The Enantiomers of the Valproic Acid Analogue 2-n-Propyl-4-pentynoic Acid (4-yn-VPA): Asymmetric Synthesis and Highly Stereoselective Teratogenicity in Mice

The teratogenic activities of R( +)- and S( – )-2-n-propyl-4-pentynoic acid (R and S-4-yn-VPA), the enantiomers of the highly teratogenic valproic acid (VPA) analogues (±)-4-yn-VPA, were investigated in mice. The enantiomers were prepared via asymmetric synthesis, each in three steps employing the chiral auxiliaries (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and S-4-benzyl-2-oxazolidinone. The determination of the absolute configurations and the optical purities is described. R( + )-4-yn-VPA contained 7%, and S( – )-4-yn-VPA 8%, of the respective antipodes. The aqueous solutions of the sodium salts of R- and S-4-yn-VPA were administered as single i.p. injections during early organogenesis in the mouse (day 8 of gestation) using the induction of exencephaly as the teratological end point. Dose/exencephaly curves indicated that S-4-yn-VPA is 7.5 times more teratogenic than its antipode, 1.9 times more teratogenic than (±)-4-yn-VPA and 3.9 times more teratogenic than the parent drug VPA. In contrast, the neurotoxicity (maternal toxicity) of the 4-yn-VPA enantiomers was found to be independent of the stereo-chemical configuration and lower than achieved after VPA administration. Due to its low neurotoxicity and highly Stereoselective neural tube-inducing activity, S-4-yn-VPA should prove an important tool for the investigation of molecular mechanism of the teratogenic action in this class of compounds; R-4-yn-VPA could act as the negative control in these studies.     

Marrow regeneration after mechanical depletion

The origin of marrow regeneration after mechanical depletion was reinvestigated in mouse chimeras. The results were compatible with the local origin of stem cells from remnants of incompletely removed marrow, but not with their origin from a common precursor of both bone and hemopoietic cell lines. In transplanted femurs depleted by a modified technique of in vivo evacuation of marrow, hemopoietic regeneration failed to occur. The presence of hemopoietic stem cells in the Haversian canals was thus excluded. The demonstration of ample hemopoiesis with minimal bone formation in nondepleted controls in which bone marrow initially became necrotic provided new evidence that osteogenesis was not a prerequisite of hemopoietic regeneration.     

A qualitative analysis of women's short accounts of labour and birth in a Western Australian public tertiary hospital

This paper reports the findings of the postnatal qualitative arm of a larger study, which investigated women's prenatal and postnatal levels of childbirth fear. Women's expectations and experiences of labour and birth in a Western Australian public tertiary hospital were identified following thematic analysis of short written accounts from 141 participants who had given birth in the previous 6 to 14 weeks. Four major categories emerged to describe features and mediating factors in the trajectory of childbirth and the early puerperium. "Anticipating Labour and Birth," "Labour and Birth Depicted," "Mediating Factors and their Consequences," and "Evaluating, Resolving, and Looking Ahead" portray women's comparative reflections on expectations and realities of birth, on mediating influences, and on moving on from their experience. These findings will provide maternity care professionals with insight into the personal and environmental features of the childbirth setting which colours women's recollections. Being aware of what women value during labour and birth will reinforce the need for professionals to provide care using a mindful approach that considers the potential psychological, emotional, and behavioural implications of events.     

Three-generation reproduction study of rats ingesting up to 10% sorbitol in the diet--and a brief review of the toxicological status of sorbitol

Groups of 12 male and 24 female 5-wk-old Charles River CD (SD) BR rats (F0) were fed a sucrose-containing ground cereal-based diet in which 0, 2.5, 5.0 and 10.0% (w/w) sorbitol was included at the expense of sucrose. The rats were first mated after 14 wk on the diet. F1a litters were born 19 wk after the start of the study and F1b litters at wk 30. Groups of 12 male and 24 female F1b rats were first mated when 18 wk old. They gave rise to F2a litters after 3 wk and to F2b litters 10 wk later. Likewise, groups of 12 male and 24 female F2b rats were first mated when 18 wk old, producing F3a and F3b litters 3 wk and 10 wk later, respectively. F0 rats were killed 33 wk after the start of the study, F1a in wk 22, F1b in wk 68, F2a in wk 57, F2b in wk 92 and F3a in wk 96. Apart from slight reductions in food consumption in sorbitol-fed F1b males and in body-weight gain in sorbitol-fed F0, F1b and F2b rats of both sexes, treatment was associated with no clinically observed effects. There were no deaths attributable to treatment and no adverse effects on mating performance or pregnancy rates in the parent animals of any generation. Treatment was associated with no consistent adverse effect on any measure of reproductive performance or behaviour during gestation or lactation. No abnormal pups were observed in any generation. Not unexpectedly, caecal enlargement was consistently observed at necropsy of sorbitol-treated rats of all generations and significant rises in serum calcium were observed in F0 males and females exposed to 10% sorbitol and in F1b males exposed to either 5 or 10% sorbitol. Differences between treated and control F3a rats in respect of T3 and TSH levels were probably spurious as they followed no consistent pattern. Similarly, between-group variations in gonadal weight were considered to have no toxicological significance because they lacked consistency and were not accompanied by any histologically-evident changes. Microscopic examination of lesions from F1a and F2a animals, of gonads from F1b and F2b and of selected tissues from the F3a generation revealed no changes of toxicological significance.(ABSTRACT TRUNCATED AT 400 WORDS)     

First-time anterior shoulder dislocations: should they be arthroscopically stabilised?

The glenohumeral joint is inherently unstable because the large humeral head articulates with the small shadow glenoid fossa. Traumatic anterior dislocation of the shoulder is a relatively common athletic injury, and the high frequency of recurrent instability in young athletes after shoulder dislocation is discouraging to both the patient and the treating physician. Management of primary traumatic shoulder dislocation remains controversial. Traditionally, treatment involves initial immobilisation for 4–6 weeks, followed by functional rehabilitation. However, in view of the high recurrence rates associated with this traditional approach, there has been an escalating interest in determining whether immediate surgical intervention can lower the rate of recurrent shoulder dislocation, improving the patient’s quality of life. This review article aims to provide an overview of the nature and pathogenesis of first-time primary anterior shoulder dislocations, the widely accepted management modalities, and the efficacy of primary surgical intervention in first-time primary anterior shoulder dislocations.     

Developing research priorities for nurses working in the gynaecology setting in Western Australia

Background

Nurses working in clinical settings are instrumental to translating research into practice. The Delphi approach has been used by clinicians worldwide to set research agendas relevant to their clinical work.

R-Modafinil Attenuates Nicotine-Taking and Nicotine-Seeking Behavior in Alcohol-Preferring Rats

(±)-Modafinil (MOD) is used clinically for the treatment of sleep disorders and has been investigated as a potential medication for the treatment of psychostimulant addiction. However, the therapeutic efficacy of (±)-MOD for addiction is inconclusive. Herein we used animal models of self-administration and in vivo microdialysis to study the pharmacological actions of R-modafinil (R-MOD) and S-modafinil (S-MOD) on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions. We found that R-MOD is more potent and effective than S-MOD in attenuating nicotine self-administration in Long–Evans rats. As Long–Evans rats did not show a robust reinstatement response to nicotine, we used alcohol-preferring rats (P-rats) that display much higher reinstatement responses to nicotine than Long–Evans rats. We found that R-MOD significantly inhibited intravenous nicotine self-administration, nicotine-induced reinstatement, and nicotine-associated cue-induced drug-seeking behavior in P-rats. R-MOD alone neither sustained self-administration in P-rats previously self-administering nicotine nor reinstated extinguished nicotine-seeking behavior. The in vivo brain microdialysis assays demonstrated that R-MOD alone produced a slow-onset moderate increase in extracellular DA. Pretreatment with R-MOD dose-dependently blocked nicotine-induced dopamine (DA) release in the nucleus accumbens (NAc) in both naive and nicotine self-administrating rats, suggesting a DA-dependent mechanism underlying mitigation of nicotine''s effects. In conclusion, the present findings support further investigation of R-MOD for treatment of nicotine dependence in humans.     

Flexible bronchoscopic implantation of Accuflex and Strecker stents in malignant bronchial stenoses

Silicone and metal stents are available for the treatment of malignant bronchial stenoses. This project sought to compare the self-expanding nitinol Accuflex stent (Boston Scientific Corp; Watertown, Mass) with the passively expandable tantalum Strecker stent (Boston Scientific Corp; Watertown, Mass), both implanted by flexible bronchoscopy under local anesthesia and sedation. In 51 patients with malignant bronchial stenosis, 14 nitinol and 51 tantalum stents were used and stenoses of 75 to 100% were treated. The intervention was successful in all but one patient, a mean patency of 93% was achieved. In the follow-up period, the probability of survival was significantly lower in patients with total bronchus occlusion than in patients with stenotic alteration (44 vs 109 days; p < 0.05). In 10 patients, lung function analysis after stent implantation revealed a significant increase in PaO2 (65 vs 71 mm Hg; p < 0.01), inspiratory vital capacity (2.5 vs 2.7 L; p < 0.05), and FEV1 (1.8 vs 2.0 L; p < 0.05). Mucus retention was the main (39%) adverse factor in the early phase after stent implantation, whereas tumor penetration became the most frequent problem (67%) in the later phase. Recanalizing interventions were necessary in 18% of the cases in which tumor penetration occurred. Stent distortion occurred in 12 patients with Strecker and in none with Accuflex stents. In comparison to the Strecker stent, the self-expanding Accuflex stent is preferable owing to its excellent flexibility and faster delivery system. Both types of stents could be sufficiently deployed within the lesions and allowed for highly precise positioning. Furthermore, no general anesthesia was required. The fiber-bronchoscopy mode of implantation under sedation is very efficient even for tumor patients with severe impairment of their physical and respiratory condition.