Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago.

BACKGROUND: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. METHODS: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. RESULTS: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P < 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. CONCLUSIONS: After 100 years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception.

Emergency resection is an independent risk factor for decreased long-term overall survival in colorectal cancer: a matched-pair analysis.

BACKGROUND: Colorectal cancer is one of the most common malignant neoplasms worldwide. Up to 30% of the patients present in an emergency setting despite an established screening program. Emergency colorectal resection is associated with increased mortality and morbidity as well as worse oncological outcome. This study aims to analyze the impact on tumor recurrence and survival in patients with an emergency colorectal resection, independent of sex, age, and tumor stage. METHODS: Patients, who underwent an oncological resection for colorectal cancer at the Medical University of Innsbruck, Department of Visceral, Transplant and Thoracic Surgery, between January 2003 and December 2018 were analyzed retrospectively and screened for emergency resections. Matched pairs were formed to analyze the impact of emergency operations on long-term outcomes, considering tumor stage, sex, and age, comparing it with elective patients. RESULTS: In total, 4.5% out of 1297 patients underwent surgery in an emergency setting. These patients had higher UICC (Union internationale contre le cancer) stages than elective patients. After matching the patients for age, sex, and tumor stage, emergency patients still had higher mortality. The incidence of recurrence was higher (47.5% vs. 25.4%, p = 0.003) and the 5-year overall survival decreased (35.6% vs. 64.4%, p < 0.001) compared to the matched patients with elective resection. Correcting for 90-day mortality still a reduction in the 5-year overall survival was demonstrated (44% vs. 70%, p = 0,001). The left-sided colon tumors were more common in the emergency group (45.8% vs. 25.4%, p = 0.006) and the rectal tumors in the elective one (21.2% vs. 3.4%, p = 0.002). CONCLUSION: Patients undergoing emergency resection for colorectal cancer have a decreased tumor-specific and overall survival compared to patients after elective resection, independent of age, sex, and tumor stage, even after correcting for 90-day mortality. These findings confirm the importance of colorectal cancer awareness and screening to reduce emergency resections.

Small bowel neuroendocrine tumors: An analysis of clinical presentation, diagnostic workup and surgical approach-A single center retrospective study.

Background: Neurocrine neoplasms (NEN) of the small bowel (SBNEN) are a rare entity and mostly asymptomatic. The aim of this study was to explore trends in the clinical presentation, diagnostic workup, surgical approach and oncological outcome in patients with SBNEN at our surgical department. Materials and methods: All patients who underwent surgical resection for SBNEN from 2004 to 2020 at our department were enrolled in this single center retrospective study. Results: A total of 32 patients were included in this study. In most cases, the diagnosis was based on incidental findings during endoscopy or radiographic imaging (n = 23; 72%). Twenty cases had a G1 tumor and 12 cases a G2 tumor. The 1-, 3- and 5-year overall survival (OS) were 96%, 86% and 81%, respectively. Patients with a tumor more than 30 mm had a significantly lower OS (p = 0.01). For G1 tumors, the estimated disease-free survival (DFS) was 109 months. Again, the DFS was significantly lower when the tumor had more than 30 mm in diameter (p = 0.013). Conclusion: Due to the mostly asymptomatic presentation, the diagnostic workup can be difficult. An aggressive approach and a strict follow-up seem to be important for the oncological outcome.

Is a less-intensive follow-up for colon cancer in early stages reasonable?

PURPOSE: Patients with colon cancer are usually included in an intensive 5-year surveillance protocol after curative resection, independent of the tumor stage, though early stages have a considerably lower risk of recurrence. The aim of this study was to analyze the adherence to an intensive follow-up and the risk of recurrence in patients with colon cancer in UICC stages I and II. METHODS: In this retrospective study, we assessed patients who underwent resection for colon cancer in UICC stages I and II between 2007 and 2016. Data were collected on demographics, tumor stages, therapy, surveillance, recurrent disease, and oncological outcome. RESULTS: Of the 232 included patients, 43.5% (n = 101) reached the 5-year follow-up disease-free. Seven (7.5%) patients in stage UICC I and sixteen (11.5%) in UICC II had a recurrence, with the highest risk in patients with pT4 (26.3%). A metachronous colon cancer was detected in four patients (1.7%). The therapy of recurrence was intended to be curative in 57.1% (n = 4) of UICC stage I and in 43.8% (n = 7) of UICC stage II, but only in one of seven patients over 80 years. 44.8% (n = 104) of the patients were lost to follow-up. CONCLUSION: A postoperative surveillance in patients with colon cancer is important and recommended as a recurrent disease can be treated successfully in many patients. However, we suggest that a less intensive surveillance protocol is reasonable for patients with colon cancer in early tumor stages, especially in UICC stage I, as the risk of recurrent disease is low. With elderly and/or frail patients in a reduced general condition, who will not endure further specific therapy in case of a recurrence, the performance of the surveillance should be discussed: we recommend a significant reduction or even renunciation.

Phrenic nerve paralysis after bipolar electrocoagulation of endometriosis of the diaphragm: case report and mini review.

Objective: To present a case of persistent postoperative elevation of the right hemidiaphragm after bipolar electrocoagulation of diaphragmatic endometriosis, highly likely because of collateral thermal damage to key branches of the phrenic nerve, and review the literature on diaphragmatic endometriosis, focusing on operative treatment. Design: Case report and mini review. Setting: Single university-based interdisciplinary endometriosis center. Patients: A 33-year-old nulliparous patient, initially presenting with right-sided shoulder and back pain accompanied by severe dysmenorrhea and diarrhea. Written consent for the use of anonymized data and images for research purposes was obtained. Interventions: Laparoscopic surgery with bipolar electrocoagulation of multiple superficial endometriotic lesions on the right hemidiaphragm and excision of bilateral deep infiltrating endometriosis on the sacrouterine ligaments. Main Outcome Measures: Outcome and complication of surgical treatment of diaphragmatic endometriosis. Results: Three weeks after surgical treatment, the patient complained of exertional dyspnea and pain in the right flank. Imaging showed a postoperative elevation of the right hemidiaphragm, which did not resolve over the following 6 months. We suspect collateral thermal damage to key branches of the phrenic nerve after bipolar electrocoagulation of extensive superficial diaphragmatic lesions. Conclusions: During laparoscopic treatment of diaphragmatic endometriosis, bipolar electrocoagulation should be used sparingly and with caution to avoid potentially damaging the phrenic nerve.

Long-term outcome after chronic anastomotic leakage following surgery for low rectal cancer.

PURPOSE: This study analyzed the prevalence and factors influencing the history of chronic anastomotic leakage following low anterior resection for rectal cancer. Furthermore, the treatment of a persisting presacral sinus and the impact of stoma reversal on outcome were evaluated. METHODS: The institutional database was scanned for all patients with anastomotic leakage, who were primarily treated for low rectal cancer between January 1995 and December 2019. Patients with rectovaginal and rectovesical fistula or an inadequate follow-up were excluded (n = 5). After applying the exclusion criteria, 71 patients remained for analysis. RESULTS: A total of 39 patients out of 71 patients with anastomotic leakage (54.9%) developed a persisting presacral sinus. Neoadjuvant radiochemotherapy or chemotherapy showed a significant impact on the formation of a chronic anastomotic leakage (radiochemotherapy: p = 0.034; chemotherapy: p = 0.050), while initial surgical treatment showed no difference for anastomotic healing (p = 0.502), but a significantly better overall survival (p = 0.042). Multiple therapies and surgical revision had a negative impact on patients' rate of natural bowel continuity (p = 0.006/ < 0.001). In addition, the stoma reversal cohort showed improved overall 10-year survival (p = 0.004) and functional results (bowel continuity: p = 0.026; pain: p = 0.031). CONCLUSION: Primary surgical therapy for chronic anastomotic leakage should consist of surgical treatment. Furthermore, the reversal of a protective stoma should be considered a viable option in treating chronic presacral sinus to improve pain symptoms and bowel continuity.

Impact of preoperative anemia, iron-deficiency and inflammation on survival after colorectal surgery-A retrospective cohort study.

BACKGROUND: Anemia is present in up to two-thirds of patients undergoing colorectal surgery mainly caused by iron deficiency and inflammation. As anemia is associated with increased risk of perioperative death, diagnosis and treatment of preoperative anemia according to etiology have been recommended. OBJECTIVE: The aim of the present study was to assess if the association between anemia and survival in patients undergoing colorectal surgery was determined by the severity of anemia alone or also by anemia etiology. METHODS: To determine the prevalence of anemia and etiology, preoperative hematological parameters, C-reactive protein, ferritin and transferrin saturation were retrospectively assessed and correlated with outcome in a cohort of patients undergoing colorectal surgery between 2005 and 2019 at the University Hospital of Innsbruck. Anemia was defined as hemoglobin <120 g/L in females and <130 g/L in males. The etiology of anemia was classified on the basis of serum iron parameters, as iron deficiency anemia, anemia of inflammation or other anemia etiologies. RESULTS: Preoperative anemia was present in 54% (1316/2458) of all patients. Anemia was associated with iron deficiency in 45% (134/299) and classified as anemia of inflammation in 32% (97/299) of patients with available serum iron parameters. The etiology of anemia was a strong and independent predictor of survival, where iron deficiency and anemia of inflammation were associated with better postoperative survival than other anemia etiologies. One year survival rates were 84.3%, 77.3% and 69.1% for patients with iron deficiency anemia, anemia of inflammation and other anemia types. Inflammation indicated by high C-reactive protein is a strong negative predictor of overall survival. CONCLUSIONS: Anemia has a high prevalence among patients undergoing colorectal surgery and rational treatment requires early assessment of serum iron parameters and C-reactive protein.

Increased expression of GABAA receptor subunits associated with tonic inhibition in patients with temporal lobe epilepsy.

Epilepsy animal models indicate pronounced changes in the expression and rearrangement of GABAA receptor subunits in the hippocampus and in para-hippocampal areas, including widespread downregulation of the subunits α5 and δ, and upregulation of α4, subunits that mediate tonic inhibition of GABA. In this case-control study, we investigated changes in the expression of subunits α4, α5 and δ in hippocampal specimens of drug resistant temporal lobe epilepsy patients who underwent epilepsy surgery. Using in situ hybridization, immunohistochemistry and α5-specific receptor autoradiography, we characterized expression of the receptor subunits in specimens from patients with and without Ammon's horn sclerosis compared to post-mortem controls. Expression of the α5-subunit was abundant throughout all subfields of the hippocampus, including the dentate gyrus, sectors CA1 and CA3, the subiculum and pre- and parasubiculum. Significant but weaker expression was detected for subunits α4 and δ notably in the granule cell/molecular layer of control specimens, but was faint in the other parts of the hippocampus. Expression of all three subunits was similarly altered in sclerotic and non-sclerotic specimens. Respective mRNA levels were increased by about 50-80% in the granule cell layer compared with post-mortem controls. Subunit α5 mRNA levels and immunoreactivities were also increased in the sector CA3 and in the subiculum. Autoradiography for α5-containing receptors using [3H]L-655,708 as ligand showed significantly increased binding in the molecular layer of the dentate gyrus in non-sclerotic specimens. Increased expression of the α5 and δ subunits is in contrast to the previously observed downregulation of these subunits in different epilepsy models, whereas increased expression of α4 in temporal lobe epilepsy patients is consistent with that in the rodent models. Our findings indicate increased tonic inhibition likely representing an endogenous anticonvulsive mechanism in temporal lobe epilepsy.

Lessons Learned in 11 Years of Experience With Open Abdomen Treatment With Negative-Pressure Therapy for Various Abdominal Emergencies.

Introduction: Open abdomen (OA) treatment with negative-pressure therapy (NPT) was initiated for perforated diverticulitis and subsequently extended to other abdominal emergencies. The aim of this retrospective study was to analyze the indications, procedures, duration of NPT, and the outcomes of all our patients. Methods: All consecutive patients treated with intra-abdominal NPT from January 1, 2008 to December 31, 2018 were retrospectively analyzed. Results: A total of 438 patients (44% females) with a median (range) age of 66 (12-94) years, BMI of 25 (14-48) kg/m2, and ASA class I, II, III, and IV scores of 36 (13%), 239 (55%), 95 (22%), and 3(1%), respectively, were treated with NPT. The indication for surgery was primary bowel perforation in 163 (37%), mesenteric ischemia in 53 (12%), anastomotic leakage in 53 (12%), ileus in 53 (12%), postoperative bowel perforation/leakage in 32 (7%), abdominal compartment in 15 (3%), pancreatic fistula in 13 (3%), gastric perforation in 13 (3%), secondary peritonitis in 11 (3%), burst abdomen in nine (2%), biliary leakage in eight (2%), and other in 15 (3%) patients. A damage control operation without reconstruction in the initial procedure was performed in 164 (37%) patients. The duration of hospital and intensive care stay were, median (range), 28 (0-278) and 4 (0-214) days. The median (range) duration of operation was 109 (22-433) min and of NPT was 3(0-33) days. A trend to shorter duration of NPT was observed over time and in the colonic perforation group. The mean operating time was shorter when only blind ends were left in situ, namely 110 vs. 133 min (p = 0.006). The mortality rates were 14% at 30 days, 21% at 90 days, and 31% at 1 year. An entero-atmospheric fistula was observed in five (1%) cases, most recently in 2014. Direct fascia closure was possible in 417 (95%) patients at the end of NPT, but least often (67%, p = 0.00) in patients with burst abdomen. During follow-up, hernia repair was observed in 52 (24%) of the surviving patients. Conclusion: Open abdomen treatment with NPT is a promising concept for various abdominal emergencies, especially when treated outside normal working hours. A low rate of entero-atmospheric fistula formation and a high rate of direct fascia closure were achieved with dynamic approximation of the fascia edges. The authors recommend an early-in and early-out strategy as the prolongation of NPT by more than 1 week ends up in a frozen abdomen and does not improve abdominal sepsis.

Prospectively Randomized Controlled Trial on Damage Control Surgery for Perforated Diverticulitis with Generalized Peritonitis.

INTRODUCTION: Damage control surgery (DCS) with abdominal negative pressure therapy and delayed anastomosis creation in patients with perforated diverticulitis and generalized peritonitis was established at our Institution in 2006 and has been published. The concept was adopted in other hospitals and published as a case series. This is the first prospectively controlled randomized study comparing DCS and conventional treatment (Group C) in this setting. METHODS: All consecutive patients from 2013 to 2018 with indication for surgery were screened and randomized to Group DCS or Group C. The primary outcome was the rate of reconstructed bowel at discharge and at 6 month. Informed consent was obtained. The trial was approved by the local ethics committee and registered at CinicalTrials.gov: NCT04034407. RESULTS: A total of 56 patients were screened; 41 patients gave informed consent to participate and ultimately 21 patients (9 female) with intraoperatively confirmed Hinchey III (n = 14, 67%) or IV (n = 7, 33%), and a median (range) age of 66 (42-92), Mannheim Peritonitis Index of 25 (12-37) and Charlson Comorbidity Index of 3 (0-10) were intraoperatively randomized and treated as Group DCS (n = 13) or Group C (n = 8). Per protocol analysis: A primary anastomosis without ileostomy (PA) was performed in 92% (11/12) patients in Group DCS at the second-look operation, one patient died before second look, and one underwent a Hartmann procedure (HP). In Group C 63% (5/8) patients received a PA and 38% (3/8) patients a HP. Two patients in Group C, but none in Group DCS experienced anastomotic leakage (AI). ICU and hospital stay was median (range) 2 (1-10) and 17.5 (12-43) in DCS and 2 (1-62) and 22 (13-65) days in group C. In Group DCS 8% (1/12) patients was discharged with a stoma versus 57% (4/7) in Group C (p = 0.038, n.s., α = 0.025); one patient died before discharge. The odds ratio (95% confidence interval) for discharge with a stoma is 0.068 (0.005-0.861). Intent to treat analysis: A PA was performed in 90% (9/10) of patients randomized to DCS, one patient died before the second look, and one patient received a HP. In group C, 70% (7/10) were treated with PA and 30% (3/10) with HP. 29% (2/7) experienced AI treated with protective ileostomy. In group DCS, 9% (1/11) were discharged with a stoma versus 40% (4/10) in group C (p = 0.14, n.s.). The odds ratio for discharge with a stoma is 0.139 (0.012-1.608). CONCLUSION: This is the first prospectively randomized controlled study showing that damage control surgery in perforated diverticulitis Hinchey III and IV enhances reconstruction of bowel continuity and can reduce the stoma rate at discharge.

Early response evaluation during preoperative chemotherapy for colorectal liver metastases: Combined size and morphology-based criteria predict pathological response and survival after resection.

BACKGROUND: Short treatment-duration with early restaging is crucial to avoid liver injury after preoperative chemotherapy (preopCTX) for colorectal liver metastases (CRLM). Response evaluation according to response evaluation criteria in solid tumors (RECIST) criteria implies several limitations. Early tumor shrinkage (ETS; ≥20% size reduction <6-12 weeks) or morphological criteria (MC) may better predict oncological outcome. METHODS: In patients undergoing resection after preopCTX between 2003-2017 pathological and radiological response was reassessed according to Blazer classification, ETS, MC, and RECIST within 90 days and correlated with survival. RESULTS: Seventy-two patients were included, with a median of two (1-10) liver lesions, 53% bilobar involvement, and 7% extrahepatic disease. PreopCTX was applied for 3 months in median (1-6). During restaging after a median of 62 days, presence of ETS was associated with improved median overall survival (OS; 57.1 vs 33.7 months; P = .010) and disease-free survival (16 vs 7.2 months; P = .025). MC significantly correlated with major pathological response (P = .021). When combining ETS with optimal MC, presence of one or both factors was associated with pathological response (61.5% and 92.3%; P = .044) and OS in log-rank (P = .011), and multivariable analysis (hazard ratio [HR] 0.41; 95% confidence interval [CI], 0.19-0.90 and HR 0.32; 95%CI, 0.11-0.97). CONCLUSION: Response-grading by combined ETS/MC criteria less than 90 days after preopCTX initiation predicts pathological response and postoperative survival in CRLM.

Primary tumour location affects survival after resection of colorectal liver metastases: A two-institutional cohort study with international validation, systematic meta-analysis and a clinical risk score.

BACKGROUND: Colorectal cancer (CRC) represents a major cause for cancer death and every third patient develops liver metastases (CRLM). Several factors including number and size of metastases and primary tumour lymph-node status have been linked to survival. The primary tumour location along the colo-rectum continuum (sidedness) was analysed in first-line chemotherapy trials, where right-sided CRCs showed decreased survival. This association has not yet been clearly established in patients undergoing resection for CRLM. METHODS: Clinicopathological differences in CRLM resections according to sidedness in two Austrian centres (2003-2016) are described and survival is compared through Kaplan-Meier and multivariable analysis. A risk-score is presented with time-dependent receiver operating curve analysis and international validation in two major hepatobiliary centres. Furthermore, a systematic meta-analysis of studies on primary tumour location and survival after CRLM resection was performed. RESULTS: 259 patients underwent hepatectomy. Right-sided CRC patients (n = 59) more often had positive primary tumour lymph-nodes (76.3%/61.3%;p = 0.043) and RAS-mutations (60%/34.9%;p = 0.036). The median overall and disease-free survival was 33.5 and 9.1 months in right-sided versus 55.5 (p = 0.051) and 12.1 months (p = 0.078) in left-sided patients. In multivariable analysis nodal-status (HR 1.52), right-sidedness (HR 1.53), extrahepatic disease (HR 1.71) and bilobar hepatic involvement (HR 1.41) were significantly associated with overall survival. Sidedness was not independently associated with disease-free survival (HR 1.33; p = 0.099). A clinical risk score including right-sidedness, nodal-positivity and extrahepatic involvement significantly predicted overall (p = 0.005) and disease-free survival (p = 0.027), which was confirmed by international validation in 527 patients (p = 0.001 and p = 0.011). Meta-analysis including 10 studies (n = 4312) showed a significant association of right-sidedness with overall survival after resection (HR 1.55;p<0.001). There was no significant association with disease-free survival (HR 1.22;p = 0.077), except when rectal-cancers were excluded (HR 1.39;p = 0.006). CONCLUSIONS: Patients with liver metastases from right-sided CRC experience worse survival after hepatic resection. Sidedness is a simple yet effective factor to predict outcome.

Damage control surgery for perforated diverticulitis: a two center experience with two different abdominal negative pressure therapy devices.

Purpose: The adoption of abdominal negative pressure therapy (NPT) during urgent laparotomy has shown to be helpful to control abdominal sepsis, improve morbidity and increase anastomosis rate. The aim of this study was to compare feasibility and outcome of two different abdominal negative pressure devices. Methods: The retrospective two-center study includes 78 consecutive patients with perforated sigmoid diverticulitis, who underwent urgent laparotomy using the ABThera™ (KCI, Wien, Austria) abdominal NPT device (Group A, n = 51) or the Suprasorb® CNP (Lohmann & Rauscher, Wien, Austria) abdominal NPT device (Group B, n = 27). Results: The mean length of abdominal NPT was 3.6 days in Group A and 2.8 days in Group B. Revisional surgery after closure of the abdomen was necessary due to surgical site infections, fascial dehiscence or anastomotic insufficiency in 25% and 29%, respectively. NPT-associated complications like fistula formation or acute bleeding were not observed. Mortality was 15% (Group A) and 7% (Group B). Conclusion: Despite the good feasibility and the well-known positive effect of abdominal NPT, perforated diverticulitis is still associated with high morbidity. However, the analysis did not show significant differences between the two abdominal NPT devices.

Hippocampal NPY Y2 receptors modulate memory depending on emotional valence and time.

Posttraumatic stress disorder is characterized by contextually inappropriate, dys-regulated and generalized fear expression and often resistant to therapy. The hippocampus integrates contextual information into spatial and emotional memories, but how diverse modulatory neurotransmitters are shaping this process is not known. Neuropeptide Y is a peptide-neurotransmitter, which modulates hippocampal excitability by activating several G-protein-coupled receptors. Postsynaptic Y1 receptors create strong anxiolytic and fear-suppressing behavior, while pre-synaptic Y2 receptors (Y2R) are mainly anxiogenic. The role of Y2Rs in spatial compared to emotional learning is, however, still controversial. Here we show that deletion of Y2Rs increased recall, but delayed extinction of contextual fear. Interestingly, spatial memory in the Barnes maze was enhanced during early and late testing, suggesting that Y2Rs suppress learning by hippocampal and extra-hippocampal mechanisms. To demonstrate sufficiency of hippocampal Y2Rs we performed viral vector-mediated, locally restricted re-expression of Y2Rs in the hippocampus of Y2KO mice. This treatment reduced spatial memory to the level of wildtype mice only during early, but not late recall. Furthermore, contextual fear was reduced, while induction of fear extinction appeared earlier. Our results suggest that hippocampal Y2R signaling inhibits learning in a time- and content-specific way, resulting in an early reduction of spatial memory and in a specific suppression of fear, by reducing fear recall and promoting fear extinction. We thus propose that reduction of hippocampal excitability through pre-synaptic Y2Rs may control the integration of contextual information into developing memories.

Effective G-protein coupling of Y2 receptors along axonal fiber tracts and its relevance for epilepsy.

Neuropeptide Y (NPY)-Y2 receptors are G-protein coupled receptors and, upon activation, induce opening of potassium channels or closing of calcium channels. They are generally presynaptically located. Depending on the neuron in which they are expressed they mediate inhibition of release of NPY and of the neuron's classical transmitter GABA, glutamate or noradrenaline, respectively. Here we provide evidence that Y2 receptor binding is inhibited dose-dependently by GTPγS along Schaffer collaterals, the stria terminalis and the fimbria indicating that Y2 receptors are functionally coupled to G-proteins along these fiber tracts. Double immune fluorescence revealed coexistence of Y2-immunoreactivity with ß-tubulin, a marker for axons in the stria terminalis, but not with synaptophysin labeling presynaptic terminals, supporting the localization of Y2 receptors along axonal tracts. After kainic acid-induced seizures in rats, GTPγS-induced inhibition of Y2 receptor binding is facilitated in the Schaffer collaterals but not in the stria terminalis. Our data indicate that Y2 receptors are not only located at nerve terminals but also along fiber tracts and are there functionally coupled to G-proteins.

Dynamic up-regulation of prodynorphin transcription in temporal lobe epilepsy.

Dynorphin neuropeptides are believed to act as endogenous anticonvulsants, though direct evidence for such a role in humans is sparse. We now report pronounced increases of prodynorphin mRNA expression in the dentate gyrus of patients with temporal lobe epilepsy in comparison to controls. We detected a conspicuously right skewed, bimodal distribution of mRNA levels among patients, suggestive of a dynamic up-regulation of prodynorphin expression in epilepsy. Highest transcript levels were seen postictally. Our data argue for an essential role of dynorphin in the termination of seizures.