Biomedical subjects
Publications and source records attributed to M Robinson.
Hurricane Andrew, one of the worst natural disasters in American history, brought out the spirit of caring in medical personnel as volunteers from all over the country came to aid the hurricane's victims. The following is an example of how one massive relief effort can make a difference in thousands of lives.
In defining medical audit as the term describing in the United Kingdom the quality assurance of medical care, the authors draw out a scheme of its historical development, of its changes in time towards a much more innovative organization of the medical profession, of its present state, its compliance with official policies at local level, and of the identification of eventual future challenges.
35 psychiatric inpatients with diagnosed with unipolar or bipolar depression were given tests of memory, depression, and affective aprosody prior to the initiation of pulse unilateral nondominant ECT. Following ECT treatment, patients were given the same battery of tests using alternate forms of the same tests. The results of this study showed significant treatment effects in all three dependent variables without significant interaction between variables. The implications of these findings were discussed.
The efficacy of a capsule formulation of mesalamine was assessed in 374 patients with mild to moderately active ulcerative colitis. Patients, stratified to pancolitis or left-sided disease, received either placebo or mesalamine at 1, 2, or 4 g daily for 8 wk. Efficacy was assessed using clinical improvement--physician global assessment, sigmoidoscopic index, biopsy score, trips to the toilet, and clinical symptoms (abdominal pain, urgency, stool consistency, and rectal bleeding)--and induction of remission (more stringent criteria for physician global assessment, sigmoidoscopic index, and biopsy score). For physician global assessment of treatment benefit, 79% and 84% of patients on the 2-g and 4-g doses of mesalamine, respectively, received treatment benefit, compared with 54% on placebo (p < or = 0.0002). For the physician global assessment of treatment success, both the 2-g and 4-g doses of mesalamine were superior to placebo (57% and 59% of patients, p = 0.0021 and 0.0012, respectively), compared with 36% on placebo. Both the 2-g and 4-g doses produced statistically significant macroscopic (endoscopic) improvement compared with placebo (p < 0.004). The 4-g dose also produced a statistically significant microscopic (histologic) improvement compared to placebo (p < 0.002). Significant improvement compared to placebo was also observed at 2 g and 4 g for the four clinical symptoms and trips to the toilet (p < or = 0.003). Oral mesalamine capsules were significantly superior to placebo for inducing remission, with 29% of patients at 2 g and 29% at 4 g achieving remission by physician global assessment, compared with 12% on placebo. Forty-four percent and 48% of patients receiving 2 g and 4 g of mesalamine, respectively, achieved remission by sigmoidoscopic index (p < 0.05), compared with 31% on placebo. Thirty-nine percent of patients at 4 g daily achieved microscopic remission, compared with 23% on placebo (p < 0.03). Treatment response was not affected by extent of disease or prior steroid or sulfasalazine therapy. These data suggest that controlled-release mesalamine capsules are a safe and effective monotherapy in doses of 2-4 g daily for treating mild to moderately active ulcerative colitis, as well as for inducing remission, regardless of prior oral steroid or sulfasalazine therapy or extent of disease.
Current long-term treatment of Crohn's disease is unsatisfactory. Based on the Crohn's Disease Activity Index (CDAI), this multicenter trial enrolled patients with either active Crohn's disease (CDAI > or = 150) or disease in remission (CDAI < 150). The primary measure of therapeutic response was mean change in CDAI from baseline to final visit. All patients began treatment with a dosage of < or = 4 g/day of mesalamine that ranged from 3.7 g at baseline to 3.4 g at final visit. Overall, 467 patients were enrolled: 333 (active disease) and 134 (remission). The median study participation time was 14 months. For patients entering with active disease, the mean reduction in CDAI was 77 points, with 42% (122/289) achieving remission by their final visit. For patients entering in remission, there was an increase in mean CDAI from 90 at baseline to 96 at final visit, with 79% (95/120) of patients in remission at final visit and 72% (31/43) in remission continuously after 12 months of therapy. From baseline to final visit, the mean prednisone dose decreased 5 mg/day in patients with active disease and 11 mg/day in patients in remission. Mesalamine was well tolerated and no adverse laboratory trends were observed. These results suggest that controlled-release mesalamine shows promise as a steroid-sparing agent and as a safe and effective long-term therapy for the induction of and maintenance of remission of mild-to-moderate Crohn's disease.
Impaired lower esophageal sphincter (LES) relaxation is highly correlated with dysphagia. A variation of the impaired relaxation of the LES of achalasia has been described, characterized by premature closure after normal relaxation. With a microtransducer system, standard manometric testing followed by food ingestion identified 33 patients (12 male, 21 female, 18-79 yr old) who exhibited premature LES closure. Twenty-three (70%) of these patients had a presenting complaint of dysphagia. Of these, seven (30%) experienced dysphagia during food ingestion. Manometry documented a concurrent motor abnormality in the esophageal body in 28 (85%) patients. Of the five remaining patients who did not have a concurrent motor abnormality, all had a presenting complaint of dysphagia, and three (60%) experienced dysphagia during food ingestion. The incidence of dysphagia during testing reported by patients with premature LES closure is comparable to that reported by patients with achalasia (45%) or diffuse esophageal spasm (38%) who have been studied during food ingestion in our laboratory.
Gamma interferon (IFN-gamma) is the product of multiple cell types within the bone marrow microenvironment and has been demonstrated to act as a potent inhibitor of myelopoiesis in vitro and in vivo. The action of this cytokine on lymphohematopoiesis has now been examined on both long-term bone marrow cultures and representative cloned cellular components of the bone marrow microenvironment. In myelopoietic (Dexter) cultures, the half maximal inhibitory concentration of IFN-gamma was between 1 and 10 U/mL. In comparable lymphopoietic (Whitlock/Witte) cultures, IFN-gamma inhibited the production of B-lineage lymphoid cells with a half maximal effective concentration of less than 1 U/mL. In a clonal assay for pre-B cells, IFN-gamma inhibited colony formation with a half maximal concentration of 1 to 5 U/mL. Not all B-lineage lymphoid cells displayed the same sensitivity, however. Growth of the IL-7-dependent B cell line (2E8) in methylcellulose assays was unaffected by IFN-gamma while the replication of other lymphoid lines was partially or completely inhibited. IFN-gamma induced the expression of cell surface proteins (MHC Class I and II) on both B-lineage cells and stromal cells. In cloned stromal cell lines, IFN-gamma increased the steady state mRNA levels for the cytokines interleukin-6 (IL-6) and JE, a member of the IL-8 family. These data indicate that IFN-gamma acts within the lymphohematopoietic microenvironment through both direct and indirect actions on the hemopoietic and stromal cell populations.
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Cervical carcinogenesis is a multistep process that appears to be initiated by infection of squamous epithelial cells in the cervix with one of a limited number of human papillomavirus (HPV) types. However, the mechanisms involved in the evolution of benign, HPV-induced lesions to malignancy have not yet been fully elucidated. Transforming growth factor-beta (TGF-beta), a multifunctional growth factor produced by cells in the skin, inhibits the proliferation of foreskin and cervical keratinocytes in vitro. We examined the effects of TGF-beta on growth and virus early-gene expression in cell lines immortalized by two HPV types associated with cervical carcinogenesis as well as the expression of TGF-beta 1 mRNA transcripts in normal and HPV-positive cells in vivo and in vitro. We found that normal and HPV-positive cells expressed similar levels of TGF-beta 1 mRNAs and exhibited similar patterns of responsiveness to three isoforms of TGF-beta in both monolayer and modified organotypic cultures. Of particular interest is our finding that the expression of the E6 and E7 early viral transforming regions of both HPV16 and HPV18 was reversibly and rapidly inhibited by TGF-beta. In one HPV16-positive cell line examined in detail, inhibition of HPV expression required protein synthesis and occurred at the level of transcription. HPV-immortalized cells selected for resistance to in vitro differentiation signals remained sensitive to TGF-beta-mediated growth inhibition. These results, showing that both growth and virus gene expression in HPV-transformed cells were responsive to TGF-beta, suggest that endogenous growth factors produced by different cell types in squamous epithelium may play a role in the progression of cervical neoplasia.
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Expression of the p53, the epidermal growth factor receptor (c-erbB-1) and c-erbB-2 protein was studied in 34 men with benign prostatic hyperplasia and 29 men with locally advanced prostate cancer by means of an immuno-histochemical method. Strong staining for p53 was found in five of 29 prostate cancers (17%; mean 21% +/- 7% of malignant cells stained in the positive tumours), but no staining was found in benign prostatic hyperplasia (p less than 0.05). On the other hand, the epithelium in benign glands was stained positively for c-erbB-2 in 18% (6/34) and for the epidermal growth factor receptor in 88% (30/34); whereas malignant epithelium stained strongly for c-erbB-2 in 21% (6/29) and for the epidermal growth factor receptor in only 17% (5/29). Prostate cancer was associated with a significant decrease in epidermal growth factor receptor staining (p less than 0.0001) and a significant increase in p53 staining (p less than 0.05). Most of the tumours were advanced and no significant relationship was observed between tumour stage and grade and expression of p53, the epidermal growth factor receptor or c-erbB-2. These findings demonstrate that altered expression of the epidermal growth factor receptor and p53 protein occurs in prostate cancer, but were not associated with other features of prognostic importance such as stage or grade.
Thirteen patients with soft tissue sarcomas were treated with a combination of intra-arterial Adriamycin, conventionally fractionated radiotherapy (2 Gy per day), and conservative surgery (trimodal therapy). Severe acute complications occurred in 10 patients: 3 brachial artery thromboses, 6 delayed wound healing, 4 wound infections, and 3 cases of necrosis of the skin plus subcutaneous tissues. Three patients have developed local recurrence. Five patients are alive, 4 of whom are disease-free, and the median follow up time of surviving patients is 56 months. One has significant impairment of limb function due to joint ankylosis. An additional 2 patients were treated with intra-arterial Adriamycin and conservative surgery for local recurrence after previous surgery and radiotherapy; both died of subsequent metastatic disease, one having a further local recurrence. One patient with multifocal angiosarcoma was treated with intra-arterial Adriamycin and radiotherapy but no surgery, and is alive free of disease 49 months later. The combination of radiotherapy and intra-arterial Adriamycin with surgery resulted in significant acute toxicity. This small study has not demonstrated any improvement in local control compared with that expected with conservative surgery and radiotherapy alone.
We have performed single pass sequencing of 1,024 human brain cDNAs, over 900 of which seem to represent new human genes. Library prescreening with total brain cDNA significantly reduced repeated sequencing of highly represented cDNAs. A subset of sequenced cDNAs were physically mapped to their chromosomal locations using gene-specific STS primers derived from 3' untranslated regions. We have also determined that human brain cDNAs represent a rich source of gene-associated polymorphic markers. Microsatellite-containing cDNAs can be physically mapped and converted to highly informative genetic markers, thus facilitating integration of the human physical, expression and genetic maps.
A multicentre, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of ranitidine 150 mg and 300 mg in 342 patients with erosive oesophagitis. Treatment was given four times daily, and continued for 12 weeks or until healing (that is, normal or only erythematous mucosa). Erosive oesophagitis healing rates, as determined by endoscopy, were significantly greater in ranitidine-treated patients by 4 weeks compared with those of placebo-treated patients. By 12 weeks, erosive oesophagitis healing rates were 83 and 81% for ranitidine-treated patients (150 and 300 mg, respectively) and 58% for placebo-treated patients (P less than or equal to 0.001, ranitidine vs. placebo). Symptomatic relief was achieved within 24 hours after starting either dosage of ranitidine. Heartburn frequency (P less than 0.001) and severity (P less than 0.001), as well as antacid consumed per week (P less than 0.001), were reduced in both ranitidine groups in comparison with placebo. Healing rates and symptom relief were similar in the two ranitidine groups. Both dosages of ranitidine were well tolerated. Ranitidine (150 mg) given four times daily appears to be as effective as 300 mg ranitidine given four times daily in patients with moderate to severe oesophageal erosions.
Mutation of the p53 gene is one of the commonest genetic abnormalities found in solid human tumours. This gene is probably concerned with the control of cellular proliferation and in view of this we carried out a study of human prostate cancer and benign prostatic hyperplasia, comparing the expression of mutated p53 with measurement of growth fractions as assessed by staining with Ki-67. A series of 29 patients with prostate cancer (CaP) were compared with 34 men with benign hyperplasia (BPH); 22 of 29 prostate cancers (76%) contained Ki-67 immunoreactivity compared with 10 of 34 (29%) BPH. With respect to p53 staining, significantly more prostate cancers (17%) were stained than BPH (0%). The mean Ki-67 score in cancers positive for p53 (4.3%) was greater than that found in cancers negative for p53 (1.2%), but no statistically significant relationship was found between tumour grade and Ki-67 staining. The use of Ki-67 and p53 staining may allow identification of tumours with a higher rate of cell growth and may permit development of prognostic factors.
We have developed a method for directly estimating the secretion rate of endogenous erythropoietin (EPO) in human subjects. Carrier-free recombinant human EPO was labeled with 125I by the chloramine T method. Human serum albumin was then added prior to removal of free iodide. Seven normal subjects and nine patients with chronic uremia and anemia were studied. Each subject received a bolus of 125I-EPO according to body size and then a constant infusion for 5 h. Secretion rate was calculated as the rate of infusion divided by serum EPO specific activity given by the protein-bound counts divided by the EPO concentration. Serum EPO concentration was significantly higher in the patients than the controls (mean 30.9 pg/ml vs. 11.1 pg/ml, P < 0.05), although all values were within the normal range. Mean EPO secretion rate was 255 in the patients (range 68-1,101) and 190 pg.kg-1 x h-1 in the normal group (range 52-382). This difference was not significant. As the subjects were in a steady state, EPO disappearance/degradation was the same in patients compared with controls despite a relatively hypoplastic marrow.
Male and female Sprague-Dawley rats were administered drinking water containing 300, 600, 1200, or 2400 mg/L chloral hydrate for 90 days. A control group received distilled water only. No animals died during the study and no differences were observed in body weight gain or food and water consumption, except for males at the highest-dose level. Minor treatment-related effects were observed for organ weights and hematological parameters and these did not appear to be of toxicological significance. Some indications of toxicity were evident in the 2400 mg/L male group (equivalent to 168 mg/kg-day) including a significant decrease in food and water consumption and in weight gain. In addition, histopathological examination of these animals revealed an apparent increase in the incidence of focal hepatocellular necrosis. Increases in AST, ALT, and LDH, which occurred at several dose levels in males, but particularly at 200 mg/L, are consistent with the hepatocellular necrosis of minimal to mild severity diagnosed by microscopic examination. These liver changes, except for sporadic enzyme changes, were not seen in the female rats which actually consumed higher doses of chloral hydrate (e.g., 288 mg/kg-day at 2400 mg/L). On the basis of the mild liver toxicity (histopathological and clinical) observed in males at the highest doses (168 mg/kg-day), the no observed adverse effect level (NOAEL) for oral exposure of rats to chloral hydrate for 90 days is considered to be 96 mg/kg-day (600 mg/L).