Anatomical evidence for the interaction of sympathetic and parasympathetic neurons in the cardiac ganglion of Necturus

Evidence of a direct interaction between sympathetic and parasympathetic elements in a cardiac parasympathetic ganglion is presented in this study. Experiments were done using acutely dissected or organ cultured parasympathetic cardiac ganglion preparations from Necturus maculosus (mudpuppy). The glyoxylic acid-induced fluorescence technique was used to visualize catecholamine-containing cells and fibers. Numerous long brightly fluorescent varicose fibers form a complex network over clusters of parasympathetic ganglion cells and strands of cardiac muscle. In addition to these fibers, there are numerous small brightly fluorescent interneurons (SIF cells) interspersed between individual parasympathetic ganglion cells. Long fibers and processes from the interneurons join to form bundles which arborize over groups of parasympathetic cells. In peripherally located smaller groups of ganglion cells there are no interneurons, but some of these parasympathetic cells appear to receive innervation from the long continuous fluorescent axons. Two experimental procedures were applied to support the conclusion that these long fibers were indeed sympathetic postganglionic axons: explants of cardiac ganglia were maintained for varying times to produce degeneration of any severed axons: chemical sympathectomy was produced by injection of 6-hydroxydopamine. The intrinsic SIF cells were apparently unaffected by both procedures. After 8 days in culture or after 6-OH dopamine treatment, all of the long continuous brightly fluorescent fibers, which normally intermingle with clusters of ganglion cells or innervate cardiac muscle, were absent. This indicates their extra-ganglionic origin. All of the isolated groups of parasympathetic ganglion cells not containing SIF cells were totally devoid of any catecholamine-containing fibers.     

The effects of therapeutic sulfide on myocardial apoptosis in response to ischemia–reperfusion injury

Objective: Ischemia–reperfusion (I/R) injury, often encountered clinically, results in myocardial apoptosis and necrosis. Hydrogen sulfide (H₂S) is produced endogenously in response to ischemia and thought to be cardioprotective, although its mechanism of action is not fully known. This study investigates cardioprotection provided by exogenous H₂S, generated as sodium sulfide on apoptosis following myocardial I/R injury. Methods: The mid-LAD coronary artery in Yorkshire swine (n = 12) was occluded for 60 min, followed by reperfusion for 120 min. Controls (n = 6) received placebo, and treatment animals (n = 6) received sulfide 10 min prior to and throughout reperfusion. Hemodynamic, global, and regional functional measurements were obtained. Evans blue/TTC staining identified the area-at-risk (AAR) and infarction. Serum CK-MB, troponin I, and FABP were assayed. Tissue expression of bcl-2, bad, apoptosis-inducing-factor (AIF), total and cleaved caspase-3, and total and cleaved PARP were assessed. PAR and TUNEL staining were performed to assess apoptotic cell counts and poly-ADP ribosylation, respectively. Results: Pre-I/R hemodynamics were similar between groups. Post-I/R, mean arterial pressure (mmHg) was reduced by 30.2 ± 4.3 in controls vs 8.2 ± 6.9 in treatment animals (p = 0.01). +LV dP/dt (mmHg/s) was reduced by 1308 ± 435 in controls vs 403 ± 283 in treatment animals (p = 0.001). Infarct size (% of AAR) in controls was 47.4 ± 6.2% vs 20.1 ± 3.3% in the treated group (p = 0.003). In treated animals, CK-MB and FABP were lower by 47.0% (p = 0.10) and 45.1% (p = 0.01), respectively. AIF, caspase-3, and PARP expression was similar between groups, whereas cleaved caspase-3 and cleaved PARP was lower in treated animals (p = 0.04). PAR staining was significantly reduced in sulfide treated groups (p = 0.04). TUNEL staining demonstrated significantly fewer apoptotic cells in sulfide treated animals (p = 0.02). Conclusions: Sodium sulfide is efficacious in reducing apoptosis in response to I/R injury. Along with its known effects on reducing necrosis, sulfide's effects on apoptosis may partially contribute to providing myocardial protection. Exogenous sulfide may have therapeutic utility in clinical settings in which I/R injury is encountered.     

Computational modeling of ovarian cancer dynamics suggests optimal strategies for therapy and screening

High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Treatment is not uniform, with some patients undergoing primary debulking surgery followed by chemotherapy (PDS) and others being treated directly with chemotherapy and only having surgery after three to four cycles (NACT). Which strategy is optimal remains controversial. We developed a mathematical framework that simulates hierarchical or stochastic models of tumor initiation and reproduces the clinical course of HGSC. After estimating parameter values, we infer that most patients harbor chemoresistant HGSC cells at diagnosis and that, if the tumor burden is not too large and complete debulking can be achieved, PDS is superior to NACT due to better depletion of resistant cells. We further predict that earlier diagnosis of primary HGSC, followed by complete debulking, could improve survival, but its benefit in relapsed patients is likely to be limited. These predictions are supported by primary clinical data from multiple cohorts. Our results have clear implications for these key issues in HGSC management.

Ovarian cancer is the eighth most common cancer and cancer death in women worldwide (1). High-grade serous tubo-ovarian cancer (HGSC) constitutes ∼70% of all ovarian malignancies and has the worst prognosis (2). Current treatment of most patients with HGSC consists of cytoreductive surgery and combination chemotherapy with platinum-containing DNA–cross-linking drugs and taxane-based microtubule-stabilizing agents (2). Although treatment significantly improves survival, most women relapse with chemotherapy-refractory disease and eventually succumb (3). Multiple mechanisms of chemoresistance have been documented (4, 5), including reduced intracellular drug accumulation (6), detoxification by increased levels of glutathione (7), altered DNA damage repair (8, 9), dysfunctional apoptotic pathways (10, 11), and hyperactivation of various cell signaling pathways (12–14). These mechanistic studies are consistent with recent genomic analyses that reveal marked clonal evolution of HGSC during therapy (15). Other evidence, however, supports a hierarchical organization of HGSC, featuring intrinsically chemoresistant “cancer stem cells” (CSCs) that can escape initial treatment and seed recurrence (16–18).Although there is uniform agreement that HGSC patients should receive surgery and chemotherapy, the optimal order and timing of these modalities remain controversial. Two main options exist: primary debulking surgery with adjuvant chemotherapy (PDS), or neoadjuvant chemotherapy, followed by interval debulking surgery (NACT) (19–24). In either case, the surgical standard of care is to seek maximal cytoreduction, with the objective being to leave no visible residual disease. However, the precise definition of such “optimal debulking” can vary among different centers, surgeons, and reports (19, 21, 24, 25).Several studies have found similar outcomes after PDS or NACT, including two highly influential randomized trials (EORTC and CHORUS) carried out across multiple countries (22, 23, 26–28). In both trials, however, the question of potential bias in patient recruitment has been raised, favoring potentially those with more extensive disease, who are less likely benefit from “upfront” surgery (23, 28). Consistent with this interpretation, overall survival in these trials was significantly shorter than that seen in other HGSC cohorts (19, 24, 29, 30). Closer examination of these reports reveals additional factors that might have influenced their conclusions. The EORTC study had inconsistencies in optimal debulking rates between participating centers, with the PDS-associated complete debulking data highly influenced by the results from a single institution (23). The CHORUS study involved 76 clinical sites, and there were substantial differences in surgery execution and chemotherapy drug selection/dosage between them (28).At Princess Margaret Cancer Center, retrospective data showed that PDS patients with no visible disease postresection survived substantially longer (7-y survival, >60%) than those receiving NACT (7-y survival, ∼10%). Furthermore, although residual tumor postresection is a critical determinant of survival, its influence on the PDS group was far more dramatic than on NACT group (24). Of course, this report suffers from deficiencies common to all retrospective analyses, including lack of randomization to account for tumor burden at diagnosis and other factors; indeed, the NACT group in this study did have more extensive disease.Another controversy in HGSC management focuses on the potential benefit of earlier diagnosis. Earlier diagnosis of primary HGSC is generally assumed to enhance patient survival and quality of life (3). Intuitively, one might predict that the same reasoning would apply to recurrent disease; however, survival is similar in relapsed patients treated earlier, based on increasing serum CA125 levels, than in those treated only when physical symptoms of recurrence appear (31). Conceivably, the lead time between CA125 rise and clinical recurrence is too short for earlier chemotherapy to be beneficial; if so, then patient survival might be extended by more sensitive methods, such as testing for circulating tumor DNA (ctDNA) (32, 33).To address these issues, we developed a mathematical framework that models the dynamics of HGSC progression, response to surgery and chemotherapy, and recurrence. Our results, generated over a wide range of parameters and accounting for hierarchical and stochastic models of tumor initiation, argue that PDS is superior to NACT when complete debulking is feasible and suggest that, with currently available therapies, the benefits of earlier detection are intrinsically restricted to primary HGSC.     

Traumatic hemoperitoneum of splenopancreatic origin. Apropos of 155 cases. Can a non-surgical treatment be proposed?]

From 1985 to 1990, we treated 155 patients presenting with a hemoperitoneum secondary to a splenic or hepatic injury (diagnosis established by sonography, puncture and washout and/or laparotomy). These were 39 children and 116 young adults (average age 33 years). Fifty-eight of them (37%) suffered from multiple injuries (11 children, 47 adults). Splenic lesions were observed in 110 cases and hepatic lesions in 45. Ninety-one patients were operated, 55 in emergency and 36 later, while a watch-and-wait policy was applied to 64 (42%), with repeated clinical and complementary (ultrasound and/or CT) examinations. The indication for surgery was based on the clinical findings and the necessity of blood transfusion (more than 40 ml/kg/24 h in children, more than 2 to 5 U/24 h in adults, according to the context). This attitude allowed us to avoid operating two-thirds of the children and one third of the adults. We assess the limitations of this method.     

Efficacy of methylnaltrexone for the treatment of opiod-induced constipation: a meta-analysis and systematic review

Objective: Constipation is a common adverse effect in patients requiring long-term opioid therapy for pain control. Methylnaltrexone, a quaternary peripheral mu-opioid receptor antagonist, is an effective treatment of opioid induced constipation (OIC) without affecting centrally mediated analgesia. Our objective was to conduct a review and meta-analysis to evaluate the efficacy of methylnaltrexone for treatment of OIC, as well as to provide a clinical discussion regarding newly developed alternatives and provide the current treatment algorithm utilized at our institution.

Methods: We performed a systematic review and meta-analysis of randomized control trials using Cochrane Collaboration Databases and MEDLINE from 2007-present. Literature related to methylnaltrexone, opioids, opioid receptors, opioid antagonists, opioid-induced constipation were reviewed. A meta-analysis was completed with the primary outcome of rescue-free bowel movement (RFBM) within four hours of administration. All pooled analyses were based on random-effects models.

Results: 1239 patients were analyzed; 599 received methylnaltrexone and 640 received placebo. With a 95% CI calculated, the true risk difference is between 0.267 and 0.385, demonstrating a statistically significant difference in RFBM between treatment and placebo groups (p < 0.0001). Both the 0.15 mg/kg, 0.30 mg/kg doses every other day, and 12 mg/day dose were found to have increased risk of RFBM compared to placebo.

Conclusion: Results support the use of methylnaltrexone. Furthermore, the use of methylnaltrexone to induce laxation may decrease use of health care resources, increase work productivity, and improve cost utilization. New treatments have been made available; however, controlled clinical studies are needed to demonstrate long–term efficacy, safety and cost–effectiveness. Possible limitations of this study include the relatively small number of randomized, placebo-controlled trials investigating the efficacy of methylnaltrexone versus placebo. There is also the possibility of publication bias, which may lead to overestimating the efficacy of methylnaltrexone in treating OIC.     

An evidence-based medicine review of lymphadenectomy extent for gastric cancer

Background

Several studies in the literature have investigated the possible role of the extent of lymphadenectomy in gastric cancer treatment failure. The current study attempted to determine the effectiveness and safety of lymphadenectomy with gastrectomy for the treatment of gastric cancer.

Methods

Randomized controlled trials (RCTs) were identified by means of MEDLINE, EMBASE, Cochrane Controlled Trials Register databases, and Chinese Biomedical Database, as well as by selecting references from relevant articles.

Results

Overall, 14 RCTs (3,432 patients) were included in the meta-analysis. Of the D1 and D2 surgery groups, the operative mortality and postoperative morbidity were higher in the D2 group than in the D1 group, but the 3- and 5-year survival rates were not statistically different. Also the operative time was shorter in D1 compared to D2. In the D2 versus the D3 surgical group, the operative mortality, percentage of postoperative complications, operative time, and hospital stay were not significantly different.

Conclusions

The results suggest that D2 and D3 surgery may not offer specific advantages for gastric cancer and instead may lead to disadvantages for patient outcomes.