Transurethral resection of the prostate, or other methods to decrease outlet resistance usually leads to relief of symptoms in patients with bladder outlet obstruction (BOO). If symptoms of underactivity persist after normalization of outflow conditions, treatment options are limited. In this review, we hypothesize, based on results from basic research, what might become treatment options for such patients in the future. The primary local treatment will still aim at reducing outlet obstruction. We speculate that local secondary treatment in the future might include transplantation of stem cells or mature bladder ganglion cells into the bladder wall. There has been some success in transplanting ganglion cells into the rat bladder. The ganglion cells will sprout into the surrounding tissue but functional connections between the axons of the transplanted neurons, and the detrusor smooth muscle have so far not been demonstrated. Neurotrophins or neurotrimin might be injected into the bladder wall to increase the sprouting of existing or transplanted neurons. Stem cell transplantation has been performed and improves detrusor function, but it has so far, been difficult to demonstrate transplanted stem cells. BOO, persisting detrusor underactivity, and decreased nerve density are often combined with inflammatory activity of the lower urinary tract. NLR family pyrin domain containing 3 (NLRP3) and its messenger RNA (mRNA) as well as cyclooxygenase-2 (Cox-2) mRNA are increased in obstructed bladders. Systemic treatment with the NLRP3 inhibitor glyburide normalized nerve density in rat bladder, and, to some extent, bladder function. It is unclear whether Cox-2 is involved in the decreased nerve density following obstruction, but Cox-2 mRNA increases 5-fold in obstructed bladder. Future therapy against bladder underactivity remaining following relief of obstruction includes either systemic treatment, perhaps by anti-inflammatory drugs, or local treatment by injection of stem cells, mature ganglion cells, and/or neurotrophins or neurotrimin into the bladder wall.

This study examined the effect of sacral neuromodulation on persistent bladder underactivity induced by prolonged pudendal nerve stimulation (PudNS). In 10 α-chloralose-anesthetized cats, repetitive application of 30-min PudNS induced bladder underactivity evident as an increase in bladder capacity during a cystometrogram (CMG). S1 or S2 dorsal root stimulation (15 or 30 Hz) at 1 or 1.5 times threshold intensity (T) for inducing reflex hindlimb movement (S1) or anal sphincter twitch (S2) was applied during a CMG to determine if the stimulation can reverse the bladder underactivity. Persistent (>3 h) bladder underactivity consisting of a significant increase in bladder capacity to 163.1 ± 11.3% of control was induced after repetitive (1-10 times) application of 30-min PudNS. S2 but not S1 dorsal root stimulation at 15 Hz and 1 T intensity reversed the PudNS-induced bladder underactivity by significantly reducing the large bladder capacity to 124.3 ± 12.9% of control. Other stimulation parameters were not effective. After the induction of persistent underactivity, recordings of reflex bladder activity under isovolumetric conditions revealed that S2 dorsal root stimulation consistently induced the largest bladder contraction at 15 Hz and 1 T when compared with other frequencies (5-40 Hz) or intensities (0.25-1.5 T). This study provides basic science evidence consistent with the hypothesis that abnormal pudendal afferent activity contributes to the bladder underactivity in Fowler\'s syndrome and that sacral neuromodulation treats this disorder by reversing the bladder inhibition induced by pudendal nerve afferent activity.

The purpose of this study is to determine whether superficial peroneal nerve stimulation (SPNS) can reverse persistent bladder underactivity induced by prolonged pudendal nerve stimulation (PNS). In 16 α-chloralose-anesthetized cats, PNS and SPNS were applied by nerve cuff electrodes. Skin surface electrodes were also used for SPNS. Bladder underactivity consisting of a significant increase in bladder capacity to 157.8 ± 10.9% of control and a significant reduction in bladder contraction amplitude to 56.0 ± 5.0% of control was induced by repetitive (4-16 times) application of 30-min PNS. SPNS (1 Hz, 0.2 ms) at 1.5-2 times threshold intensity (T) for inducing posterior thigh muscle contractions was applied either continuously (SPNSc) or intermittently (SPNSi) during a cystometrogram (CMG) to determine whether the stimulation can reverse the PNS-induced bladder underactivity. SPNSc or SPNSi applied by nerve cuff electrodes during the prolonged PNS inhibition significantly reduced bladder capacity to 124.4 ± 10.7% and 132.4 ± 14.2% of control, respectively, and increased contraction amplitude to 85.3 ± 6.2% and 75.8 ± 4.7%, respectively. Transcutaneous SPNSc and SPNSi also significantly reduced bladder capacity and increased contraction amplitude. Additional PNS applied during the bladder underactivity further increased bladder capacity, whereas SPNSc applied simultaneously with the PNS reversed the increase in bladder capacity. This study indicates that a noninvasive superficial peroneal neuromodulation therapy might be developed to treat bladder underactivity caused by abnormal pudendal nerve somatic afferent activation that is hypothesized to occur in patients with Fowler\'s syndrome.

The purpose of this study was to determine the effects of pudendal nerve stimulation (PNS) on reflex bladder activity and develop an animal model of underactive bladder (UAB). In six anesthetized cats, a bladder catheter was inserted via the urethra to infuse saline and measure pressure. A cuff electrode was implanted on the pudendal nerve. After determination of the threshold intensity (T) for PNS to induce an anal twitch, PNS (5 Hz, 0.2 ms, 2 T or 4 T) was applied during cystometrograms (CMGs). PNS (4-6 T) of 30-min duration was then applied repeatedly until bladder underactivity was produced. Following stimulation, control CMGs were performed over 1.5-2 h to determine the duration of bladder underactivity. When applied during CMGs, PNS (2 T and 4 T) significantly (P < 0.05) increased bladder capacity while PNS at 4 T also significantly (P < 0.05) reduced bladder contraction amplitude, duration, and area under contraction curve. Repeated application of 30-min PNS for a cumulative period of 3-8 h produced bladder underactivity exhibiting a significantly (P < 0.05) increased bladder capacity (173 ± 14% of control) and a significantly (P < 0.05) reduced contraction amplitude (50 ± 7% of control). The bladder underactivity lasted more than 1.5-2 h after termination of the prolonged PNS. These results provide basic science evidence supporting the proposal that abnormal afferent activity from external urethral/anal sphincter could produce central inhibition that underlies nonobstructive urinary retention (NOUR) in Fowler\'s syndrome. This cat model of UAB may be useful to investigate the mechanism by which sacral neuromodulation reverses NOUR in Fowler\'s syndrome.

Bone is a dynamic organ that undergoes constant remodeling, an energetically costly process by which old bone is replaced and localized bone defects are repaired to renew the skeleton over time, thereby maintaining skeletal health. This review provides a general overview of bone\'s main players (bone lining cells, osteocytes, osteoclasts, reversal cells, and osteoblasts) that participate in bone remodeling. Placing emphasis on the family of extracellular matrix metalloproteinases (MMPs), we describe how: (i) Convergence of multiple protease families (including MMPs and cysteine proteinases) ensures complexity and robustness of the bone remodeling process, (ii) Enzymatic activity of MMPs affects bone physiology at the molecular and cellular levels and (iii) Either overexpression or deficiency/insufficiency of individual MMPs impairs healthy bone remodeling and systemic metabolism. Today, it is generally accepted that proteolytic activity is required for the degradation of bone tissue in osteoarthritis and osteoporosis. However, it is increasingly evident that inactivating mutations in MMP genes can also lead to bone pathology including osteolysis and metabolic abnormalities such as delayed growth. We argue that there remains a need to rethink the role played by proteases in bone physiology and pathology.

To investigate the impact of preoperative detrusor underactivity (DU) on serial treatment outcomes over the course of 5 years after photovaporization (PV) or holmium laser enucleation (HoLEP) in patients with benign prostatic hyperplasia (BPH), to compare its impact after PV vs HoLEP, and to identify predictors of long-term lower urinary tract symptoms (LUTS) improvement.
This study involved 245 patients with BPH who had complete 5-year follow-up data (PV using 120W-HPS, n = 143, HoLEP, n = 102), grouped as follows: PV-HPS-DU(+), n = 114; PV-HPS-DU(-), n = 29; HoLEP-DU(+), n = 56; and HoLEP-DU(-), n = 46. Bladder contractility index (BCI) < 100 was regarded as DU. Serial treatment outcomes for the International Prostate Symptom Score (IPSS) questionnaire, uroflowmetry and serum PSA level at 6 months, and at 1, 2, 3, 4 and 5 years after surgery, were compared among the groups. LUTS improvement was defined as a reduction in total IPSS of ≥50% relative to baseline.
Improvement in total IPSS, quality of life (QoL) index and post-void residual urine volume (PVR) in the PV-HPS-DU(+) and PV-HPS-DU(-) groups were maintained up to 5 years after PV, except for maximum urinary flow rate (Qmax ) and bladder voiding efficiency. In the HoLEP-DU(+) and HoLEP-DU(-) groups, improvements in all outcome variables were maintained up to 5 years after HoLEP. Deteriorations in subtotal voiding symptom score, total IPSS and Qmax with time during the long-term period after surgery were more pronounced in the PV-HPS-DU(+) and HoLEP-DU(+) groups than in the PV-HPS-DU(-) and HoLEP-DU(-) groups. Reductions in subtotal voiding symptom score, total IPSS, QoL index, and serum PSA were greater in the HoLEP-DU(+) group than in the PV-HPS-DU(+) group throughout follow-up. The type of surgery (HoLEP vs PV) and higher baseline BCI were independent predictors of LUTS improvement at 5 years after surgery.
Generally, improvement of micturition symptoms, QoL and PVR in patients with DU appears to be maintained up to 5 years after PV or HoLEP. Deterioration of voiding symptoms and urinary flow rate at long-term follow-up visits after PV or HoLEP was more pronounced in patients with LUTS/BPH with DU than in those without DU. Patients with BPH with DU may benefit from more complete removal of prostatic adenoma by HoLEP and greater baseline bladder contractility in terms of micturition symptoms and QoL.

OBJECTIVE: This study is aimed at determining if tibial nerve stimulation (TNS) can modulate both bladder underactivity and overactivity.
METHODS: In α-chloralose anesthetized cats, tripolar cuff electrodes were implanted on both tibial nerves and TNS threshold (T) for inducing toe twitching was determined for each nerve. Normal bladder activity was elicited by slow intravesical infusion of saline; while bladder overactivity was induced by infusion of 0.25% acetic acid to irritate the bladder. Bladder underactivity was induced during saline infusion by repeated application (2-6 times) of 30-min TNS (5 Hz, 4-8T, 0.2 msec) to the left tibial nerve, while TNS (1 Hz, 4T, 0.2 msec) was applied to the right tibial nerve to reverse the bladder underactivity.
RESULTS: Prolonged 5-Hz TNS induced bladder underactivity by significantly increasing bladder capacity to 173.8% ± 10.4% of control and reducing the contraction amplitude to 40.1% ± 15.3% of control, while 1 Hz TNS normalized the contraction amplitude and significantly reduced the bladder capacity to 130%-140% of control. TNS at 1 Hz in normal bladders did not change contraction amplitude and only slightly changed the capacity, but in both normal and underactive bladders significantly increased contraction duration. The effects of 1 Hz TNS did not persist following stimulation. Under isovolumetric conditions when the bladder was underactive, TNS (0.5-3 Hz; 1-4T) induced large amplitude and sustained bladder contractions. In overactive bladders, TNS during cystometry inhibited bladder overactivity at 5 Hz but not at 1 Hz.
CONCLUSIONS: This study indicates that TNS at different frequencies might be used to treat bladder underactivity and overactivity.

To establish an animal model of bladder underactivity induced by prolonged and intense stimulation of somatic afferent axons in the tibial nerve.
In seven cats under α-chloralose anesthesia, tibial nerve stimulation (TNS) of 30-min duration was repeatedly (3-8 times) applied at 4-6 times threshold (T) intensity for inducing a toe twitch to produce bladder underactivity determined by cystometry. Naloxone (1 mg/kg, i.v.) was administered to examine the role of opioid receptors in TNS-induced bladder underactivity.
After prolonged (1.5-4 h) and intense (4-6T) TNS, a complete suppression of the micturition reflex occurred in six cats and an increase in bladder capacity to about 150% of control and a decrease in the micturition contraction amplitude to 50% of control occurred in one cat. The bladder underactivity was maintained for at least 1-1.5 h. Naloxone reversed the bladder underactivity, but an additional 30-min TNS removed the naloxone effect.
The results indicate that prolonged and intense activation of somatic afferent axons in the tibial nerve can suppress the central reflex mechanisms controlling micturition. This animal model may be useful for examining the pathophysiology of neurogenic bladder underactivity and for development of new treatments for underactive bladder symptoms.

This study aimed to determine what difference the inclusion of patients with coexisting detrusor overactivity (DO) makes to the signs and symptoms of patients with detrusor underactivity (DU).
A total of 250 male and 435 female urodynamic tests were analyzed retrospectively. Signs and symptoms which showed a statistically significant difference between DU without DO and DU with DO were identified.
Males with DO in addition to DU had higher age and number of daily micturitions, and were more likely to report urgency with or without urgency incontinence than males with DU without DO. They also had lower volumes for first desire to void, volume voided, and post void residual urine, lower abdominal pressure at Qmax and were less likely to report a history of retention or reduced bladder filling sensation than males with DU without DO. Females with DO in addition to DU had higher age and BMI, and were more likely to report urgency incontinence, higher day and night pad usage, constipation and have reduced anal tone than females with DU without DO. They also had lower volumes for first desire to void, volume voided, and post void residual urine, and lower abdominal pressure at Qmax than females who had DU without DO.
There are differences in signs and symptoms between patients who have DU without DO, compared to patients having DU with DO. This understanding will help future studies investigating treatment options for DU patients.

This study in α-chloralose-anesthetized cats aimed at investigating the bladder responses to saphenous nerve stimulation (SNS). A urethral catheter was used to infuse the bladder with saline and to record changes in bladder pressure. With the bladder fully distended, SNS at 1-Hz frequency and an intensity slightly below the threshold (T) for inducing an observable motor response of the hindlimb muscles induced large amplitude (40-150 cmH2O) bladder contractions. Application of SNS (1 Hz, 2-4T) during cystometrograms (CMGs), when the bladder was slowly (1-3 ml/min) infused with saline, significantly ( P < 0.05) increased the duration of the micturition contraction to >200% of the control without changing bladder capacity or contraction amplitude. Repeated application (1-8 times) of intense (4-8T intensity) 30-min tibial nerve stimulation (TNS) produced prolonged post-TNS inhibition that significantly ( P < 0.01) increased bladder capacity to 135.9 ± 7.6% and decreased the contraction amplitude to 44.1 ± 16.5% of the pre-TNS control level. During the period of post-TNS inhibition, SNS (1 Hz, 2-4T) applied during CMGs completely restored the bladder capacity and the contraction amplitude to the pre-TNS control level and almost doubled the duration of the micturition contraction. These results indicate that SNS at 1 Hz can facilitate the normal micturition reflex and normalize the reflex when it is suppressed during post-TNS inhibition. This study provides an opportunity to develop a novel neuromodulation therapy for underactive bladder using SNS.