Biomedical subjects
C Winter
Publications and source records attributed to C Winter.
Bioactive conformation of stromelysin inhibitors determined by transferred nuclear Overhauser effects.
The transferred nuclear Overhauser effect has been used to determine the biologically active conformations of two stromelysin inhibitors. Both inhibitors used in this study were hydroxamic acids generated via chemical synthesis. These structures, representing the conformation of each inhibitor bound to stromelysin, superimposed with excellent agreement. The study also provided information on the shape and orientation of the S2' and S1' pockets of the enzyme relative to thermolysin. Comparisons were made between stromelysin and thermolysin inhibitors to critically examine thermolysin as a template for stromelysin-inhibitor design. The enzyme-bound conformations of these stromelysin inhibitors were determined for use as a template in conformationally restricted drug design.
Randomized comparative trial and cost analysis of 3-day antimicrobial regimens for treatment of acute cystitis in women.
OBJECTIVE: To determine the efficacy, safety, and costs associated with four different 3-day regimens for the treatment of acute uncomplicated cystitis in women. DESIGN: A prospective randomized trial with a cost analysis. STUDY POPULATION: Women with acute cystitis attending a student health center. INTERVENTIONS: Treatment with 3-day oral regimens of trimethoprim-sulfamethoxazole, 160 mg/800 mg twice daily, macrocrystalline nitrofurantoin, 100 mg four times daily, cefadroxil, 500 mg twice daily, or amoxicillin, 500 mg three times daily. RESULTS: Six weeks after treatment, 32 (82%) of 39 women treated with trimethoprim-sulfamethoxazole were cured compared with 22 (61%) of 36 treated with nitrofurantoin (P = .04 vs trimethoprim-sulfamethoxazole), 21 (66%) of 32 treated with cefadroxil (P = .11 vs trimethoprim-sulfamethoxazole), and 28 (67%) of 42 treated with amoxicillin (P = .11 vs trimethoprim-sulfamethoxazole). Persistence of significant bacteriuria was less common with trimethoprim-sulfamethoxazole (3%) and cefadroxil (0%) compared with nitrofurantoin (16%; P = .05 vs trimethoprim-sulfamethoxazole) and amoxicillin (14%; P = .11 vs trimethoprim-sulfamethoxazole). Persistence of bacteriuria was associated with amoxicillin-resistant strains in the amoxicillin group but nitrofurantoin-susceptible strains in the nitrofurantoin group. Trimethoprim-sulfamethoxazole was more successful in eradicating Escherichia coli from rectal cultures soon after therapy and from urethral and vaginal cultures at all follow-up visits compared with the other treatment regimens. Adverse effects were reported by 16 (35%) of 46 patients receiving trimethoprim-sulfamethoxazole, 18 (43%) of 42 receiving nitrofurantoin, 12 (30%) of 40 receiving cefadroxil, and 13 (25%) of 52 receiving amoxicillin. The mean costs per patient were less with trimethoprim-sulfamethoxazole ($114) and amoxicillin ($131) compared with nitrofurantoin ($155) and cefadroxil ($155). CONCLUSIONS: A 3-day regimen of trimethoprim-sulfamethoxazole is more effective and less expensive than 3-day regimens of nitrofurantoin, cefadroxil, or amoxicillin for treatment of uncomplicated cystitis in women. The increased efficacy of trimethoprim-sulfamethoxazole is likely related to its antimicrobial effects against E coli in the rectum, urethra, and vagina.
Differences in androgens of HIV positive patients with and without Kaposi sarcoma.
AIM: Since most forms of Kaposi sarcoma are much more common in men than in women, the aim of this study was to examine serum concentrations of sex steroids in HIV positive men with and without Kaposi sarcoma. METHODS: Blood samples from 34 HIV positive men without Kaposi sarcoma (KS-) and 28 with Kaposi sarcoma (KS+) and from 35 HIV negative men (controls) were analysed for adrenal and gonadal steroids. Further analysis was done in subgroups classified by CD4 lymphocyte counts. RESULTS: KS+ patients had significantly higher serum dehydroepiandrosterone (DHEA) and testosterone concentrations than the KS- patients, and their DHEA, DHEA sulphate, testosterone, and androstenedione values were higher than in the controls. The KS+ patients with more than 500 CD4 lymphocytes per mm3 had significantly higher serum DHEA, DHEA sulphate, and testosterone than the KS- patients with the same CD4 counts; those with 500-200 CD4 cells/mm3 had higher serum DHEA and testosterone than the equivalent KS- men; and those with < 200 CD4 cells/mm3 had raised DHEA only compared with KS- men. Both KS+ and KS- men had higher serum progesterone and oestradiol than the controls. Glucocorticoids were not significantly altered. CONCLUSIONS: The high androgen levels in KS+ patients, particularly in the early stages of the disease (> 500 CD4 cells/mm3), may affect the immune system by inducing an abnormal cytokine profile, or by increasing T8 proliferation and activation, or both. This raises the question of the relationship between androgens and Kaposi sarcoma.
Frequent detection of genital herpes simplex virus DNA by polymerase chain reaction among pregnant women.
OBJECTIVE: To investigate the prevalence and level of genital herpes simplex virus (HSV) among women at delivery. DESIGN, PATIENTS, AND SETTING: A prospective analysis of HSV by culture and by polymerase chain reaction (PCR) of genital specimens and by HSV serologic studies in 100 asymptomatic women in labor; prospective analysis of HSV by PCR among 50 seronegative nonpregnant women at a student health center; and retrospective analysis of genital specimens for HSV by PCR from 17 HSV culture-positive women with uninfected neonates and from two HSV culture-negative women with HSV-infected neonates. All pregnant women were at a university hospital. MAIN OUTCOME MEASURES: Presence of HSV by culture and levels of HSV by quantitative, type-specific PCR in cervical and vulvar specimens; HSV serologic testing by Western blot. RESULTS: All of the 100 asymptomatic women in labor who were studied prospectively were HSV culture negative. In nine HSV was recovered by PCR. Herpes simplex virus was recovered by PCR in one of the 50 seronegative nonpregnant women; she soon became seropositive. All 17 culture-positive women had HSV recovered by PCR. High levels of HSV DNA were obtained by PCR from the two culture-negative women with infected neonates. Among those from whom HSV was recovered by PCR, HSV DNA levels were 250 times higher from culture-positive samples than from culture-negative samples (11,571 genome equivalents vs 46 genome equivalents; P < .001). CONCLUSIONS: The frequency of infant exposure to HSV DNA-containing secretions from HSV-seropositive mothers is about eight times higher than previously reported using HSV culture methods. High maternal levels of HSV DNA may be associated with an increased frequency of transmission of HSV to the infant.
Stabilization of C5a receptor--G-protein interactions through ligand binding.
Binding of biotin-C5a to the C5a receptor in membrane fragments followed by detergent solubilization and purification with streptavidin-agarose affinity chromatography resulted in the isolation of a receptor complex with associated G-proteins. In contrast, when receptor was detergent-solubilized in the absence of C5a and purified by affinity chromatography with Affigel-C5a, G-proteins did not copurify. Since the results indicate that receptor ligation stabilized the receptor--G-protein interaction to allow purification of the complex, the findings emphasize the dynamic nature of the C5a receptor-effector interactions. When biotin-C5a-ligated receptor was purified from a mouse cell line overexpressing recombinant human receptor, both Gialpha2 and Gialpha3 subunits copurified, confirming that multiple transducing systems are linked to the C5a receptor. The method of stabilization of receptor-transducer complexes offers the opportunity to further elaborate the interactions of the C5a receptor with diverse transducing elements and second messenger systems.
A randomized, double-blind, comparative trial comparing high- and standard-dose oral acyclovir for first-episode genital herpes infections.
Orally administered acyclovir ameliorates the clinical course and decreases the duration of viral shedding in patients with first-episode genital herpes infections. We investigated in a randomized, double-blind, comparative trial whether a higher (4 g) than standard (1 g) daily dose of oral acyclovir results in greater clinical benefit and influences the time to first recurrence. A total of 139 patients with first-episode genital herpes were randomized to receive orally 4 or 1 g of acyclovir daily. A total of 52 subjects were excluded from the efficacy analysis because most had recurrent disease. Of 87 eligible subjects, 28 (32%) had primary herpes simplex virus type 1 (HSV-1) infections, 48 (55%) had primary HSV-2 infections, and 11 (13%) had nonprimary HSV-2 infections. We did not find any statistically significant differences in the duration of symptoms or viral shedding between the two dose groups, nor did the median time to first recurrence differ between the two groups. Initiation of therapy with either dose within the first 3 days of the appearance of symptoms shortened the duration of the first episode. Adverse gastrointestinal effects developed in 8% of subjects receiving the higher dose, whereas no adverse reactions were observed among those receiving the standard dose (P = 0.10). We conclude that, in comparison with standard therapy, higher-dose oral acyclovir does not result in additional clinical benefit or modify the time to first recurrence. The present study may have implications for the development and efficacy of congeners of acyclovir which provide higher levels in blood than the standard dose of acyclovir.
Results of chemotherapy in 30 AIDS patients with symptomatic pulmonary Kaposi's sarcoma.
BACKGROUND: The aim of this study was to report the effects of a three-drug chemotherapy regimen in patients with symptomatic AIDS-related pulmonary Kaposi's sarcoma and to analyse prognostic factors for survival. METHODS: Thirty consecutive HIV seropositive patients with respiratory symptoms and proven pulmonary Kaposi's sarcoma were treated with the same therapeutic regimen comprising adriamycin (30 mg/m2), bleomycin (10 mg/m2), and vincristine (2 mg) administered intravenously once every four weeks. RESULTS: Two patients died during the first course of chemotherapy. In the other 28 cases dyspnoea improved and Pao2 rose despite minimal (n = 17) or no (n = 11) improvement in the chest radiographic appearance. The median survival from the beginning of chemotherapy was 6.5 months. Poor prognostic factors for survival were: (1) absence of cutaneous Kaposi's sarcoma; (2) previous opportunistic infection; (3) CD4 cell count < 100/microliters; (4) leucocytes < 3500/microliters; (5) haemoglobin < 10 g/dl; and (6) absence of radiological response. Of the 28 patients 24 experienced at least one episode of neutropenia which was associated with bacterial infection in 16 cases. CONCLUSIONS: Chemotherapy may improve respiratory impairment in patients with extensive pulmonary Kaposi's sarcoma but the outcome remains poor. The efficacy of chemotherapy may be limited by neutropenia.
Validation of primary and secondary outcomes and classification of mode of death among patients with clinical evidence of heart failure after a myocardial infarction: a report from the Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
The AIRE study--a trial involving over 2,000 patients with clinical heart failure after myocardial infarction--assessed different outcomes. The primary outcome was total mortality. The secondary outcome was time to death, or progression to severe/resistant heart failure, reinfarction or stroke. Tertiary analyses included hospitalization and mode of death. To obtain maximum quality in the validation of outcomes and to optimize the quality of the data in the study, an end-points committee reviewed all data following preset definitions prior to code break. All definitions used are reported here. Experience of the validation process demonstrated that there are wide variations in clinical practice and terminology not only among countries but also among individual investigators. Variation in the clinical handling and treatment of patients makes it imperative to validate outcomes centrally on the basis of available facts.
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[Vesiculo-pustular cutaneous eruption disclosing primary infection by HIV virus].
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[5 new cases of entomophthoromycosis observed in Cameroon. Role of immunofluorescence in thr diagnosis].
The authors present five new cases of entomophthoromycosis observed during three years of histopathology in Cameroon. Three classic cases of rhinoentomophthoromycosis. In one case, Conidiobolus coronatus was isolated. Two cases of subcutaneous entomophthoromycosis, without isolation of the germ. In one observation, the clinical and histological aspect suggested mucormycosis post entomophthoromycosis. An immunofluorescence technique showed the Basidiobolus haptosporus to be the real cause.
Single-dose and three-day regimens of ofloxacin versus trimethoprim-sulfamethoxazole for acute cystitis in women.
We compared the safety and efficacy of a single 400-mg dose of ofloxacin, ofloxacin (200 mg) once daily for 3 days, and trimethoprim-sulfamethoxazole (160:800 mg) twice daily for 7 days for the treatment of acute uncomplicated cystitis (urinary tract infection [UTI]) in women. At 5 weeks posttreatment, 35 (81%) of 43 patients treated with single-dose ofloxacin, 40 (89%) of 45 treated with 3 days of ofloxacin, and 41 (98%) of 42 treated with trimethoprim-sulfamethoxazole were cured (P = 0.03, single-dose ofloxacin group versus trimethoprim-sulfamethoxazole group). Retreatment for symptomatic recurrent UTI was given to 7 (16%) of 43 patients initially treated with single-dose ofloxacin, 3 (7%) of 45 patients treated with 3 days of ofloxacin, and 0 of 42 patients treated with trimethoprim-sulfamethoxazole (P = 0.01, single-dose ofloxacin group versus trimethoprim-sulfamethoxazole group). There was a trend in each of the three treatment groups toward an association between persistent or recurrent episodes of significant bacteriuria and a history of UTI in the past year and with diaphragm use. Ofloxacin was more effective than trimethoprim-sulfamethoxazole in eradicating Escherichia coli from rectal cultures during or soon after therapy, but there were no differences at later follow-up visits. Adverse effects were equally common among the three treatment groups. We conclude that single-dose ofloxacin was less effective than 7 days of trimethoprim-sulfamethoxazole for treatment of uncomplicated cystitis in women, while the 3-day ofloxacin regimen and the trimethoprim-sulfamethoxazole regimen were not significantly different in efficacy.
The Acute Infarction Ramipril Efficacy (AIRE) Study: rationale, design, organization, and outcome definitions.
The rationale, design, organization, and outcome definitions of the Acute Infarction Ramipril Efficacy (AIRE) Study are described prospectively. A total of 2,000 patients (1,000 per treatment group) will be recruited to this multicenter, multinational, double-blind, randomized, placebo-controlled study investigating the effect of oral treatment with ramipril (2.5 or 5 mg twice daily) on the total mortality of survivors of an acute myocardial infarction (AMI) with early clinical evidence of heart failure. Secondary outcomes of the study include progression to severe/resistant heart failure (at which time the patient will be withdrawn from the study treatment), reinfarction, and stroke. Treatment will be initiated in hospital between day 3 and day 10 following AMI, and follow-up continued for an average of 15 months and a minimum of 6 months. The study data will be analyzed on an intention-to-treat basis: a single formal interim analysis will be conducted after 175 deaths. An Independent Adjudicating Panel will act as the overall ethical supervisory body for the study and will retain the randomization code. An International Steering Committee will be responsible for the clinical definitions of the secondary study outcomes, and will regularly review progress of the study. We believe that early treatment with ramipril may reduce the total mortality of patients surviving an AMI with clinical evidence of heart failure.
Heterogenic mRNAs with an identical protein-coding region of the human embryonic myosin alkali light chain in skeletal muscle cells.
The formation of human myotubes in culture is accompanied by the induction of developmentally regulated, muscle-specific genes. We have studied the expression of human myosin light chain proteins and mRNAs during myogenesis in culture, in particular the skeletal embryonic myosin light chain 1 (MC1emb), which is indistinguishable from MLC1 of adult atrial cardiac muscle (MLC1A) as has been shown for rodent and bovine MLC1emb. We have identified distinct MLC1emb/MLC1A mRNAs in cultured human skeletal muscle cells that differ in their 5' and 3' untranslated regions but contain identical protein-coding regions. The alternative 3' untranslated region is detectable also in RNA of human atria. The different MLC1emb RNAs are likely to be encoded by one gene. It appears that the two MLC1emb 5' untranslated regions of the human gene are specific for man. In the mouse, only one 5' untranslated region of the MLC1emb gene has been detected.
[A comparison of conventional tomography and computed tomography in cases of diseases of the sacroiliac joint].
16 patients with diseases of the sacroiliac joints were examined both with computer tomography and with conventional tomography. Both techniques were characterized by a high sensitivity. Computer tomography was superior in exactly delineating the extent of the pathologic changes. In conventional tomography the joint surface was more blurred, erosions were larger, and signs of ankylosis were more expanded, so that the joints seemed to be more altered in 8 cases than demonstrated by computer tomography. Very accurate changes like subchondral cysts were recognized only in the computer tomograms. In all cases in which anteroposterior radiographs revealed no clear result, the authors recommend to additionally employ computer tomography.
Wheelchair-mounted robot manipulators. Long term use by patients with Duchenne muscular dystrophy.
This report relays practical clinical information about the modification and use of commercially available training robot manipulators. Such manipulators were used to increase independence in the activities of daily living of patients with advanced Duchenne muscular dystrophy. The control panels of five industrial robot manipulator training devices were modified for use by advanced Duchenne muscular dystrophy patients. Six patients with only residual finger movement, three of whom were dependent on respiratory support, mastered the use of these devices. The four patients with long-term access employed their manipulators for facilitation of activities of daily living an average of 8 h a day for 3 +/- 1.8 yr. There was approximately 3 h of estimated attendant care time saved per patient per day.
Development of clinically recognizable genital lesions among women previously identified as having "asymptomatic" herpes simplex virus type 2 infection.
STUDY OBJECTIVE: To determine if patients initially identified by history, clinical examination, and serologic status as having asymptomatic herpes simplex virus type 2 infection report clinically recognizable genital lesions after having a detailed instructional session on the clinical signs and symptoms of genital herpes. DESIGN: Prospective follow-up of two groups of women. SETTING: Outpatient clinic of an urban city-county hospital. PATIENTS: Two populations of women were recruited. One group was referred because they had documented asymptomatic genital herpes or were suspected of asymptomatically transmitting genital herpes to a sex partner. The other group was recruited from the hospital's general gynecologic clinic and consisted of women with herpes simplex virus type 2 antibodies who denied a history of genital herpes. INTERVENTION: Patients had a one-on-one interview describing the clinical symptoms of genital herpes. MEASUREMENTS AND MAIN RESULTS: Twelve of nineteen women with herpes simplex virus type 2 antibodies who had documented asymptomatic genital herpes or were suspected of asymptomatically transmitting infection to a sex partner, and 18 of 43 women with herpes simplex virus type 2 antibodies who were recruited from the gynecologic clinic developed clinically recognizable genital lesions during a 5-month follow-up. Symptomatic genital herpes was the most frequent gynecologic complaint identified during follow-up. CONCLUSIONS: Approximately 50% of women with herpes simplex virus type 2 antibodies who do not initially report a history of genital lesions do indeed have clinically symptomatic genital herpes. These women can be accurately counseled and taught to distinguish genital herpes from other genitourinary infections. Identification of symptomatic recurrences and counseling to avoid sexual activity during these episodes may help reduce transmission of genital herpes.