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Biomedical subjects

John Alexander

Publications and source records attributed to John Alexander.

17 recordsLinked to original sources
PubMed2025

ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time.

PURPOSE: The Clinical Genome Resource (ClinGen) Hearing Loss Gene Curation Expert Panel was assembled in 2016 and has since curated 174 gene-disease relationships (GDRs) using ClinGen's semiquantitative framework. ClinGen mandates the timely recuration of all GDRs classified as Disputed, Limited, Moderate, and Strong every 2 to 3 years. METHODS: Thirty-five GDRs met the criteria for recuration within 2 years of original curation. Previous evidence was reevaluated using the latest curation guidelines, and a comprehensive literature review was performed to obtain new evidence. Recurations were approved by the Gene Curation Expert Panel and published on the ClinGen website (www.clinicalgenome.org). RESULTS: Eight of 35 GDRs (22%) changed their classification. Two Moderate and 5 Strong GDRs were upgraded to Definitive because of new case evidence. One Strong was subsumed under another Definitive GDR after evaluation of the lumping/splitting of disease entities. Twenty-seven of 35 patients remained unchanged, with little to no new evidence reported. CONCLUSION: Genes classified as Moderate and Strong were likely to build evidence and change their classification over time, whereas Limited were unlikely to gain evidence. These findings highlight the critical role of recuration in ensuring that genetic tests and research studies incorporate the most recent evidence into their efforts.

Humans↗
PubMed2006

Modulation of anisotropy in electrospun tissue-engineering scaffolds: Analysis of fiber alignment by the fast Fourier transform.

We describe the use of the fast Fourier transform (FFT) in the measurement of anisotropy in electrospun scaffolds of gelatin as a function of the starting conditions. In electrospinning, fiber alignment and overall scaffold anisotropy can be manipulated by controlling the motion of the collecting mandrel with respect to the source electrospinning solution. By using FFT to assign relative alignment values to an electrospun matrix it is possible to systematically evaluate how different processing variables impact the structure and material properties of a scaffold. Gelatin was suspended at varying concentrations (80, 100, 130, 150 mg/ml) and electrospun from 2,2,2 trifluoroethanol onto rotating mandrels (200-7000 RPM). At each starting concentration, fiber diameter remained constant over a wide range of mandrel RPM. Scaffold anisotropy developed as a function of fiber diameter and mandrel RPM. The induction of varying degrees of anisotropy imparted distinctive material properties to the electrospun scaffolds. The FFT is a rapid method for evaluating fiber alignment in tissue-engineering materials.

Anisotropy↗
PubMed2004

Whole-blood cultures from renal-transplant patients stimulated ex vivo show that the effects of cyclosporine on lymphocyte proliferation are related to P-glycoprotein expression.

BACKGROUND: Cyclosporine (CsA) is a substrate for the MDR-1 gene product P-glycoprotein (P-gp). CsA efficacy may be modulated by lymphocyte P-gp expression levels. In this study, CsA inhibition of lymphocyte proliferation in whole-blood cultures ex vivo has been related to (1) lymphocyte P-gp expression and (2) the C3435T polymorphism in the MDR-1 gene, which has been reported to alter P-gp function. METHODS: In 30 renal-transplant recipients taking CsA monotherapy, P-gp expression was measured by flow cytometry. Whole-blood samples were stimulated with purified protein derivative (PPD) and phytohemagglutinin (PHA). CsA resistance ex vivo was defined as less than 10% reduction in proliferation with either PPD or PHA at 2 hours compared with 0 hours. RESULTS: CsA resistance was associated with greater P-gp expression using either PPD (median expression, resistant 1.89 vs. sensitive 0.96, P =0.02) or PHA (1.66 vs. 0.96, respectively, P =0.02). Whole-blood CsA levels in resistant and sensitive patients were similar. The C3435T polymorphism did not affect inhibition of proliferation by CsA (P >0.05 for all between genotype group comparisons). CONCLUSIONS: Our results indicate that lymphocyte P-gp expression determines the degree of inhibition of proliferation by CsA ex vivo; whether this also affects CsA effectiveness in vivo and therefore graft survival requires further study.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

High versus restricted use of home oxygen therapy, health care utilisation and the cost of care in chronic lung disease infants.

UNLABELLED: Use of home oxygen therapy for prematurely born infants with chronic lung disease (CLD) can facilitate early discharge, but affected infants might require more readmissions. Our aim was to determine if health care utilisation and associated costs in the first 2 years were greater in centres with a high compared to centres with restricted use of home oxygen therapy. A retrospective review of the hospital and general practitioner (GP) medical records of 235 infants with CLD (median gestational age 27 weeks; range 22-33 weeks) was performed to note their readmissions, outpatient attendances, community service referrals and cost of care in the first 2 years after birth. A total of 76 infants (64%) in the high use centres and 12 (10%) in the restricted use centres were discharged home on oxygen. Infants in the high use centres were discharged home from neonatal care at a younger age (median 37.7 versus 39.9 weeks; P<0.001), but subsequently had similar numbers of inpatient events, and less GP (P =0.012) and community care (P < 0.001) contacts, although their duration of home oxygen use was longer (P < 0.001). The post-discharge costs were similar in the two types of centre, but the neonatal costs (P < 0.0001) and total cost of care per infant over the first 2 years (P < 0.0001) were lower in the high use centres. CONCLUSION: Early discharge and high use of home oxygen therapy was not associated with an increased cost of care or increased morbidity.

Age Factors↗
PubMed2004

Diabetes on a cardiovascular ward: adherence to current recommendations.

OBJECTIVES: Improving diabetes and blood pressure control decreases the incidence and progression of microvascular disease. Likewise, screening for microvascular complications is beneficial in the early detection and treatment of these disorders. However, adherence to practice guidelines for screening and treatment in patients with diabetes is suboptimal. This study describes a group of patients with diabetes who were admitted to a cardiology service at an academic medical center. METHODS: Patient interview and chart review were used to determine glycemic control and compliance with practice guidelines. RESULTS: The mean hemoglobin A1c was 8.3%. Only 69% of patients received ophthalmologic examinations, and fewer were screened for nephropathy. Thirty-five percent of patients monitored home blood glucoses less than daily. Nearly 17% had no hemoglobin A1c or lipid checks during the 3 months before admission. CONCLUSIONS: For a group of poorly controlled patients with diabetes who are at high risk for cardiovascular disease, adherence to practice guidelines and the level of diabetes control is inadequate.

Academic Medical Centers↗
PubMed2004

Development of DX-9065a, a novel direct factor Xa antagonist, in cardiovascular disease.

The development of anticoagulants for treating patients with atherothrombotic disorders of the arterial circulatory system has focused, either directly or indirectly, on thrombin - a pleuripotential effector enzyme with prothrombotic and proinflammatory properties. The pivotal role of factor (f) Xa in thrombin generation, coupled with its direct cellular effects and widely recognized limitations of currently available anticoagulants, has led to the development of pharmacologic inhibitors of this important protease. The following review focuses on DX-9065a - first in a class of direct, selective and reversible fXa antagonists - and its potential applications in the management of patients with cardiovascular disease.

Animals↗
PubMed2003

One-year follow-up of the ASSENT-2 trial: a double-blind, randomized comparison of single-bolus tenecteplase and front-loaded alteplase in 16,949 patients with ST-elevation acute myocardial infarction.

BACKGROUND: Single-bolus tenecteplase and accelerated alteplase were shown to be equivalent for 30-day mortality rates in the double-blind Assessment of the Safety of a New Thrombolytic (ASSENT-2) study. The aim of this study is to assess mortality rates after 1-year follow-up. METHODS AND RESULTS: One-year vital status was obtained from 92.8% of the patients initially enrolled in the ASSENT-2 trial. Completeness of follow-up was similar for both groups. At 1 year, mortality rates were 9.1% for alteplase and 9.2% for tenecteplase (risk ratio, 1.01; 95% CI, 0.91-1.12). The mortality rate between 30 and 365 days after enrollment was 2.6% for alteplase and 2.8% for tenecteplase (risk, 1.07; 95% CI, 0.88-1.30). A lower 30-day mortality rate in patients treated with tenecteplase after 4 hours of symptom-onset persisted at 1-year follow-up (10.9% vs 12.6% for alteplase), but was no longer statistically significant. There were also no significant differences in mortality rates between the 2 treatments in other major subgroups. In a Cox regression model, no significant interaction was observed between treatment assignment and age, sex, time-to-treatment, Killip class, body weight, and history of previous myocardial infarction, infarction location, systolic blood pressure, or heart rate. CONCLUSIONS: One year after randomization, mortality rates remain similar in patients with acute myocardial infarction treated with an accelerated infusion of alteplase or a single bolus of tenecteplase.

Age Factors↗
PubMed2003

Randomized controlled trial of nebulized adrenaline in acute bronchiolitis.

Use of both l-epinephrine and racemic epinephrine (adrenaline) has improved clinical symptoms and composite respiratory scores in acute bronchiolitis. The objective of this randomized double-blind placebo-controlled study was to assess whether there was sufficient improvement in clinical state to reduce hospital admissions. Seventy-five infants aged 1 month to 1 year with a clinical diagnosis of acute bronchiolitis were treated with either 2 ml of 1:1000 nebulized adrenaline or 2 ml of nebulized normal saline administered after baseline assessment and 30 min later. Clinical respiratory parameters were recorded at 15-min intervals for a period of 2 h following the baseline assessment. Admission to hospital was the primary end-point and changes in respiratory parameters were secondary end-points. Fifty percent (19/38) of infants treated with adrenaline were discharged home compared with 38 percent (14/37) of those treated with saline. This 12 percent reduction in rate of admission is not statistically significant (95% CI of difference: -10% to 35%). There was no difference between treated and placebo groups in respiratory rate, oxygen saturation, heart rate or a composite respiratory distress score at 30, 60 or 120 min post-treatment. In this study, nebulized epinephrine did not confer a significant advantage over nebulized saline in the emergency room treatment of acute bronchiolitis.

Acute Disease↗
PubMed2003

Medical counterbioterrorism: the response to provide anthrax prophylaxis to New York City US Postal Service employees.

STUDY OBJECTIVE: We describe and analyze a recent rapid deployment of disaster medical assistance teams and other government agencies to provide medical screening and anthrax prophylaxis to New York City US Postal Service employees potentially exposed to letters contaminated with anthrax spores. METHODS: A description of the response effort is presented. Data were collected on standardized forms and included the numbers of postal employees screened and offered antibiotic prophylaxis, as well as the numbers of patients seen per worker hour by various medical professionals. RESULTS: One hundred members of 5 disaster medical assistance teams and other health professionals were deployed to New York City within 18 hours of activation. Over a 68-hour period, 7,076 patients were evaluated, representing all postal employees in the 6 major postal facilities in New York believed to be at risk for anthrax exposure. Of the total, 2,452 patients were seen during the first 24 hours, 3,875 during the second 24 hours, and the remaining 749 during the last 20 hours of operations. An average of 161 employees were screened per hour. The antibiotic most commonly dispensed was ciprofloxacin, followed by doxycycline and amoxicillin. CONCLUSION: The deployment of disaster medical assistance teams and other agencies to New York City to provide prophylaxis against inhalation anthrax to US Postal Service employees provides lessons for a rapid, efficient, and effective response to acts of bioterrorism. This deployment might also serve as a scaleable model for future events requiring medical prophylaxis.

Anthrax↗
PubMed2003

Underuse of analgesia in very young pediatric patients with isolated painful injuries.

STUDY OBJECTIVE: We sought to compare the use of analgesic agents in very young children with that in older children with isolated painful injuries. METHODS: We performed a retrospective chart review of patients seen between 1999 and 2000 in a pediatric emergency department. Patients aged 6 months to 10 years who sustained isolated long bone fractures or second- and third-degree burns were included. Exclusion criteria included head injury, chest or abdominal trauma, and developmental delay or neurologic disorder. Research subjects were separated into 2 study groups: very young (ages 6 to 24 months) and school age (ages 6 to 10 years). RESULTS: One hundred eighty research subjects met the inclusion and exclusion criteria: 96 in the very young group and 84 in the school age group. Research subjects in the very young group received no analgesic agents more often than school age research subjects for all injuries (64.6% versus 47.6%, respectively), all fractures (70.6% versus 48.8%, respectively), displaced fractures (55.0% versus 22.0%, respectively), and all burns (50.0% versus 25.0%, respectively). When analgesic agents were administered, very young patients were less likely to receive narcotics compared with school age patients. Analgesic dosing for both the very young and school age groups was similar and within established guidelines. CONCLUSION: Children younger than 2 years of age receive disproportionately less analgesia than school age children, despite having obviously painful conditions. Emergency physicians should consider special issues involved in assessing and managing pain in very young children.

Analgesics↗
PubMed2003

Oxidative stress in a novel model of chronic acidosis in LLC-PK1 cells.

Chronic metabolic acidosis occurs commonly in chronic renal failure (CRF). The proximal renal tubular cell is the site in the kidney of high oxidative metabolic activity and in CRF is associated with adaptive hypertrophy and hypermetabolism. We hypothesised that chronic acidosis may lead to increased generation of reactive oxygen species due to increased oxidative activity. We developed a novel model of chronic acidosis in LLC-PK1 cells and measured markers of oxidative stress and metabolism. Acidosis led to a reduction in cellular total glutathione and protein thiol content and an increase in glutathione peroxidase activity and NH3 generation. The expression of constitutively expressed heat stress protein (HSP) HSC70 and HSP60 increased at pH 7.0.

Acidosis↗
PubMed2002

Phylogenetic relationships of Empetraceae inferred from sequences of chloroplast gene matK and nuclear ribosomal DNA ITS region.

We used sequences of nrDNA ITS and chloroplast gene matK to evaluate the monophyly of Empetrum and Corema and to examine phylogenetic relationships of the Empetraceae. Sequences of these two DNA markers were obtained for 11 plant samples, representing species of Empetrum from both the Southern and Northern Hemispheres, species and subspecies of Corema, and the monotypic Ceratiola. Sequences of four species of Rhododendron were used for rooting purposes. Our results show that species of Empetrum form a clade sister to the clade containing both Corema and Ceratiola. These two clades are strongly supported in both the matK and ITS trees, suggesting that Ceratiola is more closely related to Corema than to Empetrum, and is not of a hybrid origin between the ancestors of the latter two genera. In the matK tree, Corema conradii is more closely related to Ceratiola than to Corema album and C. album subsp. azoricum, whereas in the ITS tree, Ceratiola is allied with Corema album and C. album subsp. azoricum. This suggests that C. conradii might be a hybrid between ancestral populations of Ceratiola and C. album. The monophyly of Empetrum rejects the hypothesis of its independent origin in the two Hemispheres. Our trees also suggest the fact that the modern amphitropical distribution of Empetrum is the result of long distance dispersal, not of the vicarious events.

Chloroplasts↗
PubMed2002

Research strategies in the pharmaceutical industry to cope with the problems of ageing.

The present research strategies for ageing are focussed around three areas. The first area is the demographic study of the present-day populations and those in the future. The analysis of the evolution of the metropolitan French population from 1950 to 2050 indicates that the proportion of subjects aged greater than 60 years will pass from 16% to 35%. In addition, the level of dependence of these subjects will vary considerably from one to another. The second area is the integration of epidemiological data of the pathologies related to the aged subject. Numerous epidemiological studies of the aged show that the elderly population is in better health, better informed about the diseases that affect them and also financially more secure, which allows them to take better care of themselves. The epidemiological studies of certain dementias show, for example, that if we reduce the delay to when the disease appears by five years, then we reduce the prevalence by a factor of 2. The third area relates to the important new progress in the understanding of the biological mechanisms involved in cellular ageing. The recent progress in the area of cellular biology has started to decode the complex mechanisms underlying cellular ageing. The important understanding of the phenomena of apoptose with the development of relevant biological models of the natural ageing process have anticipated future treatments and, eventually, the prophylactic treatment of specific pathologies of the elderly patient.

Aged↗