People with autism spectrum disorder (ASD) commonly experience other comorbidities. Studies indicate that between 50% and 83% of individuals with ASD have sleep problems or disorders. The most ...commonly reported sleep problems are: (a) insomnia symptoms including the inability to get to sleep or stay asleep; and (b) circadian rhythm sleep-wake disorders, defined as a misalignment between the timing of endogenous circadian rhythms and the external environment. The circadian system provides timing information for the sleep-wake cycle that is regulated by the interaction of an endogenous processes (circadian - Process C, and homeostatic - Process S) and synchronizing agents (neurohormones and neurotransmitters), which produce somnogenic activity. A clinical priority in ASD is understanding the cause of these sleep problems in order to improve treatment outcomes. This review approaches sleep in autism from several perspectives: Sleep-wake mechanisms and problems, and brain areas and molecules controlling sleep (e.g., GABA and melatonin) and wake maintenance (e.g., serotonin, acetylcholine and glutamate). Specifically, this review examines how altered sleep structure could be related to neurobiological alterations or genetic mutations and the implications this may have for potential pharmacological treatments in individuals with ASD.
Introduction Compared to the conventional approach to orthognathic surgery, “surgery first” protocols could be advantageous in terms of shortened treatment times and immediate esthetic improvement. ...However, consensus regarding patient selection, technical protocol, and stability is still lacking. Methods A systematic review of the scientific literature on surgery-first treatment (January 2000 to January 2015) was performed. The PubMED and Cochrane Library databases were accessed. Patient selection criteria, specific surgical-orthodontic protocol, treatment duration, patient and orthodontist satisfaction, and stability of results were compared with a similar population treated conventionally. Results The search yielded 179 publications. The application of strict selection criteria gave the final group of 11 articles. In total, 295 patients were managed with a surgery-first approach. A Class III malocclusion was the most prevalent underlying malocclusion (84.7%). Total treatment duration was shorter in surgery-first patients than in those treated conventionally. There was substantial heterogeneity among articles and high reporting bias regarding the inclusion and exclusion criteria, the orthodontic and surgical protocols, and the stability of results. A meta-analysis of combined data was not possible. Conclusions The surgery-first approach is a new treatment paradigm for the management of dentomaxillofacial deformity. Studies have reported satisfactory outcomes and high acceptance. However, the results should be interpreted with caution because of the wide varieties of study designs and outcome variables, reporting biases, and lack of prospective long-term follow-ups.
Purpose In some patients, “surgery first” (SF) may represent a reasonable approach for the expedited correction of a maxillofacial deformity. Based on the prospective evaluation of a large sample, ...this article provides a specific orthodontic and surgical protocol, discusses the benefits and limitations of this approach, and updates its indications. Materials and Methods Forty-five patients were managed with an SF approach. Selected cases presented symmetrical skeletal malocclusions with no need for extractions or surgically assisted rapid palatal expansion. Periodontal or temporomandibular joint problems and management by an orthodontist without experience in orthognathic surgery were considered exclusion criteria. Virtual treatment planning included a 3-dimensional orthodontic setup. Standard orthognathic osteotomies were followed by buccal interdental corticotomies to amplify the regional acceleratory phenomenon. Miniscrews were placed for postoperative skeletal stabilization. Orthodontic treatment began 2 weeks after surgery. Archwires were changed every 2 to 3 weeks. At 12-month follow-up, patient satisfaction and orthodontist satisfaction were evaluated on a visual analog scale of 1 to 10. Descriptive statistics were computed for all study variables. Results The studied sample consisted of 27 women and 18 men (mean age, 23.5 yr). The main motivation for treatment was the wish to improve facial esthetics. Bimaxillary surgery was the most common procedure. Mean duration of orthodontic treatment was 37.8 weeks, with an average of 22 orthodontic appointments. Mean patient and orthodontist satisfaction scores were 9.4 (range, 8 to 10) and 9.7 (range, 8 to 10), respectively. Conclusions The SF approach significantly shortens total treatment time and is very favorably valued by patients and orthodontists. Nevertheless, careful patient selection, precise treatment planning, and fluent bidirectional feedback between the surgeon and the orthodontist are mandatory.
Summary
Sperm DNA fragmentation (SDF) is becoming an important test to assess male infertility. Several different tests are available, but no consensus has yet been reached as to which tests are most ...predictive of infertility. Few publications have reported a comprehensive analysis comparing these methods within the same population. The objective of this study was to analyze the differences between the five most common methodologies, to study their correlations and to establish their cut‐off values, sensitivity and specificity in predicting male infertility. We found differences in SDF between fertile donors and infertile patients in TUNEL, SCSA, SCD and alkaline Comet assays, but none with the neutral Comet assay. The alkaline COMET assay was the best in predicting male infertility followed by TUNEL, SCD and SCSA, whereas the neutral COMET assay had no predictive power. For our patient population, threshold values for infertility were 20.05% for TUNEL assay, 18.90% for SCSA, 22.75% for the SCD test, 45.37% for alkaline Comet and 34.37% for neutral Comet. This work establishes in a comprehensive study that the all techniques except neutral Comet are useful to distinguish fertile and infertile men.
Summary
The primary aim of this study was to determine the effect of oral antioxidant treatment (1500 mg of l‐Carnitine; 60 mg of vitamin C; 20 mg of coenzyme Q10; 10 mg of vitamin E; 10 mg of zinc; ...200 μg of vitamin B9; 50 μg of selenium; 1 μg of vitamin B12) during a time period of 3 months upon the dynamics of sperm DNA fragmentation following varying periods of sperm storage (0 h, 2 h, 6 h, 8 h and 24 h) at 37 °C in a cohort of 20 infertile patients diagnosed with asthenoteratozoospermia. A secondary objective was to use the sperm chromatin dispersion test (SCD) to study antioxidant effects upon a specific subpopulation of highly DNA degraded sperm (DDS). Semen parameters and pregnancy rate (PR) were also determined. Results showed a significant improvement of DNA integrity at all incubation points (P < 0.01). The proportion of DDS was also significantly reduced (P < 0.05). Semen analysis data showed a significant increase in concentration, motility, vitality and morphology parameters. Our results suggest that antioxidant treatment improves sperm quality not only in terms of key seminal parameters and basal DNA damage, but also helps to maintain DNA integrity. Prior administration of antioxidants could therefore promote better outcomes following assisted reproductive techniques.
Summary
Several studies have associated telomere shortening with alterations in reproductive function. The objective of the present study was to determine telomere length (TL) in spermatozoa selected ...by either density‐gradient centrifugation (DGC) or swim‐up. The analysis of TL was performed using quantitative fluorescent in situ hybridisation (qFISH) using PNA probes in combination with a chromatin decompaction protocol in sperm cells. Results of TL were 24.64 ± 5.00 Kb and 24.95 ± 4.60 Kb before and after DGC, respectively, and 19.59 ± 8.02 Kb and 20.22 ± 5.18 Kb before and after swim‐up respectively. Sperm selected by DGC or swim‐up did not show any significant differences in TL as compared to nonselected sperm (p > .05). Negative correlations between TL and sperm motility (r = −.308; p = .049) and concentration (r = −.353; p = .028) were found. Furthermore, exposure of sperm to increasing concentrations of hydrogen peroxide during incubation resulted in a reduction in TL. These data indicate that oxidative stress may be one of the main factors involved in the reduction of TL in sperm. Preliminary clinical results from patients included in this study indicate that TL was shorter in spermatozoa from couples who never achieved a pregnancy compared to couples who did achieve at least one natural pregnancy (p < .05); however, the clinical utility of this biomarker still needs to be confirmed in further studies.
If Dark Matter is made of Weakly Interacting Massive Particles (WIMPs) with masses below
∼
20
GeV, the corresponding nuclear recoils in mainstream WIMP experiments are of energies too close, or ...below, the experimental threshold. Gas Time Projection Chambers (TPCs) can be operated with a variety of target elements, offer good tracking capabilities and, on account of the amplification in gas, very low thresholds are achievable. Recent advances in electronics and in novel radiopure TPC readouts, especially micro-mesh gas structure (Micromegas), are improving the scalability and low-background prospects of gaseous TPCs. Here we present TREX-DM, a prototype to test the concept of a Micromegas-based TPC to search for low-mass WIMPs. The detector is designed to host an active mass of
∼
0.300
kg of Ar at 10 bar, or alternatively
∼
0.160
kg of Ne at 10 bar, with an energy threshold below 0.4 keVee, and is fully built with radiopure materials. We will describe the detector in detail, the results from the commissioning phase on surface, as well as a preliminary background model. The anticipated sensitivity of this technique may go beyond current experimental limits for WIMPs of masses of 2–8 GeV.
Sperm DNA fragmentation can be produced in one (ssSDF) or both (dsSDF) DNA strands, linked to difficulties in naturally achieving a pregnancy and recurrent miscarriages, respectively. The techniques ...more frequently used to select sperm require centrifugation, which may induce sperm DNA fragmentation (SDF). The objective of this study was to assess whether the microfluidic-based device FertileChip® (now ZyMot®ICSI) can diminish the proportion of sperm with dsSDF. First, in a blinded split pilot study, the semen of nine patients diagnosed with ≥60% dsSDF, was divided into three aliquots: not processed, processed with FertileChip®, and processed with swim up. The three aliquots were all analyzed using neutral COMET for the detection of dsSDF, resulting in a reduction of 46% (P < 0.001) with FertileChip® (dsSDF: 34.9%) compared with the ejaculate and the swim up (dsSDF: 65%). Thereafter, the FertileChip® was introduced into clinical practice and a cohort of 163 consecutive ICSI cycles of patients diagnosed with ≥60% dsSDF was analyzed. Fertilization rate was 75.41%. Pregnancy rates after the first embryo transfer were 53.2% (biochemical), 37.8% (clinical), 34% (ongoing) and the live birth rate was 28.8%. Cumulative pregnancy rates after one (65.4% of patients), two (27.6% of patients) or three (6.4% of patients) transfers were 66% (biochemical), 56.4% (clinical), 53.4% (ongoing) and the live birth rate was 42%. The selection of spermatozoa using Fertile Chip® significantly diminishes the percentage of dsSDF, compared with either the fresh ejaculate or after swim up. Its applicability in ICSI cycles of patients with high dsSDF resulted in good laboratory and clinical outcomes.
Several opioids have pharmacogenetic and drug-drug interactions which may compromise their analgesic effectiveness, but are not routinely implemented into supportive pain management. We hypothesized ...that CYP2D6 phenotypes and concomitant use of CYP2D6 substrates or inhibitors would correlate with opioid analgesic outcomes.
An observational cross-sectional study was conducted with 263 adult chronic non cancer pain (CNCP) patients from a real-world pain unit under long-term CYP2D6-related opioid treatment (tramadol, hydromorphone, tapentadol or oxycodone). Metabolizer phenotype (ultrarapid UM, normal NM, intermediate IM or poor PM) was determined by the CYP2D6 genotype. The socio-demographic (sex, age, employment status), clinical (pain intensity and relief, neuropathic component, quality of life, disability, anxiety and depression), pharmacological (opioid doses and concomitant pharmacotherapy) and safety (adverse events) variables were recorded.
The whole population (66 % female, 65 (14) years old, 70 % retired and 63 % attended for low back pain) were classified as PM (5 %), IM (32 %), NM (56 %) and UM (6 %). Multiple linear and logistic regressions showed higher pain intensity and neuropathic component at younger ages when using any CYP2D6 substrate (p = 0.022) or inhibitor (p = 0.030) drug, respectively, with poorer pain relief when CYP2D6 inhibitors (p=0.030) were present.
The concomitant use of CYP2D6 substrates or inhibitors during opioid therapy for CNCP may result in lack of analgesic effectiveness. This aspect could be relevant for pharmacological decision making during CNCP management.
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•Concomitant use of opioids and CYP2D6 drugs compromise the analgesic effectiveness.•Younger chronic pain patients using concomitant CYP2D6 drugs have worse pain relief.•Extreme CYP2D6 metabolizers under analgesia show disability, depression and anxiety.
Background
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most abused recreational drugs. Its usual pattern of misuse includes repeated doses taken over a short time period that ...could influence MDMA pharmacology and toxicity.
Objective
This study aims to evaluate the pharmacokinetics and pharmacologically induced effects of two MDMA consecutive doses separated by 2 h.
Methods
A randomized, double-blind, crossover, and placebo-controlled trial included ten male volunteers participating in two experimental sessions. MDMA was administered as a single 100-mg dose or as a repeated dose (50 mg followed by 100 mg, administered at 2 h apart). Outcome variables included pharmacokinetics, physiological, subjective, and psychomotor effects.
Results
Following the repeated doses, plasma concentrations of MDMA were higher than those expected by simple dose accumulation (+16.2 % AUC; +12.8 %
C
max
), but those of HMMA and HMA were significantly lower (−29.8 % AUC; −38.2 %
C
max
). After the second dose, physiological effects, psychomotor performance, and subjective effects were lower than expected especially for euphoria and stimulation. MDMA-induced increases in diastolic and systolic arterial pressure and body temperature were in the range of those expected following MDMA concentrations.
Conclusions
MDMA pharmacokinetics and metabolic disposition following two doses separated by 2 h show that the contribution of the first dose to the MDMA-induced mechanism-based metabolic inhibition was already apparent. The concentrations of MDMA after the second dose were slightly higher than expected. The effects on blood pressure and temperature after the second administration were slightly higher than those following the first, but for heart rate and subjective variables these were lower than expected considering the MDMA concentrations achieved, suggesting a possible tolerance phenomenon.
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