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Biomedical subjects

K Smith

Publications and source records attributed to K Smith.

At least 37 records · Page 2Linked to original sources
PubMed2005

Collagen synthesis in human musculoskeletal tissues and skin.

We have developed a direct method for the measurement of human musculoskeletal collagen synthesis on the basis of the incorporation of stable isotope-labeled proline or leucine into protein and have used it to measure the rate of synthesis of collagen in tendon, ligament, muscle, and skin. In postabsorptive, healthy young men (28 +/- 6 yr) synthetic rates for tendon, ligament, muscle, and skin collagen were 0.046 +/- 0.005, 0.040 +/- 0.006, 0.016 +/- 0.002, and 0.037 +/- 0.003%/h, respectively (means +/- SD). In postabsorptive, healthy elderly men (70 +/- 6 yr) the rate of skeletal muscle collagen synthesis is greater than in the young (0.023 +/- 0.002%/h, P < 0.05 vs. young). The rates of synthesis of tendon and ligament collagen are similar to those of mixed skeletal muscle protein in the postabsorptive state, whereas the rate for muscle collagen synthesis is much lower in both young and elderly men. After nutrient provision, collagen synthesis was unaltered in tendon and skeletal muscle, remaining at postabsorptive values (young: tendon, 0.045 +/- 0.008%/h; muscle, 0.016 +/- 0.003%/h; elderly: muscle, 0.024 +/- 0.003%/h). These results demonstrate that the rate of human musculoskeletal tissue collagen synthesis can be directly and robustly measured using stable isotope methodology.

Adult↗
PubMed2005

The development and characterisation of porphyrin isothiocyanate-monoclonal antibody conjugates for photoimmunotherapy.

A promising approach to increase the specificity of photosensitizers used in photodynamic therapy has been through conjugation to monoclonal antibodies (MAb) directed against tumour-associated antigens. Many of the conjugations performed to date have relied on the activated ester method, which can lead to impure conjugate preparations and antibody crosslinking. Here, we report the development of photosensitizer-MAb conjugates utilising two porphyrin isothiocyanates. The presence of a single reactive isothiocyanate allowed facile conjugation to MAb FSP 77 and 17.1A directed against internalizing antigens, and MAb 35A7 that binds to a non-internalizing antigen. The photosensitizer-MAb conjugates substituted with 1-3 mol of photosensitizer were characterised in vitro. No appreciable loss of immunoreactivity was observed and binding specificity was comparable to that of the unconjugated MAb. Substitution with photosensitizer had a minimal effect on antibody biodistribution in vivo for the majority of the conjugates, although a decreased serum half-life was observed using a cationic photosensitizer at the higher loading ratios. Tumour-to-normal tissue ratios as high as 33.5 were observed using MAb 35A7 conjugates. The internalizing conjugate showed a higher level of phototoxicity as compared with the non-internalizing reagent, using a cell line engineered to express both target antigens. These data demonstrate the applicability of the isothiocyanate group for the development of high-quality conjugates, and the use of internalizing MAb to significantly increase the photodynamic efficiency of conjugates during photoimmunotherapy.

Animals↗
PubMed2005

Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation.

Endurance training induces a partial fast-to-slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6x10 repetitions of 3 s-bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3- and 2.7-fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by approximately 2-fold and increased PGC-1alpha protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3-fold and the phosphorylation of TSC2, mTOR, GSK-3beta at PKB-sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E-BP1, eIF-2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK-PGC-1alpha signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB-TSC2-mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the "AMPK-PKB switch." We hypothesize that the AMPK-PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.

Adaptation, Physiological↗
PubMed2005

Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study.

OBJECTIVE: To investigate the contribution of red blood cell (RBC) methotrexate polyglutamates (MTX PGs), RBC folate polyglutamates (folate PGs), and a pharmacogenetic index to the clinical status of patients with rheumatoid arthritis treated with MTX. METHODS: 226 adult patients treated with weekly MTX for more than 3 months were enrolled at three sites in a multicentred cross sectional observational study. Clinical status was assessed by the number of joint counts, physician's global assessment of disease activity, and a modified Health Assessment Questionnaire (mHAQ). RBC MTX PG and folate PG metabolite levels were measured by high performance liquid chromatography fluorometry and radioassay, respectively. A composite pharmacogenetic index comprising low penetrance genetic polymorphisms in reduced folate carrier (RFC-1 G80A), AICAR transformylase (ATIC C347G), and thymidylate synthase (TSER*2/*3) was calculated. Statistical analyses were by multivariate linear regression with clinical measures as dependent variables and metabolite levels and the pharmacogenetic index as independent variables after adjustment for other covariates. RESULTS: Multivariate analysis showed that lower RBC MTX PG levels (median 40 nmol/l) and a lower pharmacogenetic index (median 2) were associated with a higher number of joint counts, higher disease activity, and higher mHAQ (p<0.09). Multivariate analysis also established that higher RBC folate PG levels (median 1062 nmol/l) were associated with a higher number of tender and swollen joints after adjustment for RBC MTX PG levels and the pharmacogenetic index (p<0.05). CONCLUSION: Pharmacogenetic and metabolite measurements may be useful in optimising MTX treatment. Prospective studies are warranted to investigate the predictive value of these markers for MTX efficacy.

Aged↗
PubMed2005

Temporally distinct Escherichia coli 0157 outbreaks associated with alfalfa sprouts linked to a common seed source--Colorado and Minnesota, 2003.

Escherichia coli O157 outbreaks were identified in Minnesota in February 2003 involving seven persons and in Colorado in July 2003 involving 13 persons. Case isolates from the two states had matching pulsed-field gel electrophoresis (PFGE) patterns. Independent case-control studies linked infections in each outbreak with eating alfalfa sprouts that were traced to the same seed distributor. The Colorado sprouter reportedly complied with the Food and Drug Administration (FDA) sprout guidance, whereas the Minnesota sprouter did not. These investigations revealed that increased compliance with existing FDA guidance is needed and that additional research is needed to improve the alfalfa seed decontamination process. This reaffirms the FDA recommendation that raw alfalfa sprouts should be considered potentially contaminated and avoided by persons at high-risk such as the elderly, young children, and immunocompromised persons. PFGE played an essential role in linking these two temporally and geographically distinct E. coli O157 outbreaks.

Adult↗
PubMed2005

Herpesvirus infection in woodland caribou in Alberta, Canada.

Sera and genital swabs collected from 121 adult woodland caribou (Rangifer tarandus caribou) in five subpopulations in northern Alberta, Canada, between December 1997 and October 1999, were examined for evidence of infection with herpesviruses or pestiviruses. No virus was isolated from sera or swabs, and no antibodies against bovine viral diarrhea virus were detected. However, 63 (52%) of the 121 animals had neutralizing antibody titers against bovine herpesvirus 1. There was sufficient serum from 37 of the 121 caribou to allow parallel testing for antibodies against a new alphaherpesvirus isolated from an elk (Cervus elaphus nelsoni), and 20 animals had antibodies against this virus. Paired sera collected 11 mo apart from 14 caribou showed seroconversion in seven animals, indicating that an active herpesvirus infection was present. Virus neutralization data suggest that these caribou are infected with a distinct alphaherpesvirus.

Alberta↗
PubMed2004

Protein synthesis rates in human muscles: neither anatomical location nor fibre-type composition are major determinants.

In many animals the rate of protein synthesis is higher in slow-twitch, oxidative than fast-twitch, glycolytic muscles. To discover if muscles in the human body also show such differences, we measured [13C]leucine incorporation into proteins of anatomically distinct muscles of markedly different fibre-type composition (vastus lateralis, triceps, soleus) after an overnight fast and during infusion of a mixed amino acid solution (75 mg amino acids kg(-1) h(-1)) in nine healthy, young men. Type-1 fibres contributed 83 +/- 4% (mean +/-s.e.m.) of total fibres in soleus, 59 +/- 3% in vastus lateralis and 22 +/- 2% in triceps. The basal myofibrillar and sarcoplasmic protein fractional synthetic rates (FSR, % h(-1)) were 0.034 +/- 0.001 and 0.064 +/- 0.001 (soleus), 0.031 +/- 0.001 and 0.060 +/- 0.001 (vastus), and 0.027 +/- 0.001 and 0.055 +/- 0.001 (triceps). During amino acid infusion, myofibrillar protein FSR increased to 3-fold, and sarcoplasmic to 2-fold basal values (P < 0.001). The differences between muscles, although significant statistically (triceps versus soleus and vastus lateralis, P < 0.05), were within approximately 15%, biologically probably insignificant. The rates of collagen synthesis were not affected by amino acid infusion and varied by < 5% between muscles and experimental conditions.

Adult↗
PubMed2004

The construction of a genetic linkage map of red raspberry (Rubus idaeus subsp. idaeus) based on AFLPs, genomic-SSR and EST-SSR markers.

Breeding in raspberry is time-consuming due to the highly heterozygous nature of this perennial fruit crop, coupled with relatively long periods of juvenility. The speed and precision of raspberry breeding can be improved by genetic linkage maps, thus facilitating the development of diagnostic markers for polygenic traits and the identification of genes controlling complex phenotypes. A genetic linkage map (789 cM) of the red raspberry Rubus idaeus has been constructed from a cross between two phenotypically different cultivars; the recent European cultivar Glen Moy and the older North American cultivar Latham. SSR markers were developed from both genomic and cDNA libraries from Glen Moy. These SSRs, together with AFLP markers, were utilised to create a linkage map. In order to test the utility of the genetic linkage map for QTL analysis, morphological data based on easily scoreable phenotypic traits were collected. The segregation of cane spininess, and the root sucker traits of density and spread from the mother plant, was quantified in two different environments. These traits were analysed for significant linkages to mapped markers using MapQTL and were found to be located on linkage group 2 for spines and group 8 for density and diameter. The availability of co-dominant markers allowed heterozygosities to be calculated for both cultivars.

Chromosome Mapping↗
PubMed2004

Infliximab therapy for sarcoidosis (lupus pernio).

Sarcoidosis is a chronic granulomatous disease of unknown aetiology in which the primary cytokine tumour necrosis factor (TNF)-alpha appears to play a major role. Older immune-modulating drugs including corticosteroids, antimalarials and thalidomide, as well as cytotoxic drugs with immune modulatory effects, have been used to control disease. We present a patient with severe mutilating cutaneous sarcoidosis (lupus pernio) who had showed only partial response to courses of a wide spectrum of immune modulators and cytotoxic therapies, and who had developed significant side-effects due to prolonged high-dose corticosteroids. However, the patient's cutaneous disease responded rapidly to the TNF-alpha inhibitor infliximab.

Adult↗
PubMed2004

Less IS less: a randomised controlled trial comparing cautious and rapid nalbuphine dosing regimens.

OBJECTIVE: This study aimed to determine which of two paramedic administered nalbuphine dosing regimens combined the greater analgesic effect with the minimum of adverse events. METHODS: Patients suffering from chest pain or trauma were randomised to receive either a rapid dosing regimen (10 mg over 30 seconds, repeated once after three minutes if pain score remained above three) or a cautious regimen (5 mg over two minutes, repeated at three minute intervals if pain score remained above three to a maximum dose of 20 mg). Data were collected on analgesic effectiveness, changes in vital signs, and patient reported side effects. RESULTS: The pain score fell by a mean of 4.29 and 3.49 in the rapid and cautious regimen groups respectively (difference = 0.79, 95% CI 0.09 to 1.5, p = 0.028). However, over half the patients in both groups continued to suffer significant pain on arrival at hospital. There were no significant changes in vital signs after nalbuphine, but there was a greater incidence of patient reported drowsiness in rapid regimen patients (42% compared with 21%, 95% CI = 6.96 to 34.12%, p = 0.003). CONCLUSION: A rapid dosing regimen of nalbuphine using 10 mg increments is more effective than and equally as safe as a cautious regimen using 5 mg increments. Further research is required to determine if a maximum dose exceeding 20 mg would result in fewer patients continuing to suffer significant pain before arrival at hospital.

Adult↗
PubMed2004

Changes in galactose and lactic acid content of sweet whey during storage.

Whey is often stored or transported for a period of time prior to processing. During this time period, galactose and lactic acid concentrations may accumulate, reducing the quality of spray-dried whey powders in regard to stickiness and agglomeration. This study surveyed industry samples of Cheddar and mozzarella cheese whey streams to determine how galactose and lactic acid concentrations changed with storage at appropriate (4 degrees C) and abuse (37.8 degrees C) temperatures. Samples stored at 4 degrees C did not exhibit significant increases in levels of lactic acid or galactose. Mozzarella whey accumulated the greatest amount of galactose and lactic acid with storage at 37.8 degrees C. Whey samples derived from cheese made from single strains of starter culture were also evaluated to determine each culture's contribution to galactose and lactic acid production. Starter cultures evaluated included Streptococcus salivarius ssp. thermophilus. Lactobacillus helveticus, Lactobacillus delbrueckii ssp. bulgaricus, Lactococcus lactis ssp. cremoris, and Lactococcus lactis ssp. lactis. Whey derived from L. helveticus accumulated a significantly greater amount of lactic acid upon storage at 37.8 degrees C as compared with the other cultures. Galactose accumulation was significantly decreased in whey from L. lactis ssp. lactis stored at 37.8 degrees C in comparison with the other cultures. Results from this study indicate that proper storage conditions (4 degrees C) for whey prevent accumulation of galactose and lactic acid while the extent of accumulation during storage at 37.8 degrees C varies depending on the culture(s) used in cheese production.

Cheese↗
PubMed2003

The objective measurement of spinal orthosis use for the treatment of adolescent idiopathic scoliosis.

STUDY DESIGN: Technology development and prospective study. OBJECTIVES: Develop instrumentation for discrete, reliable, and objective measurement of brace use patterns between routine follow-ups and without patient involvement. BACKGROUND DATA: To understand spinal bracing efficacy and clinical effectiveness in the conservative treatment of adolescent idiopathic scoliosis, it is essential to measure and record such confounding variables as spinal physiology, force distribution, and compliance. Historically, compliance was measured using patient interviews, pad/strap forces, or temperature. These measurements were subjective, limited to laboratory or short-term monitoring only, required patient intervention, or lacked date/time recording. METHODS: Custom-fitted nonperforated thoracic lumbar sacral orthoses were instrumented with discrete data loggers to measure and record temperature at the skin-brace interface at 16-minute date/time-stamped intervals for up to 88-day periods without patient involvement. Ten female patients (age 15 years, SD 1.2) with adolescent idiopathic scoliosis who had spinal bracing as part of their treatment regimen took part in the study over 14 months, SD 4.5 months. RESULTS: Compliance with the treatment regimen ranged from 8% to 90%, average 65%. Patients tended to overestimate their compliance by 150% (SD 50%). There was no significant difference between weekday and weekend compliance but wear patterns differed. Night wear was significantly greater than day wear (P < 0.01). Patients with very good compliance only removed their brace for washing or exercise periods, but where poor compliance was evident, the brace was only worn sporadically during the day. CONCLUSIONS: Temperature provides a clear signal of the time in brace and can be used for long-term data logging using discrete instrumentation, providing a tool to help identify and understand the reasons behind poor compliance.

Adolescent↗
PubMed2003

Adolescent onset Type 2 diabetes in a non-obese Caucasian patient with an unbalanced translocation.

BACKGROUND: Childhood onset Type 2 diabetes in the UK has been reported in obese, insulin-resistant subjects. Investigation is necessary to exclude other aetiologies including genetic causes. The co-existence of diabetes and a chromosomal breakpoint may indicate the position of novel diabetes genes. CASE REPORT: We describe a novel unbalanced translocation between Xq and 10p associated with amenorrhoea and onset of Type 2 diabetes in a non-obese Caucasian adolescent. There was no evidence of an autoimmune or known genetic aetiology for the diabetes and the phenotype was not typical of youth-onset Type 2. We therefore hypothesize that the translocation is implicated in the aetiology of the diabetes. This is supported by previous reports of diabetes as a feature of Xq deletions and Turner's syndrome and linkage to the Xq region in a genome-wide scan for Type 2 genes. CONCLUSION: That this region may harbour a gene predisposing to Type 2 diabetes and that cytogenetic studies may be useful in investigating diabetes in children and young adults.

Adolescent↗
PubMed2003

Pregnancy in women with Type 2 diabetes: 12 years outcome data 1990-2002.

AIM: Twelve years' outcome analysis of pregnancies in women with Type 2 diabetes in a multiethnic geographically defined area. METHODS: Information about 182 women delivered between 1990 and 2002 was ascertained from a regional computerized database. The main outcome measures were rates of miscarriage, stillbirth, neonatal/postnatal deaths, congenital malformations, birth weight, mode of delivery, and neonatal unit care as well as maternal morbidities of polyhydramnios, postpartum haemorrhage, pregnancy-induced hypertension/pre-eclampsia. RESULTS: Among 182 singleton pregnancies, 161 (88%) resulted in a live outcome. There were 16 (8.8%) spontaneous miscarriages, two (1.2%) stillbirths, and three (1.6%) terminations. Congenital malformations occurred in 18 pregnancies (99/1000). There were two early and one late neonatal deaths and two further deaths in the postnatal period. Twenty-eight percent of infants were large for gestational age, with 15 (9.3%) greater than 4 kg. Fifty-three percent were delivered by caesarean section and 68 (37%) required admission to neonatal unit (NNU) care. Hypertension/pre-eclampsia was two times, polyhydramnios three times, and postpartum haemorrhage six times more common than in non-diabetic women. CONCLUSIONS: Women with Type 2 diabetes have a less satisfactory pregnancy outcome compared with the general population. Infants have a two-fold greater risk of stillbirth, a 2.5-fold greater risk of a perinatal mortality, a 3.5-fold greater risk of death within the first month and a six-fold greater risk of death up to 1 year compared with regional/national figures. They have an 11 times greater risk of a congenital malformation. We need to develop better educational and screening strategies if we are to improve.

Abortion, Spontaneous↗
PubMed2003

Oncology health care professionals' attitudes to cancer: a professional concern.

BACKGROUND: Despite the known benefits of screening, early detection and advances in treatment modalities, negative attitudes to cancer persist among health care professionals, and cancer remains the most feared disease in modern society. Attitudes to cancer may create a barrier to communication between patients and health care professionals, hinder early detection, treatment and rehabilitation, and may influence decision making about referral to specialist services and the selection of appropriate treatments. DESIGN: A descriptive survey was conducted, within a Regional Cancer Centre, to evaluate oncology health care professionals' attitudes towards cancer. Attitudes were measured using the Burns' Cancer Belief Scales. RESULTS: Regardless of gender, profession and clinical experience, all health care professionals displayed persistently negative attitudes towards cancer. No statistically significant difference was detected between gender, profession, clinical experience or specialist education, and although small in number, no major differences were found between group means. CONCLUSIONS: Oncology health care professionals hold negative attitudes towards cancer and changing these attitudes presents a significant challenge. Educational programmes and supportive strategies may alleviate fears and promote a more positive image of cancer. However, such strategies must be based on an understanding of current attitudes towards this phenomenon.

Adult↗
PubMed2003

Comparison of commercial DNA extraction kits for extraction of bacterial genomic DNA from whole-blood samples.

The demand for molecular diagnostic tests in medical microbiology has highlighted the need for efficient methods of DNA extraction. In addition, it is preferable for these methods to be automated. An example of such a requirement is for the confirmation of meningococcal disease where rapid, sensitive, and specific procedures are required for public health management purposes. Previous studies have shown that whole blood is the preferred method for the isolation of bacterial DNA in meningococcal disease, and in this study, we compare five commercially available kits for the extraction of bacterial genomic DNA from whole-blood samples. These include kits in a 96-well binding plate, 96-well filter plate, and metallic bead formats. The method for all five kits is described, and the sensitivity, specificity, ease of automation, and overall efficiency are determined.

Blood↗