Delayed Oral Estradiol Combined with Leuprolide Increases Endometriosis-Related Pain

Objectives:

To determine if low-dose estrogen replacement can be added to GnRH agonist therapy after three months to reduce hypoestrogenic symptoms while allowing continued relief of pain in patients with endometriosis.

Materials and Methods:

Thirteen women with endometriosis and pain were treated with six months of leuprolide acetate in a prospective, randomized double-blind placebo controlled study. After three months of therapy, six subjects initiated oral estradiol 1 mg daily, and seven received an identical placebo.

Results:

Dysmenorrhea improved in both groups, and dyspareunia significantly improved in the GnRH agonist plus placebo group. The mean pain scores of the oral estrogen group tended to be higher than the placebo group, and hot flushes tended to be less severe with estrogen treatment. However, differences observed between the study and placebo groups did not reach statistical significance.

Conclusion:

In a prospective, randomized study, low-dose estrogen replacement increases endometriosis-related pain during GnRH agonist therapy. The study was terminated after the first 13 subjects due to the concerning trend toward recurrent symptoms in women who received oral estradiol during GnRH agonist therapy for endometriosis-related pain. With the trend toward increasing pain with estrogen add-back therapy, a larger study would not seem to be justifiable.     

A Balloon-Tipped Catheter for Measuring Urethral Pressures

Background:

Better methods are needed for recording urethral function for complex urologic problems involving the bladder, urethra, and pelvic floor.

Objective:

To evaluate a balloon catheter for recording urethral pressure and function using bench-top testing and evaluation in an animal model.

Methods:

Balloon pressure–recording methods included slightly inflating the balloon with water and placing the pressure transducer on the distal end of the catheter. For bench-top testing, manual procedures and a silastic tube with a restriction were used. In 3 anesthetized dogs, pressure recorded from the skeletal urethral sphincter was induced with electrical stimulation of the sphincter. Anal sphincter pressure was also recorded.

Results:

Bench-top testing showed good pressure recordings, including a confined peak at the tube restriction. Animal tests showed urethral pressure records with rapid responses when electrical stimulation was applied. Peak pressure at the urethral skeletal sphincter was 55.7 ± 15 cmH₂O, which was significantly higher than the peak pressure recorded 2 cm distally in the proximal urethra (3.3 ± 2.3 cmH₂O). Peak anal pressures were smaller and unchanged for the 2 stimulations.

Conclusions:

Balloon-pressure recordings showed rapid responses that were adequate for the tests conducted. In the animal model, high-pressure contractions specific to the skeletal urethral sphincter were shown. Balloon-tipped catheters warrant further investigation and may have applications for the evaluation of detrusor-sphincter dyssynergia after spinal cord injury or for stress urinary incontinence.     

Finasteride monotherapy maintains stable lower urinary tract symptoms in men with benign prostatic hyperplasia following cessation of alpha blockers

Objective

Our Canadian multicentre open-label study sought to evaluate, in patients with moderate/severe lower urinary symptoms (LUTS) secondary to benign prostatic hyperplasia, the effect on symptoms of 9 months of monotherapy with finasteride 5 mg following 9 months of combination treatment (finasteride with an α-blocker) as quantified according to the International Prostate Symptom Score (IPSS).

Methods

The primary outcome measure for efficacy was the maintenance of IPSS response after cessation of the α-blocker. Subjects were treated with a combination of finasteride and an α-blocker for 9 months and then with finasteride alone for 3 or 9 months.

Results

Results showed that the IPSS scores after 3 months of monotherapy were within the criteria for equivalence to those after 9 months of combination therapy. Symptom control equivalence was also found after 9 months of monotherapy. The IPSS response rate was also similar for combination and monotherapy. The safety profile was similar and as expected with these medications.

Conclusion

Control of LUTS associated with BPH thus appears to be maintained for at least 9 months with finasteride alone, following a 9-month course of combination therapy with finasteride and an α-blocker, with similar safety profiles.     

A population-based study examining the effect of tyrosine kinase inhibitors on survival in metastatic renal cell carcinoma in Alberta and the role of nephrectomy prior to treatment

Background

We performed a retrospective population-based study to assess the impact of tyrosine kinase inhibitors (TKIs) on overall survival (OS) in patients treated for metastatic renal cell carcinoma (mRCC) in Alberta, Canada and to assess the impact of nephrectomy on OS in patients treated with TKIs.

Methods

We identified 134 patients who began taking a TKI between December 2003 and June 2007 for mRCC in Alberta. We compared survival in this group to that in an earlier cohort of 141 patients treated with interferon-α (IFN-α) between May 1995 and March 2003. We used the Kaplan–Meier method to determine OS, and we used a Cox proportional hazards model to determine hazard ratios (HRs) and confidence intervals (CIs). We performed multivariate analysis to assess the impact of neprhectomy on OS.

Results

Of the 134 patients treated with TKIs, 81 received treatment in the first-line setting, whereas 53 received treatment after prior IFN-α therapy. All 141 patients from the IFN-α cohort received treatment in the first-line setting. Patients treated with TKIs had an improved OS compared with the IFN-α cohort (HR 0.61, 95% CI 0.45–0.83, p = 0.001). The median OS was 18 months in the TKI group and 10 months in the IFN-α group. The benefit of TKIs was confined to favourable and intermediate risk groups according to the Memorial Sloan-Kettering Cancer Center prognostic model. Prior nephrectomy was associated with improved OS in the TKI cohort, independent of other prognostic factors.

Conclusion

Tyrosine kinase inhibitors improve OS compared with IFN-α in mRCC. In patients treated with TKIs, prior nephrectomy is associated with improved survival independent of other prognostic variables.     

Postoperative Immunosuppression After Open and Laparoscopic Liver Resection: Assessment of Cellular Immune Function and Monocytic HLA-DR Expression

Background and Objectives:

Major abdominal procedures are strongly associated with postoperative immunosuppression and subsequent increased patient morbidity. It is believed that laparoscopic surgery causes less depletion of the systemic immune function because of the reduced tissue trauma. Various cytokines and monocytic HLA-DR expression have been successfully implemented to assess postoperative immune function. The aim of our study was to show the difference in immunologic profiles after minimally invasive versus conventional liver resection.

Methods:

Ten animals underwent either laparoscopic or conventional open left lateral liver resection. Flow cytometric characteristics of HLA-DR expression on monocytes and lipopolysaccharide-stimulated cellular secretion of tumor necrosis factor α, interferon γ, interleukin 6, and interleukin 8 were measured and analyzed in ex vivo whole blood samples. Intraoperative and postoperative clinical outcome parameters were also documented and evaluated.

Results:

All animals survived the procedures. Postoperative complications were fever (n = 3), wound infections (n = 2), and biloma (n = 1). Open surgery showed a morbidity rate of 80% compared with 40% after laparoscopic surgery. Laparoscopic liver resection showed no postoperative immunoparalysis. Major histocompatibility complex class II expression in this group was elevated, whereas the open surgery group showed decreased major histocompatibility complex class II expression on postoperative day 1. Postoperative secretion of tumor necrosis factor α, interleukin 6, and interferon γ was lower in the open surgery group. Elevated transaminase levels after laparoscopy might have resulted from an ischemia/reperfusion injury caused by the capnoperitoneum.

Conclusion:

Major immunoparalysis depression was not observed in either group. Laparoscopic surgery shows a tendency to improve immunologic recovery after liver resection.     

β-Ecdysone Augments Peak Bone Mass in Mice of Both Sexes

Background

One of the strongest predictors for osteoporosis is peak bone mass. Interventions to augment peak bone mass have yet to be developed. β-Ecdysone (βEcd), a natural steroid-like compound produced by arthropods to initiate metamorphosis, is believed to have androgenic effects and so may be used to augment bone mass.

Questions/purposes

The purpose of this study was to use both male and female (1) gonadal-sufficient; and (2) -insufficient mice to investigate sex differences in terms of bone development and structure after βEcd administration.

Methods

Two-month-old male and female Swiss-Webster mice were randomized to receive either vehicle or βEcd (0.5 mg/kg) for 3 weeks. In a separate experiment to evaluate the effects of βEcd on sex hormone-deficient mice, gonadectomy was performed in male (orchiectomy [ORX]) and female mice (ovariectomy [OVX]). Sham-operated and the ORX/OVX mice were then treated for 3 weeks with βEcd. Primary endpoints for the study were trabecular bone structure and bone strength.

Results

In male mice, the trabecular bone volume was 0.18 ± 0.02 in the placebo-treated (PL) and 0.23 ± 0.02 in the βEcd-treated group (p < 0.05 versus PL); and 0.09 ± 0.01 in the ORX group (p < 0.05 versus PL) and 0.12 ± 0.01 in the ORX + βEcd group. Vertebral bone strength (maximum load) was 43 ± 2 in PL and 51 ± 1 in the βEcd-treated group (p < 0.05 versus PL); and 30 ± 4 in the ORX group (p < 0.05 versus PL) and 37 ± 3 in the ORX + βEcd group. In female mice, trabecular bone volume was 0.23 ± 0.02 in PL and 0.26 ± 0.02 in the βEcd-treated group (p < 0.05 versus PL); and 0.15 ± 0.01 in the OVX group (p < 0.05 versus PL) and 0.14 ± 0.01 in the OVX + βEcd group. Maximum load of the vertebrae was 45 ± 2 in PL and 48 ± 4 in the βEcd-treated group; and 39 ± 4 in the OVX group (p < 0.05 versus PL) and 44 ± 4 in the OVX + βEcd group.

Conclusions

These findings suggest the potential use of βEcd in the augmentation of bone mass in growing male and female mice. It may also partially prevent the detrimental effects of gonadectomy on trabecular bone.

Clinical Relevance

Our results support the potential use of βEcd or nature products that are rich in βEcd to augment peak bone mass. βEcd may differ from the other anabolic hormone treatments that may have severe side effects such as serious cardiac complications. However, its effects on humans remain to be determined.     

Small changes in bone structure of female α7 nicotinic acetylcholine receptor knockout mice

Background

Recently, analysis of bone from knockout mice identified muscarinic acetylcholine receptor subtype M3 (mAChR M3) and nicotinic acetylcholine receptor (nAChR) subunit α2 as positive regulator of bone mass accrual whereas of male mice deficient for α7-nAChR (α7KO) did not reveal impact in regulation of bone remodeling. Since female sex hormones are involved in fair coordination of osteoblast bone formation and osteoclast bone degradation we assigned the current study to analyze bone strength, composition and microarchitecture of female α7KO compared to their corresponding wild-type mice (α7WT).

Methods

Vertebrae and long bones of female 16-week-old α7KO (n = 10) and α7WT (n = 8) were extracted and analyzed by means of histological, radiological, biomechanical, cell- and molecular methods as well as time of flight secondary ion mass spectrometry (ToF-SIMS) and transmission electron microscopy (TEM).

Results

Bone of female α7KO revealed a significant increase in bending stiffness (p < 0.05) and cortical thickness (p < 0.05) compared to α7WT, whereas gene expression of osteoclast marker cathepsin K was declined. ToF-SIMS analysis detected a decrease in trabecular calcium content and an increase in C₄H₆N⁺ (p < 0.05) and C₄H₈N⁺ (p < 0.001) collagen fragments whereas a loss of osteoid was found by means of TEM.

Conclusions

Our results on female α7KO bone identified differences in bone strength and composition. In addition, we could demonstrate that α7-nAChRs are involved in regulation of bone remodelling. In contrast to mAChR M3 and nAChR subunit α2 the α7-nAChR favours reduction of bone strength thereby showing similar effects as α7β2-nAChR in male mice. nAChR are able to form heteropentameric receptors containing α- and β-subunits as well as the subunits α7 can be arranged as homopentameric cation channel. The different effects of homopentameric and heteropentameric α7-nAChR on bone need to be analysed in future studies as well as gender effects of cholinergic receptors on bone homeostasis.     

Importance of Extranuclear Estrogen Receptor-�� and Membrane G Protein�CCoupled Estrogen Receptor in Pancreatic Islet Survival

OBJECTIVE

We showed that 17β-estradiol (E₂) favors pancreatic β-cell survival via the estrogen receptor-α (ERα) in mice. E₂ activates nuclear estrogen receptors via an estrogen response element (ERE). E₂ also activates nongenomic signals via an extranuclear form of ERα and the G protein–coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival.

RESEARCH DESIGN AND METHODS

We used mice and islets deficient in estrogen receptor-α (αERKO^−/−), estrogen receptor-β (βERKO^−/−), estrogen receptor-α and estrogen receptor-β (αβERKO^−/−), and GPER (GPERKO^−/−); a mouse lacking ERα binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes.

RESULTS

We show that ERα protection of islet survival is ERE independent and that E₂ favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERβ plays a minor cytoprotective role compared to ERα. Accordingly, βERKO^−/− mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERα and ERβ in mice does not synergize to provoke islet apoptosis. In αβERKO^−/− mice and their islets, E₂ partially prevents apoptosis suggesting that an alternative pathway compensates for ERα/ERβ deficiency. We find that E₂ protection of islet survival is reproduced by a membrane-impermeant E₂ formulation and a selective GPER agonist. Accordingly, GPERKO^−/− mice are susceptible to streptozotocin-induced insulin deficiency.

CONCLUSIONS

E₂ protects β-cell survival through ERα and ERβ via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in β-cells and identifies GPER as a target to protect islet survival.Preserving insulin secretion by the pancreatic β-cells is critical in both type 1 and the late stages of type 2 diabetes. In type 1 diabetes, the death of insulin-producing β-cells of the pancreas by apoptosis leads to insulin dependence. Insulin replacement therapy by pancreatic islet transplantation is a treatment that most closely replicates normal physiological conditions for treatment of type 1 diabetes (1), but its effectiveness is reduced by the loss of functional islet mass from apoptosis, impairing the survival of islet grafts. Similarly, in the late stages of type 2 diabetes, evidence of β-cell apoptosis is documented in animal models (2,3) and in humans (4). Thus, in the absence of novel immunotherapy and antiapoptotic drugs, novel strategies to protect insulin-producing cells in vivo represent a major opportunity for therapeutic intervention. One promising approach to protect β-cells from apoptosis involves the cytoprotective actions of estrogens. In addition to its reproductive functions, the female sex steroid 17β-estradiol (E₂) is a neuroprotective hormone against multiple oxidative and proapoptotic insults in vivo and in vitro, acting via classic estrogen receptors (rev. in 5). Recently, we reported that E₂ protects β-cells from streptozotocin (STZ)-induced apoptosis in mice of both sexes via the estrogen receptor (ER)-α (6). In cultured mouse and human islets, E₂ has potent antiapoptotic properties against proinflammatory cytokines and reactive oxygen species (6,7). E₂ acts via classic estrogen receptors, ERα and ERβ (8). In ERα-deficient female mice, E₂ still partially protects β-cell survival via an alternative pathway (6), suggesting that ERβ may mediate the effects of E₂ in the absence of ERα.The G protein–coupled estrogen receptor (GPER), also known as GPR30, has been recognized as a membrane receptor for estrogens that mediates nongenomic signals (9). GPER is expressed in islets and has recently been suggested to mediate the estrogenic effect on islet insulin release (10). We analyzed the contribution of ERα, ERβ, and GPER to islet survival. We used mice individually deficient in ERα, ERβ, ERα and ERβ, and GPER; a mouse lacking ERα binding to the ERE; and human islets. These mutant mice and islets were exposed to oxidative stress using STZ or hydrogen peroxide, respectively, in combination with the use of specific pharmacological probes.     

Anti-TGF-β antibody combined with dendritic cells produce antitumor effects in osteosarcoma

Background

We previously reported the combination of tumor cryotreatment with dendritic cells to promote antitumor immunity. The effect of the combination treatment with dendritic cells and antitransforming growth factor-β (anti-TGF-β) antibody on the elimination of regulatory T cells and the inhibition of tumor growth was investigated.

Questions/purposes

The effects of the combination treatment with dendritic cells and anti-TGF-β antibody on the enhancement of systemic immune responses and inhibition of metastatic tumor growth were investigated in a murine osteosarcoma (LM8) model.

Materials and Methods

To evaluate activation of the immune response, we established the following three groups of C3H mice (60 mice total): (1) excision only; (2) tumor excision and administration of anti-TGF-β antibody; and (3) tumor excision and administration of dendritic cells exposed to cryotreated tumor lysates with anti-TGF-β antibody.

Results

The mice that received dendritic cells exposed to cryotreated tumor lysates with anti-TGF-β antibody showed increased numbers of CD8(+) T lymphocytes, reduced regulatory T lymphocytes in the metastatic lesion, and inhibition of metastatic growth. The combined therapy group showed reduced numbers of regulatory T lymphocytes in the spleen and high serum interferon γ level.

Conclusions

The control of the inhibitory condition induced by regulatory T cells is important to improve the suppression of the cytotoxic lymphocytes. Combining dendritic cells with anti-TGF-β antibody enhanced the systemic immune response.

Clinical Relevance

We suggest that our immunotherapy could be developed further to improve the treatment of osteosarcoma.     

The antiapoptotic effects of different doses of β-carotene in chronic ethanol-fed rats

Background

Ethanol consumption might induce hepatic apoptosis and cause liver damage. The study was to investigate the effects of different doses of β-carotene supplementation on the antioxidant capacity and hepatic apoptosis in chronic ethanol-fed rats.

Methods

Rats were divided into 6 groups: C (control liquid diet), CLB [control liquid diet with β-carotene supplementation at 0.52 mg/kg body weight (BW)/day], CHB (control liquid diet with β-carotene supplementation at 2.6 mg/kg BW/day), E (ethanol liquid diet), ELB (ethanol liquid diet with β-carotene supplementation at 0.52 mg/kg BW/day), and EHB (ethanol liquid diet with β-carotene supplementation at 2.6 mg/kg BW/day). After 12 weeks, rats were sacrificed and blood and liver samples were collected for analysis.

Results

Lipid peroxidation and hepatic cytochrome P450 2E1 (CYP2E1) expression had increased, and hepatic Fas ligand, caspase-8, cytochrome c, caspase-9, and -3 expressions had significantly increased in the E group. However, lipid peroxidation and CYP2E1, caspase-9, and -3 expressions were significantly lower and Bcl-xL expression was higher in the ELB group. The hepatic tumor necrosis factor (TNF)-α level, lipid peroxidation, and cytochrome c expression were significantly lower and Bcl-2 expression was significantly higher in the EHB group.

Conclusions

The results suggest that ethanol treatment causes oxidative stress and hepatic apoptosis leading to liver injury, and β-carotene supplementation (0.52 mg/kg BW/day) can prevent ethanol-induced liver damage by decreasing ethanol-induced oxidative stress and inhibiting apoptosis in the liver.Key Words: Alcoholic liver disease (ALD), antioxidative stress, apoptosis, β-carotene, rat     

Goal-directed fluid therapy for microvascular free flap reconstruction following mastectomy: A pilot study

BACKGROUND:

Fluid management of the surgical patient has undergone a paradigm shift over the past decade. A change from ‘wet’ to ‘dry’ to a ‘goal-directed’ approach has been witnessed. The fluid management of patients undergoing free flap reconstruction is particularly challenging. This is typically a long operation with minimal surgical stimulation, and hypotension often ensues. The use of vasopressors in these cases is contraindicated to maintain adequate flow to the flap. Hypotension is often treated with intravenous fluid boluses. However, aggressive fluid administration to maintain adequate blood pressure can result in flap edema, venous engorgement and, ultimately, flap loss.

OBJECTIVE:

The primary objective of the present study was to determine whether goal-directed fluid therapy, titrated to maintain stroke volume variation ≤13%, with the use of an arterial pulse contour device results in improved postoperative cardiac index (CI) and stroke volume index (SVI) with reduced amounts of intravenous fluid. The primary end points studied were CI, SVI and cumulative crystalloid/colloid administration.

METHODS:

Twenty female patients undergoing simultaneous microvascular free flap reconstruction immediately following mastectomy were studied. Preoperative and intraoperative care were standardized. Each patient received intra-arterial blood pressure monitoring. In all patients, cardiac output measurement occurred throughout the intraoperative period using the arterial pulse contour device. Control patients had their fluid administered at the discretion of the anesthesiologist (blinded to results from the cardiac output device). Patients in the intervention group had a baseline crystalloid infusion of 5 mL/kg/h, with intravenous colloid boluses to maintain a stroke volume variation ≤13%.

RESULTS:

There was no difference in heart rate or mean arterial pressure between groups at the end of the operation. However, at the end of the operation, the intervention group had significantly higher mean (± SD) CI (3.8±0.8 L/min/m² versus 3.0±0.5 L/min/m²; P=0.02) and SVI (51.4±2.4 mL/m² versus 43.3±2.3 mL/m²; P=0.03). This improved CI and SVI was achieved with similar amounts of administered intraoperative fluid (5.8±0.5 mL/kg/h versus 5.0±0.7 mL/kg/h, control versus intervention). The intervention group required less postoperative fluid resuscitation during the early postoperative period (total fluid administered from end of operation to midnight of the operative day, 6.4±1.9 mL/kg/h versus 10.2±3.3 mL/kg/h, intervention versus control, respectively, P<0.01).

DISCUSSION:

Goal-directed fluid therapy using minimally invasive cardiac output monitoring resulted in improved end-operative hemodynamics, with less ‘rescue’ fluid administration during the perioperative period.     

Effects of Acute Nitric Oxide Synthase Inhibition on Lower Leg Vascular Function in Chronic Tetraplegia

Background/Objective:

To improve our understanding of the lower-leg vascular responses of nitric oxide synthase inhibition in persons with tetraplegia.

Participants:

Six people with chronic tetraplegia and 6 age-matched controls.

Methods:

Lower-leg relative vascular resistance and venous volume variation were obtained by venous occlusion plethysmography and blood pressure by auscultation at baseline. Postintravenous infusion of the nitric oxide synthase inhibitor N^G-nitro-l-arginine-methyl-ester (1 mg·kg⁻¹) or placebo on separate days.

Results:

At baseline in the group with tetraplegia compared with controls, mean arterial pressure and relative vascular resistance of the leg were significantly lower. After nitric oxide synthase inhibition, mean arterial pressure and lower leg vascular resistance were significantly elevated in both groups. There were no group or intervention differences in venous volume variation.

Conclusion:

These preliminary results suggest that nitric oxide synthase inhibition with 1 mg·kg⁻¹ N^G-nitro-l-arginine-methyl-ester normalizes seated blood pressure and lower leg vascular resistance to control group baseline levels.     

Effect of hyperbaric oxygen and ulinastatin on plasma endotoxin,soluble CD14, endotoxin-neutralizing capacity and cytokines in acute necrotizing pancreatitis

Background

We sought to study the effect of a combination therapy comprised of hyperbaric oxygen (HBO) and ulinastatin on the plasma levels of endotoxin, soluble CD14 (sCD14), endotoxin neutralizing capacity (ENC) and cytokines in acute necrotizing pancreatitis (ANP) in rats.

Methods

We randomly allocated 90 Sprague–Dawley rats into 6 groups: group 1 (ordinary control), group 2 (sham operation), group 3 (ANP), group 4 (ANP with HBO), group 5 (ANP with ulinastatin) and group 6 (ANP with HBO and ulinastatin). We induced ANP by retrograde injection of 3.5% sodium taurocholate (2.5 mL/kg) via the pancreatic duct. Five minutes after induction, animals in groups 5 and 6 were infused with ulinastatin (20 000 U/kg) via the portal vein. Thirty minutes after induction, animals in groups 4 and 6 received HBO therapy. We collected samples 3, 6 and 10 hours after induction of ANP.

Results

We found that the plasma level of endotoxin in group 3 was significantly higher than in group 4 (3, 6 h, both p < 0.001), group 5 (3 h, p < 0.001; 6 h, p = 0.014) and group 6 (both p < 0.001). The level of plasma sCD14 in group 3 was significantly higher than in group 4 (3, 6 h, both p < 0.001), group 5 (3, 6 h, both p = 0.001) and group 6 (3 h, p < 0.001; 6 h, p = 0.001). The plasma endotoxin and sCD14 levels in group 6 were significantly lower than in groups 4 and 5. The plasma ENC level in group 6 was significantly higher than in groups 3, 4 and 5 (p < 0.001). The ENC level in groups 4 and 5 were higher than in group 3, but there was no significant difference. The plasma level of tumour necrosis factor-α (TNF-α) and IL-6 in group 6 were significantly lower than in groups 3, 4 and 5 (p < 0.001). The TNF-α and IL-6 levels in groups 4 and 5 were lower than in group 3, but there was no significant difference.

Conclusion

The use of an early combination therapy of HBO and ulinastatin was more effective than either therapy alone in the treatment of ANP.     

Prospective Randomized Comparison Between Transperitoneal Laparoscopic Pyeloplasty and Retroperitoneoscopic Pyeloplasty for Primary Ureteropelvic Junction Obstruction

Background and Objectives:

To compare laparoscopic transperitoneal versus retroperitoneoscopic pyeloplasty for primary ureteropelvic junction obstruction in a prospective randomized manner and assess overall results with long-term follow-up.

Methods:

In this prospective study, from 2008 to 2012, 112 cases of primary ureteropelvic junction obstruction were randomized in a 1:1 ratio into 2 groups. Group I included patients who underwent transperitoneal laparoscopic pyeloplasty, and group II consisted of patients who underwent retroperitoneoscopic laparoscopic pyeloplasty. Demographic and clinical characteristics and postoperative and operative data were collected and analyzed. The statistical analysis was performed with the Fisher exact test, χ² test, and Mann-Whitney U test for independent groups, and P < .05 was considered statistically significant.

Results:

The total operative time and intracorporeal suturing time were significantly higher in group II than in group I (P < .001). The visual analog scale score for pain on postoperative day 1 and the requirement for tramadol were significantly higher in group I than in group II (P = .004). The hospital stay and the rate of temporary ileus were significantly greater (P < .036 and P < .02, respectively) in group I than in group II. The success rate of transperitoneal laparoscopic pyeloplasty versus retroperitoneoscopic laparoscopic pyeloplasty was 96.4% versus 96.6% with a mean follow-up period of 30.75 ± 4.85 months versus 30.99 ± 5.59 months (P < .88).

Conclusion:

Transperitoneal laparoscopic pyeloplasty is associated with significantly greater postoperative pain, a higher tramadol dose, a higher rate of ileus, and a longer hospital stay in comparison with retroperitoneoscopic laparoscopic pyeloplasty. Although the operative time for retroperitoneoscopic laparoscopic pyeloplasty is significantly longer, the success rate remains the same for both procedures.     

Effects of trimetazidine in acute pancreatitis induced by L-arginine

Background

In acute pancreatitis, oxygen free radicals (OFRs) and cytokines have been shown to play a role in the failure of pancreatic microcirculation and the development of local tissue damage. We studied the effects of trimetazidine (TMZ), a potent antioxidant and anti-ischemic agent, on acute pancreatitis.

Methods

Rats were randomized into 3 groups: a control group (n = 15), a study group (n = 15) in which acute pancreatitis was induced with with L-arginine, and a treatment group (n = 15) in which pancreatitis was induced and treated with TMZ intraperitoneally. The rats were followed for 24 hours. At the 24th hour we determined serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, lactate dehydrogenase (LDH), interleukin 1-β (IL-1β), interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α), and the pancreatic tissues were analyzed histopathologically.

Results

The AST (p < 0.001), ALT (p < 0.01), amylase (p < 0.001), LDH (p < 0.01), TNF-α (p < 0.01), IL-1β (p < 0.001) and IL-6 (p < 0.001) levels, and pancreatic tissue edema (p < 0.01), hemorrhage (p < 0.05), acinar cell necrosis (p < 0.001) and level of perivascular inflammation (p < 0.01), were significantly lower in the treatment group than the study group.

Conclusion

Trimetazidine markedly decreases biochemical and histopathologic changes during the early stages of acute pancreatitis, thus preserving the pancreas histologically.     

Neuromodulation by surface electrical stimulation of peripheral nerves for reduction of detrusor overactivity in patients with spinal cord injury: A pilot study

Objectives

To demonstrate reduction in detrusor overactivity using surface electrical stimulation of posterior tibial nerve (PTN) or dorsal penile nerve (DPN) in patients with spinal cord injury (SCI).

Design

Patients with SCI with symptoms of urinary urgency/leaks, with cystometrogram (CMG) proven detrusor overactivity were recruited in this study. Ten persons with observable F-wave from tibial nerve were included in the PTN group. Five persons who had F-wave absent but preserved bulbocavernosus reflex were included in the DPN group. Stimulation was given at 20 Hz, 10–40 mA for 20 minutes/session/day for 14 consecutive days. Detrusor overactivity was recorded using CMG on days 1 and 15.

Settings

Rehabilitation Institute, Department of Physical Medicine and Rehabilitation, Christian Medical College and Hospital, Vellore, TN, India.

Participants

Patients with SCI.

Interventions

Surface stimulation of peripheral nerves for reduction of detrusor overactivity.

Outcome measures

Qualitative analysis using voiding diary data and quantitative analysis using CMG data comparing pre- and post-intervention.

Results

P value obtained from voiding chart was 0.021 for PTN and 0.062 for DPN. P value obtained from CMG data was not significant in both groups. In one subject, treatment was extended to 4 weeks and further improvement in voiding diary was seen.

Conclusions

In this pilot study of 15 patients, voiding chart data showed statistically significant improvement following PTN stimulation and trend of improvement following DPN stimulation. However, the CMG data were not statistically significant in this sample population. Further studies with larger, appropriately powered sample size would be helpful to demonstrate the associations of symptoms with CMG data.

Trial registration

CTRI no.; CTRI/2012/12/003234; CMCH Approval no.: CMC/IRB/6735/2008/12/18.     

Is the Acetabulum Retroverted in Slipped Capital Femoral Epiphysis?

Background

Recent biplanar radiographic studies have demonstrated acetabular retroversion and increased superolateral femoral head coverage in hips with slipped capital femoral epiphysis (SCFE), seemingly divergent from earlier CT-based studies suggesting normal acetabular version.

Question/purposes

We therefore asked: Are there differences in (1) acetabular version at the superior ¼ of the acetabular dome (AV_sup), (2) acetabular version at the center of the femoral head (AV_cen), and (3) superolateral femoral head coverage (lateral center-edge angle [LCEA]) among affected SCFE hips, unaffected hips, and normal controls?

Methods

We identified 32 patients with SCFE who underwent CT between 2007 and 2012. Twenty-three met our inclusion criteria. Seventy-six age- and sex-matched normal patients comprised the control group. Pelvic rotation, tilt, and inclination were corrected on each CT. AV_sup, AV_cen, and LCEA were measured.

Results

The mean AV_sup of the affected hips (−1.71°) demonstrated retroversion compared to the unaffected hips and the control group; the mean AV_sup of the unaffected hips was similar to that of the normal controls. Mean AV_cen was similar among the three groups. The LCEA was higher in affected and unaffected SCFE hips than in the control group (34.3° versus 34.5° versus 28.9°, respectively), but we found no difference between affected and unaffected hips.

Conclusions

Our data suggest an association of superior acetabular retroversion and increased superolateral femoral head coverage in SCFE. Whether this represents a primary abnormal morphology or a secondary pathologic response remains unclear. Further studies investigating the role of acetabular morphology in SCFE and its implications for development of symptomatic femoroacetabular impingement are warranted.     

Early versus late treatment of voiding dysfunction with pelvic neuromodulation

Introduction:

Pelvic neuromodulation is an established method of treating voiding dysfunction. Little is known about the pathophysiology associated with voiding dysfunction. Reports have suggested that a delay in treating patients with sacral neuromodulation therapy can impact the success rate of this type of treatment in voiding dysfunction. We examined patient response to pelvic neuromodulation when it was applied early versus late in the postdiagnosis of voiding dysfunction.

Methods:

We conducted a retrospective study of 42 patients (38 women and 4 men) with voiding dysfunction who underwent surgery for implant with the Interstim (Medtronic, Minneapolis, Minn.). Prior to implantation, patients were required to pass a percutaneous nerve evaluation (PNE) over a 1-week period. Patients were observed for 20–48 months postimplantation. All patients recorded their voiding parameters at baseline, after screening and every 6 months thereafter. Twenty patients (in the early group) underwent implant surgery with the neurostimulator 2–4 weeks post-PNE, and 22 patients (the late group) had the device implanted 6–24 months post-PNE owing to local logistical circumstances.

Results:

In the early group, 16 of 20 patients (80%) maintained a good response. In the late group, 13 of 22 (59%) patients showed a good response. Groups were well matched in terms of age, duration of voiding dysfunction and incidence of comorbidity.

Conclusion:

Patients who were delayed more than 6 months in receiving the neurostimulator implant showed a worse response than did patients who had the device implanted soon after PNE. This indicates the possibility of disease progression, which may limit the response to sacral neuromodulation.Sacral neuromodulation (SNM), using permanent foramen S3 electrode, offers an alternative treatment for patients with conditions refractory to conventional measures. SNM has been approved by the US Food and Drug Administration for 3 indications: urge incontinence (UI), urge frequency (UF) and nonobstructive urinary retention. Several reports have been published regarding the efficacy of SNM in the treatment of UI, UF and nonobstructive urinary retention.^1–4SNM is considered a minimally invasive procedure, and when compared with the more drastic procedures to control intractable overactive bladder symptoms, SNM has fewer complications and has provided patients with more durable and consistent bladder control over time.The purpose of the current study is to determine whether a delay in SNM can affect the long-term outcome of treatment in patients with voiding dysfunction.     

Indomethacin and ketorolac given preoperatively are equally effective in reducing early postoperative pain after laparoscopic cholecystectomy

Objective

To evaluate the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) on pain after laparoscopic cholecystectomy.

Design

A prospective, randomized, placebo-controlled, double-blind study.

Setting

A university hospital.

Patients

Fifty-two patients with cholelithiasis but without known allergy to one of the study drugs, history of bleeding, peptic ulcer disease, known cardiac, lung or renal disease, abnormal liver function or use of opiates or NSAIDs within 2 weeks before operation. Patients were assigned to one of three groups, and treatment was randomized by placing the drugs in sealed, numbered envelopes.

Intervention

Administration of the NSAIDs ketorolac, intramuscularly, or indomethacin, rectally, before laparoscopic cholecystectomy.

Main Outcome Measures

Postoperative pain scored on a visual analogue scale and by nurse assessment, total dose of fentanyl citrate given, and nausea or emesis.

Results

Patients in the placebo group reported significantly more pain than either NSAID group (p < 0.05) and were reported as having significantly more pain by the nurses (p < 0.05). These patients were subsequently treated with a higher mean postoperative dose of fentanyl citrate than either NSAID group (p < 0.05). Furthermore, the placebo group reported more nausea and emesis (p < 0.05). There was no significant difference in any of the parameters measured between the ketorolac or indomethacin group.

Conclusions

The data demonstrate that the NSAIDs ketolorac and indomethacin, administered preoperatively, decrease early postoperative pain and nausea after laparoscopic cholecystectomy and are equally efficacious in producing these results.     

Curcumin modulates TLR4/NF-κB inflammatory signaling pathway following traumatic spinal cord injury in rats

Background

Curcumin, a polyphenolic compound extracted from the plant turmeric, has protective effects on spinal cord injury (SCI) through attenuation of inflammatory response. This study was designed to detect whether curcumin modulates toll-like receptor 4 (TLR4) and the nuclear factor-kappa B (NF-κB) inflammatory signaling pathway in the injured rat spinal cord following SCI.

Methods

Adult male Sprague–Dawley rats were subjected to laminectomy at T8–T9 and compression with a vascular clip. There were three groups: (a) sham group; (b) SCI group; and (g) SCI + curcumin group. We measured TLR4 gene and protein expression by real-time polymerase chain reaction and western blot analysis; NF-κB activity by electrophoretic mobility shift assay, inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels by enzyme-linked immunosorbent assay, hindlimb locomotion function by Basso, Beattie, and Bresnahan rating, spinal cord edema by wet/dry weight method, and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis.

Results

The results showed that SCI induced the up-regulation of TLR4, NF-κB, and inflammatory cytokines in the injured rat spinal cord. Treatment with curcumin following SCI markedly down-regulated the levels of these agents related to the TLR4/NF-κB inflammatory signaling pathway. Administration of curcumin also significantly ameliorated SCI induced hind limb locomotion deficits, spinal cord edema, and apoptosis.

Conclusions

Post-SCI curcumin administration attenuates the TLR4/NF-κB inflammatory signaling pathway in the injured spinal cord, and this may be a mechanism whereby curcumin improves the outcome following SCI.