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Biomedical subjects

Richard Williams

Publications and source records attributed to Richard Williams.

At least 19 recordsLinked to original sources
PubMed2007

Facial Sweet's syndrome mimicking rosacea fulminans.

A 36-year-old man presented with a non-pruritic, erythematous facial rash with peri-oral and peri-orbital sparing. The initial clinicopathological diagnosis was rosacea fulminans, which was treated with 25 mg oral prednisolone and cephalexin. The patient re-presented 1 week later with exacerbation of his rash in addition to constitutional symptoms of fever and malaise. A further skin biopsy was taken and the marked neutrophilic infiltrate in the absence of vasculitis made the diagnosis of Sweet's syndrome (acute febrile neutrophilic dermatosis). High-dose prednisolone (50 mg daily), topical hydrocortisone cream and ichthammol in zinc ointment were commenced with rapid clinical improvement. This case highlights the importance of considering Sweet's syndrome as a differential diagnosis when presented with a facial eruption.

Administration, Cutaneous↗
PubMed2006

An SCN9A channelopathy causes congenital inability to experience pain.

The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the condition as an autosomal-recessive trait to chromosome 2q24.3. This region contains the gene SCN9A, encoding the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons. Sequence analysis of SCN9A in affected individuals revealed three distinct homozygous nonsense mutations (S459X, I767X and W897X). We show that these mutations cause loss of function of Na(v)1.7 by co-expression of wild-type or mutant human Na(v)1.7 with sodium channel beta(1) and beta(2) subunits in HEK293 cells. In cells expressing mutant Na(v)1.7, the currents were no greater than background. Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans. These findings should stimulate the search for novel analgesics that selectively target this sodium channel subunit.

Base Sequence↗
PubMed2006

In vivo temperature profile of intervertebral discs and vertebral endplates during vertebroplasty: an experimental study in sheep.

STUDY DESIGN: Experimental study of temperature profiles during vertebroplasty. OBJECTIVES: To define accurate temperature profiles during vertebroplasty in an in vivo animal model. SUMMARY OF BACKGROUND DATA: Controversy still exists whether vertebroplasty achieves its analgesic effect by stabilizing fracture fragments or due to thermal damage of sensory nerves inside the vertebral body. Furthermore, the energy release during cement polymerization may cause thermal injury to the spinal cord or intervertebral discs. METHODS: A total of 4.0 mL PMMA was injected into three lumbar vertebrae of four skeletally mature mixed-bred ewes. Nine separate K-type thermocouples were placed into 12 vertebrae and their adjacent intervertebral discs. Temperature changes were recorded continuously before, during, and after the injection. RESULTS: The highest peak temperatures were measured at the cranial endplate (mean 42.4 +/- 8.8 C) and in the center of the vertebral body (mean 43.3 +/- 6.9 C). Temperatures stayed above 40 C for approximately 2.5 minutes. Peak temperatures in the discs and at the dorsal wall (closest to spinal cord) did not exceed 41 C and 47 C and stayed above 40 C for approximately 1.5 minutes. CONCLUSIONS: The intervertebral discs and the spinal cord do not seem to be in danger of thermal damage during vertebroplasty. The measured energy does not seem to be sufficient for the palliative effect achieved by vertebroplasty.

Animals↗
PubMed2006

Clozapine alone versus clozapine and risperidone with refractory schizophrenia.

BACKGROUND: The treatment of schizophrenia with multiple antipsychotic drugs is common, but the benefits and risks are not known. METHODS: In a randomized, double-blind study, we evaluated patients with schizophrenia and a poor response to treatment with clozapine. The patients continued to take clozapine and were randomly assigned to receive eight weeks of daily augmentation with 3 mg of risperidone or with placebo. This course of treatment was followed by an optional 18 weeks of augmentation with risperidone. The primary outcome was reduction in the total score for severity of symptoms on the Positive and Negative Syndrome Scale (PANSS). The secondary outcomes included cognitive functioning. RESULTS: A total of 68 patients were randomly assigned to treatment. In the double-blind phase, the mean total score for the severity of symptoms decreased from baseline to eight weeks in both the risperidone and the placebo groups. There was no statistically significant difference in symptomatic benefit between augmentation with risperidone and placebo: 9 of 34 patients receiving placebo and 6 of 34 receiving risperidone responded to treatment (P=0.38). The mean difference in the change in PANSS scores from baseline to eight weeks between those receiving risperidone and those receiving placebo was 0.1 (95 percent confidence interval, -7.3 to 7.0). The verbal working-memory index showed a small decline in the risperidone group and a small improvement in the placebo group (P=0.02 for the comparison between the two groups in the change from baseline). The increase in fasting blood glucose levels was mildly greater in the risperidone group than in the placebo group (16.2 vs. 1.8 mg per deciliter [0.90 vs. 0.10 mmol per liter], P=0.04). The incidence and severity of other side effects did not differ between the two groups. CONCLUSIONS: In this short-term study, the addition of risperidone to clozapine did not improve symptoms in patients with severe schizophrenia. (ClinicalTrials.gov number, NCT00272584).

Adult↗
PubMed2006

A novel case of polyfibromatosis and interstitial granulomatous dermatitis with arthritis.

Polyfibromatosis is a rare condition in which several cutaneous fibrotic conditions, such as Dupuytren's contracture, keloid formation, Peyronie's disease and plantar fibromatosis, may coexist. Interstitial granulomatous dermatitis with arthritis is also a rare condition characterized by arthritis and infiltrated rope-like lesions with granulomatous histologic features. We report a case of the simultaneous occurrence of both conditions in the same individual. To our knowledge, this has not been previously described. The clinical course has been slow, progressive, and recalcitrant to treatment.

Aged↗
PubMed2006

Laminin, VEGF, and bone matrix protein expression in uroepithelial bone induction--a canine model.

A biological and embryological bone induction from epithelial-mesenchymal cell interactions has been noticed in some developing tissues. However, the mechanism for bone formation induced by the epithelial-mesenchymal cell interactions is not clear. The aim of our study was to reveal the role of laminin, vascular endothelial growth factor (VEGF), and bone matrix proteins in mesenchymal cell differentiation during uroepithelial bone induction using a well-established canine model. In this model, a myoperitoneal muscle flap from the abdominal rectus sheath was transplanted into the bladder wall. After 6 weeks, the bladder samples were removed and assessed by histology and immunohistochemistry. This study demonstrated that bone formation occurred in two different directions with two distinct mechanisms. We noted that bone-forming cells in two types of bone formation derived from mesenchymal stem cell differentiation induced either from uroepithelium or bone autoinduction. Laminin was only expressed in peripheral regions of uroepithelium bone formation. Type II collagen was expressed both intracellularly and extracellularly around hypertrophic chondrocytes, whereas VEGF was mostly expressed in proliferating chondrocytes. This study indicates that components in basement membrane like laminin play a role in transitional epithelium-induced differentiation of mesenchymal cells to chondrocytes in muscle tissue. The sequential expression of bone matrix proteins by differentiated osteogenetic cells indicates a subsequent sequence of bone autoinduction.

Animals↗
PubMed2006

Predicted exposures to steroid estrogens in U.K. rivers correlate with widespread sexual disruption in wild fish populations.

Steroidal estrogens, originating principally from human excretion, are likely to play a major role in causing widespread endocrine disruption in wild populations of the roach (Rutilus rutilus), a common cyprinid fish, in rivers contaminated by treated sewage effluents. Given the extent of this problem, risk assessment models are needed to predict the location and severity of endocrine disruption in river catchments and to identify areas where regulation of sewage discharges to remove these contaminants is necessary. In this study we attempted to correlate the extent of endocrine disruption in roach in British rivers, with their predicted exposure to steroid estrogens derived from the human population. The predictions of steroid estrogen exposure at each river site were determined by combining the modeled concentrations of the individual steroid estrogens [17beta-estradiol (E2), estrone (E1), and 17alpha-ethinylestradiol (EE2)] in each sewage effluent with their predicted dilution in the immediate receiving water. This model was applied to 45 sites on 39 rivers throughout the United Kingdom. Each site studied was then categorized as either high, medium, or low "risk" on the basis of the assumed additive potency of the three steroid estrogens calculated from data derived from published studies in various cyprinid fish species. We sampled 1,438 wild roach from the predicted high-, medium-, and low-risk river sites and examined them for evidence and severity of endocrine disruption. Both the incidence and the severity of intersex in wild roach were significantly correlated with the predicted concentrations of the natural estrogens (E1 and E2) and the synthetic contraceptive pill estrogen (EE2) present. Predicted steroid estrogen exposure was, however, less well correlated with the plasma vitellogenin concentration measured in the same fish. Moreover, we found no correlation between any of the end points measured in the roach and the proportion of industrial effluents entering the rivers we studied. Overall, our results provide further and substantive evidence to support the hypothesis that steroidal estrogens play a major role in causing intersex in wild freshwater fish in rivers in the United Kingdom and clearly show that the location and severity of these endocrine-disrupting effects can be predicted.

Animals↗
PubMed2005

Neuropsychological deficits, syndromes, and cognitive competency in schizophrenia.

INTRODUCTION: Neuropsychological functioning connects neuropathology and symptoms in schizophrenia. Previous work suggests that deficient initiation and inhibition underlie the psychomotor poverty and disorganisation syndromes, respectively. Furthermore, although the syndromes are associated with impairments in everyday functioning, cognitive competency (CC; cognitive skills for independent living) has been neglected as an outcome. This study tested a three-level model of schizophrenia pathology (Neuropsychological dysfunction --> Syndromes --> CC), using unstructured neuropsychological tasks to measure initiation and inhibition. METHODS: Participants were 40 adults with schizophrenia. A verbal picture description and the Tinkertoy test yielded initiation and inhibition measures with good interrater reliability. Symptoms were rated using the SANS and SAPS, and an insight scale was administered. The Cognitive Competency Test utilised simulated situations to assess CC. RESULTS: Initiation failed to predict psychomotor poverty, but affected CC directly. Only one indicator of disinhibition (intermingling of personal material into speech) predicted disorganisation, which, through mediation, led to CC deficits. Insight correlated with disorganisation and contributed to CC. Unique effects of initiation, disorganisation, and insight, combined, explained 58% of CC variance. CONCLUSIONS: Partial support for the three-level model was obtained. Specific neuropsychological abilities and symptoms explain a substantial proportion of the variance in cognitive competency.

Journal Article↗
PubMed2005

Involving patients and their carers in educating and training practitioners.

PURPOSE OF REVIEW: We summarize and discuss recent work that highlights the role of patients and carers in educating practitioners in the light of earlier findings. RECENT FINDINGS: In today's National Health Services in the UK, a changing value base is emerging based on the participation of practitioners, patients and carers, with each group contributing to the education and training of healthcare professionals. The role of patients and carers in education is changing as the value of their experience and expertise is acknowledged. Now professionals are more actively recognizing that service users can contribute usefully to teaching in more unique ways, as 'experts' in their illness. They bring different perspectives and ways of thinking that can instill a new dimension to delivering healthcare services and training. Their expertise is defined by experience, and this different perspective gives them a unique role in teaching. They represent a potential teaching resource for medical education that is grossly underutilized. SUMMARY: Patients and carers are experts in their particular circumstances and blending their expertise with that of professionals is likely to contribute to the best outcome in a particular situation. They are a valuable resource as potential teachers at all stages of medical education.

Journal Article↗
PubMed2005

Erectile dysfunction is a marker for cardiovascular disease: results of the minority health institute expert advisory panel.

INTRODUCTION: Cardiovascular disease and its related comorbidities are associated with significant morbidity and mortality and affect a disproportionately large number of African Americans and Hispanics. The prevalence of cardiovascular disease is increasing worldwide, which underscores the urgency to improve methods of prevention and early detection. AIM: To develop a risk assessment and management algorithm for primary care patients with erectile dysfunction (ED) that facilitates diagnosis, early intervention, and prevention of cardiovascular disease. METHODS: The Minority Health Institute (MHI) convened an Expert Advisory Panel of cardiologists and urologists to design a new practice model algorithm that uses ED as a clinical tool for early identification of men with systemic vascular disease. A draft of the algorithm was presented at a national symposium and comments from symposium participants were considered in the development of the final algorithm. MAIN OUTCOME MEASURES AND RESULTS: Erectile dysfunction is common and has long been considered a secondary complication of cardiovascular disease, diabetes, hypertension, and dyslipidemia. However, a growing body of evidence challenges this view, suggesting instead that ED is an early manifestation of atherosclerosis and a precursor to systemic vascular disease. Endothelial dysfunction is the etiologic factor linking ED and cardiovascular disease. CONCLUSIONS: The recognition of ED as an early sign of systemic cardiovascular disease offers an opportunity for prevention, particularly in high-risk and underserved minority populations. The MHI algorithm stipulates that all men 25 years old and older regardless of sexual dysfunction complaints should be asked about ED. The presence of ED should prompt an aggressive assessment for cardiovascular risk and occult systemic vascular disease.

Algorithms↗
PubMed2005

Atypical antipsychotics in psychiatric practice: practical implications for clinical monitoring.

OBJECTIVES: To provide practical recommendations for monitoring patients both before and during treatment with atypical antipsychotics, to assist clinicians in implementing preventative measures against diabetes, and to establish baselines according to which clinicians should initiate diabetes treatment. METHOD: A working group of Canadian specialists in psychiatry and endocrinology reviewed peer-reviewed clinical studies published in this area and other relevant papers and abstracts. RESULTS: The reviewed studies further confirm that atypical antipsychotic medications are the most effective components in the medical management of many psychotic conditions; they also further emphasize the need to more stringently monitor and recognize diabetes risk factors inherent in these patients. Recommendations are based on a review of the available data, on expert opinion and consensus, and on current Canadian guidelines for the treatment of schizophrenia and management of diabetes. CONCLUSIONS: Patients with psychiatric disorders, most particularly schizophrenia and mood disorders, have an increased risk for type 2 diabetes and should be screened frequently, especially when other risk factors are present. The resulting recommendations offer practical steps for effectively screening patients prior to and during treatment with atypical antipsychotics. They include (1) how to conduct an initial baseline assessment, (2) when and how to monitor blood glucose and lipid levels, and (3) how to educate patients regarding such lifestyle issues as nutrition, exercise, and diet.

Antipsychotic Agents↗
PubMed2004

Structure and function of the Gondwanian hemoglobin of Pseudaphritis urvillii, a primitive notothenioid fish of temperate latitudes.

The suborder Notothenioidei dominates the Antarctic ichthyofauna. The non-Antarctic monotypic family Pseudaphritidae is one of the most primitive families. The characterization of the oxygen-transport system of euryhaline Pseudaphritis urvillii is herewith reported. Similar to most Antarctic notothenioids, this temperate species has a single major hemoglobin (Hb 1, over 95% of the total). Hb 1 has strong Bohr and Root effects. It shows two very uncommon features in oxygen binding: At high pH values, the oxygen affinity is exceptionally high compared to other notothenioids, and subunit cooperativity is modulated by pH in an unusual way, namely the curve of the Hill coefficient is bell-shaped, with values approaching 1 at both extremes of pH. Molecular modeling, electronic absorption and resonance Raman spectra have been used to characterize the heme environment of Hb 1 in an attempt to explain these features, particularly in view of some potentially important nonconservative replacements found in the primary structure. Compared to human HbA, no major changes were found in the structure of the proximal cavity of the alpha-chain of Hb 1, although an altered distal histidyl and heme position was identified in the models of the beta-chain, possibly facilitated by a more open heme pocket due to reduced steric constraints on the vinyl substituent groups. This conformation may lead to the hemichrome form identified by spectroscopy in the Met state, which likely fulfils a potentially important physiological role.

Amino Acid Sequence↗
PubMed2004

Anti-TNFalpha therapy of rheumatoid arthritis: what can we learn about chronic disease?

The importance of tumour necrosis factor (TNF)alpha in rheumatoid arthritis (RA) was initially proposed on the basis of analysis of cytokine gene regulation at the local site of the disease, the synovium. This was then verified in animal models and established in an extensive series of clinical trials, culminating in now 250000 treated patients with either of two approved TNF inhibitors, antibody or fusion protein. The degree and magnitude of clinical benefit has enabled analyses of the mechanism by which anti-TNF benefits, and hence insights into important steps in the disease process. It was found that essentially all aspects of RA were ameliorated, and important mechanisms of benefit involved diminution of multiple pro-inflammatory cytokines, adhesion molecules and chemokines, leading to reduced cell trafficking, reduced angiogenesis and most importantly halting of joint destruction. What of the problems? Safety is better than prior drugs, but there is a small increase in severe infections, smaller than might have been anticipated. Cost is the major drawback limiting greater use. In view of the central pathological processes down-regulated, and their role in many diseases, the early clinical success of anti-TNF in RA led to subsequent successful trials and registration in Crohn's disease and juvenile rheumatoid arthritis, and successful trials in ankylosing spondylitis, psoriasis and psoriatic arthritis. The era of anti-cytokine therapeutics is just dawning.

Animals↗
PubMed2003

Impact of VIP and cAMP on the regulation of TNF-alpha and IL-10 production: implications for rheumatoid arthritis.

Vasoactive intestinal peptide (VIP) is an anti-inflammatory immunomodulatory neuropeptide with therapeutic potential demonstrated for collagen-induced arthritis. The aim of this study was to characterise its potential anti-arthritic effect on human monocytes, macrophages, T cells, and rheumatoid arthritis synovial membrane cells. Monocytes, macrophages, and T cells derived from human peripheral blood were treated with VIP and compared with other cAMP-elevating drugs for a range of activating stimuli. Cytokine production was assessed for cell cultures and, in addition, the ability of VIPs to activate cAMP response element binding protein. VIP partially suppressed monocyte- and macrophage-derived tumour necrosis factor alpha (TNF-alpha) with no effect on IL-10, whereas VIP fails to regulate IL-10 and TNF-alpha production by T lymphocytes. No such modulation of cytokine profile was observed for rheumatoid arthritis synovial membrane cells. Elevation of intracellular cAMP, on the other hand, potently suppressed macrophage TNF-alpha production and modulated T-cell response by inhibiting TNF-alpha and IFN-gamma. VIP's lack of effect on IL-10 and its slight effect on TNF-alpha results from cAMP being rapidly degraded as the phosphodiesterase IV inhibitor, rolipram, rescues cAMP-dependent activation of cAMP response element binding protein. Interestingly, macrophages stimulated with phorbol 12-myristate 13-acetate/ionomycin displayed an augmented IL-10 response upon addition of dibutyryl cAMP, with corresponding downregulation in TNF-alpha, suggesting a complex interaction between protein kinase C and protein kinase A in cytokine regulation. In conclusion, VIP may represent an efficaceous anti-arthritic treatment modulating macrophage and T-cell cytokine profiles when used alongside a phosphodiesterase inhibitor.

3',5'-Cyclic-AMP Phosphodiesterases↗