3D QSAR studies of hydroxylated polychlorinated biphenyls as potential xenoestrogens.

Mono-hydroxylated polychlorinated biphenyls (OH-PCBs) are found in human biological samples and lack of data on their potential estrogenic activity has been a source of concern. We have extended our previous in silico 2D QSAR study through the application of advance techniques such as docking and 3D QSAR to gain insights into their estrogen receptor (ERα) binding. The results support our earlier findings that the hydroxyl group is the most important feature on the compounds; its position, orientation and surroundings in the structure are influential for the binding of OH-PCBs to ERα. This study has also revealed the following additional interactions that influence estrogenicity of these chemicals (a) the aromatic interactions of the biphenyl moieties with the receptor, (b) hydrogen bonding interactions of the p-hydroxyl group with key amino acids ARG394 and GLU353, (c) low or no electronegative substitution at para-positions of the p-hydroxyl group, (d) enhanced electrostatic interactions at the meta position on the B ring, and (e) co-planarity of the hydroxyl group on the A ring. In combination the 2D and 3D QSAR approaches have led us to the support conclusion that the hydroxyl group is the most important feature on the OH-PCB influencing the binding to estrogen receptors, and have enhanced our understanding of the mechanistic details of estrogenicity of this class of chemicals. Such in silico computational methods could serve as useful tools in risk assessment of chemicals.

Sodium and potassium in health and disease.

Sodium and potassium are essential for human health. They are important ions in the body and are associated with many physiologic and pathophysiologic processes. The chapter summarizes the basic physiologic actions of sodium and potassium on membranes of the neurologic and muscular systems. It provides information regarding the kinetics, i.e., absorption, distribution, and excretion of these ions and their movement between the intracellular and extracellular compartments. It also explains the physiologic systems that can influence proper homeostasis between sodium and potassium. Concentrations of sodium in the blood that exceed or do not reach the normal value range are called hypernatremia or hyponatremia, respectively. Similarly, the clinicians recognize hyperkalemia and hypokalemia. Pathologies associated with these states are described and examples of some of the diseases are presented here.

Balloon-tipped catheter for measuring urethral pressures.

BACKGROUND: Better methods are needed for recording urethral function for complex urologic problems involving the bladder, urethra, and pelvic floor. OBJECTIVE: To evaluate a balloon catheter for recording urethral pressure and function using bench-top testing and evaluation in an animal model. METHODS: Balloon pressure-recording methods included slightly inflating the balloon with water and placing the pressure transducer on the distal end of the catheter. For bench-top testing, manual procedures and a silastic tube with a restriction were used. In 3 anesthetized dogs, pressure recorded from the skeletal urethral sphincter was induced with electrical stimulation of the sphincter. Anal sphincter pressure was also recorded. RESULTS: Bench-top testing showed good pressure recordings, including a confined peak at the tube restriction. Animal tests showed urethral pressure records with rapid responses when electrical stimulation was applied. Peak pressure at the urethral skeletal sphincter was 55.7 +/- 15 cmH2O, which was significantly higher than the peak pressure recorded 2 cm distally in the proximal urethra (3.3 +/- 2.3 cmH2O). Peak anal pressures were smaller and unchanged for the 2 stimulations. CONCLUSIONS: Balloon-pressure recordings showed rapid responses that were adequate for the tests conducted. In the animal model, high-pressure contractions specific to the skeletal urethral sphincter were shown. Balloon-tipped catheters warrant further investigation and may have applications for the evaluation of detrusor-sphincter dyssynergia after spinal cord injury or for stress urinary incontinence.

Effective methods of pelvic plexus nerve and bladder stimulation in anesthetized animal model.

Urinary retention is a serious urological problem associated with spinal cord injuries (SCIs) and other pelvic disorders. Effective methods of pelvic nerve stimulation were investigated for this problem. Following anesthesia in five dogs, the bladder was surgically exposed. Bladder and anal sphincter pressures were recorded. Testing was first conducted with probe electrodes. Barb electrodes were then implanted with a needle near the pelvic plexus nerves and the bladder wall. We tested different electrode arrangements and stimulating parameters to induce bladder contractions without skeletal muscle stimulation. The pelvic plexus nerves near the bladder were identified, and the barb electrodes were effectively implanted. Stimulation with bipolar and bilateral electrodes induced pressures over 30 cmH(2)O without skeletal muscle activation. Common stimulation parameters were 40 pps, 400 microseconds pulse duration, and 15 to 25 mA stimulating current applied for 3 s. Effective electrode implantation methods were shown. Also identified were electrode arrangements and stimulating parameters that induced strong bladder contractions without skeletal muscle activation. However, voiding studies were not conducted. Further studies with barb electrodes are warranted, and these methods may have applications for bladder stimulation following SCI.

A 24-hour feasibility study of intraurethral valved catheter for bladder management in males with spinal cord injury.

This feasibility study was conducted to evaluate design features of the novel intraurethral valved catheter, Surinate (Urovalve, Inc; Newark, New Jersey). The device extends from the bladder neck to just beyond the external sphincter and contains a valve that can be activated by an external magnet for bladder emptying. Five patients were recruited from the Edward Hines Jr Department of Veterans Affairs Hospital spinal cord injury population. We conducted cystometry and cystoscopy to evaluate the lower urinary tract. Then, the device was inserted for 24 hours with careful monitoring. The catheter was removed from the first patient because he developed autonomic dysreflexia during implantation. The next four patients used the catheter overnight and tolerated it well: one with independent use and two with increased abdominal pressure. Emptying time was 208 +/- 99 s, residual was 42 +/- 33 mL, and the first-stream flow rate was 1.8 +/- 0.7 mL/s. The safety tether was used in three patients because the extraction device did not work. Results showed effective implantation and stability of the device in the urethra. However, objectives for use and extraction were not met. This feasibility study provided important information that will help guide design improvements for the intraurethral valved catheter.

Long-term subjective continence status and use of alternative treatments by women with stress urinary incontinence after collagen injection therapy.

This study examined subjective continence status and use of subsequent alternative therapeutic procedures at long-term follow-up after collagen injection for stress incontinence (SI) in women. Seventy women who underwent collagen injection for SI were identified by retrospective chart review and surveyed by mail questionnaire for subjective continence status, daily pad usage pre- and post-treatment, and use of anticholinergics and alternative procedures. Questionnaire responders' versus non-responders' mean age, follow-up, and pad usage were compared. Thirty-three women (47%) responded on questionnaires. Of the 33, 50% were dry or subjectively improved at long-term follow-up and 91% had not chosen an alternative invasive treatment after collagen injection. Chart review showed responders were not significantly different from non-responders in mean age (65.9 vs. 69.2 years), pad usage (0.6 vs. 0.8 pads/day), or follow-up (4.5 vs. 4.3 years). Collagen injection, a minimally invasive treatment for SI, appears to benefit a significant number of women.

A spinal cord injured animal model of lower urinary tract function: observations using direct bladder and pelvic plexus stimulation with model microstimulators.

BACKGROUND: Microstimulators are new devices that should be considered for management of lower urinary tract problems following spinal cord injury (SCI) such as urinary retention. These devices are small (less than 25 mm by 5 mm) with the electrodes located on the ends of the stimulator. However, it is not known whether the small electrodes on these devices would be effective in stimulating the plexus of nerves that innervate the bladder. The aim of the present study was to provide preliminary observations with model microstimulators (M-Micro) for inducing bladder contractions in an SCI animal model. Bladder wall and pelvic plexus stimulation sites were compared. Additional investigations evaluated parameters such as stimulation polarity, frequency, and period as well as bladder filling volume. METHODS: In an initial survival surgery, bilateral M-Micros were implanted on the bladder wall and the pelvic plexus along the urethra in 3 female cats. A second survival surgery was conducted 3 to 5 weeks later to produce a T1 0 SCI. Studies are reported following the second survival surgery. These studies included the effects of stimulation and bladder filling. RESULTS: The postmortem location of the implanted pelvic plexus M-Micro was previously described as near the bladder neck. Therefore, the pelvic plexus location is described in this report as "pelvic plexus (bladder neck)" stimulation. The observations showed effective stimulation with pelvic plexus (bladder neck) stimulation and voiding in some cases. Stimulation was limited by side effects of increased abdominal pressure and leg movement. Other factors also affected the response to stimulation, including the initial bladder volume and stimulating parameters. Fluoroscopy showed that when stimulation did not induce voiding the striated urethral sphincter was closed. CONCLUSIONS: This case series of 3 SCI animals showed that the small electrodes on the M-Micro could be used to stimulate the bladder with contractions and voiding in some cases. The pelvic plexus (bladder neck) location for the M-Micro may be a better location than higher on the bladder wall. Limiting side effects of stimulation included leg movement and increased abdominal pressure. Additional important factors included the stimulation parameters, initial bladder volume, and the function of the skeletal urethral sphincter.

Bladder-wall and pelvic-plexus stimulation with model microstimulators: Preliminary observations.

Severe urinary retention is not a common condition, but may occur following some pelvic surgeries or other medical conditions. Electrical stimulation of the bladder has been examined as a means of managing this difficult problem. We conducted preliminary investigations in cats to prove the hypothesis that pelvic-plexus (bladder-neck) stimulation would produce greater micturition response with reduced side effects, such as animal movement or discomfort, than bladder-wall stimulation with electrodes implanted higher on the bladder wall. We used model microstimulators that mimic the look and function of commercial microstimulators, but that we constructed. We instrumented four female cats during a survival surgery. Animals recovered well and studies were conducted over a 1-month period in the conscious animal and under anesthesia. We performed a variety of studies with different stimulation parameters and electrode locations to evaluate our hypothesis. In the active animal, we supplied only low currents, but two animals responded to stimulation with bladder contractions and voiding. Following anesthesia, higher stimulating currents resulted in greater bladder contractions during stimulation in two of the three animals. In two cases, pelvic-plexus (bladder-neck) stimulation induced greater micturition responses than direct bladder-wall stimulation. In conclusion, we learned from these preliminary observations that stimulation at the pelvic plexus (bladder neck) may induce a better micturition response than stimulation higher on the bladder-wall. Newly available commercial microstimulators should be further studied for the treatment of urinary retention.

Chronic instrumentation with model microstimulators in an animal model of the lower urinary tract.

BACKGROUND: Microstimulators are a new type of neuroprosthetic device that should be considered for applications such as micturition control after spinal cord injury (SCI). These devices are small (less than 25 mm by 5 mm) and the electrodes are located on the ends of the stimulator. The aim of the current study was to develop methods for chronic implantation of model microstimulators (M-Micro) on the bladder wall and pelvic plexus of female cats. A postmortem evaluation of the effects of 3 months of implantation is reported. METHODS: Techniques to produce the M-Micro are described. Four of these devices were implanted in 4 female cats and maintained after the initial instrumentation surgery and a second survival surgery for SCI (at T10). Using a single suture tied around the M-Micro, these devices were secured to the bladder wall or the fat pads adjacent to the pelvic plexus. Additional instrumentation was implanted, including 2 catheters in the bladder, 1 abdominal balloon, and electromyography electrodes in the urethral and anal sphincters. Postmortem observations of the location of the M-Micro on the bladder wall were conducted after fixation. RESULTS: The animals' conditions were good. One animal was sacrificed early because of a skin infection. A single suture was sufficient to anchor the M-Micro. However, during the surgical implantation the pelvic plexus M-Micro ended up close to the bladder neck. Extensive fibrous connective tissue formed around the M-Micro and implanted catheters on the bladder wall. This appeared to result, in part, from multiple devices implanted on or near the bladder wall. CONCLUSIONS: These pilot studies showed that the M-Micro could be easily constructed and secured to the bladder wall or fat pads close to the pelvic plexus. There was a concern that the pelvic plexus location for the M-Micro ended near the bladder neck during the surgical implantation; however, these devices did not appear to migrate over this short, 3-month implantation period. The extensive connective tissue responses of the bladder wall to the tubes, wires, and M-Micro was a major concern. The M-Micro appears to be a good device to assess the potential of commercial microstimulators for use in micturition control.

Exposure pathway evaluations for sites that processed asbestos-contaminated vermiculite.

The Agency for Toxic Substances and Disease Registry (ATSDR) is currently evaluating the potential public health impacts associated with the processing of asbestos-contaminated vermiculite at various facilities around the country. Vermiculite ore contaminated with significant levels of asbestos was mined and milled in Libby, Montana, from the early 1920s until 1990. The majority of the Libby ore was then shipped to processing facilities for exfoliation. ATSDR initiated the National Asbestos Exposure Review (NAER) to identify and evaluate exposure pathways associated with these processing facilities. This manuscript details ATSDR's phased approach in addressing exposure potential around these sites. As this is an ongoing project, only the results from a selected set of completed site analyses are presented. Historical occupational exposures are the most significant exposure pathway for the site evaluations completed to date. Former workers also probably brought asbestos fibers home on their clothing, shoes, and hair, and their household contacts may have been exposed. Currently, most site-related worker and community exposure pathways have been eliminated. One community exposure pathway of indeterminate significance is the current exposure of individuals through direct contact with waste rock brought home for personal use as fill material, driveway surfacing, or soil amendment. Trace levels of asbestos are present in soil at many of the sites and buried waste rock has been discovered at a few sites; therefore, future worker and community exposure associated with disturbing on-site soil during construction or redevelopment at these sites is also a potential exposure pathway.

Predicting urethral area from video-urodynamics in women with voiding dysfunction.

AIMS: Mathematical models are useful for developing predictive parameters for characterizing the biomechanics of voiding dysfunction. The goal of this project was to test a one-dimensional steady flow model used to predict the minimum cross-sectional urethral area from urodynamic data. METHODS: Nine adult female subjects underwent video-urodynamic testing. By using Bernoulli's formula and the Torricelli theorem, the minimum urethral area was predicted from pressure and flow rate at the moment of maximum flow rate during voiding. This prediction was compared with the minimum cross-sectional area of the urethra, which was calculated from minimum urethral diameter as measured from fluoroscopy, assuming a circular cross-section. RESULTS: The maximum flow rate during voiding was 14.4 +/- 3.0 mL/sec. Mean bladder, abdominal, and detrusor pressures simultaneous with maximum flow rate were 63 +/- 7, 29 +/- 6, and 33 +/- 6 cm H(2)O, respectively. Mean minimum cross-sectional area of the urethra from fluoroscopy was 8.0 +/- 2.0 mm(2). Mean minimum cross-sectional area of the urethra predicted by the mathematical model was 5.0 +/- 1.0 mm(2) using bladder pressure and 7.0 +/- 2.0 mm(2) using detrusor pressure. There were no significant differences between the three cross-sectional area measures. However, when area predictions were expressed as percentage of fluoroscopic measurements, the estimate from detrusor pressure (97 +/- 13%) was significantly larger than the estimate from bladder pressure (69 +/- 7%). CONCLUSIONS: A steady flow model is accurate enough on average to describe urine flow in the urethra. However, it may not be sufficiently accurate to aid in diagnosis of individuals.

Bladder pressure monitoring during intermittent catheterization: a comparison of gauges and methods.

AIMS: We previously have investigated a technique for serial bladder pressure measurements in patients with spinal cord injury (SCI) using intermittent catheterization. In the current study, we compared an FDA-approved digital gauge with the previously studied analog gauge and studied the effects of hydrostatic pressure differences. METHODS: Either a digital or an analog pressure gauge was attached to each subject's catheter just before bladder catheterization. Both immediate and stable pressures were recorded. The bladder was then drained until nearly empty and pressure was again recorded (almost empty bladder pressure). Detrusor pressure was estimated as full minus almost empty bladder pressure. Bladder pressures greater than 40 cm H2O were presumed to represent bladder contractions. To investigate the effects of hydrostatic pressure, additional measurements, adjusting the level of the air-urine meniscus, were obtained in three subjects. RESULTS: Recordings were made from nine SCI subjects using both gauges. Estimates of detrusor pressure, with and without bladder contractions, and associated bladder volumes, were not significantly different between digital and analog gauges. In the absence of bladder contractions, detrusor pressure with the meniscus at the end of the catheter (5 +/- 1 cm H2O) was significantly lower than that recorded with no adjustment of the urine meniscus (12 +/- 1 cm H2O). CONCLUSIONS: Standardizing measurement techniques to equalize hydrostatic pressures should facilitate reliable estimates of detrusor pressure. Frequent monitoring of bladder pressure using this technique may assist with the urological care of SCI patients.

Preliminary observations of a synergistic bladder-sphincter relationship following spinal cord injury in a quadruped animal.

BACKGROUND/OBJECTIVES: High urethral resistance or detrusor-sphincter dyssynergia (DSD) is characterized by obstructed voiding during bladder contractions. DSD is caused by an exaggerated pelvic floor reflex resulting from sensory input from elevated pressure in the bladder that produces reflex constriction of the urethral sphincter. The objective of this study was to determine whether sensory input from the bladder produced synergistic or dyssynergic pelvic floor reflexes following SCI in an animal model. METHODS: A pelvic floor reflex that shares the same motor pathway with DSD is the bulbocavernosus (BC) reflex. The BC reflex was elicited with electrical stimulation in 4 male cats with T1 spinal injury, and recorded as an anal sphincter contraction. Recordings were obtained during control and elevated bladder pressures. Increased bladder pressure was induced with either manual pressure (Crede procedure) or spontaneous contractions resulting from bladder filling. RESULTS: During the control period, the BC reflex indicated by the peak anal pressure response was 23 +/- 6 cmH2O. During elevated bladder pressure of 34 +/- 18 cmH2O, the BC response decreased to 10 +/- 3 cmH2O (not significant), showing a synergistic relationship. Anal sphincter tone between BC reflex tests showed a dyssynergic response. All 4 animals showed increased tone during elevated bladder pressures that averaged 9 +/- 5 cmH2O. Because abdominal pressure was not recorded, the significance is not clear. However, there was further support of a dyssynergic relationship based on increases in the anal and urethral electromyography recordings and some pelvic floor spasms during the elevated bladder pressure. CONCLUSIONS: Because 2 different pelvic floor activities were observed during increased bladder pressures, this animal model may be described best as a mixed model. This model shows both synergistic and dyssynergic relationships between the bladder and the BC contractions. Although observed changes were not significant, the unique observations of synergistic bladder-sphincter activity shown by the inhibited BC reflex is in marked contrast to the strictly dyssynergic bladder-sphincter relationship seen in SCI patients.

Considerations and procedures in the derivation of ATSDR minimal risk levels.

Minimal risk levels (MRLs) are health-based guidance values derived for individual substances by conducting a thorough review of the literature, identifying appropriate target organs of response, and identifying a dose level where a no adverse effect or the lowest adverse effect level is seen. This level is then evaluated for uncertainty in the data base and for other extenuating factors and subsequently adjusted with uncertainty or modifying factors. The resulting calculation yields the MRL that is defined as an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure. Typically, MRLs are derived for different durations of exposure (acute, intermediate, chronic) and for different routes of exposure (oral, inhalation). The MRLs serve as useful reference values in evaluating human health from exposure to substances found at hazardous waste sites. Because of numerous requests of various programs, recent work has focused on expanding the applicability of MRLs to other situations and routes of exposure (dermal, food supply, intramuscular) beyond the traditional oral and inhalation exposure routes at waste sites. Results of work, in conjunction with the Agency for Toxic Substances and Disease Registry's computational toxicology laboratory, shows that the use of computational methods, such as physiologically based pharmacokinetic modeling, may allow the MRL process to be adapted to unique durations and routes of exposure such as intramuscular injections.

A database of self-reported secondary medical problems among VA spinal cord injury patients: its role in clinical care and management.

An interactive data management (IDM) system for the Spinal Cord Injury (SCI) Service was developed to collect self-reported patient data related to secondary medical complications and to provide feedback to the SCI rehabilitation team. The long-term objective is to improve clinical care through a process of staff review of current rehabilitation programs in the areas of prevalence, prevention, and management. Based on data from the first 99 SCI patients visiting the clinic and hospital after the installation of the IDM system, SCI patients reported high rates of current problems with spasticity (53 percent), pain (44 percent), and pressure ulcers (38 percent). Respiratory (12 percent) and bowel (14 percent) problems were less common current problems. The SCI staff questioned the reportedly high spasticity rates. They thought that the patients' answers might have indicated simply the occurrence of spasticity, rather than the more important issue of severe spasticity that interferes with daily activities. The staff suggested several additional spasticity questions to add to the study. In other areas, only a small percentage of patients wanted to talk with a therapist about prevention of pressure ulcers. Patients who had urinary problems consistently reported five urinary signs (e.g., cloudy urine). The clinical staff found these data informative and stated that they should continue to be collected.