A review of α1-antitrypsin deficiency

α(1)-Antitrypsin (AAT) deficiency is an underrecognized genetic condition that affects approximately 1 in 2,000 to 1 in 5,000 individuals and predisposes to liver disease and early-onset emphysema. AAT is mainly produced in the liver and functions to protect the lung against proteolytic damage (e.g., from neutrophil elastase). Among the approximately 120 variant alleles described to date, the Z allele is most commonly responsible for severe deficiency and disease. Z-type AAT molecules polymerize within the hepatocyte, precluding secretion into the blood and causing low serum AAT levels (～ 3-7 μM with normal serum levels of 20-53 μM). A serum AAT level of 11 μM represents the protective threshold value below which the risk of emphysema is believed to increase. In addition to the usual treatments for emphysema, infusion of purified AAT from pooled human plasma-so-called "augmentation therapy"-represents a specific therapy for AAT deficiency and raises serum levels above the protective threshold. Although definitive evidence from randomized controlled trials of augmentation therapy is lacking and therapy is expensive, the available evidence suggests that this approach is safe and can slow the decline of lung function and emphysema progression. Promising novel therapies are under active investigation.     

A Subregional Analysis of Epidemiologic and Genetic Characteristics of Influenza A(H1N1)pdm09 in Africa: Senegal,Cape Verde,Mauritania, and Guinea, 2009–2010

During the pandemic 2009 episode, we conducted laboratory-based surveillance in four countries from West Africa: Senegal, Mauritania, Cape Verde, and Guinea. Specimens were obtained from 3,155 patients: 2,264 patients from Senegal, 498 patients from Cape Verde, 227 patients from Mauritania, and 166 patients from Guinea; 911 (28.9%) patients were positive for influenza, 826 (90.7%) patients were positive for influenza A, and 85 (9.3%) patients were positive for influenza B. Among the influenza A positives, 503 (60.9%) positives were H1N1pdm09, 314 (38.0%) positives were H3N2, and 9 (1.1%) positives were seasonal H1N1. The highest detection rate for seasonal influenza viruses (17.1%) occurred in the 5–14 years age group. However, for A(H1N1)pdm09, the detection rate was highest in the 15–24 years age group (35.8%). Based on the present study data, the timeline of detection of A(H1N1)pdm09 viruses in these four countries should be Cape Verde, Guinea, Mauritania, and finally, Senegal. Genetic and antigenic analyses were performed in some isolates.     

Interaction models of CYP1A1, GSTMl polymorphisms and tobacco smoking in intestinal gastric cancer

AIM: To explore the interaction models of the cytochrome P-450 (CYP) 1A1 Va/variant and glutathione S-transferase (GST) M1 null polymorphisms with tobacco smoking in the occurrence of intestinal gastric cancer. METHODS: A community-based case-control study was conducted in Yangzhong. Subjects included 114 intestinal types of gastric cancer with endoscopic and pathological diagnosis during January 1997 and December 1998, and 693 controls selected from their spouse, siblings or siblingsin -law who had no history of digestive system cancer. Logistic regression was used to estimate the interaction models. RESULTS: The frequency of the CYP1A1 Va/variant allele in cases did not differ from that in controls. The OR of GSTM1 null genotype was 2.0 (95% confidence interval [95%CI]: 1.2-3.1, P<0.01). It showed a significant type 2 form of interaction model when both CYP1A1 Val variant allele and former tobacco smoking existed (i.e., among the multiplicative effects, the disease risk is increased by the tobacco exposure alone but not by the CYP1A1 variant alone). The interaction index y was 2.8, and OReg(95%CI) was 5.0 (1.9-13.4). GSTM1 null genotype and former tobacco smoking were significant in a type 4 interaction model (i.e., the disease risk is increased by GSTM1 null genotype or tobacco exposure alone among the multiplicative effects). The interaction index y and OReg (95%CI) were 3.4 and 8.4 (3.4-20.9), respectively. CONCLUSION: Different interaction models of CYP1A1 Va/variant allele and GSTM1 null genotype with tobacco smoking will contribute to understanding carcinogenic mechanism, but there is a need to further investigate in larger scale studies.     

Surveillance of human Campylobacter infections in France--part 1--which data? A study of microbiological laboratories, 2000

The frequency of Campylobacter infections in humans, their potential severity, and the existence of preventive measures justify the implementation of a surveillance system for these infections. Before the implementation of the surveillance system, a survey of the Campylobacter diagnostic practices in the laboratories was performed. In the laboratories that responded, most investigated for Campylobacter at least once in 1999. Identification of the Campylobacter species was carried out by 86% of hospital laboratories and 37% of private laboratories. Antibiotic sensitivity tests were carried out by 75% and 32% of them respectively. Many laboratories test for Campylobacter in stool samples using comparable methods showing the feasibility of a surveillance system.     

Therapeutic potential of panduratin A, LKB1-dependent AMP-activated protein kinase stimulator, with activation of PPARα/δ for the treatment of obesity

Aim: AMP‐activated protein kinase (AMPK) activators have shown potential as therapeutic agents for metabolic disorders. This study was conducted to evaluate therapeutic potential of panduratin (PAN) A, a natural AMPK stimulator, with activation of PPARα/δ for the treatment of obesity. Methods: We used the novel AMPK activator PAN A, a natural compound isolated from Boesenbergia pandurata rhizomes, to investigate the regulation of LKB1‐dependent AMPK–PPARα/δ signalling by western blot, reporter gene assay and small interfering RNA knockdown analysis. In addition, the antiobesity effects of PAN A were evaluated in C57BL/6J mice with high‐fat diet (HFD)‐induced obesity. Results: PAN A stimulated AMPK signalling, induced nuclear translocation of the AMPKα2 subunit and activated PPARα/δ; LKB1, a kinase that lies upstream of AMPK, mediated these effects. PAN A stimulated the direct binding of the AMPKα2 subunit to PPARα/δ, but PPARδ activation required direct interaction with PPARγ coactivator 1α (PGC‐1α). Further, PAN A (50 mg/kg/day) reduced weight gain, fat mass, fatty liver and improved serum lipid profiles in obese mice. Additionally, PAN A reduced ectopic fat accumulation and increased the proportion of slow‐twitch myofibres and mitochondria content in skeletal muscle, thereby increasing running endurance. Conclusions: PAN A, an LKB1‐dependent AMPK stimulator, activated PPARα/δ and attenuated HFD‐induced obesity and dysregulation of lipid metabolism. Our findings suggest that PAN A is a potent AMPK activator and show a novel molecular mechanism for the treatment of metabolic disorders.     

A Randomized, Controlled Study of Thymosin-α1 Therapy in Patients with Anti-HBe, HBV-DNA-Positive Chronic Hepatitis B

No consistently effective therapy is yet available for the treatment of chronic HBsAg, anti-HBe, HBV-DNA-positive hepatitis. A multicenter trial has shown that the response rates are not significantly different when patients with anti-HBe-positive hepatitis are treated with six-month course of thymosin-₁ or of interferon-. However, since among these patients, interferon's real efficacy is still debated, with sustained biochemical response achieved in only a few of the treated patients, we conducted this controlled study to investigate the safety and efficacy of thymosin-₁ as compared with no treatment. Forty-four chronic hepatitis B virus (HBV) carriers, who were anti-HBe- and HBV-DNA-positive, were randomized, with stratification for the presence of cirrhosis at baseline liver biopsy, to receive either thymosin-₁ at a dose of 900 g/m² twice a week for six months or no treatment. At entry, both groups of patients were comparable for sex, age, liver histology, ALT, IgM anti-HBc, and HBV-DNA levels. Forty-two patients were followed-up for 20 months (median; range 12–32 months) after completion of therapy: one dropped out, and one developed hepatocellular carcinoma at six months. Thymosin-₁ treatment had no side effects. Six months after the end of the therapy, HBV-DNA was negative and ALT had normalized in 14% of treated cases and in 4.5% of control group, while IgM anti-HBc was negative (<0.200) in 14% of the treated patients and in 4.5% of the controls. Among the treated patients, the median ALT levels stayed significantly lower compared to the pretreatment values during the treatment period and six months of follow-up. During the first year, there were six flares of hepatitis in the control group and five among the treated patients (P = NS), yielding a per year average of 0.3 and 0.23 flares per patient, respectively. Among the treated patients, median IgM anti-HBc levels were low with respect to baseline values 4–10 months after treatment started. None became HBsAg negative. In conclusion, these results indicate that, in anti-HBe, HBV-DNA-positive chronic hepatitis B, thymosin-₁ therapy alone does not increase the response rate, but may contribute to reduce the immune-mediated liver cell necrosis as indirectly assessed by ALT and IgM anti-HBc levels.     

A case of TAFRO syndrome,a variant of multicentric Castleman’s disease,successfully treated with corticosteroid and cyclosporine A

We report a case of a 46-year-old woman with fever, pleural effusion, massive ascites, severe edema, hepatosplenomegaly, elevation of serum creatinine level, proteinuria, and severe thrombocytopenia. Her clinical features were compatible with TAFRO syndrome proposed as a variant of multicentric Castleman’s disease, that is occasionally associated with poor prognosis. Treatment with corticosteroid improved her symptoms partially. However, thrombocytopenia, ascites, and edema persisted. The use of cyclosporine A successfully improved her condition, resulting in remission.     

Biochemical characterization of two mutants of human pyruvate dehydrogenase, F205L and T231A of the E1α subunit

Mutations in the E1alpha subunit of the pyruvate dehydrogenase multienzyme complex may result in congenital lactic acidosis, but little is known about the consequences of these mutations at the enzymatic level. Here we characterize two mutants (F205L and T231A) of human pyruvate dehydrogenase in vitro, using the enzyme expressed in Escherichia coli. Wild-type and mutant proteins were purified successfully and their kinetic parameters were measured. F205L shows impaired binding of the thiamin diphosphate cofactor, which may explain why patients carrying this mutation respond to high-dose vitamin B1 therapy. T231A has very low activity and a greatly elevated Km for pyruvate, and this combination of effects would be expected to result in severe lactic acidosis. The results lead to a better understanding of the consequences of these mutations on the functional and structural properties of the enzyme, which may lead to improved therapies for patients carrying these mutations.     

High Incidence of Malaria Along the Sino–Burmese Border Is Associated With Polymorphisms of CR1, IL-1A,IL-4R,IL-4, NOS,and TNF,But Not With G6PD Deficiency

Malaria is highly endemic in Yunnan Province, China, with the incidence of malaria being highest along the Sino–Burmese border.The aim of our study was to determine whether genetic polymorphisms are associated with the prevalence of malaria among Chinese residents of the Sino–Burmese border region. Fourteen otherwise healthy people with glucose-6-phosphate dehydrogenase (G6PD) deficiency, 50 malaria patients, and 67 healthy control subjects were included in our cross-sectional study. We analyzed the frequency of the G3093T and T520C single-nucleotide polymorphisms (SNPs) of CR1. Logistic regression was used to calculate the prevalence odds ratio (POR) and 95% confidence interval (CI) of malaria for the T520C SNP of CR1 and SNPs of G6PD, IL-4, IL-4R, IL-1A, NOS, CD40LG, TNF, and LUC7L.The frequency of the 3093T/3093T genotype of CR1 in the malaria group (0.16) was significantly higher than that in the control group (0.045, P < 0.05), and significantly lower than that in the G6PD deficiency group (0.43, P < 0.01). The frequency of the 520T/520T genotype of CR1 was significantly higher in the malaria patients (0.78) than that in the control group (0.67, P < 0.05) and G6PD-deficiency group (0.36, P < 0.05). The T allele of the T520C variant of CR1 was significantly associated with the prevalence of malaria (POR: 1.460; 95% CI: 0.703–3.034). Polymorphisms of G6PD did not significantly influence the prevalence malaria (P > 0.05). A GTGTGTC haplotype consisting of IL-1A (rs17561), IL-4 (rs2243250), TNF (rs1800750), IL-4R (rs1805015), NOS (rs8078340), CD40LG (rs1126535), and LUC7L (rs1211375) was significantly associated with the prevalence of malaria (POR: 1.822, 95% CI: 0.998–3.324).The 3093G/3093G and 520T/520T genotypes are the predominant genetic variants of CR1 among Chinese residents near the Sino–Burmese border, and the T allele of T520C is associated with the prevalence of malaria in this region. Although G6PD deficiency does not protect against malaria, it may diminish the association between malaria and the CR1 polymorphisms in this population. The GTGTGTC haplotype is also associated with the prevalence of malaria in this region.     

A Prospective,Randomized, Multicenter,Controlled Study of the Safety of Seprafilm® Adhesion Barrier in Abdominopelvic Surgery of the Intestine

INTRODUCTION: Seprafilm® adhesion barrier (Seprafilm®) has been proven to prevent adhesion formation after abdominal and pelvic surgery. This article reports safety results, including the postoperative incidence of abdominal and pelvic abscess and pulmonary embolism, from a large, multicenter trial designed to evaluate the safety and effectiveness of Seprafilm® for reduction of adhesion-related postoperative bowel obstruction after abdominopelvic surgery. METHODS: A total of 1,791 patients participated in this prospective, randomized, multicenter, multinational, single-blind, controlled study in patients undergoing abdominopelvic surgery, the majority of whom had inflammatory bowel disease. Just before closure of the abdomen, patients were randomized to a Seprafilm® or no-treatment control group. Patients received an average of 4.4 and as many as 10 Seprafilm® adhesion barriers applied to organs and tissue surfaces that sustained direct surgical trauma and to suspected adhesiogenic surfaces. Complications that occurred within the first month after surgery were evaluated. RESULTS: During the safety evaluation period, the difference between the Seprafilm® and control groups for the incidence of abscess (4 vs. 3 percent, respectively) or pulmonary embolism (<1 percent in both groups) was not statistically significant (P > 0.05). Foreign body reaction was not reported in either group. Fistula (2 vs. <1 percent) and peritonitis (2 vs. <1 percent) occurred more frequently (P 0.05) in the Seprafilm® group. In a subpopulation of patients in whom Seprafilm® was wrapped around a fresh bowel anastomosis, leak-related events, which included anastomotic leak, fistula, peritonitis, abscess, and sepsis, occurred more frequently (P 0.05). There were no other differences in the incidence, severity, or causative relationship of complications between study groups. CONCLUSIONS: This study confirmed the safety of Seprafilm® adhesion barrier with respect to abdominal abscess, pelvic abscess, and pulmonary embolism when administered to patients undergoing abdominopelvic surgery. Foreign body reaction was not reported for any patient. However, wrapping the suture or staple line of a fresh bowel anastomosis with Seprafilm® should be avoided, because the data suggest that this practice may increase the risk of sequelae associated with anastomotic leak.