Timely Access for Orofacial Cleft Repairs in a Brazilian Amazon Center.

Orofacial clefts are the most common congenital craniofacial anomalies worldwide, and if not managed in a timely manner, can lead to significant complications. We aim to examine surgical timing at one of the few cleft care centers in the North region of Brazil since its foundation in 2016. This retrospective, descriptive study analyzed medical records from 2016 to 2023. We calculated the age at surgery for each time period and each primary surgery performed. We also evaluated the number of procedures performed outside the recommended age . Of the 1439 procedures performed from 2016 to 2023, 713 procedures met our inclusion criteria. Among these, 66.67% (n=188) of primary cheiloplasties, 67.80% (n=40) of primary lip adhesions, and 54.57% (n=203) of palatoplasties were performed outside the recommended time frame. Of the surgeries performed, 45.16% (n=322) were between 2016 and 2019, while 54.84% (n=391) were from 2020 to 2023. Considering procedures performed within the ideal recommended age groups, only 32.92% (n=106) were done between 2016 and 2019, in contrast to 45.01% (n=176) between 2020 and 2023. In conclusion, since the inception of the specialized center, there has been an increase in surgical volume and an improvement in their timing. However, many surgeries are still being conducted outside the recommended time frame.

The Hemileia vastatrix effector HvEC-016 suppresses bacterial blight symptoms in coffee genotypes with the SH 1 rust resistance gene.

A number of genes that confer resistance to coffee leaf rust (SH 1-SH 9) have been identified within the genus Coffea, but despite many years of research on this pathosystem, the complementary avirulence genes of Hemileia vastatrix have not been reported. After identification of H. vastatrix effector candidate genes (HvECs) expressed at different stages of its lifecycle, we established an assay to characterize HvEC proteins by delivering them into coffee cells via the type-three secretion system (T3SS) of Pseudomonas syringae pv. garcae (Psgc). Employing a calmodulin-dependent adenylate cyclase assay, we demonstrate that Psgc recognizes a heterologous P. syringae T3SS secretion signal which enables us to translocate HvECs into the cytoplasm of coffee cells. Using this Psgc-adapted effector detector vector (EDV) system, we found that HvEC-016 suppresses the growth of Psgc on coffee genotypes with the SH 1 resistance gene. Suppression of bacterial blight symptoms in SH 1 plants was associated with reduced bacterial multiplication. By contrast, HvEC-016 enhanced bacterial multiplication in SH 1-lacking plants. Our findings suggest that HvEC-016 may be recognized by the plant immune system in a SH 1-dependent manner. Thus, our experimental approach is an effective tool for the characterization of effector/avirulence proteins of this important pathogen.

Cervico-Mental Angle Suspensory Ligament: The Keystone to Understand the Cervico-Mental Angle and the Ageing Process of the Neck.

The authors performed cadaveric dissections to investigate the existence of an anatomical structure creating and maintaining the cervical mental angle, aiming to understand the anatomical bases of the cervico-mental angle and its modifications over time. Six fresh cadaver dissections were performed; four were done in the Caen University anatomy laboratory one in Paris XV University and one in the Coventry University hospital, England. At the end of this investigation, the authors were able to demonstrate the existence of an anatomical structure in the neck, the cervico-mental angle suspensory ligament. This ligament that fixates the platysma and skin to deeper structures originated from the second branchial arch and seems to play a key role in the formation of the cervico-mental angle and in the anatomical alterations in the ageing process. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Predisposing risk factors for cleft lip and palate in an Amazonian population by focusing on nutritional factors: A case-control study.

BACKGROUND: Orofacial clefts (OFC) are the most common congenital malformation of the craniofacial skeleton. Attempts have been made to correlate the components of maternal diet as triggers for the development or prevention of OFC. OBJECTIVE: To analyze nutritional status as a predictive factor for the development of cleft lip and palate in an Amazonian population. METHODS: A total of 152 mothers within 3 months of delivery were interviewed for comparison: 51 mothers of children with nonsyndromic cleft lip and palate (CLP) (study group) and 101 mothers of children without OFC (control group). A food frequency questionnaire was used to assess maternal nutrition and to analyze the influence of macro- and micronutrients on the possible predisposition or protection for CLP. RESULTS: The study group showed higher percentage of lipid intake than did the control group (p = 0.01). Among the participants with no family history of OFC, the study group had a higher percentage of lipid intake (p = 0.002) and lower vegetable intake (p = 0.037). Maternal micronutrient intake among the participants with a positive family history was lower in the study group for vitamins B2 (p = 0.03), B5 (p = 0.036), E (p = 0.03), and folate (p = 0.022). CONCLUSIONS: Nutritional analysis indicated that higher maternal lipid intake increased the likelihood of having offsprings with nonsyndromic CLP. Moreover, families with a history of OFC and low maternal folate intake showed heightened risk of nonsyndromic CLP in their offsprings.

Cardiac mitochondrial respiration following a low-carbohydrate, high-fat diet in apolipoprotein E-deficient mice.

Low-carbohydrate diets are considered to be an effective approach to weight loss and have, subsequently, grown in popularity. Despite the apparent health benefits that these diets may provide for insulin resistance, hypertension, and dyslipidemia, their implications on cardiomyocyte oxidative capacity have yet to be investigated. To evaluate the adaptations induced by a 6-week low-carbohydrate, high-fat (LCHF) diet on mitochondrial respiration, two groups of male mice were investigated: Apolipoprotein E-deficient mice on a LCHF diet (L-DIET) and apolipoprotein E-deficient mice on a regular rodent diet (CON). Heart tissue was extracted and used for high-resolution respirometry (HRR), while immunoblotting was performed to quantify mitochondrial density and complexes. The results demonstrate increased expression of all five mitochondrial subunits in the L-DIET group compared to control condition. Furthermore, HRR revealed increased efficiency of substrate consumption, implying augmented oxidative capacity in the L-DIET group. These findings further support the notion that cardiomyocytes prefer lipids as a primary fuel source, by demonstrating that the shift in metabolism caused by a LCHF diet facilitates such an environment. This provides important information regarding the effects of a LCHF on cardiomyocytes, especially when considering free radical production and heart dysfunction.

Diuretic activity and neuropharmacological effects of an ethanol extract from Senna septemtrionalis (Viv.) H.S. Irwin & Barneby (Fabaceae).

Ethnopharmacological relevance Senna septemtrionalis (Viv.) H.S. Irwin & Barneby (Fabaceae) is a shrub empirically used as diuretic, and for the treatment of neurological disorders. These pharmacological effects have not been previously evaluated. AIM OF THE STUDY: To evaluate the diuretic and CNS effects of a standardized ethanol extract of Senna septemtrionalis aerial parts (SSE). MATERIALS AND METHODS: Gas chromatography mass spectrometry was used to perform a chemical analysis with SSE. In all tests, SSE was evaluated from 10 to 100 mg/kg p.o. The diuretic activity of SSE was assessed in mice individually placed in metabolic cages. After 6 h, the urine volume and the electrolyte excretion (Na and K) were measured. The role of prostaglandins and nitric oxide was assessed administrating mice with indomethacin and N(ω)-nitro-L-arginine methyl ester (L-NAME), prior the administration of 100 mg/kg SSE. The sedative effects of SSE were analyzed with the pentobarbital-induced sleeping time test. The effects of SSE on motor coordination in mice were evaluated with the rotarod test. The antidepressant-like activity of SSE was analyzed with the forced swimming test (FST) and the tail suspension test (TST). The role of 5-HT2 receptor, α1-and α2-adrenoceptors, or muscarinic receptors was assessed administrating mice with cyproheptadine, prazosin, yohimbine, and atropine, respectively, prior the administration of 100 mg/kg SSE in the FST. The anxiolytic-like activity of SSE (10-100 mg/kg p.o.) was assessed using the light-dark test (LDB), the elevated plus maze test (EPM), the cylinder exploratory test, and the open field test (OFT). The anticonvulsant effect of SSE (1-100 mg/kg) was evaluated in mice administered with different convulsant agents: strychnine, pentylenetetrazol (PTZ), isoniazid (INH) or yohimbine. RESULTS: The main compound found in SSE was D-pinitol (42.2%). SSE (100 mg/kg) increased the urinary volume (2.67-fold), as well as the excretion of Na (5.60-fold) and K (7.2-fold). The co-administration of SSE with L-NAME or indomethacin reverted the diuretic activity shown by SSE alone. SSE lacked sedative effects and did not affect motor coordination in mice. SSE (100 mg/kg) showed higher and similar antidepressant-like effect, compared to 20 mg/kg fluoxetine, in the FST and TST, respectively. The co-administration of SSE with yohimbine reverted the antidepressant-like activity shown by SSE alone. SSE (100 mg/kg) showed anxiolytic-like activity in the four models of anxiety, with similar activity with 1.5 mg/kg clonazepam. The seizure-protective effect of SSE was ED50 = 73.9 ±â€¯8.4 mg/kg (INH) and 40.4 ±â€¯5.2 mg/kg (yohimbine). CONCLUSION: The diuretic effects of SSE involve the possible contribution of prostaglandins and nitric oxide. SSE showed moderate anxiolytic and anticonvulsant effects, whereas the participation of α2-adrenoceptors is probably associated in the antidepressant-like effects of SSE.

Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity.

The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.

Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.

A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.

Facial Reanimation in the Seventh and Eighth Decades of Life.

BACKGROUND: Treatment of facial paralysis in the older population is often relegated to static rather than dynamic reanimation for fear of poor outcomes. This pervasive approach lacks physiologic foundation and is not evidence based. Thus, the authors present an extensive literature review demonstrating weak evidence supporting this misguided concept, followed by detailed outcomes from three centers of the largest reported series to date of patients older than 60 years after reanimation performed using three techniques-lengthening temporalis myoplasty, free functional muscle, and nerve transfers. METHODS: A PubMed search spanning over 40 years identified all reports on reanimation in patients older than 60 years. In addition, detailed demographics, surgical techniques, and outcomes of 30 patients older than 60 years were analyzed. RESULTS: Of 629 articles, only 45 patients were identified, described in case reports or small series, lacking details or consistent long-term follow-up. In the clinical series, average age, preoperative House-Brackmann score, and comorbidities were similar among the groups. Highest excursion was observed in the free functional muscle group, followed by nerve transfer and temporalis myoplasty, averaging 10.4, 6.8, and 3.1 mm, respectively. The most notable philtral deviation correction was in the lengthening temporalis myoplasty group, followed by the free muscle and nerve transfer groups, averaging 5.6, 2.2, and 1.13 mm, respectively. Complication rates were highest in the free functional muscle group. CONCLUSIONS: Facial palsy patients should not be denied dynamic restoration based on age alone. Although surgical technique may vary based on duration of palsy, surgeon experience, and preference, with each presenting advantages and disadvantages, dynamic restoration is feasible regardless of age. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Pre-clinical and clinical evaluation of solution and soft gelatin capsule formulations for a BCS class 3 compound with atypical physicochemical properties.

R1481 is a sub-type selective muscarinic receptor antagonist with the potential treatment of overactive bladder. R1481 presents two challenges for drug development. The first is the viscous semi-solid nature of the active pharmaceutical ingredient (API). The second challenge is the poor oral bioavailability of this water soluble, metabolically stable compound due to low intestinal permeability, and the P-glycoprotein (P-gp) efflux mechanism. Vitamin E TPGS is reported by others to enhance bioavailability by increasing the solubility of active compounds and by inhibiting P-gp in the intestine. In this report, compatibility of R1481 in Capmul MCM-based formulations with and without vitamin E TPGS is summarized. Review of accelerated stability studies of oral formulations led to the identification of a soft gelatin capsule formulation using neat Capmul MCM as an acceptable formulation for Phase 1 clinical studies. Soft gelatin capsules (5 mg strength) were manufactured with and without the addition of vitamin E TPGS. Clinical data show that vitamin E TPGS does not improve systemic exposure of R1481 in humans.