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Biomedical subjects

M D Miller

Publications and source records attributed to M D Miller.

At least 73 records · Page 4Linked to original sources
PubMed1999

Which elderly depressed patients remain well on maintenance interpersonal psychotherapy alone?: report from the Pittsburgh study of maintenance therapies in late-life depression.

The aim of this study was to identify elderly depressed patients who can remain well on maintenance Interpersonal Psychotherapy (IPT) alone, after discontinuation of antidepressant medication. Using Cox proportional hazards models, increased severity of depression at pretreatment was associated with increased recurrence rates, to an extent greater in patients maintained on monthly IPT than in those maintained on nortriptyline. The long-term response to maintenance IPT was correctly identified in 20/25 cases by a pretreatment Hamilton score of > or = 20. Fourteen of sixteen patients with pretreatment scores of > or = 20 experienced recurrence of major depression on maintenance IPT, while 6/9 patients with pretreatment scores of less than 20 did not. (Fisher exact P = .01). The same pattern of recurrence in relation to severity was not evident in maintenance placebo, nortriptyline, or combination treatment. In addition, Hamilton scores during continuation treatment were lower (< or = 7) among those who remained well on maintenance IPT than among those who had recurrences. Elderly patients whose depressions are milder at baseline and who show excellent symptomatic remission during acute and continuation therapy may be good candidates for monthly maintenance IPT after initial successful treatment with antidepressant medication and psychotherapy.

Age Factors↗
PubMed1999

A double-blind, placebo-controlled assessment of nortriptyline's side-effects during 3-year maintenance treatment in elderly patients with recurrent major depression.

The authors assessed the severity of nortriptyline's side-effects in older patients with recurrent major depression during placebo-controlled, double-blind maintenance therapy. Data were from 37 patients completing 2-3 years of maintenance therapy; 29 were on nortriptyline and eight were on placebo. The authors detected a time-by-treatment interaction for dry mouth (greater in nortriptyline-treated patients), but no increased association of nortriptyline with constipation, weight change or orthostatic symptoms. Heart rate was consistently higher in nortriptyline-maintained patients as compared with placebo. The total 'side-effect' score on the Asberg Rating Scale, as well as complaints of physical tiredness, daytime sleepiness and nocturnal sleep disturbance, were related primarily to residual depression rather than treatment with nortriptyline.

Aged↗
PubMed1998

Endogenous p53 regulation and function in early stage Friend virus-induced tumor progression differs from that following DNA damage.

Erythroleukemia induced by the anemia strain of Friend virus occurs in two stages. The first stage results in rapid expansion of pre-leukemic proerythroblasts (FVA cells) dependent on erythropoietin (Epo) for differentiation and survival in vitro. The second stage is characterized by emergence of erythroleukemic clones (MEL cells) which typically bear activation of the ets-oncogene, PU.1/spi.1, and loss of functional p53. We developed a Friend virus-sensitive, p53-deficient mouse model to investigate the biological advantage conferred by p53-loss during tumor progression. Here we report p53 was not required for cell survival or growth arrest during differentiation of FVA cells, nor was p53 required for induction of apoptosis upon Epo withdrawal. However, we detected induction of the p21Cip1 cyclin-dependent kinase inhibitor gene during differentiation, which was markedly enhanced in the presence of p53. p53-dependent expression of p21Cip1 occurred in the absence of an increase in p53 mRNA and protein levels and was specific for p21Cip1, since expression of gadd45, mdm-2, cyclin G and bax were unaffected by p53. In contrast, treatment of FVA cells with DNA damaging agents led to rapid accumulation of p53 protein resulting in transcription of multiple p53-regulated genes, leading to either apoptosis or growth arrest, depending on the agent used. These data demonstrate that p53-dependent activities during differentiation of preleukemic erythroblasts are distinct from those observed in response to genotoxic agents. We propose that enhancement of p53-dependent gene expression during differentiation may represent a tumor suppressor function which is necessary to monitor differentiation of preleukemic cells and which is selected against during tumor progression.

Animals↗
PubMed1998

Nailfold capillary plexus visibility in relation to schizotypy.

High plexus visibility is a potential biological marker of a schizophrenia diathesis. Plexus visibility was assessed in college students endorsing schizotypal traits and normal controls. Twenty-two (nearly 14%) of the 160 schizotypal individuals displayed the trait. None of the controls (n = 99) showed high plexus visibility. These results provide supportive evidence for an association between increased plexus visibility and schizotypy.

Adult↗
PubMed1998

Time-dependent effects of acute ethanol administration on regional cerebral blood flow in the rat.

The present study investigated the role of the postinjection interval in determining the functional consequences of acute ethanol administration in the CNS. Regional cerebral blood flow (RCBF) was determined by the [14C]iodoantipyrine method in 33 brain structures of ethanol-naive Sprague-Dawley rats. In the first experiment, changes in RCBF were assessed 5 and 15 min after a 0.8 g/kg (i.p.) dose of ethanol or water. Five minutes after treatment, rates of RCBF were increased in the motor cortex, agranular insular cortex, and the olfactory tubercle compared to water controls. No significant differences compared to control were found at the 15-min time point, despite the continued presence of ethanol in the blood. Experiment 2 tested whether blood ethanol level was the sole determinant of this response to ethanol by comparing animals with the same blood ethanol level at the 5- and 15-min time points. Greater rates of RCBF were found at 5 min postinjection compared to 15 min, in the motor cortex, agranular insular cortex, caudate/putamen, cerebellum, and the lateral septum. These data demonstrate that the rates of cerebral blood flow are increased in regionally discrete portions of the rat brain shortly after ethanol administration. Furthermore, blood ethanol level is not the exclusive factor governing this functional response.

Animals↗
PubMed1998

Spontaneous vacuum pneumarthrography revisited: the significance of the vacuum phenomenon in the lateral compartment of the knee.

We report seven cases of spontaneous vacuum phenomenon of the lateral compartment of the knee. Previous reports of the vacuum phenomenon suggest that it is related to traction on a joint or the absence of an effusion. The presence of this finding on plain radiographs, or artifacts associated with it on magnetic resonance imaging, have been said to create a false-positive indication for meniscal tears, especially in the medial compartment. We describe plain radiographic, magnetic resonance, and arthroscopic findings in seven consecutive patients with vacuum phenomenon of the lateral compartment of the knee and conclude that this finding may be a true-positive indication for degenerative meniscal tears and chondrosis. The etiology of this finding and its long-term significance remains unclear.

Arthrography↗
PubMed1998

Nutrition and swallowing in pediatric neuromuscular patients.

The management of the patient with neuromuscular disease is complex. Every child should be seen as a distinct individual and therefore merits patient-specific assessment and intervention. This article reviews nutritional management using spinal muscular atrophy and Duchenne's muscular dystrophy as representative models. The history of nutritional intake, nutritional needs, and underlying medical problems with physical examination, anthropometric, body composition, and biochemical markers are all important parts of the assessment and should be done at regular intervals. Intervention may include calorie restriction or calorie supplementation. Treatment strategies that follow diagnosis of dysphagia include positioning, increased sensory input, or direct maneuvers, such as volume changes or thickening liquid. Percutaneous endoscopic gastrostomy can be safely placed in almost all situations with minimal risk. Patients benefit most from a multidisciplinary and systematic management program.

Adolescent↗
PubMed1998

Human immunodeficiency virus type 1 reverse transcriptase expressing the K70E mutation exhibits a decrease in specific activity and processivity.

Adefovir dipivoxil [9-(2-(bispivaloyloxymethyl)phosphonylmethoxyethyl)adenine (bis-POM PMEA)], an oral prodrug of adefovir (PMEA), is currently in phase III clinical testing for the treatment of human immunodeficiency virus-1 (HIV-1) infection. Previous in vitro experiments have shown that HIV-1 recombinant viruses expressing either a K65R or a K70E mutation in reverse transcriptase (RT) have reduced sensitivity to PMEA and that the K70E mutant also has impaired replication capacity in vitro. Genotypic analyses of samples from patients enrolled in a phase I/II clinical trial of adefovir dipivoxil demonstrated that the K70E RT mutation developed in two of 29 patients during extended therapy. To further investigate the molecular mechanisms involved in the resistance to PMEA, we cloned, expressed, and purified HIV-1 RT enzymes carrying either the K65R or K70E and, for comparison, the M184V mutation. The Km values of dNTPs for these mutant enzymes were not significantly altered from wild-type RT. The Ki values for the K65R mutant were increased from wild-type by 2-5-fold against a variety of inhibitors, whereas the Ki values for the M184V mutant were increased 12-fold specifically for 2', 3'-dideoxy-3'-thiacytidine (3TC) triphosphate. The Ki values for the K70E mutant were increased for PMEA diphosphate and 3TC triphosphate by 2-3-fold. These results are in agreement with antiviral drug susceptibility assay results. The three recombinant enzymes were also evaluated for their specific activities and processivities. All mutants were reduced in specific activity with respect to wild-type RT. In single-cycle processivity studies, the M184V mutant was, as expected, notably impaired. The K70E mutant was also slightly impaired, whereas the K65R mutant was slightly more processive than wild-type. These results with recombinant K70E RT are consistent with the reduced in vitro replication capacity of the K70E RT mutant of HIV-1 and further demonstrate that the K70E mutation confers minor PMEA and 3TC resistance to HIV-1.

Adenine↗
PubMed1998

Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from AIDS patients after prolonged adefovir dipivoxil therapy.

Adefovir dipivoxil [bis(pivaloyloxymethyl)-ester prodrug], an orally bioavailable prodrug of adefovir [9-(2-phosphonylmethoxyethyl)adenine], is currently in phase III clinical trials for the treatment of human immunodeficiency virus (HIV). In vitro experiments demonstrated that either a K65R or a K70E mutation in HIV reverse transcriptase (RT) was selected in the presence of adefovir, conferring a 16- or 9-fold decrease in susceptibility to adefovir, respectively. Previous data demonstrated that patients receiving adefovir dipivoxil monotherapy (125 mg daily) for 12 weeks experienced a median decrease in HIV RNA levels of 0.5 log10 copies/ml and that resistance to adefovir dipivoxil did not arise during that period. In the present investigation, a further study was undertaken to investigate whether RT mutations developed among viruses from patients who completed the 12-week study and who opted to enroll in a maintenance phase of prolonged (6- to 12-month) adefovir dipivoxil therapy (120 mg daily). Concomitant treatment with antiretroviral agents was permitted during the maintenance phase. The median decreases in HIV RNA levels for patients who completed 6 or 12 months of maintenance-phase dosing were 0.6 and 1.14 log10 copies/ml, respectively. The reductions in the HIV RNA levels were similar among patients who received adefovir dipivoxil with or without concomitant treatment with antiretroviral agents. Viruses from 8 of 29 patients dosed for up to 12 months developed RT mutations that were not present at baseline; these mutations may have been related to adefovir dipivoxil therapy. Viruses from two of the eight patients developed the K70E mutation while the patients were on therapy, but none of the viruses from patients developed the K65R RT substitution. Despite the development of RT mutations, sustained reductions (6 to 12 months) in viral load (> or = 0.7 log10 copies/ml decrease from baseline) were observed in all eight patients.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Effects of age at onset of first lifetime episode of recurrent major depression on treatment response and illness course in elderly patients.

OBJECTIVE: The goal of this study was to examine treatment outcome differences in relation to age at onset of first lifetime episode of recurrent major depression in elderly patients. METHOD: Patients were grouped as having early-onset (N = 129) or late-onset (N = 58) depression. Early onset was defined as having a first lifetime episode of major depression at age 59 or earlier; late onset was defined as age 60 or later. The two groups of patients were compared with respect to demographic and clinical characteristics, types of treatment given (nortriptyline and interpersonal psychotherapy), and treatment outcomes. RESULTS: The groups did not differ in the percentage of patients who remitted, recovered, or relapsed during continuation treatment or in the percentage who experienced a recurrence of major depression during the first year of maintenance treatment. However, early-onset patients took 5-6 weeks longer to achieve remission than did late-onset patients, and a higher proportion had a history of suicide attempts. CONCLUSIONS: These data suggest that age at lifetime onset of recurrent major depression does not influence short- or long-term treatment response in elderly patients treated with combined interpersonal psychotherapy and nortriptyline, with the exception of slowing the speed of remission in early-onset cases. Difference in remission speed may reflect the greater number of previous episodes in the early-onset patients. Nevertheless, the likelihood of a longer time to remission, together with a higher rate of past suicide attempts, suggests that elderly depressed patients with a history of early-onset illness need particularly careful management.

Age Factors↗
PubMed1998

How common is resistance to treatment in recurrent, nonpsychotic geriatric depression?

OBJECTIVE: Effective treatments are available for major depressive disorder in later life. The purpose of this study was to elucidate the frequency of treatment resistance among the elderly. METHOD: Treatment resistance, defined as lack of recovery despite combined pharmacotherapy and psychotherapy, was prospectively examined in 180 elderly patients in an episode of recurrent, nonpsychotic major depression who were referred to a university medical center for treatment. They received open acute and continuation treatment with nortriptyline and interpersonal psychotherapy. RESULTS: Among the 159 patients who completed acute treatment, 19 (11.9%) did not experience a remission of depression. In addition, nine patients who had achieved remission relapsed during continuation therapy and did not recover despite vigorous treatment. Hence, excluding dropouts, 18.4% of the patients met the criteria for treatment resistance by their lack of response to acute treatment or by relapsing during continuation therapy and not recovering subsequently despite further vigorous treatment. CONCLUSIONS: The study suggests a relatively low rate of resistance to treatment among depressed geriatric patients referred to a university tertiary care setting.

Academic Medical Centers↗
PubMed1998

A post hoc comparison of paroxetine and nortriptyline for symptoms of traumatic grief.

BACKGROUND: This report presents the results of an open-trial pilot study of paroxetine for symptoms of traumatic grief, compared with the effects of nortriptyline in an archival contrast group. METHOD: Data are presented on 15 subjects (4 men, 11 women), ranging in age from 40 to 79 years (mean age = 57 years), who experienced the loss of a spouse (N = 8), child (N =5), grandchild (N = 1), or parent (N = 1). Subjects were required to have a baseline score on the Inventory of Complicated Grief (ICG) of > or = 20. Treatment with paroxetine began at a median of 17 months (range, 6-139 months) after the loss. Paroxetine-treated subjects received a psychotherapy tailored for traumatic grief. Depressive symptoms were assessed by using the Hamilton Rating Scale for Depression (HAM-D). The ICG and the HAM-D were administered weekly over 4 months of paroxetine treatment (median dose = 30 mg/day). The group receiving paroxetine were then compared with a group (N = 22) participating in a separate trial of nortriptyline (median dose = 77.5 mg/day) for treatment of bereavement-related major depressive episodes. RESULTS: Level of traumatic grief symptoms (ICG) decreased by 53%, and depression ratings (HAM-D) decreased by 54% in paroxetine-treated subjects. Nortriptyline showed clinical effects comparable to those of paroxetine. CONCLUSION: Paroxetine may be an effective agent in the treatment of traumatic grief symptoms. A comparison of the paroxetine-treated group with a nortriptyline-treated group suggests that both agents have comparably beneficial effects on the symptoms of traumatic grief (as well as those of depression). However, the higher rate of diagnostic comorbidity in the paroxetine-treated group, together with the greater chronicity of their symptoms and the greater safety of paroxetine in overdose, leads us to favor paroxetine over nortriptyline for traumatic grief symptoms in general psychiatric practice. Further controlled evaluation of paroxetine for traumatic grief is necessary.

Adjustment Disorders↗
PubMed1998

Long-term ECG changes in depressed elderly patients treated with nortriptyline. A double-blind, randomized, placebo-controlled evaluation.

ECGs of 50 patients who completed a long-term nortriptyline (NT) study are presented at baseline, after 7 weeks on NT, and after 1 year. The ECGs of patients with preexisting cardiac disease were compared with non-cardiac patients. Significant ECG changes and increases in heart rate were observed by Week 7 and persisted at a mean of 55 weeks (range: 24-111) in patients who were continued on NT. No significant difference was found in long-term ECG effects in patients with preexisting cardiac disease; ECG changes reverted to baseline when placebo was substituted. Patients with known cardiac disease did not show significantly worse ECG changes on NT than non-cardiac patients.

Age Factors↗
PubMed1998

Recruitment methods for intervention research in bereavement-related depression. Five years' experience.

The authors compared various strategies for recruiting elderly subjects with bereavement-related depression into a randomized clinical trial. Over 5 years, they empaneled 65 patients from a total of 441 subjects screened (14.7%). Response to media advertisements was the single most effective strategy (54% of subjects). Another effective, but labor-intensive, strategy was using letters to bereaved spouses found through newspaper obituaries (14%); another 14% were referred by friends who had seen study advertisements. Information letters to healthcare providers yielded no study participants. Pathways to study participation did not differ as a function of race or gender and did not influence study retention or remission rates. Our experience suggests that successful intake depends on a personal mode of recruitment.

Advertising↗
PubMed1997

Intravirion generation of the C-terminal core domain of HIV-1 Nef by the HIV-1 protease is insufficient to enhance viral infectivity.

Wild-type HIV-1 is more infectious than nef-deleted HIV-1 in both limiting dilution and single-cycle infectivity assays. Moreover, Nef expression from a separate plasmid in the virus-producing cells is capable of restoring the infectivity of genetically nef-deficient HIV-1. These observations indicate that the virion itself is altered by Nef expression to promote viral infectivity. Sucrose gradient-purified HIV-1 virions contain full-length Nef protein and its inclusion is dependent on N-terminal myristylation of Nef. As myristylation-defective mutants of Nef do not enhance infectivity, incorporation of Nef into virions may mediate the enhanced infectivity. Studies with recombinant Nef have further shown that HIV-1 protease can cleave Nef into two polypeptides, a 20-kDa C-terminal core domain and a small N-terminal domain. Our analysis of purified HIV-1 virions also showed a 20-kDa form of Nef. The generation of this 20-kDa form of Nef was inhibited by an HIV-1 protease inhibitor, and its C-terminal core domain identity was confirmed through epitope-tagging. Immunoblots of virions demonstrated that 60-80% of the incorporated Nef is cleaved by the HIV-1 protease. This finding raised the possibility that the Nef core domain, which may no longer be tethered to the membrane due to absence of an N-terminal myristyl anchor, might mediate the enhanced infectivity. Therefore, a panel of mutants surrounding the proteolytic cleavage site in Nef were analyzed for effects on cleavage and enhancement of viral infectivity. Although some Nef mutants both failed to cleave and did not enhance viral infectivity, other mutants proved discordant in these functions. Specifically, two mutants that contained point mutations in the N-terminal domain cleaved normally, hence generating wild-type Nef core domain, yet failed to enhance infectivity. Thus, although the majority of the Nef protein in HIV-1 virions is cleaved by the viral protease into a 20-kDa C-terminal core domain, generation of this core domain of Nef appears insufficient to enhance HIV-1 infectivity. These findings suggest that protease cleavage of the Nef protein in virions is irrelevant for the infectivity function of Nef.

Animals↗
PubMed1997

Simulation of electrostatic and hydrodynamic properties of Serratia endonuclease.

We analyze the electrostatic and hydrodynamic properties of a nuclease from the pathogenic gram-negative bacterium Serratia marcescens using finite-difference Poisson-Boltzmann methods for electrostatic calculations and a bead-model approach for diffusion coefficient calculations. Electrostatic properties are analyzed for the enzyme in monomeric and dimeric forms and also in the context of DNA binding by the nuclease. Our preliminary results show that binding of a double-stranded DNA dodecamer by nuclease causes an overall shift in the charge of the protein by approximately three units of elementary charge per monomer, resulting in a positively charged protein at physiologic pH. In these calculations, the free enzyme was found to have a negative (-1 e) charge per monomer at pH 7. The most dramatic shift in pKa involves His 89 whose pKa increases by three pH units upon DNA binding. This shift leads to a protonated residue at pH 7, in contrast to the unprotonated form in the free enzyme. DNA binding also leads to a decrease in the energetic distances between the most stable protonation states of the enzyme. Dimerization has no significant effect on the electrostatic properties of each of the monomers for both free enzyme and that bound to DNA. Results of hydrodynamic calculations are consistent with the dimeric form of the enzyme in solution. The computed translational diffusion coefficient for the dimer model of the enzyme is in very good agreement with measurements from light scattering experiments. Preliminary electrooptical calculations indicate that the dimer should possess a large dipole moment (approximately 600 Debye units) as well as substantial optical anisotropy (limiting reduced linear electric dichroism of about 0.3). Therefore, this system may serve as a good model for investigation of electric and hydrodynamic properties by relaxation electrooptical experiments.

Endonucleases↗
PubMed1997

Structure of bacterial luciferase beta 2 homodimer: implications for flavin binding.

The crystal structure of the beta 2 homodimer of Vibrio harveyi luciferase has been determined to 2.5 A resolution by molecular replacement. Crystals were grown serendipitously using the alpha beta form of the enzyme. The subunits of the homodimer share considerable structural homology to the beta subunit of the alpha beta luciferase heterodimer. The four C-terminal residues that are disordered in the alpha beta structure are fully resolved in our structure. Four peptide bonds have been flipped relative to their orientations in the beta subunit of the alpha beta structure. The dimer interface of the homodimer is smaller than the interface of the heterodimer in terms of buried surface area and number of hydrogen bonds and salt links. Inspection of the subunits of our structure suggests that FMNH2 cannot bind to the beta 2 enzyme at the site that has been proposed for the alpha beta enzyme. However, we do uncover a potential FMNH2 binding pocket in the dimer interface, and we model FMN into this site. This proposed flavin binding motif is consistent with several lines of biochemical and structural evidence and leads to several conclusions. First, only one FMNH2 binds per homodimer. Second, we predict that reduced FAD and riboflavin should be poor substrates for beta 2. Third, the reduced activity of beta 2 compared to alpha beta is due to solvent exposure of the isoalloxazine ring in the beta 2 active site. Finally, we raise the question of whether our proposed flavin binding site could also be the binding site for flavin in the alpha beta enzyme.

Binding Sites↗