Microtubules have been among the most successful targets in anticancer therapy and a large number of microtubule-targeting agents (MTAs) are in various stages of clinical development for the treatment of several malignancies. Given that injury and diseases in the central nervous system (CNS) are accompanied by acute or chronic disruption of the structural integrity of neurons and that microtubules provide structural support for the nervous system at cellular and intracellular levels, microtubules are emerging as potential therapeutic targets for treating CNS disorders. It has been postulated that exogenous application of MTAs might prevent the breakdown or degradation of microtubules after injury or during neurodegeneration, which will thereby aid in preserving the structural integrity and function of the nervous system. Here we review recent evidence that supports this notion and also discuss potential risks of targeting microtubules as a therapy for treating nerve injury and neurodegenerative diseases.
Microtubules; Neoplasms; Nerve Degeneration; Wounds and Injuries
Benign prostatic hyperplasia (BPH) is the most common prostate problem in older men. The present study aimed to investigate the inhibitory effect of Panax ginseng C.A. Meyer (P. ginseng) on a rat model of testosterone-induced BPH.
The rats were divided into 3 groups (each group, n=10): control, testosterone-induced BPH (20 mg/kg, subcutaneous injection), and P. ginseng (200 mg/kg, orally) groups. After 4 weeks, all animals were sacrificed to examine the blood biochemical profiles, prostate volume, weight, histopathological changes, alpha-1D adrenergic receptor (Adra1d) mRNA expression, and epidermal growth factor receptor (EGFR) and B-cell CLL/lymphoma 2 (BCL2) protein expression.
The group treated with P. ginseng showed significantly lesser prostate size and weight than the testosterone-induced BPH group. In addition, P. ginseng decreased the mRNA expression of Adra1d as well as the expression of EGFR and BCL2 in prostate tissue.
These results suggest that P. ginseng may inhibit the alpha-1-adrenergic receptor to suppress the development of BPH.
Prostatic Hyperplasia; Receptors, Adrenergic, alpha-1; Panax; Testosterone
Neurogenic lower urinary tract dysfunction (NLUTD) is a possible consequence of several neurological disorders. NLUTD may produce debilitating symptoms and serious complications, such as chronic renal failure, and recurrent urinary tract infections. Many animal studies of NLUTD symptoms have focused on animal models of cerebral ischemia. In the present study, we investigated the effects of treadmill exercise on memory function and its relation to cell proliferation and apoptosis in the hippocampus, following transient global ischemia in gerbils.
To induce transient global ischemia in gerbil, both common carotid arteries were occluded for 5 minutes. Gerbils in the exercise groups were forced to run on a treadmill exercise for 30 minutes once a day for 2 weeks. Step-down avoidance task and Y maze task were performed. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-staining, immunohistochemistry for 5-bromo-2'-deoxyridine, doublecortin, caspase-3, and Western blot for brain-derived neurotrophic factor (BDNF), Bax, Bcl-2, cytochrome c, caspase-3 were conducted.
Ischemia caused memory impairment with an increase of cell proliferation, BDNF expression, and apoptosis in the hippocampus. Treadmill exercise improved memory function with further increase of cell proliferation and BDNF expression and a decrease of apoptosis.
The animal model that we have developed and our assessment of the relation between exercise and brain function can be useful tools for future investigations of NLUTD symptoms associated with stroke, particularly ischemic stroke. The present study suggests that treadmill exercise promoted the recovery of brain function after cerebral ischemia.
Ischemia; Cell Proliferation; Brain-Derived Neurotrophic Factor; Apoptosis; Exercise Test
To identify the factors affecting the surgical decisions of experienced physicians when treating patients with lower urinary tract symptoms that are suggestive of benign prostatic hyperplasia (LUTS/BPH).
Patients with LUTS/BPH treated by two physicians between October 2004 and August 2013 were included in this study. The causal Bayesian network (CBN) model was used to analyze factors influencing the surgical decisions of physicians and the actual performance of surgery. The accuracies of the established CBN models were verified using linear regression (LR) analysis.
A total of 1,108 patients with LUTS/BPH were analyzed. The mean age and total prostate volume (TPV) were 66.2 (±7.3, standard deviation) years and 47.3 (±25.4) mL, respectively. Of the total 1,108 patients, 603 (54.4%) were treated by physician A and 505 (45.6%) were treated by physician B. Although surgery was recommended to 699 patients (63.1%), 589 (53.2%) actually underwent surgery. Our CBN model showed that the TPV (R=0.432), treating physician (R=0.370), bladder outlet obstruction (BOO) on urodynamic study (UDS) (R=0.324), and International Prostate Symptom Score (IPSS) question 3 (intermittency; R=0.141) were the factors directly influencing the surgical decision. The transition zone volume (R=0.396), treating physician (R=0.340), and BOO (R=0.300) directly affected the performance of surgery. Compared to the LR model, the area under the receiver operating characteristic curve of the CBN surgical decision model was slightly compromised (0.803 vs. 0.847, P<0.001), whereas that of the actual performance of surgery model was similar (0.801 vs. 0.820, P=0.063) to the LR model.
The TPV, treating physician, BOO on UDS, and the IPSS item of intermittency were factors that directly influenced decision-making in physicians treating patients with LUTS/BPH.
Bayes Theorem; Decision Support Techniques; Decision Making, Computer-Assisted; Prostatic Hyperplasia; Urodynamics
Healthy, young individuals are known to exhibit circadian variation in urinary functions. However, the effects of chronic circadian disturbance on voiding functions are largely unknown. The present work compared the effects of rotational shifts on the micturition patterns of female nurses to that in female nurses with routine daytime shifts.
A total of 19 nurses without lower urinary tract symptoms who worked rotational shifts for an average duration of 2 years were recruited. A voiding diary was kept for 9 consecutive days, and the overactive bladder symptom score (OABSS) questionnaire was completed three times, starting 3 days before their night duties until 3 days after completion of their night duties. For comparison, seven nurses with regular shifts completed a 3-day voiding diary and the OABSS questionnaire.
Female nurses working rotational shifts had lower overall urine production and had decreased urination frequency and nocturia than female nurses working regular shifts, even when the nurses who worked rotational shifts had a regular night's sleep for at least 7 days. Upon reinitiation of night duty, overall urine production increased significantly, with no significant changes in urgency and frequency. When these nurses returned to daytime duty, the volume of urine decreased but nocturnal urine production remained high, and the incidence of nocturia also increased significantly. However, the effects on OABSS score were not significant under the study design used.
Long-term rotational shifts resulted in adaptive changes such as decreased urine production and frequency in healthy, young female nurses. In addition, their micturition patterns were significantly affected by abrupt changes in their work schedules. Although working in shifts did not increase urgency or frequency of urination in healthy, young female nurses working rotational shifts for an average 2 years, large-scale studies are needed to systematically analyze the influence of shift work timings on micturition in humans.
Circadian Rhythm; Work; Rotation; Urination
The aims of this study were to investigate the efficacy of combining the systematized behavioral modification program (SBMP) with desmopressin therapy and to compare this with desmopressin monotherapy in the treatment of nocturnal polyuria (NPU).
Patients were randomized at 8 centers to receive desmopressin monotherapy (group A) or combination therapy, comprising desmopressin and the SBMP (group B). Nocturia was defined as an average of 2 or more nightly voids. The primary endpoint was a change in the mean number of nocturnal voids from baseline during the 3-month treatment period. The secondary endpoints were changes in the bladder diary parameters and questionnaires scores, and improvements in self-perception for nocturia.
A total of 200 patients were screened and 76 were excluded from the study, because they failed the screening process. A total of 124 patients were randomized to receive treatment, with group A comprising 68 patients and group B comprising 56 patients. The patients' characteristics were similar between the groups. Nocturnal voids showed a greater decline in group B (-1.5) compared with group A (-1.2), a difference that was not statistically significant. Significant differences were observed between groups A and B with respect to the NPU index (0.37 vs. 0.29, P=0.028), the change in the maximal bladder capacity (-41.3 mL vs. 13.3 mL, P<0.001), and the rate of patients lost to follow up (10.3% [7/68] vs. 0% [0/56], P=0.016). Self-perception for nocturia significantly improved in both groups.
Combination treatment did not have any additional benefits in relation to reducing nocturnal voids in patients with NPU; however, combination therapy is helpful because it increases the maximal bladder capacity and decreases the NPI. Furthermore, combination therapy increased the persistence of desmopressin in patients with NPU.
Nocturia; Polyuria; Behavior Therapy
Aminopyridines are potassium channel blockers that increase the excitability of nerve cells and axons; therefore, they are widely used to treat different neurological disorders. Here we present a patient with idiopathic downbeat nystagmus and lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia who was treated with the sustained-release form of 4-aminopyridine (4-AP). During treatment with 4-AP, the LUTS improved. This improvement was monitored by using uroflowmetry and the International Prostate Symptom Score. A significant improvement of symptoms was observed in relation to the voided volume. This included an improved emptying of the bladder without an increase in residual urine. In animal studies, both nonselective K+ channel blockade and selective voltage-sensitive potassium blockade by 4-AP resulted in increased contraction on rat detrusor strips. To our knowledge, this is the first clinical observation of the mode of action of 4-AP in urological symptoms in humans.
4-Aminopyridine; Prostatic Hyperplasia; Lower Urinary Tract Symptoms; Drug Therapy; Neurogenic Urinary Bladder
Interstitial cystitis (IC), also known as painful bladder syndrome or bladder pain syndrome, is a chronic lower urinary tract syndrome characterized by pelvic pain, urinary urgency, and increased urinary frequency in the absence of bacterial infection or identifiable clinicopathology. IC can lead to long-term adverse effects on the patient's quality of life. Therefore, early diagnosis and better understanding of the mechanisms underlying IC are needed. Metabolomic studies of biofluids have become a powerful method for assessing disease mechanisms and biomarker discovery, which potentially address these important clinical needs. However, limited intensive metabolic profiles have been elucidated in IC. The article is a short review on metabolomic analyses that provide a unique fingerprint of IC with a focus on its use in determining a potential diagnostic biomarker associated with symptoms, a response predictor of therapy, and a prognostic marker.
Interstitial cystitis; Metabolomics; Biological markers; Magnetic resonance spectroscopy; Mass spectrometry
Berberine is a type of isoquinoline alkaloid that has been used to treat various diseases. A neuroprotective effect of berberine against cerebral ischemia has been reported; however, the effects of berberine on apoptosis in relation to reactive astrogliosis and microglia activation under ischemic conditions have not yet been fully evaluated. In the present study, we investigated the effects of berberine on global ischemia-induced apoptosis, and focused on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in the hippocampus using gerbils.
Gerbils received berberine orally once a day for 14 consecutive days, starting one day after surgery. In this study, a step-down avoidance task was used to assess short-term memory. Furthermore, we employed the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay to evaluate DNA fragmentation, immunohistochemistry to investigate glial fibriallary acidic protein, CD11b, and caspase-3, and western blot to assess PI3K, Akt, Bax, Bcl-2, and cytochrome c.
Our results revealed that berberine treatment alleviated ischemia-induced short-term memory impairment. Treatment with berbeine also attenuated ischemia-induced apoptosis and inhibited reactive astrogliosis and microglia activation. Furthermore, berberine enhanced phospho-PI3K and phospho-Akt expression in the hippocampus of ischemic gerbils.
Berberine exerted a neuroprotective effect against ischemic insult by inhibiting neuronal apoptosis via activation of the PI3K/Akt signaling pathway. The antiapoptotic effect of berberine was achieved through inhibition of reactive astrogliosis and microglia activation. Berberine may therefore serve as a therapeutic agent for stroke-induced neurourological problems.
Berberine; Brain ischemia; Short-term memory; Apoptosis; Phosphatidylinositol 3-kinases
The aim of this study was to evaluate the prevalence of lower urinary tract symptoms (LUTS) among Korean men aged ≥40 years.
We performed a population-based, cross-sectional door-to-door survey on a geographically stratified random sample of men aged ≥40 years. All respondents were asked about the presence of individual LUTS using a questionnaire based on 2002 International Continence Society definitions. For comparison, we also defined nocturia as two or more nocturnal micturitions per night. The International Prostate Symptom Score (IPSS) questionnaire was used to assess LUTS severity.
Responses from 1,842 subjects were analyzed. The overall prevalence of LUTS was 83.4%. Storage LUTS (70.1%) were more prevalent than voiding (60.4%) or postmicturition LUTS (38.3%). When nocturia was defined as two or more nocturnal micturitions per night, voiding symptoms became most prevalent (storage, 39.7%; voiding, 60.4%; and postmicturition, 38.3%). More than 90% of our population described the severity of their urinary symptoms as moderate (8-19) or severe (20-35). The prevalence and severity of LUTS increased with age.
LUTS are highly prevalent among Korean men, and its prevalence increases with age. Increased public awareness and a larger number of treatment options are needed to appropriately manage symptoms and their consequences.
Lower urinary tract symptoms; Prevalence; Epidemiologic studies
To review the clinical outcomes of patients with voiding dysfunction who have detrusor overactivity with impaired contractility (DOIC) diagnosed with urodynamic studies.
Urodynamic reports from 2005 to 2009 were reviewed, and 54 male patients had findings consistent with DOIC. Patients with acontractile or neuropathic bladders were excluded. Clinical outcomes were obtained from patient records.
Of 54 men, 8 presented with voiding symptoms, 17 had storage symptoms, and 29 had mixed symptoms. Twenty-two had a previous transurethral resection of the prostate. The median follow-up was 12 months. Four patients received no intervention. Two patients were taught intermittent self-catheterization. Five patients underwent surgery to reduce outlet resistance and all reported improvement. Forty-three patients were started on pharmacotherapy; symptomatic improvement was reported by 9 of 16 patients commenced on anticholinergics alone, 6 of 16 on alpha-blockers alone, and 4 of 5 treated with a combination of alpha-blockers and anticholinergics. Eleven patients experienced no difference on pharmacotherapy and 2 reported deterioration. One patient developed acute urinary retention (18 months after commencing treatment with alpha-blockers). No patient had urosepsis.
Anticholinergics and alpha-blockers appear to be safe in patients with DOIC. The risk of urinary retention and sepsis is low. The majority of patients report symptomatic benefit from either drugs or surgical treatment.
Lower urinary tract symptoms; Overactive urinary bladder; Urodynamics; Cholinergic antagonists; Adrenergic alpha-antagonists
To identify the endoscopic vascular anatomy of the prostate during Holmium laser enucleation of the prostate (HoLEP), and analyze the clinical risk factors associated with significant arterial bleeding.
We identified 107 consecutive patients with benign prostatic hyperplasia who underwent HoLEP between September 2009 and August 2010, performed by a single surgeon (S.J.O.). Two independent reviewers reviewed the surgery video database and completed a prespecified form. The location of bleeding arteries was marked at the level of the bladder neck, proximal prostate, distal prostate, and verumontanum. Arterial bleeding was classified into one of three grades according to bleeding severity (grades 2 and 3 indicate significant bleeding).
The mean prostate volume was 65.1±31.5 mL, and the mean prostate-specific antigen (PSA) level was 3.69±3.58 ng/mL. During the HoLEP procedure, the most common locations of significant bleeders were the 2-5 and 7-10 o'clock positions in the proximal prostate. The average number of bleeding arteries was 12.1±7.9 per procedure, and 1.93±1.20 per 10 mL of prostate volume. Multivariate analysis revealed that prostate volume and serum PSA were significant parameters for estimating the number of bleeding vessels.
During the HoLEP procedure, the most common locations of significant bleeders were the 2-5 and 7-10 o'clock positions in the proximal prostate. Prostate volume was associated with the number of bleeders. A careful approach to the capsular plane of the proximal prostate facilitates early hemostasis during the HoLEP procedure, especially with larger adenomas.
Lasers; Blood supply; Anatomy; Prostatic hyperplasia; Transurethral resection of prostate
In this study, we examined the difference in the treatment efficacy depending on the sympathetic activity in men with lower urinary tract symptoms (LUTS).
In the current single-center, retrospective study, we evaluated a total of 66 male patients aged 40-70 years of age, presenting with LUTS, whose International Prostate Symptom Score (IPSS) exceeded 8 points. They had a past 3-month history of taking alfuzosin XL, and their heart rate variability (HRV) was measured before and after the treatment. In addition, we also recruited 39 healthy volunteers who visited a health promotion center for a regular medical check-up. They were aged between 40 and 70 years and had an IPSS of <8 points. We divided the patients with LUTS into two groups: the groups A and B, based on a low frequency/high frequency (LF/HF) ratio of 1.7, which was the mean value of the LF/HF ratio in the healthy volunteers. After a 3-month treatment with alfuzosin XL, we compared treatment outcomes, based on the IPSS and peak urine flow rate, between the two groups.
A 3-month treatment with alfuzosin XL, comprising the measurement of the HRV, was performed for the 23 patients of the group A (23/38) and 17 of the group B (17/28). After a 3-month treatment with alfuzosin XL, total IPSS and IPSS questionnaire 2 and 5 were significantly lower in the group A as compared with the group B. But this was not seen in the group B. Furthermore, there were no significant differences in other parameters, such as maximal flow rate and IPSS storage subscore, between the two groups.
Our results indicate that the treatment efficacy was lower in patients with sympathetic hyperactivity as compared with those with sympathetic hypoactivity. Thus, our results will provide a basis for further studies to clarify causes of LUTS in a clinical setting.
Autonomic nervous system; Heart rate; Lower urinary tract symptoms
Accurately measuring urinary urgency is important for diagnosing overactive bladder (OAB) and quantifying improvements in treatment outcome. Various methods have been recommended for evaluating urinary urgency, but these methods assess individual perceptions and preferences. To overcome the subjectivity in measuring urinary urgency, we evaluated the relationship between uroflowmetric parameters and urinary urgency in women with OAB.
Consecutive female patients with lower urinary tract symptoms (n=110) were prospectively enrolled in this study between April 2011 and September 2012. Individuals with a history of using medications that are known to affect bladder function were excluded. All enrolled patients completed uroflowmetry with a delayed time to voiding (T2V). After urination was completed, patients were asked whether they experienced any urinary hesitancy or urgency at that time.
The mean patient age was 56.1 years; 70 out of 110 patients reported some degree of urinary urgency. T2V decreased with increased urgency. Several uroflowmetric parameters were observed to have a significant correlation with urinary urgency. T2V had a meaningful correlation coefficient for individuals with urgency, regardless of the voided volume. There was no significant correlation between the presence of urinary hesitancy and T2V.
We believe that T2V would be a complementary tool for diagnosing and determining the degree of urinary urgency in women with OAB.
Analysis; Women; Overactive urinary bladder; Questionnaire; Urodynamics
The number of benign prostatic hyperplasia (BPH) subjects has been increasing worldwide, and many studies have been conducted to determine the treatment that can delay drug therapy or surgery. Subsequently, most of these studies involved physical activity (PA) and associated factors. Therefore, we aimed to determine factors associated with BPH prevalence based on a review of past and present studies and to investigate the effect of a healthy lifestyle as a protective factor of BPH occurrence.
We selected 582 subjects aged ≥40 years from an initial 779 subjects recruited from Gyeonggi, Yangpyeong, South Korea, during August 2009 to August 2011. Trained investigators surveyed International Prostate Symptom Score and demographic information, including PA and lifestyle questionnaire during face-to-face interviews; further, they performed digital rectal examination, rectal ultrasonography, and measured prostate-specific antigen levels. The statistical association between PA and BPH was analyzed by logistic regression analysis using multivariable regression models which use categorical variables by the Cochran-Mantel-Haenszel test and continuous variables by the general linear model.
Seven statistically significant variables for PA were selected. Regular exercise, frequency of exercise, sedentary time, nonsedentary time, leisure time PA (metabolic equivalent, hr/wk) were not statistically associated with prostate volume but sedentary time (hr/day) was the only factor that showed a significant association in the multivariable model, including a linear effect relationship. Subjects with lower levels of sedentary time (4.5-7.0 hr/day) had a significantly lower risk of BPH (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.52-1.67) than those with a higher sedentary time (>7 hr/day) (OR, 1.72; 95% CI, 0.96-3.09) (P for trend=0.05).
Our study showed that reducing sedentary time could have a protective effect and reduce the prevalence of BPH. Further prospective studies with a larger sample size are needed to assess the impact of reducing sedentary time on BPH risk.
Prostatic hyperplasia; Leisure activities; Quality of life
To determine the efficacy of intravesical hyaluronic acid (HA) instillation in treating patients with refractory interstitial cystitis/painful bladder syndrome (IC/PBS) and to identify any related factors that influence its therapeutic effect.
Thirty-three female IC/PBS patients who demonstrated poor or unsatisfactory responses to previous treatments between December 2010 and October 2012 were enrolled. Despite previous treatments, the enrolled patients had visual analogue scale (VAS) pain scores ≥4 and total scores (symptom and bother scores) ≥13 on the pelvic pain and urgency/frequency (PUF) questionnaire and ≥12 on the O'Leary-Sant interstitial cystitis symptoms index (ICSI)/problems index (ICPI). All patients received once weekly intravesical instillations of 40-mg HA diluted in 50-mL saline for 4 weeks. The efficacy of the HA instillation was evaluated by comparing the mean changes in the scores of the VAS and questionnaires from baseline to 4 weeks after treatment. Improvement was defined as a ≥2 decrease in the VAS. Moreover, we investigated the effects of the presence of Hunner's ulcer and previous treatment modalities on the therapeutic outcome of HA instillation.
The mean age was 57.0±1.8 years (range, 28-75 years). The VAS score significantly decreased from baseline to 4 weeks after treatment (-2.5, P<0.001). The mean changes in the PUF, ICSI, and ICPI from baseline to 4 weeks after the treatment were -3.8 (P<0.001), -2.3 (P<0.001), and -2.7 (P<0.001), respectively. Twenty patients (61%) showed improvements. Previous treatment modalities did not affect the efficacy of HA instillation and the presence of Hunner's ulcer was unrelated to outcomes. No complications were observed.
These results show that intravesical HA instillation is an effective and safe treatment for patients with refractory IC/PBS. Previous treatment modalities and presence of Hunner's ulcer do not affect the efficacy of HA instillation.
Hyaluronic acid; Intravesical administration; Interstitial cystitis
In this article we introduce modern statistical machine learning and bioinformatics approaches that have been used in learning statistical relationships from big data in medicine and behavioral science that typically include clinical, genomic (and proteomic) and environmental variables. Every year, data collected from biomedical and behavioral science is getting larger and more complicated. Thus, in medicine, we also need to be aware of this trend and understand the statistical tools that are available to analyze these datasets. Many statistical analyses that are aimed to analyze such big datasets have been introduced recently. However, given many different types of clinical, genomic, and environmental data, it is rather uncommon to see statistical methods that combine knowledge resulting from those different data types. To this extent, we will introduce big data in terms of clinical data, single nucleotide polymorphism and gene expression studies and their interactions with environment. In this article, we will introduce the concept of well-known regression analyses such as linear and logistic regressions that has been widely used in clinical data analyses and modern statistical models such as Bayesian networks that has been introduced to analyze more complicated data. Also we will discuss how to represent the interaction among clinical, genomic, and environmental data in using modern statistical models. We conclude this article with a promising modern statistical method called Bayesian networks that is suitable in analyzing big data sets that consists with different type of large data from clinical, genomic, and environmental data. Such statistical model form big data will provide us with more comprehensive understanding of human physiology and disease.
Bayesian analysis; Statistical data interpretation; Systems biology