Tomonori Yamanishi

Overexpression of RhoA, Rac1, and Cdc42 GTPases Is Associated with Progression in Testicular Cancer

The Rho family of GTPases are involved in actin cytoskeleton organization and associated with carcinogenesis and progression of human cancers. We investigated the roles of Rho family GTPases, prototypes RhoA, Rac1, and Cdc42, and the major downstream targets of RhoA, ROCK-I, and ROCK-II in testicular cancer. We quantified protein expression in paired tumor and nontumor samples from surgical specimens from 57 consecutive patients with testicular germ cell tumors using Western blotting. Protein expression of RhoA, ROCK-I, ROCK-II, Rac1, and Cdc42 was significantly higher in tumor tissue than in nontumor tissue (P < 0.0001). Expression of protein for RhoA, ROCK-I, ROCK-II, Rac1, and Cdc42 was greater in tumors of higher stages than lower stages (P < 0.0001, P < 0.001, P < 0.001, P < 0.0001, P < 0.0001, respectively). Within stage II nonseminoma (31 patients), protein levels of RhoA, ROCK-I, ROCK-II, Rac1, and Cdc42 in the primary tumor were lower in the group of 24 patients with no evidence of disease after therapy compared with 7 patients with disease that was refractory/recurrent (P < 0.05). Rho family GTPases may be involved in the progression of testicular germ cell tumors.

Micturitional disturbance after acute hemispheric stroke: analysis of the lesion site by CT and MRI

Micturitional histories and urodynamic studies were performed in 72 acute hemispheric stroke patients. Within 3 months from the onset, 53% of the patients had urinary symptoms including irritative as well as obstructive, and the most common symptom was nocturnal urinary frequency in 36%, which was followed by urge urinary incontinence in 29% and difficulty of voiding in 25% of the patients. We found a correlation between micturitional disturbance with hemiparesis (p <0.05) and not with hemianopsia (p <0.05). Micturitional disturbance was more common in lesions of the frontal lobe (p <0.05) than in those of the occipital lobe. Brain CT or MRI in symptomatic patients showed lesions of anterior and medial surface of the frontal lobe, anterior edge of the paraventricular white matter, genu of the internal capsule and large lesions of putamen or thalamus. Urodynamic studies of 22 symptomatic patients revealed various findings in 91% of them, including detrusor hyperreflexia in 68%, detrusor-sphincter dyssynergia (DSD) in 14% and uninhibited sphincter relaxation in 36%. Patients with urinary retention had atonic cystometrogram and DSD. Detrusor hyperreflexia was noted in lesions of the frontal lobe as well as the basal ganglia, uninhibited sphincter relaxation in the frontal lobe, and detrusor-sphincter dyssynergia common in the basal ganglia. Above findings seem to indicate that anteromedial frontal lobe and its descending pathway, and the basal ganglia seem to be mainly responsible for supranuclear types of pelvic and pudendal nerve dysfunction in our patients with stroke.

Urinary function in elderly people with and without leukoaraiosis: relation to cognitive and gait function

OBJECTIVES To investigate urinary function in the elderly with and without white matter lesion (leukoaraiosis) in relation to cognitive and gait function. METHODS Sixty three subjects were examined, with mean age 73 (range 62 to 86 years). Subjects with brainstem stroke or with large hemispheric lesions were excluded. Spin echo 1.5 T MRI images were graded from 0 to 4 for severity of white matter lesions. Urinary function was assessed by detailed questionnaire and urodynamic studies were performed in 33 of the subjects, including measurement of postmicturition residuals, water cystometry, and sphincter EMG. A mini mental state examination (MMSE) and examination of gait was also performed and compared with urinary function. RESULTS Urodynamic studies showed subjects with grade 1–4 white matter lesions to have detrusor hyperreflexia more commonly (82%) than those with grade 0 white matter lesions (9%) (p<0.05), indicating that leukoaraiosis was a factor associated with geriatric urinary dysfunction. Postmicturition residuals, low compliance, detrusor-sphincter dyssynergia, and uninhibited sphincter relaxation were also more common in grade 1–4 than in grade 0 white matter lesions, though the difference was not significant. In grade 1 white matter lesions urinary dysfunction (urge urinary incontinence) was more common than cognitive (MMSE<19) (p<0.05) and gait disorders (slowness, short step/festination, and loss of postural reflex) (p<0.05), which increased together with the grade of white matter lesions (p<0.05). CONCLUSIONS Urinary dysfunction is common and probably the early sign in elderly people with leukoaraiosis on MRI.

Colonic transit time and rectoanal videomanometry in Parkinson’s disease

Background: Constipation is a prominent lower gastrointestinal tract dysfunction that occurs frequently in Parkinson’s disease (PD). Objective: To investigate colonic transport and dynamic rectoanal behaviour during filling and defecation in patients with PD. Methods: Colonic transit time (CTT) and rectoanal videomanometry analyses were performed in 12 patients with PD (10 men and 2 women; mean age, 68 years, mean duration of disease, five years; mean Hoehn and Yahr grade, 3; decreased stool frequency (<3 times a week) in six, difficulty in stool expulsion in eight) and 10 age matched normal control subjects (7 men and 3 women; mean age, 62 years; decreased stool frequency in two, difficulty in stool expulsion in two). Results: In the PD patients, CTT was significantly prolonged in the rectosigmoid segment (p<0.05) and total colon (p<0.01) compared with the control subjects. At the resting state, anal closure and squeeze pressures of PD patients were lower than those in control subjects, though not statistically significant. However, the PD patients showed a smaller increase in abdominal pressure on coughing (p<0.01) and straining (p<0.01). The sphincter motor unit potentials of the patients were normal. During filling, PD patients showed normal rectal volumes at first sensation and maximum desire to defecate, and normal rectal compliance. However, they showed smaller amplitude in phasic rectal contraction (p<0.05), which was accompanied by an increase in anal pressure that normally decreased, together with leaking in two patients. During defecation, most PD patients could not defecate completely with larger post-defecation residuals (p<0.01). PD patients had weak abdominal strain and smaller rectal contraction on defecation than those in control subjects, though these differences were not statistically significant. However, the PD patients had larger anal contraction on defecation (p<0.05), evidence of paradoxical sphincter contraction on defecation (PSD). Conclusions: Slow colonic transit, decreased phasic rectal contraction, weak abdominal strain, and PSD were all features in our PD patients with frequent constipation.

Randomized, double-blind study of electrical stimulation for urinary incontinence due to detrusor overactivity.

OBJECTIVES To evaluate the usefulness of electrical stimulation for urinary incontinence due to detrusor overactivity in a randomized, double-blind manner. METHODS Sixty-eight patients (29 men, 39 women, 70.0 +/- 11.2 years) were studied. Detrusor overactivity was urodynamically defined as involuntary detrusor contractions of more than 15 cm H(2)O during the filling phase. Ten-hertz square waves of 1-ms pulse duration were used. A vaginal electrode was used in the women and an anal or surface electrode in the men. The stimulation was given for 15 minutes twice daily for 4 weeks. The efficacy was evaluated on the basis of a frequency/volume chart and urodynamic study before and after treatment. RESULTS Thirty-two patients in the active group and 28 in the sham group completed the study. The patient impressions were very good or good in 59% and 39% of the active and the sham group, respectively (P = 0.0354). On the cystometrogram, the bladder capacity at the first desire to void and the maximum desire to void increased significantly (P = 0.0104 and P = 0.0046, respectively) in the active group, but not in the sham group. Seven patients in the active group and 1 patient in the sham group were cured (P = 0.0324); 26 patients (81.3%) in the active group and 9 (32.1%) in the sham group improved (P = 0.0001). Of 17 patients in the active group, 13 remained cured or improved for an average of 8.4 months after completion of the 4-week treatment; in the sham group, 3 of 6 patients were cured or improved for an average of 4.7 months after completion of the 4-week treatment. CONCLUSIONS Electrical stimulation was useful in treating urinary incontinence due to detrusor overactivity.

Bladder and bowel dysfunction in Parkinson’s disease

Summary.Bladder dysfunction (urinary urgency/frequency) and bowel dysfunction (constipation) are common non-motor disorders in Parkinson’s disease (PD). In contrast to motor disorder, the pelvic autonomic dysfunction is often non-responsive to levodopa treatment. Brain pathology mostly accounts for the bladder dysfunction (appearance of overactivity) via altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. In contrast, peripheral enteric pathology mostly accounts for the bowel dysfunction (slow transit and decreased phasic contraction) via altered dopamine-enteric nervous system circuit, which normally promotes the peristaltic reflex. In addition, weak strain and paradoxical anal contraction might be the results of brain pathology. Pathophysiology of the pelvic organ dysfunction in PD differs from that in multiple system atrophy; therefore it might aid the differential diagnosis. Drugs to treat bladder dysfunction in PD include anticholinergic agents. Drugs to treat bowel dysfunction in PD include dietary fibers, peripheral dopaminergic antagonists, and selective serotonergic agonists. These treatments might be beneficial not only in maximizing patients’ quality of life, but also in promoting intestinal absorption of levodopa and avoiding gastrointestinal emergency.

PELVIC FLOOR ELECTRICAL STIMULATION IN THE TREATMENT OF STRESS INCONTINENCE: AN INVESTIGATIONAL STUDY AND A PLACEBO CONTROLLED DOUBLE-BLIND TRIAL

PURPOSE We designed an investigational study and a placebo controlled, double-blind study to evaluate the usefulness of electrical pelvic stimulation in stress incontinence. MATERIALS AND METHODS We studied 44 patients with stress incontinence (six men and 38 women, age 63 +/- 13), including 9 patients in the investigational study and 35 in the double-blind study. We used 50 Hz. square waves of 1 ms. pulse duration for stimulation. A vaginal electrode was used in women and an anal electrode in men. Urethral pressure profile before, during and after 15-minute stimulation was measured in the investigational study. In the double-blind trial an active device and a dummy device were used, and efficacy was judged from patient impressions, records in frequency/volume chart, results of 1-hour pad test and urodynamic parameters after 4-week treatment. RESULTS In the investigational study maximum urethral closure pressure (mean plus or minus standard deviation) before, during and after stimulation was 44.4 +/- 17.5, 64.5 +/- 28.8 and 46.8 +/- 25.6 cm. water, respectively. This parameter significantly increased (p = 0.0275) during stimulation. In the double-blind trial patient impressions were good in 60% of the active device group and 8% of the dummy device group (p = 0.0051). For the pad test significant improvement was noted in the active device group (p = 0.0100). Cure rate was 45% in the active device group and 7.7% in the dummy device group. There were significantly more cured or improved patients for frequency of leakage (p = 0.0196) and pad test (p = 0.0100). CONCLUSIONS Electrical stimulation is effective for the treatment of stress incontinence.

Urinary dysfunction and orthostatic hypotension in multiple system atrophy: which is the more common and earlier manifestation?

OBJECTIVES Urinary dysfunction and orthostatic hypotension are the prominent autonomic features in multiple system atrophy (MSA). A detailed questionnaire was given and autonomic function tests were performed in 121 patients with MSA concerning both urinary and cardiovascular systems. METHODS Replies to the questionnaire on autonomic symptoms were obtained from 121 patients including three clinical variants; olivopontocerebellar atrophy (OPCA) type in 48, striatonigral degeneration (SND) type in 17, and Shy-Drager type in 56. Urodynamic studies comprised measurement of postmicturition residuals, EMG cystometry, and bethanechol injection. Cardiovascular tests included head up tilt test, measurement of supine plasma noradrenaline (norepinephrine,NA), measurement of R-R variability (CV R-R), and intravenous infusions of NA and isoproterenol. RESULTS Urinary symptoms (96%) were found to be more common than orthostatic symptoms (43%) (p<0.01) in patients with MSA, particularly with OPCA (p<0.01) and SND (p<0.01) types. In 53 patients with both urinary and orthostatic symptoms, patients who had urinary symptoms first (48%) were more common than those who had orthostatic symptoms first (29%), and there were patients who developed both symptoms simultaneously (23%). Post-micturition residuals were noted in 74% of the patients. EMG cystometry showed detrusor hyperreflexia in 56%, low compliance in 31%, atonic curve in 5%, detrusor-sphincter dyssynergia in 45%, and neurogenic sphincter EMG in 74%. The cystometric curve tended to change from hyperreflexia to low compliance, then atonic curve in repeated tests. Bethanechol injection showed denervation supersensitivity of the bladder in 19%. Cardiovascular tests showed orthostatic hypotension below –30 mm Hg in 41%, low CV R-R below 1.5 in 57%, supine plasma NA below 100 pg/ml in 28%, and denervation supersensitivity of the vessels (α in 73%; β2 in 60%) and of the heart (β1 in 62%). CONCLUSION It is likely that urinary dysfunction is more common and often an earlier manifestation than orthostatic hypotension in patients with MSA, although subclinical cardiovascular abnormalities appear in the early stage of the disease. The responsible sites seem to be central and peripheral for both dysfunctions.

Short-term effect of a single levodopa dose on micturition disturbance in Parkinson's disease patients with the wearing-off phenomenon

We investigated the short‐term effects of a single dose of levodopa (L‐dopa) on micturition function in PD patients with wearing‐off phenomenon. Eighteen PD patients who had median Hoehn and Yahr scores of 5 during the off phase and 3 during the on phase were recruited. We carried out urodynamic studies before and about 1 hour after the patients had taken 100 mg of L‐dopa with dopa‐decarboxylase inhibitor (DCI). After taking the L‐dopa/DCI, urinary urgency and urge incontinence aggravated, whereas voiding difficulty was alleviated in all 12 patients. When compared to the baseline assessment, urodynamic study results after taking 100 mg of L‐dopa/DCI showed aggravated detrusor hyperreflexia; decreased maximum bladder capacity (P = 0.006); an increased maximum Watts Factor value (P = 0.001), reflecting the detrusor power on voiding; an increased Abrams‐Griffiths number (P = 0.042), reflecting urethral obstruction on voiding; decreased residual urine volume (P = 0.025); and increased static urethral closure pressure (P = 0.012). One hundred milligrams of L‐dopa/DCI worsened detrusor hyperreflexia, producing worsened urinary urgency and urge incontinence during the storage (bladder‐filling) phase. It also increased detrusor contractility much more than it did urethral obstruction in the voiding phase, producing overall lessening of voiding difficulty and improving voiding efficiency in our PD patients with the wearing‐off phenomenon.

Micturitional disturbance and the pontine tegmental lesion: urodynamic and MRI analyses of vascular cases

Micturitional histories were taken from 39 patients with acute brainstem stroke. Within 3 months from onset, 49% had irritative as well as obstructive urinary symptoms, the most common being voiding difficulty and nocturnal urinary frequency in 28%, followed by urinary retention in 21%. Urodynamic studies of 11 symptomatic patients revealed detrusor hyperreflexia in 73%, low compliance bladder in 9%, atonic cystometrogram in 27%, detrusor-sphincter dyssynergia in 45% and uninhibited sphincter relaxation in 27%. Three asymptomatic patients had normal urodynamic findings. Brain magnetic resonance images of the lesions of the symptomatic patients were concentrated in the dorsolateral pons including pontine reticular nucleus and the reticular formation adjacent to the medial parabrachial nucleus and the locus coeruleus. These regions seem to be mainly responsible for supranuclear types of pelvic and pudendal nerve dysfunction in our patients with brainstem stroke, corresponding to the pontine urinary storage and micturation center reported in animal studies.