic hepatitis B is a severe and frequently progressive disease. We assessed the safety and efficacy of thymosin fraction 5 and thymosin-alpha 1 in a prospective, placebo-controlled trial in 12 patients with chronic hepatitis B. All patients had histological and biochemical evidence of active liver disease for at least 6 mo before treatment and were positive for serum hepatitis B virus DNA and HBsAg. Seven patients received thymosin fraction 5 or thymosin-alpha 1 and five patients received placebo twice weekly for 6 mo. By the conclusion of the study (1 yr), serum aminotransferase levels had improved significantly in thymosin-treated patients, but not in the placebo group. Six (86%) of the thymosin treated patients and one (20%) patient given placebo cleared hepatitis B virus DNA from serum (p less than 0.04, Fisher's exact test). After treatment, replicative forms of hepatitis B virus DNA were present in the liver specimens of four of five placebo-treated patients but in only one of seven thymosin-treated patients (p less than 0.04, Fisher's exact test). Response to thymosin therapy was associated with significant improvements in peripheral blood lymphocyte and CD3 and CD4 counts and in in vitro production of interferon-gamma over initial values. No significant side effects were observed in patients given thymosin or in placebo-treated patients. Clinical, biochemical and serological improvement in patients responding to thymosin were sustained during 26 +/- 3 mo of follow-up. The results of this pilot trial suggest that thymosin therapy promotes disease remission and cessation of hepatitis B virus replication in patients with chronic viral infection.

The aim of this study was to evaluate and compare the effectiveness of N-acetylcysteine (NAC) and liposomally-encapsulated NAC (L-NAC) in ameliorating the hepatotoxic effects of lipopolysaccharide (LPS). LPS, a major cell wall molecule of Gram-negative bacteria and the principal initiator of septic shock, causes liver injury in vivo that is dependent on neutrophils, platelets, and several inflammatory mediators, including tumour necrosis factor-α (TNF-α). Male Sprague-Dawley rats were pretreated intravenously with saline, plain liposomes (dipalmitoylphosphatidylcholine [DPPC]), NAC (25 mg/kg body weight), or L-NAC (25 mg/kg NAC body weight) and 4 h later were challenged intravenously with LPS ( Escherichia coli O111:B4, 1.0 mg/kg body weight); animals were killed 20 h post-LPS challenge. Hepatic cell injury was evaluated by measuring the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in plasma. LPS-induced activation of the inflammatory response was evaluated by measuring the levels of myeloperoxidase activity and chloramine concentration in liver homogenates as well as TNF-α levels in plasma. The hepatic levels of lipid peroxidation products and non-protein thiols (NPSH) were used to assess the extent of involvement of oxidative stress mechanisms. In general, challenge of animals with LPS resulted in hepatic injuries, activation of the inflammatory response, decreases in NPSH levels and increases in the levels of lipid peroxidation products (malondialdehyde and 4-hydroxyalkenals). Pretreatment of animals with NAC or empty liposomes did not have any significant protective effect against LPS-induced hepatotoxicity. On the other hand, pretreatment of animals with an equivalent dose of L-NAC conferred protection against the liver injuries induced following LPS challenge. These data suggest that NAC when delivered as a liposomal formulation is a potentially more effective prophylactic pharmacological agent in alleviating LPS-induced liver injuries.

Hepatic ultrasound (US) is readily available and physicians usually trust the results of an US report suggesting fatty liver, but there are conflicting reports on its accuracy, especially in patients with chronic liver disease (CLD). Therefore, we retrospectively examined liver biopsies in patients with CLD and compared the histologic results to the hepatic US findings.Liver biopsies were graded for fat (grades 0 to 3), inflammation (grades 0 to 4), and fibrosis (stages 0 to 4) in 131 patients with CLD (89% had chronic hepatitis C). Hepatic US interpretations were grouped into 3 categories-"normal," "fatty liver," and "nonspecific." A secondary analysis was performed using 3 sonographic categories based on the echogenicity: normal, "increased echogenicity," and "heterogenous." The US results were then compared with the liver biopsy results.A normal US report was associated with many false negatives, as 25% of these patients had fat (grades 1 to 3) on biopsy; furthermore, 46% had "significant fibrosis" (stages 2 to 4) or "significant inflammation" (grades 2 to 4). A "fatty liver" interpretation correctly identified fat on biopsy in 36.4% and "significant fat" (grades 2 to 3) in 11.4%, but 66% had significant fibrosis or significant inflammation. An US with increased echogenicity correctly identified fat in 43.5% and significant fat in 19.4%, but 69.4% had significant fibrosis or significant inflammation. The sensitivity of an US ranged from 11.4% to 88.2% and the specificity ranged from 40.4% to 86.2%, depending on the degree of steatosis on biopsy and the sonographic interpretation being considered.US is inaccurate for diagnosing hepatic steatosis in patients with CLD. Echogenic abnormalities are more likely to be the result of fibrosis or inflammation in this setting.

Objective: This prospective study was performed on patients aged >65 years commencing therapy with venlafaxine, in order to determine the incidence of hyponatraemia induced by the drug, to investigate the underlying pathophysiological mechanisms, and to evaluate a simple approach to management of this condition. Method: All patients aged >65 years seen by one author (MR) from all referral sources were entered into the study. Baseline biochemical tests were ordered, and if hyponatraemia developed (plasma Na −1) additional tests were performed to ascertain the mechanism, while the patient continued on venlafaxine and fluid restriction was instituted. Results: A total of 58 patients were seen, of whom 10 developed hyponatraemia, giving an incidence of 17.2%. Of these 10 patients, five were excluded from prolonged observation because of either severe medical illness, side-effects from the antidepressant or being lost to follow up. When hyponatraemia developed, it invariably did so within a few days of starting venlafaxine, and was associated with non-suppression of antidiuretic hormone in the face of a low serum osmolality. Fluid restriction (800 mL day−1) was effective in raising the plasma sodium to the normal range within 2 weeks, after which the fluid restriction could be relaxed without relapse occurring. These patients remained well for the follow-up period of up to 6 months. Conclusions: Patients >65 years of age should have their electrolytes measured 3–5 days after starting venlafaxine therapy. If hyponatraemia develops, it can be managed with modest fluid restriction without discontinuing drug treatment, subject to close continued clinical observation and biochemical monitoring.

Airway instillation into rats of 2-chloroethyl ethyl sulfide (CEES), the half molecule of sulfur mustard compound, results in acute lung injury, as measured by the leak of plasma albumin into the lung. Morphologically, early changes in the lung include alveolar hemorrhage and fibrin deposition and the influx of neutrophils. Following lung contact with CEES, progressive accumulation of collagen occurred in the lung, followed by parenchymal collapse. The co-instillation with CEES of liposomes containing pegylated (PEG)-catalase (CAT), PEG-superoxide dismutase (SOD), or the combination, greatly attenuated the development of lung injury. Likewise, the co-instillation of liposomes containing the reducing agents, N-acetylcysteine (NAC), glutathione (GSH), or resveratrol (RES), significantly reduced acute lung injury. The combination of complement depletion and airway instillation of liposomes containing anti-oxidant compounds maximally attenuated CEES-induced lung injury by nearly 80%. Delayed airway instillation of anti-oxidant-containing liposomes (containing NAC or GSH, or the combination) significantly diminished lung injury even when instillation was delayed as long as 1 h after lung exposure to CEES. These data indicate that CEES-induced injury of rat lungs can be substantially diminished by the presence of reducing agents or anti-oxidant enzymes delivered via liposomes.