Comparison of fixed concentration and fixed ratio options for dilution susceptibility testing of gram-negative bacilli to ampicillin and ampicillin/sulbactam

Ampicillin combined with sulbactam was tested at both fixed ratio (2:1 and 1:1) and fixed sulbactam concentrations (4 µg/ml, 8 µg/ml and 16 µg/ml) against 2440 consecutively isolated gram-negative bacilli. Sulbactam significantly enhanced the spectrum of ampicillin activity. Overall, at 8 µg/ml ampicillin inhibited 50 % of theEnterobacteriaceae isolates, whereas 69 % to 84 % of the isolates were inhibited by the various sulbactam combinations. The widest spectrum of activity for ampicillin/sulbactam was achieved by testing at a fixed sulbactam concentration of 16 µg/ml, followed by the 1:1 ratio and the fixed 8 µg/ml (84 %, 76 % and 74 % inhibited, respectively). The amount of sulbactam at the susceptible breakpoint concentrations of ampicillin markedly affected the percentage of susceptible strains. Combinations that include 8 µg/ml of sulbactam are suggested for consideration.     

Serum concentration of N-terminal procollagen peptide of collagen type III in schistosomal liver fibrosis

The major cause of mortality in human schistosomiasis is the chronic granulomatous reaction of the liver tissue to Schistosoma mansoni eggs. Liver biopsy still provides the best evaluation of the degree of liver damage. However, liver biopsy does not provide an image of the dynamic process of fibrogenesis. Variations of concentrations of procollagen type III peptide in sera have been proposed to be significant markers of liver fibrosis. Thus, liver function tests in relation to histopathological diagnosis and procollagen type III peptide concentrations were studied in patients with schistosomiasis and revealed a high correlation between the serum procollagen type III peptide and the degree of fibrosis in liver tissue.     

Effect of chronic treatment with NNC 756, a new D-1 receptor antagonist, or raclopride, a D-2 receptor antagonist, in drug-naive Cebus monkeys: dystonia, dyskinesia and D-1/D-2 supersensitivity

When given subcutaneously in gradually increasing doses, up to 1 mg/kg, NNC 756, a dopamine (DA) D-1 antagonist, failed to produce dystonia in eight drug-naive Cebus monkeys. In contrast, raclopride, a DA D-2 antagonist, produced dystonia at low doses (0.010-0.015 mg/kg). Following pre-treatment with raclopride, NNC 756 also induced dystonia at low doses (0.015-0.025 mg/kg), but continued treatment caused tolerance, and increasing doses of NNC 756 could be administered without induction of dystonia. NNC 756 induced a dose-dependent parkinsonism (slow, stiff movements and tremor), and more sedation than raclopride. After treatment for 14 weeks, withdrawal of raclopride (0.01 mg/kg) led to mild oral dyskinesia (tardive dyskinesia), while withdrawal of NNC 756 (1.0 mg/kg) led to a special grooming syndrome, but no dyskinesia. Withdrawal of raclopride as well as NNC 756 led to behavioural D-1 and D-2 dopamine supersensitivity in the form of increased dyskinesia (including grooming after NNC 756) induced by D-1 agonist (SKF 81297) and increased arousal induced by D-2 agonist (quinpirole). These results indicate that D-1 antagonists such as NNC 756 elicit fewer extrapyramidal symptoms (both acute and tardive) than D-2 antagonists such as raclopride, although extremely high doses may cause a special grooming withdrawal syndrome.     

维生素D_3对报告载体荧光素酶表达的作用

目的：　研究１,２５－二羟维生素Ｄ３ 对结肠癌细胞系Ｃａｃｏ－２ 细胞中报告基因表达的作用,并探讨在报告载体ｐＧＬ２ 序列中存在潜在的抑制性维生素Ｄ应答元件（ＶＤＲＥ）的可能性。方法：　采用磷酸钙沉淀法将报告载体转染入Ｃａｃｏ－２ 细胞。Ｃａｃｏ－２细胞经不同浓度１,２５－二羟维生素Ｄ３ 处理后测定细胞裂解液中表达的荧光素酶活性。结果：　应用ｐＧＬ２ 报告载体时,当用ｐＳＧ５－ＶＤＲ表达载体共转染后,１,２５－二羟维生素Ｄ３显著地抑制Ｃａｃｏ－２ 细胞荧光素酶的表达（Ｐ＜ ０．０５）;而未使用该表达载体共转染则无抑制作用（Ｐ＞ ０．０５）。应用ｐＧＬ３ 报告载体时,不同浓度的１,２５－二羟维生素Ｄ３ 对ｐＬＧ３转染后Ｃａｃｏ－２ 细胞表达的荧光素酶活性均无显著抑制作用（Ｐ＞ ０．０５）,该作用不依赖是否存在有ｐＳＧ５－ＶＤＲ表达载体共转染。结论：１,２５－二羟维生素Ｄ３ 对报告载体ＰＧＬ２ 荧光素酶表达具有抑制作用,而对ｐＧＬ３ 则否;类似人类ＰＴＨ基因中的潜在抑制性ＶＤＲＥ存在于报告载体ｐＧＬ２,在ｐＧＬ３ 中该ＶＤＲＥ业已改变。     

New and old antipsychotics versus clozapine in a monkey model: adverse effects and antiamphetamine effects

Rationale: Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the ratio EPS liability/antiamphetamine efficacy [“therapeutic index” (TI)] has fit well with clinical results. Objectives: 1) To find the TIs of one new (quetiapine), three potential [NNC 756 (dopamine (DA) D₁ antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT₂ serotonergic/DA D₁ and D₂ antagonist) and DOD 647 (DA D₁ and D₂ antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to gain more insight as to clozapine’s neuropharmacology. Methods: Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI. Results: Excepting clozapine and DOD 647, all drugs induced dystonia. At 2–4 mg/kg, clozapine caused uncoordinated movements, myoclonic jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD 647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3–5 versus 4 for clozapine and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic doses. Received: 31 October 1997/Final version: 9 November 1998     

Animal models of Parkinson's disease: An empirical comparison with the phenomenology of the disease in man

Summary Animal models are an important aid in experimental medical science because they enable one to study the pathogenetic mechanisms and the therapeutic principles of treating the functional disturbances (symptoms) of human diseases. Once the causative mechanism is understood, animal models are also helpful in the development of therapeutic approaches exploiting this understanding. On the basis of experimental and clinical findings. Parkinson's disease (PD) became the first neurological disease to be treated palliatively by neurotransmitter replacement therapy.The pathological hallmark of PD is a specific degeneration of nigral and other pigmented brainstem nuclei, with a characteristic inclusion, the Lewy body, in remaining nerve cells. There is now a lot of evidence that degeneration of the dopaminergic nigral neurones and the resulting striatal dopamine-deficiency syndrome are responsible for its classic motor symptoms akinesia and bradykinesia. PD is one of many human diseases which do not appear to have spontaneously arisen in animals. The characteristic features of the disease can however be more or less faithfully imitated in animals through the administration of various neurotoxic agents and drugs disturbing the dopaminergic neurotransmission.The cause of chronic nigral cell death in PD and the underlying mechanisms remain elusive. The partial elucidation of the processes underlie the selective action of neurotoxic substances such as 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has however revealed possible molecular mechanisms that give rise to neuronal death. Accordingly, hypotheses concerning the mechanisms of these neurotoxines have been related to the pathogenesis of nigral cell death in PD.The present contribution starts out by describing some of the clinical, pathological and neurochemical phenomena of PD. The currently most important animal models (e.g. the reserpine model, neuroleptic-induced catalepsy, tremor models, experimentally-induced degeneration of nigro-striatal dopaminergic neurons with 6-OHDA, methamphetamine, MPTP, MPP⁺, tetrahydroisoquinolines, -carbolines, and iron) critically reviewed next, and are compared with the characteristic features of the disease in man.     

Systemic liberation of interleukin-1β and interleukin-1 receptor antagonist in the perioperative phase of liver transplantation

We measured systemic serum levels of interleukin-1 receptor antagonist (IL-1ra), interleukin-1 (IL-1), tumor necrosis factor (TNF-), and interleukin-6 (IL-6) during the preoperative, anhepatic, and postreperfusional phases up to the 7th postoperative day in 60 patients undergoing orthotopic liver transplantation (LTx). In contrast to IL-1, IL-1ra, TNF-, and IL-6 showed a significant elevation in relation to the early phase after reperfusion, while TNF- displayed a high grade of scatter. In addition, IL-1ra levels were significantly elevated during the anhepatic phase. Maximum serum levels were found at 15 min after reperfusion, 120 min after reperfusion, and on the 1st postoperative day, respectively. Serum levels decreased considerably at 24 h and 7 days after reperfusion. The comparative monitoring of systemic cytokine and cytokine antagonist levels, in particular the liberation of IL-1ra and IL-6 may provide useful parameters for the development of new liver preservation theories for LTx.     

Ampicillin-sulbactam susceptibility testing criteria

In vitro studies in five different medical centers documented the susceptibility of 2,440 consecutive isolates of theEnterobacteriaceae against ampicillin-sulbactam disks of different potencies. For determination of MICs, both 2:1 or 1:1 ratios were used as long as the concentrations of sulbactam at the breakpoints remained the same, i.e. MIC 16/8.0 µg/ml or 8.0/8.0 µg/ml for the susceptible category. Disks containing 10 µg of ampicillin and 10 µg of sulbactam are still to be preferred with interpretive criteria of 15 mm for susceptible and 11 mm for resistant (MIC 64/32 µg/ml or 32/32 µg/ml). The reliability of the disk test actually diminished when the amount of sulbactam in the disk was increased.