Biomedical subjects

D Cain

Publications and source records attributed to D Cain.

34 records · Page 2Linked to original sources

PubMed1997

Assembly of the warfarin-sensitive vitamin K 2,3-epoxide reductase enzyme complex in the endoplasmic reticulum membrane.

gamma-Carboxylation of vitamin K-dependent proteins requires a functional vitamin K cycle to produce the active vitamin K cofactor for the gamma-carboxylase which posttranslationally modifies precursors of these proteins to contain gamma-carboxyglutamic acid residues. The warfarin-sensitive enzyme vitamin K epoxide reductase (VKOR) of the cycle reduces vitamin K 2,3-epoxide to the active vitamin K hydroquinone cofactor. Because of the importance of warfarin as an anticoagulant in prophylactic medicine and as a poison in rodent pest control, numerous attempts have been made to understand the molecular mechanism underlying warfarin-sensitive vitamin K 2,3-epoxide reduction. In search for protein components that could be involved in this reaction we designed an in vitro gamma-carboxylation test system where the warfarin-sensitive VKOR produces the cofactor for the gamma-carboxylase. Dissection of this system by chromatographic techniques has identified a member(s) of the glutathione S-transferase gene family as one component of the VKOR enzyme complex in the endoplasmic reticulum membrane. The affinity-purified glutathione S-transferase(s) was sensitive to warfarin but lost its warfarin sensitivity and glutathione S-transferase activity upon association with lipids in the presence of Mn2+ or Ca2+. In the gamma-carboxylation test system, loss of warfarin-sensitive glutathione S-transferase activity coincided with formation of the VKOR enzyme complex. It is proposed that formation of VKOR in the endoplasmic reticulum membrane resembles formation of the lipoxygenase enzyme complex where the glutathione S-transferase-related FLAP protein binds cytosolic lipoxygenase to form a membrane enzyme complex.

Animals↗

PubMed1997

Identification of sites that act together to direct dimerization of human foamy virus RNA in vitro.

Retroviral particles contain two molecules of genomic RNA, which are noncovalently linked near their 5' ends in a region called the dimer linkage structure (DLS). By using complementary DNA oligonucleotides and deletion mutants to impair RNA dimerization of the human foamy virus (HFV), three sites, designated SI, SII, and SIII, were found within a 159-nucleotide RNA fragment of HFV that are involved in dimerization in vitro. SI overlaps the primer-binding site; and SII contains the palindromic sequence, UCCCUAGGGA, the disruption of which impairs dimer formation; and SIII extends into the gag gene. The first two sites are highly conserved in the other primate foamy viruses, SFV-1, SFV-3, and SFVcpz, whereas the third appears to be shared only by HFV and SFVcpz. RNA of HFV and SFV-3 could form heterodimers, indicating that both viruses dimerize by similar mechanisms. On testing thermal stability, dimers of the 159-nucleotide fragment dissociated between 40 and 70 degrees, with half of the dimers dissociating at 55 degrees. Since the splice donor site of HFV is located at position 51 of viral RNA, the DLS is part of the genomic RNA exclusively.

Binding Sites↗

PubMed1997

A placebo-controlled, double-blind prospective study in healthy female volunteers of dextrin sulphate gel: a novel potential intravaginal virucide.

A double-blind, placebo-controlled study was designed to evaluate the safety and tolerability of intravaginal dextrin sulphate (D2S) gel to assess its preliminary suitability as a potential vaginal virucide. Tolerability was assessed by questionnaire and patient interview. Colposcopy with vaginal biopsy was performed to assess the macroscopic and microscopic evidence of inflammation. The potential impact of the gel on normal vaginal flora was examined by quantitative lactobacilli culture with assessment of the ratio of peroxide to nonperoxide-producing organisms. Colposcopy revealed mild erythema in five of 24 subjects receiving active gel and in none of the 12 placebo recipients, but histology in all subjects revealed no evidence of inflammation. No impact on vaginal lactobacilli was found. We conclude that D2S gel is safe and well tolerated intravaginally at the dosing schedule used in this study.

Administration, Intravaginal↗

PubMed1997

Association of antibodies to Chlamydia trachomatis heat-shock protein 60 kD with chronic nongonococcal urethritis.

Ninety male patients with acute nongonococcal urethritis (NGU) who presented for follow-up 10-92 days after initiation of treatment were evaluated. A polymerase chain reaction assay and direct fluorescence antibody test were used to detect Chlamydia trachomatis at presentation and during follow-up. Chlamydial heat-shock protein 60 kD (hsp60) serology with an enzyme-linked immunosorbent assay and C. trachomatis serology with a microimmunofluoresence test were undertaken. In 62 (69%) of the men, evidence of chronic urethritis was noted during follow-up. C. trachomatis was detected in only two patients during follow-up. Chlamydial hsp60 antibody was associated with the development of chronic urethritis between 10 and 92 days after treatment began (P < .04), that is, at 10-29 days (P < .02) and at 30-92 days (P < .008). These results are consistent with the theory that immune response to hsp60 is important in the development of this chronic disease. The results also suggest that chronic NGU is not a consequence of continued production of hsp60 by C. trachomatis.

Adult↗

PubMed1997

Sound pressure transformation at the pinna of Mus domesticus.

Sound pressure transformation properties at the pinna of laboratory mice. Mus domesticus, were studied by measuring the sound pressure level of continuous tone at a series of frequencies at the tympanic membrane as a function of the position of a sound source under free-field stimulation conditions. Sound pressure transformation functions showed some prominent spectral notches throughout the frequency range of 10-80 kHz tested. When delivered from some angles within the ipsilateral frontal hemisphere, the sound pressure at the tympanic membrane of certain frequencies may be lower than that determined at the corresponding contralateral angles. For each sound frequency tested, there was an angle (the acoustic axis) within the ipsilateral frontal hemisphere from which the delivered sound reached a maximal pressure level at the tympanic membrane. However, sound delivered from the acoustic axis did not always generate a maximal pressure transformation. The isopressure contours determined within 2-5 dB of the maximal pressure were circumscribed, and their contained angular areas were found to decrease with increasing sound frequency. The 2 dB maximal pressure area may appear at more than one angular area for some test frequencies. Removal of the ipsilateral pinna or modification of pinna posture expanded isopressure contours irregularly and split the 2 dB maximal pressure area into several parts.

Animals↗

PubMed1995

Alterations in penicillin-binding proteins in strains of Streptococcus suis possessing moderate and high levels of resistance to penicillin.

We examined the penicillin-binding proteins (PBPs) of certain field strains of Streptococcus suis, as well as those from laboratory variants having different degrees of resistance to penicillin. Results indicated that (i) S. suis possesses three distinct groups of PBPs, arbitrarily named here PBP 1, PBP 2, and PBP 3, with approximate molecular weights of 97, 82, and 45 kDa respectively; (ii) PBP profiles of field strains of S. suis having different MICs (< or = 0.03) to 16.0 micrograms/ml) were not uniform (PBP 2 being difficult to detect in strains whose MICs exceeded 0.10 micrograms/ml, and PBP 3 which exhibited shifts in molecular weight of approximately 5 kDa); (iii) laboratory variant PBPs 1 and 2 showed decreased affinity for penicillin as compared to the parent strain in antibiotic competition experiments, even though the PBP profiles of both were similar. We suggest that PBP modifications (altered molecular weight and/or decreased affinity for penicillin) are involved in the mechanism of resistance to penicillin by S. suis.

Bacterial Proteins↗

PubMed1995

Comparison of two cool vests on heat-strain reduction while wearing a firefighting ensemble.

This study evaluated the effectiveness of a six-pack versus a four-pack cool vest in reducing heat strain in men dressed in firefighting ensemble, while resting and exercising in a warm/humid environment [34.4 degrees C (day bulb), 28.9 degrees C (wet bulb)]. Male volunteers (n = 12) were monitored for rectal temperature (Tre), mean skin temperature (Tsk), heart rate, and energy expenditure during three test trials: control (no cool vest), four-pack vest, and six-pack vest. The cool vests were worn under the firefighting ensemble and over Navy dungarees. The protocol consisted of two cycles of 30 min seated rest and 30 min walking on a motorized treadmill (1.12 m.s-1, 0% grade). Tolerance time for the control trial (93 min) was significantly less than both vest trials (120 min). Throughout heat exposure, energy expenditure varied during rest and exercise, but no differences existed among all trials (P > 0.05). During the first 60 min of heat exposure, physiological responses were similar for the four-pack and six-pack vests. However, during the second 60 min of heat exposure the six-pack vest had a greater impact on reducing heat strain than the four-pack vest. Peak Tre and Tsk at the end of heat exposure for 6-pack vest [mean (SD) 38.0(0.3) degrees C and 36.8(0.7) degrees C] were significantly lower compared to four-pack [38.6(0.4) degrees C and 38.1(0.5) degrees C] and controls [38.9(0.5) degrees C and 38.4(0.5) degrees C].(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Sound pressure transformation at the pinna of Mus domesticus.

Sound pressure transformation properties at the pinna of laboratory mice Mus domesticus were studied by measuring the sound pressure level of a continuous tone at a series of frequencies at the tympanic membrane as a function of the position of a sound source under free-field stimulation conditions. The spectral transformation, the interaural spectral difference, the isopressure contours and the interaural pressure difference contours were plotted. Sound pressure transformation functions showed some prominent spectral notches throughout the frequency range tested (10-80 kHz). However, the notch frequency did not appear to be systematically related to sound direction. The study of interaural pressure difference demonstrated that, when delivered from some angles within the ipsilateral frontal hemisphere, the sound pressure at the tympanic membrane of certain frequencies may be lower than that determined at the corresponding contralateral angles. For each sound frequency tested, there was an angle (the acoustic axis) within the ipsilateral frontal hemisphere from which the delivered sound reached a maximal pressure level at the tympanic membrane. However, the acoustic axis often changed to a new angle after removal of the ipsilateral pinna. In addition, sound delivered from the acoustic axis did not always generate a maximal pressure transformation. The isopressure contours determined within 2-5 dB of the maximal pressure were circumscribed, and their contained angular areas were found to decrease with increasing sound frequency. The 2 dB maximal pressure area may appear at more than one angular area for some test frequencies. Removal of the ipsilateral pinna or modification of pinna posture expanded isopressure contours irregularly and split the 2 dB maximal pressure area into several parts. The sound pressure difference determined between the angles of maximal and minimal sound pressure (the maximal directionality) increased with sound frequency regardless of pinna posture. Acoustic gain of the pinna at the acoustic axis reached 6-12 dB, depending upon sound frequency. However, the pinna gain was not always maximal at the acoustic axis for a given frequency.

Animals↗

PubMed1994

Representation of older patients in cancer treatment trials.

In 1990, the five leading causes of cancer death in men aged 65 and older were carcinomas of the lung, prostate, colon and rectum, and pancreas, and leukemia. For women in this age group, the five leading causes of cancer death were carcinomas of the lung, breast, colon and rectum, pancreas, and ovary. To determine the representation of the elderly in clinical trials, the 1992 accrual of the National Cancer Institute (NCI)-sponsored Clinical Cooperative Group treatment trials (which included more than 8000 elderly patients) for the aforementioned sites was compared with the 1990 incidence data from the NCI's Surveillance, Epidemiology, and End Results program. Of the male patients enrolled in the trials, an average of 39% were older than 65 (47.3% lung, 79.5% prostate, 47.5% colorectal, 45.6% pancreas, and 9.6% leukemia); whereas 25.9% of all women enrolled in trials were 65 or older (43.6% lung, 17.3% breast, 46.2% colorectal, 59.6% pancreas, and 35.4% ovary). With respect to incidence, older patients generally are underrepresented in cancer treatment trials. With the exception of the data on prostate cancer, each of the comparisons using the Z statistic gave probability values of less than 0.01. The most significant discrepancies between incidence and participation in cancer treatment protocols were noted for leukemia in males and breast cancer in females. Possible explanations for these findings include (1) a research focus on aggressive therapy, which may be unacceptably toxic to the elderly; (2) presence of comorbidity in the elderly; (3) fewer trials available specifically aimed at older patients; (4) limited expectations for long term benefits on the part of physicians, relatives, and the patients themselves; and (5) a lack of financial, logistic, and social support for the participation of elderly patients in clinical trials. Recognizing this situation, NCI recently sponsored a number of trials that specifically target the elderly. This paper describes the status of all major Phase II and III clinical trials that recently were closed, still are active, or now are in review that address the clinical care of this important segment of the U.S. population.

Aged↗

PubMed1993

Children and cancer. A perspective from the Cancer Therapy Evaluation Program, National Cancer Institute.

The Cancer Therapy Evaluation Program, National Cancer Institute (CTEP, NCI) strongly supports the role of controlled clinical trials in improving the care of children with cancer, and particularly the central role that the pediatric Cooperative Groups play in this process. Trends that threaten the ability to perform these trials include the increasingly limited financial resources available for clinical investigations and the sentiment within some circles that controlled clinical trials may be inappropriate for ethical reasons. The inherent risks of accepting a new therapy without rigorous comparison to existing therapy strongly support the need for randomized trials with adequate accrual to answer important therapeutic questions in a timely and reliable fashion. Retrospective analysis of multiple clinical trials is one method for identifying compelling hypotheses to be tested prospectively. Using this method, we have demonstrated the association between doxorubicin dose intensity and positive response and outcome for patients with Ewing sarcoma and osteosarcoma, thereby providing direction for the selection of important therapeutic questions to be addressed in future clinical trials for these malignancies.

Antineoplastic Agents↗

PubMed1991