Biomedical subjects
Publications and source records attributed to W Williams.
A simple, achiral monoamine sigma-1 (sigma1) receptor selective ligand (sigma2Ki/sigma1Ki>2000) is described, which could replace the chiral (+)-pentazocine or dextrallorphan as a sigma1 masking agent in sigma2 binding assays.
This cross-sectional study explored age-related differences in the frequency of diagnosis of personality disorder (PD) among 790 veterans admitted to a psychiatric inpatient unit across three age groups: 20-39, 40-59, and 60+. Older adults obtained a lower frequency (55.4%) of PD diagnosis than middle-aged adults (69.0%), who in turn obtained a lower frequency of PD diagnosis than young adults (75.9%). Older adults and middle-aged adults were less likely to receive a diagnosis of Borderline PD than young adults. Older adults were also less likely to receive a diagnosis of Mixed PD than young adults, but received significantly more diagnoses of Narcissistic PD than young adults. Patients diagnosed with PD had higher rates of psychiatric hospitalization than those with no diagnosis of PD. Older adults and middle-aged adults with PD had significantly fewer psychiatric hospitalizations than young adults with PD, whereas there were no age-related differences in the frequency of medical hospitalizations. These findings are consistent with research suggesting an overall softening of PD features with age, particularly those characteristic of the 'dramatic-erratic', Cluster B types.
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A convenient enantioselective synthesis of (1R,5R,9R)- and (1S,5S, 9S)-9-alkyl-2-benzyl-6,7-benzomorphans (2a-c) which starts with naphthaldehyde is described. These compounds were designed to gain additional information on the structure-sigma binding relationship of the 6,7-benzomorphan class of sigma ligands. In contrast to pentazocine and most 6,7-benzomorphans, the (1R,5R,9R)-isomers of 2a-c showed greater affinity for the sigma(1) receptor than the (1S, 5S,9S)-isomers. Despite reversal of enantioselectivity at the sigma(1) sites, moderate affinity and enantioselectivity at the sigma(2) sites [greater affinity for (1R,5R,9R)-isomers than (1S,5S, 9S)-isomers] were maintained. A comparison of the binding affinities of 2a-c to the more conformationally flexible trans-2-alkyl-1-benzaminoethyl-1,2-dihydronaphthalenes (10a-c) suggested that the relatively rigid structure of 2a-c played an important part in their sigma(1) binding properties. These compounds, particularly (1R,5R,9R)-2-benzyl-9-methyl-6,7-benzomorphan [(-)-2a], which has a K(i) value of 0.96 nM, will be useful in further characterization of the sigma(1) receptor.
Pericardial effusion was noted in 43 of 79 patients (54%) with severe primary pulmonary hypertension. Larger effusion was associated with hemodynamic and echocardiographic evidence of right heart failure, impaired exercise tolerance, and a poor 1-year prognosis.
Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded The Kenneth B. Schwartz Center at MGH. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, gives support to caregivers, and encourages the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. Racial discrimination is a pervasive problem with multiple damaging effects. It is naïve to believe that medicine is somehow immune to race-based practices, but there is a growing literature detailing poorer disease-specific outcomes in minority populations for a range of illnesses. A recent study in the New England Journal of Medicine has implicated physician prejudice as a significant contributing factor. The March 1999 Schwartz Center Rounds sought to explore the influence of ethnic bias on the patient-provider interaction and the quality of health care delivery. Using a different format with a current affairs video clip and an interactive panel discussion, participants were encouraged to identify the often subconscious racial prejudices which may undermine their relationships with patients. Staff members were challenged to think creatively about how institutions and individuals might promote "cultural competence" and a more equitable health care environment.
sigma Receptors have been the focus of extensive studies because of their potential functional role in several important physiological and biochemical processes. To further evaluate the properties of sigma receptors, especially sigma-1 and sigma-2 subtypes, we have synthesized a series of N,N'-disubstituted piperazine compounds (1-32). The design of these compounds was based upon the early structure-activity relationship (SAR) studies of the minimum structural requirements of a molecule necessary to elicit sigma receptor binding activity. In the N-(3-phenylpropyl)piperazine series, compounds with the ethylenediamine moiety (8-11, 15-17) showed 6-20-fold higher affinity for sigma-1 and 2-40-fold higher affinity for sigma-2 relative to their corresponding amides (1-7). The (m-nitrophenethyl)piperazine 10 exhibits a subnanomolar affinity for the sigma-1 site, whereas the corresponding o-nitro compound 9 shows the highest affinity for the sigma-2 site (Ki = 4.9 nM). Compounds with a free amino terminus were designed as precursors for use as bioconjugated affinity compounds. Some of these compounds displayed high affinity for sigma-1 and moderate affinity for sigma-2 sites and are currently used for the purification and characterization of the receptor subtypes.
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Twelve male, fasted, anesthetized rhesus monkeys were studied with positron emission tomography (PET) and [11C]alpha-methyl-L-tryptophan (alpha MTP) to determine serotonin synthesis rates as described by Diksic et al. (1991). It was expected that the serotonin synthesis rates determined for the whole brain would be correlated with CSF 5-hydroxyindole-3-acetic acid concentrations, a measure of central serotonin turnover, because both measures were obtained at steady state. However, no significant correlation was found. During data analysis, it was noticed that the calculated serotonin synthesis rates were significantly correlated to free plasma tryptophan (TP) concentrations (r = 0.88, p < .001). From repeat scans conducted in six monkeys, it was determined that day-to-day variability in free plasma TP and the percentage of protein binding (average percent difference was 48 and 37%, respectively) produced most of the variability in the calculated serotonin synthesis rates (50%); repeat K images, obtained from the PET data alone, differed by only 11%. Calculated serotonin synthesis rates reported for [11C]alpha MTP PET studies of humans (Nishizawa et al. 1997) and dogs (Diksic et al. 1991) were also highly correlated to reported differences in plasma free TP concentrations. It seems that the [11C]alpha MTP model for the computation of serotonin synthesis rates is very dependent on plasma free TP concentration and that it may not accurately determine actual serotonin synthesis rates.
Although memory disorders are frequently seen in survivors of brain injuries, remediation of patients with severe memory disorders is still relatively neglected in clinical practice due to pessimism by clinicians regarding the efficacy of such remediation. With respect to memory journal training, a further reason for this neglect is likely the lack of readily accessible protocols that therapists can use to work with these patients. The purpose of the present paper is to describe a new memory journal training protocol that was developed to teach brain injury survivors how to compensate for severe memory impairments by using three strengths of most brain injury survivors: immediate attention, procedural memory, and old learning. A training protocol is described that involves baseline testing and a needs assessment, five levels of training exercises, and discharge probe testing. It is concluded that patients with severely impaired memory abilities can learn the present system when care is taken to individualize journals, conduct proper needs assessments, and provide structured training exercises geared to the strengths of memory impaired persons.
OBJECTIVE: To compare the levels of the 9G4 idiotope (9G4 Id) in systemic lupus erythematosus (SLE) patients with a detailed disease activity index, the British Isles Lupus Assessment Group (BILAG) index, and serological parameters of disease activity by ds DNA antibody levels and serum C3 concentrations. METHODS: In a cross sectional analysis serum samples from 190 patients with SLE were studied and a further 55 serial bleeds from 14 patients. An enzyme linked immunosorbent assay was used to measure the 9G4 Id, and anti dsDNA and antimyeloperoxidase (MPO) antibodies. The C3 levels were measured by laser nephelometer. RESULTS: Seventy six of 190 (40%) of the patients tested had raised 9G4 Id levels. In the cross sectional study 9G4 Id levels were found to correlate with disease activity in the BILAG cardiovascular/respiratory renal, and haematological systems and with global BILAG score (p < 0.01). In the serial bleeds 9G4 Id levels correlated with anti-dsDNA antibody and C3 levels, but not with anti-MPO antibodies. No correlations were found with treatment. In six cases the 9G4 Id levels correlated well with global BILAG scores and dsDNA antibody levels. In four cases the BILAG global and 9G4 Id levels alone correlated well. CONCLUSIONS: Raised levels of the 9G4 Id are present in a substantial proportion of serum samples from patients with lupus, correlate with various aspects of disease activity in SLE. The Id is detectable on anti-dsDNA antibodies, though it must also be present on other immunoglobulins whose specificities remain unknown.
OBJECTIVE: Dysfunction of monoamine uptake mechanisms has been implicated in the pathogenesis of alcohol dependence. The authors explored whether serotonergic dysfunction is associated with anxiety and depression, which increase the risk of relapse in alcoholics. METHOD: The availability of serotonin and dopamine transporters in 22 male alcoholics and 13 healthy male volunteers was measured with the use of [123I] beta-CIT and single photon emission computed tomography, and psychopathological correlates were assessed. RESULTS: A significant reduction (a mean of about 30%) in the availability of brainstem serotonin transporters was found in the alcoholics, which was significantly correlated with lifetime alcohol consumption and with ratings of depression and anxiety during withdrawal. CONCLUSIONS: The findings support the hypothesis of serotonergic dysfunction in alcoholism and in withdrawal-emergent depressive symptoms.
OBJECTIVE: The relationship between hospital utilization and psychometric, demographic, and diagnostic data was examined among veterans with psychiatric problems. METHODS: Data were obtained from the records of 500 psychiatric inpatients admitted to a Veterans Affairs medical center between 1984 and 1987 and followed for four years. All patients completed the Minnesota Multiphasic Personality Inventory, the California Personality Inventory, the Millon Clinical Multiaxial Inventory, and the Psychological Inventory of Personality and Symptoms. Stepwise linear regression analysis was used to predict the number and length of inpatient stays, and Cox and logistic regression analyses predicted rehospitalization. RESULTS: Higher rates of psychiatric hospital utilization were found among patients who were unmarried, who had disabilities connected with their military service, who had lower levels of adaptive functioning, and who were diagnosed as having posttraumatic stress disorder, drug or alcohol use disorder, or passive-aggressive or antisocial personality disorder. Higher utilization was also found among those whom psychometric data characterized as less responsible and more compulsive. The data also predicted the length of subsequent medical hospitalization and identified patients who stayed out of the hospital longer and who were not rehospitalized. CONCLUSIONS: Hospital utilization was found to be a function of psychiatric diagnosis, marital status, and various personality factors. Factors relating to social disadvantage also played a role. Axis I diagnoses, particularly substance use disorders, were as important as, if not more important than, axis II diagnoses in predicting utilization.
The intensity of warfarin therapy for prevention of primary and secondary thromboembolic complications in paediatric patients, is extrapolated from guidelines for adults, which may not be optimal. Therefore, we assessed thrombin regulation ex vivo and in vitro in plasmas from 40 children (1 to 18 years old with a median age of 13 years) and 27 adults receiving warfarin with an international normalized ratio of 2 to 3 (child: 2.5 +/- 0.15; adult: 2.4 +/- 0.14). Ex vivo concentrations of prothrombin fragment 1.2 were significantly lower in children (0.30 +/- 0.03 nM) compared to adults (0.45 +/- 0.04 nM; p <0.01). Thrombin generation in defibrinated plasmas (Arvin) was decreased and delayed for children compared to adults when activated by either activated partial thromboplastin time (child = 32 +/- 1.7, adult = 45 +/- 1.9 microM x s) or prothrombin time (child = 35 +/- 0.7, adult = 46 +/- 1.0 microM x s) reagents (p <0.01 for both). Although plasma concentrations of factors (F) II, FVII, FIX, F X, protein C and protein S were similar, more of the thrombin generated was complexed to alpha2 macroglobulin (alpha2M) at times close to peak thrombin activity (60 s) in plasma from children (general linear analysis of variance; p <0.03). Thus, increased alpha2M levels may enhance thrombin regulation in paediatric compared to adult patients receiving warfarin, suggesting that clinical trials in children, using less intense warfarin treatment, may be required to determine optimum therapy.
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m-Chlorophenylpiperazine (mCPP) is a mixed serotonin agonist/antagonist used extensively in psychiatric research. Alcoholics show blunted neuroendocrine responses to mCPP, and in some settings mCPP can induce craving for alcohol, particularly among early onset alcoholics. We used 2-[18F]-2-deoxy-D-glucose positron emission tomography to examine the effects of intravenously administered mCPP (0.08 mg/kg) on brain glucose utilization in a group of 18 male alcoholics and 12 healthy male control subjects. Differences between two sequential scans (the first followed placebo and the second followed mCPP) were evaluated statistically with a Gaussian random field-based method. Among healthy volunteers mCPP significantly increased brain glucose metabolism in the right medial and posterior orbital gyrus, the cerebellar hemispheres bilaterally, the left nucleus accumbens, the head of the caudate nucleus bilaterally, the anterior and medial-dorsal nuclei of the thalamus bilaterally, the middle frontal gyrus, the left insular cortex, the left middle temporal gyrus, and the posterior cingulate gyrus. Among alcoholic subjects mCPP significantly increased brain glucose metabolism in larger areas of the cerebellum and posterior cingulate than it did in healthy volunteers, but compared with the healthy volunteers, alcoholics showed a smaller area of mCPP-induced activation in the thalamus, almost no activation in the orbital cortices, and no activation at all in the head of the caudate nucleus or the middle frontal gyrus. These results suggest that a serotoninergic challenge activates basal ganglia circuits involving orbital and prefrontal cortices among healthy volunteers but that the response of these circuits is blunted among alcoholics.
OBJECTIVES: The effects of both temporary and permanent dual-chamber pacing (DCP) were evaluated in symptomatic pediatric patients with hypertrophic obstructive cardiomyopathy (HOCM) unresponsive to medications. BACKGROUND: Permanent DCP pacing can reduce left ventricular outflow tract (LVOT) gradient and relieve symptoms in adult patients with HOCM. METHODS: Ten patients (mean [+/-SD] age 11.1 +/- 6 years, range 1 to 17.5) with HOCM and a Doppler LVOT gradient > or = 40 mm Hg were studied. The seven patients showing hemodynamic improvement during temporary pacing at cardiac catheterization underwent surgical implantation of a permanent DCP system. The effects of permanent pacing were evaluated using a questionnaire, Doppler evaluation, treadmill testing and repeat cardiac catheterization. RESULTS: At initial cardiac catheterization, three patients failed to respond to temporary pacing (inadequate pace capture in two; congenital mitral valve abnormality in one). The remaining seven patients (70%, 95% confidence interval 38.0% to 91.7%, mean age 13 +/- years, range 4 to 17.5) showed a significant reduction (p < 0.05) in LVOT gradient, left ventricular systolic pressure and pulmonary capillary wedge pressure. After pacemaker implantation, these seven patients reported a significant reduction in dyspnea on exertion and exercise intolerance. Serial Doppler evaluation showed a significant reduction in LVOT gradient. Follow-up catheterization at 23 +/- 4 months in six patients (one patient declined restudy) showed a persistent decrease in LVOT gradient (53 +/- 13 vs. 16 +/- 11 mm Hg), left ventricular systolic pressure (149 +/- 16 vs. 108 +/- 14 mm Hg) and pulmonary capillary wedge pressure (18 +/- 2 vs. 12 +/- 4 mm Hg) versus preimplantation values. CONCLUSIONS: Permanent DCP is an effective therapy for selected pediatric patients with HOCM. Rapid atrial rates and intrinsic atrioventricular conduction, as well as congenital mitral valve abnormalities, may preclude effective pacing in certain patients.
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