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Biomedical subjects

M D Miller

Publications and source records attributed to M D Miller.

At least 19 recordsLinked to original sources
PubMed2006

In vitro human immunodeficiency virus type 1 resistance selections with combinations of tenofovir and emtricitabine or abacavir and lamivudine.

Human immunodeficiency virus type 1 (HIV-1) resistance development was evaluated in vitro by using combinations of the drugs tenofovir and emtricitabine or abacavir and lamivudine, as well as by using the compounds individually. Emtricitabine- and lamivudine-resistant HIV-1 isolates with the M184I or M184V mutation in reverse transcriptase were readily selected in the cultures with emtricitabine alone, lamivudine alone, and the two drug combinations and conferred high-level resistance to emtricitabine and lamivudine. Tenofovir-resistant HIV-1 isolates with the K65R mutation occurred in both the culture with tenofovir alone and the culture with the combination of emtricitabine and tenofovir. The S68N and S68K mutations were also observed in the tenofovir cultures, with no detectable impact on resistance, suggesting a possible compensatory role in viral fitness. At low concentrations of emtricitabine and tenofovir, the M184I mutation appeared first, followed by the K65R mutation, in a subset of viruses. At intermediate concentrations of emtricitabine and tenofovir, viruses harboring the K65R mutation or a novel K65N and K70R double mutation grew before they gave rise to mutants with K65R and M184V/I double mutations at higher emtricitabine concentrations. Abacavir resistance was characterized by the accumulation of the M184V, Y115F, and K65R mutations in the abacavir culture, while the M184V and L74V mutations were selected in combination with lamivudine. In the presence of the abacavir resistance mutations, viral growth was strong even in the presence of high concentrations of abacavir. In contrast, viral growth was markedly impaired in the cultures with high tenofovir concentrations, even in the presence of K65R. In conclusion, these studies show that HIV-1 mutants with a K65R and M184V genotype are generated under maximum selection pressure from the combination of tenofovir and emtricitabine.

Adenine↗
PubMed2006

Lower limb fracture, cognitive impairment and risk of subsequent malnutrition: a prospective evaluation of dietary energy and protein intake on an orthopaedic ward.

OBJECTIVE: To report the dietary energy and protein intake of undernourished older adults (with and without cognitive impairment) admitted to hospital following a lower limb fracture and to determine whether dietary intakes met estimated requirements. DESIGN: An observational study of a sequential sample. SETTING: The orthopaedic ward of a South Australian metropolitan teaching hospital. SUBJECTS: Sixty-eight patients aged > or =70 years screened as undernourished and admitted to hospital following lower limb fracture (50% cognitively impaired) provided 3 to 5 days of dietary data. MAJOR OUTCOME METHODS: Dietary energy and protein intake. METHODS: Dietary assessment using plate waste methodology and snack record charts commenced within 6 days postinjury and continued for up to five consecutive days or until discharge. Estimated resting energy requirements were calculated and adjusted for activity equivalent to bed rest and physiological stress. Protein requirements were calculated as 1 g/kg/day. Cognition was assessed using the Short Portable Mental Status Questionnaire. RESULTS: Cognitively impaired participants and those without cognitive impairment consumed, mean (95% CI) respectively, 3661 kJ/day (3201, 4121) versus 4208 kJ/day (3798, 4619) and 38 g (33, 44) versus 47 g (41, 52) protein/day. Cognitively impaired participants consumed mean (95% CI) 48% (43, 53) of estimated total energy expenditure and 78% (69, 87) of estimated protein requirements. CONCLUSIONS: Orthopaedic fracture patients at greatest nutritional risk, including those with cognitive impairment, do not achieve estimated energy or protein requirements from diet alone. Effective methods of achieving requirements in this vulnerable group are needed before improvements in outcomes will be observed.

Aged↗
PubMed2006

Activities of daily living in children with hemiplegic cerebral palsy: a cross-sectional evaluation using the Assessment of Motor and Process Skills.

Upper limb impairment can affect the ability to perform and participate in activities of daily living. The level of activity and participation limitation in the home environment for children with hemiplegic cerebral palsy (CP) is poorly understood. A greater understanding of these limitations could be used to provide targeted and appropriate intervention programmes. Level of activity and participation limitation were investigated, with the use of the Assessment of Motor and Process Skills (AMPS) in a representative sample of 54 South Australian children (31 males, 23 females) with hemiplegic CP, aged 3 to 12 years (mean age 7y 4mo [SD 2y 5mo]). Two AMPS tasks that were familiar to the child were performed in the home under the supervision of a trained occupational therapist. Findings suggested that younger children (3-8y) performed significantly better than older children (9-12y) for motor skill ability (0.46 vs 0.09, p=0.041) but not for process skill ability (-0.25 vs -0.28, p=0.885). Functional performance for the sample was below that of age-matched normative data. Motor performance in activities of daily living as detected by the AMPS seemed to worsen with age in children with hemiplegic CP. Further investigation into what can influence this outcome is required.

Activities of Daily Living↗
PubMed2006

Efalizumab-induced autoimmune pancytopenia.

Efalizumab is a recombinant, humanized monoclonal anti-CD11a antibody used for the treatment of moderate to severe plaque psoriasis. Immune-mediated thrombocytopenia and anaemia have previously been reported with this therapy. We describe the first case of immune-mediated pancytopenia in a patient treated with efalizumab. Close monitoring of all blood cell counts is warranted in light of this case.

Adult↗
PubMed2006

Resistance development over 144 weeks in treatment-naive patients receiving tenofovir disoproxil fumarate or stavudine with lamivudine and efavirenz in Study 903.

OBJECTIVE: Study 903 was a 144-week, randomized, double-blind, active-controlled study of tenofovir disoproxil fumarate (TDF) therapy in treatment-naive HIV-1-infected patients. Patients received either TDF (n = 299) or stavudine (d4T) (n = 301) with lamivudine (3TC) and efavirenz (EFV). Resistance analyses were performed at baseline and at virological failure to determine the effects of baseline resistance and the patterns of resistance at virological failure. METHODS: Plasma HIV-1 from patients at baseline and at virological failure (>400 HIV-1 RNA copies/mL at week 144 or early discontinuation) was analysed phenotypically and by population sequencing. RESULTS: Sixteen per cent of patients were classified as having virological failure (47 on TDF and 49 on d4T; P = 0.91). Patients with non-B HIV-1 subtypes or baseline nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations responded similarly to the overall population. Resistance to EFV (K103N and others) or 3TC (M184V) developed most frequently (8.3% and 5.8%, respectively) and similarly in the two arms. In the d4T arm, a variety of NRTI mutations developed: K65R (n = 2), L74V (n = 2), V75M (n = 1), and T69A + Y115H (n = 1). K65R developed in eight TDF patients (2.7%); in seven of these eight patients, within 48 weeks. All eight patients began new regimens with a protease inhibitor (PI) and NRTIs, including two patients who remained on TDF; five of the eight patients achieved HIV RNA <50 copies/mL in second-line therapy with the remaining patients having no follow-up or being nonadherent. CONCLUSIONS: Treatment of HIV-1 with TDF, 3TC and EFV was highly effective, with <3% of patients developing resistance to TDF over 144 weeks.

Adenine↗
PubMed2005

Nutritional status and clinical outcomes of older patients in rehabilitation.

BACKGROUND: Malnutrition is associated with poor outcomes in older adults and those admitted to rehabilitation may be particularly at risk. Objective To assess the nutritional status and outcomes of older adults in rehabilitation. SUBJECTS AND METHODS: We recruited 133 adults > or = 65 years from consecutive rehabilitation admissions. Nutritional status was assessed using the mini nutritional assessment, body mass index (BMI) and corrected arm muscle area (CAMA). Outcomes measured included length of stay, admission to higher level care, function and quality of life (QOL). RESULTS: Sixty-two (47%) subjects were well nourished, 63 (47%) at risk of malnutrition and eight (6%) malnourished. Twenty-two (17%) and 27 (20%) were below the desirable reference values for BMI and CAMA respectively. Subjects at risk of malnutrition/malnourished had longer length of stay (P = 0.023) and were more likely to be admitted to higher level care (P < 0.05). These subjects also had poorer function on admission (P < 0.001) and 90 days (P = 0.002) and QOL on admission (P < 0.008) and 90 days (P = 0.001). Those with low CAMA were twice as likely to be admitted to higher level care (P < 0.05) and had poorer function at 90 days (P = 0.017). CONCLUSIONS: Over half our sample was identified as at risk of malnutrition or malnourished and this was associated with poorer clinical outcomes.

Aged↗
PubMed2005

Activity of adefovir dipivoxil against all patterns of lamivudine-resistant hepatitis B viruses in patients.

One hundred and thirty-one post-liver transplantation patients with chronic hepatitis B and failing lamivudine therapy with detectable serum hepatitis B virus (HBV) deoxyribonucleic acid by hybridization assays or > or =1 x 10(6) copies/mL by polymerase chain reaction, and elevated alanine transaminase levels despite continuous lamivudine, were enrolled in an open-label study of adefovir dipivoxil. The B and C domains of HBV polymerase were sequenced for baseline samples to determine the presence of lamivudine resistance mutations. The results showed that 98% of the samples had tyrosine-methionine-aspartate-aspartate (YMDD) mutations, indicating a strong correlation between the above clinical definition of lamivudine treatment failure and the presence of YMDD mutations. In addition to the rtM204V/I and the rtL180M mutations, the mutation rtV173L was identified in 19% of patients. Four major patterns of lamivudine-resistant HBV were identified: rtL180M + rtM204V (60%), rtV173L + rtL180M + rtM204V (19%), rtM204I (9%) and rtL180M + rtM204I (9%). Treatment with adefovir dipivoxil showed similar antiviral efficacy in patients with lamivudine-resistant virus from all four patterns.

Adenine↗
PubMed2002

Phenotypic susceptibilities to tenofovir in a large panel of clinically derived human immunodeficiency virus type 1 isolates.

Tenofovir is a nucleotide analogue human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor, and its oral prodrug, tenofovir disoproxil fumarate, has recently been approved for the treatment of HIV-1 infection in the United States. The objective of this study was to characterize the in vitro susceptibility profiles of a large panel of clinically derived HIV-1 isolates for tenofovir. The distribution of tenofovir susceptibilities in over 1,000 antiretroviral-naive, HIV-1-infected individuals worldwide was determined using the Virco Antivirogram assay. In addition, phenotypic susceptibilities to tenofovir and other RT inhibitors were determined in a panel of nearly 5,000 recombinant HIV-1 clinical isolates from predominantly treatment-experienced patients analyzed as a part of routine drug resistance testing. Greater than 97.5% of isolates from treatment-naive patients had tenofovir susceptibilities <3-fold above those of the wild-type controls by the Antivirogram. The clinically derived panel of 5,000 samples exhibited a broad range of antiretroviral drug susceptibilities, including 69, 43, and 16% having >10-fold-decreased susceptibilities to at least one, two, and three antiretroviral drug classes, respectively. Greater than 88% of these 5,000 clinical isolates were within the threefold susceptibility range for tenofovir, and >99% exhibited <10-fold-reduced susceptibilities to tenofovir. Decreased susceptibility to tenofovir was not directly associated with resistance to other RT inhibitors; r(2) values of log-log linear regression plots of susceptibility to tenofovir versus susceptibility to other RT inhibitors were <0.4. The results suggest that the majority of treatment-naive and treatment-experienced individuals harbor HIV that remains within the normal range of tenofovir susceptibilities and may be susceptible to tenofovir disoproxil fumarate therapy.

Adenine↗
PubMed2001

Adefovir and tenofovir susceptibilities of HIV-1 after 24 to 48 weeks of adefovir dipivoxil therapy: genotypic and phenotypic analyses of study GS-96-408.

OBJECTIVE: To determine whether genotypic changes in HIV-1 (HIV) reverse transcriptase (RT) occur during adefovir dipivoxil (ADV) therapy that may alter the susceptibility of HIV to adefovir or the related nucleotide inhibitor, tenofovir. DESIGN AND METHODS: GS-96-408 was a 1:1 randomized, double-blind, phase III clinical trial assessing the safety and efficacy of 120-mg daily ADV compared with placebo for the treatment of HIV when added to stable background antiretroviral therapy (ART). Of 442 patients enrolled, 142 were prospectively selected for a virology substudy. Baseline and posttreatment (weeks 24-48) plasma samples were genotypically analyzed in HIV RT. HIV from ADV-treated patients who developed RT mutations at week 24 were also phenotypically analyzed. RESULTS: Nucleoside-associated RT mutations arose with similar frequency among the ADV-and placebo-treated patients, 32% (n = 23) and 28% (n = 20), respectively, during the 24-week blinded treatment phase. RT mutations previously selected by adefovir in vitro (K70E or K65R) did not develop in any patient. Most mutations were typical zidovudine (ZDV)-resistance mutations (e.g., M41L, D67N, K70R, T215Y) in patients taking ZDV or stavudine (d4T) concomitantly, demonstrating directly in the placebo arm that d4T is able to select for these mutations. There appeared to be more patients developing D67N and K70R mutations in the ADV arm versus more T215Y mutations in the placebo arm. Between weeks 24 and 48, 19 of 50 patients (38%) in the ADV arm developed similar RT mutations. The mean HIV RNA responses at weeks 24 and 48 among the ADV-treated patients developing RT mutations were -0.68 log(10) copies/ml (n = 23) and -0.52 log(10) copies/ml (n = 19), respectively, similar to the overall week-24 and week-48 responses (-0.53 and 0.48 log(10) copies/ml, respectively). Patient-derived HIV expressing the observed RT mutations showed insignificant decreases in adefovir susceptibility compared with wild-type in 12 of 16 cases (< threefold). HIV from 1 patient showed significantly reduced susceptibility to tenofovir, which was in association with a double insertion mutation after codon 69 that was also present at baseline. CONCLUSIONS: HIV RT changes that arose during ADV therapy appear attributable to the patient's background ART. ADV therapy may have influenced the pattern of ZDV-associated resistance mutations that developed, but this did not result in an observed loss of viral load suppression. There was a trend toward decreased phenotypic susceptibility to adefovir in ADV-treated patients, with 4 of 16 analyzed patients showing mild, but significantly decreased susceptibility associated with the additional ZDV-associated mutations. Decreased susceptibility to the related nucleotide analog, tenofovir, was not observed to develop in ADV-treated patients.

Adenine↗
PubMed2001

Digital imaging considerations for gel electrophoresis analysis systems.

Gel analysis system purchasers have a large variety of digital imaging products to choose from today. Understanding the specifications presented by the manufacturers is important to ensure that the system fits the needs ofthe researcher using the system. The background information contained in this paper explains the terminology and many of the specifications along with their significance.

Computers↗
PubMed2001

Subjective health measures and acute treatment outcomes in geriatric depression.

BACKGROUND: Prior research suggests that elderly patients are less likely to respond to antidepressant treatment if they have low self-rated health. However, successful treatment for depression has been associated with improvement in self-rated health and other health measures. OBJECTIVES: To examine measures of self-rated health, physical disability, and social function as predictors of treatment response in late-life depression, and to assess these same health measures as treatment outcomes. We hypothesized that greater impairment in these measures would predict poorer treatment response, and that these measures would show significant improvements with recovery from depression. METHOD: Subjects were enrolled in a depression intervention study for people aged 60 and older with recurrent unipolar major depression; they were assessed with measures of self-rated health, physical disability, and social functioning at baseline and at the end of treatment. Baseline measures were compared between the 88 remitters, 11 non-remitters, and seven dropouts. Additionally, changes in the measures were examined in subjects who recovered from the index depressive episode. RESULTS: Subjects with poorer self-rated health at baseline were more likely both to drop out of treatment and to not respond to adequate treatment. This relationship was independent of demographic measures, severity of depression, physical and social functioning, medical illness, personality, hopelessness, overall medication use, and side effects or non-compliance with treatment. CONCLUSION: Although this finding is preliminary because of the small number of dropouts and non-remitters, it suggests that lower self-rated health may independently predict premature discontinuation of treatment for depression. Additionally, subjects who recovered from depression showed significant improvements in self-rated health, physical disability, and social functioning.

Activities of Daily Living↗
PubMed2001

Autogenous osteochondral "plug" transfer for the treatment of focal chondral defects: postoperative MR appearance with clinical correlation.

OBJECTIVE: To describe the MR appearance following autogenous osteochondral "plug" transfer for the treatment of focal chondral defects of the knee. DESIGN AND PATIENTS: Twenty-nine 1.5-T MR knee studies including dynamic gadolinium enhancement were performed on 21 patients following autogenous osteochondral "plug" transfer. Three musculoskeletal radiologists retrospectively reviewed images to evaluate graft and donor site appearance and MR findings were correlated with clinical outcomes. RESULTS: MR images demonstrated graft protuberance (n=12/21; range 1-2 mm), depression (n=2/21; range 1 mm), and surface incongruity: mild (n=17/21), moderate (n=2/21), marked (n=1/21). The T2 signal of graft cartilage was similar to that of adjacent cartilage in 25 of 29 examinations, and increased in four. Graft cartilage thickness relative to adjacent cartilage was <50% in six patients, 50-100% in 15. Graft enhancement in bone was absent at 2 weeks, but present at between 4 and 6 weeks following surgery. All patients had clinical follow-up examinations and knee outcome survey scores were obtained in 15 patients with follow-up greater than 3 months after surgery. All patients demonstrated the expected short-term progressive clinical improvement. CONCLUSION: MR images reveal a wide range of appearances following osteochondral "plug" transfer. Minor variations in graft orientation and surface congruity do not result in adverse clinical outcome in the short term.

Adult↗
PubMed2001

New antiretroviral agents: looking beyond protease and reverse transcriptase.

The clinical utility of intervention in HIV-1 disease has been proven by inhibitors targeting reverse transcriptase and protease. However, novel approaches including inhibition of viral entry, integration and assembly would provide additional options to maintain long-term suppression. The identification of specific inhibitors for each of these processes has recently validated these approaches as viable alternatives for the development of new agents to treat HIV-1 infection. The most recent preclinical advances in novel antiretroviral agents are reviewed and promising new approaches that target viral processes are highlighted.

Anti-HIV Agents↗
PubMed2001

Magnetic resonance imaging at different time periods following hamstring harvest for anterior cruciate ligament reconstruction.

PURPOSE: The purpose of this study was to evaluate the magnetic resonance imaging (MRI) appearance of the hamstring graft harvest site after harvesting the hamstring tendons to reconstruct a torn anterior cruciate ligament (ACL). TYPE OF STUDY: Case series. METHODS: We performed MRI on 21 patients who had previously undergone hamstring harvest and ACL reconstruction. Twenty of the patients (7 female and 13 male; mean age, 37 years; range, 16 to 84 years), all volunteers, were selected from a series of 45 ACL reconstructions performed by the senior author during a 20-month period. Another patient, a 32-year-old man, underwent ACL reconstruction elsewhere 32 months before. Both the semitendinosus and gracilis tendons were harvested in all cases. All MRIs were obtained on a 1.5-T magnet and were prospectively evaluated by 2 experienced musculoskeletal radiologists who were blinded to the time interval between graft harvest and MRI. RESULTS: Two weeks after graft harvest, MRI showed ill-defined intermediate signal on T1-weighted images and increased signal on T2-weighted images, consistent with fluid in the harvest site, with no discernable tendon. At 6 weeks, structures were seen at the level of the superior pole of the patella that had morphology and signal characteristics similar to native tendon. By 3 months, structures with normal morphology and signal characteristics were seen to the level of the joint line, and by 12 months, to the level of 1 to 3 cm above that of the tibial attachment. At 32 months, the tendons appeared on MRI to normalize to a level of 1 to 2 cm above their tibial attachment. CONCLUSION: Following hamstring tendon harvest, MRI demonstrates an apparent regeneration of tendons beginning proximally and extending distally over time.

Adolescent↗
PubMed2001

Anterior cruciate ligament reconstruction in an 84-year-old man.

Anterior cruciate ligament (ACL) reconstruction is typically reserved for younger patients. Several recent articles have reported expanding traditional age barriers for ACL reconstruction in patients up to 62 years old. We report a case of a successful ACL reconstruction in an active 84-year-old rancher. Physiologic age is more important than chronologic age when considering ACL reconstruction.

Aged↗
PubMed2001

CCR5, CXCR4, and CD4 are clustered and closely apposed on microvilli of human macrophages and T cells.

The chemokine receptors CCR5 and CXCR4 act synergistically with CD4 in an ordered multistep mechanism to allow the binding and entry of human immunodeficiency virus type 1 (HIV-1). The efficiency of such a coordinated mechanism depends on the spatial distribution of the participating molecules on the cell surface. Immunoelectron microscopy was performed to address the subcellular localization of the chemokine receptors and CD4 at high resolution. Cells were fixed, cryoprocessed, and frozen; 80-nm cryosections were double labeled with combinations of CCR5, CXCR4, and CD4 antibodies and then stained with immunogold. Surprisingly, CCR5, CXCR4, and CD4 were found predominantly on microvilli and appeared to form homogeneous microclusters in all cell types examined, including macrophages and T cells. Further, while mixed microclusters were not observed, homogeneous microclusters of CD4 and the chemokine receptors were frequently separated by distances less than the diameter of an HIV-1 virion. Such distributions are likely to facilitate cooperative interactions with HIV-1 during virus adsorption to and penetration of human leukocytes and have significant implications for development of therapeutically useful inhibitors of the entry process. Although the mechanism underlying clustering is not understood, clusters were observed in small trans-Golgi vesicles, implying that they were organized shortly after synthesis and well before insertion into the cellular membrane. Chemokine receptors normally act as sensors, detecting concentration gradients of their ligands and thus providing directional information for cellular migration during both normal homeostasis and inflammatory responses. Localization of these sensors on the microvilli should enable more precise monitoring of their environment, improving efficiency of the chemotactic process. Moreover, since selectins, some integrins, and actin are also located on or in the microvillus, this organelle has many of the major elements required for chemotaxis.

Animals↗
PubMed2001

Diagnostic accuracy of screening electrocardiograms in long QT syndrome I.

OBJECTIVE: Inherited long QT syndrome (LQTS) may present with syncope, seizures, and/or sudden death as a result of ventricular tachyarrhythmias. Identification of family members who are at risk because they harbor the genetic substrate for LQTS is critical. Presently, such identification relies on the 12-lead electrocardiogram (ECG). The purpose of this study was to evaluate the efficacy of the automated ECG as a screening tool for LQTS. METHOD: Molecular testing of a proband and 22 additional family members for the KVLQT1 mutation and symptomatic status facilitated the classification of each family member into the following patient groups: noncarriers (13), asymptomatic carriers (5), and symptomatic carriers (5). Each individual had a standard 12-lead ECG from which the computer and manual (lead II) corrected QT interval were determined. In addition, we determined the accuracy of the computer ECG diagnostic interpretation for each patient group. RESULTS: With the use of a corrected QT interval of >/=460 ms as a diagnostic cutoff, the positive and negative predictive values for identifying at-risk individuals were 100%. Despite this, the computer-generated ECG diagnostic interpretation erroneously classified 6 of 23 family members. Moreover, half of the family members, proved to have the ion channel defect, received the diagnostic interpretation "normal ECG." CONCLUSION: Reliance on the computer-generated ECG diagnostic interpretation alone will fail to identify many at-risk family members. It is suggested that all first-degree relatives of an identified LQTS proband have a 12-lead ECG that is reviewed independently by a physician who is familiar with LQTS in an effort to improve screening for this potentially lethal syndrome.electrocardiogram, long QT syndrome, QT interval, sudden death.

Adult↗