Fatal sibling aggression, precocial development, and androgens in neonatal spotted hyenas.

Fatal neonatal sibling aggression is common in predatory birds but has not been previously reported in wild mammals. Spotted hyena females are strongly masculinized, both anatomically and behaviorally, apparently by high levels of androgens during ontogeny. Neonates display elevated androgen levels, precocial motor development, and fully erupted front teeth. Litters are usually twins, and siblings fight violently at birth, apparently leading to the death of one sibling in same-sex litters, whereas in mixed-sex litters both siblings usually survive.

A mechanism for virilization of female spotted hyenas in utero.

Female spotted hyenas exhibit male-like genitalia and dominance over males. Hyena ovarian tissues incubated in vitro produced large quantities of the steroid hormone precursor androstenedione. The activity of aromatase, which converts androstenedione to estrogen, was one-twentieth as great in hyena versus human placental homogenates. In comparison, the activity of 17 beta-hydroxysteroid dehydrogenase, which converts androstenedione to testosterone, was equal in the two homogenates. The limited aromatase activity may allow the hyena placenta to convert high circulating concentrations of androstenedione to testosterone, which results in virilization of the fetal external genitalia and possibly destruction of fetal ovarian follicles. Androstenedione production by residual ovarian stromal cells during reproductive life accounts for the epigenetic transmission of virilization in female spotted hyenas.

Placental expression and molecular characterization of aromatase cytochrome P450 in the spotted hyena (Crocuta crocuta).

At birth, the external genitalia of female spotted hyenas (Crocuta crocuta) are the most masculinized of any known mammal, but are still sexually differentiated. Placental aromatase cytochrome P450 (P450arom) is an important route of androgen metabolism protecting human female fetuses from virilization in utero. Therefore, placental P450arom expression was examined in spotted hyenas to determine levels during genital differentiation, and to compare molecular characteristics between the hyena and human placental enzymes. Hyena placental P450arom activity was determined at gestational days (GD) 31, 35, 45, 65 and 95 (term, 110), and the relative sensitivity of hyena and human placental enzyme to inhibition by the specific inhibitor, Letrozole, was also examined. Expression of hyena P450arom in placenta was localized by immuno-histochemistry, and a full-length cDNA was cloned for phylogenetic analysis. Aromatase activity increased from GD31 to a peak at 45 and 65, apparently decreasing later in gestation. This activity was more sensitive to inhibition by Letrozole than was human placental aromatase activity. Expression of P450arom was localized to syncytiotrophoblast and giant cells of mid-gestation placentas. The coding sequence of hyena P450arom was 94% and 86% identical to the canine and human enzymes respectively, as reflected by phylogenetic analyses. These data demonstrate for the first time that hyena placental aromatase activity is comparable to that of human placentas when genital differentiation is in progress. This suggests that even in female spotted hyenas clitoral differentiation is likely protected from virilization by placental androgen metabolism. Decreased placental aromatase activity in late gestation may be equally important in allowing androgen to program behaviors at birth. Although hyena P450arom is closely related to the canine enzyme, both placental anatomy and P450arom expression differ. Other hyaenids and carnivores must be investigated to determine the morphological and functional ancestral state of their placentas, as it relates to evolutionary relationships among species in this important taxonomic group.

A continuing survey of drug-resistant tuberculosis, New York City, April 1994.

BACKGROUND: A 1991 survey showed high levels of drug resistance among tuberculosis patients in New York, NY. As a result, the tuberculosis control program was strengthened, including expanded use of directly observed therapy and improved infection control. METHODS: We collected isolates from every patient in New York City with a positive culture for Mycobacterium tuberculosis during April 1994; results were compared with those in the April 1991 survey. RESULTS: From 1991 to 1994, the number of patients decreased from 466 to 332 patients. The percentage with isolates resistant to 1 or more antituberculosis drugs decreased from 33% to 24% (P < .01); with isolates resistant to at least isoniazid decreased from 26% to 18% (P < .05); and with isolates resistant to both isoniazid and rifampin decreased from 19% to 13% (P < .05). The number of patients with isolates resistant to both isoniazid and rifampin decreased by more than 50%. Among never previously treated patients, the percentage with resistance to 1 or more drugs decreased from 22% in 1991 to 13% in 1994 (P < .05). The number of patients with consistently positive culture results for more than 4 months decreased from 130 to 44. A history of antituberculosis treatment was the strongest predictor of drug resistance (odds ratio = 3.1; P < .001). Human immunodeficiency virus infection was associated with drug resistance among patients who never had been treated for tuberculosis. CONCLUSIONS: Drug-resistant tuberculosis declined significantly in New York City from 1991 to 1994. Measures to control and prevent tuberculosis were associated with a 29% decrease in the proportion of drug resistance and a 52% decrease in the number of patients with multidrug-resistant tuberculosis.

Androgen metabolism by isolated hairs from women with idiopathic hirsutism is usually normal.

We have tested the hypothesis that idiopathic hirsutism (IH) may be due to abnormality of androgen-responsive hair follicles. Because androgen metabolism within target cells is an important determinant of androgen action, we have analyzed the rates of formation and disposition of the major mediators of androgen action, testosterone (T) and dihydrotestosterone (DHT). In normal women, the pattern of androgen metabolism by growing hairs favors T predominance over DHT and inactivation of both these 17 beta-hydroxysteroids to 17-ketosteroids. This pattern results greatly from predominance of 17 beta-hydroxysteroid dehydrogenation. For example, in normal women's scalp hair, DHT disposition to 5 alpha-androstanedione proceeded at the rate of 8.6 +/- 2.0 (SEM) %/micrograms DNA/min, whereas DHT was formed from T at a rate of 0.14 +/- 0.02, and T was formed from androstenedione at a rate of 0.60 +/- 0.12, all significantly different from one another. Both the formation of 17-ketosteroids and the apparent 5 alpha-reductase activity were exaggerated in the pubic hair of men; whether these differences are site-, sex-, or androgen-related, remains to be determined. Pubic hairs tended to metabolize androgens at a greater rate than did scalp hair. This was related to the significantly greater DNA content of plucked pubic hairs, a difference unrelated to sex or androgen levels. Women with IH had heterogeneous pubic hair abnormalities. Only 1 of the 4 IH patients studied had abnormal pubic hair follicle androgen metabolism, with the greatest abnormality being an exaggerated rate of 17 beta-hydroxysteroid inactivation to 17-ketosteroids. Two of the other 3 IH cases had increased DNA content of plucked pubic hairs, a different kind of exaggeration of normal, which suggests an abnormality of hair follicle growth unrelated to androgen sensitivity. We favor the concept that IH is related to various distinct types of sexual hair abnormalities which reflect fundamental defects in the regulation of hair growth.

Multiple androgenic abnormalities, including elevated free testosterone, in hyperprolactinemic women.

To investigate the basis of the hirsutism and elevated plasma dehydroepiandrosterone (DHA) and/or DHA sulfate (DHAS) in hyperprolactinemic women, we measured androgen binding parameters and an extensive profile of plasma androgens in normal (NL) and hyperprolactinemic women (HYPRL). ACTH tests and dexamethasone (dex) suppression tests were performed in subgroups. Free testosterone levels were higher in HYPRL (13.1 +/- 23.3 vs. 7.18 +/- 0.72 pg/ml; P less than 0.025), although total testosterone was comparable. This disparity was related to plasma testosterone-estradiol-binding globulin (TEBG) levels being one third lower in HYPRL (mean +/- SE, 27.4 +/- 4.0 nM) than in NL (41.2 +/- 3.7 nM; P less than 0.0125). Less striking elevations of plasma DHAS, androstenedione, and 11-deoxycortisol were found in HYPRL. Plasma total dihydrotestosterone [17 beta-hydroxy-5 alpha-androstan-3-one (tDHT)] was nearly 30% lower in HYPRL (11.2 +/- 2.6 ng/dl) than in NL (15.6 +/- 1.3 ng/dl; P less than 0.025), whereas free DHT was normal. Ratios of tDHT to precursors were lower in HYPRL (P less than 0.005). After ACTH stimulation, hyperresponsiveness of 17-hydroxyprogesterone and androstenedione were observed. Apparent adrenal enzyme efficiencies, judged from post-ACTH product to precursor ratios, were normal in HYPRL with one exception: the ratio of tDHT to total testosterone at 4 h was lower (P less than 0.05). Dex suppression normalized androgens and obliterated the abnormal tDHT to precursor ratios. These findings suggest an ACTH dependency of the abnormalities. In summary, we find that about 40% of HYPRL have an androgenic abnormality, and the most characteristic abnormality is an elevated free testosterone level (abnormal in 43%). Depressed TEBG and high DHAS levels were found with lesser frequency (19-21%). The plasma tDHT concentration was low, both in absolute terms and relative to its precursors. Dex suppressibility of the hyperandrogenemia was also observed. We postulate that PRL may exert multiple effects on steroid secretion and metabolism. Possibilities include the inhibition of the TEBG level.

Sexual dimorphism of perineal muscles and motoneurons in spotted hyenas.

Female spotted hyenas are known for their male-like genitalia, high levels of aggression, and dominance over males, characteristics which are attributed to exposure to elevated levels of testosterone in utero. Although the nervous system of spotted hyenas has not previously been examined, one might predict that neural systems which are sexually dimorphic in other mammals would be monomorphic in this species. Spinal motoneurons which innervate muscles associated with the phallus are located in Onuf's nucleus and are more numerous in males than in females in a wide array of mammals. Onuf's nucleus was examined in adult and neonatal spotted hyenas and, contrary to expectation, was found to be sexually dimorphic in the typical mammalian pattern: Males have significantly more motoneurons in Onuf's nucleus than do females. This dimorphism was correlated with a previously undescribed dimorphism in the relevant target musculature. Specifically, the morphology of the bulbocavernosus muscle is distinctly different in male and female spotted hyenas. Pregnant hyenas were treated with anti-androgen in an attempt to interfere with the actions of androgen during fetal development. Motoneuron number in Onuf's nucleus and the morphology of the bulbocavernosus muscle were feminized in males exposed to anti-androgen in utero.

Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity.

During the course of our investigations in the oxazolidinone antibacterial agent area, we have identified a subclass with especially potent in vitro activity against mycobacteria. The salient structural feature of these oxazolidinone analogues, 6 (U-100480), 7 (U-101603), and 8 (U-101244), is their appended thiomorpholine moiety. The rational design, synthesis, and evaluation of the in vitro antimycobacterial activity of these analogues is described. Potent activity against a screening strain of Mycobacterium tuberculosis was demonstrated by 6 and 7 (minimum inhibitory concentrations or MIC's < or = 0.125 micrograms/mL). Oxazolidinones 6 and 8 exhibit MIC90 values of 0.50 micrograms/mL or less against a panel of organisms consisting of five drug-sensitive and five multidrug-resistant strains of M. tuberculosis, with 6 being the most active congener. Potent in vitro activity against other mycobacterial species was also demonstrated by 6. For example, 6 exhibited excellent in vitro activity against multiple clinical isolates of Mycobacterium avium complex (MIC's = 0.5-4 micrograms/mL). Orally administered 6 displays in vivo efficacy against M. tuberculosis and M. avium similar to that of clinical comparators isoniazid and azithromycin, respectively. Consideration of these factors, along with a favorable pharmaco-kinetic and chronic toxicity profile in rats, suggests that 6 (U-100480) is a promising antimycobacterial agent.

Optimum processing protocols for volume determination of the liver and spleen from SPECT imaging with technetium-99m sulfur colloid.

A study of the effects of processing parameters on the determination of liver and spleen volume from SPECT data was performed. A method for volume determination using a threshold algorithm was calibrated against phantoms and applied to 60 patient studies. Good reproducibility was found using different projections and computing the volume on separate days. Variations of the measured volumes with the threshold value, reconstruction filter cutoff frequency and attenuation correction were investigated. Reconstruction parameters producing best image quality were also determined. A threshold of 25% of the maximum value in the organ was determined from phantom studies. Changes of 1% around this value yielded changes of 2-3% in the computed volume. No significant change was noted as cutoff frequencies varied between 0.4 and 0.85 of Nyquist (0.031 to 0.066 cycles/cm) for a third order Butterworth filter. Attenuation correction produced a decrease of 9% and 6% in liver and spleen measured volume respectively. Best image quality was obtained with 0.4 Nyquist (0.031 cycles/cm) cutoff frequency for third order Butterworth filter and attenuation correction. It is concluded that optimal parameters must be determined for any processing protocol, and must then be adhered to in future applications to insure clinical accuracy, especially those parameters demonstrating the most quantitative and qualitative sensitivity.

Exposure to naturally circulating androgens during foetal life incurs direct reproductive costs in female spotted hyenas, but is prerequisite for male mating.

Among all extant mammals, only the female spotted hyena (Crocuta crocuta) mates and gives birth through the tip of a peniform clitoris. Clitoral morphology is modulated by foetal exposure to endogenous, maternal androgens. First births through this organ are prolonged and remarkably difficult, often causing death in neonates. Additionally, mating poses a mechanical challenge for males, as they must reach an anterior position on the female's abdomen and then achieve entry at the site of the retracted clitoris. Here, we report that interfering with the actions of androgens prenatally permanently modifies hyena urogenital anatomy, facilitating subsequent parturition in nulliparous females who, thereby, produce live cubs. By contrast, comparable, permanent anatomical changes in males probably preclude reproduction, as exposure to prenatal anti-androgens produces a penis that is too short and has the wrong shape necessary for insertion during copulation. These data demonstrate that the reproductive costs of clitoral delivery result from exposure of the female foetus to naturally circulating androgens. Moreover, the same androgens that render an extremely unusual and laborious process even more reproductively costly in the female are apparently essential to the male's physical ability to reproduce with a normally masculinized female.

Radionuclide evaluation of liver transplants.

Orthotopic liver transplantation is now an established technique for treating patients with various forms of end stage liver disease. The number of centers performing the procedure is increasing and, as the number of transplant recipients in the population increases, many institutions performing nuclear medicine studies will be confronted with requests to evaluate these patients. While a variety of radionuclides are proving useful in this evaluation, the 99mTc iminodiacetic acid (IDA) compounds, particularly 99mTc diisopropyl IDA (DISIDA), will probably account for the majority of radionuclide evaluations of these patients because they are well suited to monitor both structural and functional changes of the graft. The primary application of radionuclide studies is focused in the postoperative period, when problems with the vascular and biliary anastomoses, rejection, infections, and bile leaks all produce alterations in radionuclide hepatobiliary studies. Abnormalities such as rejection and infection produce primarily functional, rather than structural changes and are not easily differentiated based upon the kinetics of 99mTc-DISIDA extraction and excretion by the liver, serial imaging and correlation with clinical data is necessary in such situations. Quantitative analyses of kinetic 99mTc IDA (DISIDA) studies and quantitative approaches with other compounds such as 99mTc galactosyl-neoglycoalbumin (NGA) may permit better assessments of relatively subtle changes in liver function in the posttransplant period.

Virilization of the female spotted hyena cannot be explained by alterations in the amino acid sequence of the androgen receptor (AR).

The external genitalia of the female spotted hyena are male in character, consistent with virilization by androgens during embryogenesis that results in the fusion of the vaginal labia to form a pseudo scrotum and enlargement of the clitoris to form a phallus. Explanations advanced to account for these anatomic differences have centered on the production or metabolism of androgens in utero or on abnormalities of the androgen receptor (such as a constitutively active AR). The structure of the spotted hyena AR was examined at the level of genomic DNA and cDNA. Southern analysis detected two Eco RI endonuclease cleavage fragments (4.4 and 4.7 kb) that encode the bulk of the AR hormone-binding domain. Isolation of the smaller fragment from a size fractionated genomic library revealed that it contained exons 6, 7 and 8. The remaining portions of the coding sequence were cloned by RT-PCR and RACE analyses. The spotted hyena cDNA sequence predicts protein 912 amino acids in length, which is most closely related to the sequence of the dog AR. Although a number of differences in the predicted amino acid sequence are identified, particularly within the amino terminus, only single amino acid substitutions are present in the DNA- and ligand-binding domains compared to the human AR. In transfection assays, the spotted hyena AR does not exhibit constitutive activity and responds normally to a range of androgenic and non-androgenic ligands. These findings suggest that the structural changes in the AR do not account for the abnormal virilization in the female spotted hyena. These results serve to focus attention on processes proximal (an abnormality of hormone formation in situ) or distal (activation by other mechanisms of processes normally regulated by androgen) to the AR as the cause of the virilization.

Pathophysiology and management of bowel dysfunction in multiple sclerosis.

The prevalence of bowel dysfunction in multiple sclerosis (MS) patients is higher than in the general population. Up to 70% of patients complain of constipation or faecal incontinence, which may also coexist. This overlap can relate to neurological disease affecting both the bowel and the pelvic floor muscles, or to treatments given. Bowel dysfunction is a source of considerable ongoing psychosocial disability in many patients with MS. Symptoms related to the bladder and the bowel are rated by patients as the third most important, limiting their ability to work, after spasticity and incoordination. Bowel management in patients with MS is currently empirical. Although general recommendations include maintaining a high fibre diet, high fluid intake, regular bowel routine, and the use of enemas or laxatives, the evidence to support the efficacy of these recommendations is scant. This review will examine the current state of knowledge regarding the pathophysiological mechanisms underlying bowel dysfunction in MS, outline the importance of proper clinical assessment of constipation and faecal incontinence during the diagnostic work-up, and propose various management possibilities. In the absence of clinical trial data on bowel management in MS, these should be considered as a consensus on clinical practice from a team specialized in bowel dysfunction.

Scent marking (pasting) in a colony of immature spotted hyenas (Crocuta crocuta): a developmental study.

Pasting, a stereotypic form of anal gland scent marking, was studied in 2 cohorts (N = 20) of captive spotted hyenas (Crocuta crocuta). A significant increment in the frequency of pasting occurred in both cohorts as the animals approached sexual maturity; however, gonadectomy during the early juvenile age period had no significant effects on subsequent pasting frequency. Dominant hyenas in both cohorts tended to scent-mark more frequently than subordinates during the late subadult period. Pasting was facilitated by the immediately preceding pasting activities of other hyenas, as has been reported to occur in nature, and olfactory investigation was the most common behavior preceding pasting.

The effect of aerobic exercise on self-esteem and depressive and anxiety symptoms among breast cancer survivors.

PURPOSE/OBJECTIVES: To evaluate the effects of 10 weeks of aerobic exercise on depressive and anxiety symptoms and self-esteem of breast cancer survivors. DESIGN: Experimental, crossover. SETTING: Midwestern university town. SAMPLE: Twenty-four breast cancer survivors (mean time following surgery 41.8 months; ranging from 1 to 99 months) recruited via mail and cancer support groups. The mean age of the sample was 48.9 years. METHODS: Subjects were assigned randomly into exercise (EX), exercise-plus-behavior modification (EX + BM), and control groups. EX and EX + BM groups exercised aerobically four days/week at > or = 60% of age-predicted maximum heart rate for 10 weeks. Data were collected pretest, post-test, and crossover (12 weeks following post-test). Because pretest or post-test scores showed no statistical differences between EX and EX + BM groups, data were combined to form one group. MAIN RESEARCH VARIABLES: Aerobic exercise (four days/ week; 30-40 minutes/session), depression, (Beck Depression inventory), anxiety (Speilberger State-Trait Anxiety Inventory), and self-esteem (Rosenberg Self-Esteem Inventory). FINDINGS: Pre- to post-test analyses revealed that women who exercised had significantly less depression and state and trait anxiety over time compared to controls. After the crossover, the control group demonstrated comparable improvements in both depressive and state anxiety scores. Self-esteem did not change significantly. Subjects who received exercise recommendations from their physicians exercised significantly more than subjects who received no recommendation. CONCLUSIONS: Mild to moderate aerobic exercise may be of therapeutic value to breast cancer survivors with respect to depressive and anxiety symptoms but not to self-esteem. A physician's recommendation to exercise appears to be an important factor in a patient's exercise adherence. IMPLICATIONS FOR NURSING PRACTICE: To Improve depressive and anxiety symptoms following breast cancer surgery, healthcare professionals should consider recommending mild to moderate exercise.

Pressure sore prevention in hospital patients: a clinical audit.

Pressure sores cause significant mortality and morbidity as well as being a financial burden on health-care services. Reduction of pressure sore incidence is a Department of Health priority. Pressure sores are accepted as largely preventable complications of illness and disability and the means to achieve prevention are available. The aim of this clinical audit was to identify potential contributing factors to pressure sore acquisition in an acute hospital setting. The results suggest that substantial changes in the approach to clinical management may be needed.

Medical considerations and planning for short distance road races.

Short distance road races are popular in most communities, and athletic trainers are often asked to coordinate the medical coverage for such events. The medical support needed to successfully cover marathons, triathlons, and other endurance events has been well documented. However, little information has been presented regarding medical considerations for shorter distance races. Heat illness is often seen in short distance races, especially when the environmental conditions are extreme. Successful coverage of races of any length includes thorough planning and preparation, adequate supplies, and competent personnel. Medical coverage includes organizing the medical tent at the finish line, selecting appropriate protocols for treatment, and identifying a physician who will act as the race's medical director. It may also be necessary to provide medical coverage on the race course, at other areas, and at the finish line. The purpose of this paper is to inform the medical community, and athletic trainers in particular, of some of the details that should be considered when planning race coverage. The information detailed within may also be applied to other sports-related medical coverage provided by athletic trainers.

Investing: reducing risks to enhance returns.

The financial assets of a healthcare organization can present many opportunities for investment. In order to develop a profitable investment program that avoids risky speculation, however, healthcare financial managers must fully understand the nature and risks of their organizations' investments. They must define and monitor their investment objectives, limitations, levels of acceptable risk and policies and conditions through a statement of investment policy and comprehensive investment guidelines.