A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior.

Sex hormones exert a profound influence on gendered behaviors. How individual sex hormone-responsive neuronal populations regulate diverse sex-typical behaviors is unclear. We performed orthogonal, genetically targeted sequencing of four estrogen receptor 1-expressing (Esr1+) populations and identified 1,415 genes expressed differentially between sexes or estrous states. Unique subsets of these genes were distributed across all 137 transcriptomically defined Esr1+ cell types, including estrous stage-specific ones, that comprise the four populations. We used differentially expressed genes labeling single Esr1+ cell types as entry points to functionally characterize two such cell types, BNSTprTac1/Esr1 and VMHvlCckar/Esr1. We observed that these two cell types, but not the other Esr1+ cell types in these populations, are essential for sex recognition in males and mating in females, respectively. Furthermore, VMHvlCckar/Esr1 cell type projections are distinct from those of other VMHvlEsr1 cell types. Together, projection and functional specialization of dimorphic cell types enables sex hormone-responsive populations to regulate diverse social behaviors.

Periodic Remodeling in a Neural Circuit Governs Timing of Female Sexual Behavior.

Behaviors are inextricably linked to internal state. We have identified a neural mechanism that links female sexual behavior with the estrus, the ovulatory phase of the estrous cycle. We find that progesterone-receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) are active and required during this behavior. Activating these neurons, however, does not elicit sexual behavior in non-estrus females. We show that projections of PR+ VMH neurons to the anteroventral periventricular (AVPV) nucleus change across the 5-day mouse estrous cycle, with ∼3-fold more termini and functional connections during estrus. This cyclic increase in connectivity is found in adult females, but not males, and regulated by estrogen signaling in PR+ VMH neurons. We further show that these connections are essential for sexual behavior in receptive females. Thus, estrogen-regulated structural plasticity of behaviorally salient connections in the adult female brain links sexual behavior to the estrus phase of the estrous cycle.

[Basaloid Squamous Cell Carcinoma;Report of a Case].

We report a resected case of basaloid squamous cell carcinoma (BSC). BSC is a rare type of malignant lung tumor. A 79-year-old woman had a 13 mm tumor in the left upper lobe on chest computed tomography (CT). On fluorodeoxyglucose-position emission tomography (FDG-PET), the tumor showed the accumulation of FDG with an SUVmax of 14.7. A left upper lobectomy with lymph node dissection was performed by video-assisted thoracoscopic surgery. The pathological diagnosis was BSC (pT2aN0M0, stage IB). There was no recurrence following lung cancer resection for 12 months. BSC is generally poor prognosis.

[Growth Process of Cystic Lung Cancer Followed with Computed Tomography Findings Over 5 Years].

An estimated 2~16% of primary lung cancers form cavities with cases that form thin-walled cavities being comparatively rare. We treated a patient with squamous cell carcinoma of the lung with a small cystic shadow that showed no changes for 3 years. The cyst then suddenly grew larger, after which the cyst wall thickened over time and a thin-walled cavity was seen. Here we report this important case showing the development process of lung cancer that formed a thin-walled cavity, together with a discussion of the literature.

[Fetal Adenocarcinoma of the Lung].

We report a resected case of fetal adenocarcinoma. Fetal adenocarcinoma is a rare type of malignant lung tumor. A 53-year-old man had a 25 mm tumor in the right upper lobe on chest computed tomography. On fluorodeoxyglucose-positron emission tomography( FDG-PET), the tumor showed the accumulation of FDG with a standardized uptake value( SUV) max of 5.63. He underwent bronchoscopic examination, but a diagnosis was not established. We suspected that the tumor was primary lung cancer or metastatic lung tumor of rectal cancer which was resected prior to the treatment for pulmonary lesion. A right upper lobectomy with lymph node dissection was performed and the pathological diagnosis was high-grade fetal adenocarcinoma, stage IB (pT2aN0M0). The patient was treated with postoperative adjuvant chemotherapy. There has been no recurrence after surgery resection for 9 months.

CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility.

Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders accompanied by intractable epilepsies, i.e. West syndrome or atypical Rett syndrome. Here we report generation of the Cdkl5 knockout mouse and show that CDKL5 controls postsynaptic localization of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the hippocampus and regulates seizure susceptibility. Cdkl5 -/Y mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA. In concordance with this result, electrophysiological analysis in the hippocampal CA1 region disclosed an increased ratio of NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) and a significantly larger decay time constant of NMDA receptor-mediated EPSCs (NMDA-EPSCs) as well as a stronger inhibition of the NMDA-EPSCs by the GluN2B-selective antagonist ifenprodil in Cdkl5 -/Y mice. Subcellular fractionation of the hippocampus from Cdkl5 -/Y mice revealed a significant increase of GluN2B and SAP102 in the PSD (postsynaptic density)-1T fraction, without changes in the S1 (post-nuclear) fraction or mRNA transcripts, indicating an intracellular distribution shift of these proteins to the PSD. Immunoelectron microscopic analysis of the hippocampal CA1 region further confirmed postsynaptic overaccumulation of GluN2B and SAP102 in Cdkl5 -/Y mice. Furthermore, ifenprodil abrogated the NMDA-induced hyperexcitability in Cdkl5 -/Y mice, suggesting that upregulation of GluN2B accounts for the enhanced seizure susceptibility. These data indicate that CDKL5 plays an important role in controlling postsynaptic localization of the GluN2B-SAP102 complex in the hippocampus and thereby regulates seizure susceptibility, and that aberrant NMDA receptor-mediated synaptic transmission underlies the pathological mechanisms of the CDKL5 loss-of-function.

Autoantibody profiles and their association with blood eosinophils in asthma and COPD.

BACKGROUND: Autoimmune involvement in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) has been proposed, and autoantibodies are a hallmark of autoimmunity. This study aimed to compare the autoantibody profiles of asthma and COPD, and the relationship between autoantibodies and features of these diseases. METHODS: We recruited 110 asthma patients and 92 COPD patients for a prospective study. Six autoantibody types were evaluated: antinuclear antibody, anti-cytoplasmic antibodies, rheumatoid factor, anti-cyclic citrullinated peptide antibody, myeloperoxidase-anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) and proteinase 3-ANCA. Other clinical data were also recorded concurrently. RESULTS: An antinuclear antibody titre of ≥1:160 presented only in asthma but not in COPD (10% vs. 0%, p = 0.0002). Eosinophil counts in blood were negative predictors of antinuclear antibody in asthma. Conversely, eosinophil counts in blood and immunoglobulin-E levels of ≥100 IU/mL were positively associated with rheumatoid factor in asthma but not in COPD. There was no relationship between antinuclear antibody or rheumatoid factor and disease severity. CONCLUSIONS: It is possible that asthma tends to involve autoimmunity associated with antinuclear antibody more frequently than COPD because asthma is the more robust factor for antinuclear antibody positivity. Antinuclear antibody and rheumatoid factor are associated with eosinophilic responses, but they do not work as biomarkers for disease severity.

Nocturnal Oxygen Desaturation Index is Inversely Correlated with Airflow Limitation in Patients with Chronic Obstructive Pulmonary Disease.

The concurrent diagnosis of chronic obstructive pulmonary disease (COPD) and sleep apnoea-hypopnoea syndrome (SAHS) (overlap syndrome), can contribute to worsening respiratory symptoms, but whether the severity of COPD is associated with co-morbid SAHS is unknown. We investigated whether the severity of COPD is associated with the complication of SAHS by examination of nocturnal oximetry as an alternative to polysomnography. Patients with COPD concurrently completed nocturnal oximetry, pulmonary function tests, a COPD assessment test, an Epworth sleepiness scale and a hospital anxiety and depression scale to evaluate the severity of COPD and possible concurrent presence of SAHS. We retrospectively analysed the data to assess correlation between the oxygen desaturation index (ODI) and each clinical variables and evaluated the predictors of ODI ≥ 15. This study included 103 patients (91 males, 88%) with a mean age of 72 ± 8 years and body mass index of 22 ± 3 kg/m(2). ODI was positively correlated with FEV1, FEV1/FVC and FEV1% predicted, which meant that ODI was inversely correlated with airflow limitation. Univariate logistic regression analysis revealed that FEV1% predicted and FEV1/FVC were predictors of ODI ≥ 15. ODI is inversely correlated with airflow limitation and milder COPD patients may have co-morbid SAHS.

Top-down inputs from the olfactory cortex in the postprandial period promote elimination of granule cells in the olfactory bulb.

Elimination of granule cells (GCs) in the olfactory bulb (OB) is not a continual event but is promoted during a short time window in the postprandial period, typically with postprandial sleep. However, the neuronal mechanisms for the enhanced GC elimination during the postprandial period are not understood. Here, we addressed the question of whether top-down inputs of centrifugal axons from the olfactory cortex (OC) during the postprandial period are involved in the enhanced GC elimination in the OB. Electrical stimulation of centrifugal axons from the OC of anesthetized mice increased GC apoptosis. Furthermore, pharmacological suppression of top-down inputs from the OC to the OB during the postprandial period of freely behaving mice by γ-aminobutyric acid (GABA)A receptor agonist injection in the OC significantly decreased GC apoptosis. Remarkable apoptotic GC elimination in the sensory-deprived OB was also suppressed by pharmacological blockade of top-down inputs. These results indicate that top-down inputs from the OC to the OB during the postprandial period are the crucial signal promoting GC elimination, and suggest that the life and death decision of GCs in the OB is determined by the interplay between bottom-up sensory inputs from the external world and top-down inputs from the OC.

Hormonal and circuit mechanisms controlling female sexual behavior.

Sexual behavior is crucial for reproduction in many animals. In many vertebrates, females exhibit sexual behavior only during a brief period surrounding ovulation. Over the decades, studies have identified the roles of ovarian sex hormones, which peak in levels around the time of ovulation, and the critical brain regions involved in the regulation of female sexual behavior. Modern technical innovations have enabled a deeper understanding of the neural circuit mechanisms controlling this behavior. In this review, I summarize our current knowledge and discuss the neural circuit mechanisms by which female sexual behavior occurs in association with the ovulatory phase of their cycle.

Neural basis for estrous cycle-dependent control of female behaviors.

Females display changes in distinct behaviors along the estrous cycle. Levels of circulating ovarian sex steroid hormones peak around ovulation, which occur around estrus phase of the cycle. This increase of sex hormones is thought to be important for changes in behaviors, however, neural circuit mechanisms of periodic behavioral changes in females are not understood well. Different lines of research indicate sex hormonal effects on several forms of neuronal plasticity. This review provides an overview of behavioral and plastic changes that occur in an estrous cycle-dependent manner and explores the current research linking these changes to understand neural circuit mechanisms that control female behaviors.

Heparin induces apoptosis through suppression of AKt in oral squamous cell carcinoma cells.

BACKGROUND: Heparin is a polysulfated glycosaminoglycan that has been shown to have antiproliferative and apoptotic effects in addition to its anticoagulant effects. MATERIALS AND METHODS: The present work investigated the effects of unfractioned heparin (UFH) on cell growth and apoptosis in four oral squamous cell carcinoma (SCC) cell lines and the mechanism(s) underlying its actions using MTT assay, Annexin-V-FITC and Western blotting. RESULTS: Treatment with UFH resulted in significant reduction in cell viability and increase in apoptosis in three of the four tested cell lines. Further, such treatment resulted in a significant decrease in phosphorylated AKt, and consequently led to activation of the mitochondrial pathway in heparin-sensitive cells. Moreover, pretreatment with UFH significantly increased the apoptosis induced by cisplatin. CONCLUSION: These findings indicate that heparin induces apoptosis through suppression of AKt, and suggest a potential utility of heparin for development of less toxic chemotherapy in treatment of oral SCC.

[Influence of malalignment and malocclusion on mental and physical health-consciousness in senior high school students].

OBJECTIVES: Dental examinations and a questionnaire survey were carried out simultaneously in senior high schools to investigate influence of tooth misalignment and malocclusion on mental and physical health-consciousness of the students. METHODS: The questionnaire survey concerning health-consciousness was collected after the dental examination. The students were divided into three groups by their findings: "within a normal range"; "mild-", and "severe- misalignment and malocclusion". The relationship between the severity of dental abnormality and mental and physical status in health by the questionnaire survey was studied. RESULTS: The severity of misalignment and malocclusion correlated with (1) degree of consciousness of irregular teeth, and (2) degree of negative evaluation of themselves for their health-consciousness. CONCLUSION: There is possibility that the severity of misalignment and malocclusion corresponds to a negative self evaluation and causes mental stress. It is suggested that it is very important to identify young people with such problems at an early stage, and then to consult and promote correct dental alignment and occlusion, providing not only sufficient mastication but also unhampered mental development.

Clinical validity of the Japanese version of WAIS-III short forms: Adaptation for patients with mild neurocognitive disorder and dementia.

We investigated the Japanese WAIS-III short form utility in mild neurocognitive disorder and dementia. Our sample consisted of 108 old patients (ages: 65-89; mean age = 78.3). Fifteen short forms (SFs) and full-scale (FS) IQs were compared. The SFs included Dyads (SF1, SF2), Triads (SF3), Tetrads (SF4, SF5, SF6, SF7), Pentad (SF8), Six-subtest (SF9), Seven-subtests (SF10(a)(b), SF11(a)(b), SF12), and Nine-subtest (SF13). Correlations between SFIQs and FSIQ were all significant. Significant differences also were found in paired t-test between FSIQ and 5 SFIQs (SF2: t = -4.16, SF5: t = -7.06, SF7; t = 2.59, SF10(a): t = 2.56, SF12: t = -4.82; p < .05). On the point of clinical accuracy, two SFs led to an appropriate estimated IQ (SF11(a): 84.3%, SF13: 91.7%; within 95% confidence interval and 2 standard error of measurements of FSIQ). However, SF13 was considered to still have a long administration time. The present results suggest that SF11(a) could be the most useful to estimate IQ for Japanese speaking patients with mild neurocognitive disorder and dementia. SF11(a) consists of seven subtests of Similarities, Arithmetic, Digit Span, Information, Picture Completion, Digit Symbol-Coding, and Matrix Reasoning (Ryan & Ward, 1999), and the formula (Axelrod et al., 2001) should be adopted to convert scaled scores into estimated IQ scores.

Social Control of Hypothalamus-Mediated Male Aggression.

How environmental and physiological signals interact to influence neural circuits underlying developmentally programmed social interactions such as male territorial aggression is poorly understood. We have tested the influence of sensory cues, social context, and sex hormones on progesterone receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) that are critical for male territorial aggression. We find that these neurons can drive aggressive displays in solitary males independent of pheromonal input, gonadal hormones, opponents, or social context. By contrast, these neurons cannot elicit aggression in socially housed males that intrude in another male's territory unless their pheromone-sensing is disabled. This modulation of aggression cannot be accounted for by linear integration of environmental and physiological signals. Together, our studies suggest that fundamentally non-linear computations enable social context to exert a dominant influence on developmentally hard-wired hypothalamus-mediated male territorial aggression.

Different effect of resveratrol to induction of apoptosis depending on the type of human cancer cells.

The effect of resveratrol on various human cancer cells was investigated with special focus on apoptotic cell death, in an attempt to further characterize its mechanism of action. There were great differences in the anti-viability effect of resveratrol between different types of human cancer cells. While the inhibition of cell viability by resveratrol was marked in U937 and MOLT-4 leukemia cells, resveratrol moderately inhibited cell viability in MCF-7 breast, HepG2 liver, and A549 lung cancer cells, and the effect was slight on cell viability in Caco-2, HCT116, and SW480 colon cancer cells. Following resveratrol treatment, U937 and MOLT-4 markedly increased the population of late apoptotic cells but MCF-7 and HepG2 underwent apoptosis with an increased population of early apoptosis, and resveratrol-induced DNA fragmentation was observed only in leukemic cells. Activation of sirtuin 1 and adenosine-monophosphate-activated protein kinase was not responsible for resveratrol-induced cancer cell death. Instead, resveratrol significantly reduced Akt activation with the downregulation of H-Ras, resulting in facilitation of Bax translocation to mitochondria in leukemic cells. This study suggests that resveratrol can induce apoptotic cell death in human leukemic cells to a greater extent than in human solid tumor cells via reducing Akt activation due to Ras downregulation.

Clinical characteristics and outcomes of patients with community-acquired, health-care-associated and hospital-acquired empyema.

BACKGROUND AND AIMS: Patients with pneumonia, a common cause of empyema, are stratified based on their risk factors, and the treatment of empyema might benefit from this risk stratification. METHODS: The etiology, bacteriologic profile and outcome of patients diagnosed with empyema in Shinko Hospital between May 2005 and October 2013 were retrospectively studied. The patients were stratified according to whether they had community-acquired empyema (CAE), health-care-associated empyema (HCAE) or hospital-acquired empyema (HAE). RESULTS: The study included 81 patients, 25 CAE, 40 HCAE and 16 HAE. The comorbidity rate was highest among HAE patients (100%), followed by 95% of HCAE and 72% of CAE patients (P = 0.005). The rates of cancer and central nervous system (CNS) disease were higher in patients with HCAE and HAE than in patients with CAE (P = 0.030, P = 0.018, respectively). Pleural fluid cultures were positive in 58/81 patients. Streptococcus species were the most common organisms cultured from CAE (12/15) and HCAE patients (17/30), but not from HAE patients (3/13). Anaerobic organisms were cultured from 3 CAE, 5 HCAE and 3 HAE patients. Methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa were only cultured from HCAE and HAE patients. The mortality rates were higher in HCAE (18%) and HAE (50%) than in CAE (4%) patients (log-rank test: P = 0.0012). CONCLUSIONS: Half of patients with empyema were HCAE patients, who had comorbidities, bacteriological profile and outcome different from CAE patients. The patient with HCAE should be differentiated from CAE patient, and the stratification of patients based on risk factors may be useful for treatment strategy.