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Biomedical subjects

M A Lee

Publications and source records attributed to M A Lee.

At least 91 records · Page 5Linked to original sources
PubMed1996

Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine.

The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients with neuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64 neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.

Adult↗
PubMed1996

Neuropsychologic deficits in schizophrenia: relation to social function and effect of antipsychotic drug treatment.

Cognitive impairment is present in the majority of schizophrenic patients, even at the onset of psychosis. It is a relatively stable characteristic in most patients, usually with little progression over the course of illness, but sometimes progresses to severe dementia. The results of studies of the effects of typical neuroleptic drugs on cognitive functioning in schizophrenia are conflicting. Clozapine, which has superior antipsychotic effects compared to typical neuroleptic drugs, has been reported to improve executive function, verbal fluency, attention, and recall memory in two of three studies. Cognitive measures predict work function and overall outcome on clozapine as assessed by the Global Assessment Scale and Quality-of-Life Scale in neuroleptic--resistant schizophrenia. Improvement in cognitive function by clozapine may be a major reason for expanding its currently limited utilization.

Antipsychotic Agents↗
PubMed1996

The hypertensive Ren-2 transgenic rat TGR (mREN2)27 in hypertension research. Characteristics and functional aspects.

Primary human hypertension is a polygenic disorder. It is the prevalent cause of cardiovascular disease leading to cardiac failure, stroke, chronic renal failure and, ultimately to death. Several genes are involved in cardiovascular control mechanisms and their genetics are complex. Experimental models which are well defined are needed to clarify the role of individual genes. The generation of the hypertensive transgenic rat line TGR (mREN2)27 bearing the murine Ren-2 gene cloned from the DBA/2J mouse strain provides a monogenic model of hypertension in which the genetic basis (the additional renin gene) is known. These rats develop severe hypertension, which reaches 200 mm Hg and higher at 8 weeks of age in the heterozygous animal. Homozygous rats develop even higher blood pressures than heterozygous animals, which is paralleled by a higher mortality rate in homozygous rats. Animals develop pathomorphologic alterations which are characteristic for systemic hypertension. The transgenic rats are characterized by unchanged or even suppressed concentrations of active renin, angiotensin I (ANG I), ANG II, and angiotensinogen compared to transgene-negative littermates. In contrast, plasma levels of inactive renin (prorenin) are much higher in TGR (mREN)27 rats than in control animals. In the kidneys, renin is suppressed, probably mediated through negative feedback inhibition, in other tissues, especially in the adrenal gland, murine Ren-2 mRNA is expressed at very high levels. The cascade of pathophysiologic events which finally lead to hypertension is not fully understood in this rat model. Treatment with ACE inhibitors or angiotensin II receptor antagonists such as losartan is extremely efficient, which could mean that hypertension in this model is mediated through ANG II. Since the the renin-angiotensin system (RAS) in the kidneys is suppressed, other ANG II generating sites must be considered. This favors the concept of extrarenal RASs in this model.

Animals↗
PubMed1996

Interstitial pneumonitis as a late complication of high dose therapy with cyclophosphamide/thiotepa and peripheral blood progenitor cell rescue for carcinoma of the breast.

The incurability of metastatic breast cancer with conventional chemotherapy has prompted many units to investigate the role of high dose chemotherapy and autologous stem cell rescue in patients with advanced or poor risk primary disease. Although preliminary data from centres treating patients with these modalities are encouraging, both in terms of rapidity of haemopoietic recovery and progression free survival, there is nonetheless a procedure related toxicity. We describe a patient with inflammatory carcinoma of the breast who received high dose cyclophosphamide and thiotepa prior to peripheral blood progenitor cell rescue, and developed a steroid responsive interstitial pneumonitis 10 weeks after stem cell infusion.

Adenocarcinoma↗
PubMed1996

Oregon emergency physicians' experiences with, attitudes toward, and concerns about physician-assisted suicide.

OBJECTIVE: To determine emergency physicians' (EPs') attitudes toward physician-assisted suicide (PAS), factors associated with those attitudes, current experiences with attempted suicides in terminally ill persons, and concerns about the impact of legalizing PAS on emergency medicine practice. METHODS: A cross-sectional, anonymous mailed survey was taken of EPs in the state of Oregon. RESULTS: Of 356 eligible physicians, 248 (70%) returned the survey. Of the respondents, 69% indicated that PAS should be legal, 65% considered PAS consistent with the physician's role, and 19% believed that it is immoral. The respondents were concerned that patients might feel pressure if they perceived themselves to be either a care burden on others (82%) or a financial stress to others (69%). Only 37% indicated that the Oregon initiative has enough safeguards to protect vulnerable persons. Support for legalization was not associated with gender, age, or practice location. Respondents with no religious affiliation were most supportive of PAS (p < 0.001), and Catholic respondents were least suppportive (p = 0.03). A majority (58%) had treated at least 1 terminally ill patient after an apparent overdose. Most respondents (97%) indicated at least 1 circumstance for which they would sometimes be willing to let a terminally ill patient die without resuscitation after PAS if the Oregon initiative becomes law: if verified with an advance directive from the patient (81%), with documentation in writing from the physician (73%), after speaking to the primary physician (64%), if a competent patient verbally confirmed intent (60%), or if the family verbally confirmed intent (52%). CONCLUSIONS: Although the majority of Oregon EPs favor the concept of legalization of PAS, most have concerns that safeguards in the Oregon initiative are inadequate to protect vulnerable patients. These physicians would consider not resuscitating terminally ill patients who have attempted suicide under the law's provisions, only in the setting of documentation of the patient's intent.

Adult↗
PubMed1996

Physiological characterization of the hypertensive transgenic rat TGR(mREN2)27.

Transgenic techniques represent powerful tools for the study of gene-related mechanisms of diseases such as hypertension, which results from a complex interaction between genetic and environmental factors. The renin-angiotensin system, a biochemical cascade in which renin functions as the key enzyme in the formation of the effector peptide angiotensin II, plays a major role in the regulation of blood pressure. The renin gene, therefore, represents an important candidate gene for hypertension. Because rats are more suited than mice for a number of experimental settings often employed in cardiovascular research, we modified the transgenic technique to generate the transgenic rat strain TGR(mREN2)27 harboring the murine Ren-2 gene. These transgenic rats develop fulminant hypertension at an early age despite low levels of renin in plasma and kidney. In addition, high expression of the transgene in a number of extrarenal tissues is associated with increased local formation of angiotensin II. Thus the TGR(mREN2)27 rat represents a model of hypertension with a defined genetic background. Studies on the transgenic rat may not only provide new insights into pathophysiological mechanisms of hypertension in this animal model but also offer the unique possibility to investigate the function and regulation of renin-angiotensin systems in extrarenal tissues. The aim of this review is to compile the knowledge that has been accumulated to date on this transgenic rat and to discuss possible mechanisms responsible for its hypertensive phenotype.

Animals↗
PubMed1996

Attitudes of Oregon psychiatrists toward physician-assisted suicide.

OBJECTIVE: After passage, in November 1994, of Oregon's ballot measure legalizing physician-assisted suicide for terminally ill persons, the authors surveyed psychiatrists in Oregon to determine their attitudes toward assisted suicide, the factors influencing these attitudes, and how they might both respond to and follow up a request by a primary care physician to evaluate a terminally ill patient desiring assisted suicide. METHOD: An anonymous questionnaire was sent to all 418 Oregon psychiatrists. RESULTS: Seventy-seven percent of psychiatrists (N = 321) returned the questionnaire. Two-thirds endorsed the view that a physician should be permitted, under some circumstances, to write a prescription for a medication whose sole purpose would be to allow a patient to end his or her life. One-third endorsed the view that this practice should never be permitted. Over half favored Oregon's assisted suicide initiative becoming law. Psychiatrists' position on legalization of assisted suicide influenced the likelihood that they would agree to evaluate patients requesting assisted suicide and how they would follow up an evaluation of a competent patient desiring assisted suicide. Only 6% of psychiatrists were very confident that in a single evaluation they could adequately assess whether a psychiatric disorder was impairing the judgment of a patient requesting assisted suicide. CONCLUSIONS: Psychiatrists in Oregon are divided in their belief about the ethical permissibility of assisted suicide, and their moral beliefs influence how they might evaluate a patient requesting assisted suicide, should this practice be legalized. Psychiatrists' confidence in their ability to determine whether a psychiatric disorder such as depression was impairing the judgment of a patient requesting assisted suicide was low.

Attitude of Health Personnel↗
PubMed1996

Topogenic effect of positively charged N-terminal amino acid in ER translocation of yeast alpha-factor precursor.

Expression of fusion proteins between prepro-alpha-factor and somatostatin (SRIF) in yeast, resulted in the correct processing and secretion of the heterologous 14-amino acid SRIF peptide (1). When the chimeric genes were placed under the control of yeast acid phosphatase (PHO5) promoter, significant amount of an unglycosylated form of the fusion precursor molecule accumulated intracellularly, suggesting disruption of an endoplasmic reticulum-mediated function. We report here that the appearance of the precursor is due to an alteration in the three amino terminal residues of the chimera, i.e., Met-Arg-Phe in native prepro-alpha-factor is changed to Met-Phe-Lys in the hybrids. The unglycosylated precursor represents a population of molecules that are disrupted at an early stage of targeting to or translocation across the endoplasmic reticulum membrane. Our data demonstrate that the N-terminus plays an important role in topogenesis. Furthermore, these results show that translocation and glycosylation can be uncoupled from protein synthesis in vivo, and therefore can be posttranslational events in yeast.

Amino Acids↗
PubMed1996

Application of PCR from the fine needle aspirates for the diagnosis of cervical tuberculous lymphadenitis.

Tuberculosis remains a major public health problem worldwide. A definitive and accurate diagnosis of tuberculosis in cervical lymphadenopathy is important because satisfactory results can be achieved with chemotherapy alone, obviating surgery. Recently, fine needle aspiration cytology (FNAC) has provided an alternative and easy procedure for collection of material for cytomorphologic and bacteriologic examination. But the detection rate for M. tuberculosis from the aspirate material is still low with Ziehl-Neelson stain and even with culture. The authors therefore performed polymerase chain reaction (PCR) for mycobacterial DNA sequences in 31 cases of cytodiagnosis of tuberculous lymphadenitis and compared conventional bacteriologic methods. Ziehl-Neelson staining for acid-fast bacilli (AFB) was positive in 3 cases (10%) in direct smears, and the cultures for M. tuberculosis were positive in 6 cases (19%). In 19 (61%) among 31 samples, mycobacterial DNA fragments were detected, using the PCR method. With combined conventional and PCR method, the rate of detection was increased to 68 percent high. In conclusion, PCR is the most sensitive technique in the demonstration of M. tuberculosis in patient with clinically suspected as tuberculosis, who have AFB stain or culture negative cytology. Combined conventional and PCR methods as well as cytologic findings are of further help in the detection and characterization of M. tuberculosis.

Biopsy, Needle↗
PubMed1996

When patients ask about assisted suicide. A viewpoint from Oregon.

The passage of the Oregon Death With Dignity Act has profound implications for the prevailing model of care for dying patients. Patients are already asking for assisted suicide. Most physicians have not been trained in evaluating these requests in a therapeutic way. We discuss the issues around the needs of dying patients and, regardless of the legal status, what to do when patients ask for a lethal dose of medication. With the tools to explore the meaning of these requests, physicians will be better able to understand and meet the needs of their dying patients.

Humans↗
PubMed1995

Effect of age on dopaminergic responses to protein feeding.

Renal excretory responses to protein feeding were compared in nine young (20-26 yr) and nine elderly (70-89 yr) men. Although protein increased excretion of dopamine and serotonin (5-HT, P < 0.001 for both), the basal excretion of dopamine and 5-HT was less in old than young men (P < 0.05). Protein increased sodium and water excretion in the young; responses in elderly for both were less (P < 0.025). Carbidopa markedly suppressed dopamine and 5-HT excretion in both young and old men. Carbidopa also attenuated protein-induced natriuresis and diuresis and raised serum aldosterone levels in the young but not in the old men. These age-related differences in dopamine and 5-HT excretion were not abolished by alterations in dietary NaCl. Thus, although dopamine excretion is decreased overall in elderly men, sodium and water excretion and aldosterone secretion in the old men were unaffected by alterations in dopamine production. These data suggest that impaired protein-induced natriuresis in the old men may be due to limitations in renovascular responses and that, in young men, dopamine and 5-HT may contribute to the protein-induced changes in renovascular function.

Adult↗
PubMed1995

Differential gene expression of renin and angiotensinogen in the TGR(mREN-2)27 transgenic rat.

Transgenic rats carrying the murine Ren-2 gene represent a monogenetic model of hypertension characterized by low plasma renin and high extrarenal expression of the transgene. The hypothesis has been raised that stimulated local reninangiotensin systems may be responsible for the development of hypertension in this model. This study analyzes the effects of the converting enzyme inhibitor lisinopril, which specifically interferes with the renin-angiotensin system, and the direct vasodilator dihydralazine on the renal and extrarenal expression of renin and angiotensinogen. A comparison of gene expression between heterozygous and homozygous transgenic and normal Sprague-Dawley rats was also performed. We demonstrate high sensitivity of blood pressure toward converting enzyme inhibition in transgenic TGR(mREN-2)27 rats. In the kidney, expression of the transgene and the endogenous renin gene increased, suggesting that both are modulated by lisinopril in a similar manner. On the other hand, blood pressure reduction by dihydralazine did not abolish renal renin suppression in transgenic rats, indicating that mechanisms different from direct effects of blood pressure account for renin suppression. Homozygosity for the transgene led to increased Ren-2 expression and higher blood pressure and had opposite effects on angiotensinogen expression compared with heterozygous rats. Cardiac hypertrophy was reduced by lisinopril but not dihydralazine and was positively correlated with cardiac angiotensinogen expression. Increased angiotensin II in the adrenal gland of TGR(mREN-2)27 rats, which overexpresses the transgene, provides evidence that this leads to enhanced generation of tissue angiotensin II. We conclude that expression of the mouse transgene, the endogenous rat renin gene, and the angiotensinogen gene is subject to differential tissue-specific regulation. Reversal of cardiovascular damage with the converting enzyme inhibitor but not dihydralazine suggests that angiotensin II generated locally may be involved in the pathogenesis of hypertension and structural changes in TGR(mREN-2)27 rats.

Angiotensin II↗
PubMed1995

Regulation of aldosterone biosynthesis by adrenal renin is mediated through AT1 receptors in renin transgenic rats.

The transgenic (TG) rat (mREN2)27 is characterized by overexpression of the additional mouse Ren-2d gene in the adrenal cortex with marked suppression of renal renin. We have previously shown that in salt-depleted TG rats enhanced activation of mineralocorticoid biosynthesis is associated with selective stimulation of adrenal renin. To investigate whether the local renin-angiotensin system regulates aldosterone biosynthesis in the adrenal cortex of TG rats, we studied the effects of the AT1-angiotensin subtype receptor antagonist DuP 753 on aldosterone production in 5-week-old TG rats during salt restriction. All the rats (n = 56) were shifted from regular chow to a diet containing only 0.04% NaCl for 1 week. The AT1-receptor antagonist DuP 753 (10 mg/kg per day in drinking water) was administered to 27 of these rats during low-salt diet. Subgroups of rats were killed at 0,4, and 7 days. Low-salt diet increased both adrenal renin activity (from 31 +/- 3 to 77 +/- 4 and 85 +/- 2 ng angiotensin I.h-1.mg protein-1 at 4 and 7 days, respectively; P < .001) and mRNA (by 68.4 +/- 10% and 80 +/- 17% from baseline, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1994

The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells.

The replication of human immunodeficiency virus type 1 (HIV-1) in nondividing host cells such as those of macrophage lineage is an important feature of AIDS pathogenesis. The pattern of HIV-1 replication is dictated, in part, by the nucleophilic property of the viral gag matrix (MA) protein, a component of the viral preintegration complex that facilitates nuclear localization of viral nucleic acids in the absence of mitosis. We now identify the accessory viral protein Vpr, as a second nucleophilic component that influences nuclear localization of viral nucleic acids in nondividing cells. Reverse transcription and nuclear localization of viral nucleic acids following infection of cells by viruses lacking Vpr or viruses containing mutations in a gag MA nuclear localization sequence were indistinguishable from the pattern observed in cells infected by wild-type HIV-1. These viruses retained the ability to replicate in both dividing and nondividing host cells including monocyte-derived macrophages. In contrast, introduction of both gag MA and Vpr mutations in HIV-1 attenuated nuclear localization of viral nucleic acids in nondividing cells and virus replication in monocyte-derived macrophages. These studies demonstrate redundant nucleophilic determinants of HIV-1 that independently permit nuclear localization of viral nucleic acids and virus replication in nondividing cells such as monocyte-derived macrophages. In addition, these studies provide a defined function for an accessory gene product of HIV-1.

Base Sequence↗
PubMed1994

Blunted oral body temperature response to MK-212 in cocaine addicts.

Previous studies have suggested that chronic cocaine administration may affect serotonergic function and that serotonin (5-HT) may be of importance in cocaine craving. Ten male cocaine addicts and 28 male normal controls were challenged with MK-212 (6-chlor-2-[1-piperazinyl]-pyrazine) (20 mg), a direct acting 5-HT receptor agonist which has affinity for a variety of 5-HT receptor subtypes, and placebo, on separate days. The plasma cortisol and prolactin (PRL) concentrations and oral body temperature responses to MK-212 and placebo were compared between groups. The temperature response to MK-212 was significantly blunted in cocaine addicts compared to normal controls. However, the plasma cortisol and PRL responses to MK-212 did not differ between the two groups. These results suggest selective alteration of presynaptic 5-HT1A or postsynaptic 5-HT2A/2C function in cocaine addicts.

Adult↗
PubMed1994

Effects of long-term right ventricular apical pacing on left ventricular perfusion, innervation, function and histology.

OBJECTIVES: The purpose of this study was to better understand the effects of long-term right ventricular pacing on left ventricular perfusion, innervation, function and histology. BACKGROUND: Long-term right ventricular apical pacing is associated with increased congestive heart failure and mortality compared with atrial pacing. The exact mechanism for these changes is unknown. In this study, left ventricular perfusion, sympathetic innervation, function and histologic appearance after long-term pacing were studied in dogs in an attempt to see whether basic changes might be present that might ultimately be associated with the adverse clinical outcome. METHODS: A total of 24 dogs were studied. Sixteen underwent radiofrequency ablation of the atrioventricular (AV) junction to produce complete AV block. Seven of these underwent long-term pacing from the right ventricular apex (ventricular paced group), and nine had atrial and right ventricular apical pacing with AV synchrony (dual-chamber paced group). A control group of eight dogs had sham ablations with normal AV conduction. These dogs had atrial pacing only. Regional perfusion and sympathetic innervation were studied in all dogs by imaging with thallium-201 and [I123]metaiodobenzylguanidine, respectively. The degree of innervation was also determined by assay of tissue norepinephrine levels. Left ventricular function was assessed by radionuclide ventriculography. Cardiac histology was studied with both light and electron microscopy. RESULTS: Mismatching of perfusion and innervation in the ventricular paced group was noted, with perfusion abnormalities of both the septum and free wall. Regional [I123]metaiodobenzylguanidine distribution was homogeneous. Tissue norepinephrine levels were elevated in both the ventricular and dual-chamber paced groups compared with the control group. No light or electron microscopic findings were noted in any groups. In the dual-chamber paced group, diastolic dysfunction was noted, with normal systolic function. CONCLUSIONS: Ventricular pacing resulted in regional changes in tissue perfusion and heterogeneity between perfusion and sympathetic innervation. Both ventricular and dual-chamber pacing were associated with an increase in tissue catecholamine activity. The abnormal activation of the ventricles via right ventricular apical pacing may result in multiple abnormalities of cardiac function, which may ultimately affect clinical outcome.

3-Iodobenzylguanidine↗
PubMed1994

Recent advances in the pharmacotherapy of schizophrenia.

The major advance in the psychopharmacology of schizophrenia has been the rediscovery of clozapine and the development of other novel antipsychotic drugs, all of which are superior to typical neuroleptic drugs with regard to extrapyramidal symptoms. Clozapine, the best studied of these agents, is also superior in efficacy with regard to psychopathology and cognitive function and has been shown not to cause tardive dyskinesia. A variety of other novel agents, e.g., risperidone, olanazpine, amperozide, seroquel, sertindole, zaprisidone and melperone, must be further studied to establish their efficacy relative to clozapine or the typical neuroleptics, or both. It is likely that these novel agents will displace the typical neuroleptic drugs as the primary treatment of schizophrenia.

Adult↗