Irritable bladder syndrome in an animal model: A continuous monitoring study

Irritable bladder syndrome (IBS) was induced in four female African green monkeys (Cercopithecus aethiops) by the use of intravesical instillation of acetone. The animals were housed in a modified metabolic cage for continuous micturition monitoring, and two uroflowmeters connected to a remote PC monitored the frequency, voided volumes, and peak flows. Before and after, urea absorption studies and urodynamics were obtained for each animal. Urea absorption increased significantly after acetone instillation and returned to baseline after 4 weeks (26 to 66 to 32%). Intravesical acetone instillation produced marked effects on bladder physiology in the first week. Bladder compliance dropped from a baseline of 10.47 to 0.58 ml/cm H₂O. The voiding pattern changed from a normal pattern with a mean voided volume of 17.58 ml into marked increase in frequency and dribbling pattern with few voids (mean = 5.03 ml). Systematic behavioral observations were carried out for 4 hours per day utilizing an observation program on a laptop computer. Activity patterns, attention, sterotypic behaviors, and self-directed activities were recorded for each monkey. The animals demonstrated decreased frequency of activity and increased frequency in self-directed activities (groom, scratch), behaviors consistent with an animal experiencing pain or discomfort. The findings suggested that IBS induction in monkeys is feasible and produces a clinical picture similar to interstitial cystitis in humans. It offers a suitable animal model to enhance the understanding of voiding dysfunction with its neural pathways and to test the different therapeutic modalities to control IBS. © 1995 Wiley-Liss, Inc.     

Osteon Remodeling Dynamics in Macaca mulatta: Normal Variation with Regard to Age, Sex, and Skeletal Maturity

As research into bone maintenance and turnover is accelerated and expanded due to public health concerns about osteoporosis and other age-related changes and pathologies of bone, nonhuman animal models are becoming increasingly important as they allow for enhanced experimental manipulation and environmental control relative to humans. Old World Monkeys, such as the rhesus macaque, share physiological and developmental characteristics that make these primates particularly well suited to such studies. The purpose of this study was to characterize normal age and sex variation in osteon remodeling dynamics in skeletally immature and mature rhesus macaques. Femoral cross-sections from 75 Macaca mulatta were examined to evaluate the effect of age, sex, and skeletal maturity on osteon remodeling dynamics in this popular research primate. Results indicate that sex has a significant effect on osteon area (On.Ar), but generally is not an important contributor to normal variation in intracortical remodeling dynamics. Age and skeletal maturity, however, contribute significantly to variation in osteon population density (OPD), activation frequency (Ac.f), and bone formation rate (BFR), as is the case in humans. This study is the first to characterize normal age and sex variation in osteon remodeling in growing and adult rhesus macaques and its results support the use of this animal as a model for age-related changes and pathologies in the human skeleton.     

Osteon Remodeling Dynamics in Macaca mulatta: Normal Variation with Regard to Age, Sex, and Skeletal Maturity

As research into bone maintenance and turnover is accelerated and expanded due to public health concerns about osteopororis and other age-related changes and pathologies of bone, nonhuman animal models are becoming increasingly important as they allow for enhanced experimental manipulation and environmental control relative to humans. Old World Monkeys, such as the rhesus macaque, share physiological and developmental characteristics that make these primates particularly well suited to such studies. The purpose of this study was to characterize normal age and sex variation in osteon remodeling dynamics in skeletally immature and mature rhesus macaques. Femoral cross-sections from 75 Macaca mulatta were examined to evaluate the effect of age, sex, and skeletal maturity on osteon remodeling dynamics in this popular research primate. Results indicate that sex has a significant effect on osteon area (On.Ar), but generally is not an important contributor to normal variation in intracortical remodeling dynamics. Age and skeletal maturity, however, contribute significantly to variation in osteon population density (OPD), activation frequency (Ac.f), and bone formation rate (BFR), as is the case in humans. This study is the first to characterize normal age and sex variation in osteon remodeling in growing and adult rhesus macaques and its results support the use of this animal as a model for age-related changes and pathologies in the human skeleton.     

A statistical study of the effects of urethral instrumentation on urine flow in women

Data were obtained from a retrospective review of the records of 125 women who had undergone full urodynamic studies for a variety of clinical indications, to determine whether urethral instrumentation has an adverse effect on the parameters of urine flow in women. All patients had an initial urine flow study with a spontaneous void of at least 100 ml, after which they were catheterized to measure the postvoid residual urine. All patients then underwent urethral pressure studies, complex filling cystometry, pressure-flow voiding studies and urethrocystoscopy, after which they underwent another spontaneous non-instrumented urine flow study. Peak and mean flow rates were analysed statistically by blocked analysis of variance. The data were corrected for the effects of the volume voided by converting the flow rates into a nomogram percentile ranking using a computer program.Statistical analysis indicated that peak flow rates increased from an average of 21.7 ml/s (SD±10.8 ml/s) before instrumentation to 24.3 ml/s (SD±10.5 ml/s) after instrumentation (P=0.0045). Mean flow rates also increased from 12.0 ml/s (SD±7.3 ml/s) before instrumentation to 13.3 ml/s (SD±7.3 ml/s) after instrumentation (P=0.0365). However, when these data were corrected for the effects of the volume voided, both the average peak nomogram percentile and the average mean nomogram percentiles were reduced, from 29.1% to 24.2% for the peak flow rate (P=0.0426) and from 32% to 27.9% for the mean flow rate (P=0.1019).The corrected data indicate that both peak and mean flow rates are reduced in women following urethral instrumentation. The reduction in flow for peak flow rates is statistically significant. The reduction in mean flow rates did not reach this level of significance. This must be kept in mind when female patients are being evaluated for possible voiding disorders. Further prospective studies of the effect of urethral instrumentation on urine flow in women would seem to be indicated.     

Bone pathology in experimental osteoporosis: A review

New implants for the internal fixation of porotic bone should first be evaluated in experimental animals before they can be used in humans. If relevant results are to be generated, it is imperative that there is an adequate animal model for these studies. A literature survey of procedures used to develop ostoporosis in experimental animals indicated that none of the models described satisfactorily fulfilled the requirements for an optimal model for the study of porotic bone fracture fixation. The rat model exhibits major pathological differences compared to humans (different pattern of bone remodeling, little or no secondary Haversian remodeling in cortical bone, stable skeletal mass for a life span, small body size, short life span, low blood volume, and high basal metabolic rate). Large animals, such as dogs and primates, require a much longer time to reach a steady-state bone loss and none of them suffer from bone fragility. In the optimal animal model for the study of porotic bone fracture fixation, the histopathological pattern of osteoporosis should be similar to that of humans, and bone loss should be well controlled, appear early, not reverse spontaneously, and be associated with bone fragility.     

Effects of metoclopramide on detrusor function

Metoclopramide (Reglan) has been widely used as a motility agent because of its contractile effects on gastrointestinal smooth muscle. This agent also may demonstrate significant effects in the urinary system; however, controlled studies of possible effects on bladder function have not been previously reported. Metoclopramide effects on the detrusor smooth muscle were studied using a canine model system. Metoclopramide was compared with bethanechol chloride and a control substance in a random double blind study. Preliminary data from this animal model suggests that metoclopramide significantly increased detrusor contractility as manifested by a decrease in bladder capacity, an increase in detrusor peak voiding pressure and a decrease in post-void residual volume. These effects were similar to those manifested by parenteral bethanechol chloride.     

COMPARISON OF URODYNAMIC AND FREE VOIDING PATTERN IN INFANTS WITH DILATING REFLUX

PURPOSE: We compared simultaneous investigations of free voiding pattern and urodynamic assessment in infants with dilating reflux to obtain further information on previously suspected bladder dysfunction based on abnormal urodynamic findings. MATERIAL AND METHODS: A total of 33 male and 8 female infants with dilating reflux were included in the study. Free voiding pattern was determined by 4-hour voiding observation compared to previously described voiding pattern studies of healthy infants. Simultaneous invasive urodynamic assessments were performed. RESULTS: The patients were grouped according to urodynamic bladder capacity. Half of the male patients had low bladder capacity with high voiding pressure levels (hypercontractile) and the other half had either normal or high capacity bladders. The low capacity group had frequent small voids and a high rate of interrupted voiding, the high capacity group had infrequent voids of high volumes with high residual urine, and the pattern of the normal capacity group differed only from that of healthy infants by an increase in residual urine. All female infants had the typical characteristics of high capacity bladder on free voiding and urodynamic assessments. CONCLUSIONS: Infants with abnormal invasive urodynamic investigations, including those with a small capacity hypercontractile bladder and those with a high capacity bladder, could be identified on free voiding studies, indicating that an abnormal urodynamic pattern represents bladder dysfunction.     

Application of the Blaivas-Groutz bladder outlet obstruction nomogram in women with urinary incontinence

AIMS: To test the applicability of the Blaivas-Groutz nomogram for female bladder outlet obstruction in urinary incontinent women presenting in a general gynecologic practice and to determine how the nomogram results related to the presence of obstructive symptoms according to a standardized questionnaire. METHODS: All women with complaints of urinary incontinence underwent multichannel urodynamic testing, free uroflowmetry and were asked to complete a standardized quality of life questionnaire consisting of the urogenital distress inventory (UDI). The patients were classified according to the Blaivas-Groutz nomogram. RESULTS: One hundred and nine patients were classified according to the nomogram. Thirty-three patients (30.3%) were classified as unobstructed, 63 patients (57.8%) as mildly, 12 patients (11%) as moderately, and 1 patient (0.9%) was classified as severely obstructed. Fifty patients correctly completed the UDI. There was no significant difference (P = 0.61) in the score on the domain UDI obstruction between, according to the nomogram, obstructed and unobstructed patients. Only 18% of the obstructed patients had isolated voiding symptoms suggestive of obstruction. Forty-nine percent of the obstructed patients had urgency-frequency symptoms as well as voiding symptoms suggestive of obstruction. There was no correlation (Pearson, r = -0.06, P = 0.61) between the severity of the symptoms (assessed by the UDI scale) and the degree of obstruction (the four nomogram zones). CONCLUSIONS: Application of the Blaivas-Groutz nomogram gave an unlikely high prevalence of obstruction in our patient group, which showed no correlation with symptoms when measured with the UDI.     

The Fischer-Lewis model of chronic allograft rejection--a summary.

Although the mechanisms involved in human allograft rejection differ in degree from those in animal allograft rejection, animal models are invaluable for the investigation of their cause and effect. A significant advantage of the animal model is that lesions, comparable with those seen in human allograft rejection, can be generated over a much shorter time scale. Chronic rejection in animal models seems to be driven principally by immune mechanisms, whereas a myriad of non-immune mechanisms are operating in human allograft rejection. Despite these limitations, well-established animal models allow investigators to manipulate allograft rejection and thereby make contributions to the understanding of its pathogenesis. In addition, animal models provide the opportunity of identifying mechanisms whereby the rejection process might be arrested or reversed. Furthermore, such models have the potential of investigating the induction of tolerance by means that may be applicable to the human situation. Chronic rejection has been studied using well-established and reproducible kidney allograft models in rats. In such models the histopathological changes observed in the rejecting renal allograft are similar to those occurring during chronic rejection in humans, and they provide a means of studying the underlying mechanisms involved in its pathogenesis.     

Pathophysiology of sexual dysfunction as related to pelvic floor disorders

The objective of this study was to report the initial anatomic, radiographic, and genetic evaluations of a novel form of spontaneous pelvic organ prolapse (S-POP) in mice. We observed S-POP in a colony of UPII-SV40T transgenic mice developed for studies on bladder cancer. We utilized magnetic resonance imaging and necropsy to characterize this finding. We have established a breeding colony to identify inheritance patterns and for future studies. Selective breeding isolated the S-POP phenotype from the transgene. In contrast to other animal models, the S-POP mouse does not require an obligatory antecedent event to manifest pelvic organ prolapse. Necropsy and imaging demonstrate significant displacement of the pelvic organs distal to the pelvic floor in both sexes. The appearance of the POP is similar to that seen in the human female phenotype. Preliminary breeding studies indicate an autosomal dominant inheritance pattern. This mouse may be an effective animal model for the study of POP in humans.     

Reliability of rodent animal models in biomedical research

Despite the discrepancies observed between the data generated from humans and animals, it is a usual practice that the results obtained from animal models are extrapolated on humans. This review stresses that while animal models are essential for the research and development, a critical caution needs to be practiced in interpreting the results. Uncritical reliance on the results of animal experimentation can be dangerously misleading and has resulted in damages to human health in several cases. This review also discusses the role of certain confounding factors in using animal models due to which appropriate precautions need to be taken while deciding to conduct a study using animal models and caution is warranted in extrapolating the data obtained from pre-clinical studies on humans.     

The voiding pattern in infants with dilating reflux

OBJECTIVE: To determine whether the voiding pattern in infants with dilating vesico-ureteric reflux (VUR) differs from that in healthy infants, thus supporting the existence of bladder dysfunction in infants with VUR. PATIENTS AND METHODS: Forty-one infants (33 boys and eight girls) with dilating VUR (grades 3-5) were studied using a noninvasive 4-hourly voiding record described previously in studies of the voiding pattern of healthy infants, and the results compared with those obtained from healthy infants of similar age. RESULTS: The voiding pattern in the boys with VUR was characterized by small frequent voids and interrupted voids in more patients (36%) than in healthy boys (15%). Conversely, the girls with VUR were infrequent voiders of relatively high volumes. Residual urine was significantly increased in both boys and girls, as was bladder capacity, although not significantly. CONCLUSIONS: The free voiding pattern in infants with dilating reflux differs from that seen in healthy infants of comparable age. The characteristics for boys and girls differed but was in accordance with that seen in invasive urodynamic studies, suggesting refluxing infants to have a bladder dysfunction.     

The Abrams-Griffiths nomogram

Summary The treatment of benign prostatic hyperplasia and the definition of bladder-outlet obstruction has preoccupied urologists and researchers in recent years. Bladder-outlet obstruction can be defined only by pressure-flow measurement. Various methods of analysis of pressure-flow data have been proposed. The Abrams-Griffiths nomogram is an easy method of classifying these data to distinguish between the presence or absence of obstruction. Using the values for the maximal flow and the corresponding voiding detrusor pressure a point can be plotted on the nomogram that determines whether the bladder outlet is obstructed, unobstructed, or equivocally obstructed. For those that fall in the equivocal zone, further criteria for the mean slope of the pressure-flow plot and the minimal voiding detrusor pressure are used to determine whether there is obstruction or not. The nomogram's prognostic value in predicting the outcome of prostatectomy has been studied and found to be excellent. The Abrams-Griffiths nomogram can be modified by assigning an Abrams-Griffiths number to each set of pressure-flow data. This number is easy to calculate and use and gives a continuous variable that can be used to evaluate the effects of therapy. Although the Abrams-Griffiths nomogram and number are somewhat simplistic, none of the more complex methods of pressure-flow analysis have been shown to be better predictors of treatment outcome to date.     

Rhesus monkey and human share a similar topography of the corpus callosum as revealed by diffusion tensor MRI in vivo

A recent study of the corpus callosum (CC) in humans revealed a new topographical arrangement of the cortical connectivity pattern. To explore the CC topography in nonhuman primates, we applied magnetic resonance diffusion tensor imaging and tract tracing techniques in individual rhesus monkeys in vivo. The results demonstrate that the CC topography of primates and humans is surprisingly similar. In particular, the relatively large representation and caudal extension of commissural frontal fibers in the CC is observed in both the monkey and human brain. If evolutionary changes in relative brain volumes are reflected in the arrangement of related fibers crossing the CC, the current study is in line with the fact that the relative volume of the frontal lobe did not significantly increase after the split of the hominid line from other primates.     

Does urethral competence affect urodynamic voiding parameters in women with prolapse?

AIMS: To (1) compare voiding parameters and (2) correlate symptoms and urodynamic findings in women with pelvic organ prolapse (POP) and varying degrees of urethral competence. METHODS: We compared three groups of women with stages II-IV POP. Groups 1 and 2 were symptomatically stress continent women participating in the Colpopexy and Urinary Reduction Efforts (CARE) trial; during prolapse reduction before sacrocolpopexy, Group 1 (n = 67) did not have and Group 2 (n = 84) had urodynamic stress incontinence (USI) during prolapse reduction. Group 3 participants (n = 74), recruited specifically for this study, had stress urinary incontinence (SUI) symptoms and planned sacrocolpopexy. Participants completed standardized uroflowmetry, pressure voiding studies, and validated symptom questionnaires. RESULTS: Subjects' median age was 61 years, median parity 3 and 87% had stage III or IV POP. Fourteen percent of women in Group 3 demonstrated USI without, and 70% with, prolapse reduction. Women in Groups 2 and 3 had more detrusor overactivity (DO) than Group 1 (17 and 24% vs. 6%, P = 0.02) and detrusor overactivity incontinence (DOI) (15 and 8% vs. 0%, P = 0.004). Based on the Blaivis-Groutz nomogram, 60% of all women were obstructed. Post-void residual volume (PVR), peak flow rate, detrusor pressure at peak flow, voiding mechanisms, voiding patterns, obstruction and urinary retention did not differ among groups. Women in Group 3 had higher irritative and obstructive symptom scores than Group 1 or 2; neither score differed by presence of DO nor obstruction, respectively. CONCLUSION: Women with POP have significant rates of urodynamic obstruction and retention, independent of their continence status. Symptoms of obstruction and retention correlate poorly with urodynamic findings.     

The vesical sphincter electromyogram in children with normal and abnormal voiding patterns

Recording the vesical sphincter electromyogram clarifies abnormal patterns of voiding in children. Since the electromyogram patterns in children with normal voiding patterns have not yet been evaluated, we recorded the sphincter electromyograms during voiding of 39 children with normal voiding patterns. These normal electromyograms were compared to those recorded in 86 children with abnormal voiding patterns. Each of the 39 children with a normal voiding pattern demonstrated synergy of the vesical sphincter during voiding. Of the 86 children with an abnormal voiding pattern 69 per cent demonstrated synergy and 31 per cent demonstrated dyssynergia of the vesical sphincter during voiding. Of the children with dyssynergia 89 per cent were girls and only 11 per cent were boys. Sphincter dyssynergia was demonstrated only by children with an abnormal pattern of voiding and those with a history of a normal pattern of voiding demonstrated only sphincter synergy (p less than 0.005). The electromyographic diagnoses of vesical sphincter synergy and dyssynergia obtained by surface electrode recordings correlated with the clinical voiding patterns of the children.     

Conventional,continuous, and telemetric monitoring of urodynamic parameters in non-human primates: A comparative study

A comparison between three different techniques for monitoring urodynamic parameters in non-human primates was conducted in six adult female rhesus monkeys. This study was divided into two phases. In phase I, the animals were studied by conventional and continuous methods. During the study, uroflow and micturition pattern were obtained while the animals housed in a specially designed metabolic cage. Pressure transducers and EMG electrodes were surgically implanted. Then the animals were trained for 6 weeks to sit in a specially designed chair. Upon completion of the training period, continuous monitoring of the urodynamic parameters could be carried out for periods up to 14 hours. In phase II, the animals were studied with the conventional and telemetric methods. The same type of pressure transducers and EMG electrodes were implanted but they terminated in a radio transmitter powered by a long-life battery and controlled by a radio-operated switch. Conventional studies under ketamine sedation significantly increased bladder capacity, as well as the pressure at capacity (P < 0.05). Continuous monitoring was feasible, physiological, and more sensitive than the conventional techniques. Telemetric studies are superior to continuous monitoring, since the animal is not tethered to wires and provide data over a longer period of time. It is concluded that telemetric monitoring provides significantly different parameters, which could help in diagnosis and management of different voiding dysfunctions. In normal non-human primates, lower bladder capacity, higher maximum voiding pressure, higher bladder compliance, and higher incidence of detrusor instability without urethral relaxation were found. Telemetric urodynamic data on different pathological processes are currently unavailable and further work is needed in this area. © 1996 Wiley-Liss, Inc.     

牵张成骨术整复猕猴腭裂后胰岛素样生长因子-1与碱性磷酸酶表达研究

目的 以牵张成骨术整复猕猴腭裂骨缺损,定量分析不同时段新生成骨胰岛素样生长因子-1(insulin.1ike growth factor-I,IGF-1)与碱性磷酸酶(alkaline phosphatase,ALP)表达水平,探讨其成骨调控机制.方法 用猕猴建立腭裂动物模型.实验组动物21只以牵张成骨术整复其腭部软硬组织缺损,关闭裂隙后固定.于牵张成骨术后第1、2,4…6 8 12及24周分别取材,各3只动物.采用实时定量PCR法分析比较IGF-I与ALP的mRNA表达水平,并以酶联免疫吸附试验法(ELISA)定量分析其IGF-I与ALP含量,结果与实验对照及健康对照组(动物各2只)进行比较.结果 固定期第1～2周为成骨早期,第1周时IGF-1和AIJP的mRNA表达明显上调,分别为3.67±0.35和3.30±0.21,第2周时达最高峰,分别为7.55±0.32和5.91±0.21,随后逐渐下降,至第12周与健康对照组无明显差异(P>0.05).ELISA结果显示:固定期第1～2周,IGF-1和ALP表达均增强.IGF-1含量于第2周表达最高,为(2.0±0.06)ng/mg,第4周为(1.46±0.08)ns/mg,第6周为(0.84±0.11)ng/mg,其表达逐渐下降;同期ALP则呈高水平表达,第4周为(25.34±0.44)U/mg,第6周为(26.21±0.82)U/mg.第8～12周,IGF-1和ALP的表达均下降至接近健康对照组.结论 腭骨牵张成骨区域,新骨的原位增量生成明确,增殖过程正常,最终以膜内成骨的方式形成新骨整复了腭裂骨切开牵张间隙区域.