Provocation testing of human sperm motility using energy substrates and activators of the cyclic nucleotide system. I. Establishment of conditions for response testing.

In order to establish a series of provocation tests to evaluate the integrity of the sperm cAMP pathway, manganese (Mn), 2-deoxyadenosine (DEA) (via adenylyl cyclase), and methyl-isobutyl-xanthine (MIX) (via phosphodiesterase) were tested for their capacity to activate the progressive motility of human sperm. Optimal responses were obtained using washed sperm previously incubated for 3 hours in substrate-poor medium (Hepes-buffered saline). Longer periods of incubation required the presence in addition of an energy substrate such as glucose. Exposure of sperm to seminal plasma for 24 hours prior to washing attenuated the responsiveness of the sperm to the different activators. Preliminary studies on the activation of the progressive motility of washed sperm from four normozoospermic men under fertility investigation, prepared under identical conditions, revealed differences in the pattern of response which may have pathophysiological relevance.     

Science writers' reactions to a medical "breakthrough" story

In numerous incidences, the news coverage of medical research has incited unjustified optimism or fear. The medical literature provides an archive of the scientific community's condemnation of these misleading reports, but little is known about how they are judged by newsmakers. This study explored science writers' reactions to a controversial New York Times story that inflated the hopes of thousands of cancer patients. More than 60 science writers in the US, Canada, and Great Britain participated in a 12-day email discussion triggered by the Times article. We analyzed 255 of these email postings and coded (1) positive and negative critiques of the Times story, (2) references to the article's repercussions including the creation of false hope, (3) attributions of responsibility for the resulting public misunderstanding, and (4) suggestions to improve the public's comprehension of medical research news. The participating science writers generally responded negatively to the controversial article: 83% of the critiques were unfavorable. In addition, the science writers in the sample were cognizant and concerned about the impact of their work on the public, and accepted the largest share of the responsibility for the false hope created by the news coverage of medical research. Finally, the suggestions offered by respondents to improve the public's understanding of medical research news were similar to those proposed by the scientific community. Thus, some commonality exists between how scientists and science writers believe the news coverage of medical research could be improved.     

Benzo[a]pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium

While tobacco smoke has been conclusively identified as a lung carcinogen, there is much debate over which smoke constituent(s) are primarily responsible for its carcinogenicity. Previous studies in our laboratory suggested that highly lipophilic carcinogens are slowly absorbed in the thicker epithelium of the conducting airways, potentially allowing for substantial local metabolism. The bioactivation of polycyclic aromatic hydrocarbons in airway epithelium may, hence, be important in tobacco smoke-induced carcinogenesis. In the present study, the hypothesis of slow absorption and substantial local metabolic activation of highly lipophilic carcinogen in airway epithelium was tested in dogs. A single dose of tritiated benzo[a]pyrene (BaP) dissolved in a saline/phospholipid suspension was instilled in the trachea, just anterior to the carina. At intervals of a few minutes up to 30 min over a 3-h period, blood samples were drawn from the azygous vein, which drains the area around the point of instillation, and from the systemic circulation. Tissue samples were taken at the end of the experiment. The concentration of BaP with depth into the tracheal mucosa was determined with autoradiography. BaP was slowly absorbed into the trachea with a half-time of approximately 73 min, which is consistent with diffusion-limited passage through the epithelium and lead to local doses in the tracheal epithelium that were more than a 1000-fold those of other tissues. The long retention of BaP in the epithelium provided the local metabolizing enzymes with high substrate levels over a long period, resulting in extensive metabolism. At 3 h after the exposure, 23% of the BaP-equivalent activity remained in the tracheal mucosa. Of this fraction, 13% was parent compound, 28% was organic extractable, 31% was water-soluble, and 28-7% of the instilled dose was bound to tracheal tissues. These results explain the tendency of highly lipophilic carcinogens, such as BaP, to induce tumors at the site of entry and, furthermore, indicate that the highly lipophilic components of tobacco smoke and polluted air may be the most important contributors to lung tumors of the conducting airways.      

Need for follow up in coeliac disease

The use of follow up studies was evaluated in 128 patients with coeliac disease during their first visit to a department for adults. The original diagnosis had been made in childhood in all patients. Fifty eight (45%) of the subjects were following a gluten free diet, 23 (18%) were following a gluten free diet but with occasional gluten consumption, and 47 (37%) had adopted an unrestricted, gluten containing diet for a mean of 11.2 years. There was no correlation in individual subjects between the presence of symptoms, biochemical and immunological abnormalities, severity of histological findings, and the amount of dietary gluten, despite the greater frequency of symptoms in the group following an unrestricted diet than in the other two groups. Short stature and epilepsy with cerebral calcifications only occurred in patients following an unrestricted diet. As only diagnosis based on two or three biopsy samples and regular follow up correlated positively with dietary compliance, it is suggested that a histologically confirmed diagnosis of coeliac disease and regular lifelong follow up are essential in the management of these patients.     

Elderly Patients with Suppressed Serum TSH but Normal Free Thyroid Hormone Levels Usually Have Mild Thyroid Overactivity and are at Increased Risk of Developing Overt Hyperthyroidism

The clinical and biochemical characteristics of 15 elderly patientswith low levels of thyrotrophin (TSH) (<0.1 mU/L) but normalfree tri-iodothyronine, (T3) and free thyroxine (T4) (groupS) were compared with 10 euthyroid subjects (group E) and 10hyperthyroid patients (group T). Free T3 and free T4 were significantlyhigher (p<0.05) in group S(6.3±0.5 and 18.6±1.0pmol/l, respectively) than in group E(4.6±0.3, 12.6+0.6).In common with elderly hyperthyroid patients (group T)patientsin group S had few signs or symptoms of thyrotoxocosis, butthe Wayne score (clinical index of hyperthyroidism) was higherin group S than in euthyroid subjects (p<0.05). Thyroid microsomal,thyrogolobulin or thyrotrophin receptor antibodies were commonin group T (n=9)but not in groups S(n=2) or E(n=1). This suggestsa low prevalence of Graves' disease in group S compared to groupT. Combined thyrotrophin releasing hormone (TRH; 200 µgi.v.) and gonadotrophin releasing hormone GnRH; 100 µgi.v.) tests were performed; no cases of low TSH due to hypopituitarismwere identified in group S. During a mean of 7.9 (4–12)months of observation TSH reverted to the normal range (>0.2mU/L)in 7 of 15 patients in group S; thyroid hormone concentrationsrose above the normal range in four, however, only two patientsrequired treatment for hyperthyroidism. It is unlikely thatthe suppressed TSH of patients in group S was due to mild thyroidhormone excess; although this is often a transitory phenomenon,these patients are at increased risk of developing overt hyperthyroidism.     

Body habitus in a cohort of HIV-seropositive and HIV-seronegative injection drug users

We determined anthropometric measurements (including height, weight, circumferences, and skinfolds) and self-reported symptoms related to body habitus changes in 324 HIV-seropositive and HIV-seronegative inner city injection drug users (IDUs) who participated in a substudy from the ALIVE (AIDS Linked to Intravenous Experiences) cohort. Participants who reported lipoatrophy in body parts had consistently lower anthropometric measurements and those reporting adiposity had correspondingly higher anthropometric measurements than participants who did not report these changes. Peripheral lipoatrophy was more common among all HIV-seropositive than HIV-seronegative participants, however, it was not associated with highly active antiretroviral therapy (HAART) (39% HIV-seronegatives; 58% HIV-seropositive not receiving HIV treatment [No Tx]; 49% HAART, p = 0.04). Central adiposity was more common among HAART (52%) than No Tx (26.6%) and HIV-seronegative (42%) participants (p = 0.001). However, waist circumference, while somewhat higher among HAART than No Tx participants, did not differ significantly from HIV-seronegative participants (85.2 cm HIV-seronegatives; 83.3 cm No Tx; 85.8 cm HAART). A large proportion of those who reported peripheral lipoatrophy also reported central lipoatrophy (76.9% HIV-seronegatives; 69.6% No Tx; 66.2% HAART). A large proportion of those who reported central adiposity also reported adiposity of the peripheral sites (88.1% HIV seronegatives; 66.7% No Tx; 74.3% HAART). The combination of lipoatrophy and adiposity was associated with HAART treatment (6% HIV-seronegatives; 3% No Tx; 16% HAART, p = 0.002), but may be driven by the association with adiposity. These data suggest validity of self-reports for body habitus changes among injection drug users.     

LH/hCG Responsive Adenylyl cyclase in Rat Testis and Testes from Testicular Feminized Male (Tfm) Rats and Mice: Desensitization by Homologous Hormone

Testes of testicular feminized (tfm) rats and mice, as well as of normal male rats contain an LH/hCG responsive adenylyl cyclase. Basal, as well as hCG stimulated activities were higher in tfm rats and mice than in normal rats. The presence of an LH/hCG responsive adenylyl cyclase in the testis of tfm rats and mice shows that the greatly elevated LH levels present in males having this syndrome, giving 80–90% reduction in LH//hCG receptors, do not cause an uncoupling of the remaining receptors from the adenylyl cyclase. It also shows that androgens are not essential for coupling of the LH/hCG receptors to the adenylyl cyclase.
Injection of 200 IU of hCG into adult normal rats and tfm rats caused, after 48 h, a complete loss of LH/hCG stimulated adenylyl cyclase, whereas the FSH responsive adenylyl cyclase in both animal preparations was maintained. Desensitization of the LH responsive adenylyl cyclase by hCG in normal rats, confirms previous studies showing lack of hCG stimulated cyclic-AMP secretion after a comparable dose of hCG in vivo. Similarly, hCG (50 IU) caused a transient loss of LH/hCG responsive adenylyl cyclase in tfm mice, with a complete disappearance of response after 24 h. At 48 and 72 h after injection of hCG the response gradually returned to normal. The fact that hCG caused a complete desensitization of the LH/hCG responsive adenylyl cyclase in both tfm rats and mice, proves that androgen receptor mediated events are not involved in hCG desensitization of the adenylyl cyclase in Leydig cells.     

Cellular localization of the Mn2+-dependent adenylyl cyclase (AC) in rat testis

In the present study we have examined the exact cellular localization of the Mn²⁺-dependent adenylyl cyclase (AC) in the rat testis. Several pieces of evidence indicate that this testis specific enzyme is exclusively localized to haploid cells in the testis: firstly, the appearance of the Mn²⁺-dependent adenylyl cyclase coincides in time with the occurrence of haploid cells (1C) in the rat testis. Secondly, testes of tfm rats and mice, in which little or no haploid cells are found, exhibit negligible Mn²⁺-dependent AC activity. Finally, separation of various testicular cells by BSA gradient sedimentation (Staput fractionation), revealed that this enzyme activity follows the location of haploid cells; the highest specific AC activities being found in the fractions containing elongated spermatids. Some activity found in the primary spermatocyte fraction (4C cells) can to a large extent be explained by the contamination of haploid cells in this fraction.