Relaxin concentrations in serum and urine of endangered and crazy mixed-up species.

The human population explosion has pushed many mammalian wildlife species to the brink of extinction. Conservationists are increasingly turning to captive breeding as a means of preserving the gene pool. We previously reported that serum immunoactive relaxin provided a reliable means of distinguishing between true and pseudopregnancy in domestic dogs, and this method has since been found to be a reliable indicator of true pregnancy in endangered Asian and African elephants and Sumatran rhinoceroses. Our canine relaxin radioimmunoassay (RIA) has now been adapted and validated to measure relaxin in the serum and urine of felids, including domestic and wild species. Moreover, a commercially available canine serum relaxin kit (Witness) Relaxin Kit; Synbiotics, San Diego, CA), has been adapted for reliable detection of relaxin in urine of some felid species. Our porcine relaxin RIA has also been utilized to investigate the role of relaxin in reproductive processes of the spotted hyena, a species in which the female fetuses are severely masculinized in utero. Indeed, this species might well now be extinct were it not for the timely secretion of relaxin to enable copulation and birth of young through the clitoris. Additional studies have suggested relaxin may be a useful marker of pregnancy in the northern fur seal and the maned wolf (the former species has been designated as "depleted" and the latter as "near threatened"). Given appropriate immunoassay reagents, relaxin determination in body fluids thus provides a powerful tool for conservationists and biologists investigating reproduction in a wide variety of endangered and exotic species.

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.

Endocrine differentiation of fetal ovaries and testes of the spotted hyena (Crocuta crocuta): timing of androgen-independent versus androgen-driven genital development.

Female spotted hyenas (Crocuta crocuta) have an erectile peniform clitoris and a pseudoscrotum but no external vagina, all established by day 35 of a 110-day gestation. Recent studies indicate that these events are androgen-independent, although androgen secretion by fetal ovaries and testis was hypothesized previously to induce phallic development in both sexes. We present the first data relating to the capacity of the ovaries and testes of the spotted hyena to synthesize androgens at different stages of fetal life. Specifically, spotted hyena fetal gonads were examined by immunohistochemistry at GD 30, 45, 48, 65, and 95 for androgen-synthesizing enzymes, as related to the morphological development. Enzymes included 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17), cytochrome b5, 3beta-hydroxysteroid dehydrogenase (3betaHSD), and cholesterol side-chain cleavage cytochrome P450 (P450scc). Anti-Müllerian-hormone (AMH) expression was also examined. AMH was strongly expressed in fetal Sertoli cells from GD 30 and after. P450c17 expression was detected in Leydig cells of developing testes and surprisingly in Müllerian duct epithelium. Fetal ovaries began to organize and differentiate by GD 45, and medullary cells expressed P450c17, cytochrome b5, 3betaHSD, and P450scc. The findings support the hypothesis that external genital morphology is probably androgen-independent initially, but that fetal testicular androgens modify the secondary, male-specific phallic form and accessory organs. Fetal ovaries appear to develop substantial androgen-synthesizing capacity but not until phallic differentiation is complete, i.e. after GD 45 based on circulating androstenedione concentrations. During late gestation, fetal ovaries and testes synthesize androgens, possibly organizing the neural substrates of aggressive behaviors observed at birth in spotted hyenas. These data provide an endocrine rationale for sexual dimorphisms in phallic structure and reveal a potential source of androgenic support for neonatal aggression in female and male C. crocuta.

The effect of cannabis on tremor in patients with multiple sclerosis.

BACKGROUND: Disabling tremor is common in patients with multiple sclerosis (MS). Data from animal model experiments and subjective and small objective studies involving patients suggest that cannabis may be an effective treatment for tremor associated with MS. To our knowledge, there are no published double-blind randomized controlled trials of cannabis as a treatment for tremor in MS patients. METHODS: The authors conducted a randomized double-blind placebo-controlled crossover trial to examine the effect of oral cannador (cannabis extract) on 14 patients with MS with upper limb tremors. There were eight women and six men, with a mean age of 45 years and mean Expanded Disability Status Scale score of 6.25. Patients were randomly assigned to receive each treatment and the doses escalated over a 2-week period before each assessment. The primary outcome was change on a tremor index, measured using a validated tremor rating scale. The study was powered to detect a functionally significant 50% improvement in the tremor index. Secondary outcomes included accelerometry, an ataxia scale, spiral drawing, finger tapping, and nine-hole pegboard test performance. RESULTS: Analysis of the data showed no significant improvement in any of the objective measures of upper limb tremor with cannabis extract compared to placebo. Finger tapping was faster on placebo compared to cannabis extract (p < 0.02). However, there was a nonsignificant trend for patients to experience more subjective relief from their tremors while on cannabis extract compared to placebo. CONCLUSIONS: Cannabis extract does not produce a functionally significant improvement in MS-associated tremor.

Target board test for the quantification of ataxia in tremulous patients.

OBJECTIVE: The objective was to develop and assess the validity and reliability of a target board test (TBT) for quantifying ataxia and measuring dysmetria in the presence of tremor. DESIGN: Each subject was instructed to reach out and mark a target placed at arm's length with a pen (10 times with each hand). Ten patients performed the test twice. SETTING: A hospital-based multiple sclerosis (MS) unit. SUBJECTS: Fifty-three patients with MS and upper limb tremor/ataxia and 20 healthy control subjects. The MS patients were classified into four subgroups: MS control group (n = 13), MS tremor group (n = 9), MS dysmetria group (n = 6), MS mixed (tremor and dysmetria) group (n = 25). MAIN OUTCOME MEASURES: The main outcome measures were the average radial distance away from the target (mean R) and the mean directional error (mean V) of the 10 contact points from the target. From these a dysmetria tremor index (DTI) was calculated by dividing mean V by mean R. Also used were a dysmetria scale, a dysdiadochokinesia scale and a finger-tapping test. RESULTS: Mean R correlated significantly with dysmetria, dysdiadochokinesia, kinetic tremor and (inversely) with the finger-tapping test (all p < 0.005). The median difference between two measurements of mean R for all 10 contact points was 11.3% and 19.0% and for mean V48.3% and 63.4% and DTI 57.2% and 50.5% for the right- and left-hand sides respectively, indicating the considerable directional variability within ataxia. CONCLUSION: The TBT provides simple quantitative objective measurements of upper limb ataxia.

Variation in ovarian morphology in four species of New World moles with a peniform clitoris.

Female moles of the Old World genus Talpa display a curious suite of reproductive features that include a peniform clitoris and ovaries with a discrete interstitial gland or testis-like region (so-called 'ovotestes'). The masculinization of the female external genitalia in Talpa has accordingly been linked with secretion of androgens from the interstitial gland region of the fetal gonad. Although their ovarian morphology has received less attention, some species of New World moles also have ovaries with a pronounced interstitial gland (for example star-nosed mole, Condylura cristata), whereas females of other species do not (for example eastern mole, Scalopus aquaticus). Although it is difficult to determine the sex of both Old and New World moles, published accounts describing the external genitalia of female moles are available only for Talpa. The hypothesis that masculinization of the female external genitalia in moles is associated with the presence of an ovarian interstitial gland (OIG) was tested in the present study by using a comparative approach to determine whether these features are ever found in isolation of one another. Three genera of North American moles (Scapanus, Condylura and Neurotrichus) were studied and a peniform clitoris was found in all three species, but OIG were found in only two of three genera. The ovaries of S. latimanus and S. orarius were unremarkable, with no evidence of a discrete interstitial gland or testis-like region. Mapping these results onto recent talpid phylogenies indicates that loss of the bipolar ovarian morphology is a derived trait in Scapanus, and conclusively demonstrates that masculinization of the external genitalia in female moles can develop in the presence or absence of 'ovotestes'.

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.

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.

Stereotactic lesional surgery for the treatment of tremor in multiple sclerosis: a prospective case-controlled study.

The effect of stereotactic lesional surgery for the treatment of tremor in multiple sclerosis was examined in a prospective case-controlled study. Surgery was not undertaken in 33 patients (72% of 46 cases referred for stereotactic surgery), two of whom died within 4 months of referral. Twenty-four multiple sclerosis patients were included in the study; 13 underwent surgery and were matched against 11 controls on the basis of age, sex, expanded disability system scores (EDSS) and disease duration. Assessments were carried out at baseline/preoperatively, and then 3 and 12 months later; these included accelerometric and clinical ratings of tremor, spirography, handwriting, a finger-tapping test, nine-hole peg test, tremor-related disability, general neurological examination, Barthel Activities of Daily Living (ADL) Index of general disability, EDSS, a 0-4 ataxia scale, Mini-Mental State (MMS) examination, speech and swallowing assessments and grip strength. Postoperative MRI scans demonstrated that tremor could be attenuated by lesions centred on the thalamus in seven cases, on the zona incerta in five cases and in the subthalamic nucleus in one case. Two patients developed hemiparesis and in two cases epilepsy recurred. Two surgical patients and one control patient died between the 3 and 6 months assessments. Both groups had a significant deterioration in EDSS but not Barthel ADL Index scores at 1 year, but the difference between the groups was not significant. Similarly, no differences between the groups' rates of deterioration of speech or swallowing or MMS were found. Significant improvements in contralateral upper limb postural (P2) and kinetic tremors, spiral scores and head tremor were detected at 3 and 12 months after surgery (but not handwriting or nine-hole peg test performance). Tremor-related disability and finger-tapping speed were also significantly better 12 months after surgery, the latter having significantly worsened for the control group. A 3 Hz 'filter' for postural (P2) upper limb tremor was detected by accelerometry/spectral analysis above which tremor was always abolished and at or below which some residual tremor invariably remained. Criteria for selecting multiple sclerosis patients for this form of surgery are discussed.

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.

Systemic effects of intravesical atropine sulphate.

OBJECTIVE: To investigate systemic antimuscarinic activity after the intravesical administration of 6 mg of atropine sulphate. SUBJECTS AND METHODS: Ten subjects were recruited to an open study in accordance with strict inclusion and exclusion criteria. Each subject received an instillation of 6 mg atropine sulphate diluted to 20 mL with normal saline. All variables were measured at baseline (before instillation) and the instilled solution retained for at least 2 h. After instillation systemic antimuscarinic activity was monitored every 20 min for 2 h then hourly for the next 4 h. The measurements included blood pressure, sublingual temperature, pulse rate, peak expiratory flow rate, lacrimation and salivation rates; all variables were analysed statistically. Facial skin was also observed for hyperaemia. All subjects were questioned about any known symptoms produced by antimuscarinic agents. The heart rate was recorded continuously before and after instillation using a Holter monitor. RESULTS: None of the variables changed significantly after instillation and the Holter analysis showed no relevant variation in heart rate. All subjects consistently denied any antimuscarinic symptoms. One subject had mild cutaneous hyperaemia, as reportedly occurred consistently when her bladder was distended (> 500 mL). Immediate catheterization drained 600 mL and the hyperaemia resolved. CONCLUSION: The failure to detect systemic antimuscarinic activity at a dose which has previously been shown to suppress detrusor activity suggests that intravesical atropine therapy is safe for further study by clinical trial, and might provide a treatment for detrusor hyper-reflexia that is free from side-effects.

Renal failure in patients with neurogenic lower urinary tract dysfunction.

People with multiple sclerosis, paraplegia and neural tube defects typically have neurogenic lower urinary tract dysfunction (NLUTD). This encompasses detrusor hyperreflexia with or without detrusor sphincter dyssynergia and hypo- or acontractility. Their effects undermine safe, effective and controlled storage and voiding of urine and predispose to reflux nephropathy. Therefore, patients in these diagnostic groups with NLUTD would be expected to have increased risk of renal failure. The aim of this study was to quantify this risk using the General Practice Research Database (GPRD). All patients registered in the database between 1994 and 1997 and aged 10-69 were included in the study. The prevalence and incidence of renal failure and renal replacement therapy in the general population was ascertained, as was the prevalence of multiple sclerosis, paraplegia and neural tube defects. The prevalence of renal failure in each of the special populations was then compared with the prevalence in the unaffected general population. The age-standardised prevalence of renal failure in the GPRD population aged 10-69 years was 14 per 10,000. The rate ratio of renal failure compared with the general population in each of the years 1994-1997 for neural tube defects ranged between males (M) 6.8-9.0 and females (F) 9.2-11.5, for paraplegia M 4.1-9.0, F 4.0-7.0, and for multiple sclerosis M 0.4-1.3, F 0.5-2.2. As expected, people with paraplegia or neural tube defects were found to have a substantially increased risk of renal failure compared with the general population. We could not demonstrate an increased risk of renal failure in people with multiple sclerosis. We believe this finding requires further study, but may reflect a problem in the recognition of renal failure in this group of patients. We recommend that all three patient groups should be regularly screened so that renal impairment may be detected prior to the development of renal failure.

A study of tremor in multiple sclerosis.

One hundred patients with definite multiple sclerosis, who were randomly selected from a multiple sclerosis unit in London, were examined in order to study the prevalence, subtypes, clinical features and associated disability of tremor in this population. There were 35 males and 65 females with an average age of 47 years and an average disease duration of 18.8 years. The mean tremor duration was 13 years, with a median latency of 11 years from disease onset to appearance of tremor. Tremor was reported in 37 patients but was detected in 58. Tremor affected the arms (56%), legs (10%), head (9%) and trunk (7%). There were no examples of face, tongue or jaw tremor. All the patients had action tremor, either postural or kinetic (including intention). Rest, Holmes' ('rubral') and primary orthostatic tremors were not encountered. Tremor severity ranged from minimal in 27%, to mild in 16% and moderate or severe in 15% of cases. Tremor severity correlated with the degree of dysarthria, dysmetria and dysdiadochokinesia but not with grip strength. In order to determine the clinical characteristics of these tremors, the action tremors of the upper limbs were subclassified according to the predominant site and state of tremulous activity. Of the 50 patients with tremor in the right arm, 32% had distal postural tremor, 36% had distal postural and kinetic tremor, 16% had proximal postural and kinetic tremor; 4% had proximal and distal postural and kinetic tremor and 12% isolated intention tremor. Twenty-seven percent of the overall study population had tremor-related disability and 10% had incapacitating tremor. Patients with abnormal tremor (severity grade >1/10) were more likely than those without tremor to be wheelchair dependent and have a worse Expanded Disability Systems Score, but Barthel activities of daily living indices and cognitive scores were comparable in the two groups.

Treatment of relative sialorrhoea with botulinum toxin type A: description and rationale for an injection procedure with case report.

This paper describes a technique for treatment of relative sialorrhoea by injection of botulinum toxin type A. It includes the rationale for treatment, a description of the regional anatomy, the physiological basis for treatment and the applied pharmacology of the drug. Included also is a case report which is intended to provide an illustration of the benefits of using this method for treating this condition.

A UK general practice database study of prevalence and mortality of people with neural tube defects.

OBJECTIVE: To investigate the prevalence of neural tube defects (NTDs) in the UK and to compare the mortality rate with that of the general population. METHODS: A cross-sectional study. The General Practice Research Database (GPRD) contains the prescribing and diagnostic records since 1990 of over 4 million people from throughout the UK. All patients aged 10-69 and registered on the database in the years 1994-1997 were included in the study. Patients with a diagnosis of NTD were identified from the database and prevalence and standardized mortality ratios in each year were calculated. RESULTS: The size of the GPRD reduced during the study period - there were 2116452 patients aged 10-69 years on the database in 1994, of whom 1751 had a prior record of NTD. In 1997 there were 998368 patients, of whom 842 had an NTD. The age standardized prevalence between 1994 and 1997 for NTDs ranged between 7.8 and 8.4 per 10000 for males and 9.0 and 9.4 per 10000 for females aged 10-69 years. There were 27 deaths in patients with a record of NTD over the four-year study period. The standardized mortality ratio for the years 1994 to 1997 for NTDs ranged between 1.9 and 2.9. CONCLUSIONS: These data give an estimate of the prevalence of NTDs in the general population. They also show that those who have survived to age 10 years still have double the mortality of the general population.

Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study.

OBJECTIVE: To define a safe and effective dose of Dysport for treating hip adductor spasticity. METHODS: Patients with definite or probable multiple sclerosis, and disabling spasticity affecting the hip adductor muscles of both legs, were randomised to one of four treatment groups. Dysport (500, 1000, or 1500 Units), or placebo was administered by intramuscular injection to these muscles. Patients were assessed at entry, and 2, 4 (primary analysis time-point), 8, and 12 weeks post-treatment. RESULTS: A total of 74 patients were recruited. Treatment groups were generally well matched at entry. The primary efficacy variables-passive hip abduction and distance between the knees-improved for all groups. The improvement in distance between the knees for the 1500 Unit group was significantly greater than placebo (p = 0.02). Spasm frequency was reduced in all groups, but muscle tone was reduced in the Dysport groups only. Pain was reduced in all groups, but improvements in hygiene scores were evident only in the 1000 Unit and 1500 Unit groups. Duration of benefit was significantly longer than placebo for all Dysport groups (p<0.05). Adverse events were reported by 32/58 (55%) Dysport patients, and by 10/16 (63%) placebo patients. Compared with the two lower dose groups, twice as many adverse events were reported by the 1500 Unit group (2.7/patient). The incidence of muscle weakness was higher for the 1500 Unit group (36%) than for placebo (6%). The response to treatment was considered positive by two thirds of the patients in the 500 Unit group, and by about half the patients in the other groups. CONCLUSION: Dysport reduced the degree of hip adductor spasticity associated with multiple sclerosis, and this benefit was evident despite the concomitant use of oral antispasticity medication and analgesics. Although evidence for a dose response effect was not statistically significant, there was a clear trend towards greater efficacy and duration of effect with higher doses of Dysport. Dysport treatment was well tolerated, with no major side effects seen at doses up to 1500 Units. The optimal dose for hip adductor spasticity seems to be 500-1000 Units, divided between both legs.

Evaluation of three different ways of assessing tremor in multiple sclerosis.

OBJECTIVES: To examine the comparative reliability and validity of three simple ways of rating upper limb tremor in patients with multiple sclerosis. METHODS: Three examiners independently rated severity of upper limb tremor in patients with multiple sclerosis on a 0-10 scale by studying videotape recordings of patients' examinations, spiral drawings, and handwriting samples. The correlations of the tremor severity scores with scores from arm dexterity tests and a tremor related disability scale were also assessed. RESULTS: Rating tremor on posture had a good intrarater and interrater reliability. However, these reliabilities decreased when kinetic tremor was assessed, in part because dysmetria was a confounding factor. The intrarater reliabilities of rating tremor from spirals and handwriting were also good but the interrater reliabilities were only fair to moderate. Tremor severity scored by all three methods correlated highly with scores obtained from the nine hole peg test, finger tapping test, and a tremor related activities of daily living (ADL) questionnaire, indicating that all three methods were valid ways of assessing tremor in multiple sclerosis. CONCLUSION: Multiple sclerosis tremors in posture can be scored using a clinical rating scale in a valid and reliable way, and from spirals and handwriting samples if the ratings are carried out by the same examiner. However, scoring kinetic tremor was less reliable. In addition, the nine hole peg and finger tapping tests provide useful objective assessments of upper limb function in tremulous patients with multiple sclerosis.

Urinary retention in patients with BPH treated with finasteride or placebo over 4 years. Characterization of patients and ultimate outcomes. The PLESS Study Group.

OBJECTIVES: Knowledge regarding the incidence and prevalence of acute urinary retention and the ultimate outcome is very limited. The purpose of the present analysis was to document the natural history and outcomes of acute urinary retention (AUR) further specified as being either precipitated or spontaneous, and to evaluate the potential benefit of finasteride therapy. MATERIALS AND METHODS: Three thousand and forty men with moderate to severe symptoms of BPH and enlarged prostate glands by digital rectal examination were enrolled into the 4-year placebo-controlled PLESS trial and were evaluated for occurrences of AUR and BPH-related surgery. Men in the study were seen every 4 months; discontinued patients were followed up 6 months after discontinuation and again at the end of the 4-year trial. Complete 4-year data on outcomes (occurrence of AUR or BPH-related surgery) was available for 92% of the enrolled subjects in each treatment group. An endpoint committee, blinded to treatment group and center, reviewed and categorized all study-related documentation relating to retention and surgery. RESULTS: Over the 4-year period, 99 of 1,503 placebo-treated patients (6.6%) experienced one or more episodes of AUR in comparison with 42 or 1,513 finasteride-treated patients (2.8%; p<0. 001). Approximately half of the episodes of retention were spontaneous and clearly BPH-related, while the other episodes were precipitated by another factor (PAUR). After spontaneous AUR, subsequent surgery was performed in 39 of 52 (75%) placebo-treated patients versus 8 of 20 (40%) finasteride-treated patients (p = 0. 01). BPH-related surgery was less common in men who had a prior episode of PAUR (26% in the placebo group and 14% in the finasteride group). CONCLUSION: There is a continual risk of spontaneous and precipitated acute urinary retention in men with moderate to severe lower urinary tract symptoms and an enlarged prostate gland. Fewer patients who developed precipitated AUR than spontaneous AUR go on to need subsequent BPH-related surgery. Significantly fewer finasteride-than placebo-treated patients developed AUR, and among those men, fewer ultimately needed BPH-related surgery.

Nitric oxide biomarkers increase during exercise-induced vasodilation in the forearm.

The purpose of the study was to determine if exercise-induced vasodilation was associated with an increase in forearm plasma levels of nitric oxide (NO) biomarkers (NO2- + NO3- and L-citrulline). Twelve healthy subjects (27+/-6 yrs) performed incremental rhythmic forearm exercise with the nondominant hand for 6 min each at 15, 30 and 45% of maximal voluntary contraction (MVC). Forearm blood flow (FBF) was determined in the exercise arm using venous occlusion plethysmography. Blood samples were obtained from the antecubital vein of the exercise and nonexercise arms for the measurement of NO biomarkers. In the exercise arm, FBF increased by a mean of 150%, 335% and 585% above baseline at 15, 30 and 45% of MVC, respectively. (ANOVA, P= 0.0001). Venous plasma NO2- + NO3- levels increased from 24+/-4 micromol/L at baseline, to 29+/-5, 32+/-4 and 3+/-4 micromol/L (ANOVA, P = 0.0001). Venous plasma L-citrulline levels increased from 31+/-5 micromol/L at baseline to 58+/-10, 87+/-7 and 141+/-15 micromol/L (ANOVA, P = 0.0001). There was a linear relationship between FBF and venous plasma NO2- + NO3- (slope= 0.38+/-0.10, P=0.0007) and between L-citrulline, (slope= 5.1 +/-1.3, P = 0.0004). Venous plasma levels of NO2- + NO3- and L-citrulline in the nonexercise arm were unchanged. These results demonstrate that exercise-induced vasodilation in the forearm is associated with forearm plasma levels of NO2- + NO3- and L-citrulline, in vivo markers of NO production.