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Biomedical subjects

G R Williams

Publications and source records attributed to G R Williams.

At least 19 recordsLinked to original sources

Thyroid hormone regulates heparan sulfate proteoglycan expression in the growth plate.

Thyroid hormone is essential for normal skeletal development. Hypothyroidism is associated with growth arrest, failure of chondrocyte differentiation, and abnormal matrix synthesis. Thyroid hormone modulates the Indian hedgehog/PTHrP feedback loop and regulates fibroblast growth factor (FGF)/FGF receptor signaling. Because heparan sulfate (HS) proteoglycans (Prgs) (HSPGs) are absolutely required by these signaling pathways, we have investigated whether thyroid status affects HSPG expression within the growth plate. Tibial growth plate sections were obtained from 12-wk-old rats rendered euthyroid, thyrotoxic, or hypothyroid at 6 wk of age, 14-d-old congenitally hypothyroid Pax8-null mice, and TRalpha/TRbeta double-null mice lacking all thyroid hormone receptors. HS and chondroitin sulfate Prg expression was determined by immunohistochemistry using three monoclonal antibodies. There was increased HS staining in growth plates from hypothyroid animals predominantly within the extracellular matrix of reserve and proliferative zones. Cellular HS staining was also increased particularly in prehypertrophic chondrocytes. T3 regulation of HSPG core protein and HS synthetic and modification enzyme expression was studied in ATDC5 cells using semiquantitative RT-PCR. Thyroid hormone negatively regulated expression of the core protein Gpc6, the polymerase Ext1, and the modification enzyme Hs6st2. These studies demonstrate that the expression and distribution of growth plate Prgs are regulated by thyroid hormone, and the regulation of HSPG expression provides an important additional link between FGF and Indian hedgehog signaling and T3. These novel observations suggest that the cartilage matrix and especially HSPGs are critical mediators of the skeletal response to thyroid hormone.

Animals↗

Effects of thyroid status on bone metabolism: a primary role for thyroid stimulating hormone or thyroid hormone?

Thyroid hormones are essential for normal skeletal growth and the maintenance of bone mass in adulthood, although their mechanism of action in bone is poorly understood. Hypothyroidism causes impaired bone formation and growth retardation whereas thyrotoxicosis results in accelerated growth, advanced bone age and decreased bone mass. Adults with thyrotoxicosis or a suppressed thyroid stimulating hormone (TSH) from any cause have an increased risk of osteoporotic fracture. Conventionally, bone loss in thyrotoxicosis has been regarded as a direct consequence of thyroid hormone excess acting locally on bone. Recently, however, it has been proposed that TSH may be a direct negative regulator of bone turnover acting via the TSH receptor on both osteoblasts and osteoclasts. Thus, TSH deficiency could be partly responsible for the skeletal loss seen in thyrotoxicosis. Here we provide an overview of the molecular actions of thyroid hormone in bone and discuss in detail the current evidence relating to a possible role for TSH in bone metabolism.

Animals↗

Motion artefact reduction of the photoplethysmographic signal in pulse transit time measurement.

Motion artefact is a common occurrence that contaminates photoplethysmographic (PPG) measurements. To extract timing information from signals during artefact is challenging. PPG signal is very sensitive to artefacts and can be used in applications like, pulse transit time (PTT) as part of the polysomnographic studies. A correlation cancellation or signal processing approach is implemented with the adaptive cancelling filter concept and a triaxial accelerometry. PPG signals obtained from a Masimo (Reference) pulse oximeter is used as reference to compare with the reconstructed PPG signals. Different hands are used for each PPG source, one stationary while the other involves typical movements during sleep. A second Masimo pulse oximeter is used to register intensity of timing errors on commercial PPG signals. 108 PTT measurements are recorded in three different movements with PTT estimates from unprocessed PPG signals showing 35.51+/-27.42%, Masimo 50.02+/-29.40% and reconstructed 4.32+/-3.59% difference against those from the Reference PPG. The triaxial accelerometry can be used to detect the presence of artefact on PPG signals. This is useful in PTT measurements when signal contaminated with artefacts are required for further analysis, especially after and during arousals in sleep. The suggested filtering model can then reconstruct these corrupted PPG signals.

Acceleration↗

A clinically meaningful difference was generated for a performance measure of recovery from hip fracture.

BACKGROUND AND OBJECTIVE: The Lower Extremity Gain Scale (LEGS) is a performance measure of tasks that are often impaired in hip fracture patients. This study was designed to determine a clinically meaningful difference in LEGS. METHODS: The population was 139 female patients (age >65 years) admitted to Baltimore hospitals. Recovery levels were estimated by fitting trajectory curves for the cohort for the 12 months post fracture. The clinically meaningful difference was evaluated using an anchor-based approach, examining the relationship between the LEGS recovery level and age. A second, distribution-based method used an effect size of .20. RESULTS: According to our model, a difference of 5 years in age corresponded to a difference of 1.6-3.6 points in LEGS scores. The standard deviation for LEGS at 12 months was 8.0; thus, Cohen's effect size of 0.2 would equate to a difference of 1.6 points. CONCLUSION: This suggests that a clinically meaningful difference in the LEGS scores for a population in this age range would be 2-3 points.

Activities of Daily Living↗

Analysis of thyroid hormone responsive gene expression in osteoblastic cells.

Thyroid hormones regulate gene expression to influence the development and metabolism of many tissues including bone. The identification of genes that are regulated by thyroid hormones during skeletal development requires sensitive and quantitative techniques that are not limited by small amounts of available tissue and RNA. We have compared the efficiencies of differential display and poly A PCR subtraction hybridisation methods for the detection of thyroid hormone responsive genes expressed in osteoblastic cells. The utility of each technique was evaluated with respect to its sensitivity, specificity, cost and ability to identify novel genes. Subtraction hybridisation was rapid and more efficient in all categories. Poly A PCR facilitates quantitative and representative global amplification of cDNAs from low concentrations of RNA extracted from small tissue samples. The method, in combination with microarray analyses, may prove useful as an additional, complementary strategy to subtraction hybridisation for the analysis of differential gene expression in tissues where sample size is limiting.

Animals↗

Tendon to bone healing: differences in biomechanical, structural, and compositional properties due to a range of activity levels.

Little knowledge exists about the healing process of the tendon to bone insertion, and hence little can be done to improve tissue healing. The goal of this study is to describe the healing of the supraspinatus tendon to its bony insertion under a variety of loading conditions. Tendons were surgically detached and repaired in rats. Rat shoulders were then immobilized, allowed cage activity, or exercised. Shoulders that were immobilized demonstrated superior structural (significantly higher collagen orientation), compositional (expression of extracellular matrix genes similar to the uninjured insertion), and quasilinear viscoelastic properties (A = 0.30 +/- 0.10 MPa vs. 0.16 +/- 0.08 MPa, B = 17.4 +/- 2.9 vs. 15.1 +/- 0.9, and tau 2 = 344 +/- 161 s vs. 233 +/- 40 s) compared to those that were exercised, contrary to expectations. With this knowledge of the healing response, treatment modalities for rotator cuff tears can be developed.

Animals↗

The localized expression of extracellular matrix components in healing tendon insertion sites: an in situ hybridization study.

The localized expression of a number of extracellular matrix genes was evaluated over time in a novel rat rotator cuff injury model. The supraspinatus tendons of rats were severed at the bony insertion and repaired surgically. The healing response was evaluated at 1, 2, 4, and 8 weeks post-injury using histologic and in situ hybridization techniques. Expression patterns of collagens (I, II, III, IX, X, XII), proteoglycans (decorin, aggrecan, versican, biglycan, fibromodulin), and other extracellular matrix proteins (elastin, osteocalcin, alkaline phosphatase) were evaluated at the healing tendon to bone insertion site. Histologic results indicate a poor healing response to the injury, with only partial recreation of the insertion site by 8 weeks. In situ hybridization results indicate a specific pattern of genes expressed in each zone of the insertion site (i.e., tendon, fibrocartilage, mineralized cartilage, bone). Overall, expression of collagen types I and XII, aggrecan, and biglycan was increased, while expression of collagen type X and decorin was decreased. Expression of collagen type I, collagen type XII, and biglycan decreased over time, but remained above normal at 8 weeks. Results indicate that the rat supraspinatus tendon is ineffective in recreating the original insertion site, even at 8 weeks post-injury, in the absence of biological or biomechanical enhancements.

Animals↗

Thyroid status affects number and localization of thyroid hormone receptor expressing mast cells in bone marrow.

Thyroid hormone (T(3)) plays a key role in endochondral ossification. The process relies on the coordinated synthesis and degradation of cartilage matrix and is disrupted in juvenile hypothyroidism, leading to abnormal skeletal development. Mast cells synthesize and store matrix-degrading enzymes. We examined whether thyroid status influences skeletal mast cell distribution in growing rats to determine whether they might modulate the actions of T(3) in bone. Tibiae were collected for histological, histochemical, immunohistochemical, and immunofluorescence analysis. Mast cells were increased throughout the bone marrow in hypothyroid rats compared with euthyroid, thyrotoxic, and hypothyroid-thyroxine replaced animals. Large numbers were present in metaphyseal marrow adjacent to the growth plate in hypothyroid animals and cells were distributed evenly throughout the marrow. Very few mast cells were present in metaphyseal marrow in other groups, but their numbers increased with increasing distance from the growth plate. T(3) receptor alpha1 (TRalpha1) was expressed in the nucleus and cytoplasm of skeletal mast cells, whereas TRalpha2 and TRbeta1 were restricted to the cytoplasm. Localization of TRs was not affected by altered thyroid status. Thus, disrupted endochondral ossification in hypothyroidism may be mediated in part by skeletal mast cells, which express TR proteins and may function as T(3) target cells.

Animals↗

Dexamethasone inhibits and thyroid hormone promotes differentiation of mouse chondrogenic ATDC5 cells.

The effects of glucocorticoid (GC) excess, thyrotoxicosis, and hypothyroidism on linear growth indicate that growth plate chondrocytes are exquisitely sensitive to GC and thyroid hormone (T(3)). Murine ATDC5 cells undergo chondrogenesis in vitro and were used to evaluate the effects of dexamethasone (Dex) and T(3) on cell proliferation and differentiation. Immature and differentiated ATDC5 cells expressed glucocorticoid and T(3)-receptor mRNAs. Cells proliferated and organized into cartilage-like nodules after 7 days. Chondrocyte maturation progressed over 9-40 days, with increasing alkaline phosphatase (ALP) activity, secretion of an Alcian blue-positive matrix, and mineralization of cartilage-like nodules. Dex reduced cell number over the 40 day period, causing inhibition of ALP activity and matrix production with failure of mineralization. Following withdrawal of Dex, chondrocytes proliferated and re-entered the differentiation and mineralization program, indicating that GC inhibition of chondrogenesis is reversible. In contrast, T(3) reduced cell proliferation, but induced ALP activity and increased matrix secretion earlier than in control cultures. Thus, GCs and T(3) regulate growth plate chondrocyte differentiation by distinct mechanisms. GCs arrest cell proliferation, differentiation, and cartilage mineralization and maintain chondrocyte precursors in a state of quiescence with the capacity to re-enter chondrogenesis. T(3) inhibits cell proliferation but accelerates differentiation to stimulate chondrogenesis.

Animals↗

Insight into the physiological actions of thyroid hormone receptors from genetically modified mice.

Thyroid hormones exert a range of developmental and physiological actions in all vertebrates. Serum concentrations of L-thyroxine (T4) and 3,5,3 -L-triiodothyronine (T3) are maintained by a negative feedback loop involving T3-inhibition of hypothalamic thyrotrophin releasing hormone (TRH) and pituitary thyroid stimulating hormone (TSH) secretion, and by tissue specific and hormone-regulated expression of the three iodothyronine deiodinase enzymes that activate or metabolise thyroid hormones. T3 actions are mediated by two T3-receptors, TRalpha and TRbeta, which act as hormone-inducible transcription factors. The TRalpha (NR1A1) and TRbeta (NR1A2) genes encode mRNAs that are alternatively spliced to generate 9 mRNA isoforms (TRalpha1, alpha2, alpha3, Deltaalpha1, Deltaalpha2, beta1, beta2, beta3 and Deltabeta3), of which four (TRalpha1, alpha2, beta1 and beta2) are known to be expressed at the protein level in vivo. The numerous TR mRNAs are expressed widely in tissue- and developmental stage-specific patterns, although it is important to note that levels of mRNA expression may not correlate with receptor protein concentrations in individual tissues. The TRalpha2, alpha3, Deltaalpha1 and Deltaalpha2 transcripts encode proteins that fail to bind T3 in vitro. These non-binding isoforms, in addition to TRDeltabeta3 which does bind hormone, may act as dominant negative antagonists of the true T3-binding receptors in vitro, but their physiological functions and those of the TRbeta3 isoform have not been determined. In order to obtain a new understanding of the complexities of T3 action in vivo and the role of TRs during development, many mouse models of disrupted or augmented thyroid hormone signalling have been generated. The aim of this review is to provide a picture of the physiological actions of thyroid hormones by considering the phenotypes of these genetically modified mice.

Animals↗

Incidence and characteristics of total stroke in the United States.

BACKGROUND AND PURPOSE: Stroke, increasingly referred to as a "brain attack", is one of the leading causes of death and the leading cause of adult disability in the United States. It has recently been estimated that there were three quarters of a million strokes in the United States in 1995. The aim of this study was to replicate the 1995 estimate and examine if there was an increase from 1995 to 1996 by using a large administrative claims database representative of all 1996 US inpatient discharges. METHODS: We used the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, release 5, which contains approximately 20 percent of all 1996 US inpatient discharges. We identified stroke patients by using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes from 430 to 438, and we compared the 1996 database with that of 1995. RESULTS: There were 712,000 occurrences of stroke with hospitalization (95% CI 688,000 to 737,000) and an estimated 71,000 occurrences of stroke without hospitalization. This totaled 783,000 occurrences of stroke in 1996, compared to 750,000 in 1995. The overall rate for occurrence of total stroke (first-ever and recurrent) was 269 per 100,000 population (age- and sex-adjusted to 1996 US population). CONCLUSIONS: We estimate that there were 783,000 first-ever or recurrent strokes in the United States during 1996, compared to the figure of 750,000 in 1995. This study replicates and confirms the previous annual estimates of approximately three quarters of a million total strokes. This slight increase is likely due to the aging of the population and the population gain in the US from 1995 to 1996.

Aged↗

Development of a brief measure to assess quality of life in obesity.

OBJECTIVE: Obesity researchers have a growing interest in measuring the impact of weight and weight reduction on quality of life. The Impact of Weight on Quality of Life questionnaire (IWQOL) was the first self-report instrument specifically developed to assess the effect of obesity on quality of life. Although the IWQOL has demonstrated excellent psychometric properties, its length (74 items) makes it somewhat cumbersome as an outcome measure in clinical research. This report describes the development of a 31-item version of the IWQOL (IWQOL-Lite). RESEARCH METHODS AND PROCEDURES: IWQOLs from 996 obese patients and controls were used to develop the IWQOL-Lite. Psychometric properties of the IWQOL-Lite were examined in a separate cross-validation sample of 991 patients and controls. RESULTS: Confirmatory factor analysis provided strong support for the adequacy of the scale structure. The five identified scales of the IWQOL-Lite (Physical Function, Self-Esteem, Sexual Life, Public Distress, and Work) and the total IWQOL-Lite score demonstrated excellent psychometric properties. The reliability of the IWQOL-Lite scales ranged from 0.90 to 0.94 and was 0.96 for the total score. Correlations between the IWQOL-Lite and collateral measures supported the construct validity of the IWQOL-Lite. Changes in IWQOL-Lite scales over time correlated significantly with changes in weight, supporting its sensitivity to change. Significant differences in IWQOL-Lite scale and total scores were found among groups differing in body mass index, supporting the utility of the IWQOL-Lite across the body mass index spectrum. DISCUSSION: The IWQOL-Lite appears to be a psychometrically sound and clinically sensitive brief measure of quality of life in obese persons.

Adult↗

The relationship between health-related quality of life and weight loss.

OBJECTIVE: This is a report of health-related quality of life (HRQOL) changes in obese patients completing at least 1 year of outpatient treatment in a weight reduction program combining phentermine-fenfluramine and dietary counseling. RESEARCH METHODS AND PROCEDURES: Participants were 141 women (87.6%) and 20 men (12.4%) who had an average body mass index at intake of 41.1 kg/m(2) (SD = 7.0, range = 29.5 to 67.0 kg/m(2)) and an average age of 44.9 years (SD = 9.3, range = 23 to 65 years). HRQOL was assessed at intake and at 1-year follow-up using the Impact of Weight on Quality of Life (IWQOL)-Lite questionnaire. The relationship between HRQOL changes and weight loss was examined using Pearson correlations. Clinically meaningful change in HRQOL was defined as a 1.96 SEM reduction in IWQOL-Lite total score. RESULTS: On average, participants lost 20.2 kg or 17.6% of their weight over the 1-year period. Of the participants, 15.5% lost <10% of their weight, 24.2% lost 10% to 14.9%, 23.6% lost 15% to 19.9%, and 36.6% lost 20% or more. All five IWQOL-Lite scales and total score showed statistically significant improvement over the 1-year period. Changes in IWQOL-Lite scores from intake to 1 year showed statistically significant correlations with percentage of weight loss for all subscales and total score. Subscale correlations with weight loss ranged from 0.166 (Public Distress) to 0.396 (Physical Function) and was 0.370 for the total score. Forty-four percent of participants losing <10% met the criterion of clinically meaningful change, compared with 51.3% losing 10% to 14.9%, 55.3% losing 15% to 19.95%, and 76.3% losing >20%. For total score and for three of the five IWQOL-Lite scales (Physical Function, Self-Esteem, and Sexual Life), the relationship between weight loss and clinically meaningful change was linear and was significant at p < 0.05. Physical Function and Self-Esteem were most strongly affected by weight loss. DISCUSSION: HRQOL changes, as measured by an obesity-specific instrument (IWQOL-Lite), are strongly related to weight reduction.

Adult↗

Quality of life and obesity.

Interest in the quality of life of patients with different diseases continues to grow. Recent years have witnessed a dramatic rise in the prevalence of obesity worldwide, stimulating interest in the health and quality of life consequences of this phenomenon. The body of research on the quality of life of obese individuals has grown to a point that a review of this literature is warranted. Numerous studies have demonstrated that obese persons experience significant impairments in quality of life as a result of their obesity, with greater impairments associated with greater degrees of obesity. Weight loss has been shown to improve quality of life in obese persons undergoing a variety of treatments. Further research is needed to clarify whether quality of life differs among subsets of obese persons. Until recently, there has been little standardization of quality of life measures in obesity. The SF-36 has been used in a number of studies of obese persons. Several obesity-specific instruments have also been developed and have shown great promise. The quality of life of obese individuals is an important issue that should be included in weight management treatment and research.

Ethnicity↗

Burr-hole versus twist-drill drainage for the evacuation of chronic subdural haematoma: a comparison of clinical results.

BACKGROUND: Most neurosurgeons remove clinically symptomatic subdural haematomata, but the techniques they choose remain controversial. METHOD: The results from sixty-two patients diagnosed with chronic subdural haematoma were evaluated for technique, postoperative computerized tomography (CT) scan results, and complications. RESULTS: Eleven patients had haematomata evacuated using twist-drill plus drain, 37 patients had haematomata evacuated with burr-hole only, and 14 patients were evacuated with burr-hole plus drain. Of the patients who underwent twist-drill and closed system drainage (CSD), 43% had smaller lesions on CT follow-up scans, as compared with 74% of those who underwent the burr-hole only procedure, and 65% with burr-holes with drains. Clinical outcome results showed that 64% of twist-drill and CSD patients deteriorated as compared with 16% of those with burr-hole only and 7% with burr-holes and CSDs. Sixty-four per cent of twist-drill patients required repeat evacuations as compared with 11% of those with burr-holes only, and 7% with burr-holes plus drains. CONCLUSION: The results at our institution indicate that burr-hole evacuation for chronic subdural haematoma is superior to twist-drill evacuation with respect to clinical outcomes and complications.

Adolescent↗

Genetic analysis reveals different functions for the products of the thyroid hormone receptor alpha locus.

Thyroid hormone receptors are encoded by the TRalpha (NR1A1) and TRbeta (NR1A2) loci. These genes are transcribed into multiple variants whose functions are unclear. Analysis by gene inactivation in mice has provided new insights into the functional complexity of these products. Different strategies designed to modify the TRalpha locus have led to strikingly different phenotypes. In order to analyze the molecular basis for these alterations, we generated mice devoid of all known isoforms produced from the TRalpha locus (TRalpha(0/0)). These mice are viable and exhibit reduced linear growth, bone maturation delay, moderate hypothermia, and reduced thickness of the intestinal mucosa. Compounding TRalpha(0) and TRbeta(-) mutations produces viable TRalpha(0/0)beta(-/-) mice, which display a more severe linear growth reduction and a more profound hypothermia as well as impaired hearing. A striking phenotypic difference is observed between TRalpha(0/0) and the previously described TRalpha(-/-) mice, which retain truncated TRDeltaalpha isoforms arising from a newly described promoter in intron 7. The lethality and severe impairment of the intestinal maturation in TRalpha(-/-) mice are rescued in TRalpha(0/0) animals. We demonstrate that the TRDeltaalpha protein isoforms, which are natural products of the TRalpha locus, are the key determinants of these phenotypical differences. These data reveal the functional importance of the non-T3-binding variants encoded by the TRalpha locus in vertebrate postnatal development and homeostasis.

Animals↗

Glucocorticoids, thyroid hormone and growth hormone interactions: implications for the growth plate.

Linear growth occurs during childhood and results from endochondral ossification in the growth plate. Prepubertal growth is primarily regulated by growth hormone (GH) and insulin-like growth factor (IGF)-I, with important contributions from glucocorticoids (GC) and thyroid hormone (T(3)). The somatomedin hypothesis proposed that GH stimulates hepatic IGF-I production, which then regulates growth via IGF-I receptor expressing chondrocytes in an endocrine fashion. Recent studies indicate that locally acting IGF-I is a key determinant of endochondral ossification and that GH, GC and T(3) regulate expression of IGF-I and its receptor in the growth plate directly. Analysis of hormone imbalance during childhood and studies of genetically modified mice provide support for an important GH and IGF-I autocrine/paracrine pathway and for direct effects of GC and T(3) during endochondral ossification. Thus, the epiphyseal growth plate is a key site for convergent hormone action that mediates the control of linear growth.

Animals↗

Complications of thermal capsulorrhaphy of the shoulder.

BACKGROUND: The purpose of this study was to evaluate the rate of recurrence and the prevalence of complications related to the use of thermal energy for the treatment of glenohumeral instability. METHODS: A survey was conducted of all members of the American Shoulder and Elbow Surgeons, the Arthroscopy Association of North America, and the American Orthopaedic Society for Sports Medicine. The survey focused on the rate of recurrence, the number of axillary nerve injuries, and the prevalence of capsular insufficiency seen in revision surgery after thermal capsulorrhaphy of the shoulder. RESULTS: Three hundred and seventy-nine surgeons responded to the survey. Of 236,015 shoulder procedures performed over the last five years, 14,277 (6%) involved the use of thermal energy (1,077 involved laser energy; 9,013, monopolar radiofrequency; and 4,187, bipolar radiofrequency) for the treatment of glenohumeral instability. The rates of recurrent instability after laser, monopolar radiofrequency, and bipolar radiofrequency capsulorrhaphy were 8.4%, 8.3%, and 7.1%, respectively. Of the patients with recurrent instability, 363 (twenty-one treated with laser energy, 220 treated with monopolar radiofrequency, and 122 treated with bipolar radiofrequency) required revision surgery. In this group of patients with revision surgery, seven (33%) of the twenty-one treated primarily with laser energy, thirty-nine (18%) of the 220 treated primarily with monopolar radiofrequency, and twenty-five (20%) of the 122 treated primarily with bipolar radiofrequency exhibited signs of capsular attenuation at the time of the revision. A total of 196 patients (1.4%) (three treated with laser energy; 133, with monopolar radiofrequency; and sixty, with bipolar radiofrequency) had a postoperative axillary neuropathy; 93% of the 196 had a sensory deficit only. Of these patients, 95% recovered completely, with the sensory deficits lasting an average of 2.3 months and the combined deficits, an average of four months. CONCLUSIONS: The use of thermal energy for the treatment of shoulder instability has promising short-term results. The rates of recurrent instability are low. However, when recurrent instability occurs, capsular insufficiency may be present. Axillary nerve injury was reported in 1.4% of the patients, in most of whom it resolved spontaneously.

Adult↗