Insomnia and daytime sleepiness predict 20-year mortality in older male adults: data from a population-based study.

Data regarding the possible relationship of insomnia and EDS with mortality are inconclusive. The aim of this study was to investigate the association between these sleep complaints and the risk of long-term (20 years) all-cause mortality in older adults. Between April 2000 and March 2001, 750 subjects aged 65 years and older, who resided in the seventh district of Udine, were recruited. Data on sociodemographic characteristics, past medical history, and pharmacological treatment were collected. Dementia was diagnosed using a comprehensive neurological and neuroradiological assessment. Older adults were interviewed by neuropsychologists trained in sleep disturbances in order to assess the presence of sleep complaints. Vital status was followed over 20 years until March 2020. Older male adults affected by insomnia and EDS were significantly more likely to die over the follow-up period. Indeed, males reporting poor sleep and daytime somnolence had a 60% and 48% higher chance of dying than subjects who were not affected by these sleep complaints, respectively. The HR was attenuated after adjusting for confounding variables among insomniacs, whereas that of somnolent men strengthened. Differently from men, insomnia and EDS did not have any impact on mortality in older women. In conclusion, older male adults affected by insomnia and EDS had a significant increased risk of mortality, which is independent of cancer, depression, dementia, cardiovascular diseases, and sleeping pill use.

miR-30e* is an independent subtype-specific prognostic marker in breast cancer.

BACKGROUND: Breast cancer clinical outcome is affected by tumor molecular features, and the identification of subtype-specific prognostic biomarkers is relevant for breast cancer translational research. Gene expression signatures proved to be able to complement prognostic information provided by classical clinico-pathological features. Recently, microRNAs (miRNAs) have been causally linked to tumorigenesis and cancer progression and have been associated with patient outcome, also in breast cancer. METHODS: MicroRNAs associated with the development of distant metastasis were identified in a cohort of 92 ESR1+/ERBB2- lymph node-negative breast cancers from patients not receiving adjuvant treatment. Results were confirmed and further investigated in a total of 1246 miRNA and gene expression profiles of the Molecular Taxonomy of Breast Cancer International Consortium data set. Moderated t-test, univariable and multivariable Cox regression models were used for statistical analyses. RESULTS: miR-30e* was identified as independent protective prognostic factor in lymph node-negative untreated patients with ESR1+/ERBB2- tumours and retained a significant association with a good prognosis in treated patients with the same tumor subtype as well as in the ERBB2+ subtype, but not in ESR1-/ERBB2- tumours. CONCLUSIONS: We highlighted a relevant and subtype-specific role in breast cancer for miR-30e* and demonstrated that adding miRNA markers to gene signatures and clinico-pathological features can help for a better prognostication.

Daytime sleepiness is associated with dementia and cognitive decline in older Italian adults: a population-based study.

OBJECTIVE: The occurrence of dementia among the elderly has been associated with several, often not modifiable, risk factors. Recent epidemiological studies focused their interest on a possible association between cognitive decline and sleep, a potentially modifiable risk factor. Due to controversial results and limitations of the previous studies, we decided to reexamine the relationship between disturbed sleep and cognitive impairment in the elderly. METHODS: Seven hundred fifty subjects aged 65years or older were recruited. The Mini-Mental State Examination (MMSE) and the Global Deterioration Scale (GDS) scores were used to evaluate the severity of cognitive decline. Diagnosis of dementia was made by means of the DSM-IV criteria. The older adults were interviewed in order to assess the presence of several sleep complaints (insomnia, snoring and/or witnessed sleep apneas, restlessness and/or leg jerks, sleepwalking and nightmares). Excessive daytime sleepiness was evaluated by means of a validated questionnaire. The principal caregiver of each older adult took part in the interview, providing the information if the subject was unable to answer because of mental impairment. RESULTS: Eighty-six individuals were diagnosed as demented; a large part of them (47.8%), in particular, were recognized as being affected by Alzheimer's disease. The prevalence of each sleep complaint in the older adults was as follows: insomnia 84.7%, snoring and/or witnessed sleep apneas 26.2%, restlessness and/or jerks in the legs 25.7%, sleepwalking 0.5%, nightmares 6.4% and daytime somnolence 30.6%. Among sleep disturbances, excessive daytime sleepiness was independently associated with the presence of dementia in the elderly. In addition, the frequency of excessive daytime sleepiness increased progressively across the different categories of cognitive decline, as measured by means of MMSE and GDS scores. CONCLUSIONS: Insomnia, the most common sleep complaint in our sample, was not associated with the presence of cognitive decline. As opposed to insomnia, excessive daytime sleepiness was significantly related to dementia. Further studies are needed in order to investigate the direction of this association and to evaluate the possible role of daytime somnolence as an early marker of neurodegenerative disease, particularly Alzheimer's disease, in some older adults.

Dissection of RAS downstream pathways in melanomagenesis: a role for Ral in transformation.

Cutaneous malignant melanoma is considered one of the most deadly human cancers, based on both its penchant for metastatic spread and its typical resistance to currently available therapy. Long known to harbor oncogenic NRAS mutations, melanomas were more recently reported to be frequent bearers of activating mutations in BRAF, one of the effectors situated downstream of wild-type NRAS. NRAS and BRAF mutations are rarely found in the same melanoma, suggesting that they may possess important overlapping oncogenic activities. Here, we compare and contrast the oncogenic roles of the three major NRas downstream effectors, Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine exchange factor (RalGEF), using genetically engineered Arf-deficient immortalized mouse melanocytes as a model system. Although no single downstream pathway could recapitulate all of the consequences of oncogenic NRas expression, our data indicate a prominent role for BRaf and PI3K in melanocyte senescence and invasiveness, respectively. More surprisingly, we discovered that constitutive RalGEF activation had a major impact on several malignant phenotypes, particularly anchorage-independent growth, indicating that this often overlooked pathway should be more carefully evaluated as a possible therapeutic target.

Prevalence of 'poor sleep' among patients with multiple sclerosis: an independent predictor of mental and physical status.

BACKGROUND: Patients with multiple sclerosis (MS) report sleep disturbances more frequently than the general population. Besides specific sleep disturbances, many other conditions could impair nocturnal rest in this population. In addition, information regarding the role of disrupted sleep on quality of life (QoL) in MS patients is lacking. This study was performed to bridge this gap. METHODS: A total of 120 patients with MS were enrolled into the study. Demographic, socioeconomic and clinical characteristics (clinical course and duration of MS, EDSS score, therapeutic information, presence of pain, presence of sexual and/or bladder dysfunction, localization of demyelinating plaques, and presence of anxiety and depression) were collected. The Pittsburgh Sleep Quality Index (PSQI), the Charlson Comorbidity Index (CCI) and the Italian version of the 36-item Short Form (SF-36) were used to assess quality of sleep, comorbidity and QoL, respectively. RESULTS: Nearly half (47.5%) of MS patients were classified as "poor sleepers," having significantly higher EDSS (3.1+/-1.4 vs. 2.3+/-1.4, p=0.009) and CCI scores (0.19+/-0.4 vs. 0.03+/-0.2, p=0.009) than "good sleepers." In addition, pain due to MS was more common among "poor sleepers" (33.3% vs. 17.7%, p=0.05). Scores for each domain of the SF-36, and the mental component summary (MCS) and physical component summary (PCS) scores were significantly lower in poor sleepers than in good sleepers (p<0.001 for each score). Of the different variables associated with MCS, the only independent predictors of mental status were: presence of sexual and/or bladder dysfunction and global PSQI score. The independent predictors for physical status (PCS) were age, EDSS score and global PSQI score. CONCLUSIONS: Poor sleep is common in patients with MS, representing an independent predictor of QoL. Patients with MS who are poor sleepers should receive immediate assessment and treatment, bearing in mind that, in addition to specific sleep disturbances, other clinical conditions (both related and unrelated to MS) can disrupt nocturnal sleep.

Identification of VEGF-regulated genes associated with increased lung metastatic potential: functional involvement of tenascin-C in tumor growth and lung metastasis.

Metastasis is the primary cause of death in patients with breast cancer. Overexpression of c-myc in humans correlates with metastases, but transgenic mice only show low rates of micrometastases. We have generated transgenic mice that overexpress both c-myc and vascular endothelial growth factor (VEGF) (Myc/VEGF) in the mammary gland, which develop high rates of pulmonary macrometastases. Gene expression profiling revealed a set of deregulated genes in Myc/VEGF tumors compared to Myc tumors associated with the increased metastatic phenotype. Cross-comparisons between this set of genes with a human breast cancer lung metastasis gene signature identified five common targets: tenascin-C(TNC), matrix metalloprotease-2, collagen-6-A1, mannosidase-alpha-1A and HLA-DPA1. Signaling blockade or knockdown of TNC in MDA-MB-435 cells resulted in a significant impairment of cell migration and anchorage-independent cell proliferation. Mice injected with clonal MDA-MB-435 cells with reduced expression of TNC demonstrated a significant decrease (P<0.05) in (1) primary tumor growth; (2) tumor relapse after surgical removal of the primary tumor and (3) incidence of lung metastasis. Our results demonstrate that VEGF induces complex alterations in tissue architecture and gene expression. The TNC signaling pathway plays an important role in mammary tumor growth and metastases, suggesting that TNC may be a relevant target for therapy against metastatic breast cancer.

Drugs with anticholinergic properties as a risk factor for psychosis in patients affected by Alzheimer's disease.

Emerging evidence suggests that psychosis in persons with Alzheimer's disease (AD) may be linked to the cholinergic deficit associated with the disease. This study sought to evaluate whether anticholinergic (ACH) drugs could be a risk factor for psychosis onset. A total of 230 patients affected with probable AD were recruited. Data on behavioral and psychological symptoms were collected using the Neuropsychiatric Inventory, and diagnosis of psychosis was performed. Patients were divided into those who used ACH drugs and those who used non-ACH drugs. Those using ACH drugs (18.3%) were more likely to have psychosis than those using non-ACH drugs (odds ratio (OR)=2.52; 95% confidence interval (CI), 1.27-5.00); this association remained significant even after adjusting for potential confounding variables (OR=2.13; 95% CI, 1.03-4.43). Our data suggest that patients with AD are frequently treated with ACH drugs and that ACH drug intake should be regarded as a potential risk factor for psychosis.

Restless legs syndrome: diagnosis, epidemiology, classification and consequences.

Restless legs syndrome (RLS) is a sensorimotor disorder characterised by a complaint of an almost irresistible urge to move the legs. RLS is diagnosed clinically by means of the four essential criteria of the International Restless Legs Syndrome Study Group. In doubtful cases, neurophysiological examinations, such as polysomnography and/or a suggested immobilisation test, can be performed to confirm a clinical suspicion of RLS. Several other conditions may present sensorimotor complaints with features similar to RLS; a careful sleep history is required to avoid a misdiagnosis. Three different scales have been validated to assess the severity of RLS. In the general population, RLS prevalence ranges from 0.1% to 11.5%, with a high number of patients affected by a primary form of the sleep disturbance (70%-80%). However, several clinical conditions have been associated with RLS, such as iron deficiency, uraemia, pregnancy and polyneuropathy. Furthermore, recent studies show that RLS may be associated also to type 2 diabetes mellitus and to multiple sclerosis. RLS has a negative impact on sleep, cognitive functions, quality of life and mental status. Higher awareness of RLS among physicians is required; it remains an underdiagnosed clinical condition.

Reverse radial artery bone flap reconstruction of segmental metacarpal losses.

A vascularised bone segment of the distal radius was harvested as a distally based flap to treat segmental metacarpal bone loss in three patients. One reconstruction followed resection of a giant cell tumour excision and the other two were to replace traumatic bone loss. The bone defects were in the second metacarpal in two cases and in the second and third metacarpal in one case and included three shaft and one distal metacarpal reconstruction. The mean length of the metacarpal defects was 6 cm. All of the flaps survived and no complications occurred at the donor site. Clinical and radiological union was established in all cases after an average of 3 months.

Changes in hemodynamics during isoflurane and propofol anesthesia: a comparison study.

OBJECTIVES: Volatile anesthetics are thought to impair cerebral autoregulation more than i.v. anesthetics. However, few comparative studies have been carried out in humans. The aim of our study was to evaluate the differences in cerebral hemodynamic changes after introduction of isoflurane (a volatile anesthetic) and propofol (an i.v. anesthetic). METHODS: Eighteen consecutive patients submitted to laparoscopic cholecystectomy were selected. After the induction, anesthesia was maintained by isoflurane (one minimum alveolar anesthetic concentration) during the first part of the surgical operation, and then by propofol (5 mg/kg/hour i.v.). Ventilation was adjusted to maintain a constant end-tidal CO(2). Middle artery flow velocity was assessed by means of transcranial Doppler ultrasonography. Arterial blood pressure, heart rate (HR), capnometry, pulse oxymetry, inspired fraction of O(2), and body temperature, were monitored. RESULTS: Cerebral artery velocity, HR, and mean arterial pressure all significantly increased from baseline after the introduction of isoflurane (p<0.05); the HR and mean arterial blood pressure showed no significant difference between the isoflurane and propofol phases. Isoflurane anesthesia induced a significant increase in cerebral blood velocity. Propofol introduction led to a significant decrease in cerebral artery velocity (p<0.05). CONCLUSIONS: Propofol but not isoflurane decreased cerebral blood velocity thus restoring cerebral autoregulation and the coupling between cerebral blood flow and cerebral metabolism.

[Sarcoidosis and clear cell carcinoma of the kidney: the sixth case?]. / Sarcoidosi e carcinoma renale a cellule chiare: il sesto caso clinico?

The Authors report a very rare case of clear cell renal cancer associated with sarcoidosis, incidentally discovered in a 39 year-old man, admitted for a not correlated pathology (multiple left rib fractures due to automobile crash). Problems related to a proper assessment of sarcoidosis are discussed as well as potential arising of a neoplasm during the entire follow-up period: for that, it must always be complete and accurate.

Overexpression of hepatocyte growth factor/scatter factor promotes vascularization and granulation tissue formation in vivo.

The effect of hepatocyte growth factor/scatter factor (HGF/SF) during wound healing in the skin was investigated, using HGF/SF-overexpressing transgenic mouse model. Histological analysis of HGF/SF transgenic mouse excisional wound sites revealed increased granulation tissue with marked vascularization. Northern blot analysis demonstrated that, relative to control, vascular endothelial growth factor (VEGF) expression in transgenic skin was significantly higher at baseline and was robustly up-regulated during wound healing. Elevated levels of VEGF protein were detected immunohistochemically, predominantly in endothelial cells and fibroblasts within the granulation tissue of HGF/SF transgenic skin. Serum levels of VEGF were also elevated in HGF/SF transgenic mice. Thus, results from our study suggest that HGF/SF has a significant effect on vascularization and granulation tissue formation during wound healing in vivo, involving with induction of VEGF.

Neonatal sunburn and melanoma in mice.

Retrospective epidemiological data have indicated that cutaneous malignant melanoma may arise as a consequence of intense, intermittent exposure of the skin to ultraviolet radiation, particularly in children, rather than from the cumulative lifetime exposure that is associated with other forms of skin cancer. Here we use a genetically engineered mouse model to show that a single dose of burning ultraviolet radiation to neonates, but not adults, is necessary and sufficient to induce tumours with high penetrance which are reminiscent of human melanoma. Our results provide experimental support for epidemiological evidence that childhood sunburn poses a significant risk of developing this potentially fatal disease.

[Non-parasitic splenic cysts]. / Le cisti spleniche non parassitarie.

The Authors report their experience matured during the last decade in the Institute of III Surgical Clinic of the University "La Sapienza" in Rome, relatively to 174 patients operated of splenectomy of which 8 for not parassitair benign cystic pathology. After the nosologic organization of the varied types of cystics splenopaty is examined the different symptomatology and is discussed the different treatment.

The genetics of pancreatic adenocarcinoma: a roadmap for a mouse model.

Pancreatic cancer is among the leading causes of cancer death. Although a genetic profile for pancreatic cancer is emerging, many biological aspects of this disease are poorly understood. Indeed, fundamental questions regarding progenitor cell lineages, host stromal milieu, and the role of specific genetic alterations in tumor progression remain unresolved. A mouse model engineered with signature mutations would provide a powerful ally in the study of pancreatic cancer biology and may guide improved prognostic assessment and treatment for the human disease. In this review, we discuss the molecular basis for normal pancreatic development and the genetics of human pancreatic adenocarcinoma in the hope of charting a course for the development of a faithful mouse model for this lethal cancer.

Genetic dissection of melanoma pathways in the mouse.

The frequent loss of the INK4a/ARF locus, encoding for both p16(INK4a)and p19(ARF)in human melanoma, raises the question as to which INK4a/ARF gene product functions to suppress melanoma-genesis in vivo. Studies in the mouse have shown that activated RAS mutation can cooperate with INK4a(Delta 2/3)deficiency (null for both p16(INK4a)and p19(ARF)) to promote development of melanoma, and these melanomas retain wild-type p53. Given the functional link between p19(ARF)and p53, we have now shown that activated RAS can also cooperate with p53 deficiency to produce melanoma in the mouse. Moreover, genome-wide analysis of RAS-induced p53 mutant melanomas reveals alterations of key components governing RB-regulated G1/S transition, such as c-Myc. These experimental findings suggest that both RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.

Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation.

The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are not understood. Because of the uncertainty of human cancer risk associated with peroxisome proliferators, delineating the mechanisms of carcinogenesis by these agents is of great interest. Alterations in liver growth factors were postulated to contribute to the carcinogenic effect of peroxisome proliferators. Administration of these compounds to rodents results in down-regulation of hepatocyte growth factor (HGF) and supplementing culture medium with HGF is reported to suppress cell proliferation of preneoplastic and neoplastic cells from WY-14,643-treated livers. Combined, these observations suggest that reduced levels of hepatic HGF contribute to the mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis. To determine if HGF can prevent the effects of peroxisome proliferators in liver, the short-term influence of WY-14,643 in two different lines of HGF transgenic mice was examined. Mice were fed either a control diet or one containing 0.1% WY-14-643 for one week. Hepatomegaly was found in both HGF transgenic mouse lines fed WY-14,643 compared with controls. Additionally, hepatic expression of typical mRNA markers of peroxisome proliferation including those encoding peroxisomal fatty acid metabolizing enzymes and cell cycle control proteins were all significantly elevated in HGF transgenic mice fed WY-14,643 compared with controls. Down-regulation of HGF was found to be dependent on PPARalpha since lower levels of HGF mRNA and protein were observed in wild-type mice fed WY-14,643 for 1 week and not in similarly treated PPARalpha-null mice. These results demonstrate that the early increase in hepatic mRNAs associated with peroxisome and cell proliferation induced by WY-14,643 treatment can not be prevented by overexpression of HGF in vivo.