Epidemiology and genetic characterization of HIV-1 isolates in the general population of Djibouti (Horn of Africa)

During a national survey in 2002 in Djibouti, serum samples were collected using a valid sampling scheme from 2423 Djiboutians representing the general population of urban and rural districts. The HIV-1 seroprevalence was 2%. The HIV-1 polymerase gene from 53 untreated patients was amplified. Phylogenetic analysis of 34 isolates revealed a majority of subtype C (73%) as well as other subtypes, including CRF02_AG recombinants (18%), subtype D (6%), and subtype A (3%).     

Gene conversion is a likely cause of mutation in PKD1

Approximately 70% of the gene responsible for the most common form of autosomal dominant polycystic kidney disease ( PKD1 ) is replicated in several highly homologous copies located more proximally on chromosome 16. We recently have described a novel technique for mutation detection in the duplicated region of PKD1 that circumvents the difficulties posed by these homologs. We have used this method to identify two patients with a nearly identical cluster of base pair substitutions in exon 23. Since pseudogenes are known to be reservoirs for mutation via gene conversion events for a number of other diseases, we decided to test whether these sequence differences in PKD1 could have arisen as a result of this mechanism. Using changes in restriction digest patterns, we were able to show that these sequence substitutions are also present in N23HA, a rodent-human somatic cell hybrid that contains only the PKD1 homologs. Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor this mutation in their PKD1 gene copy. This is the first example of gene conversion in PKD1 , and our findings highlight the importance of using gene-specific reagents in defining PKD1 mutations.      

Shwachman syndrome: Exocrine pancreatic dysfunction and variable phenotypic expression

BACKGROUND & AIMS: Shwachman syndrome is an inherited condition with multisystemic abnormalities, including exocrine pancreatic dysfunction. The aim of this study was to evaluate the occurrence and progression of features in a large cohort of patients. METHODS: Clinical records of 25 patients with Shwachman syndrome were reviewed. RESULTS: Mean birth weight (2.92 +/- 0.51 kg) was at the 25th percentile. However, by 6 months of age, mean heights and weights were less than the 5th percentile. After 6 months of age, growth velocity was normal. Severe fat maldigestion due to pancreatic insufficiency was present in early life (fecal fat, 26% +/- 17% of fat intake; age, < 2 years). Serial assessment of exocrine pancreatic function showed persistent deficits of enzyme secretion, but 45% of patients showed moderate age-related improvements leading to pancreatic sufficiency. Neutropenia was the most common hematologic abnormality (88%), but leukopenia, thrombocytopenia, and anemia were also frequently encountered. Patients with hypoplasia of all three bone marrow cellular lines (n = 11) had the worst prognosis; 5 patients died, 2 of sepsis and 3 of acute myelogenous leukemia. Other findings included hepatomegaly and/or abnormal liver function test results and skeletal abnormalities. CONCLUSIONS: A wide and varied spectrum of phenotypic abnormalities among patients with Shwachman syndrome is described. Pancreatic acinar dysfunction is an invariable abnormality. Patients with severe bone marrow involvement may have a guarded prognosis. (Gastroenterology 1996 Dec;111(6):1593-602)     

Increased IGF-I : IGFBP-3 ratio in patients with hepatocellular carcinoma

BACKGROUND: The development of hepatocellular carcinoma in liver cirrhosis is associated with altered synthesis and secretion of several growth factors. AIM: The aim of this prospective study was to investigate the potential implication of IGF-I and its major binding protein (IGFBP-3) in the development of hepatocellular carcinoma. PATIENTS AND METHODS: IGF-I and IGFBP-3 were measured in 150 healthy subjects, 40 patients with liver cirrhosis and 63 with liver cirrhosis and untreated hepatocellular carcinoma. The ratio between IGF-I and IGFBP-3 was also calculated. RESULTS: Serum IGF-I (70 +/- 10 and 65 +/- 7 vs. 185 +/- 6.4 microg/l, P < 0.001) and IGFBP-3 levels (1225 +/- 113 and 984 +/- 67 vs. 3017 +/ -80 microg/l, P < 0.001) were lower in patients with liver cirrhosis, without or with hepatocellular carcinoma, than in controls. Age was negatively correlated with IGF-I levels in patients with liver cirrhosis (r = -0.6; P = 0.0002) as well as in controls (r = -0.8, P < 0.0001), but not in patients with hepatocellular carcinoma (r = -0.2; P = 0.2). Additionally, in patients with liver cirrhosis (r = -0.54; P = 0.0003) and more weakly in those with hepatocellular carcinoma (r = -0.24; P = 0.04) IGF-I levels were negatively correlated with liver failure measured according with Child class. Despite patients with class C hepatocellular carcinoma being older than those in the same functional class with cirrhosis (64 +/- 2 vs. 57 +/- 12 years, P < 0.01), they had a significantly increased IGF-I : IGFBP-3 ratio (0.18 +/- 0.05 vs. 0.41 +/- 0.09, P = 0.04), due mostly to increased IGF-I levels (27.1 +/- 5.6 vs. 42 +/- 6.2 microg/l) as IGFBP-3 levels were similar to patients with cirrhosis (734 +/- 81 vs. 679 +/- 83 microg/l). CONCLUSIONS: Hepatocellular carcinoma is associated with a higher IGF-I : IGFBP-3 ratio than that found in patients with liver cirrhosis and a similar degree of liver failure.     

Maternal Apical Periodontitis Increases Insulin Resistance and Modulates the Antioxidant Defense System in the Gastrocnemius Muscle of Adult Offspring

IntroductionMaternal apical periodontitis (AP) is associated with insulin resistance (IR) in adult offspring. Oxidative stress has been linked to IR. This study investigated insulin sensitivity (IS) and oxidative stress in the gastrocnemius muscle (GM) of adult offspring of rats with AP.MethodsFifteen female Wistar rats were distributed into a control group, a group with 1 tooth with AP, and a group with 4 teeth with AP. Thirty days after AP induction, female rats were mated with healthy male rats. When male offspring reached 75 days of age, glycemia, insulinemia, and IS were determined. In the GM, the oxidative damage products (thiobarbituric acid reactive substances and carbonyl protein) and activities of enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) and nonenzymatic (glutathione and total antioxidant capacity) antioxidants were quantified. Analysis of variance was performed followed by the Tukey post hoc test (P < .05).ResultsMaternal AP was associated with decreased IS and changes in antioxidant activities (reduced superoxide dismutase and increased catalase, glutathione peroxidase, and glutathione) and decreased thiobarbituric acid reactive substance concentration in the GM of their adult offspring. However, maternal AP does not appear to affect glycemia, carbonyl protein concentration, and the nonenzymatic total antioxidant capacity in the GM of this offspring.ConclusionsMaternal AP modulates the antioxidant defense system in the GM of their adult offspring, attenuating lipid peroxidation in this tissue. This reflects part of an adaptive response of the offspring to the stimulation of the maternal chronic oral inflammatory process in which the organism acts by decreasing oxidative tissue damage in the postnatal stage. The present study improves knowledge about the impact of maternal oral inflammation on healthy offspring.     

Prostaglandin E2 potentiates platelet aggregation by priming protein kinase C

Prostaglandin E2 (PGE2) is produced by activated platelets and by several other cells, including capillary endothelial cells. PGE2 exerts a dual effect on platelet aggregation: inhibitory, at high, supraphysiologic concentrations, and potentiating, at low concentrations. No information exists on the biochemical mechanisms through which PGE2 exerts its proaggregatory effect on human platelets. We have evaluated the activity of PGE2 on human platelets and have analyzed the second messenger pathways involved. PGE2 (5 to 500 nmol/L) significantly enhanced aggregation induced by subthreshold concentrations of U46619, thrombin, adenosine diphosphate (ADP), and phorbol 12-myristate 13-acetate (PMA) without simultaneously increasing calcium transients. At a high concentration (50 mumol/L), PGE2 inhibited both aggregation and calcium movements. PGE2 (5 to 500 nmol/L) significantly enhanced secretion of beta-thromboglobulin (beta TG) and adenosine triphosphate from U46619- and ADP-stimulated platelets, but it did not affect platelet shape change. PGE2 also increased the binding of radiolabeled fibrinogen to the platelet surface and increased the phosphorylation of the 47-kD protein in 32P- labeled platelets stimulated with subthreshold doses of U46619. Finally, the amplification of U46619-induced aggregation by PGE2 (500 nmol/L) was abolished by four different protein kinase C (PKC) inhibitors (calphostin C, staurosporine, H7, and TMB8). Our results suggest that PGE2 exerts its facilitating activity on agonist-induced platelet activation by priming PKC to activation by other agonists. PGE2 potentiates platelet activation at concentrations produced by activated platelets and may thus be of pathophysiologic relevance.     

Autologous bone marrow transplantation in acute myelogenous leukemia: in vitro treatment with myeloid cell-specific monoclonal antibodies

Second or third chemotherapy-induced remissions in acute myelogenous leukemia (AML) are limited by early relapse of the leukemia. We developed monoclonal antibodies (MoAbs) that are cytotoxic to myeloid leukemia cells to treat bone marrow from these patients ex vivo for autologous transplantation. In this pilot study, bone marrow was harvested from ten patients with AML in remission, treated with one or two complement-fixing MoAbs, PM-81 and AML-2-23, which react with myeloid differentiation antigens, incubated with rabbit complement, and cryopreserved. These MoAbs were chosen because they have broad reactivity with AML cells but not with pluripotent progenitor cells. At the time of transplant, 6 patients were in second complete remission, 1 each was in third complete or partial remission, and 2 were in early first relapse. The patients were treated with cyclophosphamide (60 mg/kg a day for 2 days) and total body irradiation (200 cGy twice a day for 3 days) and given infusions of MoAb-treated bone marrow. Full bone marrow reconstitution was observed in eight patients; two patients did not recover platelets. Seven of the ten patients are surviving and disease-free at 21.0, 15.0, 13.0, 10.0, 6.0, 3.0, and 2.0 months posttransplant. Treating bone marrow with MoAbs to myeloid differentiation antigens does not interfere with pluripotential stem cell engraftment. Longer follow-up and a controlled study are necessary to prove that the apparent efficacy of this therapeutic approach in some patients is attributable to MoAb-mediated killing of leukemia cells.     

Transplantation with hyper-reduced liver grafts in children under 10 kg of weight

Background

We had previously described a left lateral segment hyper-reduction technique capable of sizing the graft according to the volume of the abdominal cavity of the recipient.

Aim

The purpose of our study was to evaluate our 14-year live-donor liver transplantation experience with in situ graft hyper-reduction in children under 10 kg of weight.

Patients and methods

Between January 1997 and May 2011, we performed 881 liver transplants. Two hundred and seventy-seven (n?=?277) involved pediatric recipients, of which 102 (37 %) were from live donors. Thirty-five (n?=?35) patients under 10 kg of weight underwent hyper-reduced living donor liver transplants. There were 21 females (60 %) and 14 males (40 %), with a median age of 12 months (range 3–23) and a median weight of 7.7 kg (range 5.6–10).

Results

Median operative time was 350 min (range 180–510). Median cold ischemia time was 180 min (range 60–300). Twenty-six (n?=?26) patients required intraoperative transfusion of blood products. There were 49 postoperative complications involving 26 patients (74 % morbidity rate). One-, 3-, and 5-year survival rates were 87, 79, and 74 %, respectively. Twenty-eight patients are currently alive.

Conclusions

Hyper-reduced grafts provide an alternative approach for low-weight pediatric recipients. The relatively high immediate postoperative morbidity could be related to the complexity of these patients.     

Long-term health outcomes of childhood sexual abuse and peer sexual contact among an urban sample of behaviourally bisexual Latino men

While previous research indicates high rates of childhood sexual abuse among Latino men who have sex with men, few studies have examined the long-term health outcomes of childhood sexual abuse specifically among behaviourally bisexual Latino men. In a sample of 148 behaviourally bisexual Latino men in New York City, we examined associations between childhood sexual abuse and multiple dimensions of adult health: sexual risk behaviours; sexually transmitted infections incidence; polydrug use; depressive symptoms; and perceived stress. We compared outcomes between those with histories of childhood sexual abuse, those reporting peer sexual contact prior to age 13 and those with no sexual contact prior to age 13. Over one-fifth (22.3%) reported a history of childhood sexual abuse, which was significantly associated with engaging in receptive condomless anal intercourse (aOR = 3.59, p < .01, SE = 2.0), high perceived stress (aOR = 2.48, p < .06, SE = 1.13) and clinically significant depressive symptoms (aOR = 2.7, p < .05, SE = 1.25). Across all variables, peer sexual contact did not impact these outcomes, underscoring a key distinction between abusive and non-abusive early sexual experiences. We recommend that sexual abuse prevention policies and programmes better engage Latino youth, and that practitioners serving this population across diverse areas of practice incorporate childhood sexual abuse screening and culturally appropriate treatment and care into practice.