Biomedical subjects

Jonathan Clark

Publications and source records attributed to Jonathan Clark.

9 recordsLinked to original sources

PubMed2026

Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.

Focal cortical dysplasias (FCDs) are malformations of cortical development associated with drug-resistant focal epilepsy. We analyzed surgical tissue from 25 consecutive cases recruited from adult and pediatric epilepsy surgery programs. We performed high-depth sequencing of lesional tissue, validated somatic variants using droplet digital PCR or amplicon sequencing, and investigated genotype-phenotype correlations. A pathogenic or likely pathogenic variant was detected in 64% (n = 16/25) of cases. Of these, five cases with FCDIIa or FCDIIb had germline variants in NPRL3 (n = 3) or DEPDC5 (n = 2). Somatic variants were identified in 44% (n = 11/25) of cases. The genetic yield for FCDIIb was 77% of cases having a pathogenic mTOR pathway variant detected (n = 10/13), and for FCDIIa 66% (n = 6/9). High depth sequencing approaches allowed detection of somatic variants with very low (down to 0.4%) variant allele fractions (VAFs). No pathogenic variants were detected in 3 cases with FCDI. 62% (n = 15/24) of the cases with ≥12 months follow up experienced a favourable seizure outcome (Engel 1-2) following surgery. Of note, n = 9 patients required repeat surgery to resect residual dysplasia. Determining a genetic diagnosis reveals aetiology and paves the way to precision therapies that may benefit those with FCD who do not respond to current treatments.

Humans↗

PubMed2007

Estimation of oxygen uptake during fast running using accelerometry and heart rate.

UNLABELLED: Previous investigations have reported that accelerometer counts plateau during running at increasingly faster speeds. PURPOSE: To assess whether biomechanical and/or device limitations cause this phenomenon and the feasibility of generating oxygen uptake (.VO2) prediction equations from the combined use of accelerometry and heart rate during walking and running. METHODS: : Sixteen endurance-trained subjects completed two exercise tests on a treadmill. The first was a continuous incremental test to volitional exhaustion to determine ventilatory threshold and peak .VO2. The second was a discontinuous incremental exercise test while walking (3, 5, and 7 km.h(-1)) and running (8, 10, 12, 14, 16, 18, and 20 km.h(-1), or until volitional exhaustion). Subjects completed 3 min of exercise at each speed, followed by 3-5 min of recovery. Activity counts from uni- and triaxial accelerometers, heart rate, and gas exchange were measured throughout exercise. RESULTS: All accelerometer outputs rose linearly with speed during walking. During running, uniaxial accelerometer outputs plateaued, whereas triaxial output rose linearly with speed up to and including 20 km.h(-1). Prediction of .VO2 during walking and running using heart rate (R2 = 0.42 and 0.59, respectively), accelerometer counts (R2 = 0.48-0.83 and 0.76, respectively), the combined methodologies (R2 = 0.54-0.85 and 0.80, respectively), and the combined methodologies calibrated with individual data (R2 = 0.99-1.00 and 0.99, respectively) was completed by linear regression. CONCLUSIONS: Uni- and triaxial accelerometer outputs have a linear relationship with speed during walking. During running, uniaxial accelerometer outputs plateau because of the biomechanics of running, whereas triaxial accelerometer output has a linear relationship. The combined methodologies predict .VO2 better than either predictor alone; a subject's individually calibrated data further improves .VO2 estimation.

Acceleration↗

PubMed2006

Hypocalcemia after neck exploration for untreated primary hyperparathyroidism.

Hypocalcemia after neck exploration for hyperparathyroidism is an important postoperative management issue. With increasing acceptance of less invasive surgical approaches, hypocalcemia is less frequent. This study was conducted to evaluate postoperative hypocalcemia after current surgical exploration techniques in patients with untreated primary hyperparathyroidism. From the University of Louisville parathyroid database, charts of patients undergoing surgery for untreated primary hyperparathyroidism from May 1, 1998 to May 30, 2004 were reviewed. Data was analyzed based on age, sex, preoperative calcium and parathyroid hormone levels, preexisting diseases, and extent of neck exploration. One hundred sixty-nine patients were identified with adequate data for analysis. Transient postoperative hypocalcemia occurred in 21 per cent (36/169) for the total group, in 18 per cent (22/125) after minimally invasive radio-guided parathyroidectomy, and in 32 per cent (14/44) after bilateral neck exploration. Patients with postoperative hypocalcemia had a statistically significant association with older age and pre-existing hypertension. Patients with postoperative hypocalcemia were more likely to have undergone longer surgical procedures and were more likely to have had pre-existing diabetes and mental disorders. These findings were not statistically significant and were considered trends. The frequency of osteoporosis in the hypocalcemia group was increased but was not significant. Transient hypocalcemia occurred in 21 per cent of patients after parathyroid surgery. It was more likely after bilateral neck exploration, a longer duration of surgery, and with hypertension, diabetes, and mental disorders.

Age Factors↗

PubMed2005

Outcome of treatment for advanced cervical metastatic squamous cell carcinoma.

BACKGROUND: Patients with advanced cervical metastases from mucosal squamous cell carcinoma have a poor prognosis because of their high risk of regional and distal failure. This study aims to evaluate the outcomes of patients with clinical N2 or N3 disease managed with surgery and postoperative radiotherapy. METHODS: From a comprehensive computerized database, 181 entered patients who had neck dissection for N2 or N3 disease between 1988 and 1999 were evaluated. The mean age was 62 years, and minimum follow-up was 3 years. RESULTS: A total of 233 neck dissections were performed in 181 patients, including 163 comprehensive and 70 selective dissections. Postoperative radiotherapy was given in 82% of cases. The local control rate was 75% at 5 years, and control of disease in the treated neck was achieved in 86%. Macroscopic extracapsular spread (ECS) significantly increased regional recurrence (p = .001). Adjuvant radiotherapy significantly improved neck control (p = .004) but did not alter survival. Patients with ECS (both microscopic and macroscopic) who received radiotherapy had a significantly better survival than did patients with ECS who did not receive radiotherapy. Disease-specific survival for the entire group was 39% at 5 years. By use of multivariate analysis, macroscopic ECS and N2c neck disease were independent adverse prognostic factors for survival (p = .001). CONCLUSIONS: Despite a high rate of control in the treated neck, the poor survival (39%) in this patient group indicates that adjuvant therapeutic strategies need to be considered.

Adult↗

PubMed2005

Salvage with supracricoid partial laryngectomy after radiation failure.

BACKGROUND: Supracricoid partial laryngectomy (SCPL) is an alternative to total laryngectomy (TL) for selected glottic and supraglottic carcinomas but its role in the setting of radiation failure is unclear. The aim of the present study was to present a series of patients with laryngeal cancer undergoing salvage surgery for local recurrence and examine the morbidity associated with this intervention. METHODS: A retrospective review of 111 patients presenting with laryngeal cancer between 1997 and 2002 was performed. A total of 21 patients with recurrent disease following radiation therapy were identified, of which salvage surgery was performed in 18 patients. Minimum follow up of survivors was 22 months. RESULTS: The 5-year cumulative local control and disease-specific survival was 76% and 85%, respectively. Surgical salvage consisted of TL in 12 patients and SCPL in six. The mortality and major morbidity rates for TL were 0% and 33%, and for SCPL they were 33% and 50%, respectively. Median length of hospital stay was similar in both groups (21 and 19 days). No patient undergoing SCPL developed recurrent disease at a median follow up of 19 months. CONCLUSIONS: Supracricoid partial laryngectomy is an oncologically sound alternative to TL as salvage for radiation failure. The operative morbidity and potential for mortality is high in this setting.

Adult↗

PubMed2005

The glaucomas.

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Aged↗

PubMed2004

H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer.

BACKGROUND: Accumulating epidemiologic and molecular evidence suggest that inflammation is an important component in the etiology of prostate cancer. Macrophage-inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor beta superfamily, is thought to play an important role in inflammation by regulating macrophage activity. We examined whether sequence variants in the MIC-1 gene are associated with the risk of prostate cancer. METHODS: The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 780 control subjects. From 94 of the control subjects, we constructed gene-specific haplotypes of MIC-1 and identified four haplotype-tagging single-nucleotide polymorphisms (SNPs): Exon1+25 (V9L), Exon1+142 (S48T), IVS1+1809, and Exon2+2423 (H6D). All study subjects were genotyped for the four SNPs, and conditional logistic regression analysis was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A statistically significant difference (P =.006) in genotype frequency was observed for the nonsynonymous change H6D (histidine to aspartic acid at position 6) between prostate cancer patients and control subjects. Carriers of the GC genotype, which results in the H6D change, experienced a lower risk of sporadic prostate cancer (OR = 0.80, 95% CI = 0.66 to 0.97) and of familial prostate cancer (OR = 0.61, 95% CI = 0.42 to 0.89) than the CC genotype carriers. In the study population, the proportion of prostate cancer cases attributable to the CC genotype was 7.2% for sporadic cancer and 19.2% for familial cancer. None of the other SNPs or haplotypes was associated with prostate cancer. CONCLUSION: This study shows an association between a nonsynonymous change (H6D) in the MIC-1 gene and prostate cancer. This finding supports the hypothesis that genetic variation in the inflammatory process contributes to prostate cancer susceptibility.

Adult↗

PubMed2004

Physical demands and injuries to the upper extremity associated with the space program.

Hand and upper-extremity overuse and repetitive injuries in astronauts have been and continue to be a common problem in the space program. The demands on upper-extremity use in the astronaut training program, the zero-gravity environment, the extreme temperature conditions of space, the effects of space travel on human physiology/anatomy, and the constraints and pressures of space suits and gloves all can negatively impact upper-extremity function in ways that can result in overuse/repetitive injuries. Future plans for space exploration include endeavors that will continue and even increase the demands on the hand and upper extremity.

Astronauts↗

PubMed2003

Oxygen activation and electron transfer in flavocytochrome P450 BM3.

In flavocytochrome P450 BM3, there is a conserved phenylalanine residue at position 393 (Phe393), close to Cys400, the thiolate ligand to the heme. Substitution of Phe393 by Ala, His, Tyr, and Trp has allowed us to modulate the reduction potential of the heme, while retaining the structural integrity of the enzyme's active site. Substrate binding triggers electron transfer in P450 BM3 by inducing a shift from a low- to high-spin ferric heme and a 140 mV increase in the heme reduction potential. Kinetic analysis of the mutants indicated that the spin-state shift alone accelerates the rate of heme reduction (the rate determining step for overall catalysis) by 200-fold and that the concomitant shift in reduction potential is only responsible for a modest 2-fold rate enhancement. The second step in the P450 catalytic cycle involves binding of dioxygen to the ferrous heme. The stabilities of the oxy-ferrous complexes in the mutant enzymes were also analyzed using stopped-flow kinetics. These were found to be surprisingly stable, decaying to superoxide and ferric heme at rates of 0.01-0.5 s(-)(1). The stability of the oxy-ferrous complexes was greater for mutants with higher reduction potentials, which had lower catalytic turnover rates but faster heme reduction rates. The catalytic rate-determining step of these enzymes can no longer be the initial heme reduction event but is likely to be either reduction of the stabilized oxy-ferrous complex, i.e., the second flavin to heme electron transfer or a subsequent protonation event. Modulating the reduction potential of P450 BM3 appears to tune the two steps in opposite directions; the potential of the wild-type enzyme appears to be optimized to maximize the overall rate of turnover. The dependence of the visible absorption spectrum of the oxy-ferrous complex on the heme reduction potential is also discussed.

Bacterial Proteins↗