Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases.

Voltage-gated ion channels are essential for membrane potential maintenance, homeostasis, electrical signal production and controlling the Ca2+ flow through the membrane. Among all ion channels, the key regulators of neuronal excitability are the voltage-gated potassium channels (KV), the largest family of K+ channels. Due to the ROS high levels in the aging brain, K+ channels might be affected by oxidative agents and be key in aging and neurodegeneration processes. This review provides new insight about channelopathies in the most studied neurodegenerative disorders, such as Alzheimer Disease, Parkinson's Disease, Huntington Disease or Spinocerebellar Ataxia. The main affected KV channels in these neurodegenerative diseases are the KV1, KV2.1, KV3, KV4 and KV7. Moreover, in order to prevent or repair the development of these neurodegenerative diseases, previous KV channel modulators have been proposed as therapeutic targets.

Recent advances in cochlear hair cell regeneration-A promising opportunity for the treatment of age-related hearing loss.

The objective of this paper is to review current information regarding the treatment of age-related hearing loss by using cochlear hair cell regeneration. Recent advances in the regeneration of the inner ear, including the usefulness of stem cells, are also presented. Based on the current literature, cochlear cell regeneration may well be possible in the short term and cochlear gene therapy may also be useful for the treatment of hearing loss associated with ageing. The present review provide further insight into the pathogenesis of Inner Ear senescence and aged-related hearing loss and facilitate the development of therapeutic strategies to repair hair cells damaged by ageing. More research will be needed in order to translate them into an effective treatment for deafness linked to cochlear senescence in humans.

A comparative morphologic and morphometric study about geniculate ganglion development in man and in rat.

CONCLUSIONS: Human-rat geniculate ganglion (GG) have multiple origins: (1) An initial proximity (20 µm) to the endocranial foramen of the IAM, suggests neural crest induction; and (2) The influence of epibranchial placodes: the tensor tympani muscle (TTM) and the otic apical coil. OBJECTIVES: This study was undertaken to determine the comparative development of human-rat GG. MATERIALS AND METHODS: A light microscopic study of the GG in human material obtained from spontaneous abortions at 9, 13, 14, 17, 18, and 30 weeks, and one neonate was done. This study examined Webster rat embryos and a post-natal series. Specimens were fixed in Bouin fluid, embedded in paraffin, cut, and stained with H&E. The histomorphometric data were obtained with image analysis software. RESULTS: The human fetus of 9 weeks presents two neuronal groups in the VII nerve: one near (20 µm) the IAM endocranial foramen, foraminal, and the other, tympanic. Neonate GG is located between the TTM and the cochlear apex (inwards). In the 16 day old rat embryo GG is placed within a canal containing the stapedial artery. In the adult rat the GG and the stapedial artery are placed within the IAM.

Effect of neonatal asphyxia on the impairment of the auditory pathway by recording auditory brainstem responses in newborn piglets: a new experimentation model to study the perinatal hypoxic-ischemic damage on the auditory system.

INTRODUCTION: Hypoxia-ischemia (HI) is a major perinatal problem that results in severe damage to the brain impairing the normal development of the auditory system. The purpose of the present study is to study the effect of perinatal asphyxia on the auditory pathway by recording auditory brain responses in a novel animal experimentation model in newborn piglets. METHOD: Hypoxia-ischemia was induced to 1.3 day-old piglets by clamping 30 minutes both carotid arteries by vascular occluders and lowering the fraction of inspired oxygen. We compared the Auditory Brain Responses (ABRs) of newborn piglets exposed to acute hypoxia/ischemia (n = 6) and a control group with no such exposure (n = 10). ABRs were recorded for both ears before the start of the experiment (baseline), after 30 minutes of HI injury, and every 30 minutes during 6 h after the HI injury. RESULTS: Auditory brain responses were altered during the hypoxic-ischemic insult but recovered 30-60 minutes later. Hypoxia/ischemia seemed to induce auditory functional damage by increasing I-V latencies and decreasing wave I, III and V amplitudes, although differences were not significant. CONCLUSION: The described experimental model of hypoxia-ischemia in newborn piglets may be useful for studying the effect of perinatal asphyxia on the impairment of the auditory pathway.

DLK1 regulates branching morphogenesis and parasympathetic innervation of salivary glands through inhibition of NOTCH signalling.

BACKGROUND INFORMATION: Delta-like proteins 1 and 2 (DLK1, 2) are NOTCH receptor ligands containing epidermal growth factor-like repeats, which regulate NOTCH signalling. We investigated the role of DLK and the NOTCH pathway in the morphogenesis of the submandibular salivary glands (SMGs), using in vitro organotypic cultures. RESULTS: DLK1 and 2 were present in all stages of SMG morphogenesis, where DLK1 inhibited both NOTCH activity and SMG branching. The addition of NOTCH inhibitory agents, either soluble DLK1 (sDLK1) or N-[N-(3, 5-difluorophenacetyl-L-alanyl]-S-phenylglycine t-buthyl ester (DAPT), to the SMG culture medium did not affect the rate of cell proliferation, but induced a strong reduction in SMG branching, increased epithelial apoptosis, and impaired innervation of the epithelial end buds by local parasympathetic ganglion neurons. SMG innervation could be restored by the acetylcholine analog carbachol (CCh), which also rescued cytokeratin 5 (CK5(+))-expressing epithelial progenitor cells. Despite this, CCh failed to restore normal branching morphogenesis in the presence of either sDLK1 or DAPT. However, it improved recovery of branching morphogenesis in SMGs, once DLK1 or DAPT were removed from the medium. CONCLUSIONS: Our data suggest that DLK1 regulates SMGs morphogenesis and parasympathetic nerve fibre outgrowth through inhibition of NOTCH signalling.

Usefulness of the BAST-24 smell and taste test in the study of diabetic patients: a new approach to the determination of renal function.

CONCLUSION: A reduction in the percentage of correct responses in the olfactory test indirectly indicated increased albuminuria and worse glomerular filtration rate (GFR) in diabetic patients. The olfactory function test is an indirect indicator of early microvascular complications in diabetic patients. OBJECTIVES: Diabetes mellitus is a highly prevalent disease that causes numerous complications. The aim of this study was to determine whether olfactory and taste sensations are related to renal failure in diabetic patients. METHODS: We studied 61 patients diagnosed with diabetes mellitus, mean age = 65.9 years (SD = 16.8), 54.1% male. We evaluated olfactory and taste sensations by determining the capacity of detection, identification and percentage of correct responses of the 29 components of the Barcelona Smell-taste Test-24 (BAST-24). We determined the relationship between these results and glycosylated haemoglobin (HbA1c), creatinine, albumin/creatinine, albuminuria and GFR (normal = GFR ≥ 60 ml/min/1.73 m(2); impaired renal function = GFR < 60 ml/min/1.73 m(2)). RESULTS: There was no significant relationship between HbA1c and olfactory and taste sensations. There was a significant relationship between the percentage of correct responses and albuminuria (p = 0.03) and between identification of odours through the olfactory nerve and GFR (p = 0.029), and the percentage of correct responses and GFR (p = 0.03). There was no significant relationship between taste and renal failure.

Morphological and morphometric study on human Scarpa ganglion development.

CONCLUSION: In Scarpa neurons the cell and nuclear area increases and nuclear/cytoplasm ratio decreases with fetal age (p < 0.0001). There are statistically significant differences in cell area between all fetal groups, except for the interval 45-74 mm crown-rump-length (CRL). Displacement of a neuron within the internal auditory meatus (IAM) occurs from 9 weeks in the fetus until the neonate. METHODS: A light microscopic histomorphometric study of the Scarpa ganglion in human fetuses from spontaneous abortions measuring 45, 74, 90, 134, 145 and 270 mm CRL and a from a 1-day-old neonate (360 mm) was carried out. Cell and nuclear area, ganglion area and distances from the Scarpa ganglion neurons to the endocranial porus of the IAM were measured. RESULTS: In the 45, 74, 90 and 134 mm CRL human fetuses the cartilaginous labyrinthine capsule appears divided by the facial nerve and the Scarpa ganglion into two compartments: rostral and dorsal. Ovoidal Scarpa ganglion in the 45 mm CRL lies within the IAM near its endocranial porus (15 µm). In the otic capsule of the 145 mm CRL fetus an endochondral ossification appears in the IAM base, where Scarpa ganglion neurons are displayed in two groups: superior and inferior divided by a vascular-connective septum. This anatomy remains from this specimen until the neonate specimen.

Cost-minimisation and cost-effectiveness analysis comparing transoral CO2 laser cordectomy, laryngofissure cordectomy and radiotherapy for the treatment of T1-2, N0, M0 glottic carcinoma.

The financial costs of laryngeal cancer treatment are a notable burden on healthcare budgets. In this study, we assess whether CO2 laser surgery is cheaper than radiotherapy or laryngofissure and cordectomy in the treatment of T1-2, N0, M0 glottic squamous cell carcinoma. 56 patients with a mean age of 65.88 years (SD = 10.04), 53 men and 3 women, with T1-2, N0, M0 glottic squamous cell carcinoma were retrospectively analysed. We conducted a comparative analysis of costs associated with three treatments: carbon dioxide laser cordectomy (n = 21), radiotherapy (n = 20), and laryngofissure cordectomy (n = 15). Complications of the radiotherapy and surgical treatments, need for tracheotomy and its permanence, length of hospital stay, occupation and ability to work and economic costs of treatments were recorded. Cost-minimisation and cost-effectiveness analysis were obtained. The cost of transoral laser cordectomy (2,289.79 euro) is statistically significantly lower than that of radiotherapy (4,804.72 euro) or laryngofissure cordectomy (13,229.75 euro) (p < 0.001). Transoral carbon dioxide laser surgery is the best option in terms of cost-effectiveness for the treatment of T1-2, N0, M0 glottic cancer.

Principles of cranial base ossification in humans and rats.

CONCLUSIONS: 1. The principle of bilateral symmetry depends on the chordal cartilage that is the keystone in cranial base ossification in rats and humans, due to its anatomical situation and for the production of the chordin protein that regulates the bone morphogenetic protein BMP-7. 2. In humans and in rats, foramen lacerum closure follows a line of intramembranous ossification that depends on BMP-7, regulated by the first branchial pouch. 3. The cranial base ossification patterns and centres are similar in humans and in rats, except in the otic capsule, palate and the lateral pterygoid plate. 4. The neural crest may induce cranial ossification through the cranial nerves. OBJECTIVES: To study the patterns of cranial base ossification in humans and in rats, considering the chordal cartilage, and the otic, nasal and orbit capsules, as well as the participation of the branchial arches and pouches. METHODS: This was a light microscopy study of human fetal specimens obtained from spontaneous abortions with the following crown-rump-lengths (crl) 45, 74, 90, 134, 145 and 270 mm, and a 1-day-old neonate (360 mm crl), who had died of sudden death syndrome. We also examined Webster albino rat embryos of 16, 18 and 20 days of gestation and a postnatal series of rats 8 h and 1, 3, 4, 6, 7, 10 and 13 days old, as well as adult animals. RESULTS: In the 45 mm human fetus, the chordal cartilage with the nasal, otic and orbit capsules initiates cranial base ossification. Foramen lacerum closure begins in the 16-day-old rat embryo, following a line of membranous ossification between the external pterygoid process and the lateral alisphenoidal wing at ovalis foramen level. This is not a timing symmetrical process, which may persist until the 10th postnatal day in the rat. In the human fetus of 74 mm, the foramen lacerum space is closed by a membranous fusion ossification between the chordal cartilage and otic capsule, finishing at the 270 mm specimen. Endochondral ossification of the human otic capsule first appeared in the 145 mm (18 weeks) fetal specimen with four ossifying centres. The rat otic cartilaginous capsule showed rapid endochondral ossification, in the third and fourth postnatal day specimens.

The predictive value of clinical and epidemiological parameters in the identification of patients with obstructive sleep apnoea (OSA): a clinical prediction algorithm in the evaluation of OSA.

We sought to analyze the predictive value of anthropometric, clinical and epidemiological parameters in the identification of patients with suspected OSA, and their relationship with apnoea/hypopnoea respiratory events during sleep. We studied retrospectively 433 patients with OSA, 361 men (83.37%) and 72 women (16.63%), with an average age of +/-47, standard deviation +/-11.10 years (range 18-75 years). The study variables for all of the patients were age, sex, spirometry, neck circumference, body mass index (BMI), Epworth sleepiness scale, nasal examination, pharyngeal examination, collapsibility of the pharynx (Müller Manoeuvre), and apnoea-hypopnoea index (AHI). Age, neck circumference, BMI, Epworth sleepiness scale, pharyngeal examination and pharyngeal collapse were the significant variables. Of the patients, 78% were correctly classified, with a sensitivity of 74.6% and a specificity of 66.3%. We found a direct relationship between the variables analysed and AHI. Based on these results, we obtained the following algorithm to calculate the prediction of AHI for a new patient: AHI = -12.04 + 0.36 neck circumference +2.2286 pharyngeal collapses (MM) + 0.1761 Epworth + 0.0017 BMI x age + 1.1949 pharyngeal examinations. The ratio variance in the number of respiratory events explained by the model was 33% (r2 = 0.33). The variables given in the algorithm are the best ones for predicting the number of respiratory events during sleep in patients studied for suspected OSA. The algorithm proposed may be a good screening method to the identification of patients with OSA.