Italian Association of Sleep Medicine (AIMS) position statement and guideline on the treatment of menopausal sleep disorders.

Insomnia, vasomotor symptoms (VMS) and depression often co-occur after the menopause, with consequent health problems and reductions in quality of life. The aim of this position statement is to provide evidence-based advice on the management of postmenopausal sleep disorders derived from a systematic review of the literature. The latter yielded results on VMS, insomnia, circadian rhythm disorders, obstructive sleep apnea (OSA) and restless leg syndrome (RLS). Overall, the studies show that menopausal hormone therapy (MHT) improves VMS, insomnia, and mood. Several antidepressants can improve insomnia, either on their own or in association with MHT; these include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and mirtazapine. Long-term benefits for postmenopausal insomnia may also be achieved with non-drug strategies such as cognitive behavioral therapy (CBT) and aerobic exercise. Continuous positive airway pressure (CPAP) and mandibular advancement devices (MADs) both reduce blood pressure and cortisol levels in postmenopausal women suffering from OSA. However, the data regarding MHT on postmenopausal restless legs syndrome are conflicting.

A High-throughput Screening of a Chemical Compound Library in Ovarian Cancer Stem Cells.

BACKGROUND: Epithelial ovarian cancer has a poor prognosis, mostly due to its late diagnosis and the development of drug resistance after a first platinum-based regimen. The presence of a specific population of "cancer stem cells" could be responsible of the relapse of the tumor and the development of resistance to therapy. For this reason, it would be important to specifically target this subpopulation of tumor cells in order to increase the response to therapy. METHOD: We screened a chemical compound library assembled during the COST CM1106 action to search for compound classes active in targeting ovarian stem cells. We here report the results of the high-throughput screening assay in two ovarian cancer stem cells and the differentiated cells derived from them. RESULTS AND CONCLUSION: Interestingly, there were compounds active only on stem cells, only on differentiated cells, and compounds active on both cell populations. Even if these data need to be validated in ad hoc dose response cytotoxic experiments, the ongoing analysis of the compound structures will open up to mechanistic drug studies to select compounds able to improve the prognosis of ovarian cancer patients.

Estimated costs attributable to events of "out-of-temperature" in the stockpiling of hexavalent vaccines occurring in Italy.

BACKGROUND: Antigens contained in vaccines are inherently unstable biologically; such a characteristic is conferred by their three-dimensional structure. Preserving the ability of the vaccines to protect against disease is necessary to ensure the supervision and monitoring of all steps of the cold chain. DTPa-HBV-IPV/Hib vaccine (Infanrix hexaTM, GSK Vaccines, Belgium) is designed to prevent disease due to diphtheria, tetanus, pertussis (DTP), hepatitis B virus (HBV), poliomyelitis and Haemophilus influenzae type b (Hib); it was first licensed for use in Europe in 2000 and is currently licensed in at least 95 countries. Since October 2013, more than 102 million doses of GSK's DTPa-HBV-IPV/Hib vaccine have been distributed globally, with nearly 15 million doses distributed in Italy. DTPa-HBV-IPV/Hib components are stable up to a temperature of 25°C for 72 hours. Lacking of officially approved stability data may generate some concern in case of cold chain accidents. METHODS: An analysis based on collected data was carried out to estimate potential costs attributable to events of "out-of-temperature" in the stockpiling of hexavalent vaccines occurring in Italy in 2014. RESULTS: The analysis, based on real data, documented that the loss for the National Health Service (NHS) was in the range of 100,000 - 400,000 euros in one year. However, the amount of money that in principle could have been lost would have ranged between nearly half and one million euros/year. CONCLUSIONS: A substantial loss of money was avoided thanks to the availability of officially approved stability data for GSK's DTPa-HBV-IPV/Hib vaccine.

Echocardiography and pulse contour analysis to assess cardiac output in trauma patients.

BACKGROUND: Echocardiography is a valuable technique to assess cardiac output (CO) in trauma patients, but it does not allow a continuous bedside monitoring. Beat-to-beat CO assessment can be obtained by other techniques, including the pulse contour method MostCare. The aim of our study was to compare CO obtained with MostCare (MC-CO) with CO estimated by transthoracic echocardiography (TTE-CO) in trauma patients. METHODS: Forty-nine patients with blunt trauma admitted to an intensive care unit and requiring hemodynamic optimization within 24 hours from admission were studied. TTE-CO and MC-CO were estimated simultaneously at baseline, after a fluid challenge and after the start of vasoactive drug therapy. RESULTS: One hundred sixteen paired CO values were obtained. TTE-CO values ranged from 2.9 to 7.6 L·min(-1), and MC-CO ranged from 2.8 to 8.2 L·min(-1). The correlation between the two methods was 0.94 (95% confidence interval [CI]=0.89 to 0.97; P<0.001). The mean bias was -0.06 L·min(-1) with limits of agreements (LoA) of -0.94 to 0.82 L·min(-1) (lower 95% CI, -1.16 to -0.72; upper 95% CI, 0.60 to 1.04) and a percentage error of 18%. Changes in CO showed a correlation of 0.91 (95% CI=0.87 to 0.95; P<0.001), a mean bias of -0.01 L·min(-1) with LoA of -0.67 to 0.65 L·min(-1) (lower 95% CI, -0.83 to -0.51; upper 95% CI, 0.48 to 0.81). CONCLUSION: CO measured by MostCare showed good agreement with CO obtained by transthoracic echocardiography. Pulse contour analysis can complement echocardiography in evaluating hemodynamics in trauma patients.

Comparison between an uncalibrated pulse contour method and thermodilution technique for cardiac output estimation in septic patients.

BACKGROUND: The purpose of this study was to evaluate the reliability of a new uncalibrated pulse contour method, the MostCare, in determining cardiac output (CO) in septic patients. METHODS: Thirty patients with septic shock admitted to an intensive care unit, receiving a norepinephrine infusion and requiring haemodynamic monitoring with a pulmonary artery catheter, were prospectively enrolled. Thermodilution measurements of CO (ThD-CO) were considered as the 'gold standard'. MostCare was connected to the monitoring system of the radial arterial pressure waveform to obtain a continuous CO calculation (MostCare-CO). ThD-CO and MostCare-CO measurements were recorded at three different haemodynamic states: baseline (T1), after raising mean arterial pressure (MAP) to 90 mm Hg by increasing the norepinephrine infusion (T2), and after returning the MAP to baseline value by decreasing vasopressor therapy (T3). A Bland-Altman and linear regression analyses were performed. RESULTS: A total of 90 paired ThD-CO and MostCare-CO measures were obtained (range 4.1-13.9 litre min(-1) for ThD-CO and 4.5-13.5 litre min(-1) for MostCare-CO). A good correlation between ThD-CO and MostCare-CO was observed (R = 0.93). The mean bias between the two techniques was -0.26 litre min(-1) (sd 0.98 litre min(-1)) and the 95% limits of agreement were -2.22 to 1.70 litre min(-1). The percentage of error was 25%. Pearson's R was 0.94, 0.92, and 0.93 at T1, T2, and T3, respectively. CONCLUSIONS: MostCare-CO and ThD-CO showed a good agreement at each time of the study. The reliability of the MostCare system was not affected by the vascular tone changes produced by a norepinephrine infusion.

Increased prevalence of restless legs syndrome in patients with acromegaly and effects on quality of life assessed by Acro-QoL.

Restless legs syndrome (RLS), a neurological sensory-motor disorder characterized by a compelling urge to move the limbs during the night, is a sleep disturbance that impairs quality of life. Prevalence of RLS and consequences on quality of life were investigated in acromegalic patients. Fifty-six patients (20 men, 55.0 ± 1.6 years), 22 with active acromegaly (group 1) and 34 with controlled disease (group 2), and 95 controls (35 men, 52.9 ± 1.1 years) were evaluated by a structured sleep interview concerning insomnia, circadian sleep disorders and excessive diurnal sleepiness (EDS). The Epworth Sleepiness Scale (ESS) questionnaire was administered to those reporting EDS. Patients were investigated by RLS diagnostic interview and International Restless Leg Syndrome-Rating Scale (IRLS-RS). Quality of life was investigated by AcroQoL questionnaire. RLS was diagnosed in 21% of acromegalics and in 4% of controls (P < 0.002). Prevalence of RLS and mean IRLS-RS was higher in group 1 than in group 2 (P < 0.05). Prevalence of insomnia (P < 0.0002) and of EDS (P < 0.05) and mean ESS score (P < 0.01) were higher in RLS-positive than in RLS-free acromegalics. Video-PSG showed that mean sleep latency (P < 0.01), micro-arousal index (P < 0.05) and wakefulness after sleep onset (P < 0.01) were higher, whereas sleep efficiency (P < 0.01) was lower, in RLS-positive than in RLS-free patients. Global and physical AcroQoL scores were significantly lower in RLS-positive than in RLS-free acromegalics (P < 0.01 and P < 0.001, respectively). Prevalence and severity of RLS is increased in patients with active acromegaly and impacts negatively on their physical performances, dramatically impairing quality of life.

Impairment of sensory-motor integration in patients affected by RLS.

Much evidence suggests that restless legs syndrome (RLS) is a disorder characterized by an unsuppressed response to sensory urges due to abnormalities in inhibitory pathways that specifically link sensory input and motor output. Therefore, in the present study, we tested sensory-motor integration in patients with RLS, measured by short latency afferent inhibition (SAI) and long latency afferent inhibition (LAI). SAI and LAI were determined using transcranial magnetic stimulation before and after 1 month of dopaminergic treatment in RLS patients. Ten naïve patients with idiopathic RLS and ten healthy age-matched controls were recruited. Patients with secondary causes for RLS (e.g. renal failure, anaemia, low iron and ferritin) were excluded, as well as those with other sleep disorders. Untreated RLS patients demonstrated deficient SAI in the human motor cortex, which proved revertible toward normal values after dopaminergic treatment. We demonstrated an alteration of sensory-motor integration, which is normalized by dopaminergic treatment, in patients affected by RLS. It is likely that the reduction of SAI might contribute significantly to the release of the involuntary movements and might account for the sensory urge typical of this condition.

Lifetime measurements of the neutron-rich N = 30 isotones 50Ca and 51Sc: orbital dependence of effective charges in the fp shell.

The lifetimes of the first excited states of the N = 30 isotones (50)Ca and (51)Sc have been determined using the Recoil Distance Doppler Shift method in combination with the CLARA-PRISMA spectrometers. This is the first time such a method is applied to measure lifetimes of neutron-rich nuclei populated via a multinucleon transfer reaction. This extends the lifetime knowledge beyond the f_{7/2} shell closure and allows us to derive the effective proton and neutron charges in the fp shell near the doubly magic nucleus (48)Ca, using large-scale, shell-model calculations. These results indicate an orbital dependence of the core polarization along the fp shell.

Lung abscess in adults: clinical comparison of immunocompromised to non-immunocompromised patients.

Information related to the clinical characteristics and isolated microbes associated with lung abscesses comparing immunocompromised (IC) to non-immunocompromised (non-IC) patients is limited. A retrospective review for 1984-1996 identified 34 consecutive adult cases of lung abscess (representing 0.2% of all cases of pneumonia), including 10 non-IC and 24 IC patients. Comparison of age, gender, tobacco use, pre-existing pulmonary disease or recognized aspiration risk factors were not significantly different between the two groups. Upper lobe involvement accounted for the majority of cases, although multi-lobe involvement was limited to IC patients. There were no differences in the need for surgical intervention, and mortality was very low for both groups. Anaerobes were the most frequent isolates for non-IC patients (30%), whereas aerobes were the most frequent isolate for IC patients (63%). Importantly, certain organisms were exclusively isolated in the IC group and multiple isolates were obtained only from the IC patients.Thus, comparing non-IC to IC patients, clinical characteristics may be similar whereas important differences may exist in the microbiology associated with lung abscess. These findings have important implications for the clinical management of these patient groups, and support a strategy to aggressively identify microbial agents in abscess material.

Effects of fluvoxamine and paroxetine on sleep structure in normal subjects: a home-based Nightcap evaluation during drug administration and withdrawal.

BACKGROUND: Acute and chronic administration of the selective serotonin reuptake inhibitors (SSRIs) have been widely reported to disrupt sleep in laboratory studies. This study examines the naturalistic, longitudinal effects of paroxetine and fluvoxamine on sleep quality in the home setting. METHOD: Fourteen healthy volunteers free of medical and neuropsychiatric symptoms entered a 31-day protocol: 7 days of drug-free baseline (days 1-7), 19 days of drug treatment (steady state during days 18-26), and 5 days of acute withdrawal (days 27-31). On day 8, the subjects were randomly assigned to receive either 100 mg/day of fluvoxamine or 20 mg/day of paroxetine (half receiving each drug) in divided morning and evening oral doses. Investigators remained blinded to drug assignment until all sleep data had been analyzed. Sleep was monitored using the Nightcap ambulatory sleep monitor. Four standard and 3 novel measures were computed and compared using multivariate analysis of variance, analysis of variance, and Bonferroni-corrected comparison of means. RESULTS: Sleep disruption was most clearly demonstrated using the novel measures eyelid quiescence index, rhythmicity, and eyelid movements per minute in non-rapid eye movement sleep, but was also apparent as determined by standard measures of sleep efficiency, number of awakenings, and sleep onset latency. Paroxetine disrupted sleep more than fluvoxamine, and paroxetine-induced sleep disruption persisted into the withdrawal phase. Rapid eye movement sleep was suppressed during treatment (especially for fluvoxamine) and rebounded during withdrawal (especially for paroxetine). CONCLUSION: We confirm laboratory polysomnographic findings of SSRI-induced sleep quality changes and demonstrate the Nightcap's efficacy as an inexpensive longitudinal monitor for objective sleep changes induced by psychotropic medication.

SSRI treatment suppresses dream recall frequency but increases subjective dream intensity in normal subjects.

Clinical lore and a small number of published studies report that the selective serotonin reuptake inhibitors (SSRIs) intensify dreaming. This study examines the dream effects of paroxetine and fluvoxamine in order to both increase clinical knowledge of these agents and to test an important potential method for probing the relationship between REM sleep neurobiology and dreaming in humans. Fourteen normal, paid volunteers (4 males, 10 females; mean age 27.4 year, range 22--39) free of medical or neuropsychiatric symptoms as well as of psychotropic or sleep affecting drugs completed a 31-day home-based study consisting of: 7 days drug-free baseline; 19 days on either 100 mg fluvoxamine (7 Ss) or 20 mg paroxetine (7 Ss) in divided morning and evening doses; and 5 days acute discontinuation. Upon awakening, subjects wrote dream reports, self-scored specific emotions in their reports and rated seven general dream characteristics using 5-point Likert scales. Dream reports were independently scored for bizarreness, movement and number of visual nouns by three judges. REM sleep-related measures were obtained using the Nightcap ambulatory sleep monitor. Mean dream recall frequency decreased during treatment compared with baseline. Dream report length and judge-rated bizarreness were greater during acute discontinuation compared with both baseline and treatment and this effect was a result of the fluvoxamine-treated subjects. The subjective intensity of dreaming increased during both treatment and acute discontinuation compared with baseline. Propensity to enter REM sleep was decreased during treatment compared with baseline and acute discontinuation and the intensity of REM sleep increased during acute discontinuation compared with baseline and treatment. The decrease in dream frequency during SSRI treatment may reflect serotonergic REM suppression while the augmented report length and bizarreness during acute SSRI discontinuation may reflect cholinergic rebound from serotonergic suppression.

Computer-assisted design, synthesis and biological evaluation of novel pyrrolyl heteroaryl sulfones targeted at HIV-1 reverse transcriptase as non-nucleoside inhibitors.

Three pyrrolyl heteroaryl sulfones (ethyl 1-[(1H-benzimidazol-2(3H)one-5-yl)sulfonyl]-1H-pyrrole-2-carboxyla te, ethyl 1-[(1H-benzimidazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate and ethyl 1-[(1H-benzotriazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate) were designed as novel HIV-1 reverse transcriptase non-nucleoside inhibitors using structure-based computational methods. Although these compounds were inactive in the cell-based assay, they inhibited the target enzyme with micromolar potency (IC50s = 2 microM, 3 microM and 9 microM, respectively).

Structure-based design, synthesis, and biological evaluation of novel pyrrolyl aryl sulfones: HIV-1 non-nucleoside reverse transcriptase inhibitors active at nanomolar concentrations.

Pyrrolyl aryl sulfones (PASs) have been recently reported as a new class of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors acting at the non-nucleoside binding site of this enzyme (Artico, M.; et al. J. Med. Chem. 1996, 39, 522-530). Compound 3, the most potent inhibitor within the series (EC(50) = 0.14 microM, IC(50) = 0.4 microM, and SI > 1429), was then selected as a lead compound for a synthetic project based on molecular modeling studies. Using the three-dimensional structure of RT cocrystallized with the alpha-APA derivative R95845, we derived a model of the RT/3 complex by taking into account previously developed structure-activity relationships. Inspection of this model and docking calculations on virtual compounds prompted the design of novel PAS derivatives and related analogues. Our computational approach proved to be effective in making qualitative predictions, that is in discriminating active versus inactive compounds. Among the compounds synthesized and tested, 20 was the most active one, with EC(50) = 0.045 microM, IC(50) = 0.05 microM, and SI = 5333. Compared with the lead 3, these values represent a 3- and 8-fold improvement in the cell-based and enzyme assays, respectively, together with the highest selectivity achieved so far in the PAS series.

1-[2-(Diphenylmethoxy)ethyl]-2-methyl-5-nitroimidazole: a potent lead for the design of novel NNRTIs.

A novel family of non-nucleoside reverse transcriptase inhibitors (NNRTIs) active at submicromolar concentrations was discovered. The new derivatives are 1-[2-(diarylmethoxy)ethyl]imidazoles bearing substituents both at benzene and imidazole rings. The most potent derivatives were those having nitro and methyl groups as substituents in the imidazole ring. Among 10 test derivatives compound 6d was found to be as potent as nevirapine and was selected as a lead for further studies.

Clozapine-induced seizures and EEG abnormalities in ambulatory psychiatric patients.

OBJECTIVE: To examine the seizure characteristics and electroencephalogram (EEG) abnormalities in psychiatric patients taking clozapine, given the estimate of a 10% cumulative risk of generalized seizures in this population. DESIGN: We reviewed all consecutive EEGs of ambulatory psychiatric patients taking clozapine performed at our laboratory during 1996 and 1997. SETTING: A university-affiliated urban teaching hospital. SUBJECTS: Twelve patients (4 F/8 M; mean age 40.1 y, range 20-63) had either presented with de novo ictal events within the first month of clozapine therapy (n = 8) or had EEGs recorded to assess seizure risk (n = 4). RESULTS: According to clinical history and interictal EEG findings, the patients were subdivided as follows: three patients with generalized tonic-clonic seizures, two with generalized myoclonic jerks (1 associated with simple partial seizures), two with complex partial seizures, and one with simple partial seizures. The EEGs revealed interictal epileptiform abnormalities (IEDs) in eight patients, two of whom had not had seizures. IEDs were focal or multifocal, with a predominance of left temporal foci. One patient showed a paroxysmal response to photic stimulation. CONCLUSIONS: Patients taking clozapine may be prone to partial seizures and focal EEG abnormalities as well as to generalized seizures and EEG abnormalities, as previously reported.

Lung abcess complicating Legionella micdadei pneumonia in an adult liver transplant recipient: case report and review.

Legionella micdadei (Pittsburgh pneumonia agent) is the second most common cause of Legionella pneumonia, and occurs predominantly in immunocompromised hosts. L micdadei is the cause of nosocomial pneumonia in renal transplant recipients, but has not been described in other adult solid organ transplant recipients. This report describes the first case of L micdadei pneumonia in an adult liver transplant recipient on immunosuppressive therapy. Importantly, this case highlights the difficulties in establishing the diagnosis, as the Legionella urinary antigen is negative, and special culture conditions are required. Furthermore, this case illustrates several atypical clinical features of L micdadei pneumonia in a transplant recipient, including a community acquired mode of transmission, occurrence several years after organ transplantation, and lung abcess formation. The patient was successfully treated with limited surgical resection and quinolone antimicrobial monotherapy.

Synthesis and biological evaluation of 5H-indolo [3,2-b][1,5]benzothiazepine derivatives, designed as conformationally constrained analogues of the human immunodeficiency virus type 1 reverse transcriptase inhibitor L-737,126.

In the presence of sodium hydride, reaction of aryl-disulphides with ethyl esters of indole-2-carboxylic acids furnished ethyl 3-arylthioindole-2-carboxylates, which were cyclized intramolecularly to afford 5H-indolo[3,2-b][1,5]benzothiazepin-6(7H)-ones or hydrolysed in alkaline medium to give 3-arylthioindole-2-carboxylic acids. These acids, also obtained by the action of aryldisulphides on indole-2-carboxylic acids, afforded tetracyclic 5H-indolo [3,2-b][1,5]benzothiazepin-6(7H)-ones upon treatment with EDCI-DMAP. Transformation of cyclic sulphides into the required sulphones was achieved by treatment with hydrogen peroxide or with m-chloroperbenzoic acid. The title derivatives are conformationally constrained analogues of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor 3-benzene-sulphonyl-5-chloroindole-2-carboxamide (L-737, 126). Although the indolobenzothiazepine derivatives, as well as the indolyl aryl sulphones used for their synthesis, were endowed with anti-HIV-1 activities in the submicromolar and micromolar range, none of them proved more potent than L-737,126.

Sulfone derivatives with anti-HIV activity.

Following the discovery of anti-HIV properties of suramin great efforts were devoted to design novel NNRT agents with the aims to find novel drugs for the clinical therapeutic management of AIDS. Sulfone and sulfonamide derivatives were studied by NCI at Bethesda as potential anti-HIV-1 agents and nitrophenyl phenyl sulfone (NPPS) was selected as lead compound for further investigations. At the same time Merck Laboratories discovered L-737,126, a potent indolyl aryl sulfone with inhibitory activity against reverse transcriptase. These studies stimulated novel search in the sulfone series and both diarylsulfones and cyclic sulfone derivatives were investigated. Our decennial interest in chemotherapeutic agents containing a pyrrole ring pulsed us to synthesize and test as anti-HIV-1 agents a number of pyrryl aryl sulfones (PASs), pyrrolobenzothiadiazepine (PBTDs) and pyrrolobenzothiazepine related sulfones. The new sulfone derivatives inhibit selectively HIV-1 and were inactive against HIV-2. Most of them were as active as, if not more active than, nevirapine.

Spiral CT with multiplanar and three-dimensional reconstructions accurately predicts tracheobronchial pathology.

BACKGROUND: This study was designed to evaluate the clinical accuracy of multiplanar reconstructions and three-dimensional shaded surface displays compared with conventional transaxial computed tomography, bronchoscopy, and surgical pathologic findings. METHODS: Transaxial computed tomographic images, two-dimensional nonstandard multiplanar reconstruction images, and three-dimensional images obtained from patients with tracheobronchial disease were prospectively evaluated for the relationship to adjacent structures, lesion characterization, and surgical anatomic correlation before invasive procedures. RESULTS: Compared with conventional transaxial computed tomographic images, multiplanar reconstructions and three-dimensional shaded surface displays provided a correlative map of bronchoscopic and surgical anatomy in patients with benign and malignant tracheobronchial pathology. The longitudinal extent of abnormalities are better demonstrated on the multiplanar reconstruction and three-dimensional images, whereas the transverse extent of disease and relationships to adjacent structures were better shown on axial computed tomographic sections. CONCLUSIONS: Three-dimensional and multiplanar two-dimensional images are additive to transaxial computed tomography for evaluation of diseases involving the central airways. They are beneficial for planning invasive procedures. More importantly, they provide consistent, highly accurate measurements for routine follow-up and for future clinical trials.