Biomedical subjects

R A Clark

Publications and source records attributed to R A Clark.

At least 163 records · Page 9Linked to original sources

PubMed1994

Disseminated Mycobacterium genavense infection in two patients with AIDS.

Mycobacterium genavense is a recently defined fastidious organism that has been identified as a cause of disseminated infection in patients with AIDS. We report the cases of two patients who had advanced AIDS and a clinical syndrome of fever, anorexia, abdominal pain, diarrhea, and weight loss. In addition, splenomegaly and lymphadenopathy were prominent in both cases, and in one patient's case radiographic findings were suggestive of splenic abscesses. Mycobacteria isolated from specimens of blood and bone marrow grew in liquid media but not on solid media. The results of DNA probe tests for Mycobacterium tuberculosis and Mycobacterium avium complex were false-positive for both patients. After treatment of the broth cultures to lyse red blood cells, the results of DNA probe tests were negative for these pathogens. Amplification and sequencing of 16S rRNA with use of the polymerase chain reaction indicated that the mycobacterial isolates from both patients had sequences identical to those previously reported for M. genavense. One patient survived 5 months after diagnosis, the other 2 months after diagnosis; only one patient responded (transiently) to antimycobacterial chemotherapy.

AIDS-Related Opportunistic Infections↗

PubMed1994

Randomized phase II trial comparing two versus three doses of ondansetron when used in combination with dexamethasone in patients receiving cisplatin > or = 100 mg/m2.

Ondansetron controls cisplatin-induced emesis when given in three 0.15 mg/kg doses, and preliminary data suggest that control may be maintained when fewer doses are employed. Prior trials have further shown improved antiemetic effects and fewer adverse effects of cisplatin treatment when neurotransmitter receptor blockers are combined with dexamethasone. This trial was undertaken to determine the effectiveness of the combination of dexamethasone and ondansetron and to see if equivalent results could be obtained with only two doses of ondansetron. There were 44 patients receiving initial cisplatin at a dose > or = 100 mg/m2, each given dexamethasone 20 mg and randomized to receive either two or three 0.15 mg/kg doses of ondansetron. Vomiting prevention was identical (35%) whether two or three doses were given. No new adverse effects were noted and cisplatin-induced diarrhea, usually seen in up to 60% of patients given this dose of cisplatin, was noted in only 5%. Although this trial did not demonstrate enhanced antiemetic effects with the combination, other investigators have done so and all agree that the regimen is safe and reduces adverse effects. Further exploration and use of the combination of ondansetron and dexamethasone, and studies testing fewer doses of ondansetron in this regimen are warranted.

Adult↗

PubMed1994

TGF-beta 1 stimulates expression of keratinocyte integrins during re-epithelialization of cutaneous wounds.

Epidermal keratinocytes migrate over a provisional matrix during the re-epithelialization of cutaneous wounds. We have investigated the expression of integrins and of transforming growth factor-beta 1 (TGF-beta 1) during re-epithelialization in a porcine model. Tissue specimens were collected at different times after injury and stained with antibodies against subunits of the fibronectin receptor, integrin alpha 5 beta 1, and the vitronectin receptor, integrin alpha v beta 5. Intense staining was observed in the migrating keratinocytes of 5-d wounds; basal and suprabasal cells were stained around the entire cell periphery. Staining returned toward normal levels in 14-d wounds. The appearance of the extracellular form of TGF-beta 1 seemed to be coordinated with the increased expression of integrin subunits: it was detected in migrating keratinocytes and in the adjacent epidermis of early wounds at 5 and 7 d. We also investigated the effect of TGF-beta 1 on cultured epidermal cells. Treating human keratinocytes with TGF-beta 1 increased the levels of mRNA for the integrin subunits alpha 5, alpha v, and beta 5, but had little effect on beta 1. The corresponding cell-surface expression of alpha 5 and alpha v was also increased after treatment. Thus, during wound repair, TGF-beta 1 may induce epidermal keratinocytes to express integrins that facilitate the migratory component of re-epithelialization.

Animals↗

PubMed1994

cAMP and inositol 1,4,5-trisphosphate increase Ca2+ in HT-29 cells by activating different Ca2+ influx pathways.

Ca2+ plays a central role in regulating transepithelial fluid and electrolyte transport in intestinal epithelial cells. To investigate the mechanisms regulating the cytosolic free Ca2+ concentration ([Ca2+]c), we examined the effect of secretory agonists on [Ca2+]c in the intestinal epithelial cell line HT-29 clone 19A cells. We found that [Ca2+]c increased after addition of either adenosine 3',5'-cyclic monophosphate (cAMP)-dependent agonists or a D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]dependent agonist carbachol. Several lines of evidence suggest that cAMP- and Ins(1,4,5)P3-dependent agonists act through separate pathways. First, isoproterenol and forskolin increased cellular levels of cAMP but not Ins(1,4,5)P3, whereas carbachol increased cellular levels of Ins(1,4,5)P3 and stimulated inositol phosphate turnover without increasing cAMP. Second, carbachol increased [Ca2+]c by stimulating the release of Ca2+ from intracellular stores and influx of extracellular Ca2+. In contrast, cAMP agonists increased [Ca2+]c by stimulating Ca2+ influx alone. Third, the responses to maximal concentrations of cAMP agonists and carbachol were approximately additive. Finally, Ins(1,4,5)P3- but not cAMP agonist-dependent Ca2+ influx was inhibited by inorganic Ca2+ channel blockers. Thus, in intestinal epithelial cells, [Ca2+]c is regulated by at least two different second-messenger pathways, involving Ins(1,4,5)P3 or cAMP. In addition, cAMP stimulates influx of extracellular Ca2+ through a pathway distinct from that mediated by Ins(1,4,5)P3.

1-Methyl-3-isobutylxanthine↗

PubMed1993

Response to the National Cancer Institute Alert. The effect of practice guidelines on two hospitals in the same medical community.

BACKGROUND: Despite the recent increase in medical practice guideline development and dissemination, physician compliance with the guidelines has often been low. Previous research has suggested that physicians at hospitals with low volumes of cases and weakened financial status were more likely to omit indicated diagnostic testing or appropriate treatment. The authors sought to determine whether differences in compliance to a widely disseminated set of guidelines would exist even among the most dominant hospital providers within the same medical community. METHODS: Two hospitals, together providing nearly half of the cancer surgery within a metropolitan area, were studied for their compliance to the May 1988 National Cancer Institute (NCI) Clinical Alert regarding adjuvant therapy after primary treatment for node negative breast cancer. A case series consecutive collection of 549 women treated at the study hospitals for 2 years before and two years after the Alert determined those patients who had received any form or combination of adjuvant therapy after primary surgical treatment (lumpectomy or modified radical mastectomy). RESULTS: Following modified radical mastectomy, for women age 50 and older, the university hospital (U) provided adjuvant therapy to a higher percentage of patients than the community hospital (C) both before (25.6% versus 4.7%, P < 0.005) and after (58.9% versus 23.2%, P < 0.001) the Alert. For women younger than 50 years of age, the two hospitals were equally likely to provide adjuvant therapy both before and after the Alert. Following lumpectomy, hospital U increased the percentage of women receiving adjuvant therapy following the Alert in women younger than 50 years of age (25-75.8%, P < 0.001) and in women age 50 and older (33.3-56.5%, P < 0.025). Hospital C provided no adjuvant therapy before or after the Alert. Preferences for breast conserving surgical treatment were significantly (P < 0.001) different with hospital U performing a higher percentage of lumpectomies than hospital C both before (50.9% versus 14.9%) and after (57.6% versus 16.8%) the Alert. CONCLUSIONS: Significant differences in compliance with practice guidelines may be found even among the most dominant hospital providers of cancer services within the same medical community. The role of the surgeon in referring patients to the oncologist greatly influences the ultimate provision of adjuvant therapy. Strategies for enhancing compliance should be considered integral to the process of guideline development.

Age Factors↗

PubMed1993

Functional domain in an arginine-rich carboxyl-terminal region of p47phox.

Activation of the neutrophil respiratory burst oxidase involves phosphorylation-dependent translocation of the cytosolic proteins p47phox and p67phox to the plasma membrane, a process in intact cells that is inhibited by staurosporine. We now report that in a cell-free oxidase system, staurosporine and protein kinase C pseudosubstrate PKC(19-36) both inhibited p47phox phosphorylation but had no effect on superoxide generation. In contrast, p47phox phosphorylation, translocation, and superoxide generation were inhibited by a peptide, p47phox(323-332) (AYRRNSVRFL), based on a putative serine phosphorylation domain. This effect was specific for the 323-332 peptide, as it was not observed with two peptides based on other p47phox phosphorylation domains. All three peptides served as substrates for phosphorylation, but the extent of peptide phosphorylation did not correlate with inhibition of oxidase function. p47phox(325-330), which represents the serine phosphorylation motif of p47phox(323-332), did not inhibit translocation or superoxide production despite its ability to block phosphorylation of p47phox. These data indicate the presence of functionally important sites within the p47phox(323-332) peptide. Although serine 328 is in a consensus phosphorylation motif, the lack of correlation in the cell-free system between p47phox phosphorylation and either protein translocation or superoxide formation suggests that a phosphorylation-independent function resides in the 323-332 segment of p47phox.

Amino Acid Sequence↗

PubMed1993

Dose-ranging antiemetic evaluation of the serotonin antagonist tropisetron in patients receiving anti-cancer chemotherapy.

BACKGROUND: Tropisetron (ICS 205-930) antagonizes the serotonin type 3 receptor and has antiemetic activity in animals given cisplatin. Its mean serum half-life in 11.1 hours. METHODS: In this dose-ranging trial, 22 patients undergoing anti-cancer chemotherapy received 24 courses of a single intravenous infusion of tropisetron beginning 30 minutes before chemotherapy. Four dose levels were explored (range, 12-48 mg/m2). RESULTS: Toxicities were mild and included headache, transient elevations of serum alanine transaminase and/or aspartate transaminase levels, and sedation. No akathisia or acute dystonic reactions were observed. Thirty-six percent of patients had no emesis, and 58% had two or fewer emetic episodes. Ten patients received high-dose cisplatin (dose, > or = 100 mg/m2) as initial chemotherapy. Of these, 30% had no emesis, and 60% had two or fewer episodes. CONCLUSIONS: Tropisetron can be administered safely in the doses tested with no dose-limiting toxicities. The encouraging antiemetic efficacy, mild toxicities, lack of extrapyramidal effects, and convenience of a single 15-minute infusion regimen make this drug appropriate for study in additional trials.

Adult↗

PubMed1993

Progress in controlling emesis with cancer chemotherapy.

Marked progress in supportive care in cancer, and in control of chemotherapy-induced emesis in particular, has been accomplished over the past several years. Several effective antiemetic agents and regimens have been tested and are widely available. Emesis due to chemotherapy can now be completely controlled in the majority of patients. Progress in both clinical trials and in neuropharmacology has resulted in a new class of agents, the serotonin antagonists. These agents have an excellent therapeutic index and are well suited for a variety of clinical settings. Problems remain especially in the control of delayed emesis, in patients given several days of chemotherapy, and in radiation-induced emesis. Achieving the best antiemetic control, and at the same time having cost-effective therapy, is an ongoing challenge.

Antiemetics↗

PubMed1993

Delayed emesis: a dilemma in antiemetic control.

Delayed emesis remains a major factor limiting successful antiemetic treatment. It is well described in patients receiving cisplatin at doses of 100 mg/m2 or greater (occurring in nearly 90% of patients), but its incidence and severity in other settings is less well known. Several studies have indicated that combinations of oral metoclopramide plus dexamethasone can decrease the incidence of this problem by one-half; however, a large number of patients remain for whom delayed emesis is their main emetic problem. To date, studies with single-agent serotonin antagonists have not shown encouraging efficacy. In addition, it appears that delayed emesis may begin as early as 16 h after chemotherapy, yielding implications for new study designs. Proper methodology for clinical studies has been demonstrated in a few well-conducted trials, which should form a basis for future research.

Antineoplastic Agents↗

PubMed1993

Dose-ranging evaluation of the substituted benzamide dazopride when used as an antiemetic in patients receiving anticancer chemotherapy.

Dazopride, a substituted benzamide structurally related to metoclopramide, is a potent gastric prokinetic agent that prevents cisplatin-induced emesis in animals. Unlike metoclopramide, dazopride has no effect on dopamine receptors and therefore should not produce extrapyramidal side effects. In this dose-ranging trial, 23 patients with cancer receiving chemotherapy known to produce nausea and vomiting received three i.v. infusions of dazopride every 2 h beginning 30 min before the chemotherapy. Seven dose levels were explored ranging from 0.5 to 4.0 mg/kg in each of the three infusions. Toxicities were mild and included sedation, dizziness, visual disturbances, and headaches. All side effects were transient and were not dose-related. Antiemetic effects were observed. Dazopride can be safely given on this schedule at doses of up to 4.0 mg/kg to patients receiving chemotherapy. On the basis of the results of this trial, further studies of this agent are warranted.

Adult↗

PubMed1993

The effect of fibronectin on cytoskeleton structure and transepithelial resistance of alveolar type II cells in primary culture.

The cytoskeleton of alveolar type II cells on different matrices has been examined, and the bioelectric properties of these cells grown as monolayers in primary culture has be measured using Ussing-type chambers, to determine whether the extracellular matrix affects the cytoskeletal organization of alveolar type II cells and whether any such interactions influence their physiological functions. Alveolar type II cells cultured on a fibronectin substratum spread slowly over a 6-day period to produce cells of extremely large diameter. The cytoskeletal structure of these cells was characterized by a more marked accumulation of large bundles of actin and a finer network of keratin than cells grown on a collagen substratum. The transepithelial resistances of monolayers grown on a fibronectin substratum were much higher than those on a collagen substratum. These results indicate that alveolar type II cells cultured on fibronectin can form tighter, better organized and more polarized monolayers in primary culture, which suggests that fibronectin may have a physiologically important role in the maintenance of the alveolar wall.

Animals↗

PubMed1993

Midazolam in patients receiving anticancer chemotherapy and antiemetics.

Benzodiazepines lessen anxiety and improve comfort in cancer patients. Midazolam is an effective benzodiazepine with a rapid onset and short duration of action, properties that could permit its use in outpatient areas or in short but stressful situations. Two consecutive trials were undertaken to study midazolam as an adjunct in patients receiving anticancer chemotherapy. Each studied midazolam given as a short infusion 30 min prior to chemotherapy at dose levels ranging from 0.01 to 0.05 mg/kg. Trial I determined the safety, sedation, and dose of midazolam in patients receiving chemotherapy of low to moderate emetic potential. Twenty-two patients were entered. No significant respiratory depression or oxygen desaturation was observed. At the optimal dose level (0.04 mg/kg), sedation began a median of 3 min following administration and continued for a median of 38 min. Sixty-four percent of patients experienced mild sedation. Trial II studied the same doses of midazolam when used in combination with intravenous metoclopramide and dexamethasone in patients receiving cisplatin > or = 100 mg/m2. Nineteen patients were entered; 79% experienced mild sedation. At the 0.04-mg/kg dose level, sedation began a median of 18 min following administration and continued for a median of 170 min. Midazolam can be given safely to patients receiving chemotherapy with and without concomitant antiemetics. The predictability and duration of its sedative effects suggest it can be used in outpatients.

Adult↗

PubMed1993

The anatomy of missed breast cancers.

Missed breast cancer continues to account for the highest percentage of medical malpractice cases in the United States. A retrospective, computer-aided study was performed to investigate the mechanisms of missed breast carcinomas, missed either by mammography or by clinical exam. In a consecutive series of 509 breast cancers found in patients registered at a University Comprehensive Breast Cancer Clinic, no tumour that was 5 mm or less in maximal diameter was clinically palpable. This subgroup consisted of seven in situ and 32 invasive carcinomas. The incidence of palpable tumours in 5 mm increments increased so that when a tumour was between 11 and 15 mm in size, 48% of the lesions were palpable, and with tumours greater than 20 mm in size, 84% were palpable. There was a good correlation between size of the tumour as judged by mammography and the eventual size determined by histologic examination. Smaller breast cancers were detected by mammography than by physical examination. In a separate analysis of 553 consecutive cases of breast cancer examined by mammography, there were 50 (9%) cases in which the cancer was not read from the mammogram. In retrospect, 10 of these mammograms were abnormal for a misinterpretation rate of 1.8%. Cancers associated with false negative mammograms occurred more often in younger women and in dense breast parenchyma than cancers detected by mammography. Cancers missed by mammography were smaller than palpable cancers detected by mammography, more often had negative nodes and presented with a lower stage of disease. Breast augmentation implants were associated more frequently with missed breast cancers, with 5/8 clinically detected breast carcinomas being undetected by mammography. An asymmetric mass was more often associated with cancers missed by mammography, accounting for the sole sign of malignancy in 3% of all cancers, but was the source of 14% of false negative exams. Architectural distortion, ill-defined or well circumscribed masses or calcifications as mammographic signs of malignancy were not associated with an increased frequency of missed cancers. Three 'interval' breast cancers occurred in this series and are included in the false negative mammograms. It is concluded that the threshold of clinically detected breast cancers is 6 mm and experienced clinicians do not detect the majority of breast cancers until the lesions are greater than 16 mm. Mammography has a defined misinterpretation and false negative rate. Likewise, asymmetric mammographic densities that are greater than 16 mm and are not palpable may be followed, since most breast cancers are palpable in this range.

Adult↗

PubMed1993

Clinical manifestations of infection with the human immunodeficiency virus in women in Louisiana.

To better understand the clinical manifestations of human immunodeficiency virus (HIV) infection in women in Louisiana, we conducted a retrospective review of the records of HIV-infected women who presented to the largest HIV outpatient clinic in Louisiana as well as to a tertiary care university hospital in New Orleans between January 1987 and December 1991. A total of 224 women were evaluated. Gynecologic examinations revealed that 17.5% had cervical intraepithelial neoplasia and that 35% had evidence of candidal vulvovaginitis or colonization. The following conditions were diagnosed among indicated percentages of patients: syphilis, 22.2%; Neisseria gonorrhoeae infection, 7.2%; Chlamydia trachomatis infection, 12.3%; pelvic inflammatory disease, 5.3%; trichomonal vulvovaginitis, 26.9%; genital ulcers due to herpes simplex virus, 16.5%; and clinically evident genital human papillomavirus infections, 16.5%. Both trichomonal vulvovaginitis and syphilis were more common among intravenous drug users. A total of 82 opportunistic processes were observed in 55 women. Pneumocystis carinii pneumonia was the most frequent complication of AIDS, followed by candidal esophagitis and wasting syndrome. Over 85% of women had received a diagnosis of AIDS before death. Gynecologic diseases occurred often in this population; the frequency of AIDS-defining events was similar to that reported previously in the literature.

AIDS-Related Opportunistic Infections↗

PubMed1993

Phase II trial of a single intravenous dose of ondansetron in patients receiving cisplatin > or = 100 mg/m2.

Ondansteron, a serotonin antagonist antiemetic, controls emesis caused by cisplatin when given as multiple 0.15 mg/kg dosages in a variety of administration schedules. This trial evaluated a single 0.45 mg/kg i.v. dose of ondansetron in 21 cancer patients receiving cisplatin at doses > or = 100 mg/m2 as initial chemotherapy. Twenty-five percent of patients had no emetic episodes (95% confidence interval: 9-49%), and 45% had two or fewer emetic episodes (95% confidence interval: 23-69%). No significant adverse effects were seen. In prior trials at this institution in similarly treated patients, ondansetron given in three divided doses yielded a 42% no emesis rate. In this trial a single i.v. 0.45 mg/kg dose of ondansetron prevented emesis in 25% of patients receiving initial cisplatin > or = 100 mg/m2. For this dose of cisplatin and ondansetron, the observed emesis complete control rate was lower than that previously seen using multiple dose schedules.

Adult↗

PubMed1993

Regulation of fibroplasia in cutaneous wound repair.

Fibroblast accumulation in a cutaneous wound requires phenotypic modulation of fibroblasts. In response to injury, resident fibroblasts in the surrounding tissue proliferate for the first 3 days and then at day 4 migrate into the wounded site. Once within the wound, they produce type I procollagen as well as other matrix molecules and deposit these extracellular matrix molecules in the local milieu. By day 7, abundant extracellular matrix has accumulated and fibroblasts switch to a myofibroblast phenotype replete with actin bundles along the cytoplasmic face of the plasma membrane. Wound contraction occurs as these myofibroblast gather in the wound extracellular matrix by extending pseudopodia, attaching to extracellular matrix molecules, such as fibronectin and collagen, then retracting the pseudopodia. Once these processes have been accomplished, the fibroblasts appear to undergo apoptosis. Therefore, during cutaneous wound repair, fibroblasts appear to progress through four phenotypes: first proliferating, second migrating, third synthesizing extracellular matrix molecules, and fourth expressing thick actin bundles as myofibroblasts.

Animals↗

PubMed1993

Preoperative evaluation of patients for liver resection. Appropriate CT imaging.

OBJECTIVE: The authors determined which combination of computed tomography scans is most helpful for preoperative assessment of patients with liver tumors. SUMMARY BACKGROUND DATA: Multi-institutional studies have shown that the most important prognostic factors for selection of patients with metastatic colorectal cancer considered for liver resection are: Dukes' stage of primary tumor, the number of hepatic metastases if greater than 3, the presence of extrahepatic cancer, and the ability to resect tumors with an adequate margin (> 1 cm.) Therefore the ability to predict the presence of extrahepatic disease and the number and location of hepatic tumors are important in these patients. METHODS: One hundred and nine consecutive patients with evidence of hepatic tumors were evaluated by computed tomography with arterial portography (CTAP) and abdominal computed tomography after a 4-hour delay (CT-D). Results of these studies and conventional computed tomography (CT-C) were compared with findings at operation. RESULTS: CTAP proved to be the most sensitive test for assessing distribution of intrahepatic disease. CT-D was no more sensitive than CT-C for the detection of hepatic or extrahepatic disease. CONCLUSIONS: CT-C in concert with CTAP provides the most reasonable CT evaluation of patients considered for operation for the treatment of hepatic tumors.

Humans↗

PubMed1993

Expression of functional alpha 4 beta 1 integrin by human dermal fibroblasts.

Fibroblasts interact with the extracellular matrix through cell-surface receptors belonging to the integrin family. In this report, we present evidence that cultured normal human fibroblasts express the integrin alpha 4 beta 1 and that this receptor facilitates fibroblast attachment to fibronectin. Fluorescence-activated cell sorter analysis and immunoprecipitation with monoclonal antibodies demonstrated that normal dermal fibroblasts express the alpha 4-subunit on the cell surface, primarily in association with the beta 1-subunit. Cell-attachment assays demonstrated that normal human fibroblasts can attach to the 40-kDa fibronectin fragment containing the type III connecting segment domain recognized by alpha 4 beta 1. Adhesion to this fragment was inhibited by anti-alpha 4 antibody. Furthermore, our results indicate that alpha 4 beta 1 collaborates with another fibronectin receptor, alpha 5 beta 1, during fibroblast attachment to full-length fibronectin. The region of fibronectin recognized by alpha 5 beta 1 contains the amino acid sequence arg-gly-asp (RGD). A short synthetic RGD peptide, or the 120-kDa fibronectin fragment containing the RGD sequence, only partially inhibited attachment to full-length fibronectin, suggesting that fibroblasts utilize more than the RGD recognition sequence for binding to fibronectin. Accordingly, RGD peptide combined with anti-alpha 4 antibody produced more potent inhibition of cell attachment than either reagent alone. These observations show for the first time that functional alpha 4 beta 1 fibronectin receptor is not restricted to lymphoid cells and transformed cells.

Amino Acid Sequence↗