Structural Brain Correlates of Sleep Microstructure in Spinocerebellar Ataxia Type 2 and its Role on Clinical Phenotype.

The influence of brain atrophy on sleep microstructure in Spinocerebellar Ataxias (SCAs) has not been extensively explored limiting the use of these sleep traits as surrogate biomarkers of neurodegeneration and clinical phenotype. The objective of the study is to explore the relationship between sleep microstructure and brain atrophy in SCA2 and its role in the clinical phenotype. Fourteen SCA2 mutation carriers (7 pre-manifest and 7 manifest subjects) underwent polysomnographic, structural MRI, and clinical assessments. Particularly, markers of REM and non-REM sleep microstructure, measures of cerebellar and brainstem atrophy, and clinical scores were analyzed through correlation and mediation analyses. The sleep spindle activity exhibited a negative correlation with the number of trials required to complete the verbal memory test (VMT), and a positive correlation with the cerebellar volume, but the significance of the latter correlation did not survive multiple testing corrections. However, the causal mediation analyses unveiled that sleep spindle activity significantly mediates the association between cerebellar atrophy and VMT performance. Regarding REM sleep, both phasic EMG activity and REM sleep without atonia exhibited significant associations with pontine atrophy and disease severity measures. However, they did not demonstrate a causal mediation effect between the atrophy measures and disease severity. Our study provides evidence about the association of the pontocerebellar atrophy with sleep microstructure in SCA2 offering insights into the cerebellar involvement in cognition via the control of the sleep spindle activity. Therefore, our findings may help to understand the disease pathogenesis and to better characterize sleep microstructure parameters as disease biomarkers.Clinical trial registration number (TRN): No applicable.

Risperidone in analgesia induced by paracetamol and meloxicam in experimental pain.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the best therapeutic options to treat pain. Their use in combination with other drugs may broaden their applicability in analgesia if their ceiling and adverse effects are reduced. The aim of this study was to evaluate the pharmacological interaction of two NSAIDs, paracetamol and meloxicam, with the antipsychotic drug risperidone in mice, in several experimental tests of nociceptive and inflammatory pain. Antinociception was assessed by dose-response curves to paracetamol and meloxicam before and after the i.p. administration of 0.5 mg/kg of risperidone. Results are presented as means ± SEM and differences were calculated by one-way ANOVA followed by Tukey's post-test. Paracetamol and meloxicam produced a dose-related antinociceptive effect with diverse potencies. Risperidone increased the analgesia mediated by paracetamol and meloxicam only in the tonic tests that detected inflammatory pain. This suggests that COX inhibition is only a partial explanation of the increased analgesic potency of paracetamol and meloxicam since the effects of NSAIDs in the CNS are mediated by multiple mechanisms. These results indicate that the combination of risperidone with paracetamol or meloxicam could be a new and effective alternative for the management of inflammatory pain.

Electromyographic Patterns and the Identification of Subtypes of Awake Bruxism.

The future of awake bruxism assessment will incorporate physiological data, possibly electromyography (EMG) of the temporal muscles. But up to now, temporal muscle contraction patterns in awake bruxism have not been characterized to demonstrate clinical utility. The present study aimed to perform surface EMG evaluations of people assessed for awake bruxism to identify possible different subtypes. A 2-year active search for people with awake bruxism in three regions of the country resulted in a total of 303 participants (223 women, 38 ± 13 years, mean and SD). Their inclusion was confirmed through non-instrumental approaches for awake bruxism: self-reported questionnaire and clinical exam, performed by three experienced and calibrated dentists (Kappa = 0.75). Also, 77 age- and sex-matched healthy controls were recruited (49 women, 36 ± 14 years). Temporalis surface EMG was performed with a portable device (Myobox; NeuroUp, Brazil). EMG signals were sent to a computer via Bluetooth 4.0 at a sampling rate of 1,000 Hz. Digital signal processing was performed using the commercial neuroUP software, transformed in RMS and then normalized for peak detection (EMG peaks/min), in a 10 min session. Cluster analysis revealed three distinct subtypes of awake bruxism: phasic, tonic, and intermediate. Individuals with a predominance of EMG peaks/min were classified as the "phasic" subtype (16.8%). Those with the highest EMG rest power were classified as the "tonic" subtype (32.3%). There was also an "intermediate" subtype (50.8%), when both variables remained low. Characterization of awake bruxism physiology is important for future establishment of instrumental assessment protocols and treatment strategies.

Morphological and functional diversity of first-order somatosensory neurons.

First-order somatosensory neurons transduce and convey information about the external or internal environment of the body to the central nervous system. They are pseudo unipolar neurons with cell bodies residing in one of several ganglia located near the central nervous system, with the short branch of the axon connecting to the spinal cord or the brain stem and the long branch extending towards the peripheral organ they innervate. Besides their sensory transducer and conductive role, somatosensory neurons also have trophic functions in the tissue they innervate and participate in local reflexes in the periphery. The cell bodies of these neurons are remarkably diverse in terms of size, molecular constitution, and electrophysiological properties. These parameters have provided criteria for classification that have proved useful to establish and study their functions. In this review, we discuss ways to measure and classify populations of neurons based on their size and action potential firing pattern. We also discuss attempts to relate the different populations to specific sensory modalities.

Novel use of cranial epidural space in rabbits as an animal model to investigate bone volume augmentation potential of different bone graft substitutes.

BACKGROUND: The success of bone augmentation to a major degree depends on the biomechanics and biological conditions of the surrounding tissues. Therefore, an animal model is needed providing anatomical sites with similar mechanical pressures for comparing its influence on different biomaterials for bone regeneration. The present report describes the new bone formation associated to biomaterial in a bursa created in the epidural space, between dura mater and cranial calvaria, under the constant pressure of cerebrospinal fluid. METHODS: Five adult California rabbits were used for the trial. In each animal, two bursae were created in the epidural spaces, in the anterior part of the skull, below both sides of the interfrontal suture. The spaces between dura mater and cranial calvaria were filled with in-situ hardening biphasic calcium phosphate containing hydroxyapatite and beta tricalcium-phosphate (BCP), in-situ hardening phase-pure beta-tricalcium phosphate (ß-TCP) or without any biomaterials (sham). After 90 days, the animals were sacrificed, and the defect sites were extracted and processed for histomorphometric analysis by optical and backscattered electron microscopy. RESULTS: The cranial epidural spaces created (n = 10) could be preserved by the application both BCP (n = 3) and ß-TCP biomaterials (n = 3) in all experimental sites. The sites augmented with BCP showed less new bone formation but a trend to better volume preservation than the sites augmented with ß-TCP. However, the bone in the BCP sites seemed to be more mature as indicated by the higher percentage of lamellar bone in the sites. In contrast, the created space could not be preserved, and new bone formation was scarce in the sham-operated sites (n = 4). CONCLUSION: The experimental bursae created bilaterally in the epidural space allows comparing objectively bone formation in relation to biomaterials for bone regeneration under permanent physiological forces from cerebrospinal fluid pressure.

Enhancement of tonic and phasic GABAergic currents following nitric oxide synthase inhibition in hippocampal CA1 pyramidal neurons.

Nitric oxide (NO) is involved in synaptic plasticity in the hippocampus through different presynaptic and postsynaptic mechanisms that include the modulation of the GABAergic neurotransmission. Inhibitory synapses on hippocampal pyramidal neurons are known to possess the molecular machinery for retrograde NO-signaling, but the modulation of GABAARs function by NO in these neurons and the mechanisms of action involved have not been fully characterized. Here we show that suppression of the endogenous NO generation by the nitric oxide synthase (NOS) inhibitor L-NAME produces significant and reversible increases in the magnitude of both tonic and phasic GABAergic currents in CA1 hippocampal pyramidal neurons. GABA-evoked chloride currents were measured in the presence or absence of L-NAME using whole-cell patch-clamp recordings in acute hippocampal slices from young adult mice. Enhancement of the tonic GABA responses induced by L-NAME was insensitive to TTX and decreased by co-incubation with the NO donor DEA/NO. Applications of DEA/NO alone did not produce significant effects on tonic GABA responses. L-NAME treatment also increased the amplitude of phasic GABAergic currents evoked by GABA-puffs. Our results indicate that the extent of tonic and phasic inhibition mediated by GABAA receptors in CA1 hippocampal pyramidal neurons is affected by endogenous NO production.

A multicenter comparative trial of triphasic and monophasic, low-dose combined oral contraceptives.

A comparative multicenter clinical trial of two combined oral contraceptives (OCs) was conducted at clinics located in the Sudan, Sri Lanka, Chile, the Dominican Republic and Ecuador. The trial was designed to determine if there were differences in efficacy, safety and acceptability between a triphasic and a low-dose monophasic OC. This report includes analysis of 1088 women. At each center, subjects were randomly allocated to one of the two OCs. Follow-up visits were scheduled at 1, 4, 8 and 12 months after admission. There were two accidental pregnancies attributed to user failure reported during the study period; one in the triphasic group and one in the monophasic group. Adverse experiences were mainly minor with headaches and dizziness being the most common complaints; frequency of reports was similar in both groups. Cycle control was good in both groups with women in the triphasic group reporting fewer complaints of intermenstrual bleeding. Both OCs were safe and effective.

PIP: Researchers compared the efficacy, safety, and acceptability of a triphasic oral contraceptive (OC), Triquilar, with those of a monophasic OC, Lo-Femenal, among 1088 women attending clinics in Chile, the Dominican Republic, Ecuador, Sri Lanka, and the Sudan. Both OCs contained levonorgestrel and ethinyl estradiol. 90% of women in each group exhibited good user compliance. Only 1 unplanned pregnancy occurred in each group, and both pregnancies were attributed to user failure. The gross cumulative efficacy rates at 11 months were 0.3/100 woman-years for the triphasic OC and 0.2/100 woman-years for the monophasic OC. The continuation rate at 11 months was lower for Lo-Femenal than it was for Triquilar (80.8% vs. 84.6%), but the difference was not significant. The leading side-effect-related reason for discontinuation in both groups was headache. Another key reason for OC discontinuation in both groups was personal reasons, such as planning a pregnancy. Most women in both groups did not have menstrual complaints (78.8% for the Triquilar group and 77.1% for the Lo-Femenal group). Intermenstrual bleeding rates were low (7.6% for the Triquilar group and 9% for the Lo-Femenal group). Significant intercenter differences for women reporting intermenstrual bleeding and side effects (e.g., headaches) existed (p .05). Women from both groups at the clinic in the Sudan always had lower reports of intermenstrual bleeding than those at the other clinics. In fact, no woman discontinued OC use because of intermenstrual bleeding in the Sudan. Women in Sri Lanka reported fewer side effects than those in other countries, suggesting they could better tolerate OCs than the other women. This multicenter study's findings indicates that both Triquilar and Lo-Femenal are effective and safe. In addition, they exhibit good cycle control.

[Oral contraceptives and metabolic changes]. / Anticonceptivos orales y alteraciones metabólicas.

PIP: Sufficient evidence has accumulated to relate oral contraceptives (OCs) to various cardiovascular diseases in which metabolic alterations play a role. Although epidemiological studies have shown OC users to be at greater risk of venous thrombosis than nonusers, blood coagulation studies of OC users have yielded conflicting results due to variations in the methodologies used, the factors studied, the different formulations and doses of OCs, and the duration of use. Moreover, no satisfactory method exists of measuring coagulability in its totality, which is the sum of the effects of individual variations in coagulation factors, fibrinolysis, and platelet function. Numerous studies have shown that OC users have increased levels of several coagulation factors, which are believed to indicate hypercoagulability and increased risk of thrombosis, but the pathogenesis of venous thrombosis is complex. Accompanying changes in the fibrinolytic system can be interpreted as attempts to equilibrate the hypercoagulability induced by OCs. Further, there is no proof that in vitro changes are related to thrombosis in vivo. The alterations appear to be dose-related, produced primarily by estrogens, unrelated to duration of use, and to disappear a few months after termination of OC use. OC users have been shown repeatedly to have elevated levels of glucose and insulin, which are especially pronounced in glucose tolerance tests. The changes vary in intensity according to the dose and progestational components and the existence of other risk factors for diabetes. Deterioration of glucose tolerance appears related to duration of OC use, but serum insulin levels maintain the same initial elevations. The estrogens have been shown to have few effects on carbohydrate metabolism in the lower doses currently used. Norgestrel has the most marked effects on glucose and insulin levels, ethynodiol diacetate has moderate effects, and norethindrone has the least effect. The combination of .15 mg levonorgestrel and 30 mcg ethinyl estradiol has no effect on oral glucose tolerance and little effect on insulin secretion. It is hypothesized that OCs affect carbohydrate metabolism by decreasing the number and affinity of insulin receptors in target tissues. The mechanisms by which OCs produce undesirable effects on the cardiovascular system are not completely understood, but are believed to be related to alterations in lipid metabolism. The majority of laboratory studies have shown that OC users had elevated levels of cholesterol, triglycerides, and the (LDL) fractions, and a diminution of the high density lipoprotein (HDL) fraction, which has antiatherogenic properties. The changes are atherogenic in nature and produce a lipid profile similar to that of men and postmenopausal women, who are at greater risk of thrombotic cardiovascular disease that premenopausal women who are protected by estrogens. .^ieng

[Clinico-pathological study of the effects of contraceptive treatment with mestranol-lynestrol by a sequential type method]. / Estudio clínico-patologico de los effectos de la terapia contraceptiva con mestranol-linestrol en una modalidad del tipo secuencial.

PIP: 100 healthy fertile women, with active sexual lives and of reproductive age, were treated during 10 cycles in 1 year with mestranol-lynestrenol of the sequential type, for the purpose of determining the effectiveness of the drug as a contraceptive and study its effects on endometrial morphology, endocervical mucus, cervicovaginal cytology and urinary excretion of pregnanediol. The changes in the menstrual cycle and side effects were observed. The results obtained clearly show that the combination of mestranol-lynestrenol is an effective contraceptive (no pregnancy occurred), safe and well tolerated, with minimal side effects.^ieng

Urinary pregnanediol during the use of different contraceptive methods.

PIP: The behavior or urinary pregnanediol in 5 groups of 172 healthy females using different hormnal oral contraceptives (OCs) and 1 group using IUDs is compared with 1 untreated control group having normal biph asic cycles. In all cases 24 hour urine samples were obtained in the follicular (phase 1) and luteal (phase 2) phases of the cycle using the thin-layer Sulli movici chromatographic method. In the control group the phase 1 mean was .91 mg/ 24 hours (h) and the phase 2 mean was 2.63 mg/24h. There were no variations in the values of phase 1 among all the contraceptive groups while in the IUD group the mean of phase 2 was significantly lower than in the control group. Among combination OCs there were no differences between phases 1 and 2; all cases measured below 1.5mg/24h in phase 2. However, estrogen-free progestogen drugs showed elevated pregnanediol values in phase 2. Although an incidence of low pregnanediol values was exhibited among all contraceptive groups, those low values are constant only in the combined and sequential OCs. In progestogen-only drugs high pregnanediol values compatible with ovulation occurred in the luteal phase at an inversely proportional rate to the dose of the drug. Further studies should be undertaken to establish the correlation of these data with the effects of these compounds on ovarian function.^ieng

[Changes in carbohydrate metabolism during the administration of progestational hormones]. / Modificaciones del metabolismo de los hidratos de carbono durante la administración de progestágenos.

PIP: Changes in the levels of plasma glucose and serum insulin and growth hormone after oral and iv administration of glucose and infusion of arginine in a group of 35 carefully selected normal women were studied. The tests were performed before and during the administration of progestins of the sequential and combination type (Oracon and Ovulen, respectively), during the 2nd or 3rd cycle of treatment. The results showed that both types of treatment produced a significant increase in the serum insulin and growth hormone levels, while the plasma glucose level remained unaltered in the various tests. It would appear that these drugs produce an increase in peripheral resistance to insulin, since the insulin-glucose index rose in the growth hormone level, may also be due to an antiinsulin action and/or to changes in the production of insulin directly caused by the drugs.^ieng

[Effects of different contraceptives upon the ovulation changes of the morphological study of the ovaries].

PIP: Bilateral ovarian wedges were performed on 46 patients scheduled for laparotomies for medical reasons. Prior to the operation, the patients were divided into 5 groups and treated as follows: 1 for control (5 patients); 1 that was given 1 of 3 different combined oral contraceptives, i.e., Anovlar, Gynovlar, or Engynon (22 patients); 1 that was given Sequens (3 patients); 1 that was injected with 200 mg of norethindrone enanthate (14 cases); and 1 given IUDs (2 cases). It was established that all experienced ovulatory cycles prior to therapy. The laparotomies were done between the 22nd-28th day of the menstrual cycle; hormonal therapy was begun between the 3rd-6th day. All but 1 of the group on combined preparations had anovulatory cycles. Detained follicles Grade 3 or 4 with precocious cystic atresic involution were observed. Of the 3 on the sequential preparation, 2 had involuted cystic corpora lutea and 1 had atresic follicles with thecal luteinization. The patients who received the injectable ovulated. There were no morphological or substantial changes in the corpora lutea of the control and IUD groups.^ieng