Drug use patterns and infection with sexually transmissible agents among young adults in a high-risk neighbourhood in New York City

Aims To determine relationships between drug use ‘hardness’ (defined in increasing order of hardness as no drug use, marijuana use, non‐injected heroin or cocaine use, crack smoking and injection drug use) and prevalences of several sexually transmissible infections among young adults in a high‐risk neighbourhood. Drug users, particularly injection drug users and crack smokers, may be a core group for some sexually transmitted infections. Design Cross‐sectional survey and assays of young adults from (a) a household probability sample and (b) a targeted sample of youth who have used injected drugs, crack, other cocaine or heroin. Setting Bushwick, an impoverished New York City minority neighbourhood with major drug markets. Participants A total of 363 18–24‐year‐olds from a household probability sample; 165 Bushwick 18–24‐year‐olds who have used injected drugs, crack, other cocaine or heroin. Measurements Drug use by self‐report; serum‐ and urine‐based assays for HIV, hepatitis B and C, syphilis, gonorrhoea, chlamydia and herpes simplex (type 2). Findings Household‐sample prevalences: HIV, hepatitis C and syphilis, 1%; gonorrhoea 3%; chlamydia 5%; past or present hepatitis B infection 8%; herpes simplex (type 2) 18%. In combined household and targeted samples, hepatitis C and HIV were concentrated among drug injectors. Herpes simplex (type 2), syphilis and hepatitis B increased among women with ‘hardest drug ever used’. Conclusions Using ‘harder’ drugs is associated with some but not all of these infections. Prevention efforts should help youth avoid unsafe sex and higher‐risk drugs.     

Glucose-6-phosphate dehydrogenase (G-6-PD) mutations in Mexico: four new G-6-PD variants

Screening for mutations at the G-6-PD gene by PCR-SSCP combined with restriction enzyme analysis and DNA sequencing was performed in nine G-6-PD deficient individuals with negative results for the presence of the most frequent G-6-PD mutations previously observed in Mexican population. The variants G-6-PD Valladolid(406T), G-6-PD Durham(713G), and G-6-PD Viangchan(871A) and four new G-6-PD mutant alleles were identified. The new mutations are located at cDNA nt 376 A --> T (126 Asn --> Tyr), nt 770 G --> T (257 Arg --> Leu), nt 1094 G --> A (365 Arg --> His), and nt 1285 A --> G (429 Lys --> Glu) and they were named G-6-PD San Luis Potosi, G-6-PD Zacatecas, G-6-PD Veracruz, and G-6-PD Yucatán, respectively. To date, a total of 18 different G-6-PD variants have been observed in Mexico and several of them are common in Africa, South Europe, and Southeast Asia.     

Efficacy and safety of ixekizumab in patients with active psoriatic arthritis with and without concomitant conventional disease-modifying antirheumatic drugs: SPIRIT-P1 and SPIRIT-P2 3-year results

Clinical Rheumatology - To evaluate the three-year efficacy and safety of ixekizumab with and without concomitant conventional synthetic disease-modifying antirheumatic drug (csDMARD) use in...     

Behavior of the pulmonary circulation at rest and during exercise in miliary tuberculosis

We studied the hemodynamic behavior of the pulmonary circulation at rest and during exercise in six patients with MTB. As a group, in contrast to advanced fibrocaseous tuberculosis, these patients exhibited normal pulmonary hemodynamics at rest and during exercise. Only minor abnormalities in pulmonary vascular resistance at exercise (increased PAd-PWP gradient) were noted in two of the patients. The increase in Rp during exercise does not appear to be related to acute hypoxic vasoconstruction but rather to functional changes (compliance or recruitment or both) of the pulmonary microvasculature. In the genesis of these functional changes, chronic alveolar hypoxia and the inflammatory-fibrotic process might be interacting.     

Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized double-blind study controlled with placebo

Backgrounds/Aims: Intense pruritus and the risk of stillbirths and premature deliveries justify the search for an effective pharmacologic treatment of intrahepatic cholestasis of pregnancy. This study was designed to test the efficacy of ursodeoxycholic acid in maternal pruritus, the biochemical abnormalities and the outcome of pregnancy, in patients with intrahepatic cholestasis of pregnancy of early onset.Methods: Pregnant patients hospitalized in a secondary case-referral center with intense pruritus and abnormal serum levels of bile salts and aminotransferases, detected before week 33 of pregnancy, were randomly assigned to receive ursodeoxycholic acid, 1 g per day orally, or an identical placebo, until delivery, in a double-blind study. A 3-week trial period was chosen to compare drug and placebo effects. The follow-up was extended for 3 months after delivery.Results: Twenty-four patients entered the trial; eight had deliveries before 2 weeks of treatment and one dropped out. The study was then completed in 15 patients: eight received ursodeoxycholic acid and seven placebo. No adverse effects were detected in the mother or in their babies. After 3 week of treatment, patients receiving ursodeoxycholic acid (mean daily) dose 16 mg/kg body weight) had a significant improvement in pruritus (p<0.02), In serum bilirubin (0.36±0.19 mg/dl (mean±SD) versus 0.95±0.48 in patients receiving placebo, p<0.01), in aspartate aminostransferase (52±42 IU/l vs 98±44, p<0.05) and in alanine aminotransferase (54±50 IU/l vs 229±154, p<0.01); serum total bile salts also tended to be lower in patients receiving ursodeoxycholic acid (26.3±33.7 μmol/l vs 55.0±44.8, p N.S.). Deliveries occurred at or near term in all mothers who received ursodeoxycholic acid (mean week of pregnancy: 38), while they occurred before week 36 of pregnancy in five patients who received placebo, including one stillbirth. All babies born alive had birth weights adequate for gestational age and they were thriving normally 3 months after delivery.Conclusions: Ursodeoxycholic acid is effective and safe in patients with intrahepatic cholestasis of pregnancy of early onset, attenuating pruritus and correcting some biochemical abnormalities in the mothers. Relevant aspects of fetal outcome were also improved in patients receiving ursodeoxycholic acid compared to placebo.     

Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation

Hutchinson-Gilford progeria syndrome (HGPS), a progeroid syndrome in children, is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a "CAAX protein" that is farnesylated and then processed further to generate mature lamin A, which is a structural protein of the nuclear lamina. The mutant prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesylation, but the 50-aa deletion prevents the subsequent processing to mature lamin A. The presence of progerin adversely affects the integrity of the nuclear lamina, resulting in misshapen nuclei and nuclear blebs. We hypothesized that interfering with protein farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothesized that the mislocalization of progerin away from the nuclear envelope would improve the nuclear blebbing phenotype. To approach this hypothesis, we created a gene-targeted mouse model of HGPS, generated genetically identical primary mouse embryonic fibroblasts, and we then examined the effect of a farnesyltransferase inhibitor on nuclear blebbing. The farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleoplasm, as determined by immunofluoresence microscopy, and resulted in a striking improvement in nuclear blebbing (P < 0.0001 by chi2 statistic). These studies suggest a possible treatment strategy for HGPS.     

Role of nucleotides in tubulin polymerization: effect of guanylyl 5''-methylenediphosphonate.

Incubation of 48,000 X g rat brain supernatants for 30 min at 37 degrees with 1-2 mM guanylyl 5'-methylenediphosphonate [Gmp(CH2)pp] results in polymerization of 95-98% of the tubulin present. This is considerably more than the 50% polymerization that can be achieved with the natural nucleotide, GTP, under optimal conditions. Gmp(CH2)pp is also much more effective than GTP in inducing polymerization of purified tubulin. Assembly of microtubules with Gmp(CH2)pp occurs at tubulin concentrations one-third of those possible with GTP. Furthermore, with Gmp(CH2)pp, microtubule assembly does not require the high molecular weight basic proteins needed with GTP. Polymerization of tubulin by Gmp(CH2)pp is neither prevented nor reversed by concentrations of calcium (2 mM) that can either prevent microtubule assembly or disrupt already formed microtubules if the nucleotide used is GTP or guanylyl imidodiphosphate. When Ca2+ is added before or after microtubule assembly, electron microscopy of the Gmp(CH2)pp preparations reveals normal microtubules turning into twisted ribbons. Low temperature (4 degrees) can both prevent and disrupt the tubulin assembled Gmp(CH2)pp although disruption proceeds much more slowly when GTP is used.     

Open clinical trial of rifabutin and clarithromycin therapy in Crohn''s disease

BACKGROUND: Crohn's disease, an inflammatory bowel disease in humans, has a suspected aetiology of Mycobacterium avium subsp. Paratuberculosis. AIMS: To evaluate the role of rifabutin and clarithromycin anti-Mycobacterium avium subsp. Paratuberculosis treatment in Crohn's disease patients using an open clinical trial. METHODS:. A total of 36 patients with acute presentations of Crohn's disease, whose sera tested positive against p35 and p36 antigens (two recombinant proteins of Mycobacterium avium subsp. Paratuberculosis), were selected for treatment with rifabutin and macrolide antibiotic therapy Rifabutin and macrolide antibiotic therapy medications included 250 mg 1 po bid clarithromycin and 150 mg 1 po bid Ri-fabutin accompanied with a probiotic. Crohn's disease patients' response to rifabutin and macrolide antibiotic therapy was monitored over a period ranging from 4 to 17 months. RESULTS: Seven patients (19.4%) withdrew from the study since they were unable to tolerate medications. Of the remaining 29 patients, 21 (58.3%) reached a sustained state of improvement, traditionally defined as a decrease of 70 points between their entrance and exit Crohn's disease activity index scores together with the absence of the need of all other Crohn's medications, such as immunosuppressants and corticosteroids. Three Crohn's disease patients [8. 3%) noticed significant improvements, but required other Crohn's medications, concurrently with rifabutin and macrolide antibiotic therapy, to achieve and sustain improvement. Only 5 Crohn's disease patients (13.8%) were non-responders, noticing no marked improvement while on rifabutin and macrolide antibiotic therapy. CONCLUSION: The data add further evidence to support the role of rifabutin and macrolide antibiotic therapy in the treatment of Crohn's disease specifically in those patients with evidence of Mycobacterium avium subsp. Paratuberculosis infection. A large multi-centre clinical trial is needed to further explore these findings.     

Characterization of von Willebrand factor in primary pulmonary hypertension

Summary The aim of this study was to determine the value of von Willebrand factor (vWF), a well-characterized endothelial cell protein secretion, as a marker for prognosis in patients with primary pulmonary hypertension (PPH). Venous and arterial blood samples were obtained from 18 clinically diagnosed PPH patients and 12 case controls matched for age and sex. Plasma vWF antigen was determined by enzymelinked immunosorbent assay (ELISA). The patients' multimeric vWF pattern was analyzed by sodium dodecylsulfate (SDS)-agarose-acrylamide electrophoresis, Western blot, and densitometric analysis. vWF sialic acid content was determined by a lectin-based ELISA. The PPH patients showed a higher content of vWF antigen in venous (P = 0.0026) and arterial (P = 0.0094) blood samples than controls. The mean vWF sialic acid content of the PPH patients corresponded to 37.7% of the mean value for the control group. On the basis of the hemodynamic response to vasodilator trial, the PPH patients were grouped as responders or nonresponders. The latter group showed a significantly higher plasma vWF antigen antecubital vein/radial artery ratio, an increased number of unusually large vWF multimers, and a diminished content of vWF sialic acid in comparison with the first group. We believe that our results establish the nature of vWF alterations that are related to endothelial cell damage in patients with primary pulmonary hypertension and that this could be of value when establishing the prognosis in this group of patients.