Differential effects of speech and Language therapy and rTMS in chronic versus subacute post-stroke aphasia: Results of the NORTHSTAR-CA trial

Background & objective: Contralesional 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the right pars triangularis combined with speech-language therapy (SLT) has shown positive results on the recovery of naming in subacute (5–45 days) post-stroke aphasia. NORTHSTAR-CA is an extension of the previously reported NORTHSTAR trial to chronic aphasia (\u3e6 months post-stroke) designed to compare the effectiveness of the same rTMS protocol in both phases. Methods: Sixty-seven patients with left middle cerebral artery infarcts (28 chronic, 39 subacute) were recruited (01-2014 to 07-2019) and randomized to receive rTMS (N = 34) or sham stimulation (N = 33) with SLT for 10 days. Primary outcome variables were Z-score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment. Chronic and subacute results were compared. Results: Adverse events were rare, mild, and did not differ between groups. Language outcomes improved significantly in all groups irrespective of treatment and recovery phase. At 30-day follow-up, there was a significant interaction of stimulation and recovery phase on naming recovery (P \u3c.001). Naming recovery with rTMS was larger in subacute (Mdn = 1.91/IQR =.77) than chronic patients (Mdn =.15/IQR = 1.68/P =.015). There was no significant rTMS effect in the chronic aphasia group. Conclusions: The addition of rTMS to SLT led to significant supplemental gains in naming recovery in the subacute phase only. While this needs confirmation in larger studies, our results clarify neuromodulatory vs training-induced effects and indicate a possible window of opportunity for contralesional inhibitory stimulation interventions in post-stroke aphasia. NORTHSTAR trial registration: https://clinicaltrials.gov/ct2/show/NCT02020421

Mutation analysis and characterization of ATR sequence variants in breast cancer cases from high-risk French Canadian breast/ovarian cancer families

BACKGROUND: Ataxia telangiectasia-mutated and Rad3-related (ATR) is a member of the PIK-related family which plays, along with ATM, a central role in cell-cycle regulation. ATR has been shown to phosphorylate several tumor suppressors like BRCA1, CHEK1 and TP53. ATR appears as a good candidate breast cancer susceptibility gene and the current study was designed to screen for ATR germline mutations potentially involved in breast cancer predisposition. METHODS: ATR direct sequencing was performed using a fluorescent method while widely available programs were used for linkage disequilibrium (LD), haplotype analyses, and tagging SNP (tSNP) identification. Expression analyses were carried out using real-time PCR. RESULTS: The complete sequence of all exons and flanking intronic sequences were analyzed in DNA samples from 54 individuals affected with breast cancer from non-BRCA1/2 high-risk French Canadian breast/ovarian families. Although no germline mutation has been identified in the coding region, we identified 41 sequence variants, including 16 coding variants, 3 of which are not reported in public databases. SNP haplotypes were established and tSNPs were identified in 73 healthy unrelated French Canadians, providing a valuable tool for further association studies involving the ATR gene, using large cohorts. Our analyses led to the identification of two novel alternative splice transcripts. In contrast to the transcript generated by an alternative splicing site in the intron 41, the one resulting from a deletion of 121 nucleotides in exon 33 is widely expressed, at significant but relatively low levels, in both normal and tumoral cells including normal breast and ovarian tissue. CONCLUSION: Although no deleterious mutations were identified in the ATR gene, the current study provides an haplotype analysis of the ATR gene polymorphisms, which allowed the identification of a set of SNPs that could be used as tSNPs for large-scale association studies. In addition, our study led to the characterization of a novel Δ33 splice form, which could generate a putative truncated protein lacking several functional domains. Additional studies in large cohorts and other populations will be needed to further evaluate if common and/or rare ATR sequence variants can be associated with a modest or intermediate breast cancer risk

Psychological interventions for coronary heart disease

A meta-analysis was conducted on 35 trials involving 10,703 individuals who had experienced a myocardial infarction and were randomised to an intervention involving some form of psychological therapy. Ten of these studies involved individuals with confirmed psychiatric diagnoses. Moderate quality evidence found no reduction of risk for total mortality or revascularisation procedures in comparison to usual care. Low quality evidence found no risk reduction for non-fatal MI although there was a 21% reduction in cardiac mortality. There was also some evidence of benefit on measures of psychological morbidity including anxiety, depression, and stress. It is concluded that psychological interventions may reduce cardiac mortality, although stronger evidence is required before this can be definitively concluded. It is also not clear who benefits most from psychological interventions

Pilot investigation of the circadian plasma melatonin rhythm across the menstrual cycle in a small group of women with premenstrual dysphoric disorder.

Women with premenstrual dysphoric disorder (PMDD) experience mood deterioration and altered circadian rhythms during the luteal phase (LP) of their menstrual cycles. Disturbed circadian rhythms may be involved in the development of clinical mood states, though this relationship is not fully characterized in PMDD. We therefore conducted an extensive chronobiological characterization of the melatonin rhythm in a small group of PMDD women and female controls. In this pilot study, participants included five women with PMDD and five age-matched controls with no evidence of menstrual-related mood disorders. Participants underwent two 24-hour laboratory visits, during the follicular phase (FP) and LP of the menstrual cycle, consisting of intensive physiological monitoring under "unmasked", time-isolation conditions. Measures included visual analogue scale for mood, ovarian hormones, and 24-hour plasma melatonin. Mood significantly (P≤.03) worsened during LP in PMDD compared to FP and controls. Progesterone was significantly (P = .025) increased during LP compared to FP, with no between-group differences. Compared to controls, PMDD women had significantly (P<.05) decreased melatonin at circadian phases spanning the biological night during both menstrual phases and reduced amplitude of its circadian rhythm during LP. PMDD women also had reduced area under the curve of melatonin during LP compared to FP. PMDD women showed affected circadian melatonin rhythms, with reduced nocturnal secretion and amplitude during the symptomatic phase compared to controls. Despite our small sample size, these pilot findings support a role for disturbed circadian rhythms in affective disorders. Possible associations with disrupted serotonergic transmission are proposed

Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder Comorbid with Huntington’s Disease: A Case Report

Huntington’s disease (HD) is a rare genetic disorder resulting in progressive neurodegeneration leading to motor, cognitive and psychiatric symptoms. A high percentage of HD patients suffer from comorbid major depressive disorder (MDD). We are not aware of any literature on the use of repetitive transcranial magnetic stimulation (rTMS) for treating comorbid MDD in HD. We present the case of a 57-year-old man suffering from HD in which comorbid MDD was successfully treated with rTMS. Further work is required to better characterize the safety, tolerability and effectiveness of rTMS to treat comorbid MDD in HD

Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder Comorbid with Huntington&rsquo;s Disease: A Case Report

Huntington&rsquo;s disease (HD) is a rare genetic disorder resulting in progressive neurodegeneration leading to motor, cognitive and psychiatric symptoms. A high percentage of HD patients suffer from comorbid major depressive disorder (MDD). We are not aware of any literature on the use of repetitive transcranial magnetic stimulation (rTMS) for treating comorbid MDD in HD. We present the case of a 57-year-old man suffering from HD in which comorbid MDD was successfully treated with rTMS. Further work is required to better characterize the safety, tolerability and effectiveness of rTMS to treat comorbid MDD in HD

Circadian variation of plasma melatonin during the follicular phase in PMDD women and an expanded group of controls.^†

<p>* indicates significant differences between controls and PMDD women (P<.05). Data are double-plotted for illustration purposes. Values are mean ± SEM. ^† This figure presents FP data from the 5 control participants and 5 PMDD participants included in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051929#pone-0051929-g001" target="_blank">Figure 1</a>, but the control group is supplemented by data from 3 other young healthy women who were studied under constant conditions in unrelated experiments. This larger group of 8 controls was compared to the 5 PMDD women of the current study during the FP in an attempt to increase sample size and further confirm results from our baseline group comparisons.</p

Circadian variation of plasma melatonin during the follicular and luteal phases in PMDD women and controls.

<p>* indicates significant differences between controls and PMDD women (P<.05). Data are double-plotted for illustration purposes. Values are mean ± SEM.</p

Circadian melatonin profile in controls and PMDD women.

<p>PMDD: premenstrual dysphoric disorder; FP: follicular phase; LP: luteal phase; DLMOn, dim light melatonin onset; DLMOff, dim light melatonin offset; AUC, area under the curve.</p><p>Values are mean ± SEM.</p>a<p>indicates different than controls at the level of P = .05 when LP values compared.</p>b<p>indicates different than PMDD FP at level of P = .03.</p