Biomedical subjects
Publications and source records attributed to F Cohen.
[formula: see text] The first enantioselective total synthesis of a batzelladine alkaloid is described. The central reaction in the synthesis of (-)-batzelladine D (2) is a tethered Biginelli condensation of a guanidine aldehyde and an acetoacetic ester to generate a 7-substituted-1-iminohexahydropyrrolo-[1,2-c]pyrimidine intermediate having the anti stereochemistry of the methine hydrogens flanking the pyrrolidine nitrogen.
BACKGROUND: Results of several studies suggest that psychological stress and negative mood can trigger genital herpes recurrences, but results are inconsistent. OBJECTIVE: To determine whether short-term or persistent psychological stress or specific negative moods are predictive of genital herpes recurrences in women. METHODS: A prospective cohort study followed up participants for 6 months using weekly assessments of stress and mood, monthly assessments of life change events, and diary reports of genital herpes recurrences confirmed by medical examination when feasible. The community sample consisted of 58 women, aged 20 to 44 years, with a 1- to 10-year history of visible genital herpes recurrence and at least 1 recurrence in the previous 6 months. RESULTS: Persistent stress predicted recurrence in the subsequent week (odds ratio, 1.08 per unit increase in stress; 95% confidence interval, 1.01-1.15; P=.03). After adjusting for recurrence in the previous week, the more weekly persistent stress reported, the greater the likelihood of recurrence the following week. Also, an increased recurrence rate occurred after the month during which participants experienced their highest levels of anxiety (P =.03). There were no significant associations between recurrence and short-term stress, life events, depressive mood, anger, or phase of menstrual cycle. CONCLUSIONS: Persistent stressors and highest level of anxiety predicted genital herpes recurrence, whereas transient mood states, short-term stressors, and life change events did not. Women with herpes can be reassured that short-term stressful life experiences and dysphoric mood states do not put them at risk for increased outbreaks of recurrent genital herpes.
This study investigated whether acute and persistent stressors and life change events were followed by changes in immune status, and whether dispositional optimism moderated these relationships. Thirty-nine healthy women ages 18-45 were followed prospectively for 3 months, with weekly assessment of acute and persistent stressors and monthly assessment of life events and immune parameters (NK cell cytotoxicity, and CD4 and CD8 T cell subsets). The study used an autoregressive linear model to examine how weekly appraised acute and persistent stress levels were associated with immune parameters in the subsequent week. Analyses revealed that the immune outcomes were differentially affected by acute and persistent stressors. Further, the association between acute stress and subsequent immune parameters was buffered by an optimistic perspective. However, when stress persisted at high levels, optimists showed more subsequent immune decrements than pessimists.
Currently raloxifene, a selective estrogen receptor modulator, is being investigated as a potential alternative for postmenopausal hormone replacement to prevent osteoporosis and cardiovascular disease. We compared the 2-year effects of raloxifene on a wide range of cardiovascular risk factors with those of placebo and conjugated equine estrogens (CEEs). Analyses were based on 56 hysterectomized but otherwise healthy postmenopausal women aged 54. 8+/-3.5 (mean+/-SD) years who entered this double-blind study and who were randomly assigned to raloxifene hydrochloride 60 mg/d (n=15) or 150 mg/d (n=13), placebo (n=13), or CEEs 0.625 mg/d (n=15). At baseline and after 6, 12, and 24 months of treatment, we assessed serum lipids, blood pressure, glucose metabolism, C-reactive protein, and various hemostatic parameters. Compared with placebo, both raloxifene and CEEs lowered the level of low density lipoprotein cholesterol by 0.53 to 0.79 mmol/L (all P<0.04) and lowered, at 24 months, the level of fibrinogen by 0.71 to 0.86 g/L (all P<0.05). The effects of raloxifene and CEEs did not differ significantly. In contrast to raloxifene, from 6 months on CEEs increased high density lipoprotein cholesterol by 0.25 to 0.29 mmol/L and reduced plasminogen activator inhibitor-1 antigen by 30.6 to 48.6 ng/mL (all P<0.02 versus both placebo and raloxifene). CEEs transiently increased C-reactive protein by 1.0 mg/L at 6 months (P<0.05 versus placebo) and prothrombin-derived fragment F1+2 by 0. 79 nmol/L at 12 months (P<0.001 versus placebo). Finally, from 12 months on, CEEs increased triglycerides by 0.33 to 0.56 mmol/L (all P<0.05 versus both placebo and raloxifene). Our findings suggest that in healthy postmenopausal women, raloxifene and estrogen monotherapy have similar beneficial effects on low density lipoprotein cholesterol and fibrinogen levels. These treatments differ, however, in their effects on high density lipoprotein cholesterol, triglycerides, and plasminogen activator inhibitor-1 and possibly in their effects on prothrombin fragment F1+2 and C-reactive protein.
We report the case of a patient with a giant interatrial septum aneurysm who was admitted to our hospital for analysis of palpitations. Transthoracic echocardiography was not contributive and cardiac magnetic resonance imaging demonstrated a small interatrial septal aneurysm. In our study, only transesophageal echocardiography provided the correct diagnosis, showing a giant interatrial septal aneurysm protruding far away into the right atrium and mimicking a right atrial cystic tumor.
PURPOSE: The potential to define liver tumors at magnetic resonance (MR) imaging was compared with a positive and a negative contrast agent (gadoxetic acid disodium, or gadolinium EOB-DTPA [a hepatocyte-directed agent], and ferumoxides, or superpara-magnetic iron oxide particles [a Kupffer cell-directed agent], respectively) in normal rats and in rats with induced acute hepatitis, fatty liver, or cirrhosis. MATERIALS AND METHODS: Rats with implanted liver adenocarcinomas were divided into four groups: no diffuse liver disease ("normal" [n = 6]) and diffuse liver diseases (induced acute hepatitis [n = 6], fatty liver [n = 6], or cirrhosis [n = 6]). Rats first received gadoxetic acid disodium (50 mumol/kg) and then, 45 minutes later, ferumoxides (10 mumol/kg). Liver signal intensity enhancement and tumor-to-liver contrast-to-noise ratio (C/N) were measured in each group. RESULTS: Mean liver signal intensity enhancement values with gadoxetic acid disodium and ferumoxides were excellent in the normal liver model (176% and -62%, respectively; P < .01) but were significantly reduced in the acute hepatitis model (82% and -36%, respectively). In the fatty livers compared with the normal livers, enhancement with gadoxetic acid disodium was reduced (57%) but with ferumoxides was excellent (-55%). In the cirrhotic livers compared with the normal livers, enhancement with gadoxetic acid disodium (174%) was virtually the same but was impaired with ferumoxides (-43%). CONCLUSION: Hepatic enhancement and tumor-to-liver C/N with either positive or negative liver-enhancing agents can be impaired by the presence of underlying liver disease. Prior knowledge of the type of diffuse liver disease may influence the choice of contrast agent for tumor detection.
Better surrogate markers need to be developed to evaluate therapy in HIV-infected children. This study evaluated plasma RNA, immune complex-dissociated p24 antigenemia, and unintegrated DNA (uDNA) in HIV-infected pediatric patients. Ten children were followed from initiation of nucleoside antiretroviral therapy at intervals up to 24 months. Prior to initiation of therapy, HIV RNA was detected in 10 of 10 patients (median, 76,000 Eq/ml), p24 antigen was detected in 8 of 10 patients (median, 193 pg/ml), and uDNA was detected in 6 of 7 patients (median, 10% uDNA). After 12 months the RNA decreased in all patients and became undetectable in six. In contrast, p24 antigenemia decreased in 6 of 10 patients, remained undetectable in 1, and increased in 3. HIV uDNA decreased in six of six patients and became undetectable in three. There was no overall change in CD4 cell count. Plasma RNA and uDNA levels are both sensitive markers of nucleoside therapy in children; however, they do not covary strongly.
DNA ploidy of pepsin digested preparations of 48 paraffin-embedded specimens from 19 patients with histologically confirmed malignant mesothelioma was determined by laser flow cytometry. Eight of the 19 tumors (42%) were diploid and 11 (58%) were aneuploid. Of the aneuploid tumors, only one showed multiploidy. The median survival time of the patients with diploid tumors was 19, 16, and 14 months from the onset of symptoms, diagnosis, and treatment, respectively. The median survival in patients with aneuploid tumors was 8, 7, and 7 months from the onset of first symptoms, diagnosis, and treatment. Thus, patients with diploid tumors lived longer than patients with aneuploid tumors. These results suggest that DNA ploidy analysis may be of prognostic value in malignant mesothelioma.
1. The purpose of this study was to examine the possibility that the cellular action of amiodarone is mediated by inhibition of thyroid hormone regulatory functions within the myocardial cell. We measured the rate of cell beating and the activity of Na-K-ATPase in cultured neonatal rat heart myocytes. 2. Amiodarone (0.25 and 1 microgram/ml) reduced beating rate up to 75% within 20 min, and Na-K-ATPase activity up to 40% within 2 hr. No toxic effects were detected in the treated cells. 3. The inhibitory actions of amiodarone on beating rate and Na-K-ATPase activity were the same in myocytes grown in the presence or absence of 3-iodothyronine (T3, 5 nM). 4. These data indicate that amiodarone affects beating rate and Na-K-ATPase activity independently of thyroid hormone. It is suggested that interference of amiodarone with thyroid hormone action is not the only mechanism by which this drug modulates some functions of the myocardial cell.
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Associations between major psychologic stressors and immune function have been documented in previous research, but few studies have investigated immune changes attending minor, normative stressors. This study examined adrenocortical and behavioral predictors of immune responses to starting kindergarten in 39 five-year-old children, who completed laboratory visits for venipunctures 1 wk before (time 1) and 1 wk after (time 2) school entry. At time 1, children were also immunized with pneumococcal vaccine. Immune responses were measured as change scores for T (CD4+ and CD8+) cells, B (CD19+) cells, lymphoproliferative responses to pokeweed mitogen (PWM), and type-specific pneumococcal antibody responses (ABR). Adrenocortical response was assessed as the change in salivary cortisol level, and behavioral difficulty with school adjustment was scored using parental ratings of behavior problems, stress due to changes in routines, and degree of adaptive challenge. Salivary cortisol rose after kindergarten entry (means = 0.39 +/- 0.28 to 0.49 +/- 0.36 micrograms/dL, p = 0.03) and was unrelated to behavioral difficulties. CD4+ cells increased in number, whereas PWM declined, and CD19+ cells showed a borderline increase. Change in salivary cortisol was positively associated with change in CD19+ (delta CD19+) and inversely related to ABR. Scores for behavioral difficulty were inversely associated with delta CD4+ and delta CD19+. These data suggest that: 1) school entry is a stressor capable of evoking elevations in cortisol and behavior problems, accompanied by shifts in functional and enumerative measures of immune status; and 2) children with greater adrenocortical reactivity have increases in B cell numbers and less effective B cell-mediated antibody production, whereas children with more behavioral difficulties show declines in all T and B cell subsets.
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Good markers for monitoring the efficacy of antiretroviral therapy in children do not currently exist. This study examined the effect of antiretroviral therapy on human immunodeficiency virus (HIV-1) unintegrated DNA (uDNA), integrated DNA (iDNA), percent uDNA, immune complex dissociated (ICD) p24 antigenemia, and plasma viral titer. Seven children were followed at therapy initiation and at approximately 3- and 10-month intervals. HIV-1 uDNA was detected in all children prior to start of therapy (average percent uDNA, 43%). At 3 months, the percent HIV uDNA decreased in all patients to an average of 18% (p = 0.01) and at 10 months decreased to an average of 1%. In contrast, the amount of HIV iDNA was relatively constant after initiation of therapy. ICD HIV p24 antigen was detected in all patients prior to therapy (average, 538 pg/ml). Over the study period, the ICD p24 antigen level decreased in three patients and remained relatively unchanged in four patients. Plasma cultures of HIV-1 were positive in only one of the seven patients prior to therapy. Among the methods evaluated, measurement of uDNA was the only parameter which reliable decreased after initiation of nucleoside therapy.
Rheumatic disease manifestations and autoimmune phenomena are common in adults infected with human immunodeficiency virus (HIV). On the other hand, rheumatic disease manifestations are rare in children congenitally infected with HIV. We studied the relationship between autoimmune phenomena and rheumatic diseases by examining HIV-infected children for the presence of rheumatoid factors (RFs), immune complexes, and complement activation fragments. RFs (principally IgA) were detected in 12 of the 24 HIV-infected patients (50%) and in none of the uninfected (HIV-exposed, seroreverted) controls (n = 22). Mean levels of complement activation fragments C3a and Bb were elevated in the HIV-infected children compared with the controls. A correlation was seen between the presence of IgA RF and alternative complement pathway activation as measured by plasma levels of Bb. None of the children had clinical or laboratory evidence of rheumatic disease.
OBJECTIVE: This study assessed the effect of gastric secretion on the rate of recurrent ulcer after parietal cell vagotomy for duodenal ulcer. SUMMARY BACKGROUND DATA: Three hundred patients who underwent parietal cell vagotomy for duodenal ulcer between 1975 and 1986 were evaluated. The mean follow-up period for 280 patients was 5 years. METHODS: The gastric secretion tests concerned basal acid output (BAO) and peak acid output stimulated by pentagastrin or insulin. Tests were preoperative for 172 patients and postoperative for 118. RESULTS: At the end of that time, the overall incidence of symptomatic recurrent ulcer was 15%. Two criteria were shown to be important predictors of recurrent ulcer: preoperative BAO > 7 mmol/hr, for which the recurrence rate 5 years after vagotomy was 30% versus 11% for values below this threshold (p = 0.01), and postoperative BAO > 1.4 mmol/hr, for which the recurrence rate at 5 years was 72% versus 8% for lower values (p = 0.0001). All patients with recurrent ulcer had either a postoperative BAO > 7 mmol/hr and/or a postoperative reduction in BAO < 80%. CONCLUSION: Preoperative BAO > 7 mmol/hr and postoperative BAO > 1.4 mmol/hr were shown to be factors predictive of RU. All patients with RU presented either with preoperative BAO > 7 mmol/hr and/or a reduction in BAO < 80%. Consequently, in our opinion, these criteria could be used either to select patients for vagotomy or to assess the effectiveness of vagotomy of different types, especially those performed by celioscopy.
Previous studies in adult populations have demonstrated alterations in immune function after psychologically stressful events, and pediatric research has shown significant associations between stress and various childhood morbidities. However, no previous work has examined stress-related immune changes in children and subsequent illness experience. Twenty children were enrolled in a study on immunologic changes after kindergarten entry and their prospective relationship to respiratory illness (RI) experience. Midway through a 12-week RI data collection period, the October 17, 1989 Loma Prieta earthquake occurred. The timing of this event created a natural experiment enabling us to study possible associations between immunologic changes at kindergarten entry, the intensity of earthquake-related stress for children and parents, and changes in RI incidence over the 6 weeks after the earthquake. Immunologic changes were measured using helper (CD4+)-suppressor (CD8+) cell ratios, lymphocyte responses to pokeweed mitogen, and type-specific antibody responses to Pneumovax, in blood sampled 1 week before and 1 week after school entry. RI incidence was assessed using home health diaries and telephone interviews completed every 2 weeks. RIs per child varied from none to six. Six children showed an increase in RI incidence after the earthquake; five experienced a decline. Changes in helper-suppressor cell ratios and pokeweed mitogen response predicted changes in RI incidence in the postearthquake period (r = .43, .46; p < .05). Children showing upregulation of immune parameters at school entry sustained a significant increase in RI incidence after the earthquake.(ABSTRACT TRUNCATED AT 250 WORDS)
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By comparing the amino acid sequences of 11 mammalian and 1 avian prion proteins (PrP), structural analyses predicted four alpha-helical regions. Peptides corresponding to these regions of Syrian hamster PrP were synthesized, and, contrary to predictions, three of the four spontaneously formed amyloids as shown by electron microscopy and Congo red staining. By IR spectroscopy, these amyloid peptides exhibited secondary structures composed largely of beta-sheets. The first of the predicted helices is the 14-amino acid peptide corresponding to residues 109-122; this peptide and the overlapping 15-residue sequence 113-127 both form amyloid. The most highly amyloidogenic peptide is AGAAAAGA, which corresponds to Syrian hamster PrP residues 113-120 and is conserved across all species for which the PrP sequence has been determined. Two other predicted alpha-helices corresponding to residues 178-191 and 202-218 form amyloids and exhibit considerable beta-sheet structure when synthesized as peptides. These findings suggest the possibility that the conversion of the cellular isoform of PrP to the scrapie isoform of PrP involves the transition of one or more putative PrP alpha-helices into beta-sheets and that prion diseases are disorders of protein conformation.