Biomedical subjects
Publications and source records attributed to M Singer.
The chromosomal acetylornithine deacetylase (argE) gene of Myxococcus xanthus was identified via homology to acetylornithine deacetylases from other bacterial species. A mutant carrying a disruption in argE was unable to grow on minimal media lacking supplemental arginine and formed fruiting bodies and spores in response to arginine starvation at high cell density.
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This report represents a committee summary of the current state of knowledge regarding aftereffects and sense of presence in virtual environments (VEs). The work presented in this article, and the proposed research agenda, are the result of a special session that was set up in the framework of the Seventh International Conference on Human Computer Interaction. Recommendations were made by the committee regarding research needs in aftereffects and sense of presence, and, where possible, priorities were suggested. The research needs were structured in terms of the short, medium, and long term and, if followed, should lead toward the effective use of VE technology. The 2 most critical research issues identified were (a) standardization and use of measurement approaches for aftereffects and (b) identification and prioritization of sensorimotor discordances that drive aftereffects. Identification of aftereffects countermeasures (i.e., techniques to assist users in readily transitioning between the real and virtual worlds), reduction of system response latencies, and improvements in tracking technology were also thought to be of critical importance.
This paper reports the findings of a study of congruence between AIDS risk perception and risk behavior in a sample of outreach-recruited out-of-treatment injection and non-injection crack cocaine using women in Hartford, CT. While rates of drug- and sex-related AIDS risk were high in this sample, perception of risk was low among many of the respondents. Variation in risk perception reflects sociodemographic differences in the sample, with those women who were most socially isolated exhibiting the greatest incongruence between personal risk and risk perception. Women who have had contact with health or social service programs were the most likely to report reductions in risk behavior.
Drug addicted women whose economic and social base is urban streets face limited options for income generation and multiple dangers of predation, assault, arrest, and illness. Exchanging sex for money or drugs offers one important source of income in this context. Yet the legal, social, and safety risks associated with these exchanges reduce the likelihood of regular safer sex practices during these encounters, thereby increasing the risk of HIV infection. Such conditions lead women engaged in sexual exchanges for money to varied and complex responses influenced by multiple and often contradictory pressures, both personal and contextual. Street-recruited women drug users in an AIDS prevention program in Hart-ford, Connecticut reported a range of condom use when engaging in sex for money exchanges. This paper explores their differences by ethnicity, economic resources, and drug use, and analyzes these and other factors that impact on street risks through sexual income generation. Surveys and in-depth interviews with drug-addicted women sex workers describe their various approaches to addressing multiple risks on the streets and suggest significant effort by women in these contexts to avoid the many risks, including HIV infection.
OBJECTIVE: This study prospectively assesses the medical costs of Parkinson's disease (PD). DESIGN: Over a period of 3 months (from July to September 1995), patients with PD documented all items of healthcare provision. These data were then used to calculate medical costs for an individual patient as well as the costs of PD. PATIENTS AND SETTING: We included 20 outpatients with idiopathic PD from the neurological outpatient clinic, Klinikum Grosshadern, Munich, and 20 patients from two office-based neurologists in South-West Germany. MAIN RESULTS: The mean 3-month medical cost of PD in 1995 deutschmarks (DM) was 5210 ($US3390, 2240 Pounds) consisting of DM1410 ($US920, 610 Pounds) for care and nursing, DM1580 ($US1030, 680 Pounds) for drug therapy, DM1320 ($US860, 570 Pounds) for inpatient hospital care, DM40 ($US26, 17 Pounds) for outpatient care and DM860 for other expenses ($US560, 370 Pounds). The expenditure was related to the disease evolution. Patients complaining of one-sided symptoms [Hoehn and Yahr stage I; (HY I)] were less expensive to treat (DM1930, $US1250, 830 Pounds) than patients who were severely incapacitated (HY V) [DM9740, $US6330, 4200 Pounds; HY V]. After 3 to 5 years of levodopa treatment approximately 50% of patients start to experience fluctuations in motor ability and dyskinesias [Unified Parkinson's disease rating scale, part IV (UPDRS IV)]. This onset of motor complications parallels an increase in costs. For patients who experienced motor fluctuations, annual costs were DM6550 ($US4260, 2820 Pounds) compared with DM3030 ($US1960, 1300 Pounds) for patients lacking this problem. Indirect non-medical costs were not calculated due to the limited number of patients. The impact of the disease on work, however, is clearly apparent from the patients' history: 19 out of 34 patients who had already stopped working attributed this to the disease, and only 6 patients were still working at the time of the survey. CONCLUSION: PD poses a major financial impact to society which is expected to increase in future years as the age distribution shifts to older age groups. On the basis of a prevalence of PD of 183 per 100,000, we calculated an annual expenditure of DM3.0 billion for the direct medical costs of PD in Germany.
In late 1990 the National Institute on Drug Abuse (NIDA) initiated the Cooperative Agreement (CA) for AIDS Community-Based Outreach/Intervention Research Program. The goal of this program was to prevent the further spread of HIV among out-of-treatment drug users, in particular injection drug users (IDUs) and crack cocaine users, their sexual partners, and those at risk for initiating injection behavior. To accomplish this goal, the CA set out to monitor drug use and HIV risk behaviors, assess the efficacy of various HIV risk reduction interventions, and develop and refine outreach and intervention strategies. Twenty-three research sites, 21 rural and urban sites in the United States and one each in Puerto Rico and Brazil, were included in the CA program. This article presents an overview of the CA as well as a synopsis of the studies covered in this special issue examining the total CA database.
This article analyzes data on drug injection frequency in a sample of more than 13,000 out-of-treatment drug injectors interviewed across 21 U.S. cities and Puerto Rico through the National Institute on Drug Abuse (NIDA) Cooperative Agreement for AIDS Community-Based Outreach/Intervention Research Program. The goals of the article are to present findings on injection frequency and to predict variation in terms of a set of variables suggested by previous research, including location, ethnicity, gender, age, educational attainment, years since first use of alcohol and marijuana, income, living arrangement, homelessness, drugs injected, and duration of injection across drugs. Three models were tested. Significant intersite differences were identified in injection frequency, although most of the other predictor variables we tested accounted for little of the variance. Ethnicity and drugs injected, however, were found to be significant. Taken together, location, ethnicity, and type of drug injected provide a configuration that differentiated and (for the variables available for the analysis) best predicted injection frequency. The public health implications of these findings are presented.
OBJECTIVE: To break the link between drug use and the human immunodeficiency virus (HIV), in 1992 the state of Connecticut rescinded a 14-year ban on pharmacy sales of syringes without a physician's prescription. In 1993, the Center for Disease Control and Prevention (CDC) evaluated the impact of the new legislation on access to syringes among injecting drug users (IDUs) and found an initial pattern of expanded access. However, it also found that some pharmacies, after negative experiences with IDU customers, reverted to requiring a prescription. This chapter reports findings from a four-year follow-up study of current IDU access to over-the-counter (OTC) pharmacy syringes in Hartford, Connecticut. METHODS: Through structured interviews, brief telephone interviews, and mailed surveys, data on nonprescription syringe sale practices were collected on 27 pharmacies, including 18 of the 21 pharmacies in Hartford and none from pharmacies in contiguous towns, during June and July 1997. Interview data on pharmacy syringe purchase from two sample of IDUs, a group of out-of-treatment injectors recruited through street outreach, and a sample of users of the Hartford Needle Exchange Program, also are reported. RESULTS: The study found that, while market trends as well as negative experiences have further limited pharmacy availability of nonprescription syringes, pharmacies remain an important source of sterile syringes for IDUs. However, the distribution of access in not even; in some areas of the city it is much easier to purchase nonprescription syringes than in other. All of the seven pharmacies located on the north end of Hartford reported that they had a policy of selling OTC syringes, whereas only six (54.5%) of the II pharmacies located on the south end have such a policy. Overt racial discrimination was not found to be a barrier to OTC access to syringes. CONCLUSIONS: To further decrease acquired immunodeficiency syndrome (AIDS) risk among IDUs, there is a need for public education to counter empirically unsupported stereotypes about IDUs that diminish their access to health care and AIDS prevention resources and services. In states or cities where pharmacy sale of nonprescription syringes is illegal, policy makers should examine the benefits of removing existing barriers to sterile syringe acquisition. In cases in which pharmacy sale of nonprescription syringes is legal, local health departments should implement educational programs to inform pharmacy staff and management about the critically important role low-cost (or cost-free), sterile syringe access can play in HIV prevention.
A competitive RT-PCR method that permits reliable quantification of minute amounts of reverse-transcribed mouse lymph node mRNA is described. Using this technique, an absolute number of cDNA copies ranging from 10(3) to 10(5) can be determined, with a precision superior to 25%. The standard templates described in the present study permit the quantitation of beta-actin, IFN gamma, IL2, IL3, IL4, IL10, IL12 (p40 subunit), TGF beta 1, inducible nitric oxide synthase, ELAM-1, VCAM-1, and ICAM-1 mouse mRNA. The expression of a particular transcript is normalized to an arbitrary number of actin transcripts. The standard templates and wild-type cDNA have nearly identical sequences, but they can be distinguished by unique restriction sites. Known amounts of these standard templates, are co-amplified with serial dilutions of the cDNA derived from the mRNA of interest. Oligonucleotide primer pairs possessing 3' octamers found infrequently in the mouse genome (< or = 0.26 x 10(-6)) are used to amplify sequences, chosen to contain no GC stretches longer than 8 (PCRare software) (Griffais et al., 1991). Samples of each PCR product are digested separately with restriction endonucleases unique either for the wild-type or the standard amplicon. The quantitation of the test product and the standard product is easily carried out following their electrophoresis in an ethidium bromide-stained agarose gel.
OBJECTIVES: To assess whether intraoperative intravascular volume optimisation improves outcome and shortens hospital stay after repair of proximal femoral fracture. DESIGN: Prospective, randomised controlled trial comparing conventional intraoperative fluid management with repeated colloid fluid challenges monitored by oesophageal Doppler ultrasonography to maintain maximal stroke volume throughout the operative period. SETTING: Teaching hospital, London. SUBJECTS: 40 patients undergoing repair of proximal femoral fracture under general anaesthesia. INTERVENTIONS: Patients were randomly assigned to receive either conventional intraoperative fluid management (control patients) or additional repeated colloid fluid challenges with oesophageal Doppler ultrasonography used to maintain maximal stroke volume throughout the operative period (protocol patients). MAIN OUTCOME MEASURES: Time declared medically fit for hospital discharge, duration of hospital stay (in acute bed; in acute plus long stay bed), mortality, perioperative haemodynamic changes. RESULTS: Intraoperative intravascular fluid loading produced significantly greater changes in stroke volume (median 15 ml (95% confidence interval 10 to 21 ml)) and cardiac output (1.2 l/min (0.1 to 2.3 l/min)) than in the conventionally managed group (-5 ml (-10 to 1 ml) and -0.4 l/min (-1.0 to 0.2 l/min)) (P < 0.001 and P < 0.05, respectively). One protocol patient and two control patients died in hospital. In the survivors, postoperative recovery was significantly faster in the protocol patients, with shorter times to being declared medically fit for discharge (median 10 (9 to 15) days v 15 (11 to 40) days, P < 0.05) and a 39% reduction in hospital stay (12 (8 to 13) days v 20 (10 to 61) days, P < 0.05). CONCLUSIONS: Proximal femoral fracture repair constitutes surgery in a high risk population. Intraoperative intravascular volume loading to optimal stroke volume resulted in a more rapid postoperative recovery and a significantly reduced hospital stay.
A sensitive and highly automated high-performance liquid chromatography (HPLC) column-switching method has been developed for the simultaneous determination of the active metabolite III and its prodrug II, both derivatives of the oral platelet inhibitor Ro 48-3657 (I), in plasma and urine of man and dog. Plasma samples were deproteinated with perchloric acid (0.5 M), while urine samples could be processed directly after dilution with phosphate buffer. The prepared samples were injected onto a pre-column of a HPLC column switching system. Polar plasma or urine components were removed by flushing the precolumn with phosphate buffer (0.1 M, pH 3.5). Retained compounds (including II and III) were backflushed onto the analytical column, separated by gradient elution and detected by means of UV detection at 240 nm. The limit of quantification for both compounds was 1 ng/ml (500 microl of plasma) and 25 ng/ml (50 microl of urine) for plasma and urine, respectively. The practicability of the new method was demonstrated by the analysis of about 6000 plasma and 1300 urine samples from various toxicokinetic studies in dogs and phase 1 studies in man.
BACKGROUND: The functional benefits of mandibular reconstruction following a composite resection remain unclear. Although microvascular surgical techniques have dramatically increased the predictability of bone and soft-tissue reconstruction towards presurgical anatomic norms, the specific factors responsible for improved function remain controversial. Objective measures of masticatory function need to be more clearly determined before the predictability and efficacy of reconstructive approaches is established. METHODS: We evaluated objective measures of oral function and patient reports of function in 10 reconstructed mandibulectomy patients, 10 without reconstruction, and 10 controls. Measures of oral function included bite force assessed at the first molar and incisal edge, a measure of tongue and cheek function, and patient reports of food they could eat. RESULTS: Both reconstructed and nonreconstructed patients presented decreased biting force, a more restricted diet, and compromised cheek and tongue function as compared with normals. However, reconstructed patients had significantly better measures of tongue function and ability to eat a varied diet than did nonreconstructed patients. Of the objective measures used to measure masticatory performance, bite force was poorly correlated, whereas measures of tongue function strongly correlated with successful mastication. CONCLUSION: Both reconstructed and nonreconstructed patients presented with a significant functional deficit when compared with normals, with reconstructed patients having better overall function than nonreconstructed patients.
Parkinson's disease (PD) causes significant expense for the national health care system due to its chronic progressive course, the duration of the disease, the high prevalence and the devastating prognosis. In Germany more than DM 320 million are spent for drugs to alleviate parkinsonian symptoms. The aim of this study was to calculate the economic burden of PD by assessing direct medical costs. Forty patients suffering from idiopathic PD were interviewed at an office of neurological specialists and at an outpatient movement disorder clinic about their use of health care resources 3 months prior to the study. The total annual costs reported were DM 14,500, consisting of DM 6500 for drug therapy and DM 8000 for other medical services, including hospital inpatient care (DM 5600), outpatient care (DM 700), medical sundries (DM 1100) and physiotherapy (DM 600). The costs were positively correlated to the extent of the disease (Hoehn and Yahr stage; HY) and the occurrence of motor fluctuations/dyskinesias. We found that both drug-therapy expenses and total medical costs doubled from HYI to HYIV. The rarely employed s.c. therapy with apomorphine additionally increased the costs of drug therapy in HYV. The occurrence of fluctuations/ dyskinesias also increased medical expenses by approximately a factor of two. Indirect burden due to increased days off of work, unemployment and earlier retirement are also significant in Parkinson's disease. This study includes that a treatment which could prevent or retard disease progression as well as a treatment that delays or reduces motor complications would not only ameliorate the situation of patients suffering from PD, but would also lead to significant reductions in cost for the national health care system.
OBJECTIVES: To investigate whether continuous venovenous haemofiltration using polyacrylonitrile filters causes activation of the contact system and intrinsic coagulation pathways and if this, and/or low plasma levels of endogenous anticoagulants, influences filter lifespan. DESIGN: Observational study. SETTING: University Teaching Hospital Intensive Care Unit. PATIENTS: Twelve critically ill patients with acute renal failure receiving continuous venovenous haemofiltration. INTERVENTIONS: Blood samples were taken before starting haemofiltration, at 15 min, 1 h, 3-4 h, 8-12 h, 24 h and at 24-h intervals thereafter until filter blockage occurred. Measurement was made of the contact and intrinsic coagulation system proteins factor XII, activated factor XII and prekallikrein and the protease inhibitors antithrombin III, heparin co-factor II, alpha 2-macroglobulin and C1-esterase inhibitor. Thrombin-antithrombin complex levels were measured to provide evidence of thrombin generation. RESULTS: (i) Factor XII, prekallikrein and contact system inhibitors were subnormal in 10/12 and activated factor XII raised in 11/12 patients at baseline, implying pre-existing contact pathway activation. (ii) No change occurred during haemofiltration in the intrinsic coagulation pathway factor or inhibitor levels. (iii) Clotting of the filter circuit within the first 24 h occurred in 5/12 and was associated with low baseline levels of antithrombin III and heparin co-factor II. Only in these patients did thrombin-antithrombin complex levels rise significantly. CONCLUSIONS: The contact system was not activated further by continuous venovenous haemofiltration using polyacrylonitrile filters in critically ill patients. Premature clotting of the haemofilter circuit was more common in patients with very low levels of antithrombin III and heparin co-factor II; although this was related to thrombin generation, the intrinsic coagulation pathway does not appear to be implicated.
Compound 4k N-[5-(4-fluoro)phenoxythien-2-yl]methanesulfonamide is representative of a new class of potent inhibitors of 5-lipoxygenase (5-LO). These versatile compounds exhibit dose-dependent inhibition of 5-LO with IC50s ranging from 20-100 nM in the rat basophilic leukemia (RBL-1) cell homogenate assay and submicromolar IC50s in both the RBL-1 and human peripheral blood leukocyte (PBL) whole cell assays. Compound 4k also showed significant anti-inflammatory activity in the adjuvant arthritic rat at an oral dose of 3 mg/kg.
Several novel 4-alkyloxy-aminoalkyl indole derivatives 3 were synthesized from 4-benzyloxyindole (1). Alkylation of 1 with 4-(2-chloroethyl)morpholine (NaH/HMPA) formed 2. Deprotection using palladium hydroxide on carbon/hydrogen followed by alkylation with the appropriate alkyl bromide gave the target compounds 3b-3j. In the synthesis of 3i and 3j, the appropriate alkyl bromides 13 and 17 were prepared from the commercially available 1-naphthylethyl bromide 9 using the chain lengthening sequences as shown in Scheme 3. In receptor binding assay and in vivo testing, the long chain alkoxy compounds 3g and 3h (Ki = 127 nM) showed affinity for the CB1 receptor which was approximately 16-35-fold less than that of WIN 55,225. However, the pharmacological profile of 3h mimics that of WIN 55,212. An examination of the SAR of these analogues shows that translocating the napthyl group in AAIs from the C-3 position to C-4 via an oxygen (ether linkage) decreases activity which is in contrast to previous findings that a naphthylcarbonyl at C-4 retains activity. The present work points to the importance of the role of a keto group in the interaction with the receptor. Molecular modeling work suggests that, although reasonable superposition of key structural features between delta 9-THC and AAIs can be made, the overlay is not straightforward. The present study also illustrates the difficulty in accommodating AAIs into the cannabinoid pharmacophore and it seems likely that a unique pharmacophore will need to be developed. Only then will the similarities to and differences from the classical cannabinoid pharmacophore be clearly delineated.
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