Is there evidence for dual causation between malaria and socioeconomic status? Findings from rural Tanzania

Malaria's relationship with socioeconomic status at the macroeconomic level has been established. This is the first study to explore this relationship at the microeconomic (household) level and estimate the direction of association. Malaria prevalence was measured by parasitemia, and household socioeconomic status was measured using an asset based index. Results from an instrumental variable probit model suggest that socioeconomic status is negatively associated with malaria parasitemia. Other variables that are significantly associated with parasitemia include age of the individual, use of a mosquito net on the night before interview, the number of people living in the household, whether the household was residing at their farm home at the time of interview, household wall construction, and the region of residence. Matching estimators indicate that malaria parasitemia is associated with reduced household socioeconomic status.     

“I Don’t Understand”: Who Is Missed When We Ask Early Adolescents, “Are You Transgender”?

Archives of Sexual Behavior -     

Recombinant factor VIIa in the treatment of non-hemophiliac bleeding

OBJECTIVE: To review the clinical evidence for the use of recombinant factor VIIa (rFVIIa) in the prevention and/or treatment of bleeding in non-hemophiliac patients. DATA SOURCES: A MEDLINE search (1966-December 2004) was conducted to identify pertinent literature. Results were limited to English-language reports and clinical trials. References of relevant articles and selected abstracts presented at scientific meetings were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Human data from prospective and retrospective studies that examined the hemostatic effect of rFVIIa in non-hemophiliac patients were reviewed, with a focus on surgical prophylaxis, liver disease, intractable bleeding associated with trauma and surgery, and anticoagulation reversal. DATA SYNTHESIS: Results from limited controlled trials on the use of rFVIIa as an adjunct for prevention of bleeding in surgery and liver diseases have not been consistent. For treatment of intractable bleeding, earlier use of rFVIIa in one trauma trial was shown to decrease the number of blood transfusions, but no differences in terms of clinical outcomes were observed in all trials. Controlled trials do not suggest an increased risk of thrombotic events. Optimal dosing and timing of administration have yet to be defined. CONCLUSIONS: Until further prospective controlled data are available, it is recommended that conventional intervention for prevention and control of hemorrhage in non-hemophiliac patients should remain the standard of care. Close monitoring of coagulation parameters is recommended before, during, and after therapy, especially in high-risk patients. Pharmacoeconomic analysis may be useful to help control costs and maximize clinical benefits.     

Amelioration of proteolipid protein 139-151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms

Copolymer 1 [Cop1, glatiramer acetate, Copaxone, poly(Y,E,A,K)n] is widely used in the treatment of relapsing/remitting multiple sclerosis in which it reduces the frequency of relapses by approximately 30%. In the present study, copolymers with modified amino acid compositions (based on the binding motif of myelin basic protein 85-99 to HLA-DR2) have been developed with the aim of suppressing multiple sclerosis more effectively. The enhanced efficacy of these copolymers in experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with proteolipid protein 139-151 was demonstrated by using three protocols: (i) simultaneous administration of autoantigen and copolymer (termed prevention), (ii) pretreatment with copolymers (vaccination), or (iii) administration of copolymers after disease onset (treatment). Strikingly, in the treatment protocol administration of soluble VWAK and FYAK after onset of disease led to stasis of its progression and suppression of histopathological evidence of EAE. The mechanisms by which these effects are achieved have been examined in several types of assays: binding of copolymers to I-A(s) in competition with proteolipid protein 139-151 (blocking), cytokine production by T cells (T helper 2 polarization), and transfer of protection by CD3(+) splenocytes or, notably, by copolymer-specific T cell lines (induction of regulatory T cells). The generation of these copolymer-specific regulatory T cells that secrete IL-4 and IL-10 and are independent of the immunizing autoantigen is very prominent among the multiple mechanisms that account for the observed suppressive effect of copolymers in EAE.     

Experimental evidence for a link among cupredoxins: red, blue, and purple copper transformations in nitrous oxide reductase

The cupredoxin fold is an important motif in numerous proteins that are central to several critical cellular processes ranging from aerobic and anaerobic respiration to catalysis and iron homeostasis. Three types of copper sites have been found to date within cupredoxin folds: blue type 1 (T1) copper, red type 2 (T2) copper, and purple Cu(A). Although as much as 90% sequence difference has been observed among some members of this superfamily of proteins that span several kingdoms, sequence alignment and phylogenic trees strongly suggest an evolutionary link and common ancestry. However, experimental evidence for such a link has been lacking. We report herein the observation of pH-dependent transformation between blue T1 copper, red T2 copper, and the native purple Cu(A) centers of nitrous oxide reductase (N2OR) from Paracoccus denitrificans. The blue and red copper centers form initially before they are transformed into purple Cu(A) center. This transformation process is pH-dependent, with lower pH resulting in fewer trapped T1 and T2 coppers and faster transition to purple Cu(A). These observations suggest that the purple Cu(A) site contains the essential elements of T1 and T2 copper centers and that the Cu(A) center is preferentially formed at low pH. Therefore, this work provides an underlying link between the various cupredoxin copper sites and possible experimental evidence in vitro for the evolutionary relationship between the cupredoxin proteins. The findings also lend physiological relevance to cupredoxin site biosynthesis.     

Risk factors for venous thromboembolism in immunoglobulin light chain amyloidosis

Patients with immunoglobulin light chain amyloidosis are at risk for both thrombotic and bleeding complications. While the hemostatic defects have been extensively studied, less is known about thrombotic complications in this disease. This retrospective study examined the frequency of venous thromboembolism in 929 patients with immunoglobulin light chain amyloidosis presenting to a single referral center, correlated risk of venous thromboembolism with clinical and laboratory factors, and examined complications of anticoagulation in this population. Sixty-five patients (7%) were documented as having at least one venous thromboembolic event. Eighty percent of these patients had events within one year prior to or following diagnosis. Lower serum albumin was associated with increased risk of VTE, with a hazard ratio of 4.30 (CI 1.60–11.55; P=0.0038) for serum albumin less than 3 g/dL compared to serum albumin greater than 4 g/dL. Severe bleeding complications were observed in 5 out of 57 patients with venous thromboembolism undergoing treatment with anticoagulation. Prospective investigation should be undertaken to better risk stratify these patients and to determine the optimal strategies for prophylaxis against and management of venous thromboembolism.     

Biomarkers of senescence in non-human primate adipose depots relate to aging

Forty-three female African green monkeys (Chlorocebus aethiops sabaeus) were selected to represent young adult to advanced geriatric ages (7–24 years) to exhibit a wide range of obesity status (8–53% body fat) and diverse metabolic syndrome criteria such as diabetes, dyslipidemia, and hypertension. Subcutaneous and visceral adipose tissues were collected and evaluated for the presence of senescence cells in both whole tissue and single-cell isolates from subcutaneous sources, utilizing senescence-associated β-galactosidase (SAβ-gal) staining. Plasma samples were analyzed for selected metabolic and inflammatory biomarkers related to the senescence-associated secretory profile. Our results indicated that tissue staining scores did not differ between subcutaneous and intra-abdominal visceral depots and were highly related within individuals. Tissue staining was significantly associated with chronological age; however, no associations with fatness or metabolic syndrome criteria were observed. Associations with age were unchanged when obesity status was included in regression models. Isolated cell staining did positively relate to age but not tissue staining, suggesting some of the SAβ-gal-positive cells were stromal vascular cells or small adipocytes, but that mature large adipocytes, filtered out in the cell isolation process, are also likely to exhibit positive SAβ-gal staining. Plasminogen activator inhibitor-1 (PAI-1) concentration in circulation was the sole inflammation-related biomarker that positively associated with age and is considered to be a marker of senescent cell burden. Our study is the largest, most comprehensive assessment of adipose SAβ-gal staining in a relevant animal model of human aging, and confirms that this senescence-associated biomarker specifically indicates an age-related process.

     

Orlistat Reverse Fatty Infiltration and Improves Hepatic Fibrosis in Obese Patients with Nonalcoholic Steatohepatitis (NASH)

Nonalcoholic steatohepatitis (NASH) may cause progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Treatment, thus far, has been restricted to diet and weight loss, but without compelling results. In this study we aimed to evaluate the efficacy of orlistat therapy in obese patients with NASH. Fourteen obese patients with NASH underwent liver biopsy prior to and subsequent to 6 months treatment with orlistat (120 mg tid). Hepatic fat extension was graded as normal, mild, moderate, or severe. Hepatic fibrosis was scored on a scale from 0 to 4, with 0 denoting no fibrosis and 4, cirrhosis. Portal inflammation was scored as 0-3, with 0 = normal, 1 = mild, 2 = moderate, and 3 = severe inflammation. Fourteen patients had NASH associated with diabetes, hyperlipidemia, or obesity. Orlistat reduced fatty infiltration in 10 patients (70%; P<0.01), 3 of whom had normal liver fat content after treatment. Orlistat improved inflammatory activity by 2 grades in 28% and by 1 grade in 50% of patients and effected no change in 22% of patients. Five patients (35%) returned to normal inflammatory activity. Orlistat improved hepatic fibrosis by 2 grades in three patients (21%) and by 1 grade in seven patients (50%). There was no change in four patients (28%). Orlistat lowered aminotransferases levels, total cholesterol, triglycerides and low-density lipoprotein, respectively. Insulin resistance index and malonyl dialdehyde levels improved significantly after orlistat therapy, whereas HbAic remained unchanged. In conclusion, in obese patients with NASH, liver fibrosis and inflammation improved after therapy with orlistat.