Long-term outcomes of intravesical dimethyl sulfoxide/heparin/hydrocortisone therapy for interstitial cystitis/bladder pain syndrome

Introduction and hypothesis

For decades, intravesical dimethyl sulfoxide (DMSO) cocktail therapy has been used for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS), but little is known about its long-term efficacy. We aimed to assess the long-term efficacy of intravesical DMSO/heparin/hydrocortisone/bupivacaine therapy in patients with IC/BPS.

Methods

Patients with IC/BPS from our institutions who underwent this therapy with >2 years follow-up were surveyed with O’Leary–Sant interstitial cystitis symptom and problem index questionnaires before and after therapy. Chart reviews and telephone surveys were then conducted to determine their posttherapy course.

Results

Of 68 eligible women, 55 (80.0%) with a median follow-up of 60 months (range 24–142) were surveyed. Their mean age at therapy onset was 44.8 years and their mean body mass index was 26.2 kg/m². There were statistically significant improvements in O’Leary–Sant and pain scores of 23–47% at both 6 weeks and the end of the follow-up period. At the end of the follow-up period, 19 of the 55 women (34.5%) were cured (requiring no further treatment) and 12 (21.8%) were significantly improved (requiring only ongoing oral medication). Univariate and multivariate analyses showed that DMSO treatment failure was more likely in patients with pretreatment day-time urinary frequency more than 15 episodes per day (OR 1.41), nocturia more than two episodes per night (OR 2.47), maximum bladder diary voided volume <200 ml (OR 1.39) and bladder capacity under anaesthesia <500 ml (OR 1.6).

Conclusions

At a median follow-up of 60 months, intravesical DMSO cocktail therapy appeared moderately effective for the treatment of IC/BPS. Treatment failure was more frequent in patients with pretreatment symptoms of reduced bladder capacity.

     

Comparative analysis with collagen type II distinguishes cartilage oligomeric matrix protein as a primary TGFβ-responsive gene

Objective

This study aims to investigate the regulation of expression of Cartilage oligomeric matrix protein (COMP), which is predominately expressed by chondrocytes and functions to organize the extracellular matrix. Mutations in COMP cause two skeletal dysplasias: pseudoachondroplasia and multiple epiphyseal dysplasia. The mechanism controlling COMP expression during chondrocyte differentiation is still poorly understood.

Design

Primary human bone marrow-derived stem cells were induced to differentiate into chondrocyte by pellet cultures. We then compared the temporal expression of COMP with the well-characterized cartilage-specific Type II collagen (Col2a1), and their response to transforming growth factor (TGF)β and Sox trio (Sox5, 6, and 9) stimulation.

Results

COMP and Col2a1 expression are differentially regulated by three distinct mechanisms. First, upregulation of COMP mRNA precedes Col2a1 by several days during chondrogenesis. Second, COMP expression is independent of high cell density but requires TGF-β1. Induction of COMP mRNA by TGF-β1 is detected within 2 h in the absence of protein synthesis and is blocked by specific inhibitors of the TGFβ signaling pathway; and therefore, COMP is a primary TFGβ-response gene. Lastly, while Col2a1 expression is intimately controlled by the Sox trio, overexpression of Sox trio fails to activate the COMP promoter.

Conclusion

COMP and Col2a1 expression are regulated differently during chondrogenesis. COMP is a primary response gene of TGFβ and its fast induction during chondrogenesis suggests that COMP is suitable for rapidly accessing the chondrogenic potential of stem cells.     

Lessons learned from one hundred right lobe living donor liver transplants

OBJECTIVE: To evaluate the first 100 adult right lobe living donor liver transplants (LDLT) in a single center to determine whether the results have improved with technical modifications and better experience. SUMMARY BACKGROUND DATA: Right lobe LDLT has been increasingly performed for adults with end-stage liver disease. Numerous modifications in technique have been introduced, and a learning curve is likely in view of its complexity. METHODS: One hundred consecutive adult right lobe LDLTs performed between May 1996 and May 2002 were retrospectively studied by comparing the first 50 (group 1) with the last 50 cases (group 2). The median follow-up was 37 (27 to 79) months for group 1 and 15 (7 to 27) months for group 2. RESULTS: The characteristics of donors and liver grafts were similar. In group 2, fewer recipients were intensive care unit (ICU)-bound or had hepatorenal syndrome before transplantation, and there was a lower disease severity as shown by a lower Child-Pugh score and Model for End-Stage Liver Disease (MELD) score. Significant improvements were found in the operation time, blood loss, ICU stay, and postoperative complication rate of the donors and in the operation time, transfusion requirements, number of reoperations, ICU stay, and hospital stay of the recipients in group 2. The hospital mortality rate of recipients was reduced from 16% to 0% (P = 0.006). Graft survival rates at 12 months and 24 months were improved from 80% and 74%, respectively, in group 1 to 100% and 96%, respectively, in group 2 (P = 0.002). After adjusting for differences in recipient risk factors (ICU-bound, hepatorenal syndrome, Child-Pugh score, and MELD score) in a multivariate Cox model, recipients in group 2 had significantly lower risk of graft loss (relative risk compared with group 1, 0.13; 95% CI, 0.03 to 0.66; P = 0.014). CONCLUSIONS: There is a learning curve in adult right lobe LDLT. The results have significantly improved with technical refinement and better experience.     

Oxidation and nitration in dopaminergic areas of the prefrontal cortex from patients with bipolar disorder and schizophrenia

Background

Increased oxidative stress is strongly implicated in bipolar disorder (BD), where protein oxidation, lipid peroxidation and oxidative damage to DNA have been consistently reported. High levels of dopamine (DA) in mania are also well-recognized in patients with BD, and DA produces reactive oxygen species and electron-deficient quinones that can oxidize proteins when it is metabolized.

Methods

Using immunohistochemistry and acceptor photobleaching Förster resonance energy transfer (FRET), we examined oxidation and nitration of areas immunoreactive for the DA transporter (DAT) and tyrosine hydroxylase (TH) in the postmortem prefrontal cortex from patients with BD, schizophrenia and major depression as well as nonpsychiatric controls.

Results

We found increased oxidation of DAT-immunoreactive regions in patients with BD (F_3,48 = 6.76, p = 0.001; Dunnett post hoc test p = 0.001) and decreased nitration of TH-immunoreactive regions in both patients with BD (F_3,45 = 3.10, p = 0.036; Dunnett post hoc test p = 0.011) and schizophrenia (p = 0.027). On the other hand, we found increased global levels of oxidation in patients with BD (F_3,44 = 6.74, p = 0.001; Dunnett post hoc test p = 0.001) and schizophrenia (p = 0.020), although nitration levels did not differ between the groups (F_3,46 = 1.75; p = 0.17).

Limitations

Limitations of this study include the use of postmortem brain sections, which may have been affected by factors such as postmortem interval and antemortem agonal states, although demographic factors and postmortem interval were accounted for in our statistical analysis.

Conclusion

These findings suggest alterations in levels of protein oxidation and nitration in DA-rich regions of the prefrontal cortex in patients with BD and schizophrenia, but more markedly in those with BD.     

4-酰胺基-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性

4′-去甲表鬼臼毒素与叠氮酸在三氟化硼乙醚存在下缩合,并经还原得4-氨基-4-脱氧-4′-去甲表鬼臼毒素。该中间体与酸或酸酐反应得相应酰胺化合物24个。经体外筛选,多数化合物抑制L₁₂₁₀和KB细胞活性相当或超过依托泊甙。与相应的醚、酯、胺等类型相比,这一类化合物活性最强。     

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腹腔镜胆囊切除手术,在世界各地已被普遍地接受为常规手术。它能成功地在一个短时间内被广泛应用,并改变了普外科医生对腹腔镜手术在其它外科领域上应用的认识。本文旨在探讨急腹症中腹腔镜的应用范围。1　急腹症的定义ＤｅＤｏｍｂａｌ在1991年所下的定义是“急腹症是以腹部疾病为主诉而时间不超过1周仍未能确认的症状”[1]。用这一定义,急腹症就不包括腹部创伤和绞窄性腹股沟疝。2　急腹症的常见原因在1986年,ＯＭＧＥ作了10320例的急腹症病例统计,非特异性腹痛和急性阑尾炎占了大约2/3。如果加上急性胆囊炎和小肠梗阻,病人的比例就上升到…     

Moderate traumatic brain injury is linked to acute behaviour deficits and long term mitochondrial alterations

Traumatic brain injury (TBI) remains one of the leading causes of death and disability worldwide. Mild TBI may lead to neuropsychiatric sequelae, including memory loss and motor impairment. Mitochondrial dysfunction and oxidative stress have a contributory role in several neurological disorders; however, their association with mitophagy in mild TBI is unclear. TBI was induced in female Sprague Dawley (SD) rats using a New York University Impactor (10 g, impactor head 2.5 mm diameter, weight drop 50 mm) and compared to sham surgery controls. The novel object recognition and error ladder tests were performed at 24 hours and for 6 weeks post injury, and the brains were examined histologically to confirm the extent of injury. Mitochondria manganese superoxide dismutase (MnSOD) and the oxidative phosphorylation (OXPHOS) complexes I‐V (CI‐CV), as well as mitophagy markers, dynamin related protein 1 (DRP‐1), LC3A/B and PTEN‐induced putative kinase 1 (PINK‐1), were measured in the penumbra by western blot. At 24 hours sham rats performed as expected on a novel object recognition test while TBI rats showed cognitive deficits at the early time points. TBI rats also showed more early motor deficits on a horizontal ladder, compared with the sham rats. MnSOD, OXPHOS CI, CIII and CV protein levels were significantly lower in the TBI group at 24 hours. DRP‐1, LC3A/B I and II, and PINK‐1 were increased at 6 weeks suggesting abnormal mitophagy. Moderate TBI caused immediate cognitive and mild motor functional deficits in the rats that did not persist. Reduced antioxidative capacity and possibly compromised mitochondrial function may affect the long term functional recovery.     

Harnessing a Physiologic Mechanism for siRNA Delivery With Mimetic Lipoprotein Particles

Therapeutics based on RNA interference (RNAi) have emerged as a potential new class of drugs for treating human disease by silencing the target messenger RNA (mRNA), thereby reducing levels of the corresponding pathogenic protein. The major challenge for RNAi therapeutics is the development of safe delivery vehicles for small interfering RNAs (siRNAs). We previously showed that cholesterol-conjugated siRNAs (chol-siRNA) associate with plasma lipoprotein particles and distribute primarily to the liver after systemic administration to mice. We further demonstrated enhancement of silencing by administration of chol-siRNA pre-associated with isolated high-density lipoprotein (HDL) or low-density lipoprotein (LDL). In this study, we investigated mimetic lipoprotein particle prepared from recombinant apolipoprotein A1 (apoA) and apolipoprotein E3 (apoE) as a delivery vehicle for chol-siRNAs. We show that apoE-containing particle (E-lip) is highly effective in functional delivery of chol-siRNA to mouse liver. E-lip delivery was found to be considerably more potent than apoA-containing particle (A-lip). Furthermore, E-lip–mediated delivery was not significantly affected by high endogenous levels of plasma LDL. These results demonstrate that E-lip has substantial potential as delivery vehicles for lipophilic conjugates of siRNAs.