Immunomodulatory Activity of A Novel Nucleoside, 7-thia-8-oxoguanosine: I. Activation of Natural Killer Cells in Mice

We reported recently that a novel immunomodulator, 7-thia-8-oxoguanosine (7T80G)² inhibited formation of pulmonary melanoma metastases (1), prevented against viral infection in mice (2) and potentiated the efficacy of a weakly immunogenic leukemia vaccine (3). Since certain tumor metastases and virus infected cells are targets to natural killer cells (NK cells), we now investigated whether 7T80G is capable of activating NK cells in mice using NK cell sensitive YAC-1 and B16 and NK cell insensitive P815 targets. CBA/CaJ spleen cells incubated in vitro with 7T80G at concentrations ranging from 0.005 to 0.5 mM responded with increased NK cell activity (32-62 %) compared to controls (4-8%) to YAC-1 targets. Similar levels of augmentation in NK cell activity were observed when 40-168 mg/kg of 7T80G was administered in vivo. In addition to the spleen, 7T80G activated NK cells in the bone marrow (BM), the lungs, the liver, and in peritoneal exudate cells (PE). Although 7T80G elicited activation of NK cells was observed as early as three hours after treatment, the maximal activity was observed after 24 h in the spleen; 12 h in the BM; 48 h in the lungs, and 72 h in PE. Administration of the drug by s.c, i.v., and i.p. routes all induced activition of NK cells in spleen, BM and PE. 7T80G was found to activate NK cells in seven inbred and an outbred mouse strain, suggesting that the induced cytotoxicity against allogeneic and syngeneic tumor cells is not strain specific as well as independent of MHC restriction. C3H/He, CBA/CaJ and BDF/1 displayed higher levels of increased NK cell activity, whereas AKR mice were low responders. Low concentrations of IL-2 (0.25-5 U/ml) that induce little or no NK cell activity, when used in combination with 7T80G, elicited significant enhancement of NK cell cytotoxicity. In contrast, IFN and 7T80G showed no such synergism.     

Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans.

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.     

Alcohol consumption of patients attending two accident and emergency departments in north-west England.

The impact of alcohol use on the workload of two accident & emergency departments in north-west England was assessed by blood alcohol concentration (BAC) measurement, inspection of clinical records and interview of all patients aged 16 and over attending throughout a two-week period. The frequency of intoxication was similar to the previous reported rate in Scotland: 13.2% of all patients had a positive BAC. Inebriated injured patients arrived at all times of the day--varying in frequency from 2.5% of midday attenders to 78% of those presenting after midnight. The incidence of alcohol-related industrial accidents was low, but 60% of all assaulted patients were inebriated, many having sustained head injuries. Of patients attending within 2 hours of an accident at home, 19% also had a positive BAC, but 92% of those with ankle sprains were sober. Patients in lower social classes reported higher rates of alcohol consumption. The popularity of beer in comparison to wines and spirits was inversely related to age and unrelated to social class. Alcohol abuse is commonly associated with injuries sustained at home and with assaults occurring in public places. Prevention campaigns directed at the reduction of these types of incidents should be as concerned with the inebriation of the patient as with the architectural, environmental and legal framework within which the 'accident' occurs.     

The effects of a 0.12% chlorhexidine-digluconate-containing mouthrinse versus a placebo on plaque and gingival inflammation over a 3-month period

Abstract Several previous studies have evaluated the effects of 0.12% chlorhexidine digluconate (ChD) mouthrinses on plaque and gingival inflammation. However, previously, none have been based in general dental practices. The aim of this study was to evaluate the potential to conduct controlled periodontal clinical trials in co-operation with general dental practitioners (gdps). The project took place in 5 general dental practices in the South of England. 121 healthy subjects (24 at 4 sites and 25 at the 5th). aged 18-65 years, mean 35 ± 12) years participated in a double-blind, randomised study during which they received full mouth assessments for plaque and gingival bleeding at baseline, 6 and 12 weeks. 60 subjects were randomly asigned to use the 0.12% ChD mouth wash and 6i the placebo. The assessments were carried out by 5 gpds, who had previously achieved inter-examiner κ scores of 0.78–0.85 (mean 0.81) for the plaque index (PlI), and of 0.73–0.94 (mean 0.87) for a modified gingival index (mGI), and who maintained κ scores of 0.51–0.90 for PII and of 0.73–1.00 for mGI during the 12 months required to complete the study. 98 subjects (48 ChD and 50 placebo) completed the study. Even though the baseline levels of plaque and gingivitis were low, by week 12, mean whole mouth piaque score of the ChD mouthwash users had fallen from 1.33 at baseline to 0.96 and was significantly lower (p < 0.001) than for the placebo users, 1.31 at baseline to 1.13. Whole-mouth gingival bleeding score fell from 0.56 to 0.42 in the ChD mouthwash group but was unchanged (0.54–0.55) in the placebo group. A subsidiary data analysis which considered the effects at sites indicated that within these overall differences, the ChD users experienced almost 2× the reduction from plaque score 2 at baseline at proximal molar sites over a 12-week period (50.6% ChD versus 27.6% placebo). It was concluded that 0.12% ChD mouthwash reduced plaque accumulation fay 28% and gingival inflammation by 25% over a 12–week period, that it is feasible for a group of gdps to maintain high levels of inter–examiner consistency in the use of PlI and mGI, that it is also feasible to carry out such a multicentre study in general dental practice, and that the use of mean mouth scores per subject to analyse the effects of mouthrinses may well mask variations in response throughout the mouth.     

Multiple Cranial Nerve Palsies in a Patient 15 Years after Curative Therapy for a Pituitary Adenoma

Over a 3-year period, a 31-year-old man developed multiple cranial nerve palsies consisting of diplopia, left-sided facial numbness and weakness, and loss of the left corneal reflex. Fifteen years prior to presentation, he had undergone curative therapy for a prolactin-secreting pituitary macroadenoma. The imaging studies were helpful in localizing the disease process, which correlated well with the clinical examination, and for focusing the differential diagnosis.     

Establishing new principles for nutrient reference values (NRVs) for food labeling purposes

Many countries such as The Republic of Korea have established their own nutritional standards, collectively termed Nutrient Reference Values(NRVs), and they vary due to the science which was reviewed, the purposes for which they are developed, and issues related to nutrition and food policy in the country. The current effort by the Codex Alimentarius Committee on Nutrition and Foods for Special Dietary Uses (CNFSDU) to update the NRVs that were established following the Helsinki Consultation in 1988 represents an opportunity to develop a set of reference values reflecting current scientific information to be used or adapted by many countries. This paper will focus on possible approaches to selecting or developing reference values which would serve the intended purpose for nutrition labeling to the greatest extent possible. Within the United States, the Food and Drug Administration (U.S. FDA) is currently reviewing regulations on nutrition labeling to better address current health issues, and is expected to enter into a process in the next few months to begin to explore how best to update nutrient Daily Values (DVs), most of which are still based on the Recommended Dietary Allowances (RDAs) of the Food and Nutrition Board, U.S. National Academy of Sciences, last reviewed and revised in 1968. In this presentation, I review the current purposes in the U.S. for nutrition labeling as identified in the 1938 Food, Drug, and Cosmetic Act as amended, the scientific basis for current nutrition labeling regulations in the United States, and the recommendations made by the recent Committee on Use of Dietary Reference Intakes in Nutrition Labeling of the Institute of Medicine (2003) regarding how to use the DRIs in developing new DVs to be used on the label in the United States and Canada. Based on these reviews, I then provide examples of the issues that arise in comparing one approach to another. Much of the discussion focuses on the appropriate role of nutrient labeling within the Nutrition Facts panel, one of the three major public nutrition education tools in the United States (along with MyPyramid and Dietary Guidelines for Americans).     

Drawing the Boundaries: Exploring gender issues in young children's classifications of work using visual representations

This study examines young children's perceptions of work through a specific example. Reception class children at an inner city school were shown pictures of the same figure washing in four different contexts, ranging from housework to paid employment, in order to examine early classifications and conceptual systems relating to the concept of work and to ascertain whether these were gender related. Individual children varied in the complexity of their ideas, but the majority had not yet began to form hierarchical classifications of work which favour paid employment. There was evidence however that some children were beginning to devalue traditional women's work, suggesting that gender stereotypes are still prevalent amongst this age group, despite efforts by the educational system to counter this.     

Thalamocortical projections activated by phrenic nerve afferents in the cat

This study identified thalamocortical projections activated by respiratory afferents. Cortical evoked potentials were recorded in the right primary somatosensory cortex of the cat following electrical stimulation of the left C5 root of the phrenic nerve. The majority of primary sites were located in the vicinity of the postcruciate dimple, in area 3a near the 3a/3b border, corresponding to the trunk region of the cortical body map. Retrograde fluorescent tracers injected at the sites of primary activation produced labeled cells in the oralis nucleus of the ventroposterior complex [4]. Control injections made in adjacent cortical areas not activated by phrenic stimulation resulted in labeling in the ventroposterior complex which did not overlap that seen with injections of primary activation sites. We conclude that respiratory muscle afferents in the phrenic nerve elicit activity in the trunk region of primary somatosensory cortex via specific thalamocortical projections originating in the oralis portion of the thalamic ventroposterior complex.