In the decade of the 1970's, the NIH was captivated by the dream of harnessing electrical stimulation for widespread therapeutic goals. After the success of pacemakers in the 1960's hopes were high that a number of compromised body functions could be helped. These included hearing loss, seizure disorders, scoliosis, pain control, and in spinal cord injury patients: the restoration of lost limb function, walking and breathing, and bladder control. It was a comprehensive program involving numerous research centers and included a wide variety of talent, from chemical and electrical engineers to PhDs and MDs from a variety of disciplines. The University of California in San Francisco was invited to be part of the program, largely because of its leadership status in the field of urodynamics at the time. Research was carried out throughout the decade in the successful attempt to make neural stimulation an everyday therapy for compromised bladder function. The program was carried out in phases. Initial efforts were directed at direct stimulation of the bladder wall, then the spinal cord directly, and Finally the sacral roots. The goal was to achieve synergic voiding. While that didn't happen, intermittent voiding was achieved and a whole new meaning to the term modulation therapy opened up. The following paper discusses the research path into the development of sacral nerve stimulation from the lab through clinical trials to FDA approval. Critical observations linking the human situation to the lab experimental observations are underscored. The pitfalls in transition from the university environment to commercial application are depicted, along with all the human roadblocks that arose. It was a 25-year program that influenced the careers of many "fellows" worldwide. It culminated in successful patient therapy because of the generous collaborative efforts of many academic centers in Europe and North America. It was an era where all the necessary elements were in place-the NIH leadership, the combination of research talent and lab animal availability, adequate funding, and a high level of subject interest. The research environment prior to and after this time period was not nearly as friendly, either politically nor fiscally, to this sort of research program. Had it not been for this mix of forces the therapy may never have evolved.

PURPOSE:Renal sympathetic innervation is involved in the maintenance of fluid homeostasis, modulation of renal secretion from juxtaglomerular cells, sodium resorption from renal tubular cells and renal hemodynamics. The understanding of central innervation and neuronal connections is important for studying the consequences of renal disease and surgical interventions compromising renal nerves.MATERIALS AND METHODS:A total of 38 individual adult male Sprague-Dawley rats were used for retrograde transneuronal mapping of the spinal cord and brain stem after pseudorabies virus (PRV) injection into the left kidney in 30 and control experiments in 8. After a survival time of 72, 96 or 120 hours the animals were sacrificed. Exploration of the abdominal and pelvic visceral organs was done, and the brain and spinal cord were harvested via dorsal laminectomy. After cutting on a freezing microtome the tissue was immunostained for PRV.RESULTS:After kidney injection inspection of the abdominal and pelvic cavity revealed an enlarged bladder with hemic urine. The urine was sterile and the bladder wall showed signs of neurogenic inflammation. Other organs were not affected. PRV positive cells were primarily found within the ipsilateral nucleus intermediolateralis of thoracic spinal cord segments T6 to T13. At the supraspinal level PRV positive cells were found within certain regions, namely the nuclei raphes, rostral ventromedial and ventrolateral medulla, A5 noradrenergic cell region, locus coeruleus and nucleus paraventricularis of the hypothalamus.CONCLUSIONS:This investigation demonstrates the anatomical basis for broad central sympathetic innervation of the kidney. The neurogenic inflammation within the spinal cord inherent to the PRV tracing method causes an inflammatory reaction within the bladder. This can be due to increased sympathetic nerve activity, followed by peripheral, neurogenically mediated inflammation.

This study examined the hypothesis that unintended-acceleration (UA) incidents, as well as other accidents caused by a foot pedal error or misapplication (PE), are related to the design of the pedal cluster. Using the North Carolina Accident Report Database, we evaluated the narrative descriptions of over 200,000 accidents to determine which accidents involved either a UA or PE. Three measures of the pedal cluster--the distance of the right edge of the brake pedal from the steering wheel centerline, the horizontal separation between the accelerator and brake pedal, and the vertical separation (the plane perpendicular to the brake-pedal face) between the accelerator and brake pedal--were evaluated to determine if the pedal cluster could be linked to a pedal-related accident. We found no differences in the pedal measurements of vehicles involved in accidents when compared with their non-accident peers. Therefore, there is no support for the notion that pedal-cluster design is a factor in pedal-error accidents.

OBJECTIVE:Based on clinical description of associated dysfunctional symptoms in patients with non-neurogenic lower urinary tract dysfunction an experimental setup was created in order to investigate the neuroanatomical basis for the clinical phenomena observed.METHODS:Using 24 male adult Sprague-Dawley rats for retrograde mapping of the spinal cord and brain, a pseudorabies virus (PRV) tracer was subsequently injected into four pertinent locations; (a) the trigone, (b) the masseter muscle (c) the forepaw and (d) the hindpaw.RESULTS:PRV tracing demonstrated clearly overlapping of labeled areas in the brain stem, diencephalon and thoracic-lumbar cord, from all injection sites of the rats.CONCLUSION:There is a diffuse overlap within the brain stem and spinal cord, of autonomic innervation to peripheral tissues based on the presented animal experiments. The described autonomic network allows an understanding of the occurrence of symptoms in distant regions of the body associated to chronic bladder dysfunction.

OBJECTIVE:Investigation of patients with chronic bladder dysfunction regarding associated general symptoms and complaints in the cervico-facial, upper and lower extremity regions.PATIENTS AND METHODS:We retrospectively evaluated history, physical and special neurourological examination and urodynamic studies in 213 patients with non-neurogenic bladder dysfunction.RESULTS:22 patients out of 213 patients with chronic bladder dysfunction reported reproducible associated symptoms involving the temporo-mandibular joint, the distal forearm/hand or feet and headache. There was an obvious clinical connection regarding the severity of bladder dysfunction and associated symptoms and possible relief of both by successful treatment.CONCLUSION:Symptomatic lower urinary tract dysfunction may accompanied by specific muscular and or sensory disturbances in different areas of the body. These associated pathologies in patients without neurological disease can be explained by functional changes in a complex autonomic peripheral and central nervous network.

Aims: Sacral nerve stimulation (SNS) can provide subjective and objective relief of pelvic pain and chronic voiding symptoms, but its mechanism is poorly understood. It is well known that a noxious stimulus applied to one part of the body can reduce the response to a subsequent stimulus elsewhere in the body. This phenomenon, known as diffuse noxious inhibitory controls (DNIC), seems to be the mechanism by which pain can be reduced by concurrent noxious stimulation. Methods: On the basis of the DNIC concept, we investigated the expression of a protein product of proto-oncogene c-Fos (c-Fos) in the rat spinal cord after acute electrical stimulation of the sacral segmental nerve with or without lower urinary tract irritation. Adult male Sprague-Dawley rats were treated either by sacral nerve stimulation (SNS) from the S1 sacral foramen or chemical irritation of the lower urinary tract (LUT) or both. Rats were perfused transcardially, and spinal cords were removed and processed for c-Fos immunohistochemistry. c-Fos expression in the central nervous system was detected by immunohistochemistry by using the avidin-biotin technique. The number of c-Fos-positive cells and their locations in the spinal cord were evaluated. Results: SNS and LUT irritation resulted in significant increases in c-Fos-positive cells in L6 and S1 spinal segments. In the animals treated by SNS and LUT irritation, counts of c-Fos-positive cells in L6 and S1 segments were significantly smaller than expected. Distribution and number of c-Fos-positive cells in rats that received SNS and LUT irritation were almost the same as those induced by SNS alone in the SI segment. Conclusions: SNS alone caused a near maximal response in c-Fos expression such that adding LUT irritation did not cause a linear increase in c-Fos. Subsequent LUT irritation could not induce additional expression of c-Fos within the spinal cord. (C) 2002 Wiley-Liss, Inc.

Prostate cancer has become the most commonly diagnosed cancer in men over recent years. The initiating mechanism for tumorigenesis within the prostate remains an unknown. The observation, that the cancer incidence in patients with chronic neurological disabilities is significantly lower than in the normal population lead to the hypothesis, that changed processing due to a barrage of aberrant sensory information within a healthy CNS can trigger events within the prostate cell, that cause malignant transformation. There is a broad overlap of cellular mechanism of gene expression, that lead to either long term potentiation, learning and memory storage or deregulated differentiation and malignant transformation.

L'invention concerne un systeme et un procede pour le diagnostic d'affections du bas appareil urinaire. Aux fins de diagnostic, on recoit des donnees urodynamiques et des impressions symptomatiques subjectives relatives a un patient. Ensuite, on affecte des elements de ponderation aux donnees, du type profils de pression uretrale resultant de la contraction des sphincters sous l'effet de facteurs comme la miction imperieuse (2) et l'incontinence d'effort (4), et on affecte aussi ces elements de ponderation aux impressions. L'etape suivante consiste a evaluer quantitativement des normes applicables a la fonction du bas appareil urinaire, en totalite ou en partie, et a evaluer quantitativement des pathologies reconnues du bas appareil urinaire sous la forme d'ecarts par rapport aux normes. Enfin, on etablit un diagnostic en fonction des ecarts, sur la base d'une serie de regles visant a comparer les elements de ponderation et les normes quantifiees. L'invention concerne egalement des recommandations liees au diagnostic et au traitement, ou bien encore des suggestions complementaires.

A Persian Gulf War veteran presented to the University Neuro-Urology service for management of severe chronic perineal pain. The overall physical and neurological exam was unremarkable. However, the rectal exam and the urodynamic study revealed a severe pelvic floor dysfunction. A neuro-behavioral approach is recommended and discussed.

Recently, various automotive manufacturers have developed and installed adjustable pedal systems that allow the pedal package (accelerator, brake, and clutch) to be moved in unison toward or away from a driver's standard (and historically fixed) position. To determine if there was a possible danger associated with adjusting or manipulating the pedals while operating the vehicle, we engaged in two separate investigations. First, we evaluated the potential risk associated with adjusting or manipulating in-vehicle controls, such as tuning the radio or moving the seat position, for an estimate of how the operation of similar devices influences vehicle safety. Our analysis of accident data from North Carolina shows that about 60 accidents per year occur while drivers are adjusting a radio, with only a few annual accidents tied to other in-vehicle controls such as wipers, mirrors, and heaters. Based on these findings, accidents associated with pedal location adjustment are likely to be extremely rare. Second, we completed a fixed-base simulator study to evaluate how the manipulation of the adjustable pedal system influenced driver behavior and vehicle control. Changes in pedal position had no detectable influence on brake reaction times. Adjusting pedal position (on demand from the experimenter) had only a very small effect on measures of speed, lane position, and brake reaction time, in all cases within the range of effects found with operation of radios, cell phones, and seat controls. Findings from this aspect of our work add further confidence to the prediction of low accident risk for pedal location adjustment. Implications for driver behavior and vehicle safety are discussed.

Objectives: To evaluate the long–term efficacy of sacral nerve stimulation for refractory urinary urge incontinence. Study Design and Methods: Urge incontinent patients qualified for surgical implantation of a neurostimulator system after trial screening with percutaneous test stimulation. Surgical implantation of the InterStim System (Medtronic Inc., Minneapolis, Minn., USA) was performed in cases where a >50% reduction in incontinence symptoms was documented during the 3– to 7–day test stimulation period. The InterStim System consists of an implantable pulse generator, a transforamenally placed quadripolar lead, and an extension that connects these two devices for unilateral stimulation of the S3 or S4 sacral nerve. Efficacy for 96 implanted patients was based on urinary symptom changes as quantified in voiding diaries collected at baseline and annually after surgical implantation. Results: As compared to baseline, the group of 96 implanted patients demonstrated significant reductions in urge incontinent symptoms at an average of 30.8±14.8 (range 12–60) months with respect to the number of urge incontinent episodes per day, severity of leaking, and the number of absorbent pads/diapers replaced per day due to incontinence (all p<0.0001, respectively). Gender, pretreatment variables, and age were not found to be relevant factors that affected these results. 11 of the 96 patients underwent device explant due to lack of efficacy, pain or bowel dysfunction. These data were conservatively included in the efficacy results. No permanent injuries associated with the devices or therapy were reported. Conclusion: Sacral nerve stimulation is an effective treatment for refractory urge incontinence with sustained long–term benefit through an average of 30.8 months.

Suffering chronic pain is a common and debilitating problem that significantly impairs the quality of life of affected patients. Because we continue to struggle with chronic pelvic pain disorders both diagnostically and therapeutically, a neuro-behavioral perspective should be used in an attempt to explain pathways and neurophysiological mechanisms, and to improve diagnostics and treatment of male pelvic pain. First, however, malignant and acute;chronic bacterial disease has to be excluded as a cause of chronic pain in every single case. Then diagnostic approaches should screen for lower urinary tract dysfunction, pelvic floor functional disorders, and disturbed reflex integrity within the pelvic area. Treatment approaches for the male chronic pelvic pain syndrome could be divided into causal and symptomatic. Causal treatment approaches try to influence basic mechanisms generating and supporting chronic pain. In most cases a symptomatic approach is needed to relieve pain immediately. Because generally accepted treatment protocols and studies are missing, the following approach in the individual patient is recommended: (1) symptomatic treatment for immediate pain relief, (2) diagnostic work-up, (3) causal treatment trial.

It has been suggested that there is a significant upregulation of the NK1 receptor (NK1R) on neurons in the dorsal spinal cord after long-term somatic inflammation. This upregulation appears to play a significant role in central sensitization in chronic pain states. However, it is not clear whether such a change is also observed after chronic visceral (bladder) inflammation. Changes in NK1R immunoreactivity after chronic bladder irritation were investigated in order to evaluate the existence of hypersensitive states in the spinal cord after chronic bladder irritation. Experiments were performed on a total of 12 adult female Sprague–Dawley rats. In six animals, cyclophosphamide (CPA) was administered intraperitoneally for 2 weeks. Another six animals were given intraperitoneal saline injections and served as the control group. After these treatments, immunohistochemical staining for NK1Rs and substance P in rat lumbosacral spinal cord was performed. In CPA-treated animals, NK1R-positive areas and staining intensity within the dorsal spinal cord were significantly increased in the L5 to S2 spinal cord areas, especially in the L6 and S1 segments. In the L6 spinal segment, CPA-treatment enhanced NK1R immunostaining in the medial and the lateral dorsal horn, as well as in the lateral laminae including the sacral parasympathetic nucleus to a lesser extent. In CPA-treated animals, substance P staining intensity increased in the same regions in which NK1R immunoreactivity was increased. This finding probably implies the upregulation of spinal NK1R and the occurrence of central sensitization within the spinal cord after chronic visceral inflammation.