KL1 Domain of Longevity Factor Klotho Mimics the Metabolome of Cognitive Stimulation and Enhances Cognition in Young and Aging Mice.

Cognitive deficits are a major biomedical challenge-and engagement of the brain in stimulating tasks improves cognition in aged individuals (Wilson et al., 2002; Gates et al., 2011) and rodents (Aidil-Carvalho et al., 2017), through unknown mechanisms. Whether cognitive stimulation alters specific metabolic pathways in the brain is unknown. Understanding which metabolic processes are involved in cognitive stimulation is important because it could lead to pharmacologic intervention that promotes biological effects of a beneficial behavior, toward the goal of effective medical treatments for cognitive deficits. Here we show using male mice that cognitive stimulation induced metabolic remodeling of the mouse hippocampus, and that pharmacologic treatment with the longevity hormone α-klotho (KL), mediated by its KL1 domain, partially mimicked this alteration. The shared, metabolic signature shared between cognitive stimulation and treatment with KL or KL1 closely correlated with individual mouse cognitive performance, indicating a link between metabolite levels and learning and memory. Importantly, the treatment of mice with KL1, an endogenous circulating factor that more closely mimicked cognitive stimulation than KL, acutely increased synaptic plasticity, a substrate of cognition. KL1 also improved cognition, itself, in young mice and countered deficits in old mice. Our data show that treatments or interventions mimicking the hippocampal metabolome of cognitive stimulation can enhance brain functions. Further, we identify the specific domain by which klotho promotes brain functions, through KL1, a metabolic mimic of cognitive stimulation.SIGNIFICANCE STATEMENT Cognitive deficits are a major biomedical challenge without truly effective pharmacologic treatments. Engaging the brain through cognitive tasks benefits cognition. Mimicking the effects of such beneficial behaviors through pharmacological treatment represents a highly valuable medical approach to treating cognitive deficits. We demonstrate that brain engagement through cognitive stimulation induces metabolic remodeling of the hippocampus that was acutely recapitulated by the longevity factor klotho, mediated by its KL1 domain. Treatment with KL1, a close mimic of cognitive stimulation, enhanced cognition and countered cognitive aging. Our findings shed light on how cognition metabolically alters the brain and provide a plausible therapeutic intervention for mimicking these alterations that, in turn, improves cognition in the young and aging brain.

Successful Management of Heterotopic Cervical Pregnancy with Ultrasonographic-guided Laser Ablation.

Heterotopic pregnancy refers to the simultaneous presence of ectopic pregnancy and intrauterine pregnancy. With the advent of assisted reproductive technology, the overall incidence of heterotopic pregnancies has risen. We report a case of a 36-year-old woman with type 2 diabetes mellitus and 1-year of primary infertility. Following oral ovulation induction cycles and intrauterine insemination, diagnosis of heterotopic cervical pregnancy was made by ultrasonography at 7.4 weeks of gestation. Laser ablation of the cervical pregnancy was performed achieving adequate homeostasis at the implantation site and preserving the intrauterine pregnancy. A healthy infant was delivered at 36 0/7 weeks by cesarean section. Laser ablation is a minimally invasive procedure that appears to lead to successful outcomes in the treatment of heterotopic cervical pregnancy.

Altered expression of diabetes-related genes in Alzheimer's disease brains: the Hisayama study.

Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM.

Sandfly (Diptera: Psychodidae: Phlebotominae) species diversity in an urban area of the municipality of Tapachula, Chiapas, Mexico.

Monitoring phlebotomine sandflies in urban areas is key for epidemiological studies in susceptible populations. This paper describes sandfly fauna that were present in an urban area of the municipality of Tapachula, Chiapas, Mexico, and were captured with Shannon and CDC light traps. During February and March of 2014, 1,442 sandflies were captured, specifically Lutzomyia cruciata (Coquillet) (98.8%), Lutzomyia cayennensis cayennensis (Floch and Abonnenc) (0.8%), Lutzomyia chiapanensis (Dampf) (0.3%) and Lutzomyia atulapai (De León) (0.1%). Lu. cruciata was the most abundant and the most frequently trapped species. This is the first record of its remarkable ability to adapt to urban green areas. The three other species trapped represent new records of geographic distribution for the study region. These results indicate the need to establish measures for reducing both human contact with this vector and the risk of possible sites of infection.

Quantitative Evaluation of Vocal Bowing Following Bilateral Thyroplasty in Age-Related Vocal Atrophy.

OBJECTIVE: Age-related vocal atrophy (ARVA) is associated with vocal fold bowing, persistent glottal gap during phonation, and dysphonia. Bilateral medialization thyroplasty is sometimes performed in patients with ARVA to improve vocal fold closure and voice. We set out to quantify stroboscopic changes in vocal fold bowing, glottal closure, and abduction angle following bilateral thyroplasty and determine how these changes affect voice quality among patients with ARVA. METHODS: Fifteen individuals with ARVA who underwent bilateral medialization thyroplasty were included in this study. Two independent investigators calculated bowing index (BI), normalized glottal gap area (NGGA), and maximum abduction angle from laryngostroboscopic exams using ImageJ™. Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) and patient-reported measures were collected before and after thyroplasty. RESULTS: Thyroplasty resulted in a 10-point improvement in overall CAPE-V (Mean dif -10; 95% CI -17, -3.3, p < 0.01) and VHI-10 (mean dif -3.8; 95% CI -9.8, 2.3, p = 0.19, n = 8). NGGA and BI significantly decreased following surgery (mean dif -78; 95% CI -155, -1.5, p = 0.05; and mean dif -2.1; 95% CI -2.4, -0.84, p < 0.01, respectively). BI correlated with CAPE-V scores (r = 0.66, 95% CI 0.22, 0.87, p < 0.01). When considering the normalized combined contributions of both NGGA and BI, there was a stronger correlation in CAPE-V scores (r = 0.87, 95% CI 0.50, 0.97, p < 0.01) compared with either measure alone. CONCLUSIONS: Thyroplasty resulted in a decrease in vocal fold bowing, glottal gap area, and CAPE-V scores in patients with ARVA. Correction of vocal bowing and glottal gap, following bilateral thyroplasty, improved voice measures following surgery. Quantitative evaluation of vocal fold morphology may be valuable when assessing the severity and treatment-response in patients with ARVA following bilateral thyroplasty. Laryngoscope, 134:835-841, 2024.

Neurophysiology of the Superior Laryngeal Nerve in an In Vivo Rat Model.

OBJECTIVE: The superior laryngeal nerve (SLN) is fundamental in laryngeal sensation, cough reflex, and pitch control. SLN injury has substantial consequences including altered sensation, aspiration, and dysphonia. To date, in vivo measurement of the SLN remains elusive. The purpose of this study was to assess the feasibility of recording motor and sensory evoked potentials in a rat SLN model. METHODS: Twenty-two rat hemi-laryngeal preparations (n = 11) were obtained from 4-month-old Sprague-Dawley rats and included in this study. Compound motor action potentials (CMAPs) and motor unit number estimation (MUNE) were calculated by stimulating the SLN at the point of medial extension near the carotid artery and by placing a recording electrode on the cricothyroid muscle. Sensory response was determined through stimulation of the SLN and laryngoscopic visualization of a laryngeal adductor reflex (LAR). SLN and cricothyroid muscle cross-sections were stained and histologic morphometrics were quantified. RESULTS: Laryngeal evoked potentials were successfully obtained in all trials. Mean CMAP latency and negative durations were 0.99 ± 0.57 ms and 1.49 ± 0.57 ms, respectively. The median MUNE was 2.06 (IQR 1.88, 3.51). LAR was induced with a mean intensity of 0.69 ± 0.20 mV. Mean axon count, myelin thickness, and g-ratio were 681 ± 192.2, 1.72 ± 0.26, and 0.45 ± 0.04, respectively. CONCLUSIONS: This study demonstrates the feasibility of recording evoked response potentials following SLN stimulation. We hypothesize that this work will provide a tractable animal model to study changes in laryngeal sensation and cricothyroid motor function with aging, neurodegenerative disease, aspiration, or nerve injury. LEVEL OF EVIDENCE: NA Laryngoscope, 134:1778-1784, 2024.

Clinical validation of RCSMS: A rapid and sensitive CRISPR-Cas12a test for the molecular detection of SARS-CoV-2 from saliva.

Peru's holds the highest COVID death rate per capita worldwide. Key to this outcome is the lack of robust, rapid, and accurate molecular tests to circumvent the elevated costs and logistics of SARS-CoV-2 detection via RT-qPCR. To facilitate massive and timely COVID-19 testing in rural and socioeconomically deprived contexts, we implemented and validated RCSMS, a rapid and sensitive CRISPR-Cas12a test for the molecular detection of SARS-CoV-2 from saliva. RCSMS uses the power of CRISPR-Cas technology and lateral flow strips to easily visualize the presence of SARS-CoV-2 even in laboratories with limited equipment. We show that a low-cost thermochemical treatment with TCEP/EDTA is sufficient to inactivate viral particles and cellular nucleases in saliva, eliminating the need to extract viral RNA with commercial kits, as well as the cumbersome nasopharyngeal swab procedure and the requirement of biosafety level 2 laboratories for molecular analyses. Notably, RCSMS performed outstandingly in a clinical validation done with 352 patients from two hospitals in Lima, detecting as low as 50 viral copies per 10 µl reaction in 40 min, with sensitivity and specificity of 96.5% and 99.0%, respectively, relative to RT-qPCR. The negative and positive predicted values obtained from this field validation indicate that RCSMS can be confidently deployed in both high and low prevalence settings. Like other CRISPR-Cas-based biosensors, RCSMS can be easily reprogrammed for the detection of new SARS-CoV-2 variants. We conclude that RCSMS is a fast, efficient and inexpensive alternative to RT-qPCR for expanding COVID-19 testing capacity in Peru and other low- and middle-income countries with precarious healthcare systems.

[Comparison of Doppler flowmetry in brachial artery in Mexican postmenopausal women with and without symptoms]. / Comparación de la flujometria doppler de la arteria braquial en mujeres posmenopáusicas mexicanas con y sin sintomas vasomotores.

BACKGROUND: Brachial artery doppler fluxometry permits to evaluate the endothelial function in a non-invasive way. OBJECTIVE: To know the effect of vasomotor symptoms in brachial artery flux ultrasonographic parameters in Mexican postmenopausal women. MATERIAL AND METHODS: A prospective study was done including postmenopausal women divided into two groups: I) without hot-flushes and II) with hot-flushes. To all them Doppler fluxometry was done. The pulsatility index resistance index and arterial diameter were determined previous and after the hyperemic stimulus. The intensity of vasomotor symptoms (hot-flushes, throbs and sweatings) was determined using an analog visual scale; and the number of each one of them was determined. For statistical analysis Student t test for independent and paired samples was used. Correlation analysis was done between age, time since menopause, hot flushes, throbs and sweating with pulsatility index, resistance index and arterial diameter previous and after hyperemic stimulus. RESULTS: Thirty patients were divided into two groups of 15 women each. No differences were found between the groups neither in age, anthropometric variables, pulsatility index, resistance index nor arterial diameter neither before nor after hyperemic stimulus; only there was a statistically significant increase in arterial diameter after hyperemic stimulus in group I (p < 0.001). In group I a positive correlation was found between age and baseline resistance index and in group II between baseline resistance index and the number of throbs per week. CONCLUSION: Women with hot-flushes have a healthier endothelium.

Results From a Virtual Clinic for the Follow-up of Patients Using the Advanced Hybrid Closed-Loop System.

BACKGROUND: Evidence regarding the implementation of medium-term strategies in advanced hybrid closed-loop (AHCL) system users is limited. Therefore, this study aimed to describe the efficacy and safety of the AHCL system in patients with type 1 diabetes (T1D) on a six-month follow-up in a virtual diabetes clinic (VDC). METHOD: A prospective cohort of adult patients with T1D treated using the AHCL system (Mini Med 780G; Medtronic, Northridge, California) in a VDC follow-up. Standardized training and follow-up were conducted virtually. Clinical data and metabolic control outcomes were reported at baseline, and at three and six months. RESULTS: Sixty-four patients (mean age = 42 ± 14.6 years, 65% men, 54% with graduate education) were included. Percentage time in range (%TIR) increased significantly regardless of prior therapy with intermittently scanned continuous glucose monitoring + multiple daily injections and sensor-augmented pump therapy with predictive low-glucose management after starting AHCL and persisted during the follow-up period with no hypoglycemic events. The %TIR 70 to 180 mg/dL according to socioeconomic strata was 73.4% ± 5.3%, 78.1% ± 8.1%, and 84.2% ± 7.5% for the lower, middle, and upper strata, respectively. The sensor was used more frequently in the population with a higher education level. Adherence to sensor use and SmartGuard retention were higher in patients who underwent the VDC follow-up. CONCLUSIONS: Medium-term follow-up of users of AHCL systems in a VDC contributes to safely achieving %TIR goals. Virtual diabetes clinic follow-up favored adherence to sensor use and continuous SmartGuard use. Socioeconomic strata were associated with a better glycemic profile and education level was associated with better adherence to sensor use.

Spontaneous rupture and upper gastrointestinal bleeding of solid pseudopapillary neoplasm of the pancreas.

The solid pseudopapillary neoplasm (SPN) of the pancreas is an uncommon, low-grade malignant tumour, mostly seen in young women. We report a rare case of a 44-year-old female who presented with spontaneous rupture and upper gastrointestinal bleeding. The emergency endoscopy revealed a 2 cm bleeding ulcer on the duodenal bulb. A computer tomography scan (CT scan) showed a 6.7 cm mass, with solid and cystic components arising in the head of the pancreas. After achieving haemostasis, she was discharged. Two months later, a new CT scan showed a persistent 6 cm mass in the head of the pancreas, now containing air and communicating with the duodenal lumen. The patient was successfully treated by pancreatoduodenectomy. Histopathological examination showed a T3N0M0 SPN with immunohistochemical expression of ß-catenin, synaptophysin, vimentin and progesterone receptor, and negativity for chromogranin. The labelling index of Ki 67 was 2%. No recurrence was present after 2 years of follow-up.

MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis.

8-Oxoguanine (8-oxoG), a major oxidative base lesion, is highly accumulated in Alzheimer's disease (AD) brains during the pathogenic process. MTH1 hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby avoiding 8-oxo-dG incorporation into DNA. 8-OxoG DNA glycosylase-1 (OGG1) excises 8-oxoG paired with cytosine in DNA, thereby minimizing 8-oxoG accumulation in DNA. Levels of MTH1 and OGG1 are significantly reduced in the brains of sporadic AD cases. To understand how 8-oxoG accumulation in the genome is involved in AD pathogenesis, we established an AD mouse model with knockout of Mth1 and Ogg1 genes in a 3xTg-AD background. MTH1 and OGG1 deficiency increased 8-oxoG accumulation in nuclear and, to a lesser extent, mitochondrial genomes, causing microglial activation and neuronal loss with impaired cognitive function at 4-5 months of age. Furthermore, minocycline, which inhibits microglial activation and reduces neuroinflammation, markedly decreased the nuclear accumulation of 8-oxoG in microglia, and inhibited microgliosis and neuronal loss. Gene expression profiling revealed that MTH1 and OGG1 efficiently suppress progression of AD by inducing various protective genes against AD pathogenesis initiated by Aß/Tau accumulation in 3xTg-AD brain. Our findings indicate that efficient suppression of 8-oxoG accumulation in brain genomes is a new approach for prevention and treatment of AD.

Urinary prolactin as a reliable marker for preeclampsia, its severity, and the occurrence of adverse pregnancy outcomes.

CONTEXT: It has been proposed that preeclampsia may result from of an imbalance in angiogenic factors. Although prolactin (PRL) is mainly related to lactation, it is also involved in other biological functions, including angiogenesis. OBJECTIVE: Our objective was to determine the relationship among preeclampsia, serum and urinary PRL (uPRL) levels, and excretion of antiangiogenic PRL fragments in urine. STUDY DESIGN: Using a cross-sectional design, uPRL and serum PRL levels, and the presence of PRL isoforms were determined in 546 pregnant women: 207 healthy pregnant, 124 with gestational hypertension, 48 with mild preeclampsia, and 167 with severe preeclampsia (sPE). RESULTS: uPRL concentrations were significantly (P < 0.001) higher in preeclampsia (11.99 ng/mg creatinine) than in healthy pregnancy (0.20 ng/mg creatinine) and gestational hypertension (0.19 ng/mg creatinine), and were even higher in sPE compared with mild preeclampsia (21.20 vs. 2.77 ng/mg creatinine, respectively; P < 0.001). Antiangiogenic PRL fragments (14-16 kDa) were detected in 21.6% of urine samples from women with sPE but in none from other groups. Patients with hemolysis, elevated liver enzymes, low platelet count syndrome, and/or eclampsia, placental abruption, acute renal failure, and pulmonary edema exhibited highest uPRL concentrations (P < or = 0.028) and frequency of antiangiogenic PRL fragments in urine (P < or = 0.036). High-serum PRL levels were associated with sPE independently of gestational age, proteinuria, and prolactinuria (P = 0.032). CONCLUSIONS: Preeclampsia is characterized by increased uPRL excretion. uPRL concentrations and their isoforms appear to be suitable markers to assess the severity of preeclampsia and occurrence of adverse outcomes. PRL and and/or its isoforms might be involved in the pathophysiology of preeclampsia.

[Umbilical artery Doppler velocimetry and adverse perinatal outcome in severe pre-eclampsia]. / Velocimetría Doppler de la arteria umbilical y resultado perinatal adverso en preeclampsia severa.

BACKGROUND: Abnormal placentation is a main preeclampsia characteristic. Its cause is a maternal spiral veins trophoblastic invasion failure, which conditions vascular resistances raise and uterus-placental perfusion decrease. OBJECTIVE: To determine the relationship between umbilical artery Doppler waveform and adverse perinatal outcome in patients with severe preeclampsia. PATIENTS AND METHOD: A prospective, observational and transversal study was done to analyze patients between 27 to 33 weeks of gestation with expectant management of severe preeclampsia from January 2004 to January 2006. Umbilical artery velocimetry studies were performed at least once a week by means of pulsed Doppler equipment with a 3.5 MHz transducer. Only the results of the last Doppler examination performed within 7 days of delivery were considered in the correlation with perinatal outcomes. The indications for delivery were maternal or fetal (non reassuring nonstress test or biophysical profile < or = 4). An abnormal Doppler velocimetry was defined as pulsatility index being higher than percentile 95 for gestational age, or absent or reversed end diastolic velocity waveforms in umbilical artery. The statistical analysis was done with chi2 test and Student t test. RESULTS: There were included 43 patients in this study. Twenty-two (52%) had an abnormal Doppler umbilical artery pulsatility index and 21 (49%) obtained a normal umbilical artery waveform. In the first group 13 (59%) had a positive end diastolic velocities with elevated pulsatility index values, end diastolic velocities were absent in seven cases (32%) and reversed in two cases (9%). Neonates with abnormal pulsatility index had a lower birth weight (1,174 vs 1,728 g), lower Apgar score at 5 minutes, higher admission to the neonatal intensive care unit (86.4 vs 43%), and significant neonatal morbidity compared with those with normal velocimetry (p < 0.05). There were no perinatal deaths with normal umbilical Doppler waveform. There were six perinatal deaths in the abnormal Doppler velocimetry. Two cases occurred with positive end diastolic velocity (15%), two cases with absent end diastolic velocity (28%) and two deaths with reversed flow of the umbilical artery (100%). CONCLUSION: An abnormal Doppler umbilical artery waveform is associated with poor perinatal outcome and is a strong predictor of perinatal mortality.

Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer's disease brain.

In normal brain, neurons in the cortex and hippocampus produce insulin, which modulates glucose metabolism and cognitive functions. It has been shown that insulin resistance impairs glucose metabolism and mitochondrial function, thus increasing production of reactive oxygen species. Recent progress in Alzheimer's disease (AD) research revealed that insulin production and signaling are severely impaired in AD brain, thereby resulting in mitochondrial dysfunction and increased oxidative stress. Among possible oxidative DNA lesions, 8-oxoguanine (8-oxoG) is highly accumulated in the brain of AD patients. Previously we have shown that incorporating 8-oxoG in nuclear and mitochondrial DNA promotes MUTYH (adenine DNA glycosylase) dependent neurodegeneration. Moreover, cortical neurons prepared from MTH1 (8-oxo-dGTPase)/OGG1 (8-oxoG DNA glycosylase)-double deficient adult mouse brains is shown to exhibit significantly poor neuritogenesis in vitro with increased 8-oxoG accumulation in mitochondrial DNA in the absence of antioxidants. Therefore, 8-oxoG can be considered involved in the neurodegenerative process in AD brain. In mild cognitive impairment, mitochondrial dysfunction and oxidative damage may induce synaptic dysfunction due to energy failures in neurons thus resulting in impaired cognitive function. If such abnormality lasts long, it can lead to vicious cycles of oxidative damage, which may then trigger the neurodegenerative process seen in Alzheimer type dementia.

Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and α-Synuclein Transgenic Mice.

Cognitive dysfunction and decreased mobility from aging and neurodegenerative conditions, such as Parkinson and Alzheimer diseases, are major biomedical challenges in need of more effective therapies. Increasing brain resilience may represent a new treatment strategy. Klotho, a longevity factor, enhances cognition when genetically and broadly overexpressed in its full, wild-type form over the mouse lifespan. Whether acute klotho treatment can rapidly enhance cognitive and motor functions or induce resilience is a gap in our knowledge of its therapeutic potential. Here, we show that an α-klotho protein fragment (αKL-F), administered peripherally, surprisingly induced cognitive enhancement and neural resilience despite impermeability to the blood-brain barrier in young, aging, and transgenic α-synuclein mice. αKL-F treatment induced cleavage of the NMDAR subunit GluN2B and also enhanced NMDAR-dependent synaptic plasticity. GluN2B blockade abolished αKL-F-mediated effects. Peripheral αKL-F treatment is sufficient to induce neural enhancement and resilience in mice and may prove therapeutic in humans.

Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation.

Alzheimer's disease (AD) is the most common form of dementia, characterized by accumulation of amyloid ß (Aß) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Aß pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App NL-G-F/NL-G-F and 3xTg-AD-H mouse models. Genes commonly altered in App NL-G-F/NL-G-F and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App NL-G-F/NL-G-F cortex as Aß amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App NL-G-F/NL-G-F cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Aß amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD.

8-Oxoguanine accumulation in mitochondrial DNA causes mitochondrial dysfunction and impairs neuritogenesis in cultured adult mouse cortical neurons under oxidative conditions.

Oxidative stress and mitochondrial dysfunction are implicated in aging-related neurodegenerative disorders. 8-Oxoguanine (8-oxoG), a common oxidised base lesion, is often highly accumulated in brains from patients with neurodegenerative disorders. MTH1 hydrolyses 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dGTP) to 8-oxo-dGMP and pyrophosphate in nucleotide pools, while OGG1 excises 8-oxoG paired with cytosine in DNA, thereby minimising the accumulation of 8-oxoG in DNA. Mth1/Ogg1-double knockout (TO-DKO) mice are highly susceptible to neurodegeneration under oxidative conditions and show increased accumulation of 8-oxoG in mitochondrial DNA (mtDNA) in neurons, suggesting that 8-oxoG accumulation in mtDNA causes mitochondrial dysfunction. Here, we evaluated the contribution of MTH1 and OGG1 to the prevention of mitochondrial dysfunction during neuritogenesis in vitro. We isolated cortical neurons from adult wild-type and TO-DKO mice and maintained them with or without antioxidants for 2 to 5 days and then examined neuritogenesis. In the presence of antioxidants, both TO-DKO and wild-type neurons exhibited efficient neurite extension and arborisation. However, in the absence of antioxidants, the accumulation of 8-oxoG in mtDNA of TO-DKO neurons was increased resulting in mitochondrial dysfunction. Cells also exhibited poor neurite outgrowth with decreased complexity of neuritic arborisation, indicating that MTH1 and OGG1 are essential for neuritogenesis under oxidative conditions.

Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer's disease.

In the mitochondria-mediated vicious cycle of Alzheimer's disease (AD), intracellular amyloid ß (Aß) induces mitochondrial dysfunction and reactive oxygen species, which further accelerate Aß accumulation. This vicious cycle is thought to play a pivotal role in the development of AD, although the molecular mechanism remains unclear. Here, we examined the effects of human mitochondrial transcriptional factor A (hTFAM) on the pathology of a mouse model of AD (3xTg-AD), because TFAM is known to protect mitochondria from oxidative stress through maintenance of mitochondrial DNA (mtDNA). Expression of hTFAM significantly improved cognitive function, reducing accumulation of both 8-oxoguanine, an oxidized form of guanine, in mtDNA and intracellular Aß in 3xTg-AD mice and increasing expression of transthyretin, known to inhibit Aß aggregation. Next, we found that AD model neurons derived from human induced pluripotent stem cells carrying a mutant PSEN1(P117L) gene, exhibited mitochondrial dysfunction, accumulation of 8-oxoguanine and single-strand breaks in mtDNA, and impaired neuritogenesis with a decreased expression of transthyretin, which is known to be downregulated by oxidative stress. Extracellular treatment with recombinant hTFAM effectively suppressed these deleterious outcomes. Moreover, the treatment increased expression of transthyretin, accompanied by reduction of intracellular Aß. These results provide new insights into potential novel therapeutic targets.

Luxación aislada de codo en niños menores de 10 años: reporte de dos casos / Isolated elbow dislocation in children under 10 years of age. Report of two cases

La luxación de codo aislada es muy infrecuente en esqueletos inmaduros. El manejo y el tratamiento no están estandarizados debido a la baja casuística. Las luxaciones aisladas en niños <10 años constituyen un cuadro descrito como evidencia compartida en estudios de niños más grandes. El objetivo de este artículo es comunicar dos casos de luxación aislada de codo en niños <10 años. Los niños consultan a la unidad de urgencias por dolor y deformidad en el codo a las pocas horas del trauma. En ambos casos, se realizaron evaluaciones clínicas y radiográficas en busca de lesiones asociadas antes de la reducción cerrada y después. Se descartó inestabilidad articular bajo anestesia y se inmovilizó por dos semanas. Los resultados funcionales fueron excelentes en ambos casos, a los tres meses de la lesión. Nivel de Evidencia: IV

Isolated elbow dislocation is extremely rare in immature skeletons. Due to the low casuistry, the management and treatment are not standardized. Isolated dislocations in children under 10 years of age constitute a pathology described as shared evidence in studies of older children. The objective of this report is to share the experience of two cases of isolated elbow dislocation in children under 10 years of age. The children consult the emergency unit about pain and elbow deformity a few hours after the trauma. For each case, a clinical and radiological evaluation was developed in search of associated lesions before and after closed reduction. Joint instability was ruled out under anesthesia and the patient is immobilized for two weeks. Excellent functional outcomes were obtained in both cases three months after the injury. Level of Evidence: IV