Search

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.

Prolactin (PRL), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) are in hormone-response pathways involved in energy metabolism during thermoregulation processes in cattle. Objective herein was to study the association between single nucleotide polymorphisms (SNP) within genes of the PRL and GH/IGF-1 pathways with fertility traits such as services per conception (SPC) and days open (DO) in Holstein cattle lactating under a hot-humid climate. Ambient temperature and relative humidity were used to calculate the temperature-humidity index (THI) which revealed that the cows were exposed to heat stress conditions from June to November of 2012 in southern Sonora, Mexico. Individual blood samples from all cows were collected, spotted on FTA cards, and used to genotype a 179 tag SNP panel within 44 genes from the PRL and GH/IGF-1 pathways. The associative analyses among SNP genotypes and fertility traits were performed using mixed-effect models. Allele substitution effects were calculated using a regression model that included the genotype term as covariate. Single-SNP association analyses indicated that eight SNP within the genes IGF-1, IGF-1R, IGFBP5, PAPPA1, PMCH, PRLR, SOCS5, and SSTR2 were associated with SPC (P

Objectives: The aims of this study are to describe two patients whose manic symptoms persisted for several months after the cessation of corticosteroids, to review the literature and to suggest treatment. Methods: The presentation of two elderly patients with persistent manic symptoms following cessation of corticosteroids several months previously afforded the author the opportunity to examine them carefully, investigate and treat them. Results: The patients were investigated to rule out other causes and were treated with sodium valproate and quetiapine (in the second patient). When well, the medications were slowly decreased and stopped. Both patients were well at one-year follow-up. Conclusions: Manic symptoms may persist for many months after stopping corticosteroids and active treatment is needed to control them.

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.

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.

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.

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.

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.

Objective: The purpose of this paper was to consider the life and contribution of Professor William Siegfried Dawson (1891–1975) by examination of school, university and hospital reports and journal articles. Conclusions: Professor Dawson made a major contribution, through his academic and professional roles and leadership, to the firm establishment of psychiatry, psychiatric scholarship and psychiatric organisations in Australia.

Liver regeneration is regulated by the orderly activation of growth-related genes. Although ethanol impairs induction of liver regeneration by partial hepatectomy, we have not identified ethanol-associated differences in the hepatic mRNA levels of several proto-oncogenes, including c-myc, which peaks 3-6 hr post-partial hepatectomy. Prothymosin alpha, a gene encoding a ubiquitous nuclear protein, is activated by c-myc in resting fibroblasts and has been implicated as a regulator of cell proliferation. Prothymosin alpha mRNA levels reportedly increase 12-32 hr post-partial hepatectomy, several hours after c-myc induction. We sought to determine if chronic ethanol intake alters the expected induction post-partial hepatectomy of prothymosin alpha steady-state mRNA expression and protein levels. Comparing rats chronically fed ethanol with pair-fed controls, we found no significant differences in steady-state levels of prothymosin alpha mRNA; however, we did see a delay in the increase of prothymosin immunoreactive peptide in rats chronically fed alcohol. This suggests that the inhibition in protein levels in ethanol fed rats is not due to lower steady-state mRNA levels, but may occur post-transcriptionally. Further data are needed to determine if this finding is important in the inhibition in cell growth following partial hepatectomy in rats chronically fed ethanol.

The study aimed to assess the prevalence and rate of development of a low (below normal) serum B12 level in clinically well persons on a total vegetarian diet (TVD) with and without supplementation/fortification with B12.Serum B12 and red cell mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were measured in participants on a TVD for 12–340 months. Ability to absorb B12 orally was tested. In addition, urinary methylmalonic acid/creatinine ratio (UMMMCr) was measured in a subgroup of 27.In 47 of 78 adults the B12 level was below 200 pg ml-1, and the MCV was 94.2 ± 4.0. The other 31 adults had a B12 level of 200 or above, averaged 293 ± 85 pg ml-1 and an MCV of 92.6 ± 4.6. Eight children and 12 adults were on the same TVD, but were using B12-fortified soy milk instead of cow's milk. Their B12 level ranged from 255 to 690 (average 417 pg ml-1) with a mean MCV of 88.8 ± 3.5 fl. The serum B12 level of seven of 16 adults with a low serum B12 who chewed a 100 μg tablet of B12 once a week for 6...

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.

Part 1 of this article (see Vol 17, pp. 168–172) described the early life of Harvey Cushing and his encounters with Australian doctors, mostly in various military hospitals, in France, in World War 1. As none of the doctors he met at that time became neurosurgeons, and hence did not shape their professional development. When World War 1 ended, HC returned to a heavy schedule of operating at the Peter Bent Brigham Hospital and to his university obligations. He received the Companion of the Bath from the British Government for his war services and wrote the history of US Base Hospital No. 5, which he directed during the War. Cushing’s reputation as a neurosurgeon was now secure and he was ready to play an even greater part as an academic neurosurgeon, teaching students from all parts of the world and continuing his researches into cerebral tumours and the pituitary gland.

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.

We reported earlier that the activation of free-radical-mediated tumor necrosis factor-alpha (TNF-alpha) cascade is the major pathway in the inflammatory lung disease induced by 2-chloroethyl ethyl sulfide (CEES), a mustard gas analog. TNF-alpha induces activating protein 1 (AP-1) activation via phosphorylation of mitogen activated protein kinases (MAPKs). The present study examines the relationship between CEES induced lung injury and MAPKs signaling pathway. Adult guinea pigs received single intratracheal injection of different doses of CEES and were sacrificed at different time points. CEES exposure caused lung injury with evidence of fibrosis. The optimum activation of all members of the MAPKs family (ERK1/2, p38 and JNK1/2) was achieved at 0.5 mg/kg dose and at 1h. No significant change was observed beyond that time point. This led to an activation of AP-1 transcription factors associated with an increase in the protein levels of Fos, activating transcription factor (ATF) and Jun family members. To explore the involvement of AP-1 in cell proliferation, we determined the protein levels of cell cycle protein cyclin D1 and cell differentiation marker proliferating cell nuclear antigen (PCNA). An up regulation of these proteins was observed. Hence it is suggested that CEES exposure causes accumulation of TNF-alpha, which is associated with an activation of MAPK/AP-1 signaling pathway and cell proliferation. Further studies are needed to clarify whether the observed effects are the adaptive responses of the lung or they contribute to the lung injury.

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.