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Biomedical subjects

G R Williams

Publications and source records attributed to G R Williams.

At least 91 records · Page 5Linked to original sources
PubMed1995

Keratin expression in the normal anal canal.

The pattern of epithelial keratin expression in the normal anal canal has not been extensively defined and is a necessary prerequisite to the interpretation of alterations in these intermediate filaments in pathological anal epithelial lesions. Thirty-five frozen tissue specimens of resected haemorrhoids were investigated immunohistologically for expression of 14 individual keratins (K) using a panel of 17 monoclonal antibodies. Perianal skin showed basal expression of keratinocyte Ks 5, 14 and 17, and suprabasal expression of keratinocyte Ks 14, 10, 1 and 16. Anal squamous epithelium showed persistent basal K5 and 17, basal and suprabasal K4, 13 and 16 positivity, with sporadic expression of K1 and 10. The expression of simple epithelial keratins in squamous epithelium adjacent to the anal transitional zone varied with basal expression of K7, K8, K18 and K19 and sporadic suprabasal expression of K7 and K19. The anal transitional zone (ATZ) expressed K19, as found in transitional epithelia elsewhere. The full thickness of epithelium was positive for the simple epithelial Ks 7, 8 18 and 19. Marked heterogeneity of keratinocyte keratin expression was seen. Basal layers expressed Ks 4, 13, 14 and 17 and variably K16, while suprabasal layers expressed Ks 4 and 13, 14 and 17 and variably K16, while suprabasal layers expressed Ks 4 and 13 and variably K14, 16 and 17. This anomalous expression of keratinocyte K4 and 13 has also been documented in transitional epithelium of the bladder. The anal glands and ducts showed a keratin distribution similar to the transition zone.(ABSTRACT TRUNCATED AT 250 WORDS)

Anal Canal↗
PubMed1995

1,25-Dihydroxyvitamin D3 and retinoid X receptor expression in human colorectal neoplasms.

Epidemiological studies suggest that 1,25-dihydroxyvitamin D3 (D3) protects against colorectal carcinogenesis. Animal and in vitro studies show an antiproliferative effect of D3 in a variety of tumours including those of large bowel origin. D3 actions are mediated by D3 receptors (VDR) alone or by VDR in conjunction with retinoid X receptors (RXRs) in all D3 responsive tissues. The expression of mRNAs encoding VDR and RXRs in normal and malignant human colorectum was determined. Full length VDR (4.6 kB), RXR alpha (5.5 kB), and RXR gamma (3.5 and 7 kB) mRNAs were expressed in all tissues, but RXR beta mRNA was not expressed in any. VDR expression was reduced in 12 carcinomas relative to paired normal mucosa, and RXR alpha expression was reduced in nine. There was no correlation between VDR or RXR alpha expression and the site, grade of differentiation, or Dukes's staging of the tumour. The finding of persistent VDR and RXR coexpression in all colorectal tumours provides a rational basis for exploring a role for D3 in the treatment of colorectal malignancy.

Blotting, Northern↗
PubMed1995

Retinoids modify regulation of endogenous gene expression by vitamin D3 and thyroid hormone in three osteosarcoma cell lines.

1 alpha,25-Dihydroxyvitamin D3 (D3), T3, and retinoids are necessary for normal skeletal development, and their actions are interdependent due to the heterodimerization capabilities of their receptors. We investigated the hypothesis that these hormones act on osteoblasts directly to produce complex target gene responses resulting from multiple hormone interactions. Physiological interactions among D3, T3, and retinoid signaling were analyzed in serum-free cultures of the osteosarcoma cell lines ROS 25/1, UMR106, and ROS 17/2.8. These cells express distinct stages of the osteoblast phenotype and coexpress appropriate hormone receptors. Regulation of collagen I alpha 1 and alpha 2, alkaline phosphatase, osteopontin, and osteocalcin messenger RNAs was dependent on the dose and duration of hormone stimulation and modified by cell confluence. Retinoids were required for comprehensive expression of phenotypic responses to D3 and T3 in each cell type and hormone interactions were both cell and target gene specific. Differing responses of target genes in each cell line may provide a molecular basis for discrete hormone actions seen at specific stages of osteoblast differentiation or skeletal development.

Animals↗
PubMed1995

Débridement of degenerative, irreparable lesions of the rotator cuff.

A modified Neer acromioplasty, subacromial decompression, and débridement of massive, irreparable lesions of the supraspinatus and infraspinatus tendons was performed in fifty-seven patients. Fifty patients (fifty-three shoulders) were followed for an average of six and one-half years. The average age of the patients was sixty years (range, thirty-eight to seventy-four years). The results, as rated on the basis of pain, function, range of motion, strength, and satisfaction of the patient, were satisfactory in forty-four shoulders (83 per cent) and unsatisfactory in nine (17 per cent). A favorable outcome was observed in shoulders in which both the anterior portion of the deltoid muscle and the long head of the biceps tendon were intact and in which a previous acromioplasties or operations on the rotator cuff had been performed. An unsatisfactory outcome was observed in shoulders in which the anterior part of the deltoid muscle was weak or absent or in which a previous acromioplasty and attempted repair of the rotator cuff had been performed. The active forward flexion of the shoulder improved from an average of 105 degrees preoperatively to an average of 140 degrees postoperatively. The results of the present study suggest that, with proper rehabilitation, adequate decompression of the subacromial space, anterior acromioplasty, and débridement of massive tears of the rotator cuff can lead to the relief of pain and the restoration of shoulder function.

Acromion↗
PubMed1995

Treatment of HL60 cells with various combinations of retinoids and 1 alpha,25 dihydroxyvitamin D3 results in differentiation towards neutrophils or monocytes or a failure to differentiate and apoptosis.

It is well documented that treatment of serum-grown HL60 cells with 10(-7) M all-trans retinoic acid (all-trans RA) induces neutrophil differentiation, whereas treatment with 10(-7) M 1 alpha,25 dihydroxyvitamin D3(D3) induces differentiation towards monocytes. In recent investigations, using serum-free grown HL60 cells, we observed that all-trans RA, at 10(-7) M, did not induce neutrophil differentiation and that all-trans RA, at 10(-8) M, reduced the D3 concentration required for monocyte differentiation to 5 x 10(-9) M. In this study, co-operative interactions between all-trans and 9-cis RA and D3 which promote neutrophil and monocyte differentiation of HL60 cells have been analysed in detail. Treatment of serum-free grown HL60 cells with 5 x 10(-7) M all-trans RA or 9-cis RA resulted in sub-optimal neutrophil differentiation (up to 25% mature cells). As shown for all-trans RA, 9-cis RA cooperated with D3 to promote monocyte differentiation. Culture of HL60 cells in 5 x 10(-7) M 9-cis RA together with a wide range of concentrations of D3 resulted in promotion of neutrophil differentiation at 10(-15)-10(-12) D3, a failure to differentiate and apoptosis at 10(-11)-10(-10) M D3, followed by co-operativity between 9-cis RA and 5 x 10(-9) M D3 in inducing monocyte differentiation in the absence of neutrophil differentiation. Similar results were obtained when HL60 cells were treated with 5 x 10(-7) all-trans RA together with a wide range of concentrations of D3. Cross titration analyses of the effects of 9-cis RA and D3 on HL60 cell differentiation were undertaken to determine the boundaries of the concentrations of each agent, alone and in combination, that give rise to optimal neutrophil and monocyte differentiation of HL60 cells. The observed cooperativities between either 9-cis RA or all-trans RA and D3 have important implications for the use of combinations of these agents in differentiation therapy.

Apoptosis↗
PubMed1994

Effects of 40Ar and 56Fe ions on retinal photoreceptor cells of the rabbit: implications for manned missions to Mars.

Losses of photoreceptor cells (rods) from the retinas of New Zealand white (NZW) rabbits were detectable within 2 years after localized acute irradiation of optic and proximal tissues with > or = 7 Gy of 530 MeV u-1 40Ar ions or > or = 2 Gy of 465 MeV u-1 56Fe ions in the Bragg plateau region of energy deposition. Those limits were determined only from an analysis of variance of dose groups because the shapes of the dose response curves at early post-irradiation times are not known, a concern being addressed by experiments in progress. Losses of photoreceptor cells for the period 0.5-2.5 years post-irradiation, determined by provisional linear regression analysis, were approximately 1.7% Gy-1 and 2.5% Gy-1 for 40Ar and 56Fe ions, respectively.

Analysis of Variance↗
PubMed1994

Physiology of the steroid-thyroid hormone nuclear receptor superfamily.

Glucocorticoids, other steroid hormones, thyroid hormones and vitamin-derived hormones (including retinoids) all exert their effects by the regulation of hormone-responsive target genes within the cell nucleus. These hormones bind to a series of specific nuclear receptor proteins that function as hormone-inducible transcription factors. The receptors are structurally homologous, are related to the avian erythroblastosis oncogene v-erbA, and exhibit remarkable evolutionary conservation. Together they form the steroid-thyroid hormone nuclear receptor superfamily. This chapter describes the structure and functions of the various family members and highlights the differences and similarities that occur between individual receptor proteins. Type I receptors, which include glucocorticoid receptor and other steroid receptor proteins, interact as homodimers with target sequences of DNA containing two receptor binding sites arranged as a palindrome. Type II receptors, which include receptors for retinoids, thyroid hormone and vitamin D3, bind as heterodimers (or homodimers) to DNA sequences in which two or more receptor-binding sites are arranged as a direct repeat or as other more complex configurations. The complexity of both receptor-DNA and receptor-receptor interactions predicts the potential for considerable cross-talk between various hormone-activated pathways. Thus, the specificity of hormone action and its regulation is discussed in relation to the structural and functional characteristics of the receptors and their molecular mechanisms of action. Finally, potential sites of regulation of hormone action, from circulating hormone levels in the periphery to their delivery to the cell and final site of action in the nucleus, are highlighted to provide a perspective for the following chapters in this volume and to indicate their clinical significance.

Animals↗
PubMed1994

Anal carcinoma--a histological review.

Epidemiological evidence of an association between anal carcinoma and symptomatic HIV-related disease suggests that the number of cases of this disease may increase significantly over the next few years. The role of oncogenic HPV types in the pathogenesis of anal carcinoma is substantiated by both epidemiological evidence that tumours are associated with a past history of anal warts and by experimental evidence showing that over 85% of tumours contain HPV 16/18 DNA on PCR. The physical state of the virus in the tumour cell genome is currently under investigation, and cellular interactions between HPV, HIV and other sexually transmitted viruses require further research. Clinical studies have shown that patients with anal warts and those who are HIV positive also show an increased tendency to develop dysplasia within the anal epithelium. However, the malignant potential of dysplasia remains unclear and, it presents problems in management, particularly when multifocal and high grade. Problems in classification of anal carcinomas involve both the site of the tumours and the histological appearance. Despite the difficulties which exist in estimating the origin of a tumour from canal or margin, this information does appear to have clinical significance and should therefore continue to be assessed. Recent morphological and keratin studies have emphasized the heterogeneity of these tumours and have revealed a similar heterogeneous profile of keratin expression in the normal anal epithelium. These results support the body of opinion which suggests that, with the exception of small cell carcinoma and adenocarcinoma, anal carcinomas should be considered as squamous cell tumours which are able to display a range of further morphological characteristics within which ductal differentiation and mucin production appear to carry the worst prognosis. Although there is no universally accepted staging system for anal carcinoma, depth of invasion and extent of spread at the time of diagnosis are the most important clinical factors determining survival and response to therapy. Randomized clinical trials are now under way to compare the outcome of various combinations of radiotherapy and chemotherapy, which have replaced radical surgery as a first line treatment and resulted in a significant decrease in patient morbidity from this disease.

Anus Neoplasms↗
PubMed1994

Thyroid hormone receptor binds with unique properties to response elements that contain hexamer domains in an inverted palindrome arrangement.

Thyroid hormone receptor (T3R)-accessory protein heterodimers preferentially bind to thyroid hormone response elements (TREs), which contain hexamer domains arranged as a direct repeat separated by a 4-basepair gap (DR + 4). T3R homodimers, however, preferentially bind to elements that consist of an inverted palindrome. We now report on unique T3R binding patterns and functional characteristics of two such elements that mediate T3 regulation. We performed mutational analysis of the chicken lysozyme silencer F2 (LysF2) TRE and demonstrated that the two functional binding domains are arranged as an inverted palindrome separated by 6 basepairs. Both the LysF2 TRE and the similarly arranged myelin basic protein TRE bind T3R dimers at very low T3R concentrations. Despite the high relative affinity for T3R dimer binding, the T3 induction conferred by these elements is low compared to that of previously characterized TREs with a DR + 4 arrangement. The laminin-B1 gene element, previously shown to bind retinoic acid receptor, contains at least four hexameric binding domains. All of the domains can bind T3R simultaneously and are involved in conferring T3 induction, but bind with a different pattern than that reported for retinoic acid receptor. T3R homodimer binding to a series of mutant laminin-B1 elements and T3 induction were significantly correlated (r = 0.82; P < 0.05). T3R homodimer binding to LysF2 element mutants was not correlated with T3 induction (r = 0.32; P > 0.05); however, T3R-nuclear protein heterodimer binding was significantly correlated (r = 0.67; P < 0.05). T3R-nuclear protein heterodimers, but not homodimers, bound consistently to mutations of the LysF2 element that altered the gap between hexamers. The overall discordance between strong T3R binding to these elements and weak T3 induction indicates that the unusual hexamer arrangement places the T3R complex in an unfavorable configuration for maximal T3-dependent transactivation. The differential T3 sensitivity of generalized resistance to thyroid hormone-associated T3R mutants to the LysF2 element compared with the DR + 4 arrangement suggests that these unique features may have physiological significance.

Animals↗
PubMed1994

Characterization of thyroid hormone (T3) receptors in three osteosarcoma cell lines of distinct osteoblast phenotype: interactions among T3, vitamin D3, and retinoid signaling.

T3 is required for normal skeletal development, but its cellular targets in bone are unknown. T3 regulates target gene transcription via a specific nuclear receptor (T3R), which can heterodimerize with 9-cis-retinoic acid, 1 alpha, 25-dihydroxyvitamin D3, or retinoic acid receptors to modify T3 responsiveness. Serum-free cultures were developed to investigate hormone interactions in three osteosarcoma cell lines, ROS25/1, UMR106, and ROS17/2.8, that express fibroblast-like, preosteoblast, and mature osteoblast phenotypes. ROS25/1 expressed T3R alpha 1, but only low levels of T3R beta 1, whereas UMR106 and ROS17/2.8 cells expressed both receptor proteins. All cells expressed c-erb-A alpha 2 protein and equal levels of 1 alpha,25-dihydroxyvitamin D3 receptor, 9-cis-retinoic acid receptor, and retinoic acid receptor messenger RNAs. Endogenous T3R activity and the effects of D3 and 9-cis-RA on T3 responsiveness were determined in transfections using reporter genes containing T3 response elements from rat malic enzyme or alpha-myosin heavy chain genes. Cell-specific T3 responses were associated with differing patterns of T3R gene expression and stages of osteoblast phenotype expression. A change in T3R beta 1 gene expression during osteoblast phenotype differentiation may modify T3 action in developing bone.

Animals↗
PubMed1994

Categorization of acromial shape: interobserver variability with MR imaging and conventional radiography.

OBJECTIVE: Our purpose was to determine interobserver variability in the interpretation of the shape of the acromion on sagittal oblique MR images and conventional radiographs. The shape of the acromion was defined according to a previously described classification scheme. MATERIALS AND METHODS: We reviewed 26 sets of sagittal oblique MR images and corresponding conventional Y- or outlet-view radiographs of the shoulder. The shape of the acromion was graded for each study independently by four reviewers. Interobserver agreement was measured by using the kappa statistic. Analysis of variance and the chi 2-test were used for univariate analysis. RESULTS: The acromion was interpreted most often as being curved. The observers scored 9% of MR images and 28% of conventional radiographs as nondiagnostic (p < .001) (41% of transscapular Y views and 3% of supraspinatus outlet views were also considered nondiagnostic [p < .0001]). Kappa values were .23 for MR images and .43 for conventional radiographs. Variability in interpretation between techniques when controlled for observer was not statistically significant. CONCLUSION: Although sagittal oblique MR images were significantly more likely than conventional radiographs to be considered diagnostic by observers, interobserver agreement for MR examinations was poor. There was moderate agreement with conventional radiographs. This calls into question the usefulness of the previous system of interpretation and suggests that it might be more applicable with conventional radiographs than with MR images.

Acromion↗
PubMed1994

All-trans retinoic acid and 1 alpha,25-dihydroxyvitamin D3 co-operate to promote differentiation of the human promyeloid leukemia cell line HL60 to monocytes.

A basis for differentiation therapy of leukemias is provided by knowledge of agents which induce specific lineage maturation. All-trans retinoic acid (RA) induces differentiation of HL60 cells to neutrophils and is used to treat acute promyelocytic leukemia. We observed that RA did not induced neutrophil differentiation in serum-free grown HL60 cells whereas 50 nM 1 alpha,25-dihydroxyvitamin D3 (D3) induced maximal monocyte differentiation. Increasing RA concentrations reduced the D3 concentration required for monocyte differentiation. Cells treated with 5 nM D3 showed little response, but differentiated maximally with 5 nM D3 and 10 nM RA. The D3 analogs MC903, EB1089 and KH1060 were more potent inducers of monocyte differentiation. The extent to which analog activity was increased after cotreatment with RA was inversely related to potency. Twenty-four hour treatment with 10 nM RA primed cells for response to 5 nM D3; the reverse sequence being ineffective. Priming with 10 nM RA, or subsequent treatment with D3 (5 nM), did not alter expression of mRNAs encoding receptors for D3 (VDR), RA (RAR alpha) or 9-CIS RA (RXR alpha, beta, gamma). That RA promotes both neutrophil and monocyte differentiation has implications for the use of RA and D3 in treatment of leukemias and provides insight into mechanisms whereby RAR, VDR and RXR facilitate monocyte differentiation.

Calcitriol↗
PubMed1993

Interaction of hypokalemia and ventricular dilatation in isolated rabbit hearts.

Potassium depletion has been implicated in the genesis of ventricular arrhythmias, especially in patients with congestive heart failure, but the nature of this interaction is unknown. We studied the electrophysiological effects of varying concentrations of extracellular K+ in 24 isolated, retrogradely perfused rabbit hearts. The left ventricular cavity was dilated with a fluid-filled balloon. Left ventricular effective refractory period decreased significantly (from 119 +/- 3 to 105 +/- 3 ms) with ventricular dilatation but was not influenced by K+ concentration. Conduction velocity was not changed by dilatation but was decreased by hypokalemia (81 +/- 2 cm/s, K+ = 4.9 mM; 75 +/- 2 cm/s, K+ = 3.5 mM; 70 +/- 2 cm/s, K+ = 2.5 mM; P < 0.05). No ventricular arrhythmias were induced in undilated hearts at a K+ concentration of 4.9 mM. Induced ventricular fibrillation was more frequent (38%; P < 0.01) in the dilated heart and increased markedly (92%; P < 0.01) with coexisting hypokalemia. The incidence of induced fibrillation was highly correlated with the wavelength of the ventricular impulse (wavelength = refractory period x conduction velocity). Thus dilatation and hypokalemia have very different electrophysiological effects that can interact synergistically to predispose the heart to reentrant arrhythmias in this model.

Animals↗
PubMed1993

Pancreatic adenocarcinoma: a review for primary care physicians.

Adenocarcinoma of the pancreas is becoming an increasingly common disease. The differential diagnosis of pancreatic adenocarcinoma is that of obstructive jaundice. Suspicious findings on history and physical examination can be confirmed with appropriate laboratory and radiologic testing. Approximately 20% of patients with small lesions and no metastatic disease may be cured with resection. The operative mortality and morbidity for major pancreatic resections is now sufficiently low to warrant a more aggressive approach to these patients.

Adenocarcinoma↗
PubMed1992

Late cataractogenesis in primates and lagomorphs after exposure to particulate radiations.

Rhesus monkeys that were exposed in 1969, at the age of approximately 2 years, to low doses of "mixed-energy" protons (10- and 110-MeV) are exhibiting progressive (degenerative) lenticular changes. We have conducted regular examinations of this group of monkeys for cataractogenic development since 1987, i.e., 18 years after irradiation, and the animals began to show enhanced degrees of lenticular opacification two years later. The lenses of age-matched controls (median lifespan in captivity approximately 24 years) continue to exhibit much lower levels of opacification (senile cataracts). Trends in the new data are consistent with the cataractogenic patterns observed for other groups of monkeys that were exposed at similar ages in 1964 and 1965 to protons of different energies, and which we began to monitor only 20-21 years later. Therefore, the new information from the mixed-energy group of monkeys provides insight into the development of late cataractogenic sequelae in the other groups of animals during the 2-3 years before we began to measure them. Comparisons are also made here among recent results from the different groups of primates and from New Zealand white (NZW) rabbits that were exposed when young to 56Fe ions and monitored continuously thereafter. This is done because analogous expression of radiation-induced degenerative cataractogenesis also occurs late in the lifespan of the lagomorphs (control median lifespan in captivity approximately 5-7 years), but in this case the cataractogenic profile has been documented through most of the post-irradiation lifespan.

Animals↗