The blood group U antigen is not located on glycophorin B.

Erythrocytes from twelve individuals with the S-s-U- phenotype and from ten with the S-S-U+ phenotype were analyzed and compared to control cells with S+/s+U+ determinants. No red cell abnormality was detected in S-s-U+ or S-s-U- carriers. Sialic acid content was similar (P greater than 0.05) for S-s-U+ and S-s-U- erythrocytes (74.6 +/- 7.14 and 71.4 +/- 8.53 nmol/10(9) red blood cells, respectively) but significantly less (P less than 0.001) than controls with 89.5 +/- 11.4 nmol/10(9) red blood cells, n = 16. Fluorographs of SDS-polyacrylamide gels showed no glycophorin B in membranes from S-s-U+ and S-s-U- erythrocytes labeled with NaB3H4. Glycophorins were extracted from red cell membranes in chloroform/methanol, labeled with 125I and analyzed by SDS-polyacrylamide gel electrophoresis. Periodic acid Schiff stain and autoradiographs of these gels also showed absence of glycophorin B in both S-s-U+ and S-s-U- cells. These findings suggested that the U antigen is not located on glycophorin B. This hypothesis was tested by determining blood group antigenicity on red cell membranes and on extracted sialoglycoproteins by the hemagglutination inhibition technique. Although U and S/s activities were detected in control red cell membranes, extracted glycoproteins demonstrated S/s activity but no U activity. Together the data indicate that both S-s-U+ and S-s-U- erythrocytes lack glycophorin B and that the U antigen is not located on glycophorin B. This deletion does not seem to affect the structure-function of the red cell.

Biogeochemical environments of streambed-sediment pore waters with and without arsenic enrichment in a sedimentary rock terrain, New Jersey Piedmont, USA.

Release of arsenic (As) from sedimentary rocks has resulted in contamination of groundwater in aquifers of the New Jersey Piedmont Physiographic Province, USA; the contamination also may affect the quality of the region's streamwater to which groundwater discharges. Biogeochemical mechanisms involved in the release process were investigated in the streambeds of Six Mile Run and Pike Run, tributaries to the Millstone River in the Piedmont. At Six Mile Run, streambed pore water and shallow groundwater were low or depleted in oxygen, and contained As at concentrations greater than 20 µg/L. At Pike Run, oxidizing conditions were present in the streambed, and the As concentration in pore water was 2.1 µg/L. The 16S rRNA gene and the As(V) respiratory reductase gene, arrA, were amplified from DNA extracted from streambed pore water at both sites and analyzed, revealing that distinct bacterial communities that corresponded to the redox conditions were present at each site. Anaerobic enrichment cultures were inoculated with pore water from gaining reaches of the streams with acetate and As(V). As(V) was reduced by microbes to As(III) in enrichments with Six Mile Run pore water and groundwater, whereas no reduction occurred in enrichments with Pike Run pore water. Cloning and sequencing of the arrA gene indicated 8 unique operational taxonomic units (OTUs) at Six Mile Run and 11 unique OTUs at Pike Run, which may be representative of the arsenite oxidase gene arxA. Low-oxygen conditions at Six Mile Run have favored microbial As reduction and release, whereas release was inhibited by oxidizing conditions at Pike Run.

Lack of pharmacokinetic interaction between cimetidine and pirenzepine.

The oral administration of pirenzepine (PRZ), an antimuscarinic agent, has a variable effect on gastric acid secretion in patients with duodenal ulcer, and it seems to potentiate cimetidine-induced inhibition of secretion. The possibility of a pharmacokinetic interaction between these drugs was examined in eight patients who received cimetidine and PRZ alone and in combination in a crossover fashion. Cimetidine, 600 mg b.i.d., PRZ, 50 mg b.i.d., or combination therapy were each given for 1 week before the study. Serum samples were serially drawn during each dosing interval for determination of cimetidine and PRZ concentrations by HPLC and RIA, respectively. Cimetidine given alone or with PRZ exhibited diurnal variation, as the peak serum concentration was lower after the nighttime dose than after the morning dose. PRZ showed intersubject variation. However, each drug failed to alter the pharmacokinetic indices of the other. The times to attain the peak serum concentration were not significantly different for cimetidine alone or with PRZ, arguing against an effect of PRZ on gastric motility in the doses we used. The greater and prolonged acid inhibition with the combination of cimetidine and PRZ, therefore, may stem from a synergistic action of both drugs on receptor sites on gastric parietal cells.

The authentic sequence of rotavirus SA11 nonstructural protein NSP4.

Recent studies demonstrate that the rotavirus nonstructural protein NSP4 functions as an enterotoxin and plays an important role in viral pathogenesis. Previous in vitro studies of NSP4 have used a cDNA clone of gene 10 derived from the prototypic rotavirus strain, SA11. We recently compared the sequence of the commonly used NSP4 cDNA with the sequence obtained from several SA11 isolates by direct sequencing of reverse transcription polymerase chain reaction products. One codon difference was identified between the cDNA clone and the SA11 virus isolates, and this resulted in a predicted amino acid substitution at position 47. The cDNA sequence specifies an asparagine at position 47, and the SA11 virus gene 10 encodes a hisitidine. To determine if this amino acid substitution altered the function of NSP4, we analyzed the ability of both NSP4-Asn47 and NSP4-His47 to regulate intracellular calcium levels and exhibit cell cytotoxicity. Our results indicate that the expression of NSP4-His47 from a recombinant baculovirus displays enhanced cytotoxicity and calcium flux.

Dipyridamole preserved platelets and reduced blood loss after cardiopulmonary bypass.

Cardiopulmonary bypass activates and depletes platelets, which may contribute to postoperative bleeding. In addition, activated platelets may be deposited in the coronary vasculature after ischemia and cardioplegia, which may delay recovery of cardiac function and metabolism and may contribute to early bypass graft occlusion. The antiplatelet agent dipyridamole reduces platelet activation and depletion and may decrease postoperative bleeding and transfusion requirements. A prospective randomized trial was conducted in 58 patients undergoing elective coronary bypass operations to compare the effects of oral (19 patients) and intravenous (21 patients) dipyridamole to the results obtained in a control group (18 patients) who received no dipyridamole. Preoperative oral administration of dipyridamole resulted in lower plasma drug concentrations in the early postoperative period than perioperative intravenous administration (p = 0.0001 by analysis of variance). Postoperative arterial platelet counts were highest in the patients receiving intravenous dipyridamole, intermediate in those receiving oral dipyridamole, and lowest in the control group (p = 0.03 by analysis of variance). Postoperative blood loss and blood product transfusions were significantly reduced with both oral and intravenous dipyridamole (p = 0.04 by analysis of variance). Dipyridamole preserved platelets and reduced postoperative bleeding. Intravenous dipyridamole resulted in higher platelet counts than oral dipyridamole and may be required to reduce postoperative bleeding in high-risk patients.

Unusual distribution of chromosome 12 in a testicular germ-cell tumor cell line (833K) and its cisplatin-resistant derivative (64CP9).

The distribution of chromosome 12 in a cisplatin-sensitive testicular germ-cell tumor (TGCT) cell line (833K), and its cisplatin-resistant derivative (64CP9), was studied by fluorescent in situ hybridization (FISH) using DNA alpha satellite and whole chromosome painting probes for chromosome 12. Chromosomes 12 and i(12p) in these cell lines were readily identified. However, chromosome 12-derived chromatin was also observed in acrocentric- and nonacrocentric-derived chromosomes. Several of the chromosome 12 painted regions resembled satellites and were separated from the chromosome by nonstaining stalk-like regions. In each cell line, different chromosomes were involved. In the 833K TGCT cell line these were a der(8), a der(14) with a 12-labeled "satellite" on the q arm and a der(14) with a 12-labeled "satellite" on the p arm. In the 64CP9 TGCT cell line, these were a der(5), a der(17), and a der(8). The der(8) observed in 64CP9 was different from the der(8) seen in 833K. These derived chromosomes were characterized using sequential FISH, Wright staining, and silver staining for nucleolar organizing regions (AgNORs). The non-staining stalk-like regions were AgNOR positive, indicating "ectopic" NORs. Chromosome 22 distribution in these cell lines was also studied. FISH, using a chromosome 22-specific painting probe, identified a small metacentric marker and a der(12)t(12;22) in each cell line. It is not known whether the differences in distribution of chromosome 12-derived chromatin between the two cell lines are related to cisplatin resistance. Our study shows that the distribution of chromosome 12 in the two TGCT cell lines is much more extensive than could be identified in GTG-banded karyotypes. FISH allows characterization of unidentified chromatin and thus is a valuable adjunct to traditional cytogenetic techniques.

Telmisartan plus hydrochlorothiazide versus telmisartan or hydrochlorothiazide monotherapy in patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: Recent surveys reveal continuing deficiencies in the awareness, treatment, and control of hypertension. In many cases, failure to achieve blood pressure targets may be attributable to the use of antihypertensive monotherapy. OBJECTIVES: This study was undertaken to identify combinations of telmisartan, a new oral angiotensin II type 1-receptor antagonist, and hydrochlorothiazide (HCTZ) that might provide greater antihypertensive efficacy than monotherapy with either agent in the treatment of mild to moderate hypertension. It also examined the dose-response surface for the 2 drugs alone and in combination. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study that employed all cells of a 4 x 5 factorial design. After a 4-week, single-blind, placebo run-in period, men and women between 18 and 80 years of age with mild to moderate hypertension (defined as mean supine diastolic blood pressure [DBP] between 95 and 114 mm Hg during the last 2 weeks of the placebo run-in period and systolic blood pressure [SBP] between 114 and 200 mm Hg immediately before randomization) were eligible to enter the 8-week, double-blind, double-dummy treatment period. Study comparisons were between once-daily telmisartan monotherapy (20, 40, 80, or 160 mg), HCTZ monotherapy (6.25, 12.5, or 25 mg), 12 combinations of these telmisartan/HCTZ doses, and placebo. The focus was on 2 combinations: telmisartan 40 mg/HCTZ 12.5 mg and telmisartan 80 mg/HCTZ 12.5 mg. The primary efficacy variable was change in supine trough DBP from baseline to the last evaluable measurement during double-blind treatment. Plasma renin activity and safety parameters, including treatment-emergent adverse events, physical findings, electrocardiograms, and serum electrolyte levels (which are known to increase with HCTZ treatment), were also assessed. RESULTS: Of 1293 patients screened, 818 (63.3%) were enrolled at 47 centers. Of these 818, 749 (91.6%) completed the study. The intent-to-treat population (randomized with > or = 1 postrandomization blood pressure measurement) consisted of 807 patients (98.7%). Telmisartan 80 mg/HCTZ 12.5 mg significantly decreased mean supine trough SBP/DBP by 23.9/14.9 mm Hg, a benefit of 8.5/3.4 mm Hg compared with telmisartan 80 mg and of 17.0/7.6 mm Hg compared with HCTZ 12.5 mg (both comparisons, P < 0.01). Telmisartan 40 mg/HCTZ 12.5 mg significantly reduced mean supine SBP by 18.8 mm Hg, a benefit of 6.6 mm Hg compared with telmisartan 40 mg and 11.9 mm Hg compared with HCTZ 12.5 mg (both, P < 0.01). This same combination significantly reduced mean supine DBP by 12.6 mm Hg, a benefit of 5.3 mm Hg compared with HCTZ 12.5 mg (P < 0.01), but was not significantly different from telmisartan 40 mg. Telmisartan 80 mg/HCTZ 12.5 mg was significantly more effective than telmisartan 40 mg/HCTZ 12.5 mg in reducing mean supine DBP and SBP (both, P < 0.05). The response surface and responder analyses confirmed the additive antihypertensive efficacy of the combination of telmisartan and HCTZ. All regimens were well tolerated. CONCLUSIONS: Once-daily telmisartan 80 mg/HCTZ 12.5 mg was effective and well tolerated when used to reduce SBP and DBP in patients with mild to moderate hypertension. In addition to enhancing efficacy, this combination protected against potassium depletion, a common side effect of thiazide monotherapy.

'Repetitive strain injury': from Australia to the UK.

The UK is now experiencing an epidemic of upper limb pain similar to that which affected Australia in the 1980s. The pain is often non-specific, and does not conform to the pattern of various well-recognized rheumatological entities. The syndrome is known by a number of terms, some of which imply an aetiological link to workplace activities unsubstantiated by hard evidence. The syndrome may well be largely psychosocial, and analogous to the chronic fatigue syndrome. It is currently the cause of many contentious and well-publicized medico-legal cases. Possible factors behind the epidemic will be discussed, and an approach to management suggested.

Mitral stenosis in systemic lupus erythematosus. Successful management by mitral valve replacement.

A female Caucasian with a history of 18 years of systemic lupus erythematosus (SLE) developed symptoms and signs of mitral stenosis, but had no history of rheumatic fever. Investigations confirmed severe stenosis, and the diseased valve was replaced by a pericardial xenograft. Histological examination was compatible with steroid-modified Libman-Sacks endocarditis. She remains well 24 months postoperatively.

Giant cell arteritis precipitated by a diagnostic trial of prednisolone in suspected polymyalgia rheumatica.

A 62-year-old woman developed symptoms of polymyalgia rheumatica (PMR), but without clinical evidence of concomitant giant cell arteritis (GCA). A single blind, placebo-controlled trial of prednisolone confirmed the diagnosis, but in addition unwittingly exposed clinically silent giant cell arteritis.

Combination treatment with telmisartan and hydrochlorothiazide in black patients with mild to moderate hypertension.

BACKGROUND: Hydrochlorothiazide (HCTZ) is commonly used to treat black patients with hypertension. To avoid the metabolic disturbances associated with high-dose HCTZ, blood pressure control may be achieved by combining low doses with another antihypertensive. HYPOTHESIS: The study was undertaken to assess the tolerability and antihypertensive dose-response efficacy of telmisartan and HCTZ and their combination in black patients with mild to moderate hypertension (mean supine blood pressure 140/95-200/114 mmHg). METHODS: Following a 4-week, single-blind, placebo run-in period, 222 black patients were randomized to once-daily treatment with one of 20 different double-blind combinations of telmisartan (0, 20, 40, 80, 160 mg) and HCTZ (0, 6.25, 12.5, 25 mg) for 8 weeks. Blood pressure was measured at baseline and after 2, 4, and 8 weeks. RESULTS: Telmisartan 80 mg/HCTZ 12.5 mg reduced supine trough diastolic blood pressure (DBP)--primary efficacy parameter--by 13.3 mmHg, and supine trough systolic blood pressure (SBP) by 21.5 mmHg. These reductions represented benefits of 13.7/8.7 mmHg over telmisartan 80 mg and 12.3/8.1 mmHg over HCTZ 12.5 mg (p < 0.01). Telmisartan 40 mg/HCTZ 12.5 mg reduced supine trough SBP/DBP by 14.3/10.0 mmHg, amounting to 12.3/3.3 mmHg more than telmisartan 40 mg and 5.1/4.8 mmHg more than HCTZ 12.5 mg. This reached significance for the comparisons with telmisartan 40 mg for SBP and HCTZ 12.5 mg for DBP (p<0.05). A response surface analysis and therapeutic response rates confirmed the additive antihypertensive effects of telmisartan and HCTZ. All treatments were well tolerated, with side-effect profiles comparable with placebo. Adverse events were mainly transient and of mild to moderate severity. CONCLUSIONS: Telmisartan 80 mg combined with HCTZ 12.5 mg is effective and well tolerated in black patients with mild to moderate hypertension, providing greater antihypertensive activity than the corresponding monotherapies.

Cerebellar ataxia in infectious mononucleosis.

The well-recognised neurological complications of infectious mononucleosis include lymphocytic meningitis, encephalomyelitis with convulsions, cranial and peripheral nerve palsies, Guillain-Barré Syndrome and hemiparesis. Cerebellar involvement is very rare, particularly in females and children. We describe a 14-year-old schoolgirl in whom cerebellar dysfunction proved a dominant feature, and who also gave a previous history of neurological presentation with mumps infection.

Current treatment concepts in arthritis.

Some forms of arthritis cause few symptoms and little or no disability, while others cause severe pain, deformity and loss of function, and may even be fatal. Management must vary accordingly between the simple and the complex, the latter necessitating the use of potentially toxic agents. This article highlights some therapeutic approaches and emphasises the factors that influence the decision making process. Some areas of difficulty are discussed, particularly the treatment of dyspepsia in chronic arthritis.

Current thinking on fibromyalgia syndrome.

Fibromyalgia (fibrositis) syndrome (FS) is a common and chronically painful form of non articular rheumatism. A high count of tender points is characteristic, but there are no confirmatory laboratory tests--the diagnosis is clinical. The cause is unknown, although a number of recognised factors are important in the expression of the condition.

Noninvasive echo-Doppler duplex measurements of common femoral artery blood flow variables during supine exercise and post-occlusive reactive hyperemia.

Noninvasive dynamic measurements of common femoral artery blood flow (CFBF) and stroke volume (CFSV) during supine exercise (SE) and staged post-occlusive reactive hyperemia (PORH) in normal subjects using an echo-Doppler duplex scanner (DS) would provide baseline hemodynamic data in the study of the peripheral circulation in resting, stressed, and diseased conditions. Heart rate (HR), CFBF, and CFSV were determined at rest (R), after 5 minutes of SE on an ergometer (30 rpm) at 30, 60, 90-watt loads and after a 3-minute recovery. The same variables were also calculated after periods of 2-, 5-, and 10-minute thigh occlusions (greater than 240 mm Hg cuff pressure). Measurements of spatial average blood velocities and lumen diameters were used to calculate CFBF. Ankle pressure (AP) and brachial pressure (BP) were determined, and the ratio of systolic AP to systolic BP, the ankle index (AI), was calculated. As in vitro validation of the DS method was accomplished using a hydraulic model of CFBF (r = 0.98). Mean values for maximal CFBF following SE and PORH were 0.81 and 1.53 l/min, respectively. With SE, increases in CFBF and CFSV and decreases in AI were significantly (p less than .05) only at 60- and 90-watt loads. Increases in CFBF and CFSV and decreases in AP and AI were significantly different (p less than .05) from rest for the three occlusion durations and show a linear trend. This study suggests that the DS method can noninvasively and quantitatively measure CFBF and CFSV at rest following SE and during PORH.

The efficacy and selectivity of pirenzepine. Review and commentary.

Pirenzepine is a new anticholinergic agent which selectively binds to gastric mucosal muscarinic receptors. We reviewed the double-blind, therapeutic studies on ulcer patients and the clinical pharmacology for evidence of healing and selectivity. Healing rates of ulcer at doses of 100-150 mg/day varied between 54-84% in trials with 718 duodenal ulcer patients and 630 patients with gastric ulcer. Total side effects incidence in these trials was 18.1%. At 150 mg/day, there was 13.5% incidence of dry mouth, 6.3% incidence of visual disturbance and 2.6% incidence of constipation. In clinical pharmacology trials, pirenzepine moderately inhibited gastric secretion with a slight inhibition of salivary secretion and esophageal motility at 100 mg/day. Higher doses produced the expected parasympatholytic profile, except for the absence of cardioacceleration. We conclude that pirenzepine in low doses, compared to classical antimuscarinic drugs, is relatively selective for gastric hyposecretion. It may be associated with a lower frequency of side effects in therapeutic trials at doses of 100-150 mg/day. Dry mouth and visual disturbance are the most common side effects. Selectivity is dose limited and has so far been demonstrated only at a daily dosage of 100 mg, in 2 divided doses.

Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial.

BACKGROUND: Dabigatran etexilate (DE) is an orally absorbed prodrug of dabigatran, a thrombin inhibitor that exerts potent anticoagulant and antithrombotic activity. OBJECTIVES: To characterize the pharmacokinetics of dabigatran in patients with non-valvular atrial fibrillation (AF) from the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial and to quantify the effect of selected factors on pharmacokinetic (PK) model parameters. PATIENTS AND METHODS: A total of 27 706 dabigatran plasma concentrations from 9522 patients who received DE 110 or 150 mg twice daily were analyzed with non-linear mixed-effects modeling. RESULTS: The pharmacokinetics of dabigatran were best described by a two-compartment disposition model with first-order absorption. The covariates creatinine clearance (CRCL), age, sex, heart failure and the ethnic subgroup 'South Asian' exhibited statistically significant effects on apparent clearance of dabigatran. Body weight and hemoglobin significantly influenced the apparent volume of distribution of the central compartment. Concomitant medication with proton-pump inhibitors, amiodarone and verapamil significantly affected the bioavailability. However, all of the statistically significant factors that were identified, except for renal function status, showed only small to moderate effects (< 26% change in exposure at steady state). On the basis of simulations from the final population PK model, a dose of 75 mg twice daily would result in similar exposure for severely renally impaired patients with CRCL of 15-30 mL min(-1) and patients with normal renal function receiving 150 mg twice daily. CONCLUSIONS: The analysis provides a thorough PK characterization of dabigatran in the AF patient population from RE-LY. None of the covariates investigated, with the exception of renal function, warrants dose adjustment.

The differential diagnosis of generalized pain.

Patients whose symptoms include widespread, diffuse musculoskeletal pain are commonly referred for rheumatological evaluation, even when the underlying cause may lie out with the remit of rheumatology. A diagnosis of fibromyalgia may seem highly probable even from the referral letter, or after a few leading questions during the consultation. However, the lack of specificity of the many symptoms associated with widespread pain means that other diagnoses have to be considered. The history and examination must bear in mind alternative and concomitant musculoskeletal disorders, such as mild systemic lupus erythematosus, polyarticular osteoarthritis, rheumatoid arthritis, polymyalgia rheumatica, hypermobility syndromes and even osteomalacia. Non-rheumatological diseases may also have symptomatic similarities to fibromyalgia, including neoplastic and neurological diseases, hypothyroidism and other endocrine disorders, chronic infections, as well as a variety of psychiatric conditions. A rational approach to investigation will usually allow other diagnostic possibilities to be excluded without reinforcing the abnormal illness behaviour so common in chronic pain states.

Role of apparent membrane growth initiation sites during photosynthetic membrane development in synchronously dividing Rhodopseudomonas sphaeroides.

Sites of intracytoplasmic membrane growth and temporal relations in the assembly of photosynthetic units were examined in synchronously dividing Rhodopseudomonas sphaeroides cells. After rate-zone sedimentation of cell-free extracts, apparent sites of initiation of intracytoplasmic membrane growth formed an upper pigmented band that sedimented more slowly than the intracytoplasmic membrane-derived chromatophore fraction. Throughout the cell cycle, the levels of the peripheral B800-850 light-harvesting pigment-protein complex relative to those of the core B875 complex in the upper pigmented fraction were only about half those of chromatophores. Pulse-labeling studies with L-[35S]methionine indicated that the rates of assembly of proteins in the upper pigmented fraction were much higher than those of chromatophores throughout the cell cycle; rates for the reaction center polypeptides were estimated to be approximately 3.5-fold higher than in chromatophores when the two membrane fractions were equalized on a protein basis. In pulse-chase studies, radioactivity of the reaction center and B875 polypeptides increased significantly in chromatophores and decreased in the upper pigmented band during cell division. These data suggest that the B875 reaction center cores of the photosynthetic units are inserted preferentially into sites of membrane growth initiation isolated in the upper pigmented band and that the incomplete photosynthetic units are transferred from their sites of assembly into the intracytoplasmic membrane during cell division. These results suggested further that B800-850 is added directly to the intracytoplasmic membrane throughout the cell cycle.