Pelvic floor muscle electrical coupling in chronic pelvic pain: Insights into pathophysiology and botulinum toxin treatment effects.

This study aimed to assess the electrical coupling between both pelvic floor muscle (PFM) sides (two-sided coupling) and within individual PFM sides (one-sided coupling) in chronic pelvic pain (CPP) before and after botulinum neurotoxin type A (BoNT/A) treatment. Surface electromyographic (sEMG) signals were recorded from the left and right PFM of 24 patients (P) with CPP before and after being treated with BoNT/A (Weeks 0,8,12,24). Recordings were also made in 24 healthy women (H). PFM two-sided and one-sided coupling was evaluated during contractions by the cross-correlation (CC) and the imaginary part of coherency (iCOH) of their sEMG signals. Significant differences between their values were assessed comparing P(0) vs. P(8,12,24) and H vs. P(0,8,12,24). This study showed that PFM two-sided coupling is similar across groups before treatment, while PFM one-sided coupling on the patients' most painful side is deranged before and also after BoNT/A treatment: amplitude coupling is lower (iCOH) than healthy women's. This could be justified by altered neuromotor control strategies developed as an adaptation to muscle pain, structural and electrical changes in PFM, and alterations in their innervation pattern, which may influence the onset, perpetuation, or recurrence of CPP after treatment.

GOIZ ZAINDU study: a FINGER-like multidomain lifestyle intervention feasibility randomized trial to prevent dementia in Southern Europe.

BACKGROUND: GOIZ ZAINDU ("caring early" in Basque) is a pilot study to adapt the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) methodology to the Basque population and evaluate the feasibility and adherence to a FINGER-like multidomain intervention program. Additional aims included the assessment of efficacy on cognition and data collection to design a large efficacy trial. METHOD: GOIZ ZAINDU is a 1-year, randomized, controlled trial of a multidomain intervention in persons aged 60+ years, with Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score ≥ 6, no diagnosis of dementia, and below-than-expected performance in at least one of three cognitive screening tests. Randomization to a multidomain intervention (MD-Int) or regular health advice (RHA) was stratified by sex, age (>/≤ 75), and cognitive status (mild cognitive impairment (MCI)/normal cognition). MD-Int included cardiovascular risk factor control, nutritional counseling, physical activity, and cognitive training. The primary outcomes were retention rate and adherence to the intervention program. Exploratory cognitive outcomes included changes in the Neuropsychological Test Battery z-scores. Analyses were performed according to the intention to treat. RESULTS: One hundred twenty-five participants were recruited (mean age: 75.64 (± 6.46); 58% women). The MD-Int (n = 61) and RHA (n = 64) groups were balanced in terms of their demographics and cognition. Fifty-two (85%) participants from the RHA group and 56 (88%) from the MD-Int group completed the study. More than 70% of the participants had high overall adherence to the intervention activities. The risk of cognitive decline was higher in the RHA group than in the MD-Int group in terms of executive function (p =.019) and processing speed scores (p =.026). CONCLUSIONS: The GOIZ-ZAINDU study proved that the FINGER methodology is adaptable and feasible in a different socio-cultural environment. The exploratory efficacy results showed a lower risk of decline in executive function and processing speed in the intervention group. These results support the design of a large-scale efficacy trial. TRIAL REGISTRATION: GOIZ ZAINDU feasibility trial was approved and registered by the Euskadi Drug Research Ethics Committee (ID: PI2017134) on 23 January 2018. Retrospectively registered in ClinicalTrials.gov (NCT06163716) on 8 December 2023.

Can Virtual Reality be Used for the Prevention of Peer Sexual Harassment in Adolescence? First Evaluation of the Virtual-PRO Program.

Objective: The present study analyzed the Virtual-PRO program's efficacy in preventing peer sexual harassment by promoting the bystanders' active intervention and incorporating a virtual reality (VR) component. The impact of the program on sexist attitudes, moral disengagement, the intention to intervene as bystanders, and the involvement in sexual aggression and victimization was tested. Method: Virtual-PRO is a VR-enhanced sexual harassment curricular prevention program of six one-hour sessions. The evaluation comprised a pre-test, a post-test after the intervention, and a follow-up measure at three months. In the study, 579 Spanish adolescent students aged between 12 and 17 years (M = 14.76, SD = 0.88; 47.1% boys) were randomly grouped into experimental (n = 286) and control (n = 293) conditions. Results: The Virtual-PRO program effectively controlled participants' levels of sexism and reduced moral disengagement in the experimental group compared to the control group three months after the intervention. The program also showed positive results in changing bystander behavior, increasing the intention to intervene when the victim was not a friend. Finally, visual/verbal and online victimization decreased in the experimental group and increased in the control group. No differences were found for physical sexual victimization and sexual aggression. Conclusions: The first trial of the Virtual-PRO program is promising and highlights the use of VR as a sexual harassment prevention tool. Follow-up measures are essential to determine the impact of interventions accurately.

Objetivo: El presente estudio analiza la eficacia del programa Virtual-PRO en la prevención del acoso sexual entre iguales promoviendo la intervención activa de los espectadores mediante el uso de la realidad virtual (RV). Se comprobó el impacto del programa en las actitudes sexistas, la desconexión moral, la intención de intervenir como espectadores y la implicación en agresión y victimización sexual. Método: Virtual-PRO es un programa curricular compuesto por seis unidades que incorpora la RV para mejorar la prevención del acoso sexual. La evaluación incluyó una medida pre-test, un post-test después de la intervención y una medida de seguimiento a los tres meses. En el estudio participaron 579 estudiantes españoles de entre 12 y 17 años (M = 14.76, DT = 0.88, 47.1% chicos), agrupados aleatoriamente en grupo experimental (n = 286) y control (n = 293). Resultados: El programa Virtual-PRO controló eficazmente los niveles de sexismo y redujo la desconexión moral en el grupo experimental en comparación con el grupo de control tres meses después de la intervención. También mostró resultados positivos en el cambio del comportamiento de los espectadores, mejorando la intención de intervenir cuando la víctima no era amigo o amiga. Por último, la victimización visual/verbal y online disminuyó en el grupo experimental y aumentó en el grupo control. No se encontraron diferencias en victimización sexual física y agresión sexual. Conclusiones: El primer ensayo del programa Virtual-PRO es prometedor y pone de relieve el uso de la RV como herramienta eficaz para la prevención del acoso sexual. Las medidas de seguimiento son esenciales para determinar con precisión el efecto de las intervenciones.

Social Support and Mental Health in the Postpartum Period in Times of SARS-CoV-2 Pandemic: Spanish Multicentre Cohort Study.

BACKGROUND: To explore the depression and anxiety symptoms in the postpartum period during the SARS-CoV-2 pandemic and to identify potential risk factors. METHODS: A multicentre observational cohort study including 536 women was performed at three hospitals in Spain. The Edinburgh Postnatal Depression Scale (EPDS), the State-Trait Anxiety Inventory (STAI) Scale, the Medical Outcomes Study Social Support Survey (MOS-SSS), and the Postpartum Bonding Questionnaire (PBQ) were assessed after birth. Depression (EPDS) and anxiety (STAI) symptoms were measured, and the cut-off scores were set at 10 and 13 for EPDS, and at 40 for STAI. RESULTS: Regarding EPDS, 32.3% (95% CI, 28% to 36.5%) of women had a score ≥ 10, and 17.3% (95% CI, 13.9% to 20.7%) had a score ≥ 13. Women with an STAI score ≥ 40 accounted for 46.8% (95% CI, 42.3% to 51.2%). A lower level of social support (MOS-SSS), a fetal malformation diagnosis and a history of depression (p = 0.000, p = 0.019 and p = 0.043) were independent risk factors for postpartum depression. A lower level of social support and a history of mental health disorders (p = 0.000, p = 0.003) were independent risk factors for postpartum anxiety. CONCLUSION: During the SARS-CoV-2 pandemic, an increase in symptoms of anxiety and depression were observed during the postpartum period.

Molecular Diagnosis of Steroid 21-Hydroxylase Deficiency: A Practical Approach.

Adrenal insufficiency in paediatric patients is mostly due to congenital adrenal hyperplasia (CAH), a severe monogenic disease caused by steroid 21-hydroxylase deficiency (21-OHD, encoded by the CYP21A2 gene) in 95% of cases. CYP21A2 genotyping requires careful analyses that guaranty gene-specific PCR, accurate definition of pseudogene-gene chimeras, gene duplications and allele dropout avoidance. A small panel of well-established disease-causing alterations enables a high diagnostic yield in confirming/discarding the disorder not only in symptomatic patients but also in those asymptomatic with borderline/positive results of 17-hydroxyprogesterone. Unfortunately, the complexity of this locus makes it today reluctant to high throughput techniques of massive sequencing. The strong relationship existing between the molecular alterations and the degree of enzymatic deficiency has allowed genetic studies to demonstrate its usefulness in predicting/classifying the clinical form of the disease. Other aspects of interest regarding molecular studies include its independence of physiological variations and analytical interferences, its usefulness in the diagnosis of simple virilizing forms in males and its inherent contribution to the genetic counseling, an aspect of great importance taking into account the high carrier frequency of CAH in the general population. Genetic testing of CYP21A2 constitutes an irreplaceable tool to detect severe alleles not just in family members of classical forms but also in mild late-onset forms of the disease and couples. It is also helpful in areas such as assisted reproduction and preimplantation diagnosis. Molecular diagnosis of 21-OHD under expert knowledge definitely contributes to a better management of the disease in every step of the clinical course.

Evaluation of Systemic Gentamicin as Translational Readthrough Therapy for a Patient With Epidermolysis Bullosa Simplex With Muscular Dystrophy Owing to PLEC1 Pathogenic Nonsense Variants.

IMPORTANCE: Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) is an autosomal recessive disorder caused by pathogenic variants in PLEC1, which encodes plectin. It is characterized by mild mucocutaneous fragility and blistering and muscle weakness. Translational readthrough-inducing drugs, such as repurposed aminoglycoside antibiotics, may represent a valuable therapeutic alternative for untreatable rare diseases caused by nonsense variants. OBJECTIVE: To evaluate whether systemic gentamicin, at a dose of 7.5 mg/kg/d for 14 consecutive days, is clinically beneficial in a patient with EBS-MD. DESIGN, SETTING, AND PARTICIPANTS: A single patient in Madrid, Spain, received 2 treatment courses with gentamicin on July 2019 and February 2020 with a follow-up period of 120 and 150 days, respectively. RESULTS: In this case report of a woman in her 30s with EBS-MD, before gentamicin treatment, the patient had mucocutaneous involvement, skeletal and respiratory muscle weakness, and myalgia that negatively affected her quality of life. Outcomes were evaluated with extensive laboratory tests and clinical scales. No nephrotoxic or ototoxic effects were detected after intravenous gentamicin administration. Gentamicin treatment was followed by plectin expression in the skin for at least 5 months. Although minimal changes were noted in skeletal muscle function (as measured by the Hammersmith functional motor scale and its expanded version: 6/40 to 7/40 and from 10/66 to 11/66, respectively) and respiratory musculature (maximal inspiratory and expiratory pressures D0 vs D16, MIP: 2.86 vs 3.63 KPa and MEP: 2.93 vs 4.63 KPa), myalgia disappeared (VAS dropped from 6 to 0), and quality of life improved (EuroQoL-5D-3L pain and anxiety dropped from 2 to 1). CONCLUSIONS AND RELEVANCE: The findings of this single case report suggest that gentamicin treatment may help suppress PLEC1 premature termination codons and induce plectin expression in EBS-MD primary keratinocytes and skin. Our study suggests that gentamicin may play an important role in treating EBS-MD owing to nonsense variants.

FPR2 DNA Aptamers for Targeted Therapy of Wound Repair.

Chronic wounds represent a major health problem worldwide. Some of the available therapies based on recombinant proteins usually fail owing to the hostile environment found at the wound bed. Aptamers appear as an attractive alternative to recombinant factors owing in part to their stability, sensitivity, specificity, and low-cost production. In this study, the Cell-Systematic Evolution of Ligands by EXponential Enrichment technology was employed to generate aptamers that specifically recognize and modulate the function of the FPR2, a receptor expressed in a variety of cells involved in wound repair. Three aptamers were obtained that specifically bound to FPR2 stable transfectants generated in HaCaT cells. The targeted aptamers were shown to act as FPR2 agonists in different in vitro functional assays, including wound healing assays, and elicited a similar pattern of response to that obtained with other known FPR2 peptide agonists, such as the human LL37 cathelicidin. We have also obtained in vivo evidence for the prohealing activities of one of these FPR2 aptamers in a skin-humanized mouse model developed by us, previously shown to accurately recreate the main phases of physiological human wound repair process. In conclusion, we provide evidence of the potential therapeutic value of FPR2 aptamers for cutaneous repair.

Diagnosing Septate Uterus Using Three-Dimensional Ultrasound Using Three Different Classifications: An Interobserver and Intraobserver Agreement Study.

OBJECTIVE: Currently, there are up to three different classifications for diagnosing septate uterus. The interobserver agreement among them has been poorly assessed. OBJECTIVE: To assess the interobserver agreement of nonexpert sonographers for classifying septate uterus using the European Society of Human Reproduction and Embryology/European Society for Gynaecological Endoscopy (ESHRE/ESGE), American Society for Reproductive Medicine (ASRM), and Congenital Uterine Malformations by Experts (CUME) classifications. METHODS: A total of 50 three-dimensional (3D) volumes of a nonconsecutive series of women with suspected uterine malformation were used. Two nonexpert examiners evaluated a single 3D volume of the uterus of each woman, blinded to each other. The following measurements were performed: indentation depth, indentation angle, uterine fundal wall thickness, external fundal indentation, and indentation-to-wall-thickness (I:WT) ratio. Each observer had to assign a diagnosis in each case, according to the three classification systems (ESHRE/ESGE, ASRM, and CUME). The interobserver agreement regarding the ESHRE/ESGE, ASRM, and CUME classifications was assessed using the Cohen weighted kappa index (k). Agreement regarding the three classifications (ASRM versus ESHRE/ESGE, ASRM versus CUME, ESHRE/ESGE versus CUME) was also assessed. RESULTS: The interobserver agreement between the 2 nonexpert examiners was good for the ESHRE/ESGE (k = 0.74; 95% confidence interval [CI]: 0.55-0.92) and very good for the ASRM and CUME classification systems (k = 0.95; 95%CI: 0.86-1.00; and k = 0.91; 95%CI: 0.79-1.00, respectively). Agreement between the ESHRE/ESGE and ASRM classifications was moderate for both examiners. Agreement between the ESHRE/ESGE and CUME classifications was moderate for examiner 1 and good for examiner 2. Agreement between the ASRM and CUME classifications was good for both examiners. CONCLUSION: The three classifications have good (ESHRE/ESGE) or very good (ASRM and CUME) interobserver agreement. Agreement between the ASRM and CUME classifications was higher than that for the ESHRE/ESGE and ASRM and ESHRE/ESGE and CUME classifications.

OBJETIVO: Atualmente, existem até três classificações diferentes para o diagnóstico de útero septado. A concordância interobservador entre eles tem sido pouco avaliada. OBJETIVO: Avaliar a concordância interobservador de ecografistas não especialistas para classificar úteros septados usando as classificações European Society of Human Reproduction and Embryology/European Society for Gynaecological Endoscopy (ESHRE/ESGE, na sigla em inglês), American Society for Reproductive Medicine (ASRM, na sigla em inglês) e Congenital Uterine Malformations by Experts (CUME, na sigla em inglês). MéTODOS: Foram utilizados 50 volumes tridimensionais (3D) de uma série não consecutiva de mulheres com suspeita de malformação uterina. Dois examinadores não especialistas avaliaram um único volume 3D do útero de cada mulher, mutuamente cegos. As seguintes medidas foram aferidas: profundidade de indentação, ângulo de indentação, espessura da parede do fundo uterino, indentação externa do fundo e relação entre indentação e a espessura da parede (I:WT, na sigla em inglês). Cada observador teve que atribuir um diagnóstico em cada caso, de acordo com os três sistemas de classificação (ESHRE/ESGE, ASRM e CUME). A concordância interobservador em relação às classificações ESHRE/ESGE, ASRM e CUME foi avaliada usando o índice kappa ponderado de Cohen (k). A concordância em relação às três classificações (ASRM versus ESHRE-ESGE, ASRM versus CUME e ESHRE-ESGE versus CUME) também foi avaliada. RESULTADOS: A concordância interobservador entre os 2 examinadores não especialistas foi boa para a classificação ESHRE/ESGE (k = 0,74, intervalo de confiança [IC] 95%: 0,55­0,92) e muito boa para os sistemas de classificação ASRM e CUME (k = 0,95; IC 95%: 0,86­1,00; e k = 0,91; IC95%: 0,79­1,00, respectivamente). A concordância entre as classificações ESHRE/ESGE e ASRM foi moderada para ambos os examinadores. A concordância entre as classificações ESHRE/ESGE e CUME foi moderada para o examinador 1 e boa para o examinador 2. A concordância entre as classificações ASRM e CUME foi boa para ambos os examinadores. CONCLUSãO: As três classificações apresentam concordância interobservador boa (ESHRE/ESGE) ou muito boa (ASRM e CUME). A concordância entre as classificações ASRM e CUME foi maior do que entre as classificações ESHRE/ESGE e ASRM e ESHRE/ESGE e CUME.

Diagnosing Septate Uterus Using Three-Dimensional Ultrasound Using Three Different Classifications: An Interobserver and Intraobserver Agreement Study / Diagnóstico de útero septado com ecografia tridimensional usando três classificações diferentes: Um estudo de concordância interobservador e intraobservador

Abstract Objective Currently, there are up to three different classifications for diagnosing septate uterus. The interobserver agreement among them has been poorly assessed. To assess the interobserver agreement of nonexpert sonographers for classifying septate uterus using the European Society of Human Reproduction and Embryology/European Society for Gynaecological Endoscopy (ESHRE/ESGE), American Society for Reproductive Medicine (ASRM), and Congenital Uterine Malformations by Experts (CUME) classifications. Methods A total of 50 three-dimensional (3D) volumes of a nonconsecutive series of women with suspected uterine malformation were used. Two nonexpert examiners evaluated a single 3D volume of the uterus of each woman, blinded to each other. The following measurements were performed: indentation depth, indentation angle, uterine fundal wall thickness, external fundal indentation, and indentation-to-wall-thickness (I:WT) ratio. Each observer had to assign a diagnosis in each case, according to the three classification systems (ESHRE/ESGE, ASRM, and CUME). The interobserver agreement regarding the ESHRE/ESGE, ASRM, and CUME classifications was assessed using the Cohen weighted kappa index (k). Agreement regarding the three classifications (ASRM versus ESHRE/ESGE, ASRM versus CUME, ESHRE/ESGE versus CUME) was also assessed. Results The interobserver agreement between the 2 nonexpert examiners was good for the ESHRE/ESGE (k = 0.74; 95% confidence interval [CI]: 0.55-0.92) and very good for the ASRM and CUME classification systems (k = 0.95; 95%CI: 0.86-1.00; and k = 0.91; 95%CI: 0.79-1.00, respectively). Agreement between the ESHRE/ESGE and ASRM classifications was moderate for both examiners. Agreement between the ESHRE/ESGE and CUME classifications was moderate for examiner 1 and good for examiner 2. Agreement between the ASRM and CUME classifications was good for both examiners. Conclusion The three classifications have good (ESHRE/ESGE) or very good (ASRM and CUME) interobserver agreement. Agreement between the ASRM and CUME classifications was higher than that for the ESHRE/ESGE and ASRM and ESHRE/ESGE and CUME classifications.

Resumo Objetivo Atualmente, existem até três classificações diferentes para o diagnóstico de útero septado. A concordância interobservador entre eles tem sido pouco avaliada. Avaliar a concordância interobservador de ecografistas não especialistas para classificar úteros septados usando as classificações European Society of Human Reproduction and Embryology/European Society for Gynaecological Endoscopy (ESHRE/ESGE, na sigla em inglês), American Society for Reproductive Medicine (ASRM, na sigla em inglês) e Congenital Uterine Malformations by Experts (CUME, na sigla em inglês). Métodos Foram utilizados50volumes tridimensionais (3D)deuma série não consecutiva de mulheres com suspeita de malformação uterina. Dois examinadores não especialistas avaliaram um único volume 3D do útero de cada mulher, mutuamente cegos. As seguintes medidas foram aferidas: profundidade de indentação, ângulo de indentação, espessura da parede do fundo uterino, indentação externa do fundo e relação entre indentação e a espessura da parede (I:WT, na sigla em inglês). Cada observador teve que atribuir um diagnóstico em cada caso, de acordo com os três sistemas de classificação (ESHRE/ESGE, ASRM e CUME). A concordância interobservador em relação às classificações ESHRE/ESGE, ASRM e CUME foi avaliada usando o índice kappa ponderado de Cohen (k). A concordância em relação às três classificações (ASRM versus ESHRE/ESGE, ASRM versus CUME e ESHRE/ ESGE versus CUME) também foi avaliada. Resultados A concordância interobservador entre os 2 examinadores não especialistas foi boa para a classificação ESHRE/ESGE (k = 0,74, intervalo de confiança [IC] 95%: 0,55-0,92) e muito boa para os sistemas de classificação ASRM e CUME (k = 0,95; IC 95%: 0,86-1,00; e k = 0,91; IC95%: 0,79-1,00, respectivamente). A concordância entre as classificações ESHRE/ESGE e ASRM foi moderada para ambos os examinadores. A concordância entre as classificações ESHRE/ESGE e CUME foi moderada para o examinador 1 e boa para o examinador 2. A concordância entre as classificações ASRM e CUME foi boa para ambos os examinadores. Conclusão As três classificações apresentam concordância interobservador boa (ESHRE/ESGE) ou muito boa (ASRM e CUME). A concordância entre as classificações ASRM e CUME foi maior do que entre as classificações ESHRE/ESGE e ASRM e ESHRE/ESGE e CUME.

Lactic Acid Bacteria Isolated from Fermented Doughs in Spain Produce Dextrans and Riboflavin.

Many lactic acid bacteria (LAB) produce metabolites with applications in the food industry, such as dextran-type exopolysaccharides (EPS) and riboflavin (vitamin B2). Here, 72 bacteria were isolated from sourdoughs made by Spanish bread-makers. In the presence of sucrose, colonies of 22 isolates showed a ropy phenotype, and NMR analysis of their EPS supported that 21 of them were dextran producers. These isolates were identified by their random amplified polymorphic DNA (RAPD) patterns and their rrs and pheS gene sequences as LAB belonging to four species (Weissella cibaria, Leuconostoc citreum, Leuconostoc falkenbergense and Leuconostoc mesenteroides). Six selected strains from the Leuconostoc (3) and Weissella (3) genera grew in the absence of riboflavin and synthesized vitamin B2. The EPS produced by these strains were characterized as dextrans by physicochemical analysis, and the L. citreum polymer showed an unusually high degree of branching. Quantification of the riboflavin and the EPS productions showed that the W. cibaria strains produce the highest levels (585-685 µg/and 6.5-7.4 g/L, respectively). Therefore, these new LAB strains would be good candidates for the development of fermented foods bio-fortified with both dextrans and riboflavin. Moreover, this is the first report of riboflavin and dextran production by L. falkenbergense.

Treatment of Dyspareunia with Botulinum Neurotoxin Type A: Clinical Improvement and Influence of Patients' Characteristics.

The treatment of chronic pelvic pain (CPP) with botulinum neurotoxin type A (BoNT/A) has increased lately, but more studies assessing its effect are needed. This study aimed to evaluate the evolution of patients after BoNT/A infiltration and identify potential responders to treatment. Twenty-four women with CPP associated with dyspareunia were treated with 90 units of BoNT/A injected into their pelvic floor muscle (PFM). Clinical status and PFM activity were monitored in a previous visit (PV) and 12 and 24 weeks after the infiltration (W12, W24) by validated clinical questionnaires and surface electromyography (sEMG). The influence of patients' characteristics on the reduction in pain at W12 and W24 was also assessed. After treatment, pain scores and the impact of symptoms on quality of life dropped significantly, sexual function improved and sEMG signal amplitude decreased on both sides of the PFM with no adverse events. Headaches and bilateral pelvic pain were risk factors for a smaller pain improvement at W24, while lower back pain was a protective factor. Apart from reporting a significant clinical improvement of patients with CPP associated with dyspareunia after BoNT/A infiltration, this study shows that clinical characteristics should be analyzed in detail to identify potential responders to treatment.

Effect of BoNT/A in the Surface Electromyographic Characteristics of the Pelvic Floor Muscles for the Treatment of Chronic Pelvic Pain.

Chronic pelvic pain (CPP) is a complex condition with a high economic and social burden. Although it is usually treated with botulinum neurotoxin type A (BoNT/A) injected into the pelvic floor muscles (PFM), its effect on their electrophysiological condition is unknown. In this study, 24 CPP patients were treated with BoNT/A. Surface electromyographic signals (sEMG) were recorded at Weeks 0 (infiltration), 8, 12 and 24 from the infiltrated, non-infiltrated, upper and lower PFM. The sEMG of 24 healthy women was also recorded for comparison. Four parameters were computed: root mean square (RMS), median frequency (MDF), Dimitrov's index (DI) and sample entropy (SampEn). An index of pelvic electrophysiological impairment (IPEI) was also defined with respect to the healthy condition. Before treatment, the CPP and healthy parameters of almost all PFM sides were significantly different. Post-treatment, there was a significant reduction in power (MDF), lower fatigue index (SampEn) in all sites in patients, mainly during PFM contractions, which brought their electrophysiological condition closer to that of healthy women (

Characterization of Pelvic Floor Activity in Healthy Subjects and with Chronic Pelvic Pain: Diagnostic Potential of Surface Electromyography.

Chronic pelvic pain (CPP) is a highly disabling disorder in women usually associated with hypertonic dysfunction of the pelvic floor musculature (PFM). The literature on the subject is not conclusive about the diagnostic potential of surface electromyography (sEMG), which could be due to poor signal characterization. In this study, we characterized the PFM activity of three groups of 24 subjects each: CPP patients with deep dyspareunia associated with a myofascial syndrome (CPP group), healthy women over 35 and/or parous (>35/P group, i.e., CPP counterparts) and under 35 and nulliparous (<35&NP). sEMG signals of the right and left PFM were recorded during contractions and relaxations. The signals were characterized by their root mean square (RMS), median frequency (MDF), Dimitrov index (DI), sample entropy (SampEn), and cross-correlation (CC). The PFM activity showed a higher power (>RMS), a predominance of low-frequency components (DI), greater complexity (>SampEn) and lower synchronization on the same side (35/P group. The same trend in differences was found between healthy women (<35&NP vs. >35/P) associated with aging and parity. These results show that sEMG can reveal alterations in PFM electrophysiology and provide clinicians with objective information for CPP diagnosis.

Plasma lipids are associated with white matter microstructural changes and axonal degeneration.

Dislipidemia is a risk factor for cognitive impairment. We studied the association between interindividual variability of plasma lipids and white matter (WM) microstructure, using diffusion tensor imaging (DTI) in 273 healthy adults. Special focus was placed on 7 regions of interest (ROI) which are structural components of cognitive neurocircuitry. We also investigated the effect of plasma lipids on cerebrospinal fluid (CSF) neurofilament light chain (NfL), an axonal degeneration marker. Low density lipoprotein (LDL) and triglyceride (TG) levels showed a negative association with axial diffusivity (AxD) in multiple regions. High density lipoproteins (HDL) showed a positive correlation. The association was independent of Apolipoprotein E (APOE) genotype, blood pressure or use of statins. LDL moderated the relation between NfL and AxD in the body of the corpus callosum (p = 0.041), right cingulum gyrus (p = 0.041), right fornix/stria terminalis (p = 0.025) and right superior longitudinal fasciculus (p = 0.020) and TG in the right inferior longitudinal fasciculus (p = 0.004) and left fornix/stria terminalis (p = 0.001). We conclude that plasma lipids are associated to WM microstructural changes and axonal degeneration and might represent a risk factor in the transition from healthy aging to disease.

Beneficial Effect of Systemic Allogeneic Adipose Derived Mesenchymal Cells on the Clinical, Inflammatory and Immunologic Status of a Patient With Recessive Dystrophic Epidermolysis Bullosa: A Case Report.

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable inherited mucocutaneous fragility disorder characterized by recurrent blisters, erosions, and wounds. Continuous blistering triggers overlapping cycles of never-ending healing and scarring commonly evolving to chronic systemic inflammation and fibrosis. The systemic treatment with allogeneic mesenchymal cells (MSC) from bone marrow has previously shown benefits in RDEB. MSC from adipose tissue (ADMSC) are easier to isolate. This is the first report on the use of systemic allogeneic ADMSC, correlating the clinical, inflammatory, and immunologic outcomes in RDEB indicating long-lasting benefits. We present the case of an RDEB patient harboring heterozygous biallelic COL7A1 gene mutations and with a diminished expression of C7. The patient presented with long-lasting refractory and painful oral ulcers distressing her quality of life. Histamine receptor antagonists, opioid analgesics, proton-pump inhibitors, and low-dose tricyclic antidepressants barely improved gastric symptoms, pain, and pruritus. Concomitantly, allogeneic ADMSC were provided as three separate intravenous injections of 106 cells/kg every 21 days. ADMSC treatment was well-tolerated. Improvements in wound healing, itch, pain and quality of life were observed, maximally at 6-9 months post-treatment, with the relief of symptoms still noticeable for up to 2 years. Remarkably, significant modifications in PBL participating in both the innate and adaptive responses, alongside regulation of levels of profibrotic factors, MCP-1/CCL2 and TGF-ß, correlated with the health improvement. This treatment might represent an alternative for non-responding patients to conventional management. It seems critical to elucidate the paracrine modulation of the immune system by MSC for their rational use in regenerative/immunoregulatory therapies.

Cerebrospinal Fluid 7-Ketocholesterol Level is Associated with Amyloid-ß42 and White Matter Microstructure in Cognitively Healthy Adults.

BACKGROUND: Abnormal cholesterol metabolism changes the neuronal membrane and may promote amyloidogenesis. Oxysterols in cerebrospinal fluid (CSF) are related to Alzheimer's disease (AD) biomarkers in mild cognitive impairment and dementia. Cholesterol turnover is important for axonal and white matter (WM) microstructure maintenance. OBJECTIVE: We aim to demonstrate that the association of oxysterols, AD biomarkers, and WM microstructure occurs early in asymptomatic individuals. METHODS: We studied the association of inter-individual variability of CSF 24-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), 7-ketocholesterol (7-KC), 7ß-hydroxycholesterol (7ß-OHC), amyloid-ß42 (Aß42), total-tau (t-tau), phosphorylated-tau (p-tau), neurofilament (NfL), and WM microstructure using diffusion tensor imaging, generalized linear models and moderation/mediation analyses in 153 healthy adults. RESULTS: Higher 7-KC levels were related to lower Aß42, indicative of greater AD pathology (p = 0.041) .  Higher 7-KC levels were related to lower fractional anisotropy (FA) and higher mean (MD), axial (AxD), and radial (RD) diffusivity. 7-KC modulated the association between AxD and NfL in the corpus callosum splenium (B = 39.39, p = 0.017), genu (B = 68.64, p = 0.000), and fornix (B = 10.97, p = 0.000). Lower Aß42 levels were associated to lower FA and higher MD, AxD, and RD in the fornix, corpus callosum, inferior longitudinal fasciculus, and hippocampus. The association between AxD and Aß42 was moderated by 7K-C (p = 0.048). CONCLUSION: This study adds clinical evidence to support the role of 7K-C on axonal integrity and the involvement of cholesterol metabolism in the Aß42 generation process.

Sevoflurane versus ketamine+diazepam anesthesia for assessing systemic and hepatic hemodynamics in rats with non-cirrhotic portal hypertension.

The selection of the anesthetic regime is a crucial component in many experimental animal studies. In rodent models of liver disease, the combination of ketamine and diazepam (KD), generally by the intramuscular (i.m.) route, has traditionally been the anesthesia of choice for the evaluation of systemic and hepatic hemodynamics but it presents several problems. Here, we compared the performance of inhalational sevoflurane (Sevo) against the KD combination as the anesthesia used for hemodynamic studies involving the measurement of portal pressure in normal rats (Ctrl) and rats with non-cirrhotic portal hypertension induced by partial portal vein ligation (PPVL). Compared with Ctrl rats, rats with PPVL presented characteristic alterations that were not influenced by the anesthetic regime, which included liver atrophy, splenomegaly, increased plasma fibrinogen, decreased alkaline phosphatase and glycemia, and frequent ascites. The use of the KD combination presented several disadvantages compared with the inhalational anesthesia with sevoflurane, including considerable mortality, a higher need of dose adjustments to maintain an optimal depth of anesthesia, increases of heart rate, and alteration of blood biochemical parameters such as the concentration of aspartate aminotransferase, lactate, and lactic dehydrogenase. Rats anesthetized with sevoflurane, on the other hand, presented lower respiratory rates. Importantly, the anesthetic regime did not influence the measurement of portal pressure either in Ctrl or PPVL rats, with the increase of portal pressure being similar in Sevo- and KD- anesthetized groups of PPVL rats compared with their respective control groups. Overall, our results suggest that anesthesia with sevoflurane is preferable to the combination of KD for performing systemic and hepatic hemodynamic studies in rats with non-cirrhotic portal hypertension.

Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients' quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

Early, Non-Invasive Sensing of Sustained Hyperglycemia in Mice Using Millimeter-Wave Spectroscopy.

Diabetes is a very complex condition affecting millions of people around the world. Its occurrence, always accompanied by sustained hyperglycemia, leads to many medical complications that can be greatly mitigated when the disease is treated in its earliest stage. In this paper, a novel sensing approach for the early non-invasive detection and monitoring of sustained hyperglycemia is presented. The sensing principle is based on millimeter-wave transmission spectroscopy through the skin and subsequent statistical analysis of the amplitude data. A classifier based on functional principal components for sustained hyperglycemia prediction was validated on a sample of twelve mice, correctly classifying the condition in diabetic mice. Using the same classifier, sixteen mice with drug-induced diabetes were studied for two weeks. The proposed sensing approach was capable of assessing the glycemic states at different stages of induced diabetes, providing a clear transition from normoglycemia to hyperglycemia typically associated with diabetes. This is believed to be the first presentation of such evolution studies using non-invasive sensing. The results obtained indicate that gradual glycemic changes associated with diabetes can be accurately detected by non-invasively sensing the metabolism using a millimeter-wave spectral sensor, with an observed temporal resolution of around four days. This unprecedented detection speed and its non-invasive character could open new opportunities for the continuous control and monitoring of diabetics and the evaluation of response to treatments (including new therapies), enabling a much more appropriate control of the condition.