Synthesis and characterization of cyclic pseudopeptide libraries containing thiomethylene and thiomethylene-sulfoxide amide bond surrogates

Resistance-modifying agents (RMAs) such as Verapamil have been proved to be effective in reversing multi-drug resistance (MDR) in many in vitro assays. In this study we have investigated the efficacy of Dex-Verapamil, the R-isomer of Verapamil, as a chemosensitizer in a murine leukemia cell line (P388) and in its resistant counterpart (P388/Dx) expressing a typical MDR phenotype. We have examined in vivo the effect of the co-administration of Dex-Verapamil and Doxorubicin in mice transplanted with P388 or P388/Dx cells. Mice treated with the combination of Doxorubicin plus RMA had a significant increase in survival rate as compared to controls; however, the effect was modest. On the contrary, in vitro Dex-Verapamil can enhance Doxorubicin cytotoxicity in P388/Dx cells with a much greater effect depending on the treatment scheme used, by increasing the intracellular content of drug. Taken together our data indicate that Dex-Verapamil can indeed increase the sensitivity to Doxorubicin in resistant cells, but the limited efficacy shown in vivo demonstrates that this phenomenon is strongly dependent on the treatment scheme used and on the maintenance of constantly elevated serum levels.     

Effect of atherogenic diet on chicken plasma lipids and lipoproteins

Adult male White Leghorn chickens were used in an experimental model system to study atherogenesis, and the effects of an atherogenic diet on plasma lipoprotein composition including carotenoids were determined. This model also included treatment with diazepam, a drug known to reduce formation of atherogenic plaques. After 6 wk consumption of a high-cholesterol, high-triglyceride diet, chickens had mean total plasma cholesterol, triglyceride, and carotenoid concentrations that were significantly increased over those from chicks that consumed the standard diet. Diazepam treatment had no significant effect on whole plasma concentrations of these lipids. Total body weight gain was unaffected by diet, but liver weight expressed as percentage of body weight was significantly increased in chickens that consumed the atherogenic diet. High density lipoprotein (HDL) and low density lipoprotein (LDL) fractions were isolated from plasma samples by ultracentrifugation. The atherogenic diet increased the carotenoid, cholesterol, and protein content of the LDL fractions but not the HDL fractions.     

p53 expression in neurofibroma and malignant peripheral nerve sheath tumor. An immunohistochemical study of sporadic and NF1-associated tumors

OBJECTIVES--(1) to evaluate regional cerebral blood flow (rCBF) with single photon emission computed tomography and 99mTc-hexamethylpropyleneamine oxime in patients with the idiopathic adult hydrocephalus syndrome (IAHS); (2) to examine regional cerebral blood flow (rCBF), gait, and psychometric functions before and after CSF removal (CSF tap test); (3) to assess abnormalities in subcortical white matter by MRI. METHODS--Thirty one patients fulfilling the criteria for IAHS (according to history and clinical and neuroradiological examination) were studied. Quantified gait measurements, psychometric testing, and rCBF before and after removal of CSF were obtained. Pressure of CSF and CSF outflow conductance were investigated with a constant pressure infusion method. Brain MRI was used to quantify the severity of white matter lesions and periventricular hyperintensities. In IAHS a widespread rCBF hypoperfusion pattern was depicted, with a caudal frontal and temporal grey matter and subcortical white matter reduction of rCBF as the dominant feature. Removal of CSF was not accompanied by a concomitant increase in rCBF. Significant white matter lesions were detected only in a minority of patients by MRI. An altered CSF hydrodynamic state with a higher CSF pressure and lower conductance was confirmed. IAHS is characterised by an abnormal CSF hydrodynamic state, associated with a widespread rCBF reduction with preference for subcortical white matter and frontal-temporal cortical regions. Furthermore in most patients MRI did not show white matter changes suggestive of a coexistent subcortical arteriosclerotic encephalopathy. At least in the idiopathic group of patients with AHS, measurements of rCBF before and after temporary relief of the CSF hydrodynamic disturbance will not provide additional information that would be helpful in the preoperative evaluation but is suggestive of a preserved autoregulation of rCBF.     

Infant affect and affect regulation during the still-face paradigm with mothers and fathers: the role of infant characteristics and parental sensitivity

This laboratory study examined mothers' and fathers' sensitivity during face-to-face interactions with their infants as well as infants' affective and regulatory responses during mother-infant versus father-infant still face (SF). The degree to which infant gender and temperament as well as parental sensitivity predicted SF responses was also examined. Participants included 94 healthy, primarily White, middle-class 4-month-olds and their parents. Results indicated that mothers and fathers were equally sensitive toward their infants. Infants' affect and regulatory behaviors were also significantly stable across mother- and father-infant SF situations, although several differences in mean levels of regulation emerged. Finally, the extent to which exogenous and endogenous variables predicted infant SF responses differed as a function of which affect or regulatory variable was being examined and with which parent the infant was experiencing SF.     

Allelotype analysis of uterine leiomyoma: localization of a potential tumor suppressor gene to a 4-cM region of chromosome 7q

The degree and nature of patient involvement in consultations with health professionals influences problem and needs recognition and management, and public accountability. This paper suggests a framework for understanding the scope for patient involvement in such consultations. Patients are defined as co-producers of formal health services, whose potential for involvement in consultations depends on their personal rights, responsibilities and preferences. Patients' rights in consultations are poorly defined and, in the National Health Service (NHS), not legally enforceable. The responsibilities of patients are also undefined. I suggest that these are not to deny, of their own volition, the rights of others, which in consultations necessitate mutuality of involvement through information-exchange and shared decision-making. Preferences should be met insofar as they do not militate against responsibilities and rights.     

Double blind, randomised, placebo controlled study of oral vancomycin in prevention of necrotising enterocolitis in preterm, very low birthweight infants

AIMS: To evaluate the effectiveness of oral vancomycin in the prophylaxis of necrotising enterocolitis in preterm, very low birthweight infants. METHODS: A prospective, double blind, randomised, placebo controlled study in a tertiary referral centre of a university teaching hospital was conducted on 140 very low birthweight infants consecutively admitted to the neonatal unit. The babies were randomly allocated to receive oral vancomycin (15 mg/kg every 8 hours for 7 days) or an equivalent volume of placebo solution. Prophylaxis was started 24 hours before the start of oral feeds. All suspected cases of necrotising enterocolitis were investigated with a full sepsis screen and serial abdominal radiographs. Necrotising enterocolitis was diagnosed and staged according to modified Bell's criteria. RESULTS: Nine of 71 infants receiving oral vancomycin and 19 of 69 infants receiving the placebo solution developed necrotising enterocolitis (p = 0.035). Infants with necrotising enterocolitis were associated with a significant increase in mortality (p = 0.026) and longer duration of hospital stay (p = 0.002). CONCLUSIONS: Prophylactic oral vancomycin conferred protection against necrotising enterocolitis in preterm, very low birthweight infants and was associated with a 50% reduction in the incidence. However, widespread implementation of this preventive measure is not recommended, as it would only be effective in necrotising enterocolitis caused by Gram positive organisms and could increase the danger of the emergence of vancomycin resistant or dependent organisms. Its use should be restricted to a high prevalence nursery for a short and well defined period in a selected group of high risk patients.     

Coordination in prehension. Information-based coupling of reaching and grasping

Research using the balanced placebo design seeks to differentiate the physiological and psychological effects of drinking alcohol. Questions regarding the validity of the design center about experimenter instructions, particularly in the antiplacebo cell at higher blood alcohol content (BAC) levels. This study tested the plausibility of two misattribution strategies designed to reduce the conflict between experimenter instructions and internal cues of drunkenness. Forty-two participants (BAC = .055) were told that they received no alcohol, with internal cues of drunkenness said to be produced by a (sham) second drug, a (placebo) tachistoscopic display, or no misattribution given. The placebo drug group reported less alcohol intoxication without reporting less physical impairment than the control or tachistoscopic groups. Doubt of instructions was expressed more frequently in the control group than in the placebo drug group. Mean time to first reported doubt of experimenter instructions was longer for the placebo drug group. A manipulation check designed to account for demand effects indicated that instituting the pharmacologic misattribution increased the success of the manipulation over the control group. Providing a credible attribution for internal symptoms of drunkenness makes experimenter's instructions more credible, improving the validity of the antiplacebo cell of the balanced placebo design.     

Antipneumococcal activities of levofloxacin and clarithromycin as determined by agar dilution, microdilution, E-test, and disk diffusion methodologies

The activities of levofloxacin and clarithromycin against 199 penicillin- and macrolide-susceptible and -resistant pneumococci were tested by agar and microdilution methods in air and by disk diffusion and E-test methods in air and CO2. For levofloxacin, >/=99. 0% of strains were susceptible at /=17 mm, regardless of incubation in air or CO2. Although zone sizes were smaller and E-test MICs were higher for clarithromycin in CO2 than those in air, category differences were minor, and susceptibility rates for clarithromycin were similar to those obtained by agar and microdilution in air (range, 76.9 to 80.9% by all methods). For clarithromycin, adjustment of breakpoints based upon distribution of results resulted in susceptibility rates which were similar by all methods (75.8 to 76.9% susceptible, 0 to 1.5% intermediate, 22.6 to 23.1% resistant). Minor discrepancies were obtained with levofloxacin for one strain (0.5%) by microdilution and two strains (1.0%) by disk diffusion in CO2. For clarithromycin, minor discrepancies were found in three strains (1.5%) by microdilution, seven strains (3.5%) by agar dilution, four strains (2.0%) by E-test in air, six strains (3.0%) by disk diffusion in air, and five strains (2.5%) by disk diffusion in CO2. Major discrepancies occurred with levofloxacin in one strain (0.5%) by microdilution but were not found with clarithromycin. Very major discrepancies were not seen with levofloxacin, but occurred with clarithromycin in five strains (2.5%) by microdilution, three strains (1.5%) by agar dilution, two strains (1.0%) by E-test in air, eight strains (4.0%) by disk diffusion in air, and one strain (0.5%) by disk diffusion in CO2.     

Logistic regression analysis of twin data: estimation of parameters of the multifactorial liability-threshold model

This study with the rat evaluated the contribution of omega-conotoxin GVIA-(omega-CgTx) and verapamil-sensitive Ca2+ channels in behavioural, antinociceptive and thermoregulatory responses to intracerebroventricular (i.c.v.) injection of [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAMGO), [D-Pen2,D-Pen5]enkephalin (DPDPE) and dynorphin A-(1-17), which are selective agonists for putative mu, delta and kappa-opioid receptors, respectively. The rats treated with omega-CgTx (8-32 pmol i.c.v.) showed transient, dose-dependent shaking behaviour, hyperalgesia and hypothermia which gradually disappeared within 4 h. The behaviour of the rats was normal by 24 h. Histological examination of brain sections showed morphological alterations of neurons in the hippocampus, medial-basal hypothalamus and pyriform cortex. antinociception, catalepsy and thermoregulatory responses elicited by DAMGO (0.4 and 2.0 nmol) were significantly prolonged and potentiated by verapamil (20 pmol i.c.v. 15 min before) or omega-CgTx (8 pmol 24 h before). Antinociception and hypothermia induced by DPDPE were antagonized by verapamil and omega-CgTx, whereas only omega-CgTx prevented the behavioural arousal observed after DPDPE. Similarly, hypothermia induced by dynorphin A-(1-17) (5.0 nmol) and by the kappa-opioid receptor agonist U50,488H (215 nmol) was antagonized by the two Ca2+ channel blockers but only omega-CgTx prevented the barrel rolling and bizarre postures caused by the opioid peptide.