臺灣博碩士論文加值系統

背景
糖尿病是一種常見的代謝性疾病並且會影響許多器官。每一位醫師都知道糖尿病的三大病變包括視網膜病變、腎臟病變、神經病變。然而，在一般文獻上則較少提及糖尿病造成膀胱病變的情形。糖尿病的膀胱病變，一般歸諸於糖尿病多形性周邊神經病變的一種。典型糖尿病膀胱病變的表現是膀胱失去充尿的感覺且產生大量的餘尿。這樣的情形可以用膀胱測量儀( cystometry )來測知，包括膀胱最初尿意容量、膀胱最大容量的明顯增加，與膀胱收縮力的降低。骨盆神經病變被認為是引起糖尿病膀胱病變的致病因。末期的糖尿病膀胱病變常會導致膀胱感覺及運動功能一起喪失，伴隨嚴重反覆性的尿路系統感染。在門診中，我們無法對每一個糖尿病的病人進行全套的尿路動力學檢查以進行糖尿病膀胱病變的篩檢。因此，我們將進行一項前瞻性研究，使用比較簡便的方法來評估糖尿病患的下泌尿道功能並找出糖尿病膀胱病變的危險因子。
目標，材料及方法
本研究有三大目標，首先是研究無干擾因子下的糖尿病膀胱病變患者，其下泌尿道症狀與尿流學的表現與型態。並以統計結果計算下泌尿道症狀評分與最大尿流速的數值。討論由此是否能達到篩檢糖尿病膀胱病變的目的。其次，由於糖尿病的膀胱病變屬於糖尿病多型性周邊神經病變的一種。我們希望藉由病人周邊神經的檢查來探知糖尿病膀胱病變患者對於電流感覺測試(current perception test)的結果，其表現如何。對照於無膀胱病變的糖尿病患者，是否能達到統計上的意義。最後，我們收集病人各種之臨床數據，來計算糖尿病膀胱病變的危險因子。本計劃已得台大醫院倫理委員會的審查通過。
我們自民國九十一年九月至民國九十一年五月，由台大糖尿病特別門診中召集180名第二型糖尿病女性患者進行研究。在收集病例的過程中，若患者具有中風或曾經接受過骨盆腔手術等病史、理學檢查發現膀胱脫垂、尿液檢查顯示正處於尿路感染的病人皆直接排除在外。病人將被詢問一組問卷，題組包括國際前列腺症狀評分表 ( IPSS )與各種糖尿病史與並記錄各種臨床相關的檢查數據。每一個病人將接受尿流儀 (uroflowmetry) 與單導測量殘尿來作為膀胱功能的評估。如有病人的膀胱容量大於500 ml 或餘尿大於100 ml或殘尿比上膀胱總尿量大於25%，則認為此人患有排尿障礙。週邊神經功能是採用電流感覺閥值 (Current perception thresholds) 測定。其主要測量中指正中神經(median nerve)與大腳趾腓神經(peroneal nerve)在三種不同頻率(5Hz、250Hz、2000Hz)的電流下，病人對電流強度的感覺，並紀錄之。通常感覺神經受損的病人需要較強的電流才能引起感覺，所以稱為閥值測定。
當實驗完成後，我們將以糖尿病膀胱病變的有無，將病人分為兩組，再加上我們從現有的583名正常女性資料庫中選取244名年齡配對的正常資料。取出其下泌尿道症狀評分與尿流速檢查的數據作為對照組進行單維變異數分析(one-way ANOVA)。並由此比較殘尿量、尿路症狀評分，與最大尿流速在糖尿病患者有無膀胱病變的差別，製作ROC (receiver operator characteristic) 曲線。作為將來臨床上，經由症狀評分加上尿流速的評估來判斷膀胱功能異常的可能。對於電流感覺閥值測定的結果則以二組樣本 t 檢定(two-sample t test)來計算糖尿病患者有無膀胱病變對電流感覺閥值的測量是否形成有意義的差別。最後以羅吉斯迴歸模型 (logistic regression model) 來分析造成膀胱功能異常的危險因子。
結果
在我們收集的180名糖尿病女性患者的有效樣本中，有55 (30.5%)名被認為患有排尿障礙，餘下的125名為排尿正常的糖尿病患者。再加上我們所選取的244名正常對照組，對症狀評分、生活品質評分、最大尿流速進行單維變異數分析與多重比較(Bonferroni method)。結果顯示糖尿病膀胱病變患者的症狀總分(14.2±1.1, mean ±standard error of means )、貯尿症狀評分(7.4±0.5)、 排空症狀評分(6.8±0.7)要明顯高於其他兩組(P<0.001)，而糖尿病無膀胱病變患者與正常對照組在這三項評分無有意義之差別。在這些糖尿病膀胱病變患者的症狀中以夜尿(71%)最為常見，其後是尿流速減弱(47.2%)。其次，在生活品質評分的比較中顯示，糖尿病膀胱病變患者的生活品質評分最大(3.8±0.2)、糖尿病無膀胱病變患者次之(2.7±0.1)、正常對照組最小(1.8±0.1) (P<0.001)。而在最大尿流速的比較中，我們發現糖尿病膀胱病變患者的最大尿流速最低(14.5 ±1.3ml/sec)，糖尿病無膀胱病變患者居中(19.3±0.7 ml/sec)，正常對照組最高(27.1±0.6 ml/sec) (P<0.001)。若以膀胱殘尿量、症狀總評分(IPSS)、最大尿流速(Qmax)三種檢查方式製作ROC曲線以篩檢膀胱功能障礙，我們可以得到這三者ROC曲線下面積分別為，膀胱殘尿(area under curve: 0.95)、症狀總評分(area under curve: 0.83)、最大尿流速(area under curve: 0.698)。
在神經測量儀(neurometer)的檢查中，我們的180位病人裡共有57 名完成這個檢查，其中有15名是患有膀胱功能障礙，另外42名無膀胱功能障礙。我們以二組樣本 t 檢定，來檢查這兩組人的電流感覺閥值。資料顯示在手指感覺的部分這兩組人的差異較小，無法顯示有意義的差別。但在大腳趾的感覺測試中，資料顯示這兩組人，當頻率為2000Hz時資料顯示並無統計上的差異(p=0.8)，在頻率為250Hz時這兩組的統計差異，處於臨界值(P=0.05)，在頻率為5Hz時出現有意義的差別(266±98vs.83±7.6, p=0.002)。
在臨床數據橫斷面的統計裡，在經過羅吉斯迴歸模型 (logistic regression model)與階梯法(stepwise method)計算選擇之後，資料顯示患病時間大於6年(odds ratio:3.3)、排尿症狀是否持續一年以上(odds ratio:2.0)、這一年中是否出現兩次以上的尿路感染(odds ratio:5.1)。與是否為膀胱功能障礙，其勝算比達統計上的意義。而其餘臨床上用來評估糖尿病疾病進展的項目於本研究中，無法顯示統計上的意義。
結論
我們的研究顯示，在一般的糖尿病患者中，有著極大比例的人，患有不同程度的膀胱功能障礙。而詳細的泌尿症狀詢問與尿流速測定，能於無侵襲性的狀況下對這些病人進行相當程度的篩檢。在最大尿流速的測量中，顯示無排尿障礙的糖尿病患者之最大尿流速也比正常對照組低，暗示著糖尿病患者膀胱逼尿肌收縮力的衰退比想像中的早。
電流感覺閥值測定的實驗結果則佐證了糖尿病膀胱功能障礙是糖尿病周邊神經病變的一種，而這疾病的發生與腓神經的小神經纖維感覺受損之間似乎存在著有趣的關聯。
由於糖尿病病變對各種系統有著不同程度的多形表現，對於這個膀胱功能障礙的問題，於本研究中除病史詢問與神經電流感覺測試外，無法得到其他系統病變的相互對應，這樣的結果雖然與前人的研究相似，但也留給我們對於此題目，研究改進的空間，或許將來收集更多的案例，更精確的定義膀胱神經病變，使用長期的追蹤資料，能為這個問題提供最好的解答。

Background
Diabetes is a common metabolic disease of multiorgan involvement. The American Diabetes Association reported that the prevalence of diagnosed and undiagnosed DM in the United States is currently 6% and rising. The increase is secondary to a rising incident in obesity, as well as a change in the criteria for the diagnosis of DM from a fasting blood glucose 140mg/dl to 126 mg/dl. Beside impaired blood glucose regulation, many direct and indirect sequelae of DM can occur. Triopathy of diabetes including retinopathy, neuropathy, and nephropathy are familiar to every internist. Lower urinary tract dysfunction is one of the most common complications in this group of patients. However, the entities of diabetic cystopathy are rarely mentioned in the literature.
Disturbances of urinary bladder function in diabetic patients are generally attributed to peripheral autonomic neuropathy. The bladder and proximal portion of urethra are innervated by the hypogastric, pelvic and pudendal nerves. The sympathetic nerves originate at T10-L2. The noradrenergic postganglionic fibers from the hypogastric or pelvic plexus innervate the smooth muscles of the bladder base, internal sphincter, and proximal urethra. The parasympathetic innervation originates in the second to fourth sacral segments and projects to the pelvic plexus. Somatic motor innervation originates in S2-3 and travels to the external urethral sphincter via the pudendal nerve. Chronic hyperglycemia is associated with the loss of myelinated and unmyelinated fibers, wallerian degeneration, and blunted nerve fiber reproduction.
The classic presentations of diabetic cystopathy include impaired bladder sensation, increased cystometric capacity, decreased bladder contractility, impaired uroflow and increased post-void residual. It could be confirmed by cystometrograms, including impaired sensation of first desire to void and a significant increased maximal bladder capacity, a decrease in detrusor contractility. The diabetic cystopathy develops insidiously and symptoms do not appear until the disease is in an advanced stage. The neuropathy of pelvic nerve is believed to be the main factor responsible for diabetic cystopathy. Patients with advanced diabetic cystopathy eventually developed flaccid type neurogenic bladder and are frequently associated with recurrent urinary tract infection.
The precise incidence and prevalence of diabetic cystopathy are difficult to determine because of the insidious onset, discrete symptoms, and differences in the definition of bladder dysfunction. About 43% to 87% of insulin-dependent diabetics developed diabetic cystopathy. Another study showed an average 25% prevalence of diabetic cystopathy in patients on oral hypoglycemic treatment. The correlation between diabetic cystopathy and peripheral neuropathy ranged from 75% to 100%. Nephropathy was seen in 30 % to 40 % of cases.
In clinic practice, it is infeasible to evaluate the bladder function of diabetic patients by complete urodynamic study and nerve biopsy. Hence, we design this prospective study to examine the lower urinary tract function and neurological defects in diabetic patients. Thus, we could find out risk factors of diabetic cystopathy.
Aims, Materials and Methods
There are three aims of this research. The first one is to find out the pattern and physiological meanings of International Prostate Symptom Score in diabetic voiding dysfunction. Thus, we can screen diabetic patients by lower urinary tract symptoms and uroflowmetry. The second aim is to set up the correlation between voiding dysfunction and peripheral neuropathy by current perception test. The third aim is to figure out the risk factors of diabetic cystopathy by logistic regression model. This project was approved by the ethic committee of National Taiwan University Hospital.
During 9 months from September 2002, we enrolled 180 Type II diabetic women in clinic. Male patients were excluded from this study due to the confounder of benign prostatic hyperplasia. Woman with cystocele, history of cerebral vascular accident or who has ever received major pelvic surgery will also be excluded. The patients will be interviewed with a questionnaire comprised of the International Prostate Symptom Score (IPSS) and their clinic histories of diabetes. The IPSS was originally used for quantitative evaluation of subjective lower urinary tract symptoms in patients with benign Prostatic hyperplasia. Subsequently this procedure was extended to evaluate lower urinary tract symptoms in various diseases, including bladder dysfunction, regardless of sex. The symptom index score on the IPSS comprises filling and emptying symptom index scores. Frequency, urgency, and nocturia may reflect the state of filling symptoms, whereas incomplete emptying, intermittency, weak stream, and straining at the beginning of urination may be indicative of emptying symptoms.
In the study, participants would be confirmed no presence of urinary tract infection by urine analysis. All patients in our study were encouraged to intake a lot of water exceeding 500ml. The uroflowmetry and post-void residual measurement were conducted. Patients were requested to void as usual pattern. After the patient voided completely, a catheter was introduced into bladder to measure the residual urine volume, immediately. Patients with a total volume of larger than 500 ml, or residual urine of more than 100 ml, or percent residual volume of greater than 25% are considered to have voiding dysfunction. The urinary symptoms score and uroflowmetry of 244 age-matched healthy females obtained from our data bank were use as control.
Of 180 diabetic women, 57 patients had ever received the current perception test. Among the 57 patients, 15 persons were considered as voiding dysfunction and 42 persons did not. The current perception thresholds were determined for 5Hz, 250Hz, and 2000Hz at the middle finger and great toe in a warm environment. The stimulus was initially increased until a sensation was reported and then short stimuli were applied at progressively lower amplitudes until a minimal threshold for consistent detection was determined. The device has a “dummy“ switch to allow the on/off status of the machine to be concealed from the patient, and forced choice paradigm was used to confirm the minimum threshold for perception. Sensation in the lower extremity was also examined by a light-touch monofilament and a tuning fork.
For statistical evaluation, ANOVA and Bonferroni test were used for lower urinary tract symptoms score and maximal flow rate comparisons. Two-tailed Student’s t test for unpaired data was used for the current perception test. All values in the text and tables give the mean ±standard error of means. In addition, the risk factors predicting diabetic cystopathy were evaluated by multiple logistic regression analysis.
Results
The average age of our diabetic patients is 63 years old. Among the 180 diabetic women, 55（30.5﹪）patients were regarded as voiding dysfunction. One of them developed into decompensation of bladder. Her voided volume was 119ml, but post-void residual volume reached 900ml. Included this one, there were 15 patients thought of high grade of voiding dysfunction due to residual volume more than 150ml. Besides, 3 women were considered as low grade of voiding dysfunction. They have larger bladder capacity without remarkable residual urine. There were 37 patients classified as moderate grade of voiding dysfunction. Of the 55 patients, 18（67.3﹪）had ever received the medical treatment for voiding dysfunction.
Urinary symptoms. These patients with voiding dysfunction had a significantly higher total score (14.2±1.1, mean ±standard error of means ), storage symptoms score (7.4±0.5), and emptying symptom score (6.8±0.7) comparing to the control groups. There were no significant difference in urinary symptoms score between the patients without voiding dysfunction and normal controls. Pearson’s correlation test indicated that the symptom index scores were correlated with residual urine volume (r=0.42, p<0.001). The most common symptom presented in patients with voiding dysfunction was nocturia (71%), followed by weak urinary stream (47.2%). Chi-square test showed the higher proportion of all urinary symptoms in voiding dysfunction group. The IPSS questionnaire included a question on general satisfaction with urinary conditions （QOL index）.When the QOL index score was ≧4, the quality of patient’s life was regarded as poor. Patients with voiding dysfunction had the highest QOL index score （3.8±0.2）.Even the diabetic patients without voiding dysfunction had higher QOL index score （2.7±0.1）than normal controls（1.8±0.1）.
Uroflowmetry findings. Uroflowmetry revealed the significant differences in the maximal flow rate of these groups. Patients with voiding dysfunction had a significantly lowest maximal flow rate（14.5 ±1.3ml/sec）. Diabetic women without voiding dysfunction also have a lower maximal flow rate （19.3±0.7 ml/sec）than normal control group. Patients with an intermittent flow pattern had the higher likelihood of developing voiding dysfunction.
ROC curve. The areas under the ROC curve are presented as a diagnostic performance rate of residual urine volume, lower urinary tract symptoms, and maximal flow rate （Fig.1）. After we chose the adequate cutoff values of these tests, table 5 showed the data for sensitivity, specificity, and the likelihood ratio for the utilization of the three tests. All methods have a high diagnostic performance（area under the ROC curve）.
Current perception test. The results provided good discrimination between the voiding dysfunction and control groups at 5Hz and 250Hz in the foot. Table 6 shows the means of the CPT measurements obtained at all frequency in the finger and toe. There were no significant differences of CPT measurements at all frequency between the voiding dysfunction and control groups in the hand. However, there seems to be a trend showing that the lower frequency of stimuli, the more significant difference between the two groups would be. Sensation test performed by light-touch monofilament and a tuning fork could not show the significance in the two groups.
Risk factors analysis. The multiple logistic regression analysis and stepwise model selection were carried out. The results of risk factors analysis were shown by Table 7. The disease duration more than six years, symptoms duration more than one year, and repeated urinary tract infection in one year were significant in the model selection. Others cannot reach the enough significant difference.
Discussion and Conclusions
The present study evaluated the prevalence of voiding dysfunction in the female patients with diabetic mellitus consecutively sampled in our metabolic department. The prevalence has been reported previously to be 25 to 85%. In most of these reports, the patients were sampled with some confounders, and it was unclear what criteria were used to identify the people with diabetic cystopathy. In our study of 180 consecutive patients, the prevalence of voiding dysfunction was found to be 30.5%, when the residual volume was significantly increased, or bladder capacity larger more than 500ml.This prevalence is similar to that previously reported by Ueda and his colleague（Ueda et al, 1997）.
The presentations of lower urinary tract symptoms in diabetic women with voiding dysfunction differed from those in control groups. Besides, the symptom index was correlated with the residual urine volume. It suggested that the higher lower urinary tact symptoms score disclose the hypocontractility of bladder and post-void residual increased in diabetic women with voiding dysfunction. In addition, the results of uroflowmetry showed the significant differences in the average of maximal flow rate of theses three groups. It means that the development of underactive detrusor in diabetic patients should be earlier more than we think. Even the diabetic patient without voiding dysfunction or symptoms had a lower maximal flow rate than normal controls. The theory about detrusor distention caused decompensation and detrusor failure may be wrong. The areas under the ROC curve of residual urine volume, lower urinary tract symptoms, and maximal flow rate showed their diagnostic performance in diabetic voiding dysfunction. This implies that the symptoms index more than 12 and a maximal flow rate below 15 ml/sec were reasonable criteria for identifying the diabetic patient with voiding dysfunction.
In the results of current perception test, we found the significant difference between the patients with and without voiding dysfunction at lower frequency in the foot. The low frequency detection thresholds correlated with tests of small fiber function, such as C fiber. It suggested that the degeneration of unmyelinated fiber in peroneal nerve would be common in diabetic patient with voiding dysfunction. In the process of lost of bladder sensation in diabetic patients, degeneration of C fiber in pelvic nerve should be important
Risk factors analysis showed the value of history taking in diagnosis of diabetic voiding dysfunction. Diabetic patients suffered from urinary symptoms, repeated urinary tract infection and had a long duration of diabetic history could be clues to indicate the existence of voiding dysfunction. The retinopathy and nephropathy are no correlation with voiding dysfunction in our study.
In conclusion, our data suggested that a high proportion of patients with diabetes had voiding dysfunction of various extents. The earlier occurrence of underactive detrusor plays an important role in the development of diabetic voiding dysfunction. Lower urinary tract symptom score and uroflowmetry evaluations provide a useful tool for the early detection of voiding dysfunction. Peripheral neuropathy detected by current perception test in voiding dysfunction group showed the correlation between neuropathy and voiding dysfunction. Carefully history taking is meaningful in screening of voiding dysfunction in diabetic patients.

封面 p.01
授權書 p.02
口試通過證明 p.03
致謝 p.04
目錄 p.05
圖表目錄 p.06
一、中文摘要 p.07
二、緒論 p.10第一部份: 糖尿病膀胱病變的基本介紹 p.11
第二部分: 文獻回顧 p.14
第三部分、研究方向 p.22
三、研究方法與材料 p.27
四、研究結果 p.31第一部份：下泌尿道症狀評分與尿流學統計 p.32
第二部份：電流感覺閥值測定 p.35
第三部份：危險因子分析 p.36
五 討論 p.37第一部份、 糖尿病排尿障礙的盛行率 p.38
第二部分、下泌尿道症狀與尿流學對糖尿病排尿障礙的意義 p.39
第三部分、糖尿病神經病變與膀胱病變的相關性：電流感覺閥值測定p.46
第四部分、糖尿病排尿障礙的風險因子評估 p.50
六、展望 p.54
第一部份、下泌尿道症狀與尿流學對糖尿病膀胱病變的重要性 p.55
第二部份、神經學檢查對糖尿病膀胱病變的意義與未來展望 p.59
第三部份、糖尿病膀胱病變危險因子研究與未來展望 p.60
七、論文英文簡述 p.62
八、參考文獻 p.70
九、圖表 p.77
十、附錄 p.86

Abraham RR, Levy DM, Abraham RM: Change in thermal sensation in diabetic patients after treatment with gangliosides., Diabetes Res.,7:129-35, 1988
Abrams P, Donovan JL, de la Rosette JJ, et al: International Continence Society “Benign prostatic hyperplasia” study: background, aims, and methodology. Neurourol Urodyn, 16:79, 1997
American Diabetes Association. Screening for type II diabetes. Diabetes Care, 21:502-22, 1998.
Amundsen CL, Lau M, English SF et al: Do urinary symptoms correlate with urodynamic findings? J Urol, 161:1871, 1999
Araki I., Kitahara M., Oida T., Kuno S.: Voiding dysfunction and Parkinson’s disease: Urodynamic abnormality and urinary symptoms. J Urol, 164:1640-3,2000.
Bates P, Bradley WE, Glen E et al. Third report on the standardization of terminology of lower urinary tract function. Procedures related to the evaluation of micturition : pressure flow, relationships residual urine. Scand J Urol Nephrol, 12:191-3, 1980
Bennett PH, FRCP MB, FFCM et al. Diabetic renal disease recommendations: Screening and management of microalbuminuria in patients with diabetes: Recommendations to the scientific advisory board of the national kidney foundation from an Ad Hoc committee of the council on diabetes mellitus of national kidney foundation. Am J Kidney Dis., 25(1): 107-12, 1995.
Blaivas JG. The neurophysiology of micturition: A clinical study of 550 patients. J Urol., 127: 958-63,1982.
Bradley WE: Diagnosis of urinary bladder dysfunction in diabetes mellitus. Ann. Intern Med. 92: 323-6, 1980.
Brown MJ, Asbury AK: Diabetic neuropathy. Ann Neurol, 15: 2-12,1984.
Buck AC, Reed PI, Siddiq YK, Chisholm GD, Fraser TR. Bladder dysfunction and neuropathy in diabetes. Diabetologia.,12:251-8, 1976.
Chai, TC,Belville WD, Mcguire EJ et al: Specificity of the American Urological Association symptoms index: comparison of unselected and selected samples of both sexs. J Urol, 150:1710-3,1993.
Clark CMJ, Lee DA: Prevention and treatment of the complications of diabetes mellitus. N Engl J Med, 332:1210-7, 1995.
Cockett ATK, Aso Y, Denis L, et al. Recommendations of the International Consensus Committee concerning: 1. Prostate symptom score (I-PSS) and quality of life assessment, 2. Diagnostic work-up of patients presenting with symptoms suggestive of prostatism, 3. Patients evaluation for research studies, and 4. BPH treatment. In: Cockett ATK, Aso Y, Chatelain C, et al, eds. Proceedings of the first International Consultation on Benign Prostatic Hyperplasia. Paris: Scientific Communication,279-340,1991.
Consensus statement (1995) Standardizing measures in diabetic neuropathy. Diabetic care 18 [Suppl 1]:59-28
Czekalski S. How to diagnose and how to interpret microalbuminuria in the diabetic patient. Nephrol Dial Transplant, 11:1509-11, 1996.
Dagogo JS. Diabetes mellitus and related disorder. In Ahya SN, Flood K, Paranjothi S. eds: The Washington manual of medical therapeutics. 3rd edition: Chap 22: 455-472, 2001.
Dail WG, Evan AP,Gerritsen GC, Dulin WE. Abnormalities in pelvic visceral nerves: A basis for neurogenic bladder in the diabetic Chinese hamster. Investigative Urol. 15(2):161-6, 1977.
Dail WG, Minosky N.: Composition of the pelvic nerve. Exp. Neurol., 92:278-83,1986.
Diokno AC: Epidemiology of female incontinence. In Raz eds: Female Urology, 2nd edition: Chap 6, 73-9,1996.
Donovan JL: Use of symptom questionnaires in the assessment and follow-up of men with benign prostatic disease. Current Opinion Urol;9:3,1999.
Ellenberg M. Development of urinary bladder dysfunction in diabetes mellitus. Annals of internal medicine.92:321-3,1980.
Ellenberg M. Diabetic neurogenic vesical dysfunction. Arch Intern Med. 117:348-54,1966.
Fernandez IF, Pinto JMP, Bono TH. Garijo PV, Camunez MAO, Delgado MAT. Rapid screening test evaluation for microalbuminuria in diabetes mellitus. Acta Diabetol, 35:199-202,1998.
Fletcher RH, Fletcher SW, Wagner EH. Diagnosis. In Fletcher RH, Fletcher SW, Wagner EH eds: Clinical Epidemiology：The Essentials. 3rd edition: Chap 3: 43-74, 1996.
Gilpin SA, Gilpin CJ, Dixon JS,Gosling JA, Kirby RS: The effect of age on the autonomic innervation of the urinary bladder. Br. J. Urol. 58:378-81, 1986
Goldman HB, Dmochowski RR: Lower urinary tract dysfunction in patients with gastroparesis. J Urol, 157:1823-5, 1997.
Goldstein I, Siroky MB, Krane RJ. Impotence in diabetes mellitus. In: Krane RJ, Sirokey MB, Goldstein I, eds. Male sextual dysfunction. Boston: Little, Brown, 77-86, 1983.
Golomb J: Uroflowmetry. In Raz eds: Female Urology, 2nd edition: Chap 9, 97-105,1996.
Greene DA, Yagihashi S, Lattimer SA, Sima AAF: Nerve Na, K-ATPase, conduction and myo-inositol in the insulin-deficient BB-rat. Am J Physiol, 247:E534-9,1984.
Griffiths CJ, Murray A, Ramsden PD. Accuracy and repeatability of bladder volume measurement using ultrasonic imaging. J Urol., 136: 808-12, 1986.
Habler HJ, Janig W, Koltrenburg M. Activation of unmyelinated afferent fibers by mechanical stimuli on inflammation of the urinary bladder in the cat. J Physiol (London), 427:281, 1990.
Hakenberg OW, Ryall RL, Langlois SL, Marshall VR. The estimation of bladder volume by sonocystography. J Urol.,130,249-51,1982.
Ioanid CP, Noica N, Pop T. Incidence and diagnostic aspects of the bladder disorder in diabetics. Eur Urol,7:211-4,1981.
Italiano G, Magri V, Paro M, Prosdocimi M. Diabetic autonomic neuropathy and bladder function: Pharmacological use of gangliosides and insulin. Functional neurology, 5(3): 203-5, 1990.
Janig W, Koltzenburg M: On the functions of spinal primary afferent fibres supplying colon and urinary bladder. J Auton. Nerve Syst.,30: S89-96, 1990.
Janig W, Morrison JEB: Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. Progress in Brain Research, 67: 87, 1986.
Jensen JK: Urodynamic evaluation. In Ostergard DR, Bent AE eds: Urogynecology and Urodynamics: Theory and Practice, 4th edition: Chap 10, 115-149, 1996.
Kaplan SA, Chancellor MB, Blaivas JG. Bladder and sphincter behavior in patients with spinal cord lesions. J urol., 146: 113-117, 1991.
Kaplan SA, TE AE, Blaivas JG. Urodynamic findings in patients with diabetic cystopathy. J Urol., 153: 342-4, 1995.
Kilaru P, Bakris GL. Microalbuminuria and progressive renal disease. J human hypertension,8:809-17, 1994.
Kirkland JL, Lye M, Levy DW, Banerjee AK: Patterns of urine flow and electrolyte excretion in healthy elderly people. BMJ 287: 1665-7, 1983.
Kurafin LJ, Coll ME. Lower urinary tract disorder in the postmenopausal woman. Med Clin North Am, 71:111-21, 1987.
Lee WC, Lee KL, Chen MY, Chen CY, Chen J, Yu HJ. Lower urinary tract symptoms in women with systemic lupus erythematosus. J Urol ROC, 11:161-6,2000.
Lavery L. Gazewood JD. Assessing the feet of patients with diabetes. [Review] Journal of Family Practice. 2000,49(11 Suppl):S9-16
Liniger C, Pernet A, Moody JF, Assal J: Effect of gangliosides on diabetic peripheral neuropathy. Diabetes Res.,7: 251, 1989
Massey JA, Abrams PH. Obstructed voiding in the female. Br J urol, 61:36-9,1998
Mastri AR. Neuropathology of diabetic neurogenic bladder. Annals of internal medicine.,92:316-8,1980.
McLean GK, Edell S. Determination of bladder volumes by gray scale ultrosonography. Radiology, 128:181-2,1978.
Mebust WK, Bosch R, Dovovan J et al. Symptom evaluation, quality of life and sexuality. In Cockett ATK, Khoury S, Aso Y et al.,eds, Proceedings of the Second International Consultation of Benign Prostatic Hyperplasia. Paris: June 27-30, 131-43, 1993
Medori R, Gambetti LA, Jenich H, Gambetti P: Changes in axon size and slow axonal transport are related in experimental diabetic neuropathy. Neurology, 38: 597-601, 1988
Moller CF. Diabetic cystopathy: Epidemiology and related disorder. Annals of internal medicine, 92:318-21, 1980
Moller CF, Mortensen S. Treatment of diabetic cystopathy. Annals of internal medicine, 92:327-8,1980.
Nestler JE, Stratton MA, Hakim CA. Effect of metaclopromide on diabetic neurogenic bladder. Clin Pharmacol 1983;2:83-5
Paro M, Prashar A, Prosdocimi M, Cherian PV, Fiori MG, Sima AAF. Urinary bladder dysfunction in the BB/W diabetic rat: Effect of ganglioside treatment on functional and structural alternations. J Urol.,151:781-6, 1994.
Paro M, Prosdocimi M, Zhang WX, Sutherland G and Sima AAF: Autonomic neuropathy in BB rates and alterations in bladder function. Diabetes, 38: 1023-30,1989.
Poppel HV, Stessens R, Damme BV, Carton H, Baert L. Diabetic cystopathy: Neuropathological examination of urinary bladder biopsies. Eur Urol.,15:128-31, 1988.
Powers AC: Diabetes Mellitus. In Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds: Harrison’s principle of internal medicine, 15th edition: Chap. 333, p.2109, 2002.
Resnick NM: Voiding dysfunction in the elderly. In Yalla SV, McGuire EJ, Elbadawi A, Blavias JG, eds: Neurology and Urodynamics: Principles and practice. New York, MacMillan Publishing Company, 1988,pp 303-330.
Rubinow DR. Nelson JC. Tricyclic exacerbation of undiagnosed diabetic uropathy. Journal of Clinical Psychiatry. 43(5):210-2, 1982.
Sommer P, Bauer T, Nielsen KK et al. Voiding patterns and prevalence of incontinence in women. A questionnaire survey. Br J Urol, 66: 12-5,1990.
Starer P, Libow L. Cystometric evaluation of bladder dysfunction in elderly diabetic patients. Arch Intern Med., 150:810-3, 1990.
Steers WD, Physiology and pharmacology of the bladder and urethra. In Walsh PC, Retik AB, Vaughan ED, Wein AJ eds: Campbell’s urology, 7th edition Chap. 26, p870-915,1998.
Sundin T, Dahlstrom A. The sympathetic innervation of the urinary bladder and urethra in the normal state and after parasympathetic denervation at the spinal root level. Scand J Urol Nephrol., 7:131-149,1973.
Tanagho EA, Lue TF: Neuropathic bladder disorders. In Tanagho EA, McAninch JW eds: Smith’s General Urology, 15th edition: Chap. 29, p498-515, 2000.
Tanagho EA: Urodynamic study. In Tanagho EA, McAninch JW eds: Smith’s General Urology, 15th edition: Chap. 30, p516-537, 2000.
Ueda T, Yoshimura N, Yoshida O. Diabetic cystopathy: Relationship to autonomic neuropathy detected by sympathetic skin response. J Urol 1997; 157:580-4
Viberti, G. Etiology and prognostic significance of albuminuria in diabetes. Diabetes care,11: 840-845,1988.
Watanabe T, Miyagawa I. Characteristics of detrusor contractility during micturition in diabetics. Neurology & Urodynamics, 18:163-71, 1999.
Wein AJ.Neuromuscular dysfunction of the lower urinary tract and its treatment. In Walsh PC, Retik AB, Vaughan ED, Wein AJ eds: Campbell’s urology, 7th edition Chap. 29, p953-1006,1998.
Welch G, Kawachi I, Barry MJ, et al: Distinction between symptoms of voiding and filling in benign prostatic hyperplasia: findings from the health professionals follow-up study, Adult Urol: 51; 422, 1998.
Yu HJ, Chen J, Lai MK, Chan KA, Chie WC. High prevalence of voiding symptoms in Taiwanese women. Br J Urol 1998;82:520-3