The toxic actions of MPTP and its metabolite MPP+ are not mimicked by analogues of MPTP lacking an N-methyl moiety

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), its metabolite 1-methyl-4-phenylpyridine (MPP+) and three analogues of MPTP, lacking an N-methyl moiety, namely, 4-phenylpiperidine (I), 4-phenyl-1,2,3,6-tetrahydropyridine (II) and 4-phenylpyridine (III), were infused continuously for a period of 4 days into the rat substantia nigra. Within 12 h of commencing the bilateral infusion of MPTP or MPP+, rats showed marked motor deficits with reduction in locomotor activity, loss of ability to move the forelimbs and grip with forepaws and, following MPP+ infusions, similar loss of movement in the hindlimbs associated with the development of limb and body rigidity. These motor deficits were not induced by the 3 analogues of MPTP on infusion into the substantia nigra. After 4 days of infusion, the motor deficits caused by MPTP and, in particular, MPP+, were still marked, and for MPP+ these correlated with marked loss of striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid. 4-Phenyl-1,2,3,6-tetrahydropyridine caused a small loss in striatal DA and DOPAC, but the other analogues failed to modify the striatal content of DA or its metabolites. Small alterations of chemical structures related to MPTP and its metabolite can critically alter ability to induce behavioural and neurochemical changes reflecting toxicity on the nigrostriatal DA system.     

Stimulation electrically and by acetylcholine of the rat hypothalamus in vitro

1. The hypophysiotrophic area of the rat hypothalamus was studied in vitro. The preparation remained viable for at least 3 hr and showed oxygen consumption varying between 68.9-120 mumole/g.hr. The tissue potassium ion content (per unit wet weight) fell to about 50% of the in vivo concentration during this time compared with 15% in the presence of ouabain (10(-4) M). Histological examination of tissue incubated for 3 hr showed variable perineuronal oedema but the nuclei were of normal appearance and none showed the pyknotic changes that would be associated with cell degeneration.2. Corticotrophin releasing hormone (CRH) in the medium pooled from five to twenty hypothalami was assayed in five to twelve rats which were median-eminence lesioned 48 hr earlier. In vitro corticosterone production of quartered adrenals was used as the end point of the assay. Regression lines of the dose-response curves for ACTH, crude CRH and different volumes of medium from electrically stimulated hypothalami were parallel. CRH output was maximal at 75 Hz and 100 muA when the square-wave pulses lasted for 1 msec. No CRH activity was found on stimulation of cerebral cortex or thalamic tissue pieces of equivalent size.3. Hypothalami taken from rats, adrenalectomized 7-14 days previously, released several-fold more CRH into the medium during electrical stimulation than the initial content of the tissue, showing that the tissue was capable of synthesizing CRH in vitro. The hypothalami taken from intact rats released considerably less CRH into the medium than tissue taken from 12 to 14 day adrenalectomized rats. The hyper-secretion of CRH observed in hypothalami taken from adrenalectomized rats was abolished by pre-treatment with 5 mg/100 g s.c. of corticosterone 24 hr before removal of the tissue. It is therefore proposed that the delayed negative feed-back action of corticosterone at the hypothalamic level is by the suppression of CRH synthesis and that the effect of secretion is secondary to the effect on synthesis.4. The presence of Ca(2+) in the medium was essential for the release of CRH.5. CRH secretion increases linearly with doses of acetylcholine from 5.5 x 10(-15)-5.5 x 10(-14) M. Cerebral cortex incubated with acetylcholine showed no CRH activity. The effect of acetylcholine was reduced by atropine (3.5 x 10(-13) M). Median eminence-pituitary stalk fragments (which contain mainly terminal axons of neurones) incubated with acetylcholine showed no CRH stimulation in the doses that activate the release of CRH using the hypophysiotrophic hypothalamus. Acetylcholine may act as a neurotransmitter at the dendritic level in the CRH neurone.     

bcl-2 transgene expression promotes survival and reduces proliferation of CD3-CD4-CD8- T cell progenitors

Proliferative expansion and apoptotic cell death play prominent roles in T cell development. The molecular control of cell cycle progression and apoptosis appear to be inter-connected since the Bcl-2 protein can inhibit apoptosis and slow cell cycle progression in cortical thymocytes and mature T cells, particularly during the transition from the quiescent state into the cell cycle. Here the impact of bcl-2 transgene expression on CD3-CD4-CD8- T cell progenitors was assessed. Bcl-2 enhanced the survival of these progenitors at all of the four major differentiation stages, CD25- CD44+ (pro-T1), CD25 + CD44+ (pro- T2), CD25 + CD44- (pro-T3) and CD25-CD44- (pro-T4). However, it reduced cell cycling and slowed turnover only in the pro-T4 subset. From an analysis of bcl-2 transgenic mice expressing a TCR transgene or bearing a mutation in the scid or rag-1 gene we conclude that Bcl-2 inhibits proliferation only of T cell progenitors that are activated via the pre- TCR, not those stimulated via c-Kit and the IL-7 receptor.      

Peri-operative myocardial injury in patients undergoing surgery for critical limb ischaemia.

INTRODUCTION: Although up to a half of patients undergoing abdominal aortic aneurysm (AAA) repair suffer myocardial injury, as indicated by a rise in cardiac troponin I (cTnI), this is infrequently accompanied by a rise in creatine kinase (CK)-MB fraction or electrocardiogram (ECG) changes. This study compares for the first time peri-operative cTnI, CK-MB and ECG changes in patients undergoing surgery for critical lower limb ischaemia (CLI). METHODS: Twenty-nine patients (20 men, median age 75 [range, 57-95] years) were studied prospectively. cTnI, CK/CK-MB ratio and ECG were performed pre-operatively and on post-operative days 1, 2 and 3. RESULTS: Eleven (38%) patients had an elevated cTnI >0.5 ng/ml. Five (17%) patients had an elevated CK-MB fraction >4% and all of these patients had an elevated cTnI. Eleven (38%) patients had ischaemic changes on ECG including seven of 11 (64%) patients with elevated cTnI and all five patients with elevated CK-MB fraction. There was no relationship between pre-operative cardiac status, antiplatelet use or type of anaesthesia and post-operative cTnI rise. Patients with a cTnI rise were younger (p=0.01), and were more likely to have presented with gangrene (p=0.04) and have a longer operation time (p=0.01) than patients who did not demonstrate a cTnI rise. Four patients developed clinically apparent cardiac complications: cardio-pulmonary arrest (n=1), cardiogenic shock (n=1), acute CCF (n=1) and rapid atrial fibrillation (n=1). Survival at 6 months was 26 of 29 (90%) patients. CONCLUSION: These data demonstrate that over a third of patients operated for CLI sustain peri-operative myocardial injury, many of which are not clinically apparent. Pre-operative medical optimisation may improve prognosis in this group of patients.     

Y染色体或将在进化中消失

美国宾夕法尼亚州立大学的2位科学家在性染色体进化变异机制的研究上取得进展。研究发现,Y染色体比X染色体的演化速率快得多,这将导致Y染色体上的基因急剧丢失,如此,Y染色体将会完全消失,人类的传宗接代将受威胁。     

Does the publication of NICE guidelines for venous thromboembolism chemical prophylaxis influence the prescribing patterns of UK hip and knee surgeons?

IntroductionWe assessed the practice of surgeons regarding venous thromboembolism (VTE) chemical prophylaxis for total hip replacement (THR) and total knee replacement (TKR), before and after issuing of updated National Institute for Health and Care Excellence (NICE) guidance in 2018.MethodsA survey, circulated through the British Hip Society and regional trainee networks/collaboratives, was completed by 306 UK surgeons at 187 units. VTE chemical prophylaxis prescribing patterns for surgeons carrying out primary THR (n=258) and TKR (n=253) in low-risk patients was assessed after publication of 2018 NICE recommendations. Prescribing patterns before and after the NICE publication were subsequently explored.ResultsFollowing the new guidance, 34% (n=87) used low-molecular-weight heparin (LMWH) alone, 33% (n=85) aspirin (commonly preceded by LMWH) and 31% (n=81) direct oral anticoagulants (DOACs: with/without preceding LMWH) for THR. For TKR, 42% (n=105) used aspirin (usually monotherapy), 31% (n=78) LMWH alone and 27% (n=68) DOAC (with/without preceding LMWH). NICE guidance changed the practice of 34% of hip surgeons and 41% of knee surgeons, with significantly increased use of aspirin preceded by LMWH for THR (before=25% vs after=73%; p<0.001), and aspirin for TKR (before=18% vs after=84%; p<0.001). Significantly more regimens were NICE guidance compliant after the 2018 update for THR (before=85.7% vs after=92.6%; p=0.011) and TKR (before=87.0% vs after=98.8%; p<0.001).ConclusionOver one-third of surveyed surgeons changed their VTE chemical prophylaxis in response to 2018 NICE recommendations, with more THR and TKR surgeons now compliant with latest NICE guidance. The major change in practice was an increased use of aspirin for VTE chemical prophylaxis.     

Occurrence of plasmids and antibiotic resistance among Campylobacter jejuni and Campylobacter coli isolated from healthy and diarrheic animals.

Serologically defined strains of Campylobacter jejuni and Campylobacter coli from healthy and diarrheic animals were examined for the occurrence of plasmid DNA in association with the antibiotic susceptibility of the bacterial host and the health status of the animal host. Of all campylobacter organisms surveyed, 53% (116 of 200) contained plasmid DNA. A plasmid occurrence rate of 73.8% was obtained for C. coli from healthy pigs, contrasted by lower plasmid occurrence rates for C. coli from diarrheic pigs (30%) and from all diarrheic animals (21.4%). For C. jejuni, in contrast, only 13.6% of healthy cattle contained plasmid DNA, contrasted by a higher plasmid occurrence rate of 31.2% from diarrheic cattle. A high plasmid occurrence rate of 75.8% was observed for C. jejuni from healthy chickens. Campylobacter plasmids ranged in size from less than or equal to 1 to 86 megadaltons. Antibiotic susceptibility for 52 animal isolates (excluding chickens) indicated that most isolates were susceptible to kanamycin, erythromycin, gentamicin, tetracycline, and compound sulfonamide, whereas few were susceptible to bacitracin (19.2%); approximately half were susceptible to ampicillin (55.8%) and streptomycin (51.9%), and no isolates were susceptible to penicillin G. More isolates containing plasmids were resistant to ampicillin, tetracycline, and gentamicin than were isolates not carrying plasmids, there being a statistically significant difference for tetracycline and gentamicin, which suggested that these two antibiotics were probably plasmid mediated. The antibiotic susceptibility patterns of 21 chicken isolates of C. jejuni, by contrast, were different in that most were susceptible to ampicillin in addition to kanamycin, erythromycin, and gentamicin, whereas few wer susceptible to compound sulfonamide, streptomycin, and tetracycline in addition to penicillin G and bacitracin. A 30- or 39-megadalton plasmid, or both, common to many of the chicken isolates was usually associated with tetracycline resistance.     

Brain graft surgery: a new treatment for Parkinson's disease

Brain graft surgery remains controversial, and the beneficial effects, though promising, are mixed. For those patients who are eligible, it offers new hope for an alternative to early disability and family hardship. Outlined here are the etiology, pathophysiology, and manifestations of Parkinson's disease, plus the surgical procedure and postoperative nursing care.