Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience.

Mental health disorders often arise as a combination of environmental and genetic factors. The FKBP5 gene, encoding the GR co-chaperone FKBP51, has been uncovered as a key genetic risk factor for stress-related illness. However, the exact cell type and region-specific mechanisms by which FKBP51 contributes to stress resilience or susceptibility processes remain to be unravelled. FKBP51 functionality is known to interact with the environmental risk factors age and sex, but so far data on behavioral, structural, and molecular consequences of these interactions are still largely unknown. Here we report the cell type- and sex-specific contribution of FKBP51 to stress susceptibility and resilience mechanisms under the high-risk environmental conditions of an older age, by using two conditional knockout models within glutamatergic (Fkbp5Nex) and GABAergic (Fkbp5Dlx) neurons of the forebrain. Specific manipulation of Fkbp51 in these two cell types led to opposing effects on behavior, brain structure and gene expression profiles in a highly sex-dependent fashion. The results emphasize the role of FKBP51 as a key player in stress-related illness and the need for more targeted and sex-specific treatment strategies.

Needle Therapy: A Minimally Invasive Therapeutic Concept as Part of Temporomandibular Single-Portal Arthroscopy.

The transition from a single portal to a double portal can be complex, necessitating time and training to minimize complications that rely on the operator's skill. Needle therapy is a simple method for treating symptoms that has several benefits. Consequently, this innovative strategy aims to introduce an intermediate technique that enables surgeons to perform therapeutic procedures during single-port arthroscopy.

Could titanium screws be an appropriate disc stabilization technique in temporomandibular joint arthroscopy?

Multiple techniques for disc fixation through temporomandibular joint arthroscopy have been described. They can be classified as non-rigid, semi-rigid, and rigid. They all offer different advantages and disadvantages, and some have greater difficulties than others. Currently, multiple modifications to the basic techniques have been described in order to facilitate the technique since disc fixation corresponds to one of the procedures that most require skill. However, each technique requires extensive evaluation and monitoring in order to avoid complications and find the benefits of each technique. For this reason, the objective of this letter to the editor is to discuss two situations observed in the previously described fixation technique with osteosynthesis screws. The first issue is the fixation mechanism, and the second is the fixation time. This is in order to continue searching for the truth among all to achieve the best results and the benefit of patients.

Long-Term Leisure-Time Physical Activity Intensity and All-Cause and Cause-Specific Mortality: A Prospective Cohort of US Adults.

BACKGROUND: The 2018 physical activity guidelines for Americans recommend a minimum of 150 to 300 min/wk of moderate physical activity (MPA), 75 to 150 min/wk of vigorous physical activity (VPA), or an equivalent combination of both. However, it remains unclear whether higher levels of long-term VPA and MPA are, independently and jointly, associated with lower mortality. METHODS: A total of 116 221 adults from 2 large prospective US cohorts (Nurses' Health Study and Health Professionals Follow-up Study, 1988-2018) were analyzed. Detailed self-reported leisure-time physical activity was assessed with a validated questionnaire, repeated up to 15 times during the follow-up. Cox regression was used to estimate the hazard ratio and 95% CI of the association between long-term leisure-time physical activity intensity and all-cause and cause-specific mortality. RESULTS: During 30 years of follow-up, we identified 47 596 deaths. In analyses mutually adjusted for MPA and VPA, hazard ratios comparing individuals meeting the long-term leisure-time VPA guideline (75-149 min/wk) versus no VPA were 0.81 (95% CI, 0.76-0.87) for all-cause mortality, 0.69 (95% CI, 0.60-0.78) for cardiovascular disease (CVD) mortality, and 0.85 (95% CI, 0.79-0.92) for non-CVD mortality. Meeting the long-term leisure-time MPA guideline (150-299 min/wk) was similarly associated with lower mortality: 19% to 25% lower risk of all-cause, CVD, and non-CVD mortality. Compared with those meeting the long-term leisure-time physical activity guidelines, participants who reported 2 to 4 times above the recommended minimum of long-term leisure-time VPA (150-299 min/wk) or MPA (300-599 min/wk) showed 2% to 4% and 3% to 13% lower mortality, respectively. Higher levels of either long-term leisure-time VPA (≥300 min/wk) or MPA (≥600 min/wk) did not clearly show further lower all-cause, CVD, and non-CVD mortality or harm. In joint analyses, for individuals who reported <300 min/wk of long-term leisure-time MPA, additional leisure-time VPA was associated with lower mortality; however, among those who reported ≥300 min/wk of long-term leisure-time MPA, additional leisure-time VPA did not appear to be associated with lower mortality beyond MPA. CONCLUSIONS: The nearly maximum association with lower mortality was achieved by performing ≈150 to 300 min/wk of long-term leisure-time VPA, 300 to 600 min/wk of long-term leisure-time MPA, or an equivalent combination of both.

Increasing resolution in stress neurobiology: from single cells to complex group behaviors.

Stress can have severe psychological and physiological consequences. Thus, inappropriate regulation of the stress response is linked to the etiology of mood and anxiety disorders. The generation and implementation of preclinical animal models represent valuable tools to explore and characterize the mechanisms underlying the pathophysiology of stress-related psychiatric disorders and the development of novel pharmacological strategies. In this commentary, we discuss the strengths and limitations of state-of-the-art molecular and computational advances employed in stress neurobiology research, with a focus on the ever-increasing spatiotemporal resolution in cell biology and behavioral science. Finally, we share our perspective on future directions in the fields of preclinical and human stress research.

Idiopathic Unilateral Intracranial Condylar Dislocation: A Case Report.

Intracranial condylar dislocation to the middle fossa is rare, as it is not reported often. Known cases have an etiology, identified as erosion of the glenoid cavity from joint prostheses and/or traumatic events. As such, this case aims to offer a predisposing reason for the idiopathic condylar dislocation to the middle cranial fossa with nonfunctional limitations.

External Jugular Thrombosis: A Previously Unreported Complication of Temporomandibular Joint Arthroscopy.

Temporomandibular joint intra-articular disorders are commonly managed using arthroscopic-assisted procedures. Arthroscopic procedures are minimally invasive, generally successful, and report a low frequency of complications. Vascular complications are particularly uncommon. This case report summarizes the diagnosis and management of jugular vein thrombosis following temporomandibular joint arthroscopy.

Is Reflex Parotitis a Forgotten or an Unknown Pathology?

Reflex parotitis is a recurrent parotid inflammation caused by an imbalance in the parasympathetic innervation of the salivary gland. However, due to a poor understanding of its pathophysiology, it can go unnoticed. Causes of ignored norms can trigger these repetitive episodes of glandular disease with a difficult diagnosis and inadequate treatment.

Pedicled Tragal Chondral Flap for Interpositional Gap Arthroplasty in a TMJ Ankyloses.

Interpositional gap arthroplasty has shown good results; however, these techniques could be improved by taking into account the biological bases of the tissue used. Therefore, we suggest the pedicled tragal chondral flap as a safe, simple, and low-morbidity alternative.

Acellular Dermal Matrix, Osseoplastic Flap, and Transnasal Endoscopic Approach for Frontal Mucocele.

PURPOUSE: The primary objective of this study is to suggest the use of acellular dermal matrix through an osteoplastic flap and transnasal endoscopic treatment for the management of frontal mucoceles. The secondary objective is to propose the characteristics to choose this approach. METHODS: A retrospective cohort study was carried out on patients with frontal mucoceles of different etiologies where an osteoplastic flap was made to address the sinus and subsequently obliterated with acellular dermal matrix. RESULTS: A cohort of 11 patients were included in the study, 6 (67%) were female and 5 (56%) were male, with a mean age of 56 years (range 35-71). The majority of patients (73%) with a history of trauma and all the patients were treated with frontal osteoplastic flap and obliteration with acellular dermal matrix. No evidence of recurrence in a follow-up period with a mean of 18 months and a low rate of complications. CONCLUSIONS: The frontal osteoplastic flap and obliteration with acellular dermal matrix is a simple and safe technique to perform with low morbidity. Also, an orbital reconstruction can be performed simultaneously.

Correlation Between Demographic Variables and Complications in Nonsyndromic Craniosynostosis.

PURPOSE: This retrospective cross-sectional, observational study aims to determine the correlation between demographic variables and nonsyndromic craniosynostosis. METHODS: A cross-sectional study was carried out. The inclusion criteria were nonsyndromic craniosynostosis and the exclusion criteria were patients who did not have complete records. RESULTS: The sample included 49 patients and mainly women. Patients with more than 4 days in the intensive care unit were related with more complications. Intracranial Hypertension was seen predominantly in patients between 6 and 8 months P =0007. CONCLUSION: Some variables can modificate complications risk but future studies are needed to further investigate the influence of such variables on craniofacial care.

miR-323a regulates ERBB4 and is involved in depression.

Major depressive disorder (MDD) is a complex and debilitating illness whose etiology remains unclear. Small RNA molecules, such as micro RNAs (miRNAs) have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified miRNA expression by small RNA sequencing in the anterior cingulate cortex and habenula of individuals with MDD and psychiatrically-healthy controls. Thirty-two miRNAs showed significantly correlated expression between the two regions (False Discovery Rate < 0.05), of which four, miR-204-5p, miR-320b, miR-323a-3p, and miR-331-3p, displayed upregulated expression in MDD. We assessed the expression of predicted target genes of differentially expressed miRNAs in the brain, and found that the expression of erb-b2 receptor tyrosine kinase 4 (ERBB4), a gene encoding a neuregulin receptor, was downregulated in both regions, and was influenced by miR-323a-3p in vitro. Finally, we assessed the effects of manipulating miRNA expression in the mouse ACC on anxiety- and depressive-like behaviors. Mice in which miR-323-3p was overexpressed or knocked-down displayed increased and decreased emotionality, respectively. Additionally, these mice displayed significantly downregulated and upregulated expression of Erbb4, respectively. Overall, our findings indicate the importance of brain miRNAs in the pathology of MDD, and emphasize the involvement of miR-323a-3p and ERBB4 in this phenotype. Future studies further characterizing miR-323a-3p and neuregulin signaling in depression are warranted.

Regulation of impulsive and aggressive behaviours by a novel lncRNA.

High impulsive and aggressive traits associate with poor behavioural self-control. Despite their importance in predicting behavioural negative outcomes including suicide, the molecular mechanisms underlying the expression of impulsive and aggressive traits remain poorly understood. Here, we identified and characterized a novel long noncoding RNA (lncRNA), acting as a regulator of the monoamine oxidase A (MAOA) gene in the brain, and named it MAOA-associated lncRNA (MAALIN). Our results show that in the brain of suicide completers, MAALIN is regulated by a combination of epigenetic mechanisms including DNA methylation and chromatin modifications. Elevated MAALIN in the dentate gyrus of impulsive-aggressive suicides was associated with lower MAOA expression. Viral overexpression of MAALIN in neuroprogenitor cells decreased MAOA expression while CRISPR-mediated knock out resulted in elevated MAOA expression. Using viral-mediated gene transfer, we confirmed that MAALIN in the hippocampus significantly decreases MAOA expression and exacerbates the expression of impulsive-aggressive behavioural traits in CD1 aggressive mice. Overall, our findings suggest that variations in DNA methylation mediate the differential expression of a novel lncRNA that acts on MAOA expression to regulate impulsive-aggressive behaviours.

The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice.

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1+ neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh+ neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response.

Probability of high-risk genetic matching with oocyte and semen donors: complete gene analysis or genotyping test?

PURPOSE: To estimate the probability of high-risk genetic matching when assisted reproductive techniques (ART) are applied with double gamete donation, following an NGS carrier test based on a complete study of the genes concerned. We then determine the results that would have been obtained if the genotyping tests most widely used in Spanish gamete banks had been applied. METHODS: In this descriptive observational study, 1818 gamete donors were characterised by NGS. The pathogenic variants detected were analysed to estimate the probability of high-risk genetic matching and to determine the results that would have been obtained if the three most commonly used genotyping tests in ART had been applied. RESULTS: The probability of high-risk genetic matching with gamete donation, screened by NGS and complete gene analysis, was 5.5%, versus the 0.6-2.7% that would have been obtained with the genotyping test. A total of 1741 variants were detected, including 607 different variants, of which only 22.6% would have been detected by all three genotyping tests considered and 44.7% of which would not have been detected by any of these tests. CONCLUSION: Our study highlights the considerable heterogeneity of the genotyping tests, which present significant differences in their ability to detect pathogenic variants. The complete study of the genes by NGS considerably reduces reproductive risks when genetic matching is performed with gamete donors. Accordingly, we recommend that carrier screening in gamete donors be carried out using NGS and a complete study with nontargeted analysis of the variants of the screened genes.

Reporting bias in the literature on the associations of health-related behaviors and statins with cardiovascular disease and all-cause mortality.

Reporting bias in the literature occurs when there is selective revealing or suppression of results, influenced by the direction of findings. We assessed the risk of reporting bias in the epidemiological literature on health-related behavior (tobacco, alcohol, diet, physical activity, and sedentary behavior) and cardiovascular disease mortality and all-cause mortality and provided a comparative assessment of reporting bias between health-related behavior and statin (in primary prevention) meta-analyses. We searched Medline, Embase, Cochrane Methodology Register Database, and Web of Science for systematic reviews synthesizing the associations of health-related behavior and statins with cardiovascular disease mortality and all-cause mortality published between 2010 and 2016. Risk of bias in systematic reviews was assessed using the ROBIS tool. Reporting bias in the literature was evaluated via small-study effect and excess significance tests. We included 49 systematic reviews in our study. The majority of these reviews exhibited a high overall risk of bias, with a higher extent in health-related behavior reviews, relative to statins. We reperformed 111 meta-analyses conducted across these reviews, of which 65% had statistically significant results (P < 0.05). Around 22% of health-related behavior meta-analyses showed small-study effect, as compared to none of statin meta-analyses. Physical activity and the smoking research areas had more than 40% of meta-analyses with small-study effect. We found evidence of excess significance in 26% of health-related behavior meta-analyses, as compared to none of statin meta-analyses. Half of the meta-analyses from physical activity, 26% from diet, 18% from sedentary behavior, 14% for smoking, and 12% from alcohol showed evidence of excess significance bias. These biases may be distorting the body of evidence available by providing inaccurate estimates of preventive effects on cardiovascular and all-cause mortality.

Muscle-strengthening activities and cancer incidence and mortality: a systematic review and meta-analysis of observational studies.

BACKGROUND: Physical activity has been associated with reduced risk of seven types of cancer. It remains unclear, however, whether muscle-strengthening activities also reduce cancer incidence and mortality. METHODS: PubMed, Embase, Web of Science and Scopus were searched from inception to March 2020. Summary hazard ratio (HR) and 95% confidence intervals (CI) were estimated using random-effects models. RESULTS: Twelve studies (11 cohorts; 1 case-control), 6 to 25 years of follow-up, including 1,297,620 participants, 32,196 cases and 31,939 deaths, met inclusion criteria. Muscle-strengthening activities were associated with a 26% lower incidence of kidney cancer (HR for high vs low levels of muscle-strengthening activities: 0.74; 95% CI 0.56 to 0.98; I2 0%; 2 studies), but not with incidence of other 12 types of cancer. Muscle-strengthening activities were associated with lower total cancer mortality: HRs for high vs low levels of muscle-strengthening activities was 0.87 (95% CI 0.73 to 1.02; I2 58%; 6 studies); and HR for ≥2 times/week vs < 2 times/week of muscle-strengthening activities was 0.81 (95% CI 0.74 to 0.87; I2 0%; 4 studies). Regarding the weekly duration of muscle-strengthening activities, HR for total cancer mortality were 0.91 (95% CI 0.82 to 1.01; I2 0%; 2 studies) for 1-59 min/week and 0.98 (95% CI 0.89 to 1.07; I2 0%) for ≥60 min/week vs none. Combined muscle-strengthening and aerobic activities (vs none) were associated with a 28% lower total cancer mortality (HR 0.72; 95% CI 0.53 to 0.98; I2 85%; 3 studies). CONCLUSIONS: Muscle-strengthening activities were associated with reduced incidence of kidney cancer and total cancer mortality. Combined muscle-strengthening and aerobic activities may provide a greater reduction in total cancer mortality.

Virtual Navigation Endoscopically Integrated Into Orbital Trauma.

ABSTRACT: Orbital reconstruction has traditionally been accomplished utilizing different techniques developed for this purpose and has been modified and improved throughout the years. However, there is a high rate of complications associated with eye globe positioning and/or migration of implants, which has created the need to continue to improve these techniques to decrease the frequency of complications. On the other hand, techniques that involve an endoscopic approach and technologies that use virtual surgical planning and three-dimensional model impressions are being used more often to decrease complication rates and seek better surgical outcomes. Combining these 2 methods results in endoscopically integrated virtual surgical navigation. When used for orbital reconstruction, it can be a great alternative and can be useful to decrease the risk of complications associated with this procedure. Therefore, this technical note aims to describe the integration of these 2 techniques into the same instrument to demonstrate the synergy of their benefits when used together.

Endoscopic Approach for Insertion of Custom-Designed Facial Implants.

ABSTRACT: The objective of this article is to describe the combination of virtual planning used to produce a custom-made facial implant, along with the minimally invasive endoscopic approach used to place it, for the reconstruction of the frontal bone. This management reduces the sequelae that occur with the traditional incisions while restoring the proper contour of facial surfaces at the same time.

Does the association between physical capability and mortality differ by deprivation? Findings from the UK Biobank population-based cohort study.

BACKGROUND: To investigate whether the excess risk of adverse health outcomes associated with a lower physical capability in adulthood differs by deprivation levels. METHODS: 279,030 participants from the UK Biobank were included. Handgrip strength and walking pace were the exposures. All-cause mortality, CVD mortality and incidence were the outcomes. Townsend deprivation index was treated as a potential effect modifier. The associations were investigated using Cox-regression models with years of follow-up as the time-varying covariate. RESULTS: A significant interaction between deprivation and handgrip strength was found for all-cause mortality (p = 0.024), CVD mortality (p = 0.006) and CVD incidence (p = 0.001). The hazard ratio for all-cause mortality was 1.18 [1.09; 1.29] per 1-tertile higher level of grip strength in the least deprived group, whereas it was 1.30 [1.18; 1.43] in the most deprived individuals. Similar results were found for CVD mortality and incidence per tertile increment in handgrip strength in the least and most deprived quintiles, respectively. No significant interactions between deprivation and walking pace were found for any of the outcomes. CONCLUSION: Low handgrip strength is a stronger predictor of morbidity and mortality in individuals living in more deprived areas.