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Background: A steroid hyalosis is a benign condition characterized by small white or yellow-white spherical opacities throughout the vitreous. The aetiology of this disorder is not clearly understood. Association of asteroid hyalosis with diabetes mellitus has been a debatable issue in ophthalmology. This study was carried out to determine the relationship between asteroid hyalosis and diabetes., Methods: The study was carried out in the Department of Ophthalmology, Military Hospital, Rawalpindi. Cases were picked up during routine eye examination that showed evidence of asteroid hyalosis. All patients of diabetes scheduled for routine follow-ups were also checked for active signs of diabetes. Fasting and two-hour postprandial blood glucose were checked and the frequency of diabetes mellitus in patients with asteroid hyalosis was determined., Results: Ninety-six cases of asteroid hyalosis were included. The median age of presentation was 55.68 years (range 40-71). It was bilateral in thirty-six cases. Twenty-eight cases were positive for diabetes., Conclusion: The association between asteroid hyalosis and diabetes appears to be significant. Patients found to be having the findings of asteroid hyalosis should be screened for diabetes.

The positive effect of testosterone replacement therapy on psychosocial well-being in hypogonadal men has been demonstrated by various psychometric tests. However, there is no report available that objectively demonstrates the effect of testosterone on the function of the central nervous system in men. In this report we studied cerebral perfusion in seven hypogonadal men on testosterone replacement therapy. The blood perfusion to the central nervous system was assessed using single-photon emission-computed tomography. (99 m)Tc-hexamethyl-propylene-amine oxime crosses the blood brain barrier and localizes in brain tissue, depending on the intensity of the local blood flow. Psychosocial well-being was assessed with an Androgen Deficiency in Aging Men questionnaire. The study demonstrated that testosterone replacement enhanced cerebral perfusion in midbrain and superior frontal gyrus (Brodman area 8) at 3-5 wk of treatment. At 12-14 wk the study continued to show increased perfusion in midbrain in addition to the appearance of a new activated region in the midcingulate gyrus (Brodman area 24). The results of this study provide objective evidence that testosterone and /or its metabolites increased cerebral perfusion in addition to the improvement in cognitive function.

Background: Insomnia is common in hospitalized patients, who become significantly vulnerable to the adverse effects of the benzodiazepines (BZDs) used to treat this condition. Consequently, there has been a logical search for non-drug alternatives (NDAs) for the treatment of insomnia., Method: Inpatient insomnia cases were surveyed over the Summer of 1999. Our hypotheses were that an attitudinal difference exists between acute and chronic users of BZDs towards NDAs; and that inpatients who were prescribed BZDs have also received proper information about alternative therapies., Results: One hundred insomnia cases met the inclusion criteria. Fifty-one per cent were younger than age 65. Short acting BZDs were used in 88% of the cases. Fourty per cent of patients had started experiencing insomnia while in the hospital. Only 11% of patients received information about NDA therapy for insomnia. Eighty-two patients felt that NDAs were healthier, and the majority (n=67) responded that if an NDA were offered in the hospital, they would be willing to accept it. Female participants were more willing to consider NDAs (P<0.01). First time users of BZDs were by far more receptive to NDA remedies than were chronic users of BZDs (P<0.002). A significant number of participants who were receiving short-acting BZDs were willing to try an NDA (P<0.001). Participants interested in NDA therapies expressed preferences for for massage therapy, sleep hygiene, music and relaxation techniques (P<0.001)., Conclusion: Significant attitudinal differences are seen in several domains of patient characteristics. First time female users of BZDs and those taking short acting BZD were more willing to try an NDA. Educational programs are needed for appropriate evidence-based management protocols for insomnia.

Background: primary and secondary insomnia, especially among older adults, is frequently encountered by family physicians. Pharmacological interventions, although effective in some circumstances, can be detrimental in others. Non-pharmacological management of insomnia may allow the patients to self-administer the treatment., Objectives: review of published literature of assessment tools and treatments for primary and secondary insomnia., Results: two frequently used self-reporting methods for obtaining sleep data are sleep diaries and Pittsburg Sleep Quality Index. A large amount of research supports the use of non-pharmacological treatments such as stimulus control, sleep restriction, sleep hygiene education, cognitive therapy, multi-component therapy and paradoxical intention., Conclusion: assessing the nature of insomnia by using an effective assessment tool and providing patients with a non-pharmacological treatment should be the first intervention for insomnia. It is shown that non-pharmacological treatments for primary and secondary insomnia are feasible and effective alternatives to the use of benzodiazepines, and that family physicians should consider these when managing older patients with insomnia.

Older adults take almost one-third of the drugs prescribed today yet represent only about 12 percent of the population. Adverse drug events are common in this population, but often these events appear to be preventable. Interest in adverse events related to the use of prescription drugs has rarely been higher or broader. The research community continues to develop new tools to study adverse effects of drugs in individuals and populations. However, the published literature on drug-related adverse events is fraught with problems, starting with the original reports and extending to systematic reviews. Prospective data are missing, adverse drug events are poorly described, and analytical methods are questionable. This leads to problems with imprecise estimates and generalizability of results.

The authors describe the results of a survey they carried out in 2000 to determine the status of cultural sensitivity training in 16 Canadian medical schools using structured telephone interviews of associate and assistant deans or curriculum directors and curriculum coordinators. Their goal was to obtain a descriptive analysis of school-specific objectives, curriculum content, methods, and evaluation formats. The survey was prompted by the growing concern that in culturally diverse societies, medical education has failed to keep pace with the changing composition of the patient population. Only one of the eight schools that integrated cultural sensitivity within their objectives made explicit mention of the topic in its clerkship evaluation form. While seven of the 16 schools did not have any statement on cultural sensitivity in their curricular objectives, they integrated cultural sensitivity in their curricula using various educational methods, with PBL cases, lectures, and small-group discussions being the commonest formats. These educational methods were primarily offered to students in their first and second years. Student participation was required, but program lengths ranged from two to 40 hours. Additional findings for each school are presented. The authors conclude that while progress has been made, lack of adequate resources and a number of obstacles to inclusion of multicultural health content in curricula appear to remain ongoing problems. Further investment in faculty development and administrative staff support for a multicultural curriculum are needed, as is more research on effective curricular components.

Background: Malnutrition in elderly patients in institutions has become an issue of clinical concern, but it remains largely unrecognized in acute care hospitals. The demonstrated benefits of intervention emphasize the need for routine nutritional assessment. The objectives of this study were to determine the prevalence of malnutrition in elderly patients admitted to a tertiary care centre and to test the sensitivity and specificity of 3 nutrition screening tools., Methods: Between July and November 1996 patients 65 years and older were consecutively recruited from the general medicine, orthopedics, general surgery and neurosciences services of The Ottawa Hospital--General Campus within 72 hours of admission. They were interviewed using 3 nutritional screening tools: one developed by Chandra and colleagues (Chandra), the Nutrition Screening Initiative (NSI) and the Mini Nutritional Assessment (MNA). A detailed nutrition assessment was then undertaken, which included anthropometric assessment, laboratory tests, determination of risk factors and assessment of dietary intake. A dietitian blinded to the screening results classified each patient as being well nourished, at risk for malnutrition or malnourished. The prevalence of malnutrition was assessed, and screening results were compared with the results of the detailed nutrition assessment for sensitivity and specificity., Results: In total, 160 patients (86 women) were recruited. Detailed nutrition assessments were completed for 152 patients, of which 62 (40.8%) were found to be well nourished, 67 (44.1%) at moderate risk for malnutrition and 23 (15.1%) malnourished. Matched comparisons showed that, of the 23 malnourished patients, 1 was found to be at high risk for malnutrition using the Chandra screening tool, 9 using the NSI and 4 using the MNA, giving sensitivities of 32%, 54% and 57%, and specificities of 85%, 61% and 69%, respectively., Interpretation: Given the high rate of malnutrition or risk of malnutrition in this study, admitting physicians need to be aware of this problem and its scope. The 3 screening tools tested performed poorly in comparison with the detailed nutrition assessment. This may have been because the score thresholds for the screening tools were set for screening purposes and because the screening tools were designed for different settings and a wider population.

To determine whether a difference in HbA(1c) could be safely sustained between a standard therapy (STD) arm and an intensive therapy (INT) arm, while maintaining HbA(1c) levels in both arms within a range acceptable in community practice. The effects of intensive treatment on various parameters were studied in this feasibility trial. We report here the results of 24 months of INT on peripheral and autonomic neuropathy.A prospective trial was conducted in five medical centers in 153 men of 60 +/- 6 years of age who had a known diagnosis of diabetes for 7.8 +/- 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: (1) an evening insulin injection, (2) the same injection adding daytime glipizide, (3) two injections of insulin alone, and (4) multiple daily injections. Peripheral neuropathy was diagnosed clinically by a history and physical examination, and by abnormal autonomic neuropathy Valsalva ratio (VR < 1.2) and RR variation (RRV < 10). An average HbA(1c) separation of 2.07% was achieved with INT, having HbA(1c) at or below 7.3% (p = 0. 001 versus STD). Baseline prevalence of peripheral neuropathy was 53% in STD, and 48% in INT. By 24 months, the prevalence increased to 69% in STD (p = 0.005 versus baseline), and to 64% in INT (p = 0. 008 versus baseline, but no different than STD). Though INT did not reverse all elements of peripheral neuropathy, there was a decreased prevalence of cranial neuropathy (p = 0.053 versus STD) and more frequent preservation of touch sensation in the upper extremities (p = 0.03 versus STD) in INT. At baseline, an abnormal Valsalva ratio and/or RR variation was seen in 38% of STD and 31% of INT. By 24 months in STD, the prevalence rose to 55% (p = 0.0067 versus baseline), and in INT, to 48% (p = 0.012 versus baseline and no different from STD). The prevalence of erectile dysfunction increased from 53% at baseline to 73% at 2 years, p = 0.002 in STD, and from 51% to 73% at 2 years (p = 0.003 versus baseline) and no different from STD. There was no change in the frequency of abnormal gastrointestinal or sweating symptoms. Our conclusion was that 2 years of meticulous glycemic control did not decrease overall prevalence of peripheral or autonomic neuropathy. In fact, the prevalence rose equivalently and significantly in both treatment arms. There was some benefit, however, in decreased frequency of cranial neuropathy and better preservation of touch sensation in INT.

Background: The Veterans Affairs Cooperative Study in Type II Diabetes Mellitus prospectively studied insulin-treated patients with type 2 (non-insulin-dependent) diabetes mellitus, achieving 2.1% glycosylated hemoglobin separation between intensive- and standard-treatment arms (P<.001) for 2 years., Objective: To assess the effect of intensive therapy on serum fibrinogen and lipid levels, compared with standard treatment., Methods: One hundred fifty-three male subjects with type 2 diabetes mellitus and who required insulin treatment were recruited from 5 Veterans Affairs medical centers. The subjects were divided into intensive- and standard-treatment arms for a randomized prospective study. Dyslipidemia was managed identically in both arms (diet, drugs). Fibrinogen levels and lipid fractions were measured in the full cohort. Lipid fractions are separately reported in patients not treated with hypolipidemic agents., Results: There were no baseline differences between arms. Fibrinogen levels rose in the intensive-treatment arm at 1 year (from 3.34+/-0.12 to 3.75+/-0.15 g/L; P<.001) but returned to baseline at 2 years (3.47+/-0.12 g/L). There was no change in the standard-treatment arm. Triglyceride levels decreased in the intensive-treatment arm from 2.25+/-0.27 to 1.54+/-0.14 mmol/L (199+/-24 to 136+/-12 mg/ dL) at 1 year (P = .004) and to 1.74+/-0.18 mmol/L (154+/-16 mg/dL) at 2 years (P = .03); there was no change in the standard-treatment arm. Cholesterol levels decreased in the intensive-treatment arm at 1 year from 5.4+/-0.21 to 4.99+/-0.13 mmol/L (207+/-8 to 193+/-5 mg/dL) (P = .02); there was no change in the standard-treatment arm. Levels of low- and high-density lipoprotein cholesterol decreased in the standard-treatment arm only by 2 years, from 3.44+/-0.13 to 3.16+/-0.10 mmol/L (133+/-5 to 122+/-4 mg/ dL) (P =.02) and from 1.10+/-0.03 to 1.00+/-0.03 mmol/L (42+/-1 to 38+/-1 mg/dL) (P<.001) for low-density and high-density lipoprotein cholesterol, respectively. Levels of apolipoprotein B decreased in both treatment arms (P<.001), and apolipoprotein A1 levels decreased in the standard-treatment arm (P<.01). Lipoprotein (a) levels did not change in either treatment arm. Lipid results were essentially identical whether examined in the full cohort or excluding those patients receiving hypolipidemic agents., Conclusions: Intensive insulin therapy led to a potentially beneficial reduction in serum triglyceride levels and preservation of high-density lipoprotein cholesterol and apolipoprotein A1 levels. However, it caused transient elevation in plasma fibrinogen levels, a possible thrombogenic effect.

We and others have identified luteinizing hormone-releasing hormone (LHRH) in cells of the immune system in both animals and humans. LHRH is an immunostimulant, and testosterone is an immunosuppressant. Because testosterone is known to modulate the concentrations of hypothalamic LHRH, we wondered whether testosterone might also alter the concentrations of rat thymic LHRH. Two weeks after castration or sham castration, adult male rats were implanted with either vehicle or testosterone capsules. All animals were killed 4 days after capsule implantation. Thymic LHRH concentration increased significantly in castrated animals. Testosterone replacement prevented this increase. The concentration of the LHRH precursor, proLHRH, decreased significantly, but testosterone replacement prevented this decrease. Steady-state concentrations of LHRH mRNA were not changed by castration or by hormonal replacement. In contrast to the post-castration increase in thymic LHRH, LHRH content of the hypothalamus decreased significantly. Whereas concentrations of LHRH were lower in the thymus than in the hypothalamus, proLHRH concentrations were much greater in the thymus. These data suggest that gonadal manipulation modulates LHRH molecular processing and its tissue concentration in the thymus in addition to those in the hypothalamus, and that the regulation of LHRH molecular processing by testosterone in the hypothalamus is different from that in the thymus.

The clinical presentation of amyotrophic lateral sclerosis (ALS) is variable and overlaps with that of other motor neuron diseases such as spinobulbar muscular atrophy (SBMA; Kennedy disease). With the identification of disease-specific mutations such as the CAG repeat expansion in the androgen receptor in SBMA, an accurate molecular diagnosis can be made in some patients with motor neuron disease. To determine the extent of misdiagnosis of ALS we screened 147 male ALS patients and 100 unrelated male patients from 100 familial ALS (FALS) kindreds for the presence of the SBMA mutation using polymerase chain reaction methods. We show that ALS was clinically misdiagnosed in 2% of sporadic cases and in two of the 100 FALS kindreds. This study underscores the difficulty in distinguishing SBMA from ALS clinically, particularly in patients who lack the classic signs of each disease.

Jurkat cells were used to study the immunomodulatory role of luteinizing hormone-releasing hormone (LHRH) in immune cells. The Jurkat cell, a human mature leukemic cell line, phenotypically resembles resting human T lymphocytes and has been widely used to study T cell physiology. The data from this study demonstrate that the Jurkat cell concentration of immunoreactive LHRH was 210 +/- 36 pg/10(6) cells and that of proLHRH was 188 +/- 27 pg/10(6) cells (means +/- S.E.M.). The authenticity of this LHRH immunoreactivity is documented in two ways. First, both Jurkat LHRH and proLHRH immunoreactivity demonstrate dilutional parallelism with hypothalamic LHRH and proLHRH. Second, Jurkat lysates show LHRH bioactivity by releasing luteinizing hormone from rat anterior pituitary cells in culture. The presence of substantial amounts of LHRH in medium in which Jurkat cells were cultured for 72 h indicated that LHRH can be released from the cells. Using specific primers to exons 2 and 4 of the LHRH gene, we have found that Jurkat cells (like human T cells) express LHRH mRNA. The LHRH agonist, des-Gly10,D-Trp6-LHRH ethylamide, significantly increases the proliferative activity of Jurkat cells, as assessed by tritiated thymidine incorporation, from 15980 +/- 1491 c.p.m. in control to 28934 +/- 3395, 30457 +/- 3861 (P = 0.05 vs control) or 35299 +/- 5586 c.p.m. (P < 0.01 vs control) with 10(-11), 10(-9) or 10(-7) M agonist respectively. LHRH antagonist, [D-pGlu1,D-Phe2,D-Trp3,6]-LHRH, at a concentration of 10(-8) M decreases Jurkat cell proliferative activity form 17145 +/- 526 c.p.m. in control medium to 10653 +/- 1323 c.p.m. (P = 0.05). Co-incubation with the LHRH antagonist completely inhibits the proliferative stimulation induced by the LHRH agonist. Furthermore, applying monoclonal LHRH antibody to Jurkat cells inhibits the cell proliferative activity assessed by tritiated thymidine incorporation from 19900 +/- 2675 c.p.m. in control to 15680 +/- 2254, 15792 +/- 1854 and 9700 +/- 908 c.p.m. in media with 1:40, 1:20 and 1:10 dilution of purified antibody respectively (P < 0.01, 1:10 dilution compared with control). In addition, the cAMP level in LHRH-stimulated Jurkat cells is decreased to 74, 27 and 57% of control levels after 15, 30 and 45 min respectively of exposure to 10(-7) M LHRH agonist. In summary, Jurkat cells produce, process and release immunoreactive and bioactive LHRH, as do normal human T cells. Endogenous and exogenous LHRH increase Jurkat cell proliferative activity, and cAMP may be involved in LHRH-induced Jurkat cell proliferation. The Jurkat cell may be a useful model with which to study the role of LHRH in human T cell function.

In mammals, males and females differ both genetically and hormonally, making it difficult to assess the relative contributions of genetic constitution and fetal environment in the process of sexual differentiation. Many reptiles lack sex chromosomes, relying instead on the temperature of incubation to determine sex. In the leopard gecko (Eublepharis macularius), an incubation temperature of 26 degrees C produces all females, whereas 32.5 degrees C results in mostly males. Incubation temperature is the primary determinant of differences both within and between the sexes in growth, physiology, and sociosexual behavior, as well as the volume and metabolic capacity of specific brain nuclei. To determine if incubation temperature organizes the brain directly rather than via gonadal sex hormones, the gonads of male and female leopard geckos from the two incubation temperatures were removed and, in some instances, animals were given exogenous testosterone. In vertebrates with sex chromosomes, the size of sexually dimorphic nuclei are sensitive to hormone levels in adulthood, but in all species studied to date, these changes are restricted to the male. Therefore, after behavior tests, morphometrics of certain limbic and nonlimbic brain areas were determined. Because nervous system tissue depends on oxidative metabolism for energy production and the level of cytochrome oxidase activity is coupled to the functional level of neuronal activity, cytochrome oxidase histochemistry also was performed on the same brains. Hormonal manipulation had little effect on the volume of the preoptic area or ventromedial hypothalamus in geckos from the all-female incubation temperature, but significantly influenced the volumes of these brain areas in males and females from the male-biased incubation temperature. A similar relationship was found for cytochrome oxidase activity of the anterior hypothalamus, amygdala, dorsal ventricular ridge, and septum. The only sex difference observed was found in the ventromedial hypothalamus; males showed no significant changes in cytochrome oxidase activity with hormonal manipulation, but females from both incubation temperatures were affected similarly. The results indicate that incubation temperature organizes the brain directly rather than via hormones arising from its sex-determining function. This is the first demonstration in a vertebrate that factors other than steroid hormones can modify the organization and functional activity of sexually differentiated brain areas.

We have previously demonstrated that both human CD4+ and CD8+ T lymphocytes produce enhanced levels of luteinizing hormone-releasing hormone (LHRH) mRNA and peptide upon stimulation with monoclonal antibody directed at the CD3 component of the T cell receptor for antigen (TCR) or mitogenic lectin. In the current study, we define the signaling pathways that control TCR-mediated LHRH production by using agents known to affect distinct signals, and compare the messenger systems required for LHRH response to other T-cell-associated activation responses, such as expression of CD69 and interleukin-2 receptor (IL-2R) molecules and production of interleukin-2 (IL-2). Results indicate that the activation of protein kinase C (PKC) is essential for LHRH production by previously nonstimulated T cells, not increased concentration of cytosolic-free calcium ([Ca2+]i). Phorbol ester (PMA), a direct activator of PKC, provoked LHRH production and cell surface expression of CD69 and IL-2R molecules by T cells, but not IL-2 synthesis. The synthesis of IL-2 by T cells required costimulation with PMA and ionomycin, a Ca2+ ionophore. Consistent with these observations, H7, an inhibitor of PKC, prevented T cells from producing LHRH upon activation with mitogen. However, LHRH production was not suppressed by HA1004, which inhibits all cyclic nucleotide-dependent protein kinases except for PKC. Genistein, a selective inhibitor of protein tyrosine kinase, blocked PMA-induced increase in LHRH production, but not CD69 and IL-2R expression, suggesting that protein tyrosine phosphorylation events distal from PKC activation may play a role in regulating LHRH response.

Continuous administration of LHRH agonist suppresses the pituitary-gonadal axis, achieving chemical castration. Thus, LHRH agonist has been used as an alternative (to surgical castration) for the treatment of steroid-dependent prostate cancer. However, recent reports have demonstrated that LHRH agonist had a direct inhibiting effect on prostate cancer cell proliferation and that cancerous prostate tissue contained a LHRH-like peptide. In this paper we are reporting for the first time that the normal rat ventral prostate contained immunoactive and bioactive LHRH as well as its precursor molecule, pro-LHRH. Our investigation showed that the LHRH concentration in prostate increased 2 weeks after castration from 1.68 +/- 0.09 to 3 +/- 0.2 pg/mg tissue (P < 0.001). At the same time, the concentration of pro-LHRH decreased from 149 +/- 6.5 to 68 +/- 6.8 pg/mg tissue (P < 0.001). Furthermore, intact rat prostate expressed LHRH mRNA, which increased 13-fold 2 weeks after castration. In summary, the prostate of intact Sprague-Dawley rats has the capacity to produce the LHRH precursor and process it to the mature decapeptide, and this production/processing increases significantly after castration.

An immunomodulatory role for LHRH was suggested when we reported the presence of immunoactive and bioactive LHRH and its mRNA in rat splenic and thymic lymphocytes. In this paper we report that human peripheral T-cells as well as its subsets CD4+ and CD8+ contained immunoactive and bioactive LHRH. Furthermore, analysis of phytohemagglutinin (PHA)-activated T-cell lysates for LHRH by RIA demonstrated that the mean concentration of LHRH in PHA-activated T-cells increased from 45 +/- 4.5 to 64 +/- 7 pg/10(6) cells after 24 h of culture and from 47 +/- 3.6 to 117 +/- 11.8 pg/10(6) cells (P < 0.01) after 48 h. While the LHRH concentration in PHA-activated cells increased over the last 24 h of culture h from 64 +/- 7 to 117 +/- 11.8 pg/10(6) cells (P < 0.001), there was no change in mean concentration of LHRH in T-cells kept in medium alone. In a preliminary study we found that fresh T-cells contain 20 +/- 1.4 pg pro-LHRH/10(6) cells, and PHA stimulation increased the pro-LHRH content similar to the increase in LHRH. As with unfractionated T-cells, a significant PHA-induced time-dependent enhancement of intracellular LHRH was noted in CD4+ and CD8+ T-cells. RNA extracted from lymphocytes was subjected to reverse transcription-polymerase chain reaction analysis using LHRH and histone-3.3, primers, the latter as an internal control. The polymerase chain reaction-generated data demonstrated that the relative amount of LHRH mRNA in cultured, but non-PHA-stimulated (resting), cells diminished dramatically between 5-24 h, but recovered by 48 h of culture. The relative amount of LHRH mRNA in PHA-stimulated cells revealed a markedly different pattern. LHRH message expression in PHA-activated cells increased slightly at 5 h of culture and was maximally stimulated by 24 h, but declined by 48 h of culture. The PHA activation-induced time-dependent enhancement of intracellular accumulation of LHRH peptide at 5 and 24 h was accompanied by increased LHRH message. However, the increased concentration of LHRH peptide at 48 h coincided with decreased LHRH message expression. The data from total protein synthesis in PHA-activated cells showed a progressive increase in protein synthesis, a pattern entirely similar to the changes in the cell content of LHRH.(ABSTRACT TRUNCATED AT 400 WORDS)

Heart disease, even in the elderly individual, need not preclude driving; however, safety for the patient and the public is dependent on close cooperation between the patient and the physician. The patient with ischemic heart disease must be in a stable condition wherein the risk of sudden incapacitation is acceptably low. The physician must take into consideration not only the symptom history, but also the potential impact of concomitant illnesses, devices (e.g., pacemakers), and medications. The patient with congestive heart failure must be assessed for functional ability. Where there is doubt about a subjective report, a practical road test may be advisable. Consideration also should be given to limited driving under preset conditions, such as daytime only, or local roads (excluding highways). Many elderly drivers already limit their driving in such a fashion. Finally, it should be realized that a driving permit is a means to independent mobility. Where heart disease precludes driving and personal transportation is not available, physicians should advise and support their patients to obtain paratransport services where communities offer such services for otherwise immobile citizens.

Pursuant to our report of an immunoreactive and bioactive luteinizing hormone-releasing hormone (LHRH)-like molecule in rat spleen lymphocytes, we sought to determine whether these cells were capable of synthesizing LHRH by determining whether lymphocytes contain LHRH mRNA. To do this, total RNA was extracted from hypothalamic tissue, anterior pituitaries and from lymphocytes, and then this was reverse transcribed to cDNA and amplified via the polymerase chain reaction (PCR) utilizing synthetic oligonucleotides bracketing a portion of the LHRH gene. Following gel electrophoresis a discrete band of the expected size of 375 base pairs was found in the hypothalamus (positive control), and in lymphocytes, but not in the anterior pituitary (negative control). Furthermore, after Southern blotting, a 32P-labelled LHRH cDNA, hybridized to the 375 base pair, was amplified in hypothalamus fragments and in lymphocytes, but not in anterior pituitary tissue. These data strongly suggest that LHRH, in addition to being an important neuropeptide, is an immune cell synthesized immunomodulator.

Previous works from our laboratory and others have shown that there is a PRL-like immunoreactive protein with immunological, chromatographic, and biological characteristics identical to those of pituitary PRL, and this is widely distributed in the rat central nervous system. Since pituitary PRL is important in controlling hypothalamic LHRH release, we have hypothesized that hypothalamic PRL-like immunoreactive protein might serve a similar role, that of an endogenous neuromodulator influencing hypothalamic LHRH release. To this end, we have examined the effect of PRL antiserum and normal rabbit serum on the release of immunoreactive LHRH from rat hypothalamic fragments cultured in vitro. In the first experiment, LHRH release from hypothalami of intact rats, bathed in PRL antiserum (1:200 in Krebs-Ringer bicarbonate buffer), was significantly lower than that from hypothalami bathed in normal rabbit serum (1:200 in Krebs-Ringer bicarbonate buffer) for 90 min of incubation. It was, however, possible that the PRL, immunoneutralized in the first experiment, was material that represented contamination from pituitary PRL. Therefore, we repeated the experiment using hypothalami from animals that had been hypophysectomized 2 weeks before death. Again, PRL antibody significantly inhibited the release of LHRH compared with that by hypothalami incubated in normal rabbit serum. Since testosterone is important to LHRH synthesis, a third experiment was carried out using hypothalami from hypophysectomized male rats that had been implanted sc with testosterone-containing capsules 72 h before death. By 72 h serum testosterone levels had normalized. PRL antibody added to medium containing hypothalamic explants from these animals substantially inhibited in vitro LHRH release, a pattern essentially similar to that seen in intact and hypophysectomized animals without testosterone replacement. From these studies we have concluded that hypothalamic PRL is an important neuromodulator that promotes the release of LHRH from the hypothalamus. Testosterone, at least under the experimental conditions employed, appears not to be essential in this hypothalamic PRL-LHRH interaction.

An interaction between the immune and endocrine systems has been long known. This association is further strengthened by the finding that splenic lymphocytes have the capacity to produce molecules similar to if not the same as classical hormones, including several members of the opiate family, PRL, GH, and neuropeptide Y. Because of such findings and because of information from other laboratories suggesting that LHRH might have direct effects upon the immune system, we hypothesized that immune cells themselves might contain LHRH. Lymphocytes were purified from spleens of intact adult male Sprague-Dawley rats and the cells were lysed with sodium hydroxide. The concentration of immunoreactive LHRH was 403 +/- 184 pg/20 X 10(6) lymphocytes. Increasing amounts of lymphocyte lysate displaced [125-I]LHRH from LHRH antibody in a manner parallel to that produced by synthetic hypothalamic LHRH, suggesting immunologic similarity between lymphocyte and hypothalamic LHRH. Lymphocyte LHRH-like immunoactivity coeluted from Nova-Pak C18 columns with synthetic hypothalamic LHRH. When lymphocyte lysates were applied to rat anterior pituitary cells in monolayer culture, significant stimulation of LHRH secretion was seen, from 2,144 +/- 54 pg LH/ml.4 h to 15,364 +/- 587 pg LH/ml.4 h (P less than 0.001), a finding verified in five additional experiments. In other studies, this LH response evoked by lymphocyte lysates was found to be dose dependent and could be significantly inhibited by an LHRH-antagonist. Furthermore, when lymphocyte lysate and identically treated synthetic LHRH were HPLC fractionated, there was coelution of lysate and hypothalamic LHRH bioactivity. The lysate itself contained no substantial LH immunoreactivity. Thus, lymphocytes from spleens of adult male rats contain an immunoactive and bioactive LHRH, a finding further strengthening an association between the endocrine and immune systems.

Although estrogen-induced prolactinomas have been widely studied, little attention has been accorded to local pressure effects of the tumor on the hypothalamus and portal vasculature. To portray the magnitude of this phenomenon, four groups of 12-13-week-old female Fisher 344 rats were studied. Group 1 was an intact control receiving a subcutaneously (SC) placed placebo pellet; group 2 was an ovariectomized control with a SC placed placebo pellet; group 3 was ovariectomized with a 10 mg SC placed diethylstilbestrol (DES) pellet; and group 4 was ovariectomized receiving both 10 mg DES and 10 mg SC placed bromocriptine pellets. Blood samples were obtained at 4 weeks, and the animals were sacrificed at 8 weeks after pellet implantation at which time blood, pituitary and hypothalami were obtained. At 4 weeks serum prolactin levels were similarly and significantly elevated above the control groups in both the DES and DES/bromocriptine groups. By 8 weeks, however, serum prolactin level(s) in the DES-treated animals had tripled from the 4-week value, while levels in the DES/bromocriptine-treated animals were unchanged from the 4-week values. This finding matched the observation that the DES-treated animals had pituitaries 2.5-fold heavier than the DES/bromocriptine animals. The gross and histologic structure of the hypothalami and portal vessels were markedly disrupted in DES-treated rats and much less so in the DES/bromocriptine-treated group. These findings lead us to speculate that the pathogenesis of DES-induced prolactinomas proceeds in two phases: First, there is an early chemical induction phase in which estrogen directly and indirectly stimulates lactotrope proliferation and, second, a mechanical disinhibition phase, where tumor-induced destruction of the hypothalamus and portal vessels unleashes the pituitary from the dopaminergic restraining effects of the hypothalamus.

Pursuant to our identification of prolactin-like immunoreactivity (PLI), widely distributed in rat brain, the spinal cord was examined for the presence of this pituitary-hormone-like protein. PLI was present in all spinal cord extracts examined and averaged 500 +/- 53 pg/mg protein. Hypophysectomy, causing a fall in serum prolactin to undetectable levels, was not associated with any change in levels of PLI in spinal cord. Recovery of rat prolactin standards added to spinal cord homogenates was 97.6 +/- 3.9%. When increasing concentrations of spinal cord extract were assayed in a prolactin radioimmunoassay, displacement of rat 125I-Prolactin from antiserum was parallel to that displacement produced by increasing concentrations of rat anterior pituitary standards. Upon subjection to gel permeation chromatography, the elution profiles of immunoreactive prolactin from spinal cord were different from the profiles of anterior pituitary prolactin. In addition to an immunoreactive prolactin peak eluting with pituitary prolactin, spinal cord extracts showed a large void volume peak and late eluting low-molecular-weight materials not seen with anterior pituitary. In the Nb2 lymphoma cell assay, all spinal cord extracts demonstrated prolactin-like bioactivity with a bioactivity/immunoreactivity ratio of 1.05 +/- 0.13. We conclude: (1) PLI, widely distributed in rat brain, is also present in spinal cord; (2) spinal cord prolactin levels are independent of levels in pituitary and peripheral circulation; (3) this immunoreactive prolactin is bioactive, and (4) differing gel permeation chromatographic elution profiles indicate that there may be some molecular differences between pituitary and spinal cord prolactin.