Cell cycle. The NIMA kinase joins forces with Cdc2

The NIMA and Cdc2 protein kinases cooperate to regulate mitosis in Aspergillus nidulans. NIMA-related pathways have now begun to emerge in higher eukaryotes.     

Plateletapheresis with a next generation blood cell separator

Baeyer-Villiger monooxygenases (BVMOs) are enzymes able to perform highly regio-plus steroselective nucleophilic and electrophilic biooxygenations on various substrates. The resultant chiral products (lactones and sulfoxides) can be valuable for the chemoenzymatic synthesis of a wide range of useful compounds. Recent studies have provided a number of alternative active-site models that attempt to explain the exquisite and unusual selectivity of BVMOs. This article reviews some of the established applications, and considers the merits of the various predictive models.     

Movement sequencing disorders in Parkinson's disease

Ten PD patients and ten age-matched normal controls learned a sequence of 3 or 4 different hand movements to a criterion of 5 consecutive correct trials. They also performed a control sequence of 3 or 4 movements which involved the repetition of the same hand posture. Trials to reach criterion, errors, total response time and its components, response time for each movement and inter-response time were examined. There were no group differences in trials to criterion or errors. Total movement time as well as response and inter-response times were significantly longer for the PD patients, however, but only for sequences involving different hand movements not for the repetitive sequences. The relative timing of the responses was also different with the PD patients spending proportionately more time on each response and the controls spending more time between responses. The implications of these findings for understanding the movement sequencing impairments in PD are discussed.     

Bone marrow and renal injury associated with haloalkene cysteine conjugates in calves

Almost 40 years ago, it was reported that cattle-feed which had been extracted with hot trichloroethylene and then fed to calves produced renal injury and a fatal aplastic anaemia. The toxic factor was subsequently identified as S-(1,2-dichlorovinyl)-L-cysteine (DCVC). These original findings have been confirmed, a single intravenous dose of DCVC at 4 mg/kg, or 0.4 mg/kg intravenously per day administered for 10 days to calves produced aplastic anaemia, and renal injury after a single dose of 4 mg/kg. The toxicity to calves of a number of other haloalkene cysteine conjugates has been examined to ascertain whether, like DCVC, they produce bone marrow and renal injury. Intravenous administration of the N-acetyl cysteine conjugate of DCVC produced renal but not bone marrow injury at a molar equivalent dose to DCVC, indicating that the calf can deacetylate the mercapturic acid and further that sufficient chemical had reached the kidney to be a substrate for the enzyme cysteine conjugate beta-lyase. However, intravenous administration of the alpha-methyl analogue of DCVC, which cannot undergo metabolism via the enzyme cysteine conjugate beta-lyase, was without toxicity at doses about five-fold higher than DCVC. These latter findings provide strong evidence that metabolism of DCVC via the enzyme beta-lyase is necessary for bone marrow and renal injury to occur. The cysteine conjugates of perchloroethylene and hexachloro-1,3-butadiene(HCBD) when given intravenously to calves at molar equivalent doses to DCVC, or above, did not produce either bone marrow or renal injury. In contrast, intravenous administration of the cysteine conjugate of tetrafluoroethylene (TFEC) produced severe renal tubular injury in calves without affecting the bone marrow. In vitro studies with these haloalkene cysteine conjugates showed, like DCVC, that they were good substrates for calf renal cysteine conjugate beta-lyase and toxic to renal cells as judged by their ability to reduce organic anion and cation transport by slices of calf renal cortex and inhibit the renal enzyme glutathione reductase. Calves were also dosed either orally or intravenously with HCBD to assess its toxicity. HCBD at higher molar equivalent doses than DCVC produced mid-zonal necrosis in the liver, renal tubular necrosis but no bone marrow injury in calves. The key findings emerging from these studies are (1) that none of the other cysteine conjugates, at molar equivalent doses to DCVC and above, produce bone marrow injury in calves, (2) TFEC produced only renal injury, suggesting that sufficient of the other conjugates had not reached the kidney for metabolism by beta-lyase to produce cytotoxicity and (3) that HCBD itself is more toxic than its cysteine or mercapturic acid conjugate, suggesting that pharmaco-kinetics and disposition are important factors in determining the toxicity of these conjugates to calves. Further studies are needed to understand the basis for the selective toxicity of DCVC to the bone marrow of calves.     

A new epitope presenting system displays a HIV-1 V3 loop sequence and induces neutralizing antibodies

The principal neutralizing domain, IGPGRAF sequence, from the V3-loop of HIV-1 was inserted in two positions on the surface of the protein that makes up the capside shell of the insect Flock House Virus. The hybrid proteins were expressed in insect cells via recombinant baculoviruses. Three different hybrids were used as immunogens: two with a single copy of the insert in different positions of the carrier protein and a third with two copies of the insert at the same positions as before. All hybrid proteins induced strong and broad specific immune response in guinea pigs against different V3-loop sequences. However, only one of the hybrid proteins was able to induce a strong neutralizing response against MN and IIIB HIV-1 isolates. Our results demonstrate that a very short peptide sequence of HIV-1 can constitute a valuable immunogen able to induce a neutralizing response if presented to the immune system in the context of the FHV capsomer structure.     

The ovarian hyperstimulation syndrome in extracorporeal oocyte fertilization and the transfer of cleavage-stage embryos

Major clinical characteristics of ovarian hyperstimulation syndrome are described and criteria of predicting the course of this disease and measures to prevent it presented. Statistical data on the presence of this syndrome in various forms during various schemes of superovulation stimulation are offered. Optimal schemes for the treatment of the condition are suggested.     

The role of mineralocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation in humans

In rodents, two types of glucocorticoid receptors, the mineralocorticoid (MR; type I) and the glucocorticoid (type II) receptors, have been demonstrated to play a role in hypothalamic-pituitary-adrenal (HPA) axis regulation. Because MR shows a very high affinity for cortisol, it has been suggested that MR plays an important role in restraint of CRH and ACTH secretion during the nadir of the circadian rhythm. Although a number of studies have established the importance of MR in rodents, the functional role of MR in humans has not been determined. These studies evaluated whether spironolactone, an MR antagonist, had a detectable effect on HPA axis regulation in humans, and whether the effect was greatest during the evening, when plasma cortisol concentrations are in the MR range. Compared to the placebo day, after a single dose of spironolactone at either 0800 or 1600 h, there is a significant increase in plasma cortisol, which is preceded by a rise in ACTH and beta-endorphin. A significant effect of spironolactone on cortisol secretion was demonstrated with no differences between the morning and evening. Because the effect of spironolactone on cortisol was short lived, a second experiment was conducted using two doses of spironolactone, again sampling in the morning and evening. After two doses of spironolactone, plasma cortisol levels showed a significant and sustained spironolactone-induced elevation for the entire sampling period. However, neither plasma beta-endorphin nor ACTH was increased compared to levels on the placebo day. These data suggest that MR appear to play a clear role in HPA axis regulation during the time of the circadian peak as well as the trough. Furthermore, MR blockade may affect the sensitivity of the adrenal to ACTH.     

Caudascopic experiences and a new patho-anatomic concept for treatment of sciatica

Osteotomy has been used in treatment of unstable intertrochanteric hip fractures in an attempt to increase the stability of the fracture fragments. We have assessed this stability in a randomised prospective study on 138 patients, all having been fixed by dynamic hip screen, comparing anatomical reduction with medialisation osteotomy. The groups were similar in terms of age, gender and fracture configuration. There was no difference in final results in both groups except that operation time was longer in osteotomy group and the blood loss was more. We found no clear benefit from osteotomy and therefore recommend anatomical reduction and fixation by a sliding hip screw in most cases. Rarely, a fracture configuration which does not allow anatomical reduction may benefit from an osteotomy.