Biomedical subjects

S R Weiss

Publications and source records attributed to S R Weiss.

At least 19 recordsLinked to original sources

PubMed1998

Efficacy and safety of simvastatin 80 mg/day in hypercholesterolemic patients. The Expanded Dose Simvastatin U.S. Study Group.

This randomized, multicenter, double-blind parallel-group study was performed to evaluate the lipid-altering efficacy and safety of simvastatin 80 mg/day, a dose twice the current maximum recommended dose. At 20 centers in the United States, 521 male and female hypercholesterolemic patients were randomly assigned in a ratio of 2:3 to receive simvastatin 40 or 80 mg once daily, respectively, for 24 weeks in conjunction with a lipid-lowering diet. Patients met National Cholesterol Education Program (NCEP) low-density lipoprotein (LDL) cholesterol criteria for pharmacologic treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol averaged at weeks 18 and 24 were 38% (-40 to -36) and 46% (-47 to -45) for the 40- and 80-mg groups, respectively (p <0.001 between groups). One third of patients on the 40- and 80-mg doses achieved an LDL cholesterol reduction of 46% and > or = 53%, respectively. Decreases in apolipoprotein B, total cholesterol, and triglycerides were also significantly greater among patients receiving 80 mg/day. Simvastatin was well tolerated in both groups. Two patients (0.6%) in the 80-mg group developed myopathy. Consecutive, clinically significant hepatic transaminase elevations occurred in 3 (1.0%) and 6 (1.9%) patients in the 40- and 80-mg groups, respectively (p= 0.486). In conclusion, simvastatin 80 mg/day provided substantial reductions in LDL cholesterol, allowing most patients to reach their NCEP target levels; it also had an excellent safety and tolerability profile.

Adult↗

PubMed1998

Sensitization and kindling phenomena in mood, anxiety, and obsessive-compulsive disorders: the role of serotonergic mechanisms in illness progression.

A number of untreated or inadequately treated psychiatric illnesses often demonstrate syndrome progression manifested by either increasing frequency, severity, or spontaneity of episodes. Behavioral sensitization to psychomotor stimulants (and its cross sensitization to stress) and electrophysiological kindling provide two very different models for conceptualizing physiological and behavioral abnormalities that progress in severity in response to the same inducing stimulation over time. These models are highly indirect, and the behaviors induced and specific pharmacologic interventions do not directly parallel those in many of these psychiatric syndromes. Nonetheless, these preclinical models help us conceptualize potential mechanisms involved in syndrome progression based on experience-dependent modifications of the genome at the level of transcriptional regulation. In both preclinical models, agents that are effective in the earlier developmental phase of sensitization or kindling are not necessarily effective in amelioration of the full-blown syndromes, and vice versa. Thus these models also suggest a variety of intervention principles that can be directly tested in the clinic, such as differential efficacy of treatment as a function of stage of evolution of the given syndrome. Although serotonergic mechanisms do not appear central to the basic phenomena of sensitization and kindling, they appear capable of modulating their development and severity. As such, it becomes of considerable importance to assess whether serotonergic mechanisms that have been implicated in acute treatment of mood and anxiety syndromes are also involved in the longitudinal course and prevention of syndrome progression or occurrence. Identification of the more precise molecular mechanisms involved might provide a target for new therapeutic approaches to these recurrent and potentially disabling major psychiatric illnesses.

Affect↗

PubMed1998

Roles in cell-to-cell fusion of two conserved hydrophobic regions in the murine coronavirus spike protein.

The spike (S) protein of coronavirus mouse hepatitis virus (MHV), mediates attachment and fusion during viral entry and cell-to-cell fusion later in infection. By analogy with other viral proteins that induce cell fusion the MHV S protein would be expected to have a hydrophobic stretch of amino acids that serves as a fusion peptide. Sequence analysis suggests that the S protein falls within the group of fusion proteins having internal rather than N-terminal fusion peptides. Based on the features of known viral fusion peptides, we identified two regions (PEP1 and PEP2) of MHV-A59 S2 as possible fusion peptides. Site-directed mutagenesis and an in viro cell-to-cell fusion assay were used to evaluate the roles of PEP1 and PEP2, as well as a third previously identified putative fusion domain (PEP3) in membrane fusion. Substitution of bulky hydrophobic residues with charged residues within PEP1 affects the fusion activity of the S protein without affecting processing and surface expression. Similar substitutions within PEP2 result in a fusion-negative phenotype; however, these mutant S proteins also exhibit defects in protein processing and surface expression which likely explain the loss of the ability to induce fusion. Thus PEP1 remains a candidate fusion peptide, while PEP2 may play a significant role in the overall structure or oligomerization of the S protein. PEP3 is an unlikely putative fusion peptide since it is not conserved among coronaviruses and nonconservative amino acid substitutions in PEP3 have minimal effects on cell-to-cell fusion.

Amino Acid Sequence↗

PubMed1998

Anticonvulsant effects of intra-hippocampal injection of TRH in amygdala kindled rats.

The anticonvulsant effects of intra-hippocampal thyrotropin-release hormone (TRH) were examined in amygdala kindled rats. Subjects were implanted unilaterally with an electrode in the amygdala and bilaterally with guide cannulae in the hippocampus, aimed at the dorsal and ventral dentate gyri. Rats were kindled daily with suprathreshold electrical stimulation (800 microA, 1 ms pulse width, 100 Hz, duration 0.5 s) until seizures were reliably elicited. The afterdischarge (AD) duration, seizure duration, and seizure stage were recorded daily, and AD thresholds were determined after kindling was completed. TRH was infused into each of the four cannulae of freely moving rats at doses of 0 (vehicle), 1.25, 2.5 and 5 microg/site. Five minutes after the last infusion, the rats received electrical stimulation at their AD threshold (mean = 135 microA) + 50 microA. TRH reduced the AD and seizure duration in a dose-dependent manner. At the dose of 2.5 microg/site, TRH also reduced AD and seizure duration in rats stimulated with suprathreshold current (800 microA). However, TRH had minimal effects on seizure stage irrespective of the stimulation intensity. These results suggest that the seizure-induced elevations of TRH in the hippocampus, as demonstrated in previous studies, may be part of an endogenous anticonvulsant compensatory mechanism and that further elevations of TRH in the hippocampus can produce anticonvulsant effects mainly by reducing the AD and seizure duration.

Amygdala↗

PubMed1998

Bidirectional synaptic plasticity in the rat basolateral amygdala: characterization of an activity-dependent switch sensitive to the presynaptic metabotropic glutamate receptor antagonist 2S-alpha-ethylglutamic acid.

This study examines forms of activity-dependent synaptic plasticity in the basolateral amygdala in vitro and demonstrates that a brief high frequency stimulus (HFS) train can induce a switch in the direction of the enduring change in synaptic strength induced by subsequent low-frequency stimulation (LFS). LFS (1 Hz, 15 min) of the external capsule (EC) induced a persistent 1.7-fold enhancement in the amplitude of synaptic potentials recorded intracellularly in basolateral amygdala neurons. The enhancement occurred gradually during the stimulation and was maintained for >30 min after termination of the stimulus train. LFS-induced enduring synaptic facilitation was not affected by the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoate (APV; 100 microM). Brief high-frequency EC stimulation (HFS; 100 Hz, 1 sec) induced APV-sensitive short-term potentiation (2.5-fold) that generally decayed within 10 min. When LFS was applied after recovery from the short-term potentiating effect of HFS (HFS/LFS), there was an initial transient (<10 min) enhancement of the synaptic response followed by persistent synaptic depression (synaptic potential amplitude reduced by 22% at 30 min). This represents the first demonstration of stimulus-dependent long-lasting synaptic depression in the amygdala. Application of the presynaptic (group II) metabotropic glutamate receptor antagonist 2S-alpha-ethylglutamic acid (EGLU; 50 microM) prevented the HFS-dependent switch from synaptic facilitation to depression. Thus, LFS in the in vitro amygdala slice can induce either enduring synaptic potentiation or depression, depending on whether a priming HFS train has been applied. This experience-dependent switch, a novel form of metaplasticity, is not dependent on NMDA receptors but may require group II metabotropic glutamate receptors. In the amygdala, experiential modification of activity-dependent long-term synaptic plasticity adds flexibility to the ways in which synaptic strength can be modified and could play a role in diverse amygdala-dependent processes, including the formation, storage, and extinction of emotional memory and the regulation of epileptogenesis.

Amygdala↗

PubMed1998

Isolated acute papillary muscle infarction in the absence of coronary artery disease resulting in cardiogenic shock and emergent mitral valve replacement.

A 76-year-old woman presented to our institution with shortness of breath, weakness, and syncope. Evaluation revealed severe mitral regurgitation and cardiogenic shock secondary to a flail posterior mitral valve leaflet. An emergency cardiac catheterization did not demonstrate significant coronary artery disease. The patient was sent for an emergency mitral valve replacement. Intraoperatively, the posteromedial papillary muscle was found to be transected. Histological analysis, clinical presentation, and a review of the literature of isolated papillary muscle infarction are presented.

Acute Disease↗

PubMed1998

Quenching revisited: low level direct current inhibits amygdala-kindled seizures.

We have reported that low frequency stimulation (1 Hz for 15 min), applied after kindling stimulation of the amygdala, inhibited the development and expression of amygdala-kindled seizures, an effect we termed quenching. Subsequently, we discovered that this effect could only be achieved when certain stimulators were used that also emitted a low-level direct current (DC). The studies reported here indicate that DC, applied once daily for 15 min at intensities of 5-15 microA, produced an intensity-related attenuation of kindling development and an increase in the afterdischarge threshold. This effect persisted in some animals for at least 1 month after discontinuation of the DC. In fully kindled animals, a robust increase in seizure threshold and persistent seizure inhibition were also observed using 10 microA of DC administered for 14 days. These results clarify and extend our original findings of a quenching effect; however, the mechanisms by which low level DC induces quenching require further elucidation.

Amygdala↗

PubMed1998

Mutational analysis of fusion peptide-like regions in the mouse hepatitis virus strain A59 spike protein.

The coronavirus peplomer protein S is responsible for attachment and fusion during viral entry as well as for the induction of cell to cell fusion. While several regions within S have been shown to influence the ability to induce fusion, the region of the protein actually responsible for fusion, the fusion peptide, has not yet been identified. We identified two hydrophobic peptides (peptides #1 and #2) within MHV-A59 S2 as possible fusion domains. This was based on hydrophobicity, conservation among coronavirus S proteins and the prediction of a sided helix conformation. Using site directed mutagenesis and an in vitro cell to cell fusion assay we showed that substitution of hydrophobic amino acids with charged amino acids, within the predicted hydrophobic face of either of these two peptides eliminated fusion. Within peptide #1 substitution of the same hydrophobic amino acids with other hydrophobic amino acids or substitution of polar amino acids with charged or polar amino acids had little effect on fusion. Thus peptides #1 and #2 remain likely candidates for the MHV fusion peptide. A third previously identified peptide within S2 (Chambers et al., 1990) is unlikely as a fusion peptide as it is not well conserved among coronaviruses and substitution within the hydrophobic face with charged amino acids does not effect fusion.

Amino Acid Sequence↗

PubMed1998

The mouse hepatitis virus A59 spike protein is not cleaved in primary hepatocyte and glial cell cultures.

Mouse hepatitis virus strain A59 (MHV-A59) produces mild meningoencephalitis and severe hepatitis during acute infection. To determine whether an in vitro system could be established which would mimic in vivo replication of the virus, we examined the ability of MHV-A59 to replicate in primary cultures of hepatocytes derived from C57BL/6 mice. Infection of hepatocytes with MHV-A59 resulted in low levels of replication, with virus remaining cell associated. Maximum viral yield was observed at 24 hours postinfection, while occasional syncytia were observed at 48 hours postinfection. Primary glial cell culture represents a potential in vitro system representing the second main target of MHV-A59, namely the brain. It is known that MHV-A59 produces a productive, but nonlytic infection in these cultures. Since cell-to-cell fusion is associated with the cleavage of S, the observation of little or no syncytia following MHV-A59 infection of both hepatocytes and glial cells prompted us to examine the cleavage of the spike protein (S) by Western blot analysis. The cleavage of S is inefficient in MHV-A59 infected hepatocytes and in glial cells. Furthermore, no cleavage of this protein was detected in liver homogenates from C57BL/6 mice infected with MHV-A59. These data suggest that cleavage of the MHV-A59 S protein, and by inference cell-to-cell fusion, does not seem to be essential for entry and spread of the virus in vivo and in vitro.

Animals↗

PubMed1998

The C12 mutant of MHV-A59 is very weakly demyelinating and has five amino acid substitutions restricted to the spike and replicase genes.

C12, an attenuated, fusion defective, very weakly hepatotropic mutant of MHV-A59 has been further characterized. Analysis of C12 in vivo in C57BL/6 mice has shown that despite the fact that this virus replicates in the brain to titers at least as high as wild type and causes acute encephalitis similar to wild type, this virus causes minimal demyelination. Thus acute encephalitis is not sufficient for induction of demyelination by wild type MHV-A59. We have previously shown that C12 has two amino acid substitutions relative to wild type virus in the spike gene, Q159L (in the receptor binding domain of S1) and H716D (in the signal sequence for cleavage of S). We have now sequenced the rest of the 31 kb genome of C12 and compared it to wild type virus. Only three additional amino acids substitutions were found, all within the replicase gene, one in the predicted papain like proteinase (PLP)-2 domain and one in the predicted helicase domain. Thus, determinants of virulence, hepatotropism, and demyelination may map to the replicase gene as well as to the spike gene.

Amino Acid Substitution↗

PubMed1998

Cancer recurrences and secondary primary cancers after use of antihistamines or antidepressants.

OBJECTIVES: Reports in the scientific literature have described accelerated tumor growth in association with antidepressant and antihistamine exposure in experimental rodent cancer models. This study was designed to determine whether exposure to prescription antidepressants or antihistamines is associated with tumor growth in humans. METHODS: Two nested case-control studies were conducted with a cohort of 1467 patients with breast cancer, colon cancer, or melanoma diagnosed between 1988 and 1994. Eligible patients included 95 with a cancer recurrence and 78 with a second primary lesion diagnosed during the follow-up period. Five control subjects were matched to each case patient according to cancer site, stage, and follow-up time. Conditional logistic regression was used to compare risk for tumor recurrence or occurrence of a second primary tumor among patients using antidepressants or antihistamines with risk among unexposed patients. RESULTS: For a cohort of patients who were predominantly female (78%), with breast cancer (57%) and with a tumor in situ or with localized disease (79%), the average age was 62 years at cancer diagnosis and average duration of follow-up period was 2.2 years. Use of antidepressants or antihistamines was unrelated to risk for tumor recurrence (odds ratio, 0.97; 95% confidence interval, 0.52 to 1.78) or second primary tumors (odds ratio, 0.94; 95% confidence interval, 0.50 to 1.77). CONCLUSION: Typical use of antidepressant or antihistamine drugs did not increase risk for recurrent or second primary tumors among patients with cancer.

Adult↗

PubMed1998

Apoptosis of hippocampal neurons after amygdala kindled seizures.

Seizure-induced neuronal damage may involve both excitotoxic and apoptotic (programmed cell death) mechanisms. In the present study, we used an amygdala kindled seizure model to study whether apoptotic cell death occurs. To evaluate apoptosis, we counted the numbers of cells that had DNA fragments labeled at the 3' end with digoxigenin using terminal transferase (ApopTag, Oncor). Additionally, the expression of Bax and Bcl-2, two genes associated with apoptotic cell death, was also measured following kindled seizures. We found that the number of ApopTag-positive cells in the hippocampus increased 30.4% after one kindled seizure and 82.5% after 20 seizures compared to sham controls. The ApopTag-labeled cells could be mainly interneurons of the hippocampal formation, although additional studies are required. Preferential vulnerability of inhibitory interneurons is consistent with previous studies on seizure-induced cell loss. These results, coupled with our findings that the ratio of Bax/Bcl-2 expression is increased in the hippocampus by seizures, suggest that apoptosis of hippocampal interneurons may lead to dysinhibition in the hippocampus and increased seizure susceptibility.

Amygdala↗

PubMed1998

Neural plasticity and emotional memory.

Posttraumatic stress disorder is the pathological replay of emotional memory formed in response to painful, life-threatening, or horrifying events. In contrast, depression is often precipitated by more social context-related stressors. New data suggest that different types of life experiences can differentially impact biochemistry, physiology, anatomy, and behavior at the level of changes in gene expression. Repeated separation of neonatal rat pups from their mother results in many long-lasting alterations in biology and behavior paralleling that in depression, including hypercortisolism. The role of the amygdala in modulating emotional memory is highlighted, as well as some of its unique properties such as metaplasticity (i.e., the differential direction of long-term adaptation, either potentiation or depression) in response to the same input as a function of the prior history of stimulation. The implications of these emerging data on the physiological and molecular mechanisms underlying emotional memory emphasize the particular importance of prevention and early intervention.

Amygdala↗

PubMed1998

Targeted recombination within the spike gene of murine coronavirus mouse hepatitis virus-A59: Q159 is a determinant of hepatotropism.

Previous studies of a group of mutants of the murine coronavirus mouse hepatitis virus (MHV)-A59, isolated from persistently infected glial cells, have shown a strong correlation between a Q159L amino acid substitution in the S1 subunit of the spike gene and a loss in the ability to induce hepatitis and demyelination. To determine if Q159L alone is sufficient to cause these altered pathogenic properties, targeted RNA recombination was used to introduce a Q159L amino acid substitution into the spike gene of MHV-A59. Recombination was carried out between the genome of a temperature-sensitive mutant of MHV-A59 (Alb4) and RNA transcribed from a plasmid (pFV1) containing the spike gene as well as downstream regions, through the 3' end, of the MHV-A59 genome. We have selected and characterized two recombinant viruses containing Q159L. These recombinant viruses (159R36 and 159R40) replicate in the brains of C57BL/6 mice and induce encephalitis to a similar extent as wild-type MHV-A59. However, they exhibit a markedly reduced ability to replicate in the liver or produce hepatitis compared to wild-type MHV-A59. These viruses also exhibit reduced virulence and reduced demyelination. A recombinant virus containing the wild-type MHV-A59 spike gene, wtR10, behaved essentially like wild-type MHV-A59. This is the first report of the isolation of recombinant viruses containing a site-directed mutation, encoding an amino acid substitution, within the spike gene of any coronavirus. This technology will allow us to begin to map the molecular determinants of pathogenesis within the spike glycoprotein.

Amino Acid Substitution↗

PubMed1998

The spike protein of murine coronavirus mouse hepatitis virus strain A59 is not cleaved in primary glial cells and primary hepatocytes.

Mouse hepatitis virus strain A59 (MHV-A59) produces meningoencephalitis and severe hepatitis during acute infection. Infection of primary cells derived from the central nervous system (CNS) and liver was examined to analyze the interaction of virus with individual cell types derived from the two principal sites of viral replication in vivo. In glial cell cultures derived from C57BL/6 mice, MHV-A59 produces a productive but nonlytic infection, with no evidence of cell-to-cell fusion. In contrast, in continuously cultured cells, this virus produces a lytic infection with extensive formation of syncytia. The observation of few and delayed syncytia following MHV-A59 infection of hepatocytes more closely resembles infection of glial cells than that of continuously cultured cell lines. For MHV-A59, lack of syncytium formation correlates with lack of cleavage of the fusion glycoprotein, or spike (S) protein. The absence of cell-to-cell fusion following infection of both primary cell types prompted us to examine the cleavage of the spike protein. Cleavage of S protein was below the level of detection by Western blot analysis in MHV-A59-infected hepatocytes and glial cells. Furthermore, no cleavage of this protein was detected in liver homogenates from C57BL/6 mice infected with MHV-A59. Thus, cleavage of the spike protein does not seem to be essential for entry and spread of the virus in vivo, as well as for replication in vitro.

Animals↗

PubMed1998

Kindling: separate vs. shared mechanisms in affective disorders and epilepsy.

Kindling is discussed in relation to affective illness as a nonhomologous model, which shares the feature of increasing illness severity and evolution over time following repeated exposures to certain forms of stimulation. This progressive aspect of kindling has proven useful in the study of approaches to pharmacotherapeutics, mechanisms and characteristics of drug tolerance, and, most recently, illness suppression through physiological rather than pharmacological strategies. Each of these themes is described and the mechanisms that have been uncovered using the kindling model are discussed in relation to how similar principles might apply in affective illness or epilepsy. It is hoped that some of the lessons from the kindling model will provide useful and novel insights into aspects of treatment and mechanisms of psychiatric and neurologic illnesses.

Amygdala↗

PubMed1998

Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study.

OBJECTIVE: Obesity is an important risk factor for type 2 diabetes. Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors, but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise. The purpose of this study was to assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications. RESEARCH DESIGN AND METHODS: In a multicenter 57-week randomized double-blind placebo-controlled study, 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years, had a BMI of 28-40 kg/m2, and were clinically stable on oral sulfonylureas. Changes in body weight, glycemic control, lipid levels, and drug tolerability were measured. RESULTS: After 1 year of treatment, the orlistat group lost 6.2 +/- 0.45% (mean +/- SEM) of initial body weight vs. 4.3 +/- 0.49% in the placebo group (P < 0.001). Twice as many patients receiving orlistat (49 vs. 23%) lost > or = 5% of initial body weight (P < 0.001). Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control, as reflected in decreases in HbA1c (P < 0.001) and fasting plasma glucose (P < 0.001) and in dosage reductions of oral sulfonylurea medication (P < 0.01). Orlistat therapy also resulted in significantly greater improvements than placebo in several lipid parameters, namely, greater reductions in total cholesterol, (P < 0.001), LDL cholesterol (P < 0.001), triglycerides (P < 0.05), apolipoprotein B (P < 0.001), and the LDL-to-HDL cholesterol ratio (P < 0.001). Mild to moderate and transient gastrointestinal events were reported with orlistat therapy, although their association with study withdrawal was low. Fat-soluble vitamin levels generally remained within the reference range, and vitamin supplementation was required in only a few patients. CONCLUSIONS: Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.

Adult↗

PubMed1998

Lipoprotein(A) and coronary heart disease risk factors in a racially mixed population: the Johns Hopkins Sibling Study.

OBJECTIVES: To determine if heart disease risk factors differentially affect lipoprotein(a) concentration by race, we assessed the association of lipoprotein(a) with heart disease risk factors in healthy Caucasians and African Americans with family histories of premature heart disease. METHODS: Participants (403 Caucasian and 148 African American), all less than 60 years old and free of heart disease, were recruited through a brother or sister diagnosed with coronary heart disease before age 60. Risk factor information was elicited through an interview and medical examination. RESULTS: As expected, lipoprotein(a) was significantly higher among African Americans than among Caucasians. Mean lipoprotein(a) concentrations were positively associated with smoking status and age, and negatively associated with hypertension in African Americans. Smokers had lipoprotein(a) levels 38% higher than nonsmokers. Conversely, lipoprotein(a) concentrations were unrelated to heart disease risk factors among Caucasians. CONCLUSION: While this study confirms that lipoprotein(a) concentration is independent of CHD risk factors in Caucasians, lipoprotein(a) appears to be related to several CHD risk factors in African Americans at high risk for premature heart disease. Given the high levels of lipoprotein(a) in people of African descent and lipoprotein(a)'s link to cardiovascular diseases, more research is needed to understand the relationship of lipoprotein(a) to heart disease risk factors and the subsequent disease in African-American populations.

Adult↗