Alterations in Synaptic Plasticity and Oxidative Stress Following Long-Term Paracetamol Treatment in Rat Brain

Neurotoxicity Research - Several studies have recently revealed that cognitive function can be affected by paracetamol (APAP) treatment. However, the exact impact of this drug treatment on learning...     

N-acetylserotonin promotes hippocampal neuroprogenitor cell proliferation in sleep-deprived mice

N-acetylserotonin (NAS), the immediate precursor of melatonin, the pineal gland indole, is regulated in a circadian rhythm. NAS swiftly activates TrkB in a circadian manner and exhibits antidepressant effect in a TrkB-dependent manner. Here we show that NAS regulates an early event of neurogenesis by increasing neuronal progenitor cell (NPC) proliferation. Subchronic and chronic NAS administration induces NPC proliferation in adult mice. Chronic NAS treatment triggers TrkB receptor activation and its downstream signaling in NPCs. Blockade of TrkB abolishes NAS-elicited neurogenesis in TrkBF616A knockin mice, suggesting that TrkB activation is essential for the effect of NAS-induced NPC proliferation. Moreover, NAS induces NPC proliferation in both active and sleeping phases of the mice. Strikingly, NAS significantly enhances NPC proliferation in sleep-deprived mice. Thus, our finding demonstrates a unique function of NAS in promoting robust NPC proliferation, which may contribute to hippocampal plasticity during sleeping period.     

Complexin II plays a positive role in Ca2+-triggered exocytosis by facilitating vesicle priming

SNARE-mediated exocytosis is a multistage process central to synaptic transmission and hormone release. Complexins (CPXs) are small proteins that bind very rapidly and with a high affinity to the SNARE core complex, where they have been proposed recently to inhibit exocytosis by clamping the complex and inhibiting membrane fusion. However, several other studies also suggest that CPXs are positive regulators of neurotransmitter release. Thus, whether CPXs are positive or negative regulators of exocytosis is not known, much less the stage in the vesicle life cycle at which they function. Here, we systematically dissect the vesicle stages leading up to exocytosis using a knockout-rescue strategy in a mammalian model system. We show that adrenal chromaffin cells from CPX II knockout mice exhibit markedly diminished releasable vesicle pools (comprising the readily and slowly releasable pools), while showing no change in the kinetics of fusion pore dilation or morphological vesicle docking. Overexpression of WT CPX II—but not of SNARE-binding-deficient mutants—restores the size of the the releasable pools in knockout cells, and in WT cells it markedly enlarges them. Our results show that CPXs regulate the size of the primed vesicle pools and have a positive role in Ca²⁺-triggered exocytosis.     

Comparison of 1,800 laparoscopic and open partial nephrectomies for single renal tumors

PURPOSE: Laparoscopic partial nephrectomy is an increasingly performed, minimally invasive alternative to open partial nephrectomy. We compared early postoperative outcomes in 1,800 patients undergoing open partial nephrectomy by experienced surgeons with the initial experience with laparoscopic partial nephrectomy in patients with a single renal tumor 7 cm or less. MATERIALS AND METHODS: Data on 1,800 consecutive open or laparoscopic partial nephrectomies were collected prospectively or retrospectively in tumor registries at 3 large referral centers. Demographic, intraoperative, postoperative and followup data were compared between the 2 groups. RESULTS: Compared to the laparoscopic partial nephrectomy group of 771 patients the 1,028 undergoing open partial nephrectomy were a higher risk group with a greater percent presenting symptomatically with decreased performance status, impaired renal function and tumor in a solitary functioning kidney (p<0.0001). More tumors in the open partial nephrectomy group were more than 4 cm and centrally located and more proved to be malignant (p<0.0001 and 0.0003, respectively). Based on multivariate analysis laparoscopic partial nephrectomy was associated with shorter operative time (p<0.0001), decreased operative blood loss (p<0.0001) and shorter hospital stay (p<0.0001). The chance of intraoperative complications was comparable in the 2 groups. However, laparoscopic partial nephrectomy was associated with longer ischemia time (p<0.0001), more postoperative complications, particularly urological (p<0.0001), and an increased number of subsequent procedures (p<0.0001). Renal functional outcomes were similar 3 months after laparoscopic and open partial nephrectomy with 97.9% and 99.6% of renal units retaining function, respectively. Three-year cancer specific survival for patients with a single cT1N0M0 renal cell carcinoma was 99.3% and 99.2% after laparoscopic and open partial nephrectomy, respectively. CONCLUSIONS: Early experience with laparoscopic partial nephrectomy is promising. Laparoscopic partial nephrectomy offered the advantages of less operative time, decreased operative blood loss and a shorter hospital stay. When applied to patients with a single renal tumor 7 cm or less, laparoscopic partial nephrectomy was associated with additional postoperative morbidity compared to open partial nephrectomy. However, equivalent functional and early oncological outcomes were achieved.     

Prophylactic gelatin sponge tract injection to prevent bleeding after percutaneous renal cryoablation in a swine model

PURPOSE: Achievement of hemostasis can be a challenge during percutaneous renal cryoablation (PRC). This study describes the use of a porcine model to test the ability of gelatin sponge injection into the tract to limit bleeding at the site of cryoprobe puncture. MATERIALS AND METHODS: A total of nine swine (18 kidneys) underwent bilateral ultrasound-guided PRC with double freeze/thaw cycle protocol with use of a 2.4-mm cryoprobe. The cryoablation location and protocol were applied identically to both kidneys in each pig; however, only one side received gelatin sponge injection after cryoablation through a coaxial sheath (3 mm). After removal of the sheath, a midline laparotomy incision was performed and sponges were placed around the kidneys. Blood loss was measured by calculating the change in weight of the sponges after 30 minutes of absorption time. Acute blood loss was compared between the two groups. The kidneys treated with gelatin sponge were removed and grossly and histologically examined to identify the gelatin sponge at the puncture cryolesion. RESULTS: The use of gelatin sponge resulted in significantly less blood loss (mean, 8.24 mg +/- 4.68) compared with the control kidneys (mean, 20.24 mg +/- 8.14; P = .001). Gross and histopathologic results confirmed that the gelatin sponge was in the cryoablation puncture sites. Mean diameters of cryoablation ice balls on the gelatin sponge and control sides were 3.9 cm +/- 0.2 and 3.8 cm +/- 0.4, respectively. The lesions were not significantly different between sides. CONCLUSION: Percutaneous tract injection of gelatin sponge appears promising as a method to decrease acute blood loss from PRC.     

Percutaneous bladder cryoablation in porcine model

PURPOSE: To demonstrate the morphologic changes of full-thickness bladder cryoablation utilizing contemporary percutaneous technology. MATERIALS AND METHODS: Cryoablation of the bladder wall was conducted in 24 pigs. The bladders were exposed laparoscopically and inspected cystoscopically. The animals underwent either extravesical (serosal) or transvesical (mucosal) approaches for the creation of the cryoablation lesion. Single or double freeze/thaw cycles were applied, and no bladder drainage was used. The bladder was evaluated for perforation, and histologic examination was undertaken to assess the extent of acute, subacute (2 weeks), or chronic (1 month) lesions. RESULTS: Cryoablation reliably produced a controlled transmural area of necrosis (both serosa and mucosa) by both techniques. The size and extent of the lesion were directly proportional to the duration of freezing and the type of cryoprobe used. The pathology report confirmed the full-thickness coagulative necrosis of muscle. Bladder perforation was not detected clinically or at autopsy. CONCLUSION: Cryoablation produces reliable zones of tissue destruction without bladder perforation. These preliminary data show the safety and feasibility for trials in the treatment of bladder tumors by laparoscopic, cystoscopic, or image-guided techniques.     

Cost analysis of open, laparoscopic, and percutaneous treatment options for nephron-sparing surgery

BACKGROUND AND PURPOSES: A variety of nephron-sparing options exist for the management of small renal masses. The perioperative cost of open (OPN) and laparoscopic (LPN) partial nephrectomy, laparoscopic (LCA), and CT-guided percutaneous (PCA) cryoablation was compared using a detailed computer model. PATIENTS AND METHODS: The model incorporates operative time, consumables, anesthesia, CT usage, percutaneous biopsy, hospitalization, and transfusion expenses. Starting values were derived from a retrospective review of 317 patients treated at the Johns Hopkins Medical Institutions within the past 7 years. Hypothesis testing was performed with sensitivity analysis. RESULTS: The PCA was 2.2 to 2.7 times less costly than the other options and resulted in a cost savings of $3625 to $5155 per case. For OPN, LPN, and LCA, the operative time and hospitalization accounted for 69% to 91% of the cost. In contrast, cryoprobe consumables were responsible for >70% of total cost of PCA. An OPN was 1.2x as costly as LPN and could achieve cost equivalence only with operative times of <2.8 hours or hospitalization of <3 days. An LCA was more costly than all forms of extirpative surgery if more than two cryoprobes were used. Reusing cryoprobes during LCA was always a less-costly option than adding a second cryoprobe to the procedure. The LCA was no longer cost advantageous over OPN if more than four CT scans were obtained during the first postoperative year or if local recurrence rates exceeded 23%. CONCLUSIONS: This model defines and simplifies a series of complex cost relations between the options for nephron-sparing surgery.     

Percutaneous computerized tomography guided renal cryoablation using local anesthesia: pain assessment

PURPOSE: The administration of intravenous sedation during prone computerized tomography guided, percutaneous procedures has the potential for complications. We assessed the pain associated with computerized tomography guided, percutaneous renal cryoablation using straight local anesthesia. MATERIALS AND METHODS: Patients were treated with cryoablation probes inserted into the renal tumor under computerized tomography guidance with local anesthesia. Patients were asked to rate the pain experienced during needle placement and cryoablation using a visual 10-degree pain score scale. Sedation was given when pain was greater than 7 or when requested by the patient. Parameters assessed were cardiopulmonary complications, the need for intravenous supplementation, the pain score during the procedure and the postoperative score. RESULTS: A total of 25 patients (30 tumors) underwent a total of 26 cryoablation sessions with only local anesthesia. Mean patient age +/- SD was 67 +/- 13 years (range 33 to 88). Average tumor and ice ball size was 2.1 +/- 0.7 (range 1.1 to 4.3) and 4.1 +/- 1.0 cm (range 2.6 to 5.9), respectively. The mean dose of 1% lidocaine was 43.89 +/- 24.97 ml (range 10 to 110). All procedures were completed in an average of 68.78 +/- 20.7 minutes (range 40 to 120). Vital signs were not significantly changed during the procedure. Successful completion of percutaneous computerized tomography guided cryoablation using local anesthesia was accomplished in 22 of the 26 sessions (84.62%) without sedation. Four patients required intravenous supplementation. CONCLUSIONS: Percutaneous computerized tomography guided cryoablation for renal tumors can be performed using local anesthesia with minimal discomfort in most patients.