Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke.

Ischemic strokes are highly prevalent in the elderly population and are a leading cause of mortality and morbidity worldwide. The risk of ischemic stroke increases in advanced age, corresponding with a noted decrease in circulating insulin growth factor-1 (IGF-1). IGF-1 is a known neuroprotectant involved in embryonic development, neurogenesis, neurotransmission, cognition, and lifespan. Clinically, several studies have shown that reduced levels of IGF-1 correlate with increased mortality rate, poorer functional outcomes, and increased morbidities following an ischemic stroke. In animal models of ischemia, administering exogenous IGF-1 using various routes of administration (intranasal, intravenous, subcutaneous, or topical) at various time points prior to and following insult attenuates neurological damage and accompanying behavioral changes caused by ischemia. However, there are some contrasting findings in select clinical and preclinical studies. This review discusses the role of IGF-1 as a determinant factor of ischemic stroke outcomes, both within the clinical settings and preclinical animal models. Furthermore, the review provides insight on the role of IGF-1 in mechanisms and cellular processes that contribute to stroke damage.

Clinical repercussions and epidemiological considerations of supernumerary canines: A 26 case series.

BACKGROUND: To establish the prevalence of supernumerary canines (SNC) in a sector of the population of Madrid (Spain), as well possible complications associated with this unusual developmental variation. STUDY DESIGN: This observational study was performed between 2005 and 2017, among 21,615 patients seeking dental treatment at the Faculty of Dentistry, Complutense University of Madrid (Spain), and at the Virgen de la Paloma Hospital, Madrid (Spain); 22 patients with 26 SNCs were diagnosed. These 22 patients underwent clinical and radiological exploration, registering patient data. RESULTS: SNCs presented a prevalence of 0.10% of the study population. The supernumerary teeth (SNT) were located in the upper maxilla more frequently (61.54%) than the mandible (38.46%). 69.23% were found to be impacted, also causing the impaction of the permanent canine in 53.85% of these cases. In 15.38%, follicular expansion > 3mm was observed. SNCs were associated with other SNT in only four patients. CONCLUSIONS: Despite of the fact that the SNCs are usually diagnosed casually in the course of radiological exploration, in the present study over half of them (53.85%) caused impaction of the permanent canine. Early diagnosis allows optimal patient management and treatment planning, with intervention at an appropriate time to prevent complications in development and so reduce later treatment need.

Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype.

Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2+/+ and Nrf2-/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2-/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.

Correction to: Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice.

The original version of this article unfortunately contained an error.

Masseter and temporalis muscle electromyography findings after lower third molar extraction.

BACKGROUND: The main clinical application of electromyography is to detect abnormalities in muscle function, to assess muscle activity for purposes of recruitment, and in the biomechanics of movement. OBJECTIVES: To analyze electromyography (EMG) findings for masticatory muscles during chewing following surgical extraction of lower third molars, and to determine any correlation between pain, inflammation, trismus, and the EMG data registered. MATERIAL AND METHODS: This prospective study included 31 patients. Surface EMG was used to study masseter and temporalis muscle function before lower third molar extraction and 72 hours and seven days after surgery. Clinical variables, pain, inflammation, and trismus were registered before and after surgery. RESULTS: Studying the area and size of the masticatory muscles, higher values were found for temporalis than masseter muscles, regardless of the surgical side, which points to the greater involvement of the temporalis muscle in mastication. Comparing the side where surgery had been performed with the non-surgical side, a sharp and statistically significant reduction in amplitude and area were noted on the surgical side reflecting major functional affectation. One week after surgery, amplitude and area had almost returned to base-line values, indicating almost complete recovery. While pain decreased progressively after surgery, inflammation peaked at 72 hours, while mouth opening reached a minimum at this time, returning to normality within the week. CONCLUSIONS: Surgical extraction of lower third molars produces changes to electromyography activity that are more evident during the first hours after surgery and closely related to the intensity of pain suffered and the patient's inflammatory responses, although they are not related to mouth opening capacity.

Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice.

There is correlative evidence that impaired cerebral blood flow (CBF) regulation, in addition to promoting cognitive impairment, is also associated with alterations in gait and development of falls in elderly people. CBF is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism becomes progressively impaired with age. To establish a direct cause-and-effect relationship between impaired NVC and gait abnormalities, we induced neurovascular uncoupling pharmacologically in young C57BL/6 mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MSPPOH, the NO synthase inhibitor L-NAME, and the COX inhibitor indomethacin significantly decreased NVC mimicking the aging phenotype. Pharmacologically induced neurovascular uncoupling significantly decreased the dynamic gait parameter duty cycle, altered footfall patterns, and significantly increased phase dispersion, indicating impaired interlimb coordination. Impaired NVC also tended to increase gait variability. Thus, selective experimental disruption of NVC causes subclinical gait abnormalities, supporting the importance of CBF in both cognitive function and gait regulation.

Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer's disease.

Hypertension in the elderly substantially increases both the risk of vascular cognitive impairment (VCI) and Alzheimer's disease (AD); however, the underlying mechanisms are not completely understood. This review discusses the effects of hypertension on structural and functional integrity of cerebral microcirculation, including hypertension-induced alterations in neurovascular coupling responses, cellular and molecular mechanisms involved in microvascular damage (capillary rarefaction, blood-brain barrier disruption), and the genesis of cerebral microhemorrhages and their potential role in exacerbation of cognitive decline associated with AD. Understanding and targeting the hypertension-induced cerebromicrovascular alterations that are involved in the onset and progression of AD and contribute to cognitive impairment are expected to have a major role in preserving brain health in high-risk older individuals.

Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype: implications for the pathogenesis of vascular cognitive impairment.

Strong epidemiological and experimental evidence indicates that hypertension has detrimental effects on the cerebral microcirculation and thereby promotes accelerated brain aging. Hypertension is an independent risk factor for both vascular cognitive impairment (VCI) and Alzheimer's disease (AD). However, the pathophysiological link between hypertension-induced cerebromicrovascular injury (e.g., blood-brain barrier disruption, increased microvascular oxidative stress, and inflammation) and cognitive decline remains elusive. The present study was designed to characterize neuronal functional and morphological alterations induced by chronic hypertension and compare them to those induced by aging. To achieve that goal, we induced hypertension in young C57BL/6 mice by chronic (4 weeks) infusion of angiotensin II. We found that long-term potentiation (LTP) of performant path synapses following high-frequency stimulation of afferent fibers was decreased in hippocampal slices obtained from hypertensive mice, mimicking the aging phenotype. Hypertension and advanced age were associated with comparable decline in synaptic density in the stratum radiatum of the mouse hippocampus. Hypertension, similar to aging, was associated with changes in mRNA expression of several genes involved in regulation of neuronal function, including down-regulation of Bdnf, Homer1, and Dlg4, which may have a role in impaired synaptic plasticity. Collectively, hypertension impairs synaptic plasticity, reduces synaptic density, and promotes dysregulation of genes involved in synaptic function in the mouse hippocampus mimicking the aging phenotype. These hypertension-induced neuronal alterations may impair establishment of memories in the hippocampus and contribute to the pathogenesis and clinical manifestation of both vascular cognitive impairment (VCI) and Alzheimer's disease (AD).

Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence.

Whole brain irradiation (WBI) is a mainstream therapy for patients with both identifiable brain metastases and prophylaxis for microscopic malignancies. However, it also promotes accelerated senescence in healthy tissues and leads to progressive cognitive dysfunction in up to 50% of tumor patients surviving long term after treatment, due to γ-irradiation-induced cerebromicrovascular injury. Moment-to-moment adjustment of cerebral blood flow (CBF) via neuronal activity-dependent cerebromicrovascular dilation (functional hyperemia) has a critical role in maintenance of healthy cognitive function. To determine whether cognitive decline induced by WBI associates with impaired cerebromicrovascular function, C56BL/6 mice (3 months) subjected to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks) and control mice were compared. Mice were tested for spatial memory performance (radial arm water maze), sensorimotor coordination (computerized gait analysis, CatWalk), and cerebromicrovascular function (whisker-stimulation-induced increases in CBF, measured by laser Doppler flowmetry) at 3 to 6 months post-irradiation. We found that mice with WBI exhibited impaired cerebromicrovascular function at 3 months post-irradiation, which was associated with impaired performance in the radial arm water maze. At 6 months, post-irradiation progressive impairment in gait coordination (including changes in the regularity index and phase dispersion) was also evident. Collectively, our findings provide evidence for early and persisting neurovascular impairment after a clinically relevant protocol of fractionated WBI, which predict early manifestations of cognitive impairment.

Unicystic Ameloblastoma: Rehabilitation with Chin Graft Harvested and Implant-Supported Fixed Prosthesis.

OBJECTIVE: The objective is to present a clinical case of a 38-year-old male with a maxillary unicystic ameloblastoma treated by means of tumor block resection followed by chin-harvested graft placement in order to place two dental implants for esthetic and functional rehabilitation. METHODS: Ameloblastoma is a benign odontogenic tumor characterized by local aggression and a high rate of recurrence; the latter partly depends on how it is treated. Complete resection of the tumor, which usually prevents recurrence, produces bone defects of varying size that must be reconstructed later on. In most cases this is done using bone grafts and implant-supported prostheses. Grafts harvested from the chin are relatively easy to obtain and enjoy a fairly uneventful post-operative with few complications; they are suitable for cases in which the defect generated by resection is of small size. RESULTS: Functional and esthetic rehabilitation and the tumor has not relapsed during a 7-year follow-up. CONCLUSION: Tumor block resection followed by chin-harvested graft placement and dental implants is a safe treatment for patients with unicystic ameloblastoma.

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging.

Strong epidemiological and experimental evidence indicate that both age and hypertension lead to significant functional and structural impairment of the cerebral microcirculation, predisposing to the development of vascular cognitive impairment (VCI) and Alzheimer's disease. Preclinical studies establish a causal link between cognitive decline and microvascular rarefaction in the hippocampus, an area of brain important for learning and memory. Age-related decline in circulating IGF-1 levels results in functional impairment of the cerebral microvessels; however, the mechanistic role of IGF-1 deficiency in impaired hippocampal microvascularization remains elusive. The present study was designed to characterize the additive/synergistic effects of IGF-1 deficiency and hypertension on microvascular density and expression of genes involved in angiogenesis and microvascular regression in the hippocampus. To achieve that goal, we induced hypertension in control and IGF-1 deficient mice (Igf1 f/f  + TBG-Cre-AAV8) by chronic infusion of angiotensin II. We found that circulating IGF-1 deficiency is associated with decreased microvascular density and exacerbates hypertension-induced microvascular rarefaction both in the hippocampus and the neocortex. The anti-angiogenic hippocampal gene expression signature observed in hypertensive IGF-1 deficient mice in the present study provides important clues for subsequent studies to elucidate mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of VCI. In conclusion, adult-onset, isolated endocrine IGF-1 deficiency exerts deleterious effects on the cerebral microcirculation, leading to a significant decline in cortical and hippocampal capillarity and exacerbating hypertension-induced cerebromicrovascular rarefaction. The morphological impairment of the cerebral microvasculature induced by IGF-1 deficiency and hypertension reported here, in combination with neurovascular uncoupling, increased blood-brain barrier disruption and neuroinflammation reported in previous studies likely contribute to the pathogenesis of vascular cognitive impairment in elderly hypertensive humans.

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis.

Epidemiological findings support the concept of Developmental Origins of Health and Disease, suggesting that early-life hormonal influences during a sensitive period of development have a fundamental impact on vascular health later in life. The endocrine changes that occur during development are highly conserved across mammalian species and include dramatic increases in circulating IGF-1 levels during adolescence. The present study was designed to characterize the effect of developmental IGF-1 deficiency on the vascular aging phenotype. To achieve that goal, early-onset endocrine IGF-1 deficiency was induced in mice by knockdown of IGF-1 in the liver using Cre-lox technology (Igf1 f/f mice crossed with mice expressing albumin-driven Cre recombinase). This model exhibits low-circulating IGF-1 levels during the peripubertal phase of development, which is critical for the biology of aging. Due to the emergence of miRNAs as important regulators of the vascular aging phenotype, the effect of early-life IGF-1 deficiency on miRNA expression profile in the aorta was examined in animals at 27 months of age. We found that developmental IGF-1 deficiency elicits persisting late-life changes in miRNA expression in the vasculature, which significantly differed from those in mice with adult-onset IGF-1 deficiency (TBG-Cre-AAV8-mediated knockdown of IGF-1 at 5 month of age in Igf1 f/f mice). Using a novel computational approach, we identified miRNA target genes that are co-expressed with IGF-1 and associate with aging and vascular pathophysiology. We found that among the predicted targets, the expression of multiple extracellular matrix-related genes, including collagen-encoding genes, were downregulated in mice with developmental IGF-1 deficiency. Collectively, IGF-1 deficiency during a critical period during early in life results in persistent changes in post-transcriptional miRNA-mediated control of genes critical targets for vascular health, which likely contribute to the deleterious late-life cardiovascular effects known to occur with developmental IGF-1 deficiency.

Implant survival and complications in cases of inferior alveolar nerve lateralization and atrophied mandibles with 5-year follow-up.

The objectives of this study were to evaluate the survival after 5 years of implants placed using inferior alveolar nerve (IAN) lateralization in cases of mandibular atrophy and to determine the incidence of complications. Twenty-seven patients received 74 implants by means of the IAN lateralization technique. Implant survival after 5 years of loading was 98.6%. Eighteen months after surgery, the recovery of sensitivity was complete in 26 cases. Implant placement with IAN lateralization was seen to be a satisfactory and predictable technique. IAN lateralization requires a high level of technical skill, and strict criteria should be applied when prescribing this treatment.

A general method for the quantitative assessment of mineral pigments.

A general method for the estimation of mineral pigment contents in different bases has been proposed using a sole set of calibration curves, (one for each pigment), calculated for a white standard base, thus elaborating patterns for each utilized base is not necessary. The method can be used in different bases and its validity had ev en been proved in strongly tinted bases. The method consists of a novel procedure that combines diffuse reflectance spectroscopy, second derivatives and the Kubelka-Munk function. This technique has proved to be at least one order of magnitude more sensitive than X-Ray diffraction for colored compounds, since it allowed the determination of the pigment amount in colored samples containing 0.5 wt% of pigment that was not detected by X-Ray Diffraction. The method can be used to estimate the concentration of mineral pigments in a wide variety of either natural or artificial materials, since it does not requiere the calculation of each pigment pattern in every base. This fact could have important industrial consequences, as the proposed method would be more convenient, faster and cheaper.

Validación de Sensibacter pylori test® como prueba de ureasa para el diagnóstico de infección por Helicobacter pylori en Chile / Validation of Sensibacter pylori test ® as urease tests for the diagnosis of Helicobacter pylori infection in Chile

Introduction: Helicobacter pylori is a highly prevalent bacterium in Chile that causes various gastric pathologies including gastric cancer, which corresponds to the leading cause of cancer-related death in Chile in men. This is why early detection of an Helicobacter pylori infection is gaining importance, for tis purpose there are various diagnostic methods, including rapid urease tests (RUT) such as the Sensibacter pylori test®. Objectives: To validate the Sensibacter pylori test® in Chile, so that it may be used in healthcare centres in our country. Materials and Methods: Upper gastrointestinal endoscopies were performed on symptomatic patients in 3 healthcare centres and gastric mucosa samples were obtained following established protocols. These underwent the health centre ́s RUT and the Sensibacter pylori test®, and the results were compared to the gastric mucosa histology (gold standard) Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each test. Kappa test was used to assess agreement between the RUT’s and the turning time of each test was measured. Results: Sensibacter pylori test® showed a sensitivity of 82.6 percent, specificity 92.3 percent, PPV 95 percent and NPV 75 percent. The consistency with the other RUT’s was 0.958 (p < 0.001) and 0.872 (p < 0.001). The turning time was 15 min. Conclusion: Sensibacter pylori test® is a sensitive and specific method, similar to other tests used daily in Chile, which has the advantage of yielding results within a few minutes.

Introducción: Helicobacter pylori es una bacteria de gran prevalencia en Chile y es causante de variadas patologías gástricas, entre las cuales se encuentra el cáncer gástrico, que corresponde a la primera causa de muerte por cáncer en Chile en hombres. Por esto, cobra relevancia detectar a tiempo la existencia de Helicobacter pylori, para lo cual existen diversos métodos diagnósticos, entre los que se encuentran los test rápidos de ureasa (TRU) como Sensibacter pylori test®. Objetivos: Validar Sensibacter pylori test® en Chile, para poder ser utilizado en centros de salud de nuestro país. Materiales y Métodos:Se realizaron endoscopias digestivas altas a pacientes sintomáticos en tres centros de salud y se obtuvieron muestras de mucosa gástrica según protocolos establecidos. Estas se sometieron al TRU del centro de salud y a Sensibacter pylori test®, comparándose el resultado con histología de la mucosa gástrica (estándar de oro), calculándose sensibilidad, especificidad, valor predictivo positivo (VPP) y valor predictivo negativo (VPN). Se utilizó test kappapara evaluar concordancia entre TRU y se midió el tiempo de viraje de cada test. Resultados: Sensibacter pylori test® demostró una sensibilidad de 82,6 por ciento, especificidad de 92,3 por ciento, VPP de 95 por ciento y VPN de 75 por ciento. La concordancia con los otros TRUs fue de 0,958 (p < 0,001) y 0,872 (p < 0,001). El tiempo de viraje fue de 15 min. Conclusión: Sensibacter pylori test® es un método sensible y específico comparable con otros test de uso diario en Chile, y tiene la ventaja de mostrar resultados en pocos minutos.

Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex.

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of cognitive impairment associated with aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g., hypertension, obesity). Although previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in endothelial NO synthase (eNOS), and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS(-/-)) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice, the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation-induced and ATP-mediated CBF responses, whereas, in eNOS(-/-) mice, the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio-endothelial coupling during neuronal activity, highlighting the role of ATP-mediated activation of eNOS via P2Y1 receptors in functional hyperemia.

Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice.

There is increasing evidence that vascular risk factors, including aging, hypertension, diabetes mellitus, and obesity, promote cognitive impairment; however, the underlying mechanisms remain obscure. Cerebral blood flow (CBF) is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism is known to be impaired in the aforementioned pathophysiologic conditions. To establish a direct relationship between impaired NVC and cognitive decline, we induced neurovascular uncoupling pharmacologically in mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH), the NO synthase inhibitor l-NG-Nitroarginine methyl ester (L-NAME), and the COX inhibitor indomethacin decreased NVC by over 60% mimicking the aging phenotype, which was associated with significantly impaired spatial working memory (Y-maze), recognition memory (Novel object recognition), and impairment in motor coordination (Rotarod). Blood pressure (tail cuff) and basal cerebral perfusion (arterial spin labeling perfusion MRI) were unaffected. Thus, selective experimental disruption of NVC is associated with significant impairment of cognitive and sensorimotor function, recapitulating neurologic symptoms and signs observed in brain aging and pathophysiologic conditions associated with accelerated cerebromicrovascular aging.

Efficacy of platelet-rich plasma applied to post-extraction retained lower third molar alveoli. A systematic review.

UNLABELLED: Dental retentions have a high prevalence among the general population and their removal can involve multiple complications. The use of platelet rich plasma has been proposed in an attempt to avoid these complications, as it contains high growth factors and stimulates diverse biological functions that facilitate the healing of soft and hard tissues. OBJECTIVES: To evaluate the available scientific evidence related to the application of platelet-rich plasma in the post-extraction alveoli of a retained lower third molars. MATERIAL AND METHODS: A systematic review of published literature registered in the Medline, EMBASE, Cochrane and NIH databases. The following categories were included: human randomized clinical studies. Key search words were: platelet rich plasma; platelet rich plasma and oral surgery; platelet rich in growth factors and third molar. RESULTS: Of 101 potentially valid articles, seven were selected, of which four were rejected as they failed to meet quality criteria. Three studies fulfilled all selection and quality criteria: Ogundipe et al.; Rutkowski et al.; Haraji et al. The studies all measured osteoblast activity by means of sintigraphy, and also registered pain, bleeding, inflammation, temperature, numbness as perceived by the patients, radiological bone density and the incidence of alveolar osteitis. CONCLUSIONS: Scientific evidence for the use of PRP in retained third molar surgery is poor. For this reason randomized clinical trials are needed before recommendations for the clinical application of PRP can be made.