Long-acting exenatide does not prevent cognitive decline in mild cognitive impairment: a proof-of-concept clinical trial.

PURPOSE: According to preclinical evidence, GLP-1 receptor may be an actionable target in neurodegenerative disorders, including Alzheimer's disease (AD). Previous clinical trials of GLP-1 receptor agonists were conducted in patients with early AD, yielding mixed results. The aim was to assess in a proof-of-concept study whether slow-release exenatide, a long-acting GLP-1 agonist, can benefit the cognitive performance of people with mild cognitive impairment (MCI). METHODS: Thirty-two (16 females) patients were randomized to either slow-release exenatide (n = 17; 2 mg s.c. once a week) or no treatment (n = 15) for 32 weeks. The primary endpoint was the change in ADAS-Cog11 cognitive test score at 32 weeks vs baseline. Secondary endpoints herein reported included additional cognitive tests and plasma readouts of GLP-1 receptor engagement. Statistical analysis was conducted by intention to treat. RESULTS: No significant between-group effects of exenatide on ADAS-Cog11 score (p = 0.17) were detected. A gender interaction with treatment was observed (p = 0.04), due to worsening of the ADAS-Cog11 score in women randomized to exenatide (p = 0.018), after correction for age, scholar level, dysglycemia, and ADAS-Cog score baseline value. Fasting plasma glucose (p = 0.02) and body weight (p = 0.03) decreased in patients randomized to exenatide. CONCLUSION: In patients with MCI, a 32-week trial with slow-release exenatide had no beneficial effect on cognitive performance. TRIAL REGISTRATION NUMBER: NCT03881371, registered on 21 July, 2016.

Nasopharyngeal microbiota in hospitalized children with Bordetella pertussis and Rhinovirus infection.

Despite great advances in describing Bordetella pertussis infection, the role of the host microbiota in pertussis pathogenesis remains unexplored. Indeed, the microbiota plays important role in defending against bacterial and viral respiratory infections. We investigated the nasopharyngeal microbiota in infants infected by B. pertussis (Bp), Rhinovirus (Rv) and simultaneously by both infectious agents (Bp + Rv). We demonstrated a specific nasopharyngeal microbiome profiles for Bp group, compared to Rv and Bp + Rv groups, and a reduction of microbial richness during coinfection compared to the single infections. The comparison amongst the three groups showed the increase of Alcaligenaceae and Achromobacter in Bp and Moraxellaceae and Moraxella in Rv group. Furthermore, correlation analysis between patients' features and nasopharyngeal microbiota profile highlighted a link between delivery and feeding modality, antibiotic administration and B. pertussis infection. A model classification demonstrated a microbiota fingerprinting specific of Bp and Rv infections. In conclusion, external factors since the first moments of life contribute to the alteration of nasopharyngeal microbiota, indeed increasing the susceptibility of the host to the pathogens' infections. When the infection is triggered, the presence of infectious agents modifies the microbiota favoring the overgrowth of commensal bacteria that turn in pathobionts, hence contributing to the disease severity.

Diagnostic accuracy of ex vivo fluorescence confocal microscopy in Mohs surgery of basal cell carcinomas: a prospective study on 753 margins.

BACKGROUND: Frozen histological sections are used for intraoperative margin assessment during Mohs surgery. Fluorescence confocal microscopy (FCM) is a new tool that offers a promising and faster alternative to frozen histology. OBJECTIVES: To evaluate prospectively in a clinical setting the accuracy of FCM vs. frozen sections in margin assessment of basal cell carcinoma (BCC). METHODS: Patients with BCC scheduled for Mohs surgery were prospectively enrolled. Freshly excised surgical specimens were examined by FCM and then frozen sections were evaluated. Permanent sections were obtained, in order to validate the sample technique. A blind re-evaluation was also performed for discordant cases. Sensitivity and specificity levels, as well as positive and negative predictive values (PPV and NPV, respectively), were calculated and receiver-operating characteristic curves generated. RESULTS: We enrolled 127 BCCs in as many patients (40·2% females). Seven hundred and fifty-three sections were examined. All BCCs were located in the head and neck area. In evaluating the performance of FCM vs. frozen sections, sensitivity was 79·8%, specificity was 95·8%, PPV was 80·5% and NPV was 95·7% [area under the curve 0·88, 95% confidence interval 0·84-0·92 (P < 0·001)]. Forty-nine discordant cases were re-evaluated; 24 were false positive and 25 false negative. The performance of FCM and frozen sections was also evaluated according to the final histopathological assessment. CONCLUSIONS: We found high levels of accuracy for FCM vs. frozen section evaluation in intraoperative BCC margin assessment during Mohs surgery. Some technical issues prevent the wide use of this technique, but new devices promise to overcome these limitations.

Evaluating ex vivo fluorescence confocal microscopy images of basal cell carcinomas in Mohs excised tissue.

BACKGROUND: Fluorescence confocal microscopy (FCM) is an emerging technology for rapid imaging of excised tissue, without the need for frozen- or fixed-section processing. Basal cell carcinomas (BCCs) can be detected in Mohs excisions although few studies have described the major BCC findings as seen on FCM. OBJECTIVES: To describe the major BCC findings of excised tissue during Mohs surgery and to correlate them with histopathology. METHODS: Freshly excised tumours and frozen-thawed discarded tissue of BCC during Mohs surgery were analysed by means of FCM. A side-by-side correlation between FCM images and histological sections was performed. The FCM features of overlying skin and adnexal structures were also described. RESULTS: Sixty-four BCC cases were analysed. Distinct BCC types appeared unique in terms of shape and size of tumour islands [bigger in nodular (18/25), smaller and rounded in micronodular (7/7) and tiny cords for infiltrative ones (24/30)] and for the presence of clefting, palisading and increased nucleus/cytoplasm ratio. An excellent correlation was found between FCM and histological findings (Cohen's κ statistics = 0·9). In six cases, the presence of sebaceous glands and intense stroma reaction represented possible confounders. CONCLUSIONS: Fluorescence confocal microscopy is a fast and new imaging technique that allows an excellent visualization of skin structures and BCC findings during Mohs surgery.

Stereotypic behaviors in degenerative dementias.

Stereotypies are simple or complex involuntary/unvoluntary behaviors, common in fronto-temporal dementia (FTD), but not studied in other types of degenerative dementias. The aim was to investigate stereotypy frequency and type in patients with FTD, Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and Parkinson's disease with dementia (PDD) in a multicenter observational study; and to investigate the relation of stereotypies to cognitive, behavioral and motor impairment. One hundred fifty-five consecutive outpatients (45 AD, 40 FTD, 35 PSP and 35 PDD) were studied in four hospitals in northern Italy. Stereotypies were examined by the five-domain Stereotypy Rating Inventory. Cognition was examined by the Mini Mental State and Frontal Assessment Battery, neuropsychiatric symptoms by the Neuropsychiatric Inventory, and motor impairment and invalidity by the Unified Parkinson's Disease Rating Scale part III, and activities of daily living. Stereotypies were present in all groups. FTD and PDD had the greatest frequency of one-domain stereotypies; FTD also had the greatest frequency of two-or-more domain stereotypies; movement stereotypies were the most common stereotypies in all groups. AD patients had fewer stereotypies than the other groups. Stereotypies are not exclusive to FTD, but are also fairly common in PSP and PDD, though less so in AD. Stereotypies may be underpinned by dysfunctional striato-frontal circuits, known to be damaged in PSP and PDD, as well as FTD.

Confocal microscopy of recurrent naevi and recurrent melanomas: a retrospective morphological study.

BACKGROUND: Repigmentation within a scar after different procedures (shave biopsy, partial excision, cryotherapy, laser) is a challenging diagnostic situation. OBJECTIVES: To determine distinct dermoscopic and confocal microscopic features in a series of histopathologically proven melanocytic proliferations within a scar. METHODS: Clinical, dermoscopic and confocal microscopic images were acquired before surgical excision in seven patients with repigmentation within a scar. The evaluation of the dermoscopic and confocal features was performed in blind to the final histopathological diagnosis that was obtained in all cases. RESULTS: Dermoscopically, the repigmentation in recurrent naevi (three patients) was confined within the scar while it extended beyond the scar in melanomas. This clue was more evident upon reflectance confocal microscopy (RCM). Confocally, recurrent naevi failed to exhibit prominent pagetoid or lateral spread of melanocytes and atypical nests at the junction, even though some cases showed atypical cells in the junctional component. However, these were few in number and cytologically monomorphous and allowed the diagnosis of a benign neoplasm with confidence. On the other hand, melanomas arising on a scar (four patients) revealed dendritic-shaped melanocytes arranged in sheets, and pagetoid and lateral spread of dendritic cells extending beyond the scar. Those confocal aspects were well correlated with the histopathological findings. CONCLUSIONS: The integration of clinical, dermoscopic and RCM aspects offers the possibility to discern reliably the nature in cases of repigmentation on a scar.

Substance use among high-school students: relationships with temperament, personality traits, and parental care perception.

Alcohol use, "alcohol abuse," and illicit drug use were investigated in a representative sample of 1076 urban, northern Italian high school students aged 14 to 19 years in 2001. In addition to questions on substance use, the participants were asked about school achievements and perceived substance use among friends. All the students were submitted to Zuckerman Sensation Seeking Scale (SSS) scale, Eysenck Personality Questionnaire (EPQ), Buss-Durkee Hostility Inventory (BDHI), and Parental Bonding Instrument (PBI). Lifetime alcohol use was found in 80.5%, "alcohol abuse" in 37.7%, cannabis use in 26.2%, ecstasy in 2.8%, heroin in 3.8%, and cocaine in 8.3% of the students: gender differences were significant for alcohol use, "alcohol abuse" and ecstasy use, with male subjects outnumbering females, but not for reported cannabis, heroin, and cocaine use. Early substance use onset among adolescents aged 14-16 years was detected. Higher sensation seeking on SSS, social coping impairment on EPQ, direct aggressiveness on BDHI, poor school achievements, and lower parental care on PBI were found associated with illicit drug use and "alcohol abuse" (multiple drugs users). Increased levels of aggressiveness and sensation seeking were evidenced both in minimal experimenters (ME) and habitual users (HU), without any significant difference, in comparison with abstinent students. Similarly, ME scored higher than abstinent subjects on EPQ for social coping impairment, but lower than HU. Parental care perception was lower in HU, but not in ME with, respect to abstinent subjects. Pearson inverse correlation was demonstrated between PBI scores and EPQ maladaptation and BDHI aggressiveness. Data from this preliminary pilot study suggest that temperamental traits and personality changes may be associated to early substance use "proneness" and reduced perception of parental care.

Lofexidine versus clonidine in rapid opiate detoxification.

The aim of the present study is to evaluate lofexidine and clonidine, in an accelerated opiate detoxification procedure (3 days), without anaesthesia. Forty heroin-dependent individuals were detoxified, evaluating withdrawal symptoms, craving levels, mood changes, urine toxicologic screens, and dropout during therapy with either (1) clonidine, oxazepam, baclofen, and ketoprofene, with naloxone and naltrexone for 3 days (20 subjects) or (2) lofexidine, oxazepam, baclofen, and ketoprofene with naloxone and naltrexone for 3 days (20 subjects). Both clonidine and lofexidine rapid detoxifications were found effective. The subjects treated with lofexidine showed significantly lower levels of withdrawal symptoms, fewer mood problems, less sedation and hypotension. No significant differences in craving levels, morphine metabolites in urine, or dropout rate were evidenced between the two groups. The early use of naltrexone during detoxification in combination with either alpha-2-agonist facilitated the acceptance for long-term naltrexone treatment. Lofexidine appeared to be more useful than clonidine in a 3-day accelerated opiate detoxification, not only to counteract withdrawal symptoms, but also in the treatment of dysphoria and mood changes. Because lofexidine does not produce hypotension, safe outpatient treatment, without hospital support, could be possible.

Neuroendocrine responses to experimentally-induced psychological stress in healthy humans.

Previous studies of hormonal and neurophysiological changes in response to psychological stress in humans have produced contrasting findings due to differing experimental procedures and consistent individual variability. Habituation effects, which influence physiological coping in response to exposure to repeated stress, need to be investigated more extensively. In the present study, twenty healthy male subjects were each exposed twice to the same psychosocial stressor (Stroop Color Word Interference task, public speaking and mental arithmetic in front of an audience) during a first session (day 1) and a second session (day 8). Plasma concentrations of norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH), cortisol (CORT) and prolactin (PRL) were measured immediately before the beginning of the tests and at their end, 30 min later, on both experimental days. For the total group, NE, EPI, ACTH, and CORT levels were significantly elevated, and PRL levels were significantly decreased, after stress exposure on day 1. ACTH and CORT levels showed less significant increases after stress on day 8. In contrast, NE and EPI responses to stress were not significantly blunted, and PRL response was unchanged on day 8. Cluster analysis revealed two groups of subjects who showed different habituation patterns for ACTH and CORT. The first group (n=12) of subjects showed a reduction of ACTH and CORT responses to stress on day 8. The subjects of the second group (n=8) displayed a significant increase of ACTH and cortisol in response to stress on day 8, without any habituation effect. These results increase the evidence concerning the involvement of the HPA axis and catecholamines in response to psychological stress, and suggest that possible individual differences in the neuroendocrine coping mechanisms may affect mood regulation and the state of health.

Urinary excretion of glycosaminoglycans in patients with isolated nocturnal enuresis or combined with diurnal incontinence.

OBJECTIVE: To determine variations in the amount of glycosaminoglycans (GAGs) excreted by patients with nocturnal enuresis and/or diurnal incontinence. PATIENTS, SUBJECTS AND METHODS: The study included 27 patients (aged 5-15 years) with nocturnal enuresis and/or diurnal incontinence, and 27 healthy age-matched children. Their urinary GAG excretion was assessed over 24 h using the sodium tetraborate-carbazole method. RESULTS: Patients with nocturnal enuresis and/or diurnal incontinence had higher mean values of urinary GAG excretion than age-matched controls. There were significant differences in GAG excretion between those with nocturnal enuresis and diurnal incontinence and those with nocturnal enuresis alone. CONCLUSIONS: GAG excretion in patients with nocturnal enuresis and/or diurnal incontinence was significantly higher than in normal children, suggesting that measuring urinary GAGs may be useful in evaluating physiopathological conditions of the bladder wall, and hence in monitoring potential damage in the bladder mucosa.

Sensitivity of FEV1 and indices of flow volume curve in the methacholine test.

Our aim was to asses the association between the decrease of FEV1 and the modifications of the indices (PEF, MEF25, MEF50 and MEF75% of FVC) during methacholine challenge. 105 patients of both sexes with mild bronchial asthma were included in this study and were subjected to methacholine test according to ATS standards. The results were analysed using analysis of variance (MANOVA), discriminant stepwise and multiple regression. The reduction of FEV1 induced by increasing dosage of methacholine was associated with a significant decrease of the other flow-volume curve indices but we can observe a different flow behaviour. The MEF50 was more significant during the first level of variations and the MEF75 and MEF25 being more significant during the subsequent phases. We conclude that the evaluation of the flow volume indices can be important for better study the site of action of methacholine.

[Variations in lymphocyte subsets in chronic inflammatory and neoplastic pathology in the elderly. II. Discriminant stepwise analysis]. / Variazioni delle sottoclassi linfocitarie nelle patologie infiammatorie croniche e neoplastiche dell'anziano. II. Analisi discriminante stepwise.

The variations of lymphocyte subsets in chronic inflammatory and neoplastic diseases in an elderly population, have been previously reported. The different behavior of all the subsets that had shown significant variations of frequencies and absolute values within the groups with the Multivariate Analysis of Variance, have been studied. The use of the Discriminant Stepwise Analysis has given the chance to spot the discriminant subsets and their ability in discriminating the inflammatory and the neoplastic groups from each other and from the controls and finally in pointing out all the subsets which did not affect such differentiation.

[Changes in lymphocyte subsets in chronic inflammatory diseases and neoplasms in the elderly. I. Multivariate analysis of variance and factoral analysis]. / Variazioni delle sottoclassi linfocitarie nelle patologie infiammatorie croniche e neoplastiche dell'anziano. I. Analisi della varianza multivariata ed analisi fattoriale.

The variations of lymphocyte subsets have been studied both in neoplastic and chronic inflammatory elderly patients compared to a control group. The interpretation of the Multivariate Analysis of Variance (MANOVA) and of the Factorial Analysis has demonstrated the opposite role of TCD4 subset, mainly involved in the inflammatory process, and of TCD8 subset in regard of the neoplastic ones. We report the slight and yet significant increase of NK related to age. Independently from the disease pattern, factorial analysis permitted a comparison between the variations of lymphocyte subsets and the different grades of immunoresponse.

Effect of Bifidobacterium bifidum and Lactobacillus acidophilus on gut mucosa and peripheral blood B lymphocytes.

In 15 elderly individuals lyophilized Bifidobacterium bifidum (BB) and Lactobacillus acidophilus (LA) (Infloran) were administered in capsules (two capsules 4 times per day) for 28 days, while in 10 elderly controls placebo were given the same posology and for an equal period of time. The effects of this treatment on the immune system both at the periphery or the intestinal level were investigated. Results show that BB and LA significantly reduced the colonic inflammatory infiltration, without altering T, B and Leu7 + cell percentage. At the same time, a significant increase of B cell frequency in the peripheral blood was noted, in comparison to controls. The overall results suggest that the regular administration of BB and LA leads to a modulation of the immunological and inflammatory response in elderly subjects.

Membrane lipid alterations and Na+-pumping activity in erythrocytes from IDDM and NIDDM subjects.

The Na+-pumping activity of the erythrocyte plasma membrane in diabetic subjects was studied together with the lipid composition. Insulin-dependent diabetes mellitus (IDDM) patients (n = 25) were divided into young (28.1 +/- 7.4 yr old, mean +/- SD; n = 16) and old (7.17 +/- 9.8 yr old; n = 10) subjects; the age of non-insulin-dependent (NIDDM) patients was 70.7 +/- 11.5 yr (n = 10). The Na+-pumping activity, estimated from both Na+-K+-ATPase and ouabain binding, was significantly decreased in IDDM and NIDDM subjects, but its insulin sensitivity was retained only in young IDDM subjects. The total cholesterol and phospholipid content of the erythrocyte plasma membrane was lowered in IDDM subjects, and cholesterol-to-phospholipid molar ratio was significantly decreased. In NIDDM subjects the significant decreased of the two lipid components did not alter their ratio. The analysis of major phospholipid components of erythrocyte membranes revealed that only phosphatidylcholine is significantly increased in young diabetic subjects. The fatty acid composition of major phospholipid classes was significantly altered in all cases: the unsaturation index appeared to be increased in phosphatidylserine and sphingomyelin for both IDDM and NIDDM subjects and was also increased in phosphatidylcholine in the latter group.

Reduction and disappearance of anomalous fluorescence patterns by means of absorption of HIV and EBV positive sera to guinea pig kidney and calf erythrocytes: a preliminary study.

Anomalous pictures observed in HIV infected H9 line cells by immunofluorescence technique, were investigated on sera of drug addicts and on controls. Strong fluorescence artifacts were markedly reduced after an overnight incubation at 4 degrees C. A complete disappearance was obtained after absorption to guinea pig kidney and calf erythrocytes of anti EBV positive sera. This result was fully independent of any anti HIV positivity.

[CEA and CA 19.9: an evaluation by new statistical technics on a group of elderly patients]. / Il CEA ed il CA 19.9: una valutazione con nuove tecniche statistiche in un gruppo di pazienti in età geriatrica.

New parametric and non parametric statistical methods have been compared in the evaluation of experimental data of CEA and CA 19.9 using a brief program in BASIC. We have found that the distribution of the two markers is the same of that described in literature except for both the means that we have found being slightly higher than that ones described by other authors.