Biomedical subjects

M D Miller

Publications and source records attributed to M D Miller.

At least 37 records · Page 2Linked to original sources

PubMed2001

Treatment outcome in suicidal vs. non-suicidal elderly patients.

The authors investigated treatment outcome in elderly suicidal and non-suicidal patients with recurrent major depression. Patients without suicidal ideation in the current episode (Non-Ideators; n=150) were compared with 30 patients who expressed suicidal ideation (Ideators). Patients received combined pharmacotherapy and psychotherapy during acute and continuation treatment. Ideators had higher numbers of lifetime suicide attempts and reported significantly higher levels of depression, anxiety, and hopelessness before starting treatment. Ideators and Non-Ideators had almost identical remission rates (77% vs. 78%), but Ideators had higher relapse rates during continuation treatment (26% vs. 13%) and were more likely to receive augmentation pharmacotherapy. Anxiety and use of adjunctive medication, but not suicidal ideation, were negatively related to both remission and relapse. Our data suggest that elderly suicidal patients have an overall favorable treatment outcome. However, treatment response may be more brittle and may require the continuing use of adjunctive medications to prevent early relapse.

Aged↗

PubMed2001

Increased drug susceptibility of HIV-1 reverse transcriptase mutants containing M184V and zidovudine-associated mutations: analysis of enzyme processivity, chain-terminator removal and viral replication.

The presence of the HIV reverse transcriptase (RT) resistance mutation, M184V, induced by lamivudine and abacavir treatment results in increased tenofovir, adefovir and zidovudine susceptibility for HIV-1 with zidovudine-associated RT mutations in vitro. Treatment with oral prodrugs of tenofovir and adefovir has resulted in substantial HIV-1 RNA reductions in antiretroviral-experienced patient populations who have lamivudine- and zidovudine-resistant HIV-1. An enzymatic analysis was undertaken to elucidate the mechanisms of altered drug susceptibilities of HIV-1 containing zidovudine-associated mutations in the presence or absence of M184V. The inhibition constants (Ki) for the active metabolites of tenofovir, adefovir and zidovudine did not vary significantly between recombinant mutant and wild-type RT enzymes. Although increased removal of chain-terminating inhibitors by pyrophosphorolysis and ATP-dependent unblocking correlated with reduced susceptibility of viruses with zidovudine-associated mutations, a reduction in the removal of chain-terminators was not observed, which would explain the increased drug susceptibility of mutants containing M184V plus zidovudine-associated mutations. However, analyses of single-cycle processivity of the mutant RT enzymes on heteropolymeric RNA templates showed that all M184V-containing mutant RT enzymes were less processive than wild-type RT, most notably for mutants expressing both zidovudine-associated mutations and M184V. Similarly, the in vitro replication capacity of a mutant virus expressing a zidovudine-associated mutation and M184V was significantly reduced compared with wild-type virus. The observed decrease in enzymatic processivity of the M184V-expressing RT enzymes might result in decreased viral replication, which then might contribute to the increased drug susceptibility of HIV-1 expressing these RT mutations.

Anti-HIV Agents↗

PubMed2001

Mechanisms of HIV-1 nucleoside reverse transcriptase inhibitor resistance: is it all figured out?

The mechanistic basis for some examples of HIV-1 NRTI-resistance can be examined using altered incorporation of nucleoside analogs and surveying what is known about the more recently described mechanisms of chain-terminator removal. The complexity of these resistance mechanisms and the interplay with other factors that contribute to NRT1 resistance are only just beginning to be appreciated.

Adenine↗

PubMed2001

Interpersonal psychotherapy for late-life depression: past, present, and future.

Interpersonal psychotherapy (IPT) has demonstrated efficacy in protecting against a recurrence of major depression in elderly subjects when used alone on a monthly basis and when combined with antidepressant medication. The authors summarize their experience using IPT over the past 10 years and discuss a variety of treatment correlates. In addition, preliminary results using IPT combined with paroxetine in depressed elders reveals no difference in remission rates between cognitively intact and cognitively impaired depressed elders.

Age of Onset↗

PubMed2001

A twelve-week, double-blind, randomized comparison of nortriptyline and paroxetine in older depressed inpatients and outpatients.

Selective serotonin reuptake inhibitors may be less efficacious than tricyclic antidepressants in the treatment of severe depression in older patients. The authors compared the 12-week clinical outcome of older depressed patients treated with nortriptyline or paroxetine in a double-blind randomized comparison in 116 psychiatric inpatients and outpatients (mean age: 72+/-8 years) who presented with a major depressive episode or melancholic depression. Discontinuation and response rates were compared in patients who began or who completed treatment. The discontinuation rate due to side effects was significantly higher with nortriptyline than with paroxetine (33% vs. 16%). There were no significant differences between the rates of response in the Intent-to-Treat analysis (nortriptyline: 57% vs. paroxetine: 55% ), or the Completer analysis (nortriptyline: 78% vs. paroxetine: 84%). Although paroxetine appears to be better tolerated than nortriptyline, the efficacy of these two drugs does not appear to differ in the acute treatment of older depressed patients, including hospitalized patients and those with melancholic features.

Aged↗

PubMed2001

The assessment of unidimensionality of normal and lognormal data: a look at two nonparametric procedures.

In this Monte Carlo study, the Type I error rate and the power of the Stout T procedure (DIMTEST) and the Holland-Rosenbaum procedure (HR) were examined for normal and lognormal data sets. Both procedures are based on a nonparametric item response model, where the key assumption is the item response function is monotonically nondecreasing. The two procedures performed adequately under certain conditions for both normal and lognormal data sets. Of the two, however, the Stout T procedure showed adequate power under more conditions than the Holland-Rosenbaum procedure.

Models, Statistical↗

PubMed2000

Efavirenz- and adefovir dipivoxil-based salvage therapy in highly treatment-experienced patients: clinical and genotypic predictors of virologic response.

OBJECTIVE: To determine the impact of prior nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy, genotypic resistance, and other variables on response to efavirenz (EFV)- and adefovir dipivoxil (ADV)-based salvage therapy. DESIGN: Retrospective clinical cohort study. SETTING: One university and one community-based HIV clinic. STUDY SUBJECTS: All 33 patients who were coenrolled in both the EFV and ADV expanded access programs. INTERVENTIONS: Patients received EFV 600 mg/day and ADV 120 mg/day in addition to other antiretroviral agents. OUTCOME MEASURE: HIV viral load (<500 copies/ml) at 12 and 24 weeks. RESULTS: 10 of 33 (30%) patients at 12 weeks and 8 of 33 (24%) patients at 24 weeks had viral loads <500 copies/ml. Prior NNRTI use and a history of any NNRTI-associated mutations predicted failure. Patients with Y181C or G190A single mutations had an initial greater magnitude of viral load suppression than those with K103N, but this advantage was short lived. No one with any NNRTI mutations responded with a viral load <500 copies/ml at 12 or 24 weeks. CONCLUSIONS: EFV/ADV-based salvage yielded viral load suppression at 24 weeks in 42% (8 of 19) of patients who were highly NRTI and protease inhibitor experienced but NNRTI naive. NNRTI-experienced study subjects had a poor response regardless of the specific NNRTI resistance mutation they harbored.

Adenine↗

PubMed2000

Smooth pursuit eye tracking and visual fixation in psychosis-prone individuals.

Subjects identified by Perceptual Aberration-Magical Ideation (Per-Mag) scores (n=97), Social Anhedonia (SocAnh) scores (n=45), and Physical Anhedonia (PhysAnh) scores (n=31) as well as normal controls (n=94), underwent psychophysiological and clinical assessment. This is the first published investigation of pursuit system functioning in three groups of questionnaire-identified at-risk individuals. Pursuit during a simple non-monitor tracking task was measured using root-mean-square error (RMSE) scores and pursuit gain scores. Fixation performance was measured in terms of number of saccades away from the central fixation point. The at-risk subjects were more likely to display aberrant smooth pursuit tracking than controls, though there were no significant differences between the at-risk subjects endorsing items relevant to positive-symptom schizotypy and those endorsing items pertaining to negative-symptom schizotypy. The groups did not differ significantly in their visual fixation performance. Participants were also evaluated for the presence of Axis I symptomatology and psychotic-like experiences. Neither the experimental subjects nor the control subjects displayed a significant association between ocular motor performance and psychotic-like experiences. These findings are consistent with prior evidence that pursuit tracking is a trait characteristic, independent of clinical status.

Adolescent↗

PubMed2000

Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells.

Integrase is essential for human immunodeficiency virus-type 1 (HIV-1) replication; however, potent inhibition of the isolated enzyme in biochemical assays has not readily translated into antiviral activity in a manner consistent with inhibition of integration. In this report, we describe diketo acid inhibitors of HIV-1 integrase that manifest antiviral activity as a consequence of their effect on integration. The antiviral activity of these compounds is due exclusively to inhibition of one of the two catalytic functions of integrase, strand transfer.

Acetoacetates↗

PubMed2000

Pectoralis major muscle and tendon tears: diagnosis and grading using magnetic resonance imaging.

OBJECTIVE: To assess the accuracy and utility of magnetic resonance (MR) imaging in the detection and grading of pectoralis major muscle and tendon tears. DESIGN AND PATIENTS: A retrospective review was carried out of 10 patients referred for MR imaging for suspected pectoralis muscle injury and possible operative therapy. The pectoralis muscle and tendon were imaged using thin (3-4 mm) axial sections with a variety of sequences combined for anatomical delineation (T1-weighted SE or PD SE) and fluid detection (T2-weighted SE, T2-weighted FSE with fat suppression, or STIR). Surgical correlation was available in six patients. Clinical follow-up was available in four patients treated by nonoperative therapy. RESULTS: MR imaging identified five complete tears, four partial tears and one normal tendon. One complete and one partial tear were at the myotendinous junction. The remaining seven injuries were at the enthesis. Surgical correlation consisted of five complete tears and one partial tear. One complete and one partial tear were at the myotendinous junction with the remaining four complete tears at the enthesis. The MR interpretation and surgical findings were in agreement in all six cases. All four patients treated with nonoperative therapy demonstrated improvement at a clinical follow-up examination, with restoration of function and strength consistent with a healed prior partial injury. CONCLUSION: MR imaging is accurate and useful in detecting and grading tears involving the pectoralis major muscle and tendon, facilitating the identification of patients with complete tears who are candidates for operative therapy.

Adolescent↗

PubMed2000

Knee dislocation. Complications of nonoperative and operative management.

Because of the nature and extreme severity of the injury, complications will continue to be a common denominator in traumatic knee dislocations. The major complications that cause significant morbidity, including amputation and death, are now relatively infrequent. Prompt recognition and treatment of these complications are of utmost importance to assure functional viability of the extremity. These complications must continue to be addressed preoperatively and postoperatively. Minor complications will persist after significant knee surgery. New complications will evolve as newer techniques, instrumentation, and procedures are introduced. Ligament reconstructive surgery is relatively new and technically demanding. The surgeon must continue to use meticulous technique and attention to detail. Orthopedic surgeons must continue to closely evaluate the procedures they perform, making sure they are as technically correct as possible. Each surgeon must observe and determine what technique will be of true benefit to the patient. Most complications that do occur can be corrected or at least improved if they are handled early and with a true understanding of the problem.

Bone Screws↗

PubMed2000

Retroviral cDNA integration: stimulation by HMG I family proteins.

To replicate, a retrovirus must synthesize a cDNA copy of the viral RNA genome and integrate that cDNA into a chromosome of the host. We have investigated the role of a host cell cofactor, HMG I(Y) protein, in integration of human immunodeficiency virus type 1 (HIV-1) and Moloney murine leukemia virus (MoMLV) cDNA. Previously we reported that HMG I(Y) cofractionates with HIV-1 preintegration complexes (PICs) isolated from freshly infected cells. PICs depleted of required components by treatment with high concentrations of salt could be reconstituted by addition of purified HMG I(Y) in vitro. Here we report studies using immunoprecipitation that indicate that HMG I(Y) is associated with MoMLV preintegration complexes. In mechanistic studies, we show for both HIV-1 and MoMLV that each HMG I(Y) monomer must contain multiple DNA binding domains to stimulate integration by HMG I(Y)-depleted PICs. We also find that HMG I(Y) can condense model HIV-1 or MoMLV cDNA in vitro as measured by stimulation of intermolecular ligation. This reaction, like reconstitution of integration, depends on the presence of multiple DNA binding domains in each HMG I(Y) monomer. These data suggest that binding of multivalent HMG I(Y) monomers to multiple cDNA sites compacts retroviral cDNA, thereby promoting formation of active integrase-cDNA complexes.

DNA, Complementary↗

PubMed2000

Prophylactic and therapeutic benefits of short-term 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) administration to newborn macaques following oral inoculation with simian immunodeficiency virus with reduced susceptibility to PMPA.

Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of human pediatric AIDS to study pathogenesis and to develop intervention strategies aimed at preventing infection or delaying disease progression. In previous studies, we demonstrated that 9-¿2-(R)-(phosphonomethoxy)propylădenine (PMPA; tenofovir) was highly effective in protecting newborn macaques against infection with virulent wild-type (i.e., drug-susceptible) SIVmac251. In the present study, we determined how reduced drug susceptibility of the virus inoculum affects the chemoprophylactic success. SIVmac055 is a virulent isolate that has a fivefold-reduced in vitro susceptibility to PMPA, associated with a K65R mutation and additional amino acid changes (N69T, R82K, A158S, S211N) in reverse transcriptase (RT). Eight newborn macaques were inoculated orally with SIVmac055. The three untreated control animals became SIVmac055 infected; these animals had persistently high viremia and developed fatal immunodeficiency within 3 months. Five animals were treated once daily with PMPA (at 30 mg/kg of body weight) for 4 weeks, starting 24 h prior to oral SIVmac055 inoculation. Two of the five PMPA-treated animals had no evidence of infection. The other three PMPA-treated infant macaques became infected but had a delayed viremia, enhanced antiviral antibody responses, and a slower disease course (AIDS in 5 to 15 months). No reversion to wild-type susceptibility or loss of the K65R mutation was detected in virus isolates from any of the PMPA-treated or untreated SIVmac055-infected animals. Several additional amino acid changes developed in RT, but they were not exclusively associated with PMPA therapy. The results of this study suggest that prophylactic administration of PMPA to human newborns and to adults following exposure to human immunodeficiency virus will still be beneficial even in the presence of viral variants with reduced susceptibility to PMPA.

Adenine↗

PubMed2000

Local loss of proprioception results in disruption of interjoint coordination during locomotion in the cat.

To investigate the role of localized, proprioceptive feedback in the regulation of interjoint coordination during locomotion, we substantially attenuated neural feedback from the triceps surae muscles in one hindlimb in each of four cats using the method of self-reinnervation. After allowing the recovery of motor innervation, the animals were filmed during level and ramp walking. Deficits were small or undetectable during walking on the level surface or up the ramp, behaviors that require a large range of forces in the triceps surae muscles. During walking down the ramp, when the triceps surae muscles normally undergo active lengthening, the ankle joint underwent a large yield and the coordination between ankle and knee was disrupted. The correlation of the deficit with the direction of length change and not muscle force suggested that a loss of feedback from muscle spindle receptors was primarily responsible for the deficit. These results indicate an important role for the stretch reflex and stiffness regulation during locomotion.

Animals↗

PubMed2000

Fluvoxamine pharmacotherapy of anxiety disorders in later life: preliminary open-trial data.

The authors present data from an open trial of fluvoxamine (median daily dosage: 200 mg) in the treatment of generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder in 19 older outpatients (mean age = 66.8). Of the 12 subjects completing the 21-week trial, 8 achieved a good response (50% reduction in symptom measures) and 7 were rated as much or very much improved. Fluvoxamine pharmacotherapy also had a significant effect in reducing comorbid depressive symptoms and in increasing levels of functioning. These data support the effectiveness of fluvoxamine in older subjects with anxiety disorders (particularly generalized anxiety disorder) and warrant further double-blind, placebo-controlled evaluation.

Aged↗

PubMed2000

Effect of nortriptyline and paroxetine on extrapyramidal signs and symptoms: A prospective double-blind study in depressed elderly patients.

Selective serotonin-reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) have been reported to induce extrapyramidal signs and symptoms (EPS). The authors examined the change from baseline EPS, measured by an objective rating scale, in a group of elderly depressed patients participating in an ongoing randomized, double-blind comparison of nortriptyline and paroxetine. Mild baseline EPS were present in both groups. After 6 weeks of antidepressant treatment, patients in the nortriptyline group showed a significant decrease in total EPS scores. Patients in the paroxetine group showed a similar decrease in EPS from baseline, which did not reach statistical significance. There was no significant difference between nortriptyline and paroxetine in the change in EPS.

Aged↗

PubMed1999

The active site of Serratia endonuclease contains a conserved magnesium-water cluster.

Serratia endonuclease is an important member of a class of magnesium dependent nucleases that are widely distributed in nature. Here, we describe the location and geometry of a magnesium-water cluster within the active site of this enzyme. The sole protein ligand of the magnesium atom is Asn119; this metal ion is also associated with five water molecules to complete an octahedral coordination complex. These water molecules are very well ordered and there is no evidence of rotational disorder or motion. Glu127 and His89 are located nearby and each is hydrogen bonded to water molecules in the coordination sphere. Asp86 is not chelated to the magnesium or its surrounding water molecules. Results of kinetics and site-specific mutagenesis experiments suggest that this metal-water cluster contains the catalytic metal ion of this enzyme. All residues which hydrogen bond to the water molecules that coordinate the magnesium atom are conserved in nucleases homologous to Serratia endonuclease, suggesting that the water cluster is a conserved feature of this family of enzymes. We offer a detailed structural comparison to one other nuclease, the homing endonuclease I-PpoI, that has recently been shown, in spite of a lack of sequence homology, to share a similar active site geometry to Serratia endonuclease. Evidence from both of these structures suggests that the magnesium of Serratia nuclease participates in catalysis via an inner sphere mechanism.

Amino Acid Sequence↗

PubMed1999

SQ: a program for rapidly producing pharmacophorically relevent molecular superpositions.

A new method SQ has been developed to provide fast, automatic, and objective pairwise three-dimensional molecular alignments. SQ uses an atom-based clique-matching step followed by an alignment scoring function that has been parametrized to recognize pharmacologically relevant atomic properties. Molecular alignments from SQ are consistent with known drug-receptor interactions. We demonstrate this with six pairs of receptor-ligand complexes from the Brookhaven Protein Data Bank. The SQ-generated alignment of one isolated ligand onto another is shown to approximate the alignment of the ligands when the receptors are superimposed. SQ appears to be better than its predecessor SEAL (Kearsley and Smith, Tetrahedron Comput. Methodol. 1990, 3, 615-633) in this regard. SQ has been tailored so that, given one molecule as a probe, it can be used to routinely scan large chemical databases for which precomputed conformations have been stored. The SQ score, a measure of 3D similarity of each candidate molecule to the probe, can be used to rank compounds for the purposes of chemical screening. We demonstrate this with three probes (a thrombin inhibitor, an HIV protease inhibitor, and a model for angiotensin II). In each case SQ can preferentially select from the MDDR database other compounds with the same activity as the probe. We further show, using the angiotensin example, how SQ can identify topologically diverse compounds with the same activity.

Algorithms↗