Translatome analysis of tuberous sclerosis complex 1 patient-derived neural progenitor cells reveals rapamycin-dependent and independent alterations.

BACKGROUND: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD) and intellectual disability. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using TSC1 patient-derived neural progenitor cells (NPCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in TSC1-null NPCs, which were unaffected by the mTORC1 inhibitor rapamycin. METHODS: Here, we used polysome profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level, to compare CRISPR-edited TSC1-null with CRISPR-corrected TSC1-WT NPCs generated from one TSC donor (one clone/genotype). To assess the relevance of identified gene expression alterations, we performed polysome profiling in postmortem brains from ASD donors and age-matched controls. We further compared effects on translation of a subset of transcripts and rescue of early ND phenotypes in NPCs following inhibition of mTORC1 using the allosteric inhibitor rapamycin versus a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272. RESULTS: Polysome profiling of NPCs revealed numerous TSC1-associated alterations in mRNA translation that were largely recapitulated in human ASD brains. Moreover, although rapamycin treatment partially reversed the TSC1-associated alterations in mRNA translation, most genes related to neural activity/synaptic regulation or ASD were rapamycin-insensitive. In contrast, treatment with RMC-6272 inhibited rapamycin-insensitive translation and reversed TSC1-associated early ND phenotypes including proliferation and neurite outgrowth that were unaffected by rapamycin. CONCLUSIONS: Our work reveals ample mRNA translation alterations in TSC1 patient-derived NPCs that recapitulate mRNA translation in ASD brain samples. Further, suppression of TSC1-associated but rapamycin-insensitive translation and ND phenotypes by RMC-6272 unveils potential implications for more efficient targeting of mTORC1 as a superior treatment strategy for TAND.

Translatome analysis of Tuberous Sclerosis Complex-1 patient-derived neural progenitor cells reveal rapamycin-dependent and independent alterations.

Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD). The hamartin-tuberin (TSC1-TSC2) protein complex inactivates mechanistic target of rapamycin complex 1 (mTORC1) signaling, leading to increased protein synthesis via inactivation of translational repressor eIF4E-binding proteins (4E-BPs). In TSC1-null neural progenitor cells (NPCs), we previously reported early ND phenotypic changes, including increased proliferation/altered neurite outgrowth, which were unaffected by mTORC1-inhibitor rapamycin. Here, using polysome-profiling to quantify translational efficiencies at a transcriptome-wide level, we observed numerous TSC1-dependent alterations in NPCs, largely recapitulated in post-mortem brains from ASD donors. Although rapamycin partially reversed TSC1-associated alterations, most neural activity/synaptic- or ASD-related genes remained insensitive but were inhibited by third-generation bi-steric, mTORC1-selective inhibitor RMC-6272, which also reversed altered ND phenotypes. Together these data reveal potential implications for treatment of TAND.

Locational and Clinical Varieties of Warthin Tumor: Two Rare Case Presentations.

Warthin tumor (WT) is the second most common benign tumor of the parotid gland with male predominance and is seen in the elderly population in the left mandibular and cervical regions. Extraparotid WT rarely presents as a mass in the right cervical region in middle-aged adults. Here, we present two extraordinary cases of WT seen in middle age, both in the right cervical region. The first is a 50-year-old man with an asymptomatic neck mass, and the second is a 60-year-old woman with a fast-growing mass with enhancement in positron emission tomography-computed tomography (PET-CT) with suspicions of malignancy.

Synthesis of Some Novel 2-Substitutedbenzyl-(4)7-phenyl-1H-benzo[d]imidazoles in Mild Conditions as Potent Anti-Tyrosinase and Antioxidant Agents.

Novel 2-substitutedbenzyl-4(7)-phenyl-1H-benzo[d]imidazole compounds were synthesized and characterized. Although 2a and 2b were reported previously in the literature, 11 compounds were synthesized (nine of them were newly synthesized) and the tyrosinase inhibitory effects and antioxidant activities of these compounds were studied for the first time. All of the synthesized compounds displayed certain inhibitory effects on tyrosinase, with IC50 values ranging from 37.86 ± 0.24 to 75.81 ± 2.49 µM. Among the compounds, 2j exhibited similar tyrosinase inhibitory effect (IC50 = 37.86 ± 0.24 µM) to the positive control, kojic acid (IC50 = 21.93 ± 0.11 µM). Kinetic studies revealed it to act as non-competitive tyrosinase inhibitor with a Ki value of 50.2 µM. The antioxidant activities of the compounds were investigated by using in vitro antioxidant assays, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP). All of these results indicated that the compounds might have potential application as tyrosinase inhibitors.

Assessment of effect of irbesartan and nebivolol on the left atrium volume and deformation in the patients with mild-moderate hypertension.

BACKGROUND: We aimed to assess the effects of irbesartan and nebivolol on the left atrium (LA) volume and deformation in the patients with mild-moderate hypertension. PATIENTS AND METHODS: The study comprised of 160 patients (mean age: 55.6±9.6 years), who had Stage 1 or 2 hypertension according to the European Society of Cardiology (ESC) and have not been receiving antihypertensive therapy. The patients were assigned to treatment groups; irbesartan (n=80) and nebivolol (n=80). The patients were clinically and echocardiographically reevaluated on the 6th and 12th months after the onset of treatment. RESULTS: There was no difference between the two treatment groups in terms of baseline demographic, clinical and echocardiographic characteristics. Moreover, no difference was observed between the treatment groups on the 6th and 12th months. Intragroup analyses revealed that systolic blood pressure (SBP) and diastolic blood pressure (DBP) significantly decreased in time and diastolic function parameters were improved. However, whilst significant increase was observed in conduit volume, decrease was observed in other volumes of the LA in the irbesartan and nebivolol groups. This significant change was observed on the 6th month in both treatment groups. LA global peak systolic strain (LAGLSs), LA global peak systolic strain rate (LAGLSRs), LA global peak strain rate during early ventricular diastole (LAGLSRe) and LA global peak strain rate (LAGLSRa) during late ventricular diastole (LAGLSRa) values began to be significantly increased after 6 months of treatment in both treatment groups. CONCLUSIONS: We found that nebivolol, which is a new generation beta blocker, is effective as irbesartan with proven efficacy in improving LA volume and LA myocardial performance in patients with mild-moderate hypertension. Moreover, we determined that strain and strain rate, which are the new echocardiographic parameters, are effective as LA volumes in assessing LA functions.

Synthesis of some novel 1,2,4-triazol-3-one derivatives bearing the salicyl moiety and their anticonvulsant activities.

A series of new 1,2,4-triazole-3-one derivatives bearing the salicyl moiety were synthesized by using microwave irradiation, and their chemical structures were identified by IR, (1) H NMR, (13) C NMR, elemental analysis, and LC-MS. The anticonvulsant activities of the compounds 4a-c, 4e, and 5a-e were evaluated by the Anticonvulsant Screening Program of the National Institute of Health, USA. The compounds had moderate anticonvulsant activities in the maximum electroshock-induced seizure and minimal clonic seizure models in mice, without any neurotoxic effects.

Predictors of reintervention after coronary artery bypass grafting.

AIM: Percutaneous and surgical reintervention after coronary artery bypass grafting (CABG) is frequent. The purpose of this study was to determine the predictors of reintervention in patients with symptoms of recurrent ischemia after coronary artery bypass graft surgery (CABG). PATIENTS AND METHODS: The data of 20000 patients who had coronary angiography (CAG) from 2003 to 2010 in our centre were retrospectively analysed. 485 of these patients with CABG who had CAG were included in this study. Demographic characteristics, the presence of coronary artery disease (CAD), risk factors for CAD, electrocardiographic (ECG) changes, troponin and CKMB levels, and left ventricular function were evaluated in terms of time elapsed after CABG. RESULTS: Reintervention was performed significantly more frequent in patients with acute coronary syndrome, diabetes mellitus (DM), hypertension (HT), family history of CAD, ECG changes, positive troponin level, elevated CKMB, ejection fraction (EF) > 50% and in smoker patients (p < 0.05). Multivariate backward logistic regression analysis revealed that DM, smoking, family history of CAD, HT, ECG changes and patients with EF > 50% were found the independent predictors of reintervention. CONCLUSIONS: Reintervention after CABG is especially higher in patients with risk factors for atherosclerosis and those who have ECG changes and normal EF. Knowledge of these risk factors is useful in the determination of CAG requirement and modification of risk factors for  atherosclerosis may play an important role in reducing reintervention.

Acute myocardial infarction during the early postpartum period successfully treated with tirofiban.

Acute myocardial infarction (AMI) during the early postpartum period is rare but may be associated with poor maternal outcome. We report an inferior AMI in 30-year-old woman with mitral valve replacement during early postpartum period successfully treated with tirofiban. For a patient that has got AMI due to massive thrombus and that is not suitable for percutaneous coronary intervention and has got contraindication to thrombolytic therapy, glikoprotein IIb-IIIa inhibitor (tirofiban) infusion must be kept in mind.

Cerebral alveolar echinoccosis mimicking primary brain tumor.

We present a case of cerebral infestation by Echinococcosis multilocularis mimicking an infiltrative primary brain tumor. A heavily calcified mass invading the midbrain enhanced in a cauliflower-like fashion with small peripheral nodules present on MR imaging. Perfusion-weighted MR imaging revealed low relative cerebral blood volume within the calcified lesion and peripheral hyperemia. Single-voxel proton MR spectroscopy with an echo time of 135 milliseconds was normal.

Nimodipine attenuates lipid peroxidation during the acute phase of head trauma in rats.

Oxygen free radical-mediated lipid peroxidation is one of the major mechanisms of secondary damage in traumatic brain injury. We assessed the effects of nimodipine on lipid peroxidation 1 h after head trauma in rats. Nimodipine (1.5 microg/kg IV bolus injection) was given immediately after head trauma by either the carotid artery or the jugular vein. Placebo treated rats received saline by the same routes. Control rats received head trauma only. Sham-operated rats were the group without head trauma. Malondialdehyde (MDA), which is the end product of lipid peroxidation, was measured as an indicator of oxygen free radical formation in the brain tissue. The mean values for MDA in sham operated rats were 92.4 +/- 4.9 nanomoles/gram wet weight (nmol/gww) of brain tissue. In the control group, MDA content of the brain tissue was 120.8 +/- 9.4 nmol/gww. In placebo treated rats, the results were similar. In the groups receiving nimodipine via carotid artery or jugular vein, the mean values were 101.1 +/- 6.9 and 106.5 +/- 6.0 nmol/gww, respectively. These results indicate that nimodipine caused a significant decrease in lipid peroxidation when given in the acute phase of head trauma in rats. This occurred regardless of the route of injection.

Intrapontomesencephalic colloid cyst: an unusual location. Case report.

Colloid cysts appear most commonly in the third ventricle; the occurrence of a colloid cyst in the brainstem is very unusual. The authors report on a patient with an intrapontomesencephalic colloid cyst. This 15-year-old girl complained of a headache associated with diplopia. Her neurological examination revealed right-sided sixth nerve paresis and a mild left hemiparesis. Radiological investigations revealed an intraparenchymal pontomesencephalic cystic mass. Surgical removal of the lesion was achieved via the pterional transsylvian approach and the patient experienced an excellent recovery. Histopathological examination revealed that the lesion was a typical colloid cyst. To the best of the authors' knowledge, this is the first case in which an intraparenchymal upper brainstem colloid cyst was surgically excised totally. In addition to describing this case, the authors also review other brainstem neuroepithelial cysts described in the literature and briefly discuss the concept of their origin.

Intracranial aneurysms and arterial hypertension: a review and hypothesis.

BACKGROUND: Intracranial aneurysms and systemic arterial hypertension coexist in a high percentage of patients. The relationship between intracranial aneurysms and hypertension is poorly defined. METHODS: Therefore, we reviewed the role of hypertension in the pathogenesis of saccular aneurysms as previously reported in clinical, experimental, and autopsy studies. RESULTS: Among 24 relevant clinical and/or autopsy studies, the mean incidence of pre-existing hypertension was 43.5% in aneurysm patients compared to 24.4% in the normal population. Although definitive evidence is lacking, data from multiple types of investigations indicate that systemic arterial hypertension creates a greater risk for the development of intracranial aneurysms than previously believed. The underlying pathophysiological mechanism(s) are also poorly defined. CONCLUSIONS: We propose a unifying hypothesis: Endothelial injury, occlusion of the vasa vasorum, and disruption of the synthesis of collagen and elastin are likely the most important factors in initiating the development of aneurysms. Chronic hypertension potentially affects all of these factors. Consequently, chronic hypertension may cause intimal thickening, necrosis of the tunica media, changes in the compositional matrix, and degeneration of the internal elastic lamina to develop in the arterial wall. These structural changes could cause a focal weakening in the arterial wall with resultant bulging. This theory accounts for the high incidence of intracranial aneurysms in the absence of any known associated hereditary or connective-tissue disease. Nor does it exclude the possibility of other etiological factors. From the perspective of prevention, however, it offers clear opportunities for prophylaxis.

Catecholamine-secreting carotid body tumor and intracranial aneurysm: coincidence?

BACKGROUND: An extremely rare case of intracranial aneurysm associated with catecholamine-secreting carotid body tumor is presented. CASE DESCRIPTION: A 64-year-old woman suffering from hypertensive attacks was admitted first to the Otolaryngology Department with a neck swelling. Right common carotid angiography revealed a hypervascular mass at the carotid bifurcation. On the same angiogram a middle cerebral artery aneurysm was discovered incidentally and the patient was referred to the Neurosurgical Department. Because of her history the tumor was considered to be endocrinologically active and the patient underwent alpha- and beta-blockade to protect intraoperative cardiovascular instability. Despite all precautions, during the operation hypertensive crises developed and the aneurysm was clipped with difficulty. CONCLUSION: Perioperative management designed to avoid complications in treating this rare association is discussed. Although this is the first reported case of an intracranial aneurysm associated with a functional carotid body tumor, a possible etiopathogenesis of the relationship between the aneurysm and hypertensive attacks due to an acute catecholamine-discharging tumor is presented.

An unusual fatal complication of low basilar trunk aneurysm surgery: isolated prepontine tension pneumocephalus.

OBJECTIVE: A case of postoperative tension pneumocephalus after low basilar trunk aneurysm clipping is presented. To our knowledge, this is the first case of isolated prepontine tension pneumocephalus. BACKGROUND: A 63-year-old woman was admitted for repair of a basilar aneurysm that had caused a subarachnoid hemorrhage. She was cooperative and partially oriented. According to Hunt & Hess classification, she was considered Grade III. METHOD: The aneurysm was clipped, using a right lateral suboccipital craniectomy with the patient in the sitting position. In the early postoperative period, she had no new neurological deficit. However, 2 hours later the patient became lethargic and unresponsive to verbal commands. Emergency CT scan revealed an isolated prepontine tension pneumocephalus with prominent posterior displacement of the pons. She was immediately taken back to surgery. Upon incision of the dura mater, air could be heard escaping under pressure from the posterior fossa cavity. The clip was in its proper position and all arteries were patent. Spontaneous respiration and pupil reflexes returned soon after surgery, but she remained unconscious and died 3 days later. CONCLUSION: We believe that this death was directly attributable to the tension pneumocephalus and the distortion of the pons. Postoperative prepontine tension pneumocephalus, although this is an extremely rare condition, should be considered if a patient deteriorates after basilar aneurysm surgery in the sitting position.

Aneurysms of the distal anterior cerebral artery: report of 14 cases and a review of the literature.

BACKGROUND: Distal anterior cerebral artery aneurysms are rare and compose about 4.5% of all intracranial aneurysms. They generally arise at the bifurcation of the pericallosal and callosomarginal arteries. Their surgical approach is different from those of other anterior circulation aneurysms. These aneurysms present some special difficulties for neurosurgeons, including narrow exposure in the interhemispheric fissure, dense adhesions between the cingulate gyri, difficulty in controlling the parent artery, and the association of multiple aneurysms and vascular anomalies. METHODS: Between January 1975 and May 1996, 14 cases of saccular aneurysms of the distal anterior cerebral artery were operated at the University of Hacettepe. The clinical presentations, neuroradiological findings, and operative approaches of these aneurysms were analyzed. In addition, the clinical series and isolated case reports in the English literature were also extensively reviewed. RESULTS: The incidence of the aneurysms in this location was 2.8% of a total of 494 surgically treated cases in our center. Of 14 patients, eight were women and six were men. Multiple aneurysms were found in five patients (35%). All patients were operated via the interhemispheric route. Thirteen patients had good outcome and one patient died. CONCLUSIONS: We believe that all difficulties related to distal anterior cerebral artery aneurysms can be minimized with sufficient knowledge of microsurgery and surgical anatomy, using microtechniques and experience.

Time-level relationship for lipid peroxidation and the protective effect of alpha-tocopherol in experimental mild and severe brain injury.

OBJECTIVE: Oxygen free radical-mediated lipid peroxidation has been proposed to be one of the major mechanisms of secondary damage in traumatic brain injury. The first purpose of this study was to establish the time-level relationship for lipid peroxidation in injured brain tissue. The second purpose was to examine the protective effect of alpha-tocopherol against lipid peroxidation. METHODS: For this study, 65 guinea pigs in five groups were studied. Five of the animals were identified as a control group, and the remaining 60 animals were divided equally into four groups (Groups A, B, C, and D). Mild injury (200 g x cm) (Groups A and C) and severe injury (1000 g x cm) (Groups B and D) were produced by the method of Feeney et al. Alpha-tocopherol (100 mg/kg) was administered intraperitoneally before brain injury in Groups C and D. Five animals from each group were killed immediately after trauma, five after 1 hour, and the remaining five animals after 36 hours. Lipid peroxidation in traumatized brain tissues was assessed using the thiobarbituric acid method. RESULTS: In all groups with traumatic brain injuries, levels of malondialdehyde, a lipid peroxidation product, were higher than in the control group. The amount of lipid peroxidation was increased by the severity of the trauma. Alpha-tocopherol significantly suppressed the rise in lipid peroxide levels in traumatized brain tissues. CONCLUSION: This study demonstrates that lipid peroxidation is increased by the severity of trauma and that alpha-tocopherol has a protective effect against oxygen free radical-mediated lipid peroxidation in mild and severe brain injury.

Pheochromocytoma and multiple intracranial aneurysms: is it a coincidence? Case report.

The authors present a case of multiple intracranial aneurysms associated with a pheochromocytoma. The aneurysms were successfully clipped, and a suprarenal tumor located on the left side was totally removed. To the authors' knowledge this is the fourth reported case of these combined entities in the literature. The authors speculate on the possible etiopathogenesis of the relationship between intracranial aneurysms and attacks of hypertension caused by the presence of neoplasms that discharge acute and irregular levels of catecholamines, especially pheochromocytomas. Perioperative management designed to avoid undesired complications in this rare association is also discussed.

Antinociceptive effect of some amaryllidaceae plants in mice.

The antinociceptive effects of ethanolic extracts of Pancratium maritimum L., Narcissus tazetta subspecies tazetta and Leucojum aestivum L. bulbs have been investigated in mice using the p-benzoquinone-induced abdominal constriction and hot-plate tests. In the p-benzoquinone-induced abdominal constriction test the ethanolic extracts of P. maritimum (300, 600 or 1200 mg kg-1, s.c.) and N. tazetta subsp. tazetta (5, 50, 100 or 200 mg kg-1, s.c.) caused dose-dependent inhibition of abdominal constrictions whereas a fluctuating response was obtained from ethanolic extracts of L aestivum (2.5-500 mg kg-1, s.c.). In the hot-plate test P. maritimum and L. aestivum caused a significant increase of latency only at the highest concentrations used (1200 mg kg-1 and 500 mg kg-1, i.p., respectively). However, at these concentrations they also caused significant toxic effects. In contrast with P. maritimum and L. aestivum, N. tazetta subsp. tazetta (5-500 mg kg-1, i.p.) extracts had no antinociceptive effect in this test. These findings indicate that the antinociceptive effect of Amaryllidaceae plants differs depending on the model of nociception investigated.

Microsurgical removal of a free segment of microcatheter in the anterior circulation as a complication of embolization.

Endovascular therapy for cerebral arteriovenous malformations, although generally accepted to be a safe procedure, is not without risks. We present a patient with a 20 cm free segment of a catheter in the anterior circulation as a complication of embolization. This is a very rare complication. To our knowledge, only six cases have been reported in the literature. We believe this to be the first reported case of this complication treated surgically via craniotomy and arteriotomy.