Muramyl peptides augment cytotoxic effect of tumor necrosis factor-alpha in combination with cytotoxic drugs on tumor cells

We have demonstrated that biologically active muramyl peptides, in particular, glucosaminylmuramyl dipeptide (GMDP), augmented in vitro cytotoxic activity of tumor necrosis factor-alpha (TNF-alpha) against murine fibrosarcoma L929 cells. The introduction of GMDP resulted in cytotoxic effect characteristic for substantially higher dose of cytokine. Even more potent was the combination of GMDP, TNF-alpha and Actinomycin D (ActD). According to clonogenic and MTT assays 100% L929 cells could be killed in culture with low doses of TNF-alpha and ActD if GMDP was present. When cisplatin was substituted for ActD similar results were obtained. GMDP also enhanced cytotoxicity of TNF-alpha and cisplatin against human breast carcinoma MCF7 and histiocytic lymphoma U937 cells. Normal cells, namely human peripheral blood leucocytes and murine peritoneal macrophages, were resistant to selected doses of TNF-alpha/cisplatin/GMDP.     

Proposal for panayiotopoulos syndrome criteria

Panayiotopoulos syndrome (PS) occurs commonly and is recognized by most authors, but there is hardly a diagnostic criterion for the condition that would not absolutise some clinical or electroencephalographic symptom. The AIM of the present study was to introduce and investigate clinical criteria for Panayiotopoulos syndrome that lack a mandatory symptom. PATIENTS AND METHODS: A group of 34 cases with idiopathic partial epilepsy was selected among 170 children with epilepsy. The children were diagnosed and treated at the Pediatric Neurology Unit at the Department of Pediatrics and Medical Genetics, Medical University, Plovdiv. The following 8 criteria for Panayiotopoulos syndrome were applied to them: infrequent seizures (up to 5), prolonged seizures (> 5 min.), ictal vomiting, ictal eye deviation, ictal autonomic manifestations, ictal behavioural disturbances, gradual suppression of consciousness during seizures; convulsions. RESULTS: The distribution of the 34 cases by number of criteria they met was as follows: a single child met 8 criteria for PS, another child met 7 criteria, 2 children satisfied 6 criteria, 8 children - 5,2 children - 4,2 children - 3, 7 children - 2, 10 children - 1 and one child - 0 PS criteria. Cases with 5 or more positive criteria were recognized as Panayiotopoulos syndrome. One of the two cases satisfying 4 criteria was additionally included in the PS group after consultation. The clinical and electroencephalographic manifestations of the group of children with Panayiotopoulos syndrome did not differ from those of previously reported cases in the literature. CONCLUSION: Panayiotopoulos syndrome can be reliably differentiated from other cases of idiopathic partial epilepsy by the presence of at least 5 of the 8 criteria presented above.     

Left ventricular reconstruction: Early and late results

OBJECTIVES: In patients with coronary disease and poor left ventricular function, ventricular reconstruction with revascularization is a surgical option. Details of patient selection and optimal surgical technique are still debated. This study reports results achieved with ventricular reconstruction in 285 patients who had akinesia or dyskinesia associated with relative wall thinning. METHODS: Data were prospectively collected. Reconstruction on the beating heart was accomplished by a modified linear closure plus septoplasty, when indicated, (dyskinetic septum). Preoperatively, 237 (83%) were in symptom class III or IV with congestive heart failure (n =174; 61%), angina (n = 157; 55%), or ventricular tachycardia (n = 107; 38%). Average ejection fraction was 24% +/- 11%, and 144 (51%) had preoperative grade 2+ mitral regurgitation. Operative procedures included coronary artery bypass grafting in 262 (92%), septoplasty in 64 (22%), ablation of ventricular tachycardia in 118 (41%), and a mitral valve procedure in 6 (2%). RESULTS: Operating room mortality was 2.8%. Perioperative support included intra-aortic balloon pumping in 49 (17%) and inotropic drugs in 154 (54%). During a mean follow-up of 63 +/- 48 months, 8 patients required transplantation (interval of 49 +/- 41 months), 2 needed mitral valve replacement, and 9 required use of an implantable cardioverter-defibrillator for ventricular tachycardia. At 1, 5, and 10 years actuarial survivals were 92%, 82%, and 62%. Freedom from sudden death was 99%, 97%, and 94%. Among survivors, symptom class improved in 140 of 208 patients (67%), mean improvement 1.3 +/- 1.1 functional class per patient. Average increase in ejection fraction postoperatively was 10% +/- 9%. CONCLUSIONS: Using wall thinning as a criterion for patient selection, left ventricular reconstruction can be performed with low operative mortality, provides good control of symptoms, excellent long-term survival, and freedom from sudden death. This approach should be considered in all patients with coronary disease, poor left ventricular function, and relative wall thinning.     

Radiation and epidemiological analysis for solid cancer incidence among nuclear workers who participated in recovery operations following the accident at the Chernobyl NPP

This paper discusses the results of the analysis of the relationship between dose and solid cancer incidence among nuclear workers (males) who worked as liquidators after the Chernobyl accident. Information on this cohort of individuals is available at the regional center of Russian National Medical and Dosimetric Registry operating at the RF State Research Centre-Institute of Biophysics. Medical and dosimetric information on 8,654 persons 18-60 years of age with documented external radiation doses is used for the analysis. These data were gathered in the period from 1996 to 2001 and cover a total of 45,166.5 follow-up person-years. In the cohort under study, 179 solid cancers occurred during this period. The average age of liquidators at the time of exposure was 35.8 years, and the average dose as a result of the Chernobyl exposure was about 0.05 Sv. For an analysis of the dose-effect relationship (induction of radiation-induced malignant neoplasms) the statistical software EPICURE was used. The results of the analysis show that the cancer incidence in this cohort does not exceed cancer incidence in relevant age groups of the Russian population. The mean value of SIR for all cancer diseases was 0.88 (0.76, 1.02, 95% CI) for the whole period of follow-up. Risks for the induction of radiation-related cancer diseases were not statistically meaningful. Excess relative risk per 1 Sv was 0.95 (-1.52, 4.49, 95% CI).     

Febrigenic signaling to the brain does not involve nitric oxide

1. The involvement of peripheral nitric oxide (NO) in febrigenic signaling to the brain has been proposed because peripherally administered NO synthase (NOS) inhibitors attenuate lipopolysaccharide (LPS)-induced fever in rodents. However, how the unstable molecule of NO can reach the brain to trigger fever is unclear. It is also unclear whether NOS inhibitors attenuate fever by blocking febrigenic signaling or, alternatively, by suppressing thermogenesis in brown fat. 2. Male Wistar rats were chronically implanted with jugular catheters; their colonic and tail skin temperatures (T(c) and T(sk)) were monitored. 3. Study 1 was designed to determine whether the relatively stable, physiologically relevant forms of NO, that is, S-nitrosoalbumin (SNA) and S-nitrosoglutathione (SNG), are pyrogenic and whether they enhance LPS fever. At a neutral ambient temperature (T(a)) of 31 degrees C, afebrile or LPS (1 microg kg(-1), i.v.)-treated rats were infused i.v. with SNA (0.34 or 4.1 micromol kg(-1); the controls received NaNO(2) and albumin) or SNG (10 or 60 micromol kg(-1); the controls received glutathione). T(c) of SNA- or SNG-treated rats never exceeded that of the controls. 4. In Study 2, we tested whether the known fever-attenuating effect of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) at a subneutral T(a) (when fever is brought about by thermogenesis) also occurs at a neutral T(a) (when fever is brought about by skin vasoconstriction). At a subneutral T(a) of 24 degrees C, L-NAME (2.5 mg kg(-1), i.v.) attenuated LPS (10 microg kg(-1), i.v.) fever, presumably by inhibiting thermogenesis. At 31 degrees C, L-NAME enhanced LPS fever by augmenting skin vasoconstriction (T(sk) fall). 5. In summary, both SNA and SNG had no pyrogenic effect of their own and failed to enhance LPS fever; peripheral L-NAME attenuated only fever brought about by increased thermogenesis. It is concluded that NO is uninvolved in febrigenic signaling to the brain.     

Uncharged AZT and D4T derivatives of phosphonoformic and phosphonoacetic acids as anti-HIV pronucleosides

Two series of new lipophilic phosphonoformate and phosphonoacetate derivatives of AZT and d4T were synthesized and evaluated as anti-HIV agents. The efficacy of some of the synthesized compounds in cell cultures infected with HIV-1 was higher than that of the parent nucleosides and only slightly correlated to their stability in the phosphate buffer and human blood serum. The synthesized phosphonates are most probably prodrug forms of the corresponding nucleosides.