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Nonalcoholic fatty liver disease, which is highly associated with obesity, includes nonalcoholic steatohepatitis. Lipopolysaccharides from the intestine would induce inflammation in the liver in nonalcoholic fatty liver disease. This study aimed to examine the role of the bilio-pancreatic limb in the effect of duodenal–jejunal bypass on nonalcoholic steatohepatitis, with respect to the gut–liver axis, using a rat model. Nonalcoholic steatohepatitis model rats were randomly assigned into 3 groups as follows: 1 sham group and 2 duodenal–jejunal bypass groups. The 2 duodenal–jejunal bypass groups were defined according to the bilio-pancreatic limb length: 30 cm (30-DJB group) and 0 cm (0-DJB group). Pathology findings and blood biochemistry, inflammatory cytokine and lipopolysaccharides receptor mRNA in the liver and common channel, and lipopolysaccharide-binding protein level in the portal vein were assessed. The reduction in plasma alanine aminotransferase and nonalcoholic fatty liver disease activity score in the 30-DJB group was not observed in the 0-DJB group, similar to the sham group. In the liver tissue, mRNA of inflammatory cytokines and lipopolysaccharide receptors, the area occupied by CD68-positive macrophages, and the number of CD3-positive T-lymphocytes on immunostaining were lower in the 30-DJB group; however, these findings were not observed in the 0-DJB group, and lipopolysaccharide-binding protein levels in the portal vein and mRNA expressions of inflammation-related genes in the common channel showed similar tendencies. The bilio-pancreatic limb plays an important role in the beneficial effect of duodenal–jejunal bypass for nonalcoholic steatohepatitis. The bilio-pancreatic limb may suppress lipopolysaccharides-related cascades in the liver by reducing intestinal inflammation. [ABSTRACT FROM AUTHOR]

Background: Recently, virtual navigation system has been applied to hepatic surgery, enabling better visualization of intrahepatic vascular branches and location of tumor. Intraoperative ultrasonography (IOUS) is the most common form of image guidance during liver surgery. However, during laparoscopic hepatectomies (LH), IOUS has several limitations and its reliability has been poorly evaluated. The objective of this work is to evaluate VRCT (virtual real-time CT-guided volume navigation) during LH. This system aims to provide accurate anatomical orientation for surgeons enhancing the safety of LH. Methods: Twenty-seven hepatic neoplasms were resected laparoscopically at our institution under reference guidance of VRCT. During operation, electromagnetic tracking of the surgical instrument was used for navigating the direction of accurate liver transection. Results: Twenty-six (96.3%) of the 27 lesions (mean diameter 11 mm) were successfully performed under VRCT guidance. Average registration time was < 2 min. Average setup time was approximately 7 min per procedure. VRCT allows the surgeon to navigate liver transection with acceptable accuracy. The mean error was 12 mm. All surgical margins were negative and the mean histologic resection margin was 9 mm. Conclusions: VRCT-guided LH is feasible and provides valuable real-time anatomical feedback during hepatic resections. Advancement of such systems to improve accuracy might greatly compensate for the limitation of laparoscopic IOUS. [ABSTRACT FROM AUTHOR]

Highlights • IMF kernel is less attractive than MOX powder for those intending NED production. • Complex recovery process needed for IMF kernel declines its material attractiveness. • Massive IMF kernel decline attractiveness against imperfect but quick processing. • Fresh IMF kernel is regarded as irradiated fuel grade in material attractiveness. Abstract The impacts of chemical stability of inert-matrix-fuel (IMF) on the material attractiveness for states and non-state actors were evaluated in an open transuranic fuel cycle employing high temperature gas cooled reactors. The methodology for material attractiveness evaluation was developed to assess material attractiveness for states and treat IMF which is chemically inert for nitric acid solution. The material attractiveness was relatively assessed with physical properties of material in each of three discrete phases in the development of a nuclear explosive device. The material attractiveness assessment for non-state actors revealed that the non-irradiated TRISO fuel particle and IMF kernel for high temperature gas cooled reactors and the non-irradiated mixed oxide fuel (MOX) powder for MOX light water reactors were the most vulnerable targets in each fuel cycles. The TRISO fuel particle and IMF kernel would have less material attractiveness than the MOX powder because of their greater processing time and complexity. The material attractiveness assessment for states aiming concealed diversion revealed that the TRISO fuel particle and IMF kernel have less material attractiveness than the MOX powder, and are regarded as irradiated uranium fuel grade in the material attractiveness. [ABSTRACT FROM AUTHOR]

Introduction Spontaneous esophageal rupture is a life-threatening condition which is difficult to diagnose early, and is usually treated surgically. Prolonged hospitalization is common. Non-operative treatment of esophageal rupture localized to the mediastinum has been reported. We report three patients with spontaneous esophageal rupture successfully managed with endoscopic clipping. Case presentations Two patients had ruptures localized to the mediastinum, and were discharged within one week of undergoing closure. The third patient presented with Boerhaave’s syndrome with a leak into the pleural space and needed prolonged hospitalization (34 days), but she did not need surgery and began oral intake two days after endoscopic clipping. The patient had an uneventful recovery. [ABSTRACT FROM AUTHOR]

It is important to predict the outcome of tissue plasminogen activator (tPA)–treated patients early after the treatment for considering the post-tPA treatment option. We assessed cerebral blood flow (CBF) of tPA-treated patients with single-photon emission computed tomography (SPECT) 1 hour after tPA infusion to predict the patient outcome. Technetium-99m-hexamethylpropyleneamine oxime SPECT was performed in 35 consecutive tPA-treated patients. Asymmetry index, a contralateral-to-ipsilateral ratio of CBF, was calculated to analyze CBF quantitatively. Hypoperfusion or hyperperfusion was defined as a decrease of 25% or more or a increase of 25% or more in asymmetry index, respectively. Of all 35 patients, 23 had only hypoperfusion, 8 had both hypoperfusion and hyperperfusion, 2 had only hyperperfusion, and 2 had no perfusion abnormality. When evaluating the association between hypoperfusion and outcome, hypoperfusion volumes were significantly correlated with the modified Rankin Scale at 3 months (r = .634, P < .001). Hyperperfusion was observed in 10 patients (28.6%) and they showed a marked National Institutes of Health Stroke Scale score improvement in the first 24-hour period, which were significantly greater than those of 25 patients without hyperperfusion (P = .033). Eight patients (22.9%) with intracerebral hemorrhage (ICH) were all asymptomatic. Most ICHs were located in hypoperfusion areas, and no ICH was related to hyperperfusion. The results of the present study demonstrated that hypoperfusion volume was associated with poor outcome, whereas the presence of hyperperfusion seemed to be predictive of symptom improvement but not of development of ICH. Taken together, early post-treatment SPECT imaging seems to be a useful biomarker of outcome in tPA-treated patients. [Copyright &y& Elsevier]

Objectives: During carotid artery stenting (CAS), hemodynamics may be affected by the carotid sinus reflex in some cases. Although general anesthesia has been reported to stabilize intraoperative hemodynamics, the patient's neurological condition must be assessed indirectly. Therefore, we investigated the changes in intraoperative hemodynamics and perioperative complications of CAS under general anesthesia and evaluated the efficacy of somatosensory evoked potential (SEP) monitoring in detecting a reduction in perfusion during CAS.Materials and Methods: From April 2011 to August 2016,57 consecutive patients who underwent CAS under general anesthesia were evaluated. The follow-up period ranged from 3 to 8 years. During CAS, anesthesiologists monitored and managed the hemodynamics. SEP monitoring was performed during the CAS procedure in all patients.Results: Intraoperative hypotension (systolic blood pressure ≤ 100 mmHg) was evident in 16 patients (28.1%), and 13 patients (22.8%) experienced intraoperative bradycardia; however, all of these cases were promptly managed under general anesthesia. None of the patients showed systolic blood pressure < 50 mmHg from baseline. Regarding perioperative complications, none of the patients exhibited myocardial infarction or postoperative hyperperfusion symptoms, and there was no mortality. Among 21 patients (36.8%) with a decrease in the intraoperative SEP, 3 (5.3%) exhibited transient ischemic symptoms and 1 (1.8%) had postoperative infarction.Conclusions: CAS under general anesthesia is a safe and effective management option in terms of intraoperative hemodynamic stability. In addition, our findings indicate that SEP monitoring could be helpful in evaluating transient postoperative cerebral ischemia or cerebral infarction after CAS. [ABSTRACT FROM AUTHOR]

Abstract: Wideband quadrature frequency resolved spectroscopy (QFRS) expanded from 2ns to 160s revealed that the triple-peaked lifetime distribution observed in the photoluminescence (PL) of a-Si:H consists of the well-known double-peak structure and a newly identified third component. By the exploring dependence of the lifetime distribution on the generation rate G, temperature T, PL emission energy E PL, PL excitation energy E X and external magnetic field, the former is assigned to excitonic recombination and the latter to distant-pair (DP) or nongeminate recombination. The DP component gives the same sublinear G and T dependence as light-induced electron spin resonance (LESR) results. The present paper also shows that the residual PL decay in a-Si:H persists for more than 104 s, which corresponds the DP component and agrees with the LESR results. The residual PL decay reveals that the DP recombination kinetics is monomolecular at low T and low G. [Copyright &y& Elsevier]

The present study was designed to investigate whether endoplasmic inositol 1,4,5-trisphosphate (IP3) receptor-mediated intracellular signaling pathway could be involved in the morphine-induced antinociception in the mouse. An intracerebroventricular (i.c.v.) pretreatment with xestospongin C (10–100 pmol per mouse, i.c.v.), a membrane permeable and selective antagonist for IP3 receptor, produced a dose-dependent reduction in the supraspinal antinociceptive effect produced by i.c.v. administration of morphine (0.3–10 nmol). In addition, the dose-response curve for morphine-induced antinociception was significantly shifted to the right by i.c.v. pretreatment with xestospongin C at 100 pmol. In the present study, we confirmed that the IP3R1 mRNA in opisthonos (opt) heterozygote mice was approximately 50% reduced as compared to that in wild-type mice. Under these conditions, a significant antinociception produced by subcutaneous (s.c.) injection of morphine (5 mg/kg) observed in wild-type mice was markedly reduced in opt heterozygote mice. These findings suggest that IP3 receptor-, especially type 1 IP3 receptor-mediated intracellular signaling pathway may be implicated in the expression of antinociceptive effect induced by morphine in mice. [Copyright &y& Elsevier]

Abstract: Spontaneous regression of an intracranial mass is rare. We report a 77-year-old man with spontaneous regression of an anterior skull base mass suspected to be an inflammatory pseudotumor. The patient attended our outpatient department approximately once per month for a regular check-up following a brain stem infarction. A small mass was detected at the anterior skull base by MRI. The mass gradually grew to about 3cm over a period of 5years and then remained stable for 3years. Thereafter, the mass showed spontaneous regression 8years after it was first visible on MRI. ‘Inflammatory pseudotumor’ is a broad category and the natural history of these lesions is highly variable. Although the definition does include some types of malignant lesion, most masses are benign lesions that can regress spontaneously, as in our patient. A ‘wait-and-see’ policy is appropriate for such patients. [Copyright &y& Elsevier]

Abstract: Although vestibular schwannoma is a common tumor in the cerebellopontine angle, calcified vestibular schwannoma is rare. A 59-year-old woman with sudden onset epileptic seizures, was referred to Hokkaido Neurosurgical Memorial Hospital. Neurological examination revealed left Bruns nystagmus, left deafness and left cerebellar ataxia. Brain MRI revealed a mass, about 3cm in diameter, in the left cerebellopontine angle. The mass showed heterogeneous intensity on T1- and T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. Hydrocephalus was seen. On CT scan, the tumor was calcified. Preoperatively, vestibular schwannoma, meningioma, cavernous hemangioma, or thrombosed giant aneurysm were considered as differential diagnoses. The pathological diagnosis was schwannoma. For a calcified mass in the cerebellopontine angle, vestibular schwannoma should be considered in the differential diagnosis to plan appropriate treatment strategies. [Copyright &y& Elsevier]

• Proliferation resistance evaluation of an inert matrix fuel (IMF) in the transuranic nuclear fuel cycle (NFC) of a high temperature gas cooled reactor (HTGR). • Impacts of chemical stability of IMF and fuel irradiation on the proliferation resistance. • Study shows scope for a more reasonable, cost-effective, and reduced safeguards inspection frequency to manage the fresh IMF block with a high proliferation resistance. The proliferation resistance (PR) of an inert matrix fuel (IMF) in the transuranic nuclear fuel cycle (NFC) of a high temperature gas cooled reactor is evaluated relative to the uranium and plutonium mixed-oxide (MOX) NFC of a light water reactor using PRAETOR code and sixty-eight input attributes. The objective is to determine the impacts of chemical stability of IMF and fuel irradiation on the PR. Specific material properties of the IMF, such as lower plutonium content, carbide ceramics coating, and absence of 235U, contribute to enhance its relative PR compared to MOX fuel. The overall PR value of the fresh IMF (an unirradiated direct use material with a one-month diversion detection timeliness goal) is nearly equal to that of the spent MOX fuel (an irradiated direct use nuclear material with a three-month diversion detection timeliness goal). Final results suggest a reduced safeguards inspection frequency to manage the IMF. [ABSTRACT FROM AUTHOR]

• Progesteron receptor (PgR) is associated with insulin-production. • PgR and insulin colocalize in pancreatic neuroendocrine tumors. • PgR might contribute cell growth inhibition in insulinomas. Progesterone receptor (PgR) inhibits cell proliferation in pancreatic neuroendocrine neoplasms (PanNEN). In non-neoplastic pancreas, loss of PgR induces β-cell proliferation and insulin production. However, detailed association between PgR and insulin producing PanNENs is poorly understood. Insulin, proinsulin, and PgR were immunolocalized in 82 PanNENs (54 non-functioning PanNENs: NF-PanNENs and 28 insulinomas). The status of immunoreactivity was compared to the clinicopathological factors of the patients. Immunoreactivity was also confirmed by employing the double-immunohistochemistry. These results were also compared with those in non-neoplastic Langerhans islets. PgR immunoreactivity was significantly higher in insulinomas than that in NF-PanNENs (p < 0.001). Insulin and proinsulin immunoreactivity was also detected in 20 (37 %) of (single cell) insulin positive NFs (Inspos-NF-PanNEN), in which PgR expression was higher than in insulin negative NF-PanNENs (Insneg-NF-PanNEN, p = 0.03). The ratio of PgR-insulin double positive cells to overall insulin positive cells, as well as PgR-proinsulin double positive cells to proinsulin positive cells, was detected to the same degree in insulinoma (PgR-insulin 70 %, PgR-proinsulin 66 %), Inspos-NF-PanNENs (PgR-insulin 65 %, PgR-proinsulin 68 %) and normal islet (PgR-insulin 80 %, PgR-proinsulin 72 %). PgR and insulin expressing cells colocalize in tumor cells of the PanNENs regardless of the hormone-related symptoms of the patients. Inhibitory effect of PgR on tumor cells might be associated with the favourable clinical outcome of insulinoma patients. [ABSTRACT FROM AUTHOR]

The design, synthesis, and structure activity relationships of the novel class of pyrazolylethylbenzamide orexin receptor 1-selective antagonists are described. Further derivatization of the prototype dual orexin receptor 1/2 antagonist lead ( 1 ) by installing a ( S )-methyl group into the ethyl linker moiety between the pyrazole ring and benzamide resulted in an increase of the antagonist potency against orexin receptor 1/2 receptors. Optimization of the benzamide and pyrazole parts of compounds 2 and 9b led to the identification of N -ethyl-5-fluoro- N -{(2 S )-1-[5-(4-fluorophenyl)-2 H -tetrazol-2-yl]propan-2-yl}-2-(pyrimidin-2-yl)benzamide ( 24 ), which exhibited excellent antagonistic activity against orexin receptor 1 with an IC 50 of 2.01 nM and a 265-fold selectivity for orexin receptor 1 over orexin receptor 2. [ABSTRACT FROM AUTHOR]

Orexins play an important role in sleep/wake regulation, and orexin receptor antagonists are a focus of novel therapy for the treatment of insomnia. We identified 27e (TASP0428980) as a potent dual orexin receptor antagonist through the systematic modification of our original designed lead A. We demonstrated the potent sleep-promoting effects of 27e at ip dose of 3 mg/kg in a rat polysomnogram study. 27e exhibited relatively short half-life profiles in rats and dogs. Furthermore, accumulating evidence regarding ADME profiles indicates that the predicted human half-life of 27e should be 1.2–1.4 h. These data indicated that 27e has a short-acting hypnotic property, suggesting that 27e might be useful for treating primary insomnia while exhibiting a low risk of next-day residual somnolence. Thus, 27e and its related compounds should be further evaluated to enable advancement to clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: A new MnIII (μ-O)2MnVI dimer, [(OH2)(Py-terpy)Mn(μ-O)2Mn(Py-terpy)(OH2)]3+ (Py-terpy=4′-(4-pyridyl)-2,2′:6′,2″-terpyridine) (1Py) with electron-withdrawing pyridyl (Py) groups was synthesized and characterized by UV–Vis and IR spectroscopic, X-ray crystallographic, magnetometric, and electrochemical techniques. 1Py is stable in an aqueous solution at room temperature, in contrast to the unstable Cl and Br derivatives with R-terpy (R=Cl or Br of electron-withdrawing groups). The maximum concentrations of 1Py adsorbed on saponite suggests that 1Py is adsorbed on saponite or mica as a pentavalence cation, like [1Py2H]5+ with protonation of Py groups on Py-terpy ligands. Water oxidation catalyses by 1Py were examined in homogenous solution and heterogeneous saponite or mica adsorbate systems. O2 was evolved in a reaction of 1Py with a Ce(IV) oxidant in an aqueous solution. However, the maximum turnover number (TN) of 1Py for O2 evolution was 0.63 for 4days, showing that 1Py does not work as a catalyst for water oxidation in solution. The reactions of the 1Py/saponite or mica adsorbate with a CeIV oxidant in water catalytically produced the significant amount of O2. The maximum TNs of 1Py on saponite and mica for O2 evolution are 5.6 and 16 for 4days, respectively. The kinetic analysis of O2 evolution suggested that the unimolecular decomposition reaction of 1Py involving O2 evolution competes with the cooperative catalysis by two equivalents of 1Py on saponite or mica. The k 2 values of 1Py adsorbates were lower than those of 1 adsorbates for saponite and mica systems, in contradiction to the magnitude relationship predicted from the E 1/2 values of 1Py and 1 based on our previous work (Yamazaki et al., 2012 [29]). The lower k 2 values could be explained most possibly by electrostatic repulsion between a pentavalent [1Py2H]5+ cation on saponite and mica, compared with a trivalent 1 cation. [Copyright &y& Elsevier]

Abstract: In the course of our screening program for novel glycine transporter inhibitors, we obtained a novel cyclic tetrapeptide (WSS2220) from the culture broth of Nonomuraea sp. The structure of WSS2220 was elucidated based on physicochemical data. WSS2220 contained a novel amino acid (4-oxo-3′-sulfoisoleucine), the absolute stereochemistry of which was determined by chemical modifications and the modified Mosher’s method. WSS2220 selectively inhibited glycine transporter type1 with an IC50 of 20nM. [Copyright &y& Elsevier]

Abstract: Background: Cerebral amyloid angiopathy is a well-known disease that is predominantly recognized in elderly people and repeatedly causes large subcortical hemorrhages. These hemorrhages may be derived from vessel wall weakness because of Aβ depositions in the wall of the cortical and leptomeningeal arteries. Although vessel ruptures in CAA have been thought to occur in cortical arteries, it was recently demonstrated that the primary hemorrhage occurs in the subarachnoid space, particularly the cerebral sulci, as a result of multiple ruptures of meningeal arteries in some cases of subcortical hematoma caused by CAA. Case Description: Case patient 1 was a 74-year-old woman who presented with epileptic seizure. A restricted SAH in the right frontal lobe was observed on MRI. Thirty-three days later, left hemiparesis occurred suddenly and a huge subcortical hematoma was observed in the right frontal lobe on CT. The hematoma was removed, and the patient was pathologically diagnosed with amyloid angiopathy. Case patient 2 was a 73-year-old man who presented with epileptic seizure. A restricted SAH in the right frontal lobe was observed on MRI. Twenty days later, left hemiparesis occurred suddenly and a huge subcortical hematoma was observed in the right frontoparietal area on CT. Hematoma removal was performed on both patients, and they were diagnosed pathologically with amyloid angiopathy. Conclusions: We report on the cases of 2 patients with CAA who presented with epileptic seizure and were found to have a restricted subarachnoid hematoma in the cerebral sulcus on MRI before their subcortical hemorrhages occurred. Both cases were diagnosed pathologically. This demonstrated that vessel ruptures in CAA can occur in the subarachnoid space, particularly the cerebral sulci, as a result of ruptures of meningeal arteries. A restricted SAH on CT/MRI could be a warning sign of a huge subcortical hemorrhage in CAA. [Copyright &y& Elsevier]

Abstract: Background: Rupture of cerebral aneurysms results in subarachnoid hemorrhage. In many cases, bleeding from aneurysms spontaneously arrests. Although bleeding from cerebral aneurysms has been reported to arrest from outside, bleeding from some aneurysms can arrest in different ways. Methods: Between April 2002 and March 2004, we prospectively investigated mechanisms of spontaneous hemostasis in ruptured aneurysms by macroscopic examination when performing craniotomy and clipping surgeries. Results: Hemostatic mechanisms were investigated in 247 patients with ruptured aneurysm (77 men, 170 women; age range, 25-95 years). Hemostatic mechanisms were divided into 3 different patterns. In the most common pattern (79.4%), the surface of the aneurysm rupture point was sealed from the outside by a platelet plug or fibrin net (outside-arrest pattern). In some aneurysms (10.1%), a thrombus or platelet plug was attached to the rupture point from inside the aneurysm (inside-arrest pattern). In a very small number of aneurysms (1.6%), a naked thrombus covered the hole made on the arterial wall or small remnant of the aneurysmal dome (bursting pattern) The mechanism remained unclear in the remaining 8.9% of aneurysms. Multivariate analysis revealed that alert consciousness on admission (WFNS grade I) significantly associated with usual hemostasis (outside arrest pattern: OR, 3.8; 95% CI, 1.4-10.0; P = .008). Borderline association with usual hemostasis was found in aneurysms with a size of 5 or smaller than 5 mm (OR, 2.6; 95% CI, 0.99-7.1; P = .052). Conclusions: The present preliminary study revealed that arrest of bleeding from a ruptured cerebral aneurysm does not always occur from outside the aneurysm. Unusual mechanisms of hemostasis are seen in approximately 12% of ruptured aneurysm. The outside-arrest-pattern aneurysm was more common for smaller aneurysms, and these patients tended to be of better grade. Further studies are necessary to explore the mechanism of hemostasis for ruptured cerebral aneurysms. [Copyright &y& Elsevier]

Abstract: Critical illness polyneuropathy (CIP) is a sensorimotor polyneuropathy recognized in adult intensive care patients with sepsis and multiple organ dysfunction and only a few cases have been reported in children. Here we report a 13-year-old Japanese boy with CIP that developed during the course of encephalopathy. Two months after the onset of encephalopathy, he developed tetraplegia although consciousness had already recovered. Deep tendon reflex was absent. MRI of the brain and spinal cord was normal and no abnormality in the cerebrospinal fluid was detected. Motor and sensory nerve conduction velocities of the lower limbs and somatosensory evoked potential could not be detected. The motor activity subsequently showed gradual recovery, although standing and walking could not be achieved. Sural nerve biopsy performed 3 years after the onset showed severe reduction of the number of myelinated large-diameter fibers, thin myelin in almost all fibers and cluster formation of myelinated small-diameter fibers, indicating primary axonal degeneration with regeneration. We report here for the first time the neuropathological changes in peripheral nerves during the chronic stage of CIP in children. [Copyright &y& Elsevier]

Abstract: A growing body of evidence indicates that the mesolimbic dopaminergic (DAergic) pathway projecting from the ventral tegmental area (VTA) to the nucleus accumbens (N.Acc.) play a critical role in the initiation of psychological dependence on morphine. As well as DAergic system, the involvement of non-DAergic neurotransmitter and neuromodulator systems in rewarding effects induced by morphine has been recently documented. We previously demonstrated that the morphine-induced rewarding effect was dramatically suppressed by co-treatment with NMDA receptor antagonists, such as dizocilpine (MK-801), ketamine and ifenprodil. Therefore, we propose here that inhibiting the N-methyl-d-aspartate (NMDA) receptor and its associated protein kinase in the N.Acc. is useful for the treatment for psychological dependence on morphine. The following review provides a summary of recent our findings regarding the role of NMDA receptor and its associated protein kinase in the development of psychological dependence on morphine. [Copyright &y& Elsevier]

Background: Several studies have identified beta2-microglobulin-negative (β2M-) cells as a potential stem cell fraction in the bone marrow of rats and humans. We studied the ability of bone marrow–derived β2M- cells to differentiate into cardiomyocytes and reconstitute the myocardium in a model of myocardial infarction.Methods: β2M- cells were purified from bone marrow of Lewis rats using a magnetic activated cell-sorting technique. β2M- cells, 2.5 × 106 cells in 100 μl of phosphate-buffered saline (PBS), were transplanted 7 days after infarction into a transmural myocardial scar induced by cryoinjury in Lewis rats (n = 9). Control Group 1(n = 10) received a 100-μl injection of PBS, and Control Group 2 (n = 15) received no injection. The β2M- cells were labeled before transplantation, using the membrane fluorescent intercalated dye, PKH26. Repopulation was examined at 6 and 8 weeks after transplantation. Differentiation of β2M- cells into cardiac myocytes was determined by the colocalization of troponin and PKH26 to the same cell, utilizing immunohistochemistry, ultraviolet photomicroscopy and fluorescence microscopy on 6-μm serial sections. Area of engraftment within the scar was calculated by planimetry.Results: The treatment group had multiple islands of de novo–formed myocardium within the fibrous matrix of the transmural scar (mean area 35 ± 4.2% of scar area at 6 and 8 weeks). These cells colocalized cardiac-specific troponin and PKH26. Using these techniques, no myocardial islands were seen in the control groups. Before transplantation, β2M- cells were troponin-negative.Conclusions: This study demonstrates that β2M- cells represent a novel sub-population of bone marrow–derived stem cells capable of successful and substantial engraftment in areas of transmural myocardial scar, with de novo formation of cardiac myocytes. The functional significance of this observation is being studied. [Copyright &y& Elsevier]

The aim of the present study was to investigate whether in vivo morphine treatment could participate in the activation of phospholipase Cγ1 (PLCγ1) isoform in the mouse periaqueductal gray matter (PAG) which can be accompanied by antinociceptive responses induced by morphine. As well as μ-opioid receptor-like immunoreactivity (MOR-IR), moderate PLCγ1-like immunoreactivity (PLCγ1-IR) was noted in the mouse PAG section. After s.c. treatment with morphine, the intensive PLCγ1-IR was detected in the cell surface of the positive cells. Treatment s.c. with morphine produced a robust increase in the number of phosphorylated-PLCγ1 (p-PLCγ1) expressing cells in the PAG. Deletion of PLCγ1 gene by i.c.v. pretreatment with antisense oligodeoxynucleotide against PLCγ1 revealed a significant inhibition of supraspinal antinociception induced by a selective μ-opioid receptor agonist [d-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO). Furthermore, i.c.v. pretreatment with a specific antibody to PLCγ1 caused a concentration-dependent attenuation of antinociception produced by i.c.v. treatment with either morphine or DAMGO. These findings suggest that in vivo morphine treatment can activate PLCγ1 isoform in the mouse PAG which can be, at least in part, associated with the expression of supraspinal antinociception induced by μ-opioid receptor agonists in the mouse. [Copyright &y& Elsevier]

Abstract: In the course of our search for natural antipsychotic agents, we isolated five new cyclic tetrapeptides from the fermentation broth of Nonomuraea sp. TA-0426. These compounds turned out to be analogues of WSS2220, which had been produced by the same actinomycete and showed strong inhibitory activity against GlyT1. Four of the present peptides exhibit more potent GlyT1 inhibitory activities than WSS2220. [Copyright &y& Elsevier]

Here, we present the design, synthesis, and SAR of dual orexin 1 and 2 receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compound 1 , ring construction and the insertion of an additional heteroatom into the resulting ring led to the discovery of orexin 1 and 2 receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivatives. Within these derivatives, (−)- 3h enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Compound (−)- 3h exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study, and optimal PK properties with a rapid T max and short half-lives in rats and dogs were observed, indicating a predicted human half-life of 0.9–2.0 h. Thus, (−)- 3h (ORN0829 ; investigation code name, TS-142) was selected as a viable candidate and is currently in clinical development for the treatment of insomnia. [ABSTRACT FROM AUTHOR]

The article describes the case of a 44-year-old male patient with cavernous angioma in the brain's septum pellucidum. The medical history of the patient and the symptoms he manifested are presented. Physical examination, laboratory tests and imaging done on the patient are mentioned. Background information on the condition is provided.