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Biomedical subjects

V McDonald

Publications and source records attributed to V McDonald.

At least 37 records · Page 2Linked to original sources
PubMed1998

Comparative pharmacokinetics of three doses of percutaneous dihydrotestosterone gel in healthy elderly men--a clinical research center study.

Twenty-five men, 60-80 yr old, participated in a pharmacokinetic study to compare three doses (16, 32, and 64 mg/day, n = 8 or 9 in each group) of 5alpha-dihydrotestosterone (DHT) gel (0.7% hydroalcoholic gel with 2.3 g gel delivering 16 mg DHT) applied daily over one upper arm (16 mg); both arms and shoulders (32 mg); and bilateral arms, shoulders, and upper abdomen (64 mg), respectively. Multiple blood samples for the pharmacokinetic profile for DHT and testosterone (T) were drawn over a 24-h period before application, after first application, and after 14 days of daily application of DHT gel. Additional blood samples for DHT, T, and estradiol were obtained 24 h after application on days 3, 5, 7, and 11 and after discontinuation of DHT gel for 3, 5, 7, and 14 days (days 17, 19, 21, and 28 after first instituting treatment). No skin irritation was observed in any of the subjects. Before treatment, mean serum DHT and T levels were not different among the three dose groups. The serum DHT levels increased gradually after gel application on the first day, reaching a plateau between 12-18 h. During the 14 days of daily application of DHT gel, the mean baseline DHT levels reached steady state by day 2 or 3 and were elevated considerably above baseline. Mean serum DHT levels varied between 8-11, 12-17, and 14-24 nmol/L in the 16-, 32-, and 64-mg groups, respectively. The area under curve (AUC) of serum DHT levels over 24 h on day 14 were 6.0-, 6.9-, and 16.1-fold above pretreatment levels for the three doses. Concomitant with the increase in serum DHT levels, the AUC produced by endogenous serum T levels decreased to 75, 56, and 36% of baseline after 14 days of 16, 32, and 64 mg/day DHT gel. Similar patterns of decreases in AUC of serum estradiol levels were found. The calculated mean total androgen levels (T + DHT) rose with DHT gel application in all groups (P < 0.0001) on both days 1 and 14. We conclude that the three doses of DHT gel tested might provide adequate androgen replacement in hypogonadal men at the low, middle, and high physiological androgen (T + DHT) range.

Administration, Cutaneous↗
PubMed1997

Androgen-behavior correlations in hypogonadal men and eugonadal men. I. Mood and response to auditory sexual stimuli.

Mood and response to auditory sexual stimuli were assessed in 33 hypogonadal men receiving testosterone (T) replacement therapy, 10 eugonadal men receiving T in a male contraceptive clinical trial, and 19 eugonadal men not administered T. Prior to and after 6 weeks of hormone administration, men completed a mood questionnaire, rated sexual arousal to and sexual enjoyment of auditory sexual stimuli, and performed a dichotic listening task measuring selective attention for sexual stimuli. Mood questionnaire results suggest that T has positive effects on mood in hypogonadal men when hormone levels are well below the normal male range of values, but does not have any effects on mood when hormone levels are within or above the normal range. However, increased sexual arousal and sexual enjoyment were associated with T administration regardless of gonadal status. Eugonadal men administered T also increased in the bias to attend to sexual stimuli. In contrast, the comparison group of eugonadal men not administered T showed no mood or sexual behavior changes across the two test sessions. These data support a positive relationship between T and sexual interest, sexual arousal, and sexual enjoyment in men.

Administration, Sublingual↗
PubMed1997

Cryptosporidium infection in major histocompatibility complex congeneic strains of mice: variation in susceptibility and the role of T-cell cytokine responses.

Studies with murine infection models have shown that immunity to the protozoan parasite Cryptosporidium involves T-cells and interferon-gamma (IFN-gamma) activity. The present study was performed to compare the course of infection of Cryptosporidium muris in major histocompatibility complex (MHC) congeneic strains of mice and examine the relationship between susceptibility to infection and production of T-cell cytokines. In experiments with BALB mice, the BALB/c strain (H-2d) produced significantly fewer oocysts and recovered from infection sooner than the BALB/B (H-2b) or BALB/K (H-2k) strains. BALB/B X BALB/c F1 hybrid mice were found to express the more susceptible phenotype of the BALB/B parent strain, indicating that the gene(s) in the H-2 locus conferring increased susceptibility to C. muris infection was dominant. At different times during infection of the resistant BALB/c strain and the susceptible BALB/B strain, splenocytes were cultured with soluble parasite antigen and measurements were made of production of a number of T-cell cytokines. Similar patterns of increasing levels of IFN-gamma and interleukin 2 (IL-2) were observed in both the resistant and susceptible strains during the patent stage of infection, indicating that production of these type 1 T-helper-cell (TH1) cytokines (i.e. involved in cell-mediated responses) correlated with the development of immunity. This also suggested that the increased susceptibility of BALB/B mice was not associated with a defective TH1 cytokine response. In the study of TH2 cytokines (involved in induction of an antibody response), low levels of IL-10 were detected during infection of BALB/c and BALB/B mice. In contrast, although IL-4 was released by splenocytes of both strains, significantly larger amounts were obtained from cells of the susceptible BALB/B mice in the early stages of infection. Thus, the H-2-dependent variation in susceptibility to infection between these BALB strains correlated with a difference in the pattern of IL-4 secretion.

Animals↗
PubMed1997

Effect of increased scrotal temperature on sperm production in normal men.

OBJECTIVE: To determine whether application of polyester-lined athletic supports to bring the testes closer to the abdomen increases scrotal temperature and decreases sperm production. DESIGN: Prospective clinical study. SETTING: University academic medical center. PATIENT(S): Twenty-one healthy male volunteers. INTERVENTION(S): The study consisted of a pretreatment period of 6 weeks, a treatment phase of 52 weeks, and a recovery phase until return to normal sperm production. During the treatment phase, the men wore polyester-lined athletic supports (single layer, double layer, or double layer impregnated with aluminum) throughout the day. MAIN OUTCOME MEASURE(S): Semen parameters and sperm function tests. RESULT(S): In all three groups of subjects, scrotal temperature was consistently increased by 0.8 to 1 degree C while the subjects were wearing the athletic supports. Mean sperm concentration; sperm motility, morphology, and viability; sperm hyperactivation; and ability of spermatozoa to penetrate zone-free hamster oocytes were not affected by the increase in scrotal temperature. CONCLUSION(S): The increase in scrotal temperature induced by polyester-lined athletic supports was insufficient to cause significant suppression of spermatogenesis or alteration of sperm function.

Adult↗
PubMed1997

Gut intraepithelial lymphocytes induce immunity against Cryptosporidium infection through a mechanism involving gamma interferon production.

Immunological control of infection with cryptosporidia in mice is dependent on CD4+ T cells and the production of gamma interferon (IFN-gamma), but to date, the mucosal T cells which produce IFN-gamma local to the infection have not been characterized. We previously showed that immunity against the gastric parasite Cryptosporidium muris could be adoptively transferred to adult SCID (severe combined immunodeficiency) mice with small intestinal intraepithelial lymphocytes (IEL) from previously infected immunocompetent mice, but only if the donor CD4+ T cells were intact. The present investigation examined whether IFN-gamma was important in the effector mechanisms mediated by immune IEL in SCID mice. The development of resistance against C. muris infection in SCID mice given immune IEL was prevented by treatment with a hamster anti-mouse IFN-gamma-neutralizing monoclonal antibody, but following cessation of antibody treatment, the mice recovered from infection. In further experiments, an enzyme-linked immunospot (ELISPOT) technique was used to compare frequencies of IFN-gamma-producing cells in activated T-cell populations from C. muris-immune and naive donor mice. Stimulation with concanavalin A or a rat anti-mouse CD3 monoclonal antibody resulted in detection of greater numbers of cells producing IFN-gamma from immune than naive IEL populations. Small numbers of IEL from C. muris-immune mice, but not from naive mice, also produced IFN-gamma when cultured with soluble oocyst antigen, but this occurred only if gamma-irradiated spleen cells were cocultured with the immune IEL. These results suggested that IEL were important in the generation of immunity to Cryptosporidium and that one of their crucial functions was to produce IFN-gamma at the site of infection.

Animals↗
PubMed1996

The use of a new viability assay to determine the susceptibility of Cryptosporidium and Eimeria sporozoites to respiratory inhibitors and extremes of pH.

A new viability assay for Cryptosporidium and Eimeria sporozoites is described. It involves the use of both acridine orange and bis-benzimide and is more rapid, easier and less subjective than procedures used previously. The assay has been used to investigate the effects of respiratory inhibitors and pH on the sporozoites of C. parvum, C. muris and E. tenella. Neither cyanide nor azide reduced the viability of C. parvum or E. tenella, whereas they had some effect on C. muris. This latter organism, an intracellular parasite of stomach epithelial cells, also differed from the other two in being able to survive pH 2 for as long as 1 h.

Acridine Orange↗
PubMed1996

Immunity to Cryptosporidium muris infection in mice is expressed through gut CD4+ intraepithelial lymphocytes.

The role of gut intraepithelial lymphocytes (IEL) in immunity to cryptosporidial infection was investigated with a murine infection model involving Cryptosporidium muris. Oocyst shedding was monitored in severe combined immunodeficiency (SCID) mice infected with C. muris following intravenous injection of mesenteric lymph node (MLN) cells or intestinal IEL from BALB/c donor mice which were naive or previously infected with C. muris. SCID mice receiving no lymphoid cells developed chronic infections and excreted large numbers of oocysts until the end of the experiment. SCID mice injected with IEL from immune animals, however, were able to overcome the infection, and furthermore, these animals produced fewer oocysts and recovered sooner than ones which received IEL or MLN cells from naive BALB/c donors. Similar levels of protection were obtained in SCID mice injected with either 2 X 10(6) IEL or MLN cells from immune donor mice. Depletion of CD4+ cells from immune IEL, however, abrogated the ability to transfer immunity to SCID mice, while depletion of CD8+ cells only marginally reduced the protective capacity of immune IEL. Finally, control SCID mice which received no lymphocytes had < or = 1% CD4+ cells in the IEL from the small intestine, whereas the IEL from SCID mice recovered from infection, as a result of injection with immune IEL, contained 15% CD4+ cells. Thus, the ability to control C. muris infection correlated with the presence of the protective CD4+ cells in the gut epithelium.

Animals↗
PubMed1996

Parents' responses to predictive genetic testing in their children: report of a single case study.

There is a widely held view among health professionals that predictive genetic testing of children for late onset diseases is not desirable clinical practice. Yet, little is known about the views of parents, or their responses, to predictive genetic testing in their children. Since such testing is being carried out in some genetic centres, the opportunity was taken to conduct a single case study of the parents of 2 and 4 year old sisters who were tested for the gene for familial adenomatous polyposis. Interviews before testing, after, and 15 months later showed a stable attitude, that parental responsibility included making decisions about such testing, and that the role of health professionals should be one of information giving rather than decision making. These parents had no regrets about having their children tested and reported no changes in their behaviour towards either the child who tested positively or the child who tested negatively. Using standardised scales, mood was found to be within the normal range both before and after testing in the mother and father. This case study is a first step towards systematic empirical studies determining the consequences of acquiescing to parents' requests for genetic testing in their children.

Adenomatous Polyposis Coli↗
PubMed1996

Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study.

The effect of testosterone (T) replacement on changes in mood was studied for 60 days in 51 hypogonadal men. All patients were withdrawn from their prior T replacement for at least 6 weeks before enrollment. Of these patients, 18 received T enanthate 200 mg im every 20 days, 16 received sublingual T cyclodextrin (SLT) at a dose of 2.5 mg three times daily, and 17 received SLT at a dose of 5.0 mg three times daily. The total treatment period was 60 days. The patients were asked to respond to a questionnaire on 7 consecutive days before the start of treatment and on 7 consecutive days before their visits to the clinic on days 21, 41, and 60 of treatment. The following mood parameters were assessed using a 7-point Likert rating scale: angry, alert, irritable, full of pep (energy), sad/blue, tired, friendly, nervous, and well/good. When compared with the baseline period, T replacement led to significant decreases in anger (P = 0.0045), irritability (P = 0.0009), sadness (P = 0.0033), tiredness (P = 0.0035), and nervousness (P = 0.0291), and significant improvement in energy level (P = 0.0020), friendliness (P = 0.0072), and sense of well-being (P = 0.024) in all subjects as a group. Analyses of the area under the curve (AUC) of baseline serum T levels before T replacement showed significant positive correlations between serum T (AUC) and friendliness (r = 0.29, P < 0.05) and sense of well-being (r = 0.27, P < 0.05), and significant negative correlations with nervousness (r = -0.27, P < 0.05), irritability (r = -0.29, P < 0.05) and tiredness (r = -0.28, P < 0.05). Similar correlations were found between serum dihydrotestosterone (DHT) and some of the mood parameters. After T replacement in the hypogonadal men, these correlations between AUC of serum T levels and the positive and negative mood scores disappeared. These results were corroborated in a subsequent study in which 30 hypogonadal men were supplemented with SLT 5 mg three times daily for 6 months. The patients were less nervous (P = 0.0025) and more alert (P = 0.0004), friendly (P = 0.042), and energetic (P = 0.0001) during the 6-month treatment period compared with baseline. We conclude that T replacement therapy in hypogonadal men improved their positive mood parameters, such as energy, well/good feelings, and friendliness and decreased negative mood parameters including anger, nervousness, and irritability, and direct correlations between serum T and DHT with mood scores were only observed in the baseline period when serum androgen levels were below the normal range. The latter observation suggests that once a minimally adequate serum T/DHT level was achieved by T replacement therapy, further increases in serum T/DHT levels did not further contribute to the improvement in mood variables.

Administration, Sublingual↗
PubMed1995

Cleavable CD40Ig fusion proteins and the binding to sgp39.

Recombinant immunoglobulin (Ig) fusion proteins of cell surface and intracellular proteins have wide applications. For example, fusion proteins have been used in the isolation, identification and study of ligands and the effects of binding or blocking a receptor-ligand pair, either in vivo or in vitro. For some applications, removal of the immunoglobulin Fc region is advantageous. We have developed two vectors for the expression of Ig fusion proteins that contain recognition sequences for protease cleavage using thrombin. In one vector, the sequence encoding the thrombin cleavage site is located at the junction of the DNA fragment encoding the protein or protein fragment to be studied and the hinge and constant regions of the immunoglobulin, allowing the generation of a monomeric form of the protein of interest. In the second vector, the sequence encoding the thrombin cleavage site is located between the sequences encoding the hinge and constant regions of the immunoglobulin, allowing for the generation of covalent dimers of the recombinant protein without the constant Fc domains. We have used these vectors to produce the constructs encoding two forms of the extracellular domain of CD40, CD40ThrIg and CD40HinThrIg, allowing production of a monomeric and dimeric form of recombinant CD40. Cleavage is efficient and complete. Following cleavage, there was no detectable binding of the monomeric form of CD40 to a soluble form of gp39, the ligand of CD40, while the dimeric form was able to bind. These vectors have been constructed to allow facile substitution with other sequences to generate cleavable forms of other proteins of interest.

Base Sequence↗
PubMed1995

A live attenuated vaccine for the control of avian coccidiosis: trials in broiler breeders and replacement layer flocks in the United Kingdom.

Losses caused by coccidiosis are a significant problem in the rearing of breeder and layer flocks. A live vaccine has been developed that contains attenuated lines of the seven species of Eimeria that infect the chicken. The attenuated lines were derived from virulent strains by selection for earlier development in chickens. In 11 field trials, the performance of vaccinated chicks was compared with that of matched controls receiving conventional drug prophylaxis. The vaccine was given in the drinking water to 116,600 young chickens and provided excellent control of coccidiosis. The occurrence of coccidial oocysts in the litter, coccidial lesions post mortem and overt coccidiosis was markedly lower in the vaccinated birds than in the controls.

Animals↗
PubMed1995

Differentiation between human and animal strains of Cryptosporidium parvum using isoenzyme typing.

Isoenzyme typing was used to study a number of oocyst isolates of Cryptosporidium parvum from different geographical locations and of human or animal origin. All isolates showed identical enzyme motility when glucose phosphate isomerase (GPI; 23 isolates tested) or lactate dehydrogenases (LDH; 20 isolates tested) was assayed. However, two isoenzyme forms were observed with phosphoglucomutase (PGM; 9 animal isolates showed one form, while 8/9 human isolates showed a second form) and hexokinase (HK; 4 human isolates showed one form and 6 animal isolates showed a second form). Thus, PGM and HK each exhibit 2 isoenzymes corresponding to 2 parasite populations associated with separate hosts. The data from this study, plus supportive evidence obtained by different methods and by independent researchers, lend support to the hypothesis that separate cycles of transmission of C. parvum may exist within human and animal hosts.

Animals↗
PubMed1995

Localization of parasite antigens in Cryptosporidium parvum-infected epithelial cells using monoclonal antibodies.

An immunogold ultrastructural study was made of Cryptosporidium parvum-infected intestinal cells from SCID mice to locate parasite antigens recognized by monoclonal antibodies raised against sporozoite or oocyst wall antigens. The results suggested that these antigens were present in more than one life-cycle stage and demonstrated that the intracellular parasite modified the parasitophorous vacuole membrane and villous membrane surrounding the parasite. In an immunofluorescence antibody test monoclonal antibody (MAb) 1B5 reacted with the oocyst wall, MAb 2C3 with the whole sporozoite and MAb 2B2 with the sporozoite surface. Western and dot-blot studies demonstrated that different carbohydrate epitopes were recognized by the respective sporozoite-reactive antibodies. In the ultrastructural examination MAb 1B5 reacted with macro- and microgametocytes as well as the oocyst wall. In the macrogametocyte MAb 1B5 recognized the large electron-dense bodies characteristic of this stage and, in some parasites, the parasitophorous vacuole and the parasite pellicle. The sporozoite-reactive MAbs were able to bind to all developmental stages. These antibodies recognized the parasite cytoplasm and, additionally, MAb 2B2 produced substantial labelling of the parasite membrane. Significantly, both these antibodies also detected antigen in the parasitophorous vacuole membrane and, to a lesser extent, the villous membrane surrounding the parasite.

Animals↗
PubMed1995

Resolution of cryptosporidial infection in mice correlates with parasite-specific lymphocyte proliferation associated with both Th1 and Th2 cytokine secretion.

This study was designed to investigate and characterize T-cell responses which lead to elimination of a primary infection of Cryptosporidium muris in BALB/c mice. The proliferative response of spleen cells to parasite antigen was measured by uptake of 3H-thymidine and, in parallel, supernatants were removed from cells to measure levels of IFN-gamma, TNF, IL-2 and IL-4 by ELISA. Oocyst excretion in faeces was first detected on day 10 post infection (p.i.); the level of shedding subsequently increased until day 14 and then declined until no oocysts were detected by day 25. The proliferative response of spleen cells from infected animals was similar to control levels up to day 14 p.i. but increased significantly on day 21 and was even greater on day 26. IFN-gamma and IL-2 were detected initially on day 14 p.i. and significantly higher concentrations were found on days 21 and 26. IL-4 secretion was also detected, but not until day 21 p.i., and production of TNF was not found at any time. Depletion of T-cells or CD4+ cells from spleen cells cultured with antigen resulted in a significant decrease in the levels of cytokine detected. These results indicated, therefore, that in BALB/c mice there was a correlation between the development of immunity to C. muris infection and both a parasite antigen-specific proliferative response and Th1 and Th2 cytokine production by spleen cells.

Animals↗
PubMed1995

Murine infection model for maintenance and amplification of Cryptosporidium parvum oocysts.

Propagation of Cryptosporidium parvum is problematic because in vitro development of the parasite is poor and animals are only briefly susceptible as neonates. At present oocysts of the parasite are usually procured by passage in neonatal sheep or cattle. In the present study, large numbers of oocysts of C. parvum could be isolated following infection of dexamethasone-treated adult C57BL/6 mice. The amount of immunosuppressive drug and the regimen of administration were critical for successful maintenance of the parasite, however. Routinely, 10 mice (age, 8 to 12 weeks) were injected four times on alternate days with 1.0 mg of dexamethasone, and the last injection was given on the same day as oral inoculation with 10(6) oocysts. By using a simplified procedure for oocyst purification from mouse feces, approximately 10(9) oocysts were obtained. This model is inexpensive and comparatively safe to handle, and the numbers of animals inoculated can be varied to obtain the required number of oocysts. Thus, this murine infection model would be a suitable alternative to the use of neonatal calves or sheep for efficient oocyst propagation.

Animals↗
PubMed1995

Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate--a clinical research center study.

We studied and compared the pharmacokinetics and bioefficacy of two doses of sublingual testosterone cyclodextrin (SLT; 2.5 and 5.0 mg, administered three times per day) with testosterone enanthate (TE; 200 mg) given once every 20 days by im injections over a 60-day study period in 63 hypogonadal men. After SLT administration, serum testosterone (T) levels peaked at 20 min and then fell, reaching baseline levels by 360 min. The calculated half-lives were 60.3 +/- 7.5 and 68.8 +/- 5.0 min after a single dose of 2.5 and 5.0 mg SLT, respectively. The mean area under curve (AUC) of serum T was computed over 20-day periods for the 3 treatment groups. The mean net AUC of serum T after TE administration was about 4- and 2-fold higher than that in the 2.5 and 5 mg groups over the last 20 days. Serum estradiol and dihydrotestosterone followed the same pattern as serum T. Serum estradiol to T ratios decreased after T replacement in all 3 groups, whereas serum dihydrotestosterone to T ratios were not significantly changed by T treatment. Suppression of serum LH and FSH levels was more marked in the patients treated with TE than in those given SLT. Similarly, serum sex hormone-binding globulin levels showed significant decreases with androgen replacement only in the TE and SLT 5.0 mg range groups. There were no significant adverse effects based on comprehensive physical examinations, urea, electrolytes, and renal or liver function tests. Hematocrit levels increased in the TE-treated group, but remained slightly lower than baseline levels in the SLT groups. Serum high density lipoprotein cholesterol showed a small, but significant, decrease with time of treatment in all groups. Despite the differences in the AUC of serum T levels achieved by different androgen replacement therapies, all patients showed significant improvements in sexual motivation and performance, with no significant difference between the treatment groups. We conclude that SLT may be a useful addition to the currently available injectable and transdermal delivery systems for treatment of hypogonadal men. Because of the ease of administration, rapid reversibility of effects, and lower AUC of serum T levels achieved compared to those of TE injections, SLT may be especially suitable for treatment of boys with delayed puberty and older men with androgen deficiency.

Administration, Sublingual↗