The impact of 3,4-methylendioxymetamphetamine (MDMA) abstinence on seeking behavior and the expression of the D2-like and mGlu5 receptors in the rat brain using saturation binding analyses.

The abundance of research indicates that enriched environment acts as a beneficial factor reducing the risks of relapse in substance use disorder. There is also strong evidence showing the engagement of brain dopaminergic and glutamatergic signaling through the dopamine D2-like and metabotropic glutamate type 5 (mGlu5) receptors, respectively, that has a direct impact on drug reward and drug abstinence. The present study involved 3,4-methylendioxymethamphetamine (MDMA) self-administration with the yoked-triad procedure in rats kept under different housing conditions during abstinence - enriched environment (EE) or isolation cage (IC) conditions - aimed at evaluating changes in brain receptors affecting drug-seeking behavior as well as density and affinity of the D2-like and mGlu5 receptors in several regions of the animal brain. Our results show that exposure to EE conditions strongly reduced active lever presses during cue-induced drug-seeking. At the neurochemical level, we demonstrated marked decreases of D2-like receptor affinity in the dorsal striatum in rats previously self-administering MDMA under EE and increases in density under IC conditions. Moreover, we found the increases in the density and decreases in the affinity of the D2-like receptor in the prefrontal cortex and nucleus accumbens provoked by IC conditions. The mGlu5 receptor density decreased only in the prefrontal cortex after IC and EE abstinence. Moreover, our study has revealed a clear decrease in mGlu5 receptor density in the nucleus accumbens in the group actively administering MDMA only under EE conditions. This study demonstrates that housing conditions have impact on drug-seeking behavior in rats during abstinence from MDMA self-administration. The observed changes in the dopamine D2-like and mGlu5 receptor Bmax and/or Kd values were brain-region specific and related to either pharmacological and/or motivational features of MDMA.

Real-world longitudinal data collected from the SleepHealth mobile app study.

Conducting biomedical research using smartphones is a novel approach to studying health and disease that is only beginning to be meaningfully explored. Gathering large-scale, real-world data to track disease manifestation and long-term trajectory in this manner is quite practical and largely untapped. Researchers can assess large study cohorts using surveys and sensor-based activities that can be interspersed with participants' daily routines. In addition, this approach offers a medium for researchers to collect contextual and environmental data via device-based sensors, data aggregator frameworks, and connected wearable devices. The main aim of the SleepHealth Mobile App Study (SHMAS) was to gain a better understanding of the relationship between sleep habits and daytime functioning utilizing a novel digital health approach. Secondary goals included assessing the feasibility of a fully-remote approach to obtaining clinical characteristics of participants, evaluating data validity, and examining user retention patterns and data-sharing preferences. Here, we provide a description of data collected from 7,250 participants living in the United States who chose to share their data broadly with the study team and qualified researchers worldwide.

Synthetic cannabinoid JWH-018 and its halogenated derivatives JWH-018-Cl and JWH-018-Br impair Novel Object Recognition in mice: Behavioral, electrophysiological and neurochemical evidence.

It is well known that an impairment of learning and memory function is one of the major physiological effects caused by natural or synthetic cannabinoid consumption in rodents, nonhuman primates and in humans. JWH-018 and its halogenated derivatives (JWH-018-Cl and JWH-018-Br) are synthetic CB1/CB2 cannabinoid agonists, illegally marketed as "Spice" and "herbal blend" for their Cannabis-like psychoactive effects. In the present study the effects of acute exposure to JWH-018, JWH-018-Cl, JWH-018-Br (JWH-018-R compounds) and Δ(9)-THC (for comparison) on Novel Object Recognition test (NOR) has been investigated in mice. Moreover, to better characterize the effects of JWH-018-R compounds on memory function, in vitro electrophysiological and neurochemical studies in hippocampal preparations have been performed. JWH-018, JWH-018-Cl and JWH-018-Br dose-dependently impaired both short- and long-memory retention in mice (respectively 2 and 24 h after training session). Their effects resulted more potent respect to that evoked by Δ(9)-THC. Moreover, in vitro studies showed as JWH-018-R compounds negatively affected electrically evoked synaptic transmission, LTP and aminoacid (glutamate and GABA) release in hippocampal slices. Behavioral, electrophysiological and neurochemical effects were fully prevented by CB1 receptor antagonist AM251 pretreatment, suggesting a CB1 receptor involvement. These data support the hypothesis that synthetic JWH-018-R compounds, as Δ(9)-THC, impair cognitive function in mice by interfering with hippocampal synaptic transmission and memory mechanisms. This data outline the danger that the use and/or abuse of these synthetic cannabinoids may represent for the cognitive process in human consumer.

CDKL5 knockout leads to altered inhibitory transmission in the cerebellum of adult mice.

Mutations in the X-linked cyclin-dependent kinase-like 5 gene (CDKL5) are associated to severe neurodevelopmental alterations including motor symptoms. In order to elucidate the neurobiological substrate of motor symptoms in CDKL5 syndrome, we investigated the motor function, GABA and glutamate pathways in the cerebellum of CDKL5 knockout female mice. Behavioural data indicate that CDKL5-KO mice displayed impaired motor coordination on the Rotarod test, and altered steps, as measured by the gait analysis using the CatWalk test. A higher reduction in spontaneous GABA efflux, than that in glutamate, was observed in CDKL5-KO mouse cerebellar synaptosomes, leading to a significant increase of spontaneous glutamate/GABA efflux ratio in these animals. On the contrary, there were no differences between groups in K(+) -evoked GABA and glutamate efflux. The anatomical analysis of cerebellar excitatory and inhibitory pathways showed a selective defect of the GABA-related marker GAD67 in the molecular layer in CDKL5-KO mice, while the glutamatergic marker VGLUT1 was unchanged in the same area. Fine cerebellar structural abnormalities such as a reduction of the inhibitory basket 'net' estimated volume and an increase of the pinceau estimated volume were also observed in CDKL5-KO mice. Finally, the BDNF mRNA expression level in the cerebellum, but not in the hippocampus, was reduced compared with WT animals. These data suggest that CDKL5 deletion during development more markedly impairs the establishment of a correct GABAergic cerebellar network than that of glutamatergic one, leading to the behavioural symptoms associated with CDKL5 mutation.

The new compound GET73, N-[(4-trifluoromethyl)benzyl]4-methoxybutyramide, Regulates hippocampal Aminoacidergic transmission possibly via an allosteric modulation of mGlu5 receptor. Behavioural evidence of its "anti-alcohol" and anxiolytic properties.

The present article attempts to provide, on the basis of data emerging from studies carried out in our laboratories, a summary of the chemical and pharmacological properties of the new compound N-[(4-trifluoromethyl)benzyl]4- methoxybutyramide (GET73). Particular emphasis is given to findings obtained in vivo and in vitro suggesting that an allosteric modulation of metabotropic glutamate receptor 5 (mGlu5 receptor) by GET73 may represent the mechanism underlying the effects of the compound produced on rat hippocampal glutamate and GABA transmission. Furthermore, behavioural findings demonstrating how this new compound reduces alcohol intake, displays anxiolytic properties, and influences spatial memory in rats are also summarized. Since mGlu5 receptors play an important role in regulating several central actions of drugs of abuse, and the hippocampus is a crucial brain area involved in addiction, anxiety, and spatial memory, a possible link between mGlu5 receptor allosteric modulation and the profiles of action of GET73 is proposed, although to date no studies have yet explored GET73 binding at the mGlu5 receptor orthosteric and/or allosteric sites. Following a brief overview of glutamatergic neurotransmission, mGlu receptor structures and activation mechanisms, the general properties of mGlu5 receptor and its allosteric modulators are described in the first part of the review.

Técnicas radiográficas intra e extrabucal na avaliação dentária de cães com doença periodontal / Comparison between intra e extraoral radiologic procedures on dental evaluation of dogs with periodontal disease

Foram avaliadas as técnicas radiográficas dentárias intra (TIB) e extrabucal (TEB) em 50 cães com doença periodontal, no intuito de padronizar os procedimentos de diagnóstico dessa síndrome. A TIB revelou que 16 animais não apresentaram lesões ósseas visíveis, enquanto a TEB apontou que 39 pacientes foram negativos para as mesmas lesões. Em resumo, a TIB foi mais eficaz na detecção de sinais radiográficos, especialmente as chamadas lesões finas, que a TEB, sendo a técnica de escolha na síndrome periodontal.

The intra (IOT) and extraoral (EOT) dental radiographic techniques in 50 dogs with periodontal disease were compared to standardize the most appropriate procedure for accurate diagnosis of abnormalities that occur in this syndrome. For IOT, 16 animals showed no visible radiographic lesions, whereas in EOT, 39 patients were negative for the same radiographic lesions. For incisor and canine teeth, IOT presented the highest sensitivity of lesion detection, while there was no significant difference for the premolar and molar teeth group. It is concluded that IOT is more effective in detecting radiographic signs (especially the so-called thin lesions) than the EOT and should therefore be the technique of choice in the periodontal syndrome.

Improvement of adynamic bone disease after renal transplantation.

Low bone remodeling and relatively low serum parathyroid hormone (PTH) levels characterize adynamic bone disease (ABD). The impact of renal transplantation (RT) on the course of ABD is unknown. We studied prospectively 13 patients with biopsy-proven ABD after RT. Bone histomorphometry and bone mineral density (BMD) measurements were performed in the 1st and 12th months after RT. Serum PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and osteocalcin were measured regularly throughout the study. Serum PTH levels were slightly elevated at transplantation, normalized at the end of the third month and remained stable thereafter. Bone biopsies performed in the first month after RT revealed low bone turnover in all patients, with positive bone aluminum staining in 5. In the 12th month, second biopsies were performed on 12 patients. Bone histomorphometric dynamic parameters improved in 9 and were completely normalized in 6, whereas no bone mineralization was detected in 3 of these 12 patients. At 12 months post-RT, no bone aluminum was detected in any patient. We also found a decrease in lumbar BMD and an increase in femoral BMD. Patients suffering from ABD, even those with a reduction in PTH levels, may present partial or complete recovery of bone turnover after successful renal transplantation. However, it is not possible to positively identify the mechanisms responsible for the improvement. Identifying these mechanisms should lead to a better understanding of the physiopathology of ABD and to the development of more effective treatments.

Improvement of adynamic bone disease after renal transplantation

Low bone remodeling and relatively low serum parathyroid hormone (PTH) levels characterize adynamic bone disease (ABD). The impact of renal transplantation (RT) on the course of ABD is unknown. We studied prospectively 13 patients with biopsy-proven ABD after RT. Bone histomorphometry and bone mineral density (BMD) measurements were performed in the 1st and 12th months after RT. Serum PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and osteocalcin were measured regularly throughout the study. Serum PTH levels were slightly elevated at transplantation, normalized at the end of the third month and remained stable thereafter. Bone biopsies performed in the first month after RT revealed low bone turnover in all patients, with positive bone aluminum staining in 5. In the 12th month, second biopsies were performed on 12 patients. Bone histomorphometric dynamic parameters improved in 9 and were completely normalized in 6, whereas no bone mineralization was detected in 3 of these 12 patients. At 12 months post-RT, no bone aluminum was detected in any patient. We also found a decrease in lumbar BMD and an increase in femoral BMD. Patients suffering from ABD, even those with a reduction in PTH levels, may present partial or complete recovery of bone turnover after successful renal transplantation. However, it is not possible to positively identify the mechanisms responsible for the improvement. Identifying these mechanisms should lead to a better understanding of the physiopathology of ABD and to the development of more effective treatments.

Contribution of calcium and other dietary components to global variations in bone mineral density in young adults.

A research project on comparative international studies of osteoporosis using isotope techniques was organized by the International Atomic Energy Agency (IAEA) with the participation of 12 countries (Brazil, Canada, Chile, China, Croatia, Hungary, Philippines, Russia, Singapore, South Africa, Turkey, and the United Kingdom). Participating centers in 11 countries (all but the UK) made measurements and collected data on men and women aged 15 to 49 years. In addition to studies of bone mineral density (BMD) at the femoral neck and lumbar spine using DEXA, anthropometric, lifestyle, and nutritional data were also collected. The results of the nutritional studies are reviewed in this paper. Overall, about 8% of the observed variability in spine BMD could be attributed to nutritional factors in men and women; in men, no such relationship could be determined. No single nutritional component (not even calcium) stood out as being of particular importance across all participating centers.

Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window.

1. The efficacy of the free radical trapping agent NXY-059 in reducing the infarct volume following both transient and permanent focal ischaemia has been examined in rats. 2. In the transient ischaemia model, rats were subjected to a 2 h occlusion of the middle cerebral artery (MCA). Intravenous infusion of NXY-059 (1, 10 and 30 mg kg(-1) h) for 21.75 h starting 2.25 h after the occlusion, produced a dose-dependent decrease in both neurological impairment and the histologically measured infarct volume (a mean 59% decrease at 10 mg kg(-1) h). 3. In the permanent ischaemia model, animals were injected (s.c.) with a loading dose of NXY-059 of 32.5, 53.8 or 75.4 mg kg(-1) and osmotic minipumps were implanted which had been primed to deliver respectively 30, 50 or 70 mg kg(-1) h. When treatment was initiated 5 min after MCA occlusion there was a dose dependent protection of both cortical and sub-cortical tissue (cortex: 63% at the mid-range dose). Protection was related linearly to plasma concentration (plasma unbound NXY-059 concentration at 1 h: 37+/-16 micromol l(-1) at the mid-range dose). 4. When the mid range dose was administered between 5 min - 4 h after MCA occlusion, a marked and statistically significant protection was seen at all time points (44% protection in cortex at 4 h). 5. These data demonstrate the substantial neuroprotective efficacy of NXY-059 at plasma concentrations that can be achieved clinically and indicate that NXY-059 also has a therapeutic window of opportunity that is clinically relevant.

Influence of disease activity and chronicity on ankylosing spondylitis bone mass loss.

We investigated 30 consecutive Brazilian patients with definite ankylosing spondylitis (AS) fulfilling the New York and the European spondyloarthropathy study group classification criteria. The mean age at study was 37 years old and the mean disease duration was 17 years. Bone densitometry employed the dual-energy X-ray absorptiometry (DEXA) technique, using a Hologic QDR-1000/W densitometer. Axial bone mineral density (BMD) was measured in the lumbar spine (L1-L4) and appendicular BMD was measured in the total proximal femur and sub-regions (neck, greater trochanter, intertrochanter and Ward's triangle). Based on World Health Organisation criteria, the lumbar spine showed osteopenia or osteoporosis in 50% of the patients, while 86% had osteopenia or osteoporosis in the total proximal femur. When compared with the normal population, the patients showed a significant BMD decrease in the lumbar spine and total proximal femur with sub-regions, except for the femoral neck. A comparison of BMD between patients with active and inactive disease did not reveal a significant effect of clinical disease activity on the lumbar spine and total proximal femur with sub-regions, except for Ward's triangle. Concerning disease chronicity, there were significant positive correlations between disease duration and lumbar spine, total proximal femur, greater trochanter and intertrochanteric regional BMD. This false increase in lumbar spine BMD found mostly in patients with long standing AS was due to the presence of paravertebral calcification and ossification. We conclude that the bone mass loss in AS is better evaluated in the proximal femur, because of the greater sensitivity of bone densitometry in this region, which is almost free of artefacts.

Instrumental neutron activation analysis of rib bone samples and of bone reference materials.

The instrumental neutron activation analysis method was used for the determination of trace elements in rib bone samples taken from autopsies of accident victims. The elements Br, Ca, Cl, Cr, Fe, Mg, Mn, Na, P, Sr, Rb, and Zn were determined in cortical tissues by using short and long irradiations with thermal neutron flux of the IEA-R1m nuclear reactor. The reference materials NIST SRM 1400 Bone Ash and NIST SRM 1486 Bone Meal were also analyzed in order to evaluate the precision and the accuracy of the results. It was verified that lyophilization is the most convenient process for drying bone samples because it does not cause any element losses. Comparisons were made between the results obtained for rib samples and the literature values as well as between the results obtained for different ribs from a single individual and for bones from different individuals.

A novel nonsense mutation in the first zinc finger of the vitamin D receptor causing hereditary 1,25-dihydroxyvitamin D3-resistant rickets.

Hereditary 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-resistant rickets (HVDRR) is a rare autosomal recessive disorder resulting in target organ resistance to the active form of vitamin D [1,25-(OH)2D3]. Point mutations in the vitamin D receptor (VDR) gene have been identified in HVDRR. We investigated the molecular basis of HVDRR in a Brazilian family with two affected siblings. The propositus is a 12-yr-old boy born to first cousin parents who exhibited the classical pattern of the HVDRR, including early-onset rickets, total alopecia, convulsions, hypocalcemia, secondary hyperparathyroidism, and elevated 1,25-(OH)2D3 serum levels. His younger sister also developed clinical and biochemical features of HVDRR at 1 month of age and died at 4 yr of age. Genomic DNA was isolated from peripheral blood of the boy and from dried umbilical cord tissue of his affected sister. We amplified exons 2 and 3 of the VDR gene, which encode the zinc finger DNA-binding domain by PCR. Direct sequencing of the PCR products revealed a homozygous substitution of cytosine for thymine at nucleotide position 88 in exon 2 of the VDR gene in both affected siblings. This point mutation determined the substitution of a stop codon (TGA) for arginine (CGA) at amino acid position 30 at the first zinc finger of the DNA-binding domain of the VDR. This substitution generated a truncated receptor missing 397 residues. The parents and a normal sister were heterozygous for this mutation. In conclusion, we describe a novel nonsense mutation in the first zinc finger of the VDR that generated a severely truncated form of this receptor.

[Aging of the aorta: a morphological study]. / L'invecchiamento dell'aorta: studio morfologico.

Aim of this study was to evaluate the aging of aorta with respect to atherosclerotic modifications: abdominal aorta echotomography is the preferred approach for this study. In 354 elderly patients, 65 and over, we have evaluated the diameter and the course of the aorta, the presence of atherosclerotic plaques in the aorta and iliac vessels, and the presence of aneurysms. Two kinds of findings could be identified by echotomography: age-related physiologic modifications, represented essentially by an increase of the aortic diameter; pathologic changes, characteristic for atherosclerosis, of which aneurysms are the most dangerous complications.

Aluminium-related osteodystrophy and desferrioxamine treatment: role of phosphorus.

We investigated (1) the prevalence of aluminium overload among 96 patients with symptomatic bone disease haemodialysed from 1987 to 1989 in the Sao Paulo area, Brazil; (2) the effect of 6 months desferrioxamine (DFO) treatment (1-2g/week). All patients underwent a first bone biopsy. Aluminium overload (extent of stainable bone aluminium more than 20% trabecular surface) was observed in 74 of 96 patients. Forty overloaded patients were divided into patients with high bone formation rate (BFR) (group 1; n = 17) and patients with low BFR (group 2; n = 23), and had a second biopsy after DFO therapy. In both groups aluminium surface was reduced after treatment (P < 0.001), osteoblast surface (P < 0.02-P < 0.01) and plasma parathyroid hormone (iPTH) (P < 0.01) increased. In group 1 BFR remained high. In group 2 BFR remained low in 16 patients (2a) and increased in seven (P < 0.02) (2b). In group 2a plasma phosphorus was below that in group 2b patients, before (P < 0.03) and after (P < 0.01) DFO. The histological features of group 2a patients resembled hypophosphataemic osteomalacia, those of group 2b patients aluminium osteodystrophy. These data show a high prevalence of aluminium overload in Brazilian patients. Low-dose DFO therapy was safe, decreased bone pain, prevented fractures, and reduced stainable bone aluminium. Bone lesions only partially improved, suggesting that low phosphorus intake and/or plasma calcitriol concentrations may have prevented improvement of bone formation and mineralization.

Reversal of aluminum-related bone disease after renal transplantation.

We evaluated the course of severe aluminum-related bone disease (ARBD) after the first year of a successful renal transplantation (RTx) in 11 adult patients. Bone pain and muscle weakness, presented in all patients previously to RTx, subsided, and all were able to walk, even the ones who were confined to wheelchairs. Bone necrosis developed in 6 patients, but none required surgical repair. Serum alkaline phosphatase activity increased 2.5 times the upper normal level, up to the 5th month and then declined to normal levels up the 12th month (p < 0.05). The inverse profile was observed in both serum calcium and phosphorus levels. In bone biopsies, there was a significant decrease in all of the following histomorphometric static parameters: osteoid volume, thickness and surface and also in aluminum surface. Also, there was a significant increase in all the dynamic parameters of mineralization: mineral apposition rate, mineralization surface, bone formation rate and adjusted apposition rate. In conclusion, ARBD remarkably improves after 1 year of successful RTx.

Bone histomorphometry in Cushing's syndrome.

Bone involvement is a common finding in Cushing's syndrome. The actions of corticosteroids on bone have been studied quite intensively but only a few studies of bone histomorphometry in this syndrome have been published. In this paper we present histomorphometric measurements of bone activity in 7 patients with a postoperative reevaluation in two. The results show irregular alterations on histomorphometric parameters with an increased bone resorption and decreased bone formation rate. After surgery the abnormalities changed towards normal.

Effect of testosterone on bone mineralization of the hypophosphataemic rat.

Clinical observations in patients with X-linked hypophosphataemic rickets, that bone changes can be corrected during puberty, suggest that androgen can participate actively in the process of bone mineralization. In the present study we investigated the role of testosterone on the bone mineralization of male rats placed on a low phosphorus and vitamin D diet and kept in complete darkness after weaning. After 15 days the animals presented hypophosphataemia, rickets and osteomalacia, as assessed by histomorphometry of the tibia and seventh caudal vertebra calcification fronts respectively. Testosterone propionate administration for five days, while the animals were kept on the same rachitogenic diet, induced an improvement in the bone mineralization process of the hypophosphataemic rat independently of serum phosphate levels. Testosterone-treated rats were cured of rickets but not of osteomalacia, despite the reduction in osteoid seam area.