Lack of effects of pramipexole on REM sleep behavior disorder in Parkinson disease

STUDY OBJECTIVES: REM sleep behavior disorder (RBD) is a common manifestation of Parkinson disease (PD) which is characterized by dream-enacting behaviors, unpleasant dreams, and loss of muscle atonia during REM sleep. Dopaminergic mechanisms are thought to play a role in RBD pathogenesis. To further asses such a role, we have evaluated the effect of pramipexole, a dopamine receptor agonist, on RBD features in PD patients. SETTING: University hospital sleep disorder center. PARTICIPANTS: Eleven PD patients with untreated RBD. interventions: Not applicable. MEASUREMENTS AND RESULTS: In a prospective study, 11 consecutive PD patients with untreated RBD on levodopa monotherapy were placed on pramipexole to further ameliorate their parkinsonism. The effects on RBD were evaluated before and 3 months after stable pramipexole therapy through patient and bed partner interviews and blind assessment of video-polysomnographic measures. Pramipexole improved parkinsonism in all patients. Patients and bed partners reported no significant changes in frequency and severity of the abnormal RBD related motor and vocal sleep behaviors or the frequency of unpleasant dreams. Video-polysomnography analyses showed no differences in RBD related sleep measures including tonic submental electromyographic activity, phasic submental electromyographic activity, percentage of REM sleep time spent with abnormal behaviors, and severity of the abnormal behaviors detected on the videotapes. CONCLUSION: In PD, pramipexole improved parkinsonism but did not modify RBD related symptoms and objective video-polysomnographic abnormalities. This observation suggests that in PD, dopamine mechanisms do not play a central role in the pathogenesis of RBD.     

Does human papillomavirus infection imply a different prognosis in vulvar squamous cell carcinoma?

Background

Two independent pathways in the development of vulvar squamous cell carcinoma (VSCC) have been described, one related to and the other independent of high-risk human papillomavirus (HR-HPV). The aim of our study was to evaluate whether the HPV status has a prognostic significance or can predict response to radiotherapy.

Methods

All VSCC diagnosed from 1995 to 2009 were retrospectively evaluated (n = 98). HPV infection was detected by amplification of HPV DNA by PCR using SPF-10 primers and typed by the INNO-LIPA HPV research assay. p16^INK4a expression was determined by immunohistochemistry. Disease-free and overall survival (DFS and OS) were estimated by Kaplan-Meier analysis with the log-rank test and a multivariate Cox proportional hazard's model.

Results

HR-HPV DNA was detected in 19.4% of patients. HPV16 was the most prevalent genotype (73.7% of cases). p16^INK4a stained 100% HPV-positive and 1.3% HPV-negative tumors (p < .001). No differences were found between HPV-positive and -negative tumors in terms of either DFS (39.8% vs. 49.8% at 5 years; p = .831), or OS (67.2% vs. 71.4% at 5 years; p = .791). No differences in survival were observed between HPV-positive and -negative patients requiring radiotherapy (hazard ratio [HR] 1.04, 95% confidence interval [CI] .45 to 2.41). FIGO stages III-IV (p = .002), lymph node metastasis (p = .030), size ≥ 20 mm (p = .023), invasion depth (p = .020) and ulceration (p = .032) were associated with increased mortality but in multivariated only lymph node metastasis retained the association (HR 13.28, 95% CI 1.19 to 148.61).

Conclusions

HPV-positive and -negative VSCCs have a similar prognosis. Radiotherapy does not increase survival in HPV-positive women.     

Thalamic diffusion differences related to cognitive function in white matter lesions

Cerebral white matter lesions (WMLs) are related to cognitive deficits, probably due to a disruption of frontal–subcortical circuits. We explored thalamic diffusion differences related to white matter lesions (WMLs) and their association with cognitive function in middle-aged individuals. Ninety-six participants from the Barcelona-AsIA Neuropsychology Study were included. Participants were classified into groups based on low grade and high grade of periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs). Tract-Based Spatial Statistics was used to study thalamic diffusion differences between groups. Mean fractional anisotropy (FA) values in significant areas were calculated for each subject and correlated with cognitive performance. Participants with high-grade PVHs and DWMHs showed lower FA thalamic values compared to those with low-grade PVHs and DWMHs, respectively. Decreased FA thalamic values in high-grade DWMHs, but not high-grade PVH, were related to lower levels of performance in psychomotor speed, verbal fluency, and visuospatial skills. Thalamic diffusion differences are related to lower cognitive function only in participants with high-grade DWMHs. These results support the hypothesis that fronto–subcortical disruption is associated with cognitive function only in DWMHs.     

Decreased hypocretin-1 (Orexin-A) levels in the cerebrospinal fluid of patients with myotonic dystrophy and excessive daytime sleepiness

STUDY OBJECTIVE: Myotonic dystrophy type 1 is a multisystem disorder with myotonia, muscle weakness, cataracts, endocrine dysfunction, and intellectual impairment. This disorder is caused by a CTG triplet expansion in the 3' untranslated region of the DMPK gene on 19q13. Myotonic dystrophy type 1 is frequently associated with excessive daytime sleepiness, sharing with narcolepsy a short sleep latency and the presence of sleep-onset rapid eye movement periods during the Multiple Sleep Latency Test. Since narcolepsy is characterized by a dysfunction of the hypothalamic hypocretin system, we investigated whether patients with myotonic dystrophy type 1 with excessive daytime sleepiness have abnormalities in the hypocretin system. DESIGN/PARTICIPANTS: Six patients with myotonic dystrophy type 1 complaining of excessive daytime sleepiness and 13 healthy controls without a sleep disorder were included. The patients with myotonic dystrophy type 1 were evaluated using clinical interviews, nocturnal polysomnograms, and Multiple Sleep Latency Tests. All patients had a confirmed genetic diagnosis for DM1 and were HLA typed. Cerebrospinal fluid hypocretin-1 levels were measured using a direct radioimmunoassay in patients and controls. Setting: University hospital sleep laboratory. INTERVENTIONS: N/A. MEASUREMENT AND RESULTS: The mean sleep latency on Multiple Sleep Latency Tests was abnormal in all patients (< 5 minutes in 2, < or = 8 in 4) and 2 sleep-onset rapid eye movement periods were observed in 2 subjects. All patients were HLA-DQB1*0602 negative. Hypocretin-1 levels were significantly lower in patients versus controls (p < 0.001); 1 case with 2 sleep-onset rapid eye movement periods had hypocretin-1 levels in the range generally observed in narcolepsy (< 110 pg/mL). Three cases had intermediate levels (110-200 pg/mL). Hypocretin-1 levels did not correlate clinically with disease severity or duration or with subjective or objective sleepiness reports. CONCLUSIONS: A dysfunction of the hypothalamic hypocretin system may mediate sleepiness and abnormal Multiple Sleep Latency Test results in patients with myotonic dystrophy type 1.     

External validation of putative biomarkers in eutopic endometrium of women with endometriosis using NanoString technology

PurposeTo combine different independent endometrial markers to classify the presence of endometriosis.MethodsEndometrial biopsies were obtained from 109 women with endometriosis as well as 110 control women. Nine candidate biomarkers independent of cycle phase were selected from the literature and NanoString was performed. We compared differentially expressed genes between groups and generated generalized linear models to find a classifier for the disease.ResultsGeneralized linear models correctly detected 68% of women with endometriosis (combining deep infiltrating and ovarian endometriosis). However, we were not able to distinguish between individual types of endometriosis compared to controls. From the 9 tested genes, FOS, MMP7, and MMP11 seem to be important for disease classification, and FOS was the most over-expressed gene in endometriosis.Conclusion(s)Although generalized linear models may allow identification of endometriosis, we did not obtain perfect classification with the selected gene candidates.Electronic supplementary materialThe online version of this article (10.1007/s10815-020-01965-6) contains supplementary material, which is available to authorized users.     

Hirschsprung associated GDNF mutations do not prevent RET activation

Hirschsprung disease (HSCR) is a complex disorder characterised by aganglia of distal gastrointestinal tracts. The highest proportion of both familial and sporadic cases is due to mutations of the RET proto-oncogene. Five germline mutations in the glial cell-line-derived neurotrophic factor (GDNF) gene, one of the RET ligands, have been detected in HSCR patients. Pedigrees analysis and the observed association between these GDNF alterations and RET variants in the same patients raised the question of whether the GDNF gene plays any causative/predisposing role in HSCR pathogenesis. In the present work, we have studied the ability of GDNF proteins, each bearing one of the reported mutations, to activate RET by performing a functional test in cultured neuroblastoma cells. Consistently with the lack of genotype/phenotype correlation in human subjects, our results indicate absence of detectable alterations of mutant GDNF induced RET activation.     

CD154-dependent priming of diabetogenic CD4(+) T cells dissociated from activation of antigen-presenting cells

We followed the fate of K(d)- or I-A(g7)-restricted beta cell-autoreactive T cells in monoclonal TCR-transgenic NOD mice expressing or lacking CD154. 8.3-NOD.RAG-2(-/-)/CD154(-/-) mice, which bear autoreactive CD8(+) T cells, developed diabetes with the same incidence and tempo as 8.3-NOD.RAG-2(-/-)/CD154(+) mice. Recruitment of CD154(-/-) 8.3-CD8(+) CTL was accelerated by CD154(+)CD4(+) T cells, by expression of a B7.1 transgene in beta cells or by treatment of the mice with CpG-DNA or an agonistic anti-CD40 antibody. In contrast, the autoreactive CD4(+) T cells maturing in 4.1-NOD.RAG-2(-/-) mice lost their diabetogenic potential if they lacked CD154, even in the presence of CD154(+)CD4(+) T cells, B7.1 molecules on beta cells, CpG-DNA treatment, or systemic CD40 ligation. These results demonstrate the existence of a novel, CD154-dependent pathway of CD4(+) T cell activation that is independent of CD40-mediated activation of APCs.     

Myo-inositol may prevent gestational diabetes onset in overweight women: a randomized,controlled trial

Objective: To evaluate whether myo-inositol supplementation may reduce gestational diabetes mellitus (GDM) rate in overweight women.

Methods: In an open-label, randomized trial, myo-inositol (2?g plus 200?μg folic acid twice a day) or placebo (200?μg folic acid twice a day) was administered from the first trimester to delivery in pregnant overweight non-obese women (pre-pregnancy body mass index?≥?25 and?<?30 kg/m²). The primary outcome was the incidence of GDM.

Results: From January 2012 to December 2014, 220 pregnant women were randomized at two Italian University hospitals, 110 to myo-inositol and 110 to placebo. The incidence of GDM was significantly lower in the myo-inositol group compared to the placebo group (11.6% versus 27.4%, respectively, p?=?0.004). Myo-inositol treatment was associated with a 67% risk reduction of developing GDM (OR 0.33; 95% CI 0.15–0.70).

Conclusions: Myo-inositol supplementation, administered since early pregnancy, reduces GDM incidence in overweight non-obese women.