Immune tolerance induction in haemophilia A patients with inhibitors by treatment with recombinant factor VIII: a retrospective non-interventional study.

Immune tolerance induction (ITI) can overcome inhibitory factor VIII (FVIII) antibodies in haemophilia A patients receiving FVIII replacement therapy. The objective was to evaluate the use of sucrose-formulated, full-length recombinant FVIII (rFVIII-FS) for ITI therapy. Patients (<8 years at ITI start) with severe haemophilia A and a peak inhibitor titre >5 Bethesda units (BU) who underwent ITI with any rFVIII-FS dose for ≥ 9 months (or until success) were eligible for this retrospective study. Efficacy analyses included descriptions of ITI treatment regimens and outcomes; ITI success was determined solely at the discretion of the investigator. Safety analyses included assessment of adverse events. Of 51 enrolled patients, 32 [high dose (≥ 85 IU kg(-1) day(-1)), n = 21; low dose, n = 11] were eligible for analysis. ITI was successful in 69% (22/32) of patients (high dose, 66.7%; low dose, 72.7%) after a median of 1.4 years (range, 0.1-3.6 years). Influencing factors for ITI success were start of ITI <1 year after inhibitor detection and an inhibitor titre <10 BU at ITI start. All patients successfully tolerized with ITI continued to receive rFVIII-FS prophylaxis as maintenance therapy, with no inhibitor recurrence from the end of ITI until study enrolment. Use of rFVIII-FS for ITI was effective and well tolerated; success rates were similar to those in published studies.

Effect of depolarizing GABA(A)-mediated membrane responses on excitability of Cajal-Retzius cells in the immature rat neocortex.

In immature neurons activation of ionotropic GABA receptors induces depolarizing membrane responses due to a high intracellular Cl(-) concentration ([Cl(-)](i)). However, it is difficult to draw conclusions about the functional consequences of subthreshold GABAergic depolarizations, since GABAergic membrane shunting and additional effects on voltage-dependent ion channels or action potential threshold must be considered. To systematically investigate factors that determine the GABAergic effect on neuronal excitability we performed whole cell patch-clamp recordings from Cajal-Retzius cells in immature rat neocortex, using [Cl(-)](i) between 10 and 50 mM. The effect of focal GABA application was quantified by measuring various parameters of GABAergic responses including the shift in minimal threshold current (rheobase). The rheobase shift was correlated with other parameters of the GABAergic responses by multiple linear regression analyses with a set of simple mathematical models. Our experiments demonstrate that focal GABA application induces heterogeneous rheobase shifts in Cajal-Retzius cells that could not be predicted reliably from [Cl(-)](i) or the GABAergic membrane depolarization. Implementation of a linear mathematical model, which takes the GABAergic membrane conductance and the difference between action potential threshold and GABA reversal potential into account, resulted in a close correlation between calculated and experimentally obtained rheobase shifts. Addition of a linear term proportional to the GABAergic membrane depolarization improved the accuracy of correlation. The main advantage of using multiple linear regression with simple models is that direction and strength of GABAergic excitability shifts can be analyzed by using only measured parameters of GABAergic responses and with minimal a priori information about cellular parameters.

Postmarketing surveillance study of KOGENATE Bayer with Bio-Set in patients with haemophilia A: evaluation of patients' satisfaction after switch to the new reconstitution system.

KOGENATE Bayer (rFVIII-FS) with Bio-Set is designed to prevent patient contact with exposed needles during recombinant factor VIII reconstitution. This postmarketing surveillance study evaluated patient satisfaction before and after switching to the new Bio-Set reconstitution method. Male children and adults with haemophilia A were enrolled from nine European countries. A preference questionnaire was administered to patients after Bio-Set training and at the end of the observation period (> or =20 exposure days or 3 months). Physician assessments of patient compliance and satisfaction were conducted at the end of the observation period. Patients (N = 306) received a mean +/- SD of 28 +/- 23 infusions of rFVIII-FS with Bio-Set. A majority of patients (82%) preferred the Bio-Set method, with domain scores for ease of use, safety from needlesticks, and speed of reconstitution being highest after training and at the end of the observation period. The Bio-Set method received higher mean scores than previous reconstitution methods for worry/safety and ease/confidence domains at both time points. Physician-reported patient compliance with the Bio-Set method was similar or greater compared with the previous method for 94% of the patients, with physicians reporting that 92% of the patients were satisfied or very satisfied with Bio-Set. Thirteen adverse events (AEs) occurred in nine patients, and five serious AEs occurred in five patients; none was related to rFVIII-FS. No de novo or recurrent inhibitor development was observed during the observation period. rFVIII-FS with Bio-Set was well tolerated and well accepted by haemophilia A patients, which may improve treatment compliance.

Image of nursing profession as viewed by secondary schools students in Ilala District, Dar es Salaam

Objectives: The Broad objective: To assess knowledge and attitudes of secondary school students in Ilala district towards the nursing profession Specific objectives: To determine the awareness of nursing as a profession by secondary school students in Ilala district; explore factors that promote aspiration to enroll in nursing schools and to explore factors that deter aspiration to enroll in nursing schools. Methods: The study was exploratory cross sectional using both qualitative and quantitative methods and was conducted in Azania and Jangwani secondary schools in Ilala district. The sample size included 50 male and 50 female students who were opting for Physics; Chemistry and Biology from form III to form VI in the above mentioned schools. Results: Awareness above 50for males was 79.2(95CI: 66.6; 91.8) while that of females was 76.9(95CI: 65.4; 88.4). Awareness below 50was 31.4(95CI: 8.4; 54.4) for the males while that for females was 31.1(95CI: 11.3; 50.9). Non awareness was mostly about nurses being capable of independent practice; making decisions for themselves; working with high technology; following physician's orders without questioning and feeling good about what they do. Factors that were pointed out included: social; economical; educational and individual perceptions of different students. Although students were aware of nursing; they did not want to opt to join the profession. Conclusion: This study has shown that students are at least aware of the profession but they do not want to opt for it due to the image they have of it from the public. The factors that have been addressed in this research have to be put in consideration if at all we are to increase the nurse patientratio in Tanzania

[Epidemiology, course and prognosis of Staphylococcus aureus bacteremia--Preliminary results from the INSTINCT (INvasive STaphylococcus aureus INfection CohorT) cohort]. / Epidemiologie, Verlauf und Prognose der Staphylococcus-aureus-Bakteriämie--Erste Ergebnisse der INSTINCT-Kohorte.

OBJECTIVE: Staphylococcus aureus is a leading cause of bloodstream infection and S. aureus bacteremia (SAB) is one of the most severe infections acquired in hospital or in the community. The epidemiology and prognosis of this infection in Germany is not fully understood because of the lack of prospective data. METHODS: A prospective, multicenter cohort study (INSTINCT, Invasive Staphylococcus aureus Infection Cohort) was initiated to record and analyse data on patients with SAB through an internet-based documentation. Data are being obtained by specially trained personnel. Clinical variables recorded are comorbidities, risk factors, clinical course, therapy, complications and outcome. Prospectively acquired data from 1 January 2006 to 31 October 2007 are now available from two of the study centers. RESULTS: During this period 263 patients with SAB were identified. 52 % of patients had hospital-acquired infections, 28 % had non-nosocomial but healthcare-associated infections, and 20 % had community-acquired infections. The mean patient age was 61 years, 38 % of patients were female. 62 % of the patients had primary bloodstream infections, while 38 % had a secondary bacteremia, diagnosed on the basis of an underlying organ infection with S. AUREUS. The mean duration of bacteremia was 3.3 days. Average duration of hospitalization was 27 days. The seven-day mortality was 8 % and in-hospital mortality 22 %. CONCLUSIONS: SAB is a common infection in Germany with a serious prognosis.

Kinetic model studies on the chemical ligation of oligonucleotides via hydrazone formation.

We report on the suitability of hydrazone formation for activator-free ligation of oligonucleotides. 5'-Acyl hydrazides were synthesized using a previously described phosphoramidite modifier, whereas 3'-hydrazides resulted from a hydrazinolysis of an ester group serving as a linker to the solid support. Aromatic aldehydes could be directly introduced on the 5'-terminus via the respective phosphoramidates. Aliphatic aldehydes were generated by periodate cleavage of the corresponding 3'- and 5'-modified diol precursors. Ligation of a 3'-hydrazide-modified oligonucleotide with oligonucleotides bearing an aromatic aldehyde in 5'-position showed a fast reaction kinetics (k(1) about 10(-1) M(-1)s(-1)) [corrected] and irreversible hydrazone formation. The ligation of a 5'-hydrazide-modified oligonucleotide and a 3'-ribobisaldehyde appeared to proceed reversibly at the beginning, but became irreversible with increasing reaction time. Hydrazide-modified oligonucleotides were found to be somewhat unstable in aqueous solutions.

Coumarin derivatives as protease-sensitive prodrugs.

To overcome the lack of selectivity of anticancer drugs toward malignant cells, the development of prodrugs, which could be activated selectively by tumour-specific proteases is the goal of these studies. In this work tripartate prodrugs have been evaluated consisting of a carrier unit and a spacer group, which allows for intramolecular cyclisation while releasing the third component, the compound attached to the carboxylic acid moiety of the spacer group. As carrier units amino acids or peptides have been used, which are required for recognition by the protease. As the spacer unit the "trimethyl-lock"-spacer has been applied; as a model leaving group p-anisidine was attached to the carboxylic acid moiety. It was intended to test the compounds for their releasing rate of p-anisidine. Two of the evaluated compounds, 9b and 9h, were degraded with half-lives of 46 min at room temperature. However, the poor solubility in aqueous solutions proved the major disadvantage of the TML-based prodrugs.

beta-Lactam derivatives as enzyme inhibitors: N-substituted derivatives of (S)-4-oxoazetidine-2-carboxylate as inhibitors of elastase and papain.

N-Alkyl and N-acyl substituted 4-oxoazetidine-2-carboxylates are synthesized and evaluated as inhibitors of the proteases porcine pancreatic elastase (PPE) and papain. The compounds are obtained by alkylation or acylation at the nitrogen of benzyl (S)-4-oxoazetidine-2-carboxylate, which is synthesized by a modified literature procedure. The enzymatic assays prove some derivatives to be effective inhibitors of PPE and/or papain. The N-BOC protected amino acid derivatives 10 and 13 inhibit PPE reversibly with KI-values in the micromolar range. On the other hand, papain is inactivated irreversibly by benzyl (S)-2-(benzyloxycarbonyl)azetidin-1-acetate (6).

beta-Lactam derivatives as enzyme inhibitors: 1-peptidyl derivatives of 4-phenylazetidin-2-one as inhibitors of elastase and papain.

N-Peptidyl substituted azetidin-2-ones were synthesized and evaluated as inhibitors of the serine protease elastase, and the cysteine protease papain. All compounds were synthesized from 4-phenylazetidin-2-one, either from the racemate or from the pure enantiomers. The (S)-enantiomer was prepared by enantioselective synthesis from (S)-beta-phenyl-beta-alanine, while the (R)-enantiomer was obtained by enzymatic resolution with alpha-chymotrypsin. N-Alkylation with bromoacetates introduced a spacer group which, after hydrolysis to the free acid, was acylated with amino acid esters or di- or tripeptide esters. The enzymatic assays proved some derivatives to be effective inhibitors of PPE and/or papain. N-BOC protected amino acid derivatives without a spacer group inhibited PPE reversibly, while derivatives with spacer group showed either weak or no inhibitory properties. On the other hand, papain was inactivated irreversibly by ethyl (RS)-2-oxo-4-phenylazetidin-1-acetate. The highest inhibitory activity against papain was found for the diastereomers of N-(2-oxo-4-phenylazetidin-1-acetyl)-L-alanyl-L-valine benzyl ester, a compound with a spacer group.