Ruptured Mycotic Cerebral Aneurysm Secondary to Disseminated Nocardiosis.

We report a case of a ruptured mycotic cerebral aneurysm caused by Nocardia infection. A 22-year-old immunocompromised woman with adult-onset Still's disease developed a subarachnoid hemorrhage (SAH). Digital subtraction angiography revealed a small aneurysm at the M2-3 bifurcation of the right middle cerebral artery. Cardiac ultrasonography showed vegetation at the posterior cardiac wall, suspecting infective endocarditis (IE). Gram-positive filamentous bacteria were observed in the necrotic tissue surrounding the aneurysm obtained during trapping surgery. Long-term blood culture showed that the cause of her cerebral mycotic aneurysm was nocardiosis. A mycotic ruptured cerebral aneurysm is an important cause of SAH in immunocompromised patients. Early diagnosis of IE, detection of gram-positive rods by Gram staining, and long-term culture to identify the bacteria is crucial in diagnosing nocardiosis.

[Cognitive Dysfunction in Children who Underwent Surgery after a Traumatic Brain Injury:A Single Institute Investigation].

The cognitive function of children who underwent surgical therapy after a traumatic brain injury is poorly studied. In this study, we investigated the characteristics of 27 children who received surgical therapy at our institution. The children were between 1 and 16 years of age, of which 15 had cognitive dysfunction. Their Glasgow Coma Scale score at the acute stage of dysfunction was worse than in children who did not have cognitive dysfunction. Acute subdural hematoma was more frequent in the cognitive dysfunction group. Moreover, all children in this group showed brain injury by imaging analysis. Differences in imaging characteristics and the association with cognitive dysfunction could not be readily associated with a specific injury. Memory and verbal disorder were the most common cognitive dysfunctions:these symptoms were present among children of all ages;conversely, behavior disorder, impaired attention, and infeasibility were limited to the children under 9 years of age. Since the immature brain is developing, the acquisition of new abilities may be blocked by the injury;thus, we speculate that brain injury at a younger age causes greater cognitive dysfunction.

Treatment Outcomes of Burr-Hole Surgery for Chronic Subdural Hematoma in the Elderly Living Beyond Life Expectancy: A Study Comparing Cure, Recurrence, and Complications in Patients Aged ≥80 Years versus ≤79 Years.

BACKGROUND: Few reports have focused on chronic subdural hematoma (CSDH) in the very elderly, who have lived beyond average life expectancy. Our aim is to appraise treatment outcomes of burr-hole craniotomy for CSDH in the elderly, focusing on cure, recurrence, and complications. METHODS: Fifty patients ≤79 years of age (group A) and 73 patients ≥80 years of age (group B) were studied. Recurrence was defined as requiring reoperation for hematoma regrowth or symptomatic failure. A cure was regarded as having been achieved in the absence of hematoma on postoperative computed tomography. Complications were defined as any harmful event related to the treatment procedure for CSDH. RESULTS: Cure was documented in 31 patients in group A (63%) and 24 patients in group B (33%) (P = 0.0017). Median intervals to cure were 2.76 and 3.73 months, respectively (P = 0.06). Cumulative cure rates were 51%/76% and 36%/59%, respectively, at the sixth/twelfth postoperative months. Recurrence was documented in 2 patients (4%) and 11 patients (15%), respectively (P = 0.07). Median intervals to recurrence were 0.81 and 1.25 months, respectively (P = 0.049). Cumulative recurrence-free rates were 96%/92% and 87%/75%, respectively, at the third/sixth postoperative months. Complications were observed in 2 patients (4%) and 4 patients (5%), respectively (P = 1.00). CONCLUSIONS: With advancing age, CSDH might show a greater tendency to recur and a longer time is required to achieve a cure. However, complications developed only in high-risk patients. Thus, surgical treatment for CSDH in elderly patients, even those who have lived beyond life expectancy, might provide acceptably effective results.

Structure-based design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors.

We identified novel potent inhibitors of p38 MAP kinase using structure-based design strategy. X-ray crystallography showed that when p38 MAP kinase is complexed with TAK-715 (1) in a co-crystal structure, Phe169 adopts two conformations, where one interacts with 1 and the other shows no interaction with 1. Our structure-based design strategy shows that these two conformations converge into one via enhanced protein-ligand hydrophobic interactions. According to the strategy, we focused on scaffold transformation to identify imidazo[1,2-b]pyridazine derivatives as potent inhibitors of p38 MAP kinase. Among the herein described and evaluated compounds, N-oxide 16 exhibited potent inhibition of p38 MAP kinase and LPS-induced TNF-α production in human monocytic THP-1 cells, and significant in vivo efficacy in rat collagen-induced arthritis models. In this article, we report the discovery of potent, selective and orally bioavailable imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors with pyridine N-oxide group.

Discovery of a novel B-cell lymphoma 6 (BCL6)-corepressor interaction inhibitor by utilizing structure-based drug design.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein-protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6-corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a, we identified a novel BCL6-corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay [ELISA] IC50=0.10µM, cell-based mammalian two-hybrid [M2H] assay IC50=0.72µM) by utilizing structure-based drug design (SBDD) based on an X-ray crystal structure of 1a bound to BCL6. Compound 8c also showed a good pharmacokinetic profile, which was acceptable for both in vitro and in vivo studies.

[Dural Arteriovenous Fistula with Acute Visual Loss Manifestation:A Case Report].

In this report, we are describing a rare case of dural arteriovenous fistula(DAVF)followed by an isolated symptom of bilateral visual acuity disturbance. The patient was a 67-year-old man suffering from progressive bilateral visual acuity disturbance. Angiography revealed a diffuse arteriovenous fistula in the left transverse-sigmoid sinus affected by severe venous congestion. Visual acuity disturbance is likely to have been caused by increased intracranial pressure(IICP). Venous congestion as well as visual acuity were gradually improved following three transarterial embolizations. It is possible that a gradual progression of the clinical condition has caused only visual acuity disturbance without any other IICP symptoms, which is similar to pseudotumor cerebri. Should an unexplained visual acuity loss occur, the case should be investigated by considering DAVF.

Primary Multiple Cardiac Myxomas in a Patient without the Carney Complex.

Cardiac tumors are rare, and multiple myxomas are even rarer. The latter phenomenon is mostly associated with the Carney complex, a dominantly inherited disease characterized by multiple primary cardiac myxomas, endocrinopathy, and spotty pigmentation of the skin. We report the rare case of a patient who did not have the Carney complex but had multiple primary cardiac tumors. A 78-year-old woman with a past history of breast cancer was referred to our hospital for further examination of multiple cardiac tumors. Echocardiography showed 4 tumors in the left atrium and left ventricle. We could not diagnose them preoperatively and decided to resect them surgically because they were mobile and could have caused embolism and obstruction. The postoperative pathological findings of all 4 tumors were myxomas, although the patient did not meet the diagnostic criteria of the Carney complex. Therefore, a rare case of multiple primary cardiac myxomas was diagnosed.

The association between obesity and acute myocardial infarction is age- and gender-dependent in a Japanese population.

Controversies concerning the association between obesity and acute myocardial infarction (AMI) are still ongoing in Japan. We investigated the association between obesity defined by body mass index of 25 kg/m(2) or higher and AMI by a case-control study using data from 1199 AMI cases and 4056 apparently healthy controls. The analysis was performed in age- and sex-matched samples of 621 case-control pairs younger than 80 years and in crude samples aged 40-79 years divided into 10-year age groups. Prevalence of obesity, diabetes, current smoking, hypertension, and hypercholesterolemia were compared between cases and controls, and a multivariable odds ratio (OR) of AMI was calculated for each risk factor in various age groups. The OR (95 % confidence interval (CI)) of AMI for obesity was 1.63 (1.23-2.17), P = 0.0008 in men younger than 80 years; 2.65 (1.41-5.00), P = 0.0025 in women younger than 80 years; 2.23 (1.46-3.41), P = 0.0002 in men aged 59 years or younger; 1.34 (0.90-2.01), P = 0.1510 in men aged 60-79 years; and 2.98 (1.56-5.71), P = 0.0010 in women aged 60-79 years using paired samples. The OR (95 % CI) of AMI for obesity was 4.92 (2.53-9.58), P < 0.0001 in men aged 40-49 years; 1.54 (1.07-2.21), P = 0.0197 in men aged 50-59 years; 1.07 (0.69-1.66), P = 0.7717 in men aged 60-69 years; 2.24 (1.20-4.20), P = 0.0118 in men aged 70-79 years; 2.48 (1.12-5.48), P = 0.0245 in women aged 60-69 years; and 3.05 (1.46-6.37), P = 0.0029 in women aged 70-79 years using crude samples. The association between obesity and AMI was age- and gender-dependent in a Japanese population.

Von Hippel-Lindau tumor suppressor protein transforms human neuroblastoma cells into functional neuron-like cells.

Von Hippel-Lindau (VHL) tumor suppressor protein is expressed in neurons of the central nervous system and plays an important role during the neuronal differentiation of central nervous system progenitor cells. To elucidate the neuronal differentiating potential of VHL protein in neuroblastoma cells, we overexpressed or inhibited VHL protein in human neuroblastoma cells (SY-SH5Y), and examined the morphological change, expressions of neuronal markers, and electrophysiological functions. Here we show that with VHL gene transduction SY-SH5Y cells stably expressing the VHL protein had neurite-like processes with varicosities, showed the distinct expression of the neuronal markers neuropeptide Y and neurofilament 200, acquired regulated neurosecretion competence in response to depolarizing and cholinergic stimuli, and had large voltage-gated fast sodium currents and delayed rectifier potassium (Kv) currents compatible with those of functional neurons. In addition, they displayed inactivated ether-á-go-go potassium channels related to the promotion of the cell cycle and to the termination of differentiation. Also, by treatment with retinoic acid, they rapidly underwent cell death related to apoptosis. These findings suggest that the induction of neuronal function by VHL protein is associated with down-regulation of the cell cycle. In contrast, the inhibition of endogenous expression of VHL protein with antisense-orientated VHL gene transduction reduced such neuronal properties inherent to these cells, including the capacity for activation of ether-á-go-go channels. In conclusion, VHL protein has a neuronal differentiating potential to transform neuroblastoma cells into functional neuron-like cells. Our finding of the neuronal differentiation of neuroblastoma cells under the control of the VHL gene may contribute to the development of clinical techniques for neuronal regeneration in the case of intractable neuronal diseases and for differentiation therapy against neuroblastomas.