膀胱及小肠受量对直肠癌术后放疗副反应的影响

目的:探讨直肠癌术后放疗患者膀胱平均受量及直肠受量对放射性膀胱炎及放射性肠炎的影响。方法:收集我院2005年7月至2010年12月收治的直肠癌根治术后给予放疗的患者130例,收集临床因素、病理因素、放疗因素资料,统计放疗后6个月内放射性肠炎、放射性膀胱炎发生情况。结果:放疗因素中,膀胱壁平均照射剂量对放射性肠炎及膀胱炎的发生有显著影响(P0.05),即膀胱壁剂量越高,副反应发生率越大;当膀胱壁平均剂量达到49.12 Gy时,放射性膀胱炎的发生率显著升高。小肠平均剂量控制在50 Gy以下,其值与放射性肠炎的发生无相关性。结论:直肠癌术后放疗患者膀胱壁平均受量控制在49.12 Gy以下,对减少放射性膀胱炎的发生率有意义。     

A Case Control Study Reveals that Polyomaviruria Is Significantly Associated with Interstitial Cystitis and Vesical Ulceration

Objectives

To investigate whether polyomaviruses contribute to interstitial cystitis pathogenesis.

Subjects and Methods

A prospective study was performed with 50 interstitial cystitis cases compared with 50 age-matched, disease-free controls for the frequency of polyomaviruria. Associations between polyomaviruria and disease characteristics were analysed in cases. Polyomavirus in urine and bladder tissue was detected with species (JC virus vs. BK virus) specific, real-time PCR.

Results

Case patients were reflective of interstitial cystitis epidemiology with age range from 26–88 years (median 58) and female predominance (41/50 F). There was a significant increase in the frequency of polyomavirus shedding between cases and controls (p<0.02). Polyomavirus shedding, in particular BK viruria, was associated with vesical ulceration, a marker of disease severity, among interstitial cystitis cases after adjustment for age and sex (OR 6.8, 95% CI 1.89–24.4). There was a significant association among cases between the presence of BK viruria and response to intravesical Clorpactin therapy (OR 4.50, 95% CI 1.17–17.4).

Conclusion

The presence of polyomaviruria was found to be associated with the ulcerative form of interstitial cystitis. Clorpactin, which has anti-DNA virus activity, was more likely to improve symptoms in the presence of BK viruria. These data from this pilot study suggest associations between polyomaviruria and interstitial cystitis warranting further investigation.     

Etiology, pathogenesis, and diagnosis of interstitial cystitis

Interstitial cystitis (IC) is a bladder syndrome of unknown etiology. The cause of IC is most likely multifactorial and includes genetic and environmental factors. Various pathophysiological changes in the bladder, pelvis, and peripheral and central nervous systems have been identified, and this has led to the emergence of biologically specific treatment modalities. Interstitial cystitis is being diagnosed with increasing frequency; however, current diagnostic criteria are non-uniform, and there is significant overlap between chronic pelvic pain syndromes in men and women, interstitial cystitis, recurrent "cystitis," and the overactive bladder syndrome. The diagnosis of interstitial cystitis can be made clinically and by cystoscopy and hydrodistension. The sensitivity and specificity of urinary markers and the potassium sensitivity test have not been prospectively studied.     

Propensity score matching with time-dependent covariates

In observational studies with a time-dependent treatment and time-dependent covariates, it is desirable to balance the distribution of the covariates at every time point. A time-dependent propensity score based on the Cox proportional hazards model is proposed and used in risk set matching. Matching on this propensity score is shown to achieve a balanced distribution of the covariates in both treated and control groups. Optimal matching with various designs is conducted and compared in a study of a surgical treatment, cystoscopy and hydrodistention, given in response to a chronic bladder disease, interstitial cystitis. Simulation studies also suggest that the statistical analysis after matching outperforms the analysis without matching in terms of both point and interval estimations.     

Complementary and alternative therapies as treatment approaches for interstitial cystitis

The management of interstitial cystitis (IC) is predominantly the reduction of the symptoms of frequency, urgency, and pain. Multimodal treatment approaches for IC are helpful in customizing therapy for individual patients. Complementary and alternative therapies are a quintessential addition to the therapeutic armamentarium and frequently include dietary modification, nutraceuticals, bladder training, neuromodulation, stress reduction, and sex therapy. Dietary modification involves elimination of bladder irritants, fluid regulation, and a bowel regimen. Nutraceuticals studied for the treatment of IC include calcium glycerophosphate, L-arginine, mucopolysaccharides, bioflavinoids, and Chinese herbs. Bladder training is effective after pain reduction. The neuromodulation of high-tone pelvic-floor muscle dysfunction is achieved with physical therapy and acupuncture. Stress reduction and sex therapy are best administered by a qualified stress manager and sex therapist. Multimodal, nonconventional management may add efficacy to the treatment of IC.     

State of the art in intravesical therapy for lower urinary tract symptoms

Intravesical therapy is the routine first-line treatment for effectively delaying or preventing the recurrence of bladder cancer. This route of drug administration has also shown tremendous promise in the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS) and potentially overactive bladder to justify investments for further improvements. This review takes a bird's eye view into the current status of intravesical therapy, with emphasis on liposomal nanoparticles, in diseases associated with lower urinary tract symptoms (LUTS). Ongoing efforts to advance the field of intravesical drug delivery include development of sustained-release drug implants and efforts to improve delivery of biotechnological products including large protein acting as neurotoxins and small interfering RNAs.     

EXPERIENCES WITH ACTH AND CORTISONE IN SELECTED DERMATOSES

Fifty patients with various kinds of skin diseases who were not adequately relieved by conventional therapy were treated with ACTH or cortisone given systemically.Almost all patients with disseminated neurodermatitis had dramatic initial response, but in only about half the cases was improvement maintained when use of the drugs was discontinued.It appeared that in other skin diseases, such as lupus erythematosus, scleroderma, psoriasis, dermatomyositis and pemphigus, while improvement may be noted for a time, relapse to the original state occurs after the treatment is stopped.In four cases of chronic discoid lupus erythematosus, although some improvement was observed when steroid therapy was given, the histologic pattern of biopsy material taken from the lesions after treatment still was characteristic of the disease.     

Arterial Hypertension and Ischemic Heart Disease: Comparison in Epidemiological Studies

Forty cases of gonococcal urethritis were treated with oxytetracycline using various dosage schedules; there were 37 cures and three failures. The most convenient and most effective dosage was found to be 250 mg. oxytetracycline, given as a single intramuscular injection of 5 c.c.A series of 40 patients with non-gono-coccal urethritis was also collected. Two cases of urethritis due to Trichomonas vaginalis and two due to Candida albicans were removed from the series. Of the 36 cases which remained, cure was obtained with the use of oxytetracycline in different dosages in 30 cases; six cases were failures. The dosage which gave the best result in the therapy of non-gonococcal urethritis was 250 mg. oxytetracycline (5 c.c.), given as a single intramuscular injection, plus 250 mg. orally, four times a day for four days.The effectiveness of oxytetracycline in the treatment of urethritis has not decreased.     

RESULTS OF LONG-CONTINUED CORTISONE ADMINISTRATION IN RHEUMATOID ARTHRITIS

The administration of cortisone acetate to patients with rheumatoid arthritis usually produces prompt and often dramatic suppression of the disease manifestations. The effects of the hormone are not lasting, however, and after withdrawal relapse ensues. For sustained improvement in a chronic disease such as rheumatoid arthritis, it appears that cortisone must be given more or less continuously. This raises the question whether administration may be continued effectively and safely for long periods.Seventy-six patients with rheumatoid arthritis were given cortisone in the hope that treatment could be continued uninterruptedly for extended periods. For various clinical reasons it was necessary to discontinue treatment in 16 of these before six months, but the remaining 60 patients received the hormone uninterruptedly for six to 15 months. By using initial large suppressive amounts, then gradually reducing the dosage, and finally employing smaller maintenance doses, adequate degrees of rheumatic control were maintained in approximately two-thirds of the original 76 patients. The ability to sustain satisfactory improvement varied indirectly, in general, with the severity of the rheumatoid arthritis. The chief detriment to better results in the more severe cases was the intervention of adverse hormonal side effects which developed frequently when large or relatively large maintenance doses were required to support satisfactory improvement.Unwanted signs of hormonal excess developed in 40 per cent of cases at some time during the course of treatment. Most of them were mild or transient and disappeared or lessened when the dose of cortisone was reduced, but when the dose was reduced the degree of improvement often declined also.During prolonged cortisone therapy evidence of functional suppression of the adrenal cortices, as indicated by a decreased response of circulating eosinophils to exogenous ACTH, was present. The depression of cortical function was temporary, however. Whether irreversible damage may result when the drug is employed for longer periods cannot yet be answered.     

Detrusor Myocyte Autophagy Protects the Bladder Function via Inhibiting the Inflammation in Cyclophosphamide-Induced Cystitis in Rats

Autophagy, a highly conserved homeostatic cellular process that removes and recycles damaged proteins and organelles in response to cellular stress, is believed to play a crucial role in the immune response and inflammation. The role of autophagy in bladder cystitis, however, has not well been clarified. Here we investigate the role of detrusor myocytes autophagy (DMA) in cyclophosphamide-induced cystitis animal model. 164 female Sprague-Dawley rats were randomized into three experimental groups and compared to three control groups, respectively. The expressions of microtubule-associated protein 1 light chain 3 (LC3), p-p70s6k (the phosphorylated form of ribosomal protein S6), SOD2 (superoxide dismutase 2) in the bladder muscular layer were measured using western blot. The co-location of LC3, alpha-smooth muscle actin (α-SMA), and autophagic vacuoles were investigated with double-labeled immunofluorescence and transmission electron microscopy (TEM). The expression of lL-1β, IL-6, IL-8, malondialdehyde (MDA), and glutathione (GSH) in the detrusor layer were analyzed using ELISA. The bladder inflammation and the number of mast cells in the muscular layer were analyzed by histology. The bladder function was evaluated using cystometry. In cyclophosphamide-induced cystitis, autophagy was detected in detrusor myocytes by increased LC3, p-p70s6k expression, and autophagosomes. However, the presence of enhanced inflammation and oxidative stress in the cyclophosphamide-treated group suggest autophagy of detrusor myocytes may not be sufficiently activated. Inflammation and oxidative stress were significantly decreased and the bladder histology and micturition function were significantly improved with rapamycin (RAPA, autophagy agonist) pre-treatment. In contrast, inflammation and oxidative stress were dramatically increased and the bladder histology and function were negatively affected with chloroquine (CQ, autophagy blocker) pre-treated. These findings preferentially provide evidence of the association between DMA and cyclophosphamide-induced cystitis in rats. The autophagy agonist RAPA significantly decreased the inflammation and protected the bladder function, which might be considered as a potential treatment for interstitial cystitis.     

A型肉毒素在间质性膀胱炎治疗中的研究进展

间质性膀胱炎（interstitial cystitis,IC）好发生于30-70岁女性,平均43岁,美国妇女的发病率为197／10万,而男性发病率为41／10万。国内尚无明确的流行病学统计资料。间质性膀胱炎严重影响着患者的生活质量,其发病率高,但发病原因和发病机理至今仍未明确。近年来,随着国内外学者对肉毒素进行深入和广泛的研究,提出了A型肉毒素在间质性膀胱炎的新疗法。本文就A型肉毒素在问质性膀胱炎治疗中的研究进展进行综述,临床医师实际工作中参考应用。     

Upregulation of macrophage migration inhibitory factor (MIF) and CD74, receptor for MIF, in rat bladder during persistent cyclophosphamide-induced inflammation

The objective of this study was to determine if macrophage migration inhibitory factor (MIF) is upregulated in the bladder during persistent cystitis. MIF is a pro-inflammatory cytokine found pre-formed in the urothelium. Previous findings showed that acute bladder inflammation increased MIF release into the bladder lumen while upregulating MIF and CD74 (MIF receptor) in the bladder. Because the effects of persistent cystitis on MIF and CD74 are not known, MIF and CD74 changes in the bladder were examined after short-term (1-day) or persistent (8-day) cyclophosphamide (CYP)-induced bladder inflammation. Anesthetized male Sprague-Dawley rats received either a single CYP treatment (150 mg/kg, ip; saline, control) and examined 1 day after treatment (short-term), or repeated CYP doses (20-75 mg/ kg, ip; saline, control; every third day for 8 days) and examined after 8 days of treatment (persistent). MIF protein levels in urine and bladder were determined. In addition, Mif, CD74, and cox-2 expression in the bladder was determined. Histology verified cystitis and MIF and CD74 immunoreactivity in the bladder. Repeated CYP doses were decreased to avoid toxicity. Short-term or repeated low CYP doses (40 mg/kg; 8 days) increased urinary MIF and decreased bladder MIF amounts while upregulating bladder Mif and CD74 mRNA expression. Persistent CYP-induced bladder inflammation (even at 40 mg/kg; 8-day treatment) also upregulated other inflammatory cytokines (CCL5, IL-11, iNOS) in the bladder. Short-term and persistent (low dose) CYP cystitis are associated with markedly increased MIF release into the urine and upregulation of Mif and CD74 in bladder. This supports the hypothesis that MIF and CD74 play a significant role in both acute and persistent stages of bladder inflammation.     

Altered Detrusor Gap Junction Communications Induce Storage Symptoms in Bladder Inflammation: A Mouse Cyclophosphamide-Induced Model of Cystitis

Lower urinary tract symptoms (LUTS) include storage, voiding and post-micturition symptoms, featuring many urological diseases. Storage symptoms are the most frequent among these and associated with overactive bladder and non-bacterial bladder inflammation such as interstitial cystitis/bladder pain syndrome (IC/BPS). Gap junction, a key regulator of hyperactive conditions in the bladder, has been reported to be involved in pathological bladder inflammation. Here we report involvement of gap junction in the etiology of storage symptoms in bladder inflammation. In this study, cyclophosphamide-induced cystitis was adapted as a model of bladder inflammation. Cyclophosphamide-treated mice showed typical storage symptoms including increased urinary frequency and reduced bladder capacity, with concurrent up-regulation of connexin 43 (GJA1), one of the major gap junction proteins in the bladder. In isometric tension study, bladder smooth muscle strips taken from the treated mice showed more pronounced spontaneous contraction than controls, which was attenuated by carbenoxolone, a gap junction inhibitor. In voiding behavior studies, the storage symptoms in the treated mice characterized by frequent voiding were alleviated by 18α-glycyrrhetinic acid, another gap junction inhibitor. These results demonstrate that cyclophosphamide-induced mouse model of cystitis shows clinical storage symptoms related with bladder inflammation and that gap junction in the bladder may be a key molecule of these storage symptoms. Therefore, gap junction in the bladder might be an alternative therapeutic target for storage symptoms in bladder inflammation.     

Interstitial cystitis: characterization and management of an enigmatic urologic syndrome

The enigmatic urologic condition known as interstitial cystitis has an estimated prevalence of 0.01% to 0.50% of the female population. Its etiology is unknown but may involve microbiologic, immunologic, mucosal, neurogenic, and/or other, as yet undefined, agents. There is no gold standard for the diagnosis of interstitial cystitis; rather, it is a diagnosis of exclusion. It is impossible to provide a purely evidence-based treatment strategy, but review of available evidence suggests that conservative supportive therapy (including diet modification); oral treatment with pentosan polysulfate, amitriptyline, hydroxyzine, or cimetidine; and intravesical treatments with heparinoids, dimethyl sulfoxide, alkalized lidocaine, or bacille Calmette-Guérin may be effective in some patients.     

Diagnosis of interstitial cystitis/ painful bladder syndrome in patients with overactive bladder symptoms

Overactive bladder (OAB) and interstitial cystitis (IC) have similar symptoms, including urinary urgency/frequency and nocturia, making them difficult to differentiate on the basis of clinical presentation alone. Both conditions may represent a clinical manifestation of a hypersensitive bladder and should be included in the differential diagnosis for patients who present with urgency/ frequency. It is especially important that IC be considered in patients with OAB that is refractory to treatment. The proposed diagnostic framework may be useful for differentiating IC from OAB and for facilitating appropriate treatment.     

Alterations in spinal cord Fos protein expression induced by bladder stimulation following cystitis

These studies examined Fos protein expression in spinal cord neurons synaptically activated by stimulation of bladder afferent pathways after cyclophosphamide (CYP)-induced bladder inflammation. In urethan-anesthetized Wistar rats with cystitis, intravesical saline distension significantly (P 相似文献   

Effect of silymarin on bladder overactivity in cyclophosphamide-induced cystitis rat model

The purpose of this study was to investigate the effects of silymarin, a phytotherapeutic agent, on bladder overactivity in a cyclophosphamide (CYP)-induced cystitis rat model. Female Wistar Albino rats received a single intraperitoneal injection of CYP (150 mg/kg) or saline and after 72 h, bladder function was evaluated by in vitro preparations of whole bladders and cystometry with continuous saline infusion under urethane anesthesia. Silymarin or a vehicle was orally given for 7 days in rats. CYP was injected on the 5th day of silymarin or vehicle treatment and then the animals were killed on the 8th day. CYP-treatment dramatically potentiated the basal spontaneous contractions of isolated whole bladders compared to control rats. In anesthetized rats, during continuous infusion cystometry, intercontraction interval (ICI) was significantly shorter, but bladder voiding pressure was not significantly changed in CYP-injected rats compared to control rats. In the CYP-injected group, silymarin treatment significantly decreased the amplitude, frequency (contractions/min) and area under the curve of spontaneous contractions, but failed to change carbachol-induced contraction in isolated whole bladder. Also, silymarin treatment significantly increased the ICI in comparison to the vehicle treatment. In the saline-injected group, no significant changes in the bladder function were observed between the silymarin and vehicle-treated groups. Histopathological examination showed that CYP-induced bladder inflammation tended to be lower in the silymarin+CYP-treated group. In conclusion, the oral administration of silymarin suppressed CYP-induced bladder overactivity. Silymarin may be considered as an attractive treatment for CYP-induced bladder overactivity.     

Cell signaling in interstitial cystitis/painful bladder syndrome

Evidence for several types of cell signaling abnormalities has been presented for patients with interstitial cystitis/painful bladder syndrome (IC/PBS), a poorly understood chronic painful bladder disorder for which currently there is no reliable effective therapy. Increases or decreases in various urine cytokines and growth factors have been found in patient specimens, along with abnormal expression of epithelial differentiation markers, growth factors, cell membrane proteins, neurotransmitters, and other cytokines in tissue biopsies and/or explanted bladder cells from IC/PBS patients. Some of the abnormalities found in bladder epithelial cells from IC/PBS patients have been shown to be induced in normal cells by an antiproliferative factor from IC/PBS bladder epithelial cells that binds to a functional cell membrane receptor (CKAP4/p63). Greater understanding of cell signaling events associated with this debilitating disorder may lead to the development of more effective therapies.     

Quantitative proteomics identifies a beta-catenin network as an element of the signaling response to Frizzled-8 protein-related antiproliferative factor

Antiproliferative factor (APF), a Frizzled-8 protein-related sialoglycopeptide involved in the pathogenesis of interstitial cystitis, potently inhibits proliferation of normal urothelial cells as well as certain cancer cells. To elucidate the molecular mechanisms of the growth-inhibitory effect of APF, we performed stable isotope labeling by amino acids in cell culture analysis of T24 bladder cancer cells treated with and without APF. Among over 2000 proteins identified, 54 were significantly up-regulated and 48 were down-regulated by APF treatment. Bioinformatic analysis revealed that a protein network involved in cell adhesion was substantially altered by APF and that β-catenin was a prominent node in this network. Functional assays demonstrated that APF down-regulated β-catenin, at least in part, via proteasomal and lysosomal degradation. Moreover, silencing of β-catenin mimicked the antiproliferative effect of APF whereas ectopic expression of nondegradable β-catenin rescued growth inhibition in response to APF, confirming that β-catenin is a key mediator of APF signaling. Notably, the key role of β-catenin in APF signaling is not restricted to T24 cells, but was also observed in an hTERT-immortalized human bladder epithelial cell line, TRT-HU1. In addition, the network model suggested that β-catenin is linked to cyclooxygenase-2 (COX-2), implying a potential connection between APF and inflammation. Functional assays verified that APF increased the production of prostaglandin E(2) and that down-modulation of β-catenin elevated COX-2 expression, whereas forced expression of nondegradable β-catenin inhibited APF-induced up-regulation of COX-2. Furthermore, we confirmed that β-catenin was down-regulated whereas COX-2 was up-regulated in epithelial cells explanted from IC bladder biopsies compared with control tissues. In summary, our quantitative proteomics study describes the first provisional APF-regulated protein network, within which β-catenin is a key node, and provides new insight that targeting the β-catenin signaling pathway may be a rational approach toward treating interstitial cystitis.     

p53 mediates interstitial cystitis antiproliferative factor (APF)-induced growth inhibition of human urothelial cells

Antiproliferative factor (APF) is a sialoglycopeptide elevated in the urine of patients with interstitial cystitis, a urinary bladder disorder of unknown etiology that is characterized by chronic pelvic pain. The present study was directed toward uncovering a pathway through which APF signals. Treatment of human urothelial cells with native APF resulted in growth inhibition accompanied by blockade of cell cycle transit and increased p53. Reduced expression of p53 by RNA interference diminished, while ectopic expression of p53 mimicked, the effects of APF. These are the first findings implicating the network of p53 target genes in urothelial defects associated with interstitial cystitis.