Differential effect of 5 alpha-reductase inhibition and castration on androgen-regulated gene expression in rat prostate.

Castration reduces prostate size and causes intraprostatic testosterone (T) and dihydrotestosterone (DHT) to fall to very low levels. 5 alpha-Reductase inhibition also reduces prostate size, but results in a marked increase in intraprostatic T levels. To compare the effects of 5 alpha-reductase inhibition and castration on prostate physiology, male Sprague-Dawley rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride for up to 9 days. To be sure that finasteride itself did not directly affect gene expression, an additional group of rats was castrated and given finasteride for 4 days. The prostates were weighed, intraprostatic RNA, DNA, and androgen levels were measured, and mRNAs for two androgen-regulated genes, prostate steroid-binding protein (PSBP; an androgen-induced gene) and testosterone-repressed prostate message (TRPM-2), were quantitated by Northern and slot blot analyses. Finasteride caused a 95% reduction in intraprostatic DHT levels and a 10-fold increase in intraprostatic T levels. Finasteride, as expected, caused a pronounced decrease in prostate weight (45% on day 4). DNA content fell correspondingly (48% on day 4). Intraprostatic DNA (micrograms of DNA per gland) on day 4 was 328 +/- 53 in control rats, 171 +/- 10 in finasteride-treated rats (P less than 0.001 compared to controls), 115 +/- 2 in castrated rats (P less than 0.05 compared to finasteride), and 107 +/- 43 in finasteride-treated plus castrated rats (P = NS compared to castration alone). There were no significant differences in DNA levels among the groups when expressed per mg prostate tissue, indicating that mean prostate cell size was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for atrophy and apoptosis in the ventral prostate of rats given the 5 alpha-reductase inhibitor finasteride.

Castration causes cell loss in the rat ventral prostate through a process called apoptosis. Although 5 alpha-reductase inhibition also causes prostate cell loss, the mechanisms involved have been debated. To investigate this question further, we have evaluated the histological responses of the rat ventral prostate to both castration and 5 alpha-reductase inhibition. Rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride. After 4, 9, 14, and 21 days the prostates were excised, the androgen and DNA content determined, and the tissue was subjected to histological and histomorphometric analysis. Finasteride and castration decreased prostate weight at day 21 by 65% and 93%, respectively. Castration decreased DNA content (micrograms per prostate) by a maximum of 88% at 14 days. Finasteride had no significant effect on DNA content after 4 days and decreased DNA content by a maximum of 52% at 14 days. When castrate prostate sections were stained for tissue transglutaminase, a marker of apoptotic cell death, a maximum of 23% of epithelial cells were stained by day 14 with a return to control levels by day 21. Finasteride caused a less intense increase in staining in which 16% of epithelial cells stained for tissue transglutaminase on day 9 with a return to baseline by day 14. When prostate sections were stained for DNA breaks, another marker of cell death, castration, caused a peak of staining on day 4 with 6% of epithelial cells staining and a return to near control levels by day 21. Finasteride-induced staining was less intense with peak staining at day 4 (0.7% of epithelial cells) and a return to control values by day 9. Morphometrics were used to assess the effect of castration and finasteride on prostate duct size and epithelial cell mass. After 4 days of finasteride treatment, the mean ductal mass decreased by 47%, with no significant change thereafter. The mean epithelial cell mass decreased by 15% on day 4 and 60% on day 9, with no further decrease thereafter. Castration caused a more rapid and greater decrease in both morphometric parameters with a 95% reduction in the mass of prostate ducts and a 93% decrease in epithelial cell mass by day 9. We conclude that castration induces a more profound involution of the rat ventral prostate than does 5 alpha-reductase inhibition. Cell loss occurs in both groups, but the degree of cell loss is less with finasteride.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for atrophy and apoptosis in the prostates of men given finasteride.

Finasteride, a 5 alpha-reductase inhibitor, decreases prostate size and improves symptoms in men with benign prostatic hyperplasia. However, little is known about prostate histopathology in men taking finasteride. To determine the mechanism by which finasteride reduces prostate size, tissue was collected at the time of prostatectomy from men taking either no medication (n = 10) or 5 mg finasteride daily for 6-18 days (n = 6; group 1), 23-73 days (n = 5; group 2), or 3 months to 4 yr (n = 5; group 3). To assess whether finasteride causes epithelial atrophy, morphometric measurement of epithelial cell and duct width was used. The mean epithelial cell width in control prostates (mean +/- SEM, 21 +/- 0.7 microns) decreased with duration of treatment to 19 +/- 1 microns in group 1, 15 +/- 2 microns in group 2, and 8 +/- 0.3 microns in group 3. Mean duct width decreased from 135 +/- 6 microns in the control prostates to 128 +/- 10 microns in group 1, 103 +/- 3 microns in group 2, and 63 +/- 6 microns in group 3. To assess whether prostate cell death was occurring, sections were in situ end labeled for DNA breaks and immunostained for tissue transglutaminase (tTG), a marker of apoptosis (programmed cell death). The percentage of epithelial cells staining for DNA breaks was 0.4 +/- 0.2 in control prostates, 2.8 +/- 0.9 in group 1, 1.7 +/- 0.5 in group 2, and 0.7 +/- 0.3 microns in group 3. Anti-tTG staining of epithelial cells was graded on a scale of 0-4. In control prostates, 3 +/- 1% of the ducts were grade 3 or 4 (> 50% of epithelial cells staining). In finasteride-treated prostates, 2 +/- 2% of the prostates in group 1, 13 +/- 4% of the prostates in group 2, and 0.5 +/- 0.5% of the prostates in group 3 were grade 3-4. These results indicate that a progressive decrease in epithelial cell size and function occurs during the first several months in the prostates of men treated with finasteride. The staining for DNA breaks and the tTG staining also indicate that an increased rate of apoptosis is occurring transiently in these prostates. We conclude that finasteride causes prostate involution through a combination of atrophy and cell death.

Androstanediol glucuronide production in human liver, prostate, and skin. Evidence for the importance of the liver in 5 alpha-reduced androgen metabolism.

Androstanediol glucuronide (Adiol G) has been reported to be a marker of peripheral androgen metabolism and action. It consists of two isomers, Adiol 3-G and Adiol 17-G. Adiol G is formed from unconjugated precursors by the enzyme glucuronyl transferase. To determine the likely source of Adiol G formation in man, we developed a glucuronyl transferase assay and measured the activity of this enzyme in human liver, abdominal and scalp skin, and prostate. In human liver, glucuronyl transferase activity was linear with respect to time (up to 120 min) and tissue concentration (up to 1 mg/ml). Apparent Michaelis-Menten constant Km (micromolar) and maximum velocity (Vmax) (picomoles per mg/30 min) were 5.6 and 140 for dihydrotestosterone, 8.9 and 1300 for androstanediol, and 3.1 and 46 for androsterone, respectively. Conversion of androstanediol to Adiol G (/0.5 mg tissue.30 min) was 5.8-13.2%. Over 80% of the Adiol G formed in human liver was Adiol 17-G, similar to what has been previously found in human serum. Glucuronyl transferase activity was present at low levels in human prostate (conversion of androstanediol to Adiol G was 0.04-4.6%/50 mg tissue.120 min). Analogous conversion rates (/50 mg tissue.120 min) for human scalp skin were 0.2-0.4% and for human abdominal skin were 0.07-0.14%. Although dihydrotestosterone may be converted to androstanediol in peripheral tissues such as skin and prostate, our results suggest that the principal site of androgen conjugation to glucuronic acid is the liver. The present results cast doubt upon the role of androstanediol glucuronide as a specific marker of cutaneous androgen metabolism.

"Mirror pain" as an unusual presentation of renal colic.

Although most patients suffering from pain related to upper urinary tract stones feel the discomfort on the same side as the stone, rarely it is perceived on the opposite side. We sought to identify the prevalence of this clinical scenario and to review possible explanations. The charts and x-rays of all patients with unilateral, symptomatic, radiologically identifiable upper urinary tract stones, seen at an outpatient clinic between June 1993 and August 1996, were reviewed retrospectively in terms of the side of the discomfort in comparison to the side of the stone. Three of 631 patients presented with contralateral or "mirror pain" secondary to a renal or ureteric calculus. In each case the symptoms resolved completely following successful extracorporeal shock wave lithotripsy or spontaneous passage of the stone.

Effects of dietary fat on the urinary risk factors of calcium stone disease.

OBJECTIVES: To assess the association between dietary fat and various urinary risk factors of calcium stone disease in a group of calcium stoneformers attending an outpatient stone clinic. METHODS: Mean daily fat intake from self-recorded 4-day dietary food records and mean 24-hour urinary risk factors from two separate collections were evaluated in 476 patients selected randomly from an adult population attending an outpatient stone clinic for the first time. RESULTS: Mean daily total fat intake for men and women was significantly different at 105.6 and 78.1 g, respectively. Examination of the relationship between total fat intake and 24-hour urinary volume, pH, and excretions of magnesium, citrate, oxalate, calcium, and uric acid revealed no significant regressions in men and only a weak association between fat intake and urinary uric acid in women. CONCLUSIONS: Dietary fat does not have a significant effect on the urinary risk factors of calcium stone disease.

Impact of a shared decision-making program on patients with benign prostatic hyperplasia.

OBJECTIVES: To determine patient views about the Shared Decision-Making Program (SDP), an interactive videodisk program designed to inform patients with benign prostatic hyperplasia (BPH) about their condition and treatment options and to determine its impact on perceived knowledge and treatment preference. METHODS: Six hundred seventy-eight patients with symptomatic BPH from eight Canadian centers viewed the SDP. Before and after viewing the video, patients answered questionnaires designed to assess treatment preference, knowledge gained, and satisfaction with this educational format. A 1-year follow-up survey was also conducted. RESULTS: Most patients showed a high desire for information and high satisfaction with the SDP; this satisfaction persisted at 1 year. Patients' self-reported knowledge increased significantly (P <0.0001). However, the SDP did not alter initial treatment preferences among those with already formed preferences, although it aided almost half of those initially undecided in forming a preference. Viewing the SDP also appeared to enhance the physician-patient relationship. CONCLUSIONS: Patients saw the SDP as an effective method for teaching patients about BPH and the risks and benefits of various treatments, clarifying particular areas about which many patients appear to have a desire for more information than is often provided. Patients were enthusiastic about the educational value of the program, and their active participation in the decision-making process may actually enhance the physician-patient relationship. Contrary to other studies, we found no significant alterations in treatment preferences. Problems relating to the cost and timely updating of the software need to be addressed for these kinds of programs to realize their full potential.

Lumbar spine loads during the lifting of extremely heavy weights.

The reaction moments at the knee, hip, and L4/L5 joints, and the compressive and shearing forces on L4/L5 are documented in powerlifters competing in a national powerlifting championship. Analyses were made of 13 female and 44 male competitors. The joint moments and forces were estimated from a linked segment model (WATBAK) that incorporated functional low back extensor musculature with a moment arm of 6 cm and a line action that was oriented 5 degrees posteriorly to the L4/L5 compression axis. This oblique orientation of the extensor muscles reduced the anterior shearing load on the vertebral motion unit. Average compressive loads on L4/L5 were estimated up to 17,192 N while the highest average L4/L5 and hip moments were 988 and 1047 N.m, respectively. The sumo deadlift style resulted in a 10% reduction in the joint moment and 8% reduction in the load shear force at the L4/L5 level when compared with the conventional lifting style. Formulation of linear regression equations to predict the load lifted using reaction joint moments yielded substantial unexplained variability, though significant relationships were found. This analysis suggested that there is large variability in the pattern of loading joints among national class powerlifters.

Effects of an anatomically detailed erector spinae model on L4/L5 disc compression and shear.

Biomechanical models utilized for analysis of tasks that load the lumbar spine often predict the resultant moment, disc compression and sometimes shear. Usually the extensor muscular and ligament forces of the lumbar spine are assumed to act 5 cm posterior to a disc centre of rotation. This study has re-examined the generation and pathways of muscular force transmission within the extensor musculature. The effects on L4/L5 disc compression and shear estimates of an anatomically and biomechanically justifiable range of tissue moment arms, lines of force and force generating capacity of muscle, input to a computer model, have been determined. Results indicated that L4/L5 compression estimates could be reduced by up to 35% when the output from a more realistic anatomical model of the erector spinae muscle group was compared with that from the frequently reported and simplified single muscle equivalent with a 5 cm moment arm. The shear force estimates could be altered from more than 500 N (L4 tending to shear anteriorly on L5) to less than 200 N with L4 tending to shear posteriorly on L5. Using the combination of input variables considered by the authors to be most feasible to estimate compression, a single 'equivalent' extensor soft tissue moment arm of 7.5 rather than 5 cm would be needed to equate the compression. This simplification of course, does not accommodate the shear force estimate problem.

Least-squares identification of the dynamic relation between the electromyogram and joint moment.

The dynamic relation between surface EMG of an agonist and isometric joint moment is important in models for the prediction of dynamic joint moment from EMG. An efficient approach for determining the best-fitting linear transfer function relating EMG and isometric moment, using a least-squares approach, is presented and illustrated for a second-order model.

Dynamically and statically determined low back moments during lifting.

Assessment of the effects of lifting on the low back has most frequently been done with the aid of static models. Many lifting movements appear to have substantial inertial components. It was of interest, therefore, to determine the size of the difference between statically and dynamically calculated lumbar moments during a demanding but not unusual manual lift observed in a metal fabrication industry. The results of several trials by four young men showed that the dynamic model resulted in peak L4/L5 moments 19% higher on average, with a maximum difference of 52%, than those determined from the static model. The technique adopted in the lift could minimize the difference. When the inertial forces of the load itself and the load weight were incorporated into an otherwise static model (quasi-dynamic) then the resulting L4/L5 moments exceeded those of the fully dynamic model by 25%. In many industrial tasks static analyses may severely underestimate the demands of dynamic lifts. These results show that a reasonably inexpensive approach in lifting task analysis is to measure the dynamic forces of the load on the hands and to use these in an otherwise static model. This results in a conservative assessment of the injury risk of lifts at least of the type reported in this study.

Measurement of the trunk musculature of active males using CT scan radiography: implications for force and moment generating capacity about the L4/L5 joint.

The purpose of this study was to add to the growing database of cross-sectional areas and moment arm lengths of trunk musculature using the methods of computerized tomographic scanning. An attempt was also made to estimate muscle force and moment generating capacity under various reported values of muscle force per unit cross-sectional area. The data were obtained on 13 active men 40.5 +/- 11.9 years of age, 173.8 +/- 5.9 cm tall and 89.1 +/- 11.7 kg body mass. Transverse CT scans were taken at the level of the L4/L5 disc with the subjects supine. Muscle cross-sectional areas were measured from 35 mm slides of the scans using a planimeter and moment arm length in the transverse plane were taken from the centroid of the L4/L5 disc to the centroid of the muscle section. Prior to estimating force and moment generating capacity, areas were corrected, where necessary, for fibre pennation angle to produce a physiological cross-sectional area. The physiological cross-sectional areas (cm2) for one side of the body were (mean +/- S.D.): sacrospinalis (SS) 15.9 +/- 2.5; multifidus (Mu) 4.2 +/- 0.7; psoas (Ps) 17.6 +/- 4.0; rectus abdominis (RA) 7.9 +/- 2.5; external oblique (EO) 9.4 +/- 2.7; internal oblique (IO) 8.1 +/- 2.3; transverse abdominus (TA) 2.9 +/- 1.3. The anterior posterior moment arm lengths were: erector mass (SS and Mu combined) 5.90 +/- 0.52; Ps 0.58 +/- 0.40; R.A. 10.28 +/- 2.07; E.O. (anterior portion) 5.94 +/- 1.39; E.O. (posterior portion) 2.08 +/- 1.39; I.O. (anterior portion) 6.92 +/- 1.63; I.O. (posterior portion) 3.85 +/- 1.54. The corresponding lateral moment arm lengths were: 3.26 +/- 0.36; 4.88 +/- 0.36; 4.35 +/- 1.31; 12.86 +/- 1.93; 13.95 +/- 1.16; 10.77 +/- 2.02; 12.52 +/- 1.26. The maximum force per unit cross-section that human muscles are capable of generating is not well defined. However, assuming an intermediate value of 50 N cm-2 of physiological cross-section, the erector musculature observed at the L4/L5 level should be capable of generating an extensor moment of about 118 N.m. At a muscle stress of 30 or 90 N cm-2, values also reported on human muscle, the moment would be 71 and 213 Nm, respectively. It must be remembered, however, that muscles not observable at the L4/L5 level can create moments around that center of rotation.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of muscle forces and joint load from an optimization and EMG assisted lumbar spine model: towards development of a hybrid approach.

The purpose of this study was to determine whether the same estimates of individual muscle and L4/L5 lumbar joint compressive forces result from an optimization (OPT) compared to an electromyography (EMG) assisted approach for solving the inderminate moment equilibrium equations in the same anatomical model. Four male subjects performed near maximum, isometric, ramp efforts in trunk flexion, extension and lateral bending in a testing apparatus. The EMG approach was sensitive to subject and trial differences in the magnitudes of individual muscle forces needed to produce the same reaction moment. In contrast, the OPT method converged on a similar estimate of muscle forces for all subjects and trials producing the same moment. The OPT method predicted lower L4/L5 joint compression values, on average, by 32, 43 and 23% in trunk extension, flexion and lateral bending, respectively, because, unlike the EMG method, it could not predict co-contraction of anatomically antagonistic muscles. We incorporated the OPT method's advantage of forcing an equilibrium in the reaction moments into the EMG method in a new approach we have called 'EMG assisted optimization' (EMGAO). Muscle force estimates from the EMG and EMGAO methods differed from those from the OPT method, on average, by 123% (RMS) for flexion and extension and by 218% for lateral bends. Data from the two approaches result in different conclusions about spine mechanics. We have more confidence in the EMG assisted methods because they respond to variation in muscle synergy and co-contraction patterns commonly observed in different trials and subjects for the same reaction moments.

Partitioning of the L4-L5 dynamic moment into disc, ligamentous, and muscular components during lifting.

This work describes a dynamic model of the low back that incorporates extensive anatomical detail of a three-dimensional musculo-ligamentous-skeletal system. The reactive moment about L4-L5, determined from sagittal plane lifts, was partitioned into restorative components provided by the disc in bending, ligament strain, and active muscle contraction. Skeletal kinematics were obtained from cine analysis of markers on the rib cage and pelvis. The musculature was driven from surface EMG collected from six sites. When compared with past models, features of this model included improved anatomical modeling, improved monitoring of vertebral motion unit kinematics, improved estimation of neural activation of the musculature, and consideration of the effects of muscle length, velocity, cross-sectional area and passive elasticity in force estimation. Estimations of L4-L5 disc compression and shear were, on average, 16.2% and 42.5% lower, respectively, than those calculated from a simple 5 cm erector tissue moment arm length. There was no need to invoke intra-abdominal pressure or other contentious compression-reducing mechanisms. Muscle activity, particularly that of the sacrospinalis, dominated the generation of the restorative moment. Ligaments played a very minor role in the lifts studied. High muscle loads are consistent with the common clinical observation of muscle strain often produced by load handling.

Trunk muscle and lumbar ligament contributions to dynamic lifts with varying degrees of trunk flexion.

This study was done to assess the interplay between muscular and ligamentous sources of extensor moment during dynamic lifting with various loads and flexion angles of the trunk segment for 15 subjects lifting a total of 150 loads. Ligament forces predicted from an anatomically detailed biomechanical model did not generally contribute more than 60 Nm for most of the lifts because the lumbar spine was only flexed to a moderate and constant degree for each load condition. In contrast, additional moment demands associated with increases in hand load were supported by muscle. Although the compression forces on the L4-5 intervertebral disc were fairly insensitive to the interplay between the recruitment of muscle and ligament, the shear force was significantly higher with a greater degree of lumbar flexion. The risk of injury may be influenced more by the degree of lumbar flexion than the choice of stoop or squat technique.

Disability resulting from occupational low back pain. Part I: What do we know about primary prevention? A review of the scientific evidence on prevention before disability begins.

This is the first of two papers that systematically review available scientific evidence on the causes of disability from occupational low back pain, and the effectiveness of interventions to prevent it-before disability begins (primary prevention-Part I) and after its onset (secondary prevention-Part II). This first paper reviews the risk factors for the onset of pain and associated disability followed by a critical summary of intervention studies attempting to achieve prevention and to evaluate the results.

Disability resulting from occupational low back pain. Part II: What do we know about secondary prevention? A review of the scientific evidence on prevention after disability begins.

This is the second of two papers that systematically review available scientific evidence on the causes of disability from occupational low back pain, and the effectiveness of interventions to prevent it after its onset (secondary prevention). This paper reviews the national history of how back pain and the risk factors for its extension into chronic disability, followed by a critical summary of intervention studies attempting to reduce the duration of this disability, and to evaluate the results.

An evaluation of football helmets under impact conditions.

The impact attenuating characteristics of a sample of 81 football helmets used in competitive high school programs were determined using a Hodgson-Wayne State University (WSU) headform and a modified National Operating Committee on Standards for Athletic Equipment (NOCSAE) test protocol. The helmets, classified by liner type as suspension (37), padded-suspension (22), and padded (22) had been in use for 6 to 8 years. Each was subjected to two consecutive right rear boss impacts from a drop height of 1.5 m, onto a rigid anvil covered with a 45 durometer hardness rubber pad. Analogue signals from a triaxial accelerometer located at the center of gravity of the headform were analogue to digital (A/D) converted at 6060.6 Hz and processed on a Hewlett Packard 9845B minicomputer to yield a resultant acceleration-time curve from which peak acceleration (gpeak) and the Gadd Severity Index (GSI) were determined. The mean gpeak was 205 g for helmets with suspension liners, 165 g for helmets with padded-suspension liners, and 156 g for helmets with padded liners. Twenty-four suspension helmets and five padded or padded-suspension helmets had GSI values greater than 1200. Using a criterion of GSI1500, the failure rate for suspension helmets was 19% compared to 2% for padded and padded-suspension helmets combined. If the criterion chosen was GSI1200, the failure rate for suspension helmets was 65% as opposed to 11% for the padded and padded-suspension helmets combined. Suspension helmets are decidedly inferior under impact conditions to the padded and padded-suspension helmets.

Comparison of four peak spinal loading exposure measurement methods and their association with low-back pain.

OBJECTIVES: This paper examines the performance of 4 different methods of estimating peak spinal loading and their relationship with the reporting of low-back pain. METHODS: The data used for this comparison was a subset of subjects from a case-referent study of low-back-pain reporting in the automotive industry, in which 130 random referents and 105 cases (or job-matched proxies) were studied. The peak load on the lumbar spine was determined using a biomechanical model with model inputs coming from a detailed self-report questionnaire, a task-based check list, a video digitization method, and a posture and load sampling technique. RESULTS: The methods were directly comparable through a common metric of newtons or newton meters of spinal loading in compression, shear, or moment modes. All the methods showed significant and substantial associations with low-back pain in all modes (odds ratios 1.6-2.3). The intraclass correlation coefficients (ICC) showed strong similarities between the checklist and video digitized techniques (ICC 0.84-0.91), moderate similarities between these techniques and the work sampling method (ICC 0.49-0.52), and poor correlations (ICC 0.16-0.40) between the self-report questionnaire and the observer recorded measures. CONCLUSIONS: While all the methods detected significant odds ratios, they cannot all be used interchangeably for risk assessment at the individual level. Peak spinal compression, moment, and shear are important risk factors for low-back pain reporting, no matter which measurement method is used. Questionnaires can be used for large-scale studies. At the individual level a task-based checklist provides biomechanical model inputs at lower cost and equal performance compared with the criterion video digitization system.

Dietary aspects of uric acid stone disease.

Kidney stones composed of uric acid present a treatment challenge, particularly in terms of successful prevention of recurrence over the long term. Between 5-12% of all stone patients form calculi composed partially or completely of uric acid. These stones have traditionally been treated with a combination of pharmacological and surgical techniques. The role of diet and fluids in the pathogenesis and management is gradually being recognized and there is potential for dietary intervention to become a major treatment modality for this type of stone. This paper discusses the stone formation process, the metabolism or uric acid and its physical and chemical properties. Specific risk factors for uric acid calculi formation are covered. Dietary protein is reviewed in detail. A comprehensive strategy for the dietary management of uric acid renal calculi disease is suggested.