Loss of ARHGAP15 affects the directional control of migrating interneurons in the embryonic cortex and increases susceptibility to epilepsy.

GTPases of the Rho family are components of signaling pathways linking extracellular signals to the control of cytoskeleton dynamics. Among these, RAC1 plays key roles during brain development, ranging from neuronal migration to neuritogenesis, synaptogenesis, and plasticity. RAC1 activity is positively and negatively controlled by guanine nucleotide exchange factors (GEFs), guanosine nucleotide dissociation inhibitors (GDIs), and GTPase-activating proteins (GAPs), but the specific role of each regulator in vivo is poorly known. ARHGAP15 is a RAC1-specific GAP expressed during development in a fraction of migrating cortical interneurons (CINs) and in the majority of adult CINs. During development, loss of ARHGAP15 causes altered directionality of the leading process of tangentially migrating CINs, along with altered morphology in vitro. Likewise, time-lapse imaging of embryonic CINs revealed a poorly coordinated directional control during radial migration, possibly due to a hyper-exploratory behavior. In the adult cortex, the observed defects lead to subtle alteration in the distribution of CALB2-, SST-, and VIP-positive interneurons. Adult Arhgap15-knock-out mice also show reduced CINs intrinsic excitability, spontaneous subclinical seizures, and increased susceptibility to the pro-epileptic drug pilocarpine. These results indicate that ARHGAP15 imposes a fine negative regulation on RAC1 that is required for morphological maturation and directional control during CIN migration, with consequences on their laminar distribution and inhibitory function.

p140Cap Controls Female Fertility in Mice Acting via Glutamatergic Afference on Hypothalamic Gonadotropin-Releasing Hormone Neurons.

p140Cap, encoded by the gene SRCIN1 (SRC kinase signaling inhibitor 1), is an adaptor/scaffold protein highly expressed in the mouse brain, participating in several pre- and post-synaptic mechanisms. p140Cap knock-out (KO) female mice show severe hypofertility, delayed puberty onset, altered estrus cycle, reduced ovulation, and defective production of luteinizing hormone and estradiol during proestrus. We investigated the role of p140Cap in the development and maturation of the hypothalamic gonadotropic system. During embryonic development, migration of Gonadotropin-Releasing Hormone (GnRH) neurons from the nasal placode to the forebrain in p140Cap KO mice appeared normal, and young p140Cap KO animals showed a normal number of GnRH-immunoreactive (-ir) neurons. In contrast, adult p140Cap KO mice showed a significant loss of GnRH-ir neurons and a decreased density of GnRH-ir projections in the median eminence, accompanied by reduced levels of GnRH and LH mRNAs in the hypothalamus and pituitary gland, respectively. We examined the number of kisspeptin (KP) neurons in the rostral periventricular region of the third ventricle, the number of KP-ir fibers in the arcuate nucleus, and the number of KP-ir punctae on GnRH neurons but we found no significant changes. Consistently, the responsiveness to exogenous KP in vivo was unchanged, excluding a cell-autonomous defect on the GnRH neurons at the level of KP receptor or its signal transduction. Since glutamatergic signaling in the hypothalamus is critical for both puberty onset and modulation of GnRH secretion, we examined the density of glutamatergic synapses in p140Cap KO mice and observed a significant reduction in the density of VGLUT-ir punctae both in the preoptic area and on GnRH neurons. Our data suggest that the glutamatergic circuitry in the hypothalamus is altered in the absence of p140Cap and is required for female fertility.

Functional status and mortality in older women with gynecological cancer.

BACKGROUND: Screening tools for the identification of vulnerable older patients with cancer are needed. Aim of this study is to measure the prognostic value of multiple screening tools for the assessment of mortality risk in oncogeriatrics. METHODS: The prognostic value of the following assessment tools was tested in 200 older women with gynecological cancer (mean age = 73.5 years) for 1-year mortality: Short Physical Performance Battery, usual gait speed, handgrip strength, Eastern Cooperative Oncology Group Performance Status scale, Karnofsky Performance Status scale, Vulnerable Elders Scale-13, activities of daily living, and instrumental activities of daily living. Cox proportional hazard models were performed to estimate the associations of the performance measures with mortality. Areas under receiver operating characteristic curves were also estimated. RESULTS: Twenty-three participants (11.5%) died during the follow-up. The Short Physical Performance Battery, usual gait speed, and instrumental activities of daily living were the only parameters significantly associated with mortality, even after adjustment for confounders. No statistically significant results were reported for other functional measures. Similar results were obtained when testing the predictive values of the performance measures at the receiver operating characteristic analyses. CONCLUSIONS: The Short Physical Performance Battery and especially the usual gait speed may represent promising tools for measuring the mortality risk of older cancer patients, thus potentially supporting clinical decisions. Further studies are needed to confirm and extend the present findings.

Comorbidity and physical function: results from the aging and longevity study in the Sirente geographic area (ilSIRENTE study).

BACKGROUND: Physical function measures have gained increased importance in the evaluation of older persons. The presence of comorbidity is a major and growing issue in geriatrics. OBJECTIVE: To evaluate the relationship between comorbidity and physical function in community-dwelling older persons. METHODS: Data are from baseline evaluation of the ilSIRENTE study (n = 364). Physical performance was assessed using the Short Physical Performance Battery (SPPB) and the 4-meter walking test. Muscle strength was measured by hand-grip strength. Functional performance was assessed using Basic and Instrumental Activities of Daily Living (ADLs and IADLs, respectively). Comorbidity was defined as >or=3 clinical conditions. Analyses of covariance and linear regressions were performed to evaluate the relationship between comorbidity and physical function. RESULTS: The mean age of participants was 85.9 (SD = 4.9) years. About one third (37.4%) of participants reported >or=3 clinical conditions. Participants with comorbidity had significantly worse results in all the physical function tests. Participants with comorbidity had significantly lower adjusted results for the 4-meter walking test (0.444 m/s) and the SPPB score (6.131) compared to those without comorbidity (0.531 m/s and 7.221; all p = 0.001, respectively). Participants with comorbidity were more IADL-impaired (3.152) than participants without comorbidity (2.767; p = 0.04). No significant association of ADLs and hand-grip strength with comorbidity was reported. Similar strengths of association for the 4-meter walking test (per SD increase, beta = -0.280; p = 0.001) and the SPPB (per SD increase, beta = -0.285; p = 0.001) with comorbidity were reported. CONCLUSIONS: Physical function measures, especially walking speed and SPPB, are associated with comorbidity. Physical performance measures may improve the clinical evaluation of older persons.

The ilSIRENTE study: a prospective cohort study on persons aged 80 years and older living in a mountain community of Central Italy.

BACKGROUND AND AIMS: "Invecchiamento e Longevità nel Sirente" (Aging and Longevity in the Sirente geographic area, ilSIRENTE) aims at investigating the socio-demographic, functional, clinical and biological characteristics of all subjects aged 80 years and older residing in a well-defined mountain area of Central Italy. METHODS: Data are from the baseline evaluation of the ilSIRENTE prospective cohort study. A list of all persons living in the Sirente area was obtained from the Registry Offices of the 13 municipalities involved in the study. Data collection started in December 2003 and was completed in September 2004. Among the 429 residents older than 80 years eligible for the study, 364 accepted to participate (response rate 84%). Participants were assessed by trained staff who collected information on socio-demographic factors, clinical conditions, medication use, physical performance and muscle strength. All participants were also evaluated using the Minimum Data Set for Home Care (MDS-HC) form and a slightly modified version of the "Invecchiare in CHIANTI" study. RESULTS: The mean age of participants was 85.6 +/- 4.8 years (range 80-102 years), with over 20% of participants aged 90 years or older. More than 65% of participants were women. Most participants (70%) were independent or required limited assistance in performing basic activities of daily living (ADL), whereas 30% of participants were independent in instrumental activities of daily living (IADL). Cognitive function (assessed by the Cognitive Performance Score) was normal in 80% of the sample. Higher degrees of disabilities (defined as the sum of dependencies in ADLs and IADLs) were associated with worse physical performance and lower muscle strength. CONCLUSIONS: Data on the socio-demographic characteristics and health status of very old people living in the Sirente mountain community are discussed and compared with findings from other epidemiological studies.