Lethal Staphylococcus aureus-induced shock in primates: prevention of death with anti-TNF antibody.

A successful experimental treatment for gram-positive sepsis to our knowledge has not been achieved. The objectives of this study were to develop a nonhuman primate model of lethal gram-positive sepsis employing the micro-organism Staphylococcus aureus and to determine the efficacy of treatment using monoclonal antibody (MAb) to tumor necrosis factor alpha (TNF). The antibody was administered intravenously, 15 mg/kg, 30 minutes after the beginning of a 2-hour infusion of S. aureus, 4 x 10(10) colony forming units/kilogram. The baboons infused with S. aureus demonstrated the release of the cytokines TNF and interleukin-6 (IL-6), but endotoxin was not observed in the plasma at any time. Treatment with antibody to TNF abolished the rise in serum TNF levels and reduced the increased levels of IL-6. Treatment with MAb to TNF prevented multiple organ failure and achieved permanent (> 7 day) survival of all baboons.     

Effect of Food on the Pharmacokinetics of a New Hydroxypropyl-β-Cyclodextrin Formulation of Itraconazole

Study Objective . To compare the pharmacokinetics of a single 100-mg oral dose of itraconazole administered as 10 ml of a 10-mg/ml itraconazole solution in hydroxypropyl-β-cyclodextrin under fasting versus postprandial conditions. Design . Open-label, two-way, randomized, crossover study. Setting . Janssen Research Foundation, Belgium. Patients . Twelve healthy volunteers. Interventions . Blood samples were obtained for pharmacokinetic analyses immediately before dosing and at regular intervals up to 96 hours after each dose. Blood and urine samples were obtained for hematologic, biochemical, and urinary safety analyses at baseline and at the end of the study. Measurements and Main Results . The mean peak plasma concentrations of both itraconazole and its active metabolite hydroxy-itraconazole were significantly higher under fasting conditions than under postprandial conditions. The mean times to peak concentration for both the parent compound and its metabolite were significantly shorter under fasting than under nonfasting conditions. The mean areas under the curve (AUC_0–∞ and AUC_{0–24 hrs}) were also significantly higher under fasting than under postprandial conditions. Conclusions . Our findings suggest that the higher bioavailability of this new formulation of itraconazole may be of benefit in seriously ill patients who are not able to ingest adequate quantities of food. The fact that the solution was also well tolerated and was not associated with clinically significant changes in any laboratory value further underscores the potential utility of this dosing form.     

Single-dose and steady-state pharmacokinetics of sabeluzole in senile dementia of Alzheimer type patients

Summary The single- and repeated-dose pharmacokinetics of sabeluzole have been determined in six elderly patients with [senile] dementia of the Alzheimer type.After a single oral dose of 10 mg sabeluzole, the peak plasma concentration was attained at 1 to 4 h; it averaged 42 ng·ml^–1. On repeated dosing (10 mg b. d.), steady-state was virtually attained after 3 days of treatment. Steadystate mean trough and peak plasma concentrations fluctuated between 53 and 94 ng·ml^–1. The mean terminal half-life after a single dose and at steady-state was of the order of 33 h.Sabeluzole was well tolerated and at the end of treatment, no systematic changes in blood haematology, biochemistry or urinalysis were seen.     

Molecular epidemiology of hepatitis B virus infections in Denmark.

BACKGROUND: Denmark has a low incidence of acute hepatitis B (HBV) infections but the impact of an increasing number of immigrants with chronic HBV infection on HBV transmission is unknown. OBJECTIVES: To characterise individuals with chronic and acute HBV infection in a defined region and to examine the importance of different risk groups for the current HBV transmission. METHODS: During 2000-2001 all consecutive HBV infected individuals routinely diagnosed through the regional HBV serology laboratory in the County of Funen were classified according to ethnicity, presumed route of transmission and stage of infection based on clinical data mainly supplied by the requesting physician. HBV DNA was sequenced and subjected to phylogenetic analysis. RESULTS: Of 309 identified cases, 91 (29%) were classified as acute infection. HBV DNA sequencing was possible in 54 (59%) of these cases. Phylogenetic analysis showed that HBV isolated from injecting drug users (IDUs) was identical or closely related. Among acute cases acquired in Denmark 89% (74/83) were seen in IDUs (65) or in individuals presumably exposed to IDUs (nine) and phylogenetic analysis corroborated the assumption of IDU related transmission in every case with available sequence data. Among 83 ethnic Danes who acquired their HBV infection in Denmark, no new cases of transmission from immigrants were detected. CONCLUSION: Injecting drug use was the single most important factor for hepatitis B transmission in Denmark. The current Danish vaccination strategy is unable to protect IDUs from HBV infection and IDUs pose a greater risk of HBV transmission to the general population than immigrants.     

Predicting protein cellular localization using a domain projection method

We investigate the co-occurrence of domain families in eukaryotic proteins to predict protein cellular localization. Approximately half (300) of SMART domains form a "small-world network", linked by no more than seven degrees of separation. Projection of the domains onto two-dimensional space reveals three clusters that correspond to cellular compartments containing secreted, cytoplasmic, and nuclear proteins. The projection method takes into account the existence of "bridging" domains, that is, instances where two domains might not occur with each other but frequently co-occur with a third domain; in such circumstances the domains are neighbors in the projection. While the majority of domains are specific to a compartment ("locale"), and hence may be used to localize any protein that contains such a domain, a small subset of domains either are present in multiple locales or occur in transmembrane proteins. Comparison with previously annotated proteins shows that SMART domain data used with this approach can predict, with 92% accuracy, the localizations of 23% of eukaryotic proteins. The coverage and accuracy will increase with improvements in domain database coverage. This method is complementary to approaches that use amino-acid composition or identify sorting sequences; these methods may be combined to further enhance prediction accuracy.     

Are subjective health complaints a result of modern civilization?

Subjective health complaints without or with minimal somatic findings (pain, fatigue) are common and frequent reasons for encounter with the general practitioner and for long-term sickness leave and disability. The complaints are often attributed to the stressors of modern life. Is this true? We interviewed 120 Aborigine Mangyans (native population, M age = 33.5 years, 72.5% women) living under primitive conditions in the jungle of Mindoro, an island in the Philippines, and 101 persons living in a small coastal town on the same island (coastal population, M age = 33.8 years, 60.4% women). Both groups had more musculoskeletal complaints, fatigue, mood changes, and gastrointestinal complaints than a representative sample from the Norwegian population (N = 1,243). Our common subjective health complaints, therefore, are not specific for industrialized societies.     

Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome

Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra‐renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one‐day‐old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post‐zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow‐up studies for presumed de novo and low‐level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.     

A combined specific target site binding and pharmacokinetic model to explore the non-linear disposition of draflazine

The capacity-limited high-affinity target site binding of draflazine to the nucleoside transporters located on the erythrocytes is a source of nonlinearity in the pharmacokinetics of the drug. An attractive feature of draflazine is that the specific target site binding characteristics can be determined easily by simultaneously measuring plasma and whole blood concentrations of the drug. Measured drug concentrations following various infusion rates and infusion durations were used to develop a model in which the interrelated blood-plasma distribution, elimination, and specific target site binding of draflazine were incorporated simultaneously. The estimated binding (dissociation) constant Kd was 0.57 ng/ml plasma and the maximal specific erythrocyte binding capacity (BmaxRBC) was 163 ng/ml RBC. The maximal specific binding capacity to the tissues (Bmaxtissue) was estimated to be about 1 mg. The estimated volume of the central compartment (Vplasma + tissue fluids) was 12.9 L and the total intrinsic CL was 645 ml/min. After validation, the model was used to further investigate the impact of the specific high-affinity target site binding of draflazine on its disposition in plasma. The time required to reach steady-state plasma concentrations of draflazine decreased with an increasing infusion rate. Time profiles of the plasma concentrations were not always representative for the time profiles of the specific target site (RBC) occupancy of draflazine, but the t1/2,z in plasma paralleled that of the drug at target sites. The apparent Vd and the t1/2,z decreased with increasing single doses whereas the total CL remained constant. The recovery of draflazine was also dose dependent and increased with increasing doses. Finally, the total CL and apparent Vd of the first dose were greater than those of the second dose of draflazine.