Skin lesions in neurofibromatosis type 2: diagnostic and prognostic significance of cutaneous (plexiform) schwannomas.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a genetic disease characterized by the appearance of multiple tumours in the nervous system. Cutaneous lesions are common and may provide useful diagnostic and prognostic information, but they have not been widely studied. OBJECTIVES: To characterize cutaneous lesions in a Spanish cohort of patients with NF2 and investigate associations with clinical and genetic severity. METHODS: We studied the clinical and histologic characteristics of cutaneous lesions in 49 patients with NF2 and analysed correlations with phenotype- and genotype-based severity scores. We collected information on the presence/absence of cutaneous lesions, location, age at onset, type of lesion, and histologic features. We also studied level of systemic involvement and genetic mutations involved. RESULTS: Forty-nine patients (31 women [63.3%] and 18 men [36.7%]) were analysed, and 33 (67.3%) had cutaneous lesions presumed to be schwannomas. According to their clinical form, they were distributed as follows: 24 patients (48%) had deep tumours, 21 (42%) had plaque-like lesions, and 3 (6%) had superficial tumours. Histologic examination from 27 lesions analysed out 23 patients showed classic schwannoma or hybrid schwannoma-neurofibroma features in the 8 deep tumours biopsied and plexiform schwannoma features in the 17 plaque-like lesions and the 2 superficial tumours analysed. Early onset (first 2 decades of life) was reported by all patients with plaques and superficial tumours. In our cohort, 100% of the patients with plaque-like lesions and superficial tumours with microscopic features of plexiform schwannoma were in the 2 groups with the most severe clinical phenotypes, and 82.6% of them were in the 3 most severe genotype-based classes. CONCLUSIONS AND RELEVANCE: Cutaneous lesions, specially plexiform schwannomas, are common in NF2, and they usually appear at an early age providing useful diagnostic and prognostic information. These tumours are part of the spectrum of cutaneous manifestations in this disease. Although its diagnostic and prognostic value has been pointed out, there are few studies focussed on their analysis.

Association of physical fitness with health-related quality of life in early postmenopause.

OBJECTIVE: To assess the association of different components of physical fitness with HRQoL in early postmenopause and to test which physical fitness components are independently associated with the physical and mental components of HRQoL. METHODS: The final sample comprised 67 early postmenopausal women. Physical fitness was assessed with the Senior Fitness Test battery (additionally including handgrip strength test), and HRQoL was evaluated with the Short-Form Health Survey-36 (SF-36). We also analyzed plasma gonadotropic hormones and estradiol. RESULTS: Overall, most of the fitness components were positively associated with HRQoL. Lower-body flexibility, upper-body muscle strength and cardiorespiratory fitness were the fitness components more strongly associated with HRQoL (r range from 0.28 to 0.56). Static balance was especially associated with mental health (r = -0.46, P < 0.001). Lower-body flexibility (assessed with the chair sit-and-reach test) and upper-body muscle strength (assessed with handgrip dynamometry) were independently associated with the SF-36 Physical Component Summary (both, P < 0.001). Upper-body muscle strength (P < 0.01) and cardiorespiratory fitness (assessed with the 6-min walk test, P < 0.05) were independently associated with the SF-36 Mental Component Summary. CONCLUSIONS: Higher physical fitness is associated with better HRQoL in early postmenopause. Lower-body flexibility and upper-body muscle strength were the most important independent fitness indicators, explaining ~30 % of HRQoL.

Raman spectroscopy analysis of the skin of patients with melasma before standard treatment with topical corticosteroids, retinoic acid, and hydroquinone mixture.

BACKGROUND: Melasma is an abnormal acquired hyperpigmentation of the face of unknown origin, it is considered a single disease and very little has been found regarding its pathogenesis. It is usually assumed that melasma is due to excessive melanin production, but previous work using Raman spectroscopy showed degraded molecules of melanin in some melasma subjects, which may help to explain the success or failure of the standard therapy. METHODS: We perform Raman spectroscopy measurements on in vivo skin from melasma patients before treatment to identify the molecular structure of melanin within every melasma lesion. The Raman spectra were grouped according to the treatment response from patient, and the Raman spectra were analyzed. RESULTS: Raman spectroscopy measurements showed a different molecular structure of the patients who did not respond to treatment, those patients shows atypical Raman skin spectrum with peaks associated with melanin not well defined, which is consistent with molecular degradation and protein breakdown. CONCLUSION: Our results are consistent with our previous work in the sense that melasma patients who do not respond to treatment have an abnormal melanin. We believe it will eventually help to decide the treatment of melasma in clinical dermatology.

Skin conditions in primary care: an analysis of referral demand.

INTRODUCTION: Skin conditions are among the main reasons for seeking primary health care. Primary care physicians (PCPs) must diagnose skin conditions and determine their impact, and must therefore incorporate the relevant knowledge and skills into their education. The present study analyzes the reasons for primary care referral to dermatology (referral demand) as well as diagnostic agreement between PCPs and dermatologists informed by pathology where appropriate. MATERIAL AND METHODS: Data were collected for 755 patients and 882 initial dermatology appointments from February 1, 2012 through April 30, 2012 following primary care referral. Data obtained included age, sex, occupation, reason for referral, primary care diagnosis, and dermatologic diagnosis. Statistical analysis of the data for each diagnosed condition identified frequency, reasons for referral, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the κ statistic for diagnostic agreement. RESULTS: The most common diagnoses were seborrheic keratosis, melanocytic nevus, actinic keratosis, and acne. The main reason for referral was diagnostic assessment (52.5%). For skin tumors, sensitivity of primary care diagnosis was 22.4%, specificity 94.7%, PPV 40.7%, and NPV 88.3%, with a κ of 0.211. For the more common diagnoses, primary care sensitivity was generally low and specificity high. CONCLUSIONS: According to our results, primary care physicians are better qualified to rule out a given skin condition in a patient (high specificity) than to establish an accurate clinical diagnosis (poor sensitivity). This suggests that knowledge and skills training should be organized for primary care physicians to improve management of skin conditions-especially skin cancer, because of its impact. A more responsive system would ensue, with shorter waiting lists and better health care.

Outcomes after septal myectomy in a cohort of patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) with left ventricular outflow tract obstruction that doesn't improve with pharmacological management often requires septal myectomy. However, there are few centers with experience in the practice of this procedure in our country. We describe the clinical and echocardiographic characteristics and postoperative outcomes of patients with HCM indicated for septal myectomy at a reference center in Colombia. MATERIALS AND METHODS: Retrospective cohort study. Patients undergoing septal myectomy between 2010 and 2023 were included. Data were collected before and two years after surgery. RESULTS: 18 patients were included. The mean age was 50 years. The predominant functional class was NYHA II/III (94 %). Asymmetric septal variant (83.3 %) was the most frequent as well as obstructive phenotype (88.8 %). After myectomy, 70.5 % improved to NYHA I and 62.4 % had no significant gradient (<30 mmHg), and the most of patient improved SAM. One patient died post-procedure, anymore complications were presented. DISCUSSION/CONCLUSIONS: Septal myectomy is a safe procedure, with clinical and echocardiographic improvement, with low complication rates.

WNT/ß-catenin pathway activation in Myc immortalised cerebellar progenitor cells inhibits neuronal differentiation and generates tumours resembling medulloblastoma.

BACKGROUND: Medulloblastoma is the most common malignant childhood brain tumour. Aberrant activation of the WNT/ß-catenin pathway occurs in approximately 25% of medulloblastomas. However, its role in medulloblastoma pathogenesis is not understood. METHODS: We have developed a model of WNT/ß-catenin pathway-activated medulloblastoma. Pathway activation was induced in a Myc immortalised cerebellar progenitor cell line through stable expression of Wnt1. In vitro and in vivo analysis was undertaken to understand the effect of pathway activation and identify the potential cell of origin. RESULTS: Tumours that histologically resembled classical medulloblastoma formed in vivo using cells overexpressing Wnt1, but not with the control cell line. Wnt1 overexpression inhibited neuronal differentiation in vitro, suggesting WNT/ß-catenin pathway activation prevents cells terminally differentiating, maintaining them in a more 'stem-like' state. Analysis of cerebellar progenitor cell markers demonstrated the cell line resembled cells from the cerebellar ventricular zone. CONCLUSION: We have developed a cell line with the means of orthotopically modelling WNT/ß-catenin pathway-activated medulloblastoma. We provide evidence of the role pathway activation is playing in tumour pathogenesis and suggest medulloblastomas can arise from cells other than granule cell progenitors. This cell line is a valuable resource to further understand the role of pathway activation in tumorigenesis and for investigation of targeted therapies.

Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor.

Neuropeptide Y (NPY), a 36-amino-acid peptide widely expressed in the brain is involved in many physiological responses, including hypothalamic control of food intake and cardiovascular homeostasis. NPY mediates its effects through binding to the Y1, Y2 and Y5 G-protein-coupled receptors. Little is known of the role of the Y2 receptor in mediating the different NPY effects. We inactivated the Y2 receptor subtype in mice and found that these mice developed increased body weight, food intake and fat deposition. The null mutant mice showed an attenuated response to leptin administration but a normal response to NPY-induced food intake and intact regulation of re-feeding and body weight after starvation. An absence of the Y2 receptor subtype also affected the basal control of heart rate, but did not influence blood pressure. These findings indicate an inhibitory role for the Y2 receptor subtype in the central regulation of body weight and control of food intake.

Medical and Legal Aspects of the Practice of Teledermatology in Spain. / Aspectos medicolegales de la práctica de la teledermatología en España.

Teledermatology is now fully incorporated into our clinical practice. However, after reviewing current legislation on the ethical aspects of teledermatology (data confidentiality, quality of care, patient autonomy, and privacy) as well as insurance and professional responsibility, we observed that a specific regulatory framework is still lacking and related legal aspects are still at a preliminary stage of development. Safeguarding confidentiality and patient autonomy and ensuring secure storage and transfer of data are essential aspects of telemedicine. One of the main topics of debate has been the responsibilities of the physicians involved in the process, with the concept of designating a single responsible clinician emerging as a determining factor in the allocation of responsibility in this setting. A specific legal and regulatory framework must be put in place to ensure the safe practice of teledermatology for medical professionals and their patients.

Neurotrophins promote the survival and development of neurons in the cerebellum of hypothyroid rats in vivo.

The development of cerebellar cortex is strongly impaired by thyroid hormone (T3) deficiency, leading to altered migration, differentiation, synaptogenesis, and survival of neurons. To determine whether alteration in the expression of neurotrophins and/or their receptors may contribute to these impairments, we first analyzed their expression using a sensitive RNAse protection assay and in situ hybridization; second, we administered the deficient neurotrophins to hypothyroid animals. We found that early hypothyroidism disrupted the developmental pattern of expression of the four neurotrophins, leading to relatively higher levels of NGF and neurotrophin 4/5 mRNAs and to a severe deficit in NT-3 and brain-derived neurotrophic factor (BDNF) mRNA expression, without alteration in the levels of the full-length tyrosine kinase (trk) B and trkC receptor mRNAs. Grafting of P3 hypothyroid rats with cell lines expressing high levels of neurotrophin 3 (NT-3) or BDNF prevented hypothyroidism-induced cell death in neurons of the internal granule cell layer at P15. In addition, we found that NT-3, but not BDNF, induced the differentiation and/or migration of neurons in the external granule cell layer, stimulated the elaboration of the dendritic tree by Purkinje cells, and promoted the formation of the mature pattern of synaptic afferents to Purkinje cell somas. Thus, our results indicate that both granule and Purkinje neurons require appropriate levels of NT-3 for normal development in vivo and suggest that T3 may regulate the levels of neurotrophins to promote the development of cerebellum.

Identification of brain-derived neurotrophic factor promoter regions mediating tissue-specific, axotomy-, and neuronal activity-induced expression in transgenic mice.

The structure of rat brain-derived neurotrophic factor (BDNF) gene is complex; four 5' exons are linked to separate promoters and one 3' exon is encoding the BDNF protein. To analyze the relative importance of the regulatory regions in vivo, we have generated transgenic mice with six different promoter constructs of the BDNF gene fused to the chloramphenicol acetyl transferase reporter gene. High level and neuronal expression of the reporter gene, that in many respects recapitulated BDNF gene expression, was achieved by using 9 kb of genomic sequences covering the promoter regions that lie adjacent to each other in the genome (promoters I and II and promoters III and IV, respectively) and by including sequences of BDNF intron-exon splice junctions and 3' untranslated region in the constructs. The genomic regions responsible for the in vivo upregulation of BDNF expression in the axotomized sciatic nerve and in the brain after kainic acid-induced seizures and KCl-induced spreading depression were mapped. These data show that regulation of the different aspects of BDNF expression is controlled by different regions in vivo, and they suggest that these promoter constructs may be useful for targeted expression of heterologous genes to specific regions of the central and peripheral nervous systems in an inducible manner.

Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons.

Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic polypeptide, distantly related to transforming growth factor-beta (TGF-beta), originally isolated by virtue of its ability to induce dopamine uptake and cell survival in cultures of embryonic ventral midbrain dopaminergic neurons, and more recently shown to be a potent neurotrophic factor for motorneurons. The biological activities and distribution of this molecule outside the central nervous system are presently unknown. We report here on the mRNA expression, biological activities and initial receptor binding characterization of GDNF and a shorter spliced variant termed GDNF beta in different organs and peripheral neurons of the developing rat. Both GDNF mRNA forms were found to be most highly expressed in developing skin, whisker pad, kidney, stomach and testis. Lower expression was also detected in developing skeletal muscle, ovary, lung, and adrenal gland. Developing spinal cord, superior cervical ganglion (SCG) and dorsal root ganglion (DRG) also expressed low levels of GDNF mRNA. Two days after nerve transection, GDNF mRNA levels increased dramatically in the sciatic nerve. Overall, GDNF mRNA expression was significantly higher in peripheral organs than in neuronal tissues. Expression of either GDNF mRNA isoform in insect cells resulted in the production of indistinguishable mature GDNF polypeptides. Purified recombinant GDNF promoted neurite outgrowth and survival of embryonic chick sympathetic neurons. GDNF produced robust bundle-like, fasciculated outgrowth from chick sympathetic ganglion explants. Although GDNF displayed only low activity on survival of newborn rat SCG neurons, this protein was found to increase the expression of vasoactive intestinal peptide and preprotachykinin-A mRNAs in cultured SCG neurons. GDNF also promoted survival of about half of the neurons in embryonic chick nodose ganglion and a small subpopulation of embryonic sensory neurons in chick dorsal root and rat trigeminal ganglia. Embryonic chick sympathetic neurons expressed receptors for GDNF with Kd 1-5 x 10(-9) M, as measured by saturation and displacement binding assays. Our findings indicate GDNF is a new neurotrophic factor for developing peripheral neurons and suggest possible non-neuronal roles for GDNF in the developing reproductive system.

Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons.

The production of neurotrophin-4 (NT-4) in rat skeletal muscle was found to depend on muscle activity. The amounts of NT-4 messenger RNA present decreased after blockade of neuromuscular transmission with alpha-bungarotoxin and increased during postnatal development and after electrical stimulation in a dose-dependent manner. NT-4 immunoreactivity was detected in slow, type I muscle fibers. Intramuscular administration of NT-4 induced sprouting of intact adult motor nerves. Thus, muscle-derived NT-4 acted as an activity-dependent neurotrophic signal for growth and remodeling of adult motor neuron innervation. NT-4 may thus be partly responsible for the effects of exercise and electrical stimulation on neuromuscular performance.

Combined intrastromal injection of ganciclovir and depot betamethasone for the management of nummular keratitis: Case series. / Inyección intraestromal combinada con ganciclovir y betametasona de depósito para el manejo de la queratitis numular: serie de casos.

Nummular keratitis is an inflammatory process of the cornea that is characterised by multiple sub-epithelial deposits, for which a variety of therapeutic approaches have been proposed. A retrospective review was performed using the medical records of patients diagnosed with nummular keratitis and treated with a combined intrastromal injection of ganciclovir and depot betamethasone between the years 2009 and 2017. A total of 21 eyes of 16 patients were finally included. Upon termination of the treatment, 18 eyes (85.71%) were asymptomatic. This improvement was maintained during a mean follow-up time of 22.90 months. Depot betamethasone mixed with ganciclovir by intrastromal application is a good alternative for the treatment of nummular keratitis.

GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo.

The locus coeruleus (LC), the main noradrenergic center in the brain, participates in many neural functions, as diverse as memory and motor output, and is severely affected in several neurodegenerative disorders of the CNS. GDNF, a neurotrophic factor initially identified as dopaminotrophic, was found to be expressed in several targets of central noradrenergic neurons in the adult rat brain. Grafting of genetically engineered fibroblasts expressing high levels of GDNF prevented > 80% of the 6-hydroxydopamine-induced degeneration of noradrenergic neurons in the LC in vivo. Moreover, GDNF induced a fasciculated sprouting and increased by 2.5-fold both tyrosine hydroxylase levels and the soma size of lesioned LC neurons. These findings reveal a novel and potent neurotrophic activity of GDNF that may have therapeutic applications in neurodegenerative disorders affecting central noradrenergic neurons, such as Alzheimer's, Parkinson's, and Huntington's diseases.

BDNF regulates reelin expression and Cajal-Retzius cell development in the cerebral cortex.

Cajal-Retzius (CR) cells of the cerebral cortex express receptors for the neurotrophin brain-derived neurotrophic factor (BDNF) and downregulate expression of the extracellular matrix protein Reelin during early postnatal development, coincident with the onset of cortical BDNF expression. During this period, mice lacking BDNF have elevated levels of Reelin in CR cells. Acute BDNF stimulation of cortical neuron cultures and overexpression of BDNF in the developing brain of transgenic mice prior to the onset of endogenous production causes a profound, dose-dependent reduction of Reelin expression in CR cells. In addition, overexpression of BDNF produces gaps and heterotopias in the marginal zone and disorganization and aggregation of cortical CR cells and induces several other malformations, including aberrant cortical lamination, similar to the phenotype of reeler mutant mice, which lack Reelin. These results demonstrate a role for BDNF on cortical CR cells and identify Reelin as a direct effector of this neurotrophin during brain development.

Motion deficit in nodal interphalangeal joint osteoarthritis by digital goniometer in housewives.

Range of motion (ROM) measured objectively in nodal hand osteoarthritis (NHOA) is missing. Evaluation of collateral ligaments by ultrasound (US) is unknown in NHOA also. To compare ROM in interphalangeal joints in housewives with nodal OA, with a control group by a digital system using angle to voltage (Multielgon). The second objective was to assess correlation between collateral radial and ulnar ligaments thickness and ROM. For this cross-sectional observational study, we assessed 60 hands with symptomatic NHOA and 30 hands of healthy housewives matched for age. We obtained clinical and demographic characteristics (a complete standardized physical examination of hand joints, DASH questionnaire, pain surveys, gross grasp hand goniometer, and ROM measurements by Multielgon. Presence of synovitis, power Doppler signal, osteophytes, and collateral ligaments thickness was evaluated by US. We used descriptive statistics, Spearman correlation, X2 test, t test and odds ratio. Significant less gross grasp and ROM in the right hand were observed in NHOA (p = 0.01 for both). Presence of OA, painful joints, disease duration, and score DASH were significant correlated with reduced ROM (OR 4.12, 4.12, 1.04 and 1.09, respectively). Reduced ROM was statistical significant in thumb MCP and IP joints, second and third DIP in dominant hand. There was no association between collateral radial and ulnar ligaments and reduced ROM. Synovitis and osteophytes were more prevalent in OA group. Multielgon demonstrated the pattern of reduced ROM in nodal OA of housewives particularly in MCP and IP thumb joints, second and third distal interphalangeal joints.

Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes.

The implementation of neural stem cell lines as a source material for brain tissue transplants is currently limited by the ability to induce specific neurochemical phenotypes in these cells. Here, we show that coordinated induction of a ventral mesencephalic dopaminergic phenotype in an immortalized multipotent neural stem cell line can be achieved in vitro. This process requires both the overexpression of the nuclear receptor Nurr1 and factors derived from local type 1 astrocytes. Over 80% of cells obtained by this method demonstrate a phenotype indistinguishable from that of endogenous dopaminergic neurons. Moreover, this procedure yields an unlimited number of cells that can engraft in vivo and that may constitute a useful source material for neuronal replacement in Parkinson's disease.

[Prevention of respiratory risks]. / Prevención de riesgos respiratorios.

A need for oxygen is determined by the base pathology a patient suffers which produces immobilization, due to being bedridden and due to the problems which began due to an organic insufficiency associated with muscular weakness, a failure in the respiratory system, insufficient sputum, and cardiovascular alterations. This article deals with those alterations which cause a need to provide oxygen to a patient and its prevention in bedridden patients.

Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition.

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.

Effect of perfluorooctane sulfonate on viability, maturation and gap junctional intercellular communication of porcine oocytes in vitro.

Perfluorooctane sulfonate (PFOS) is a broadly used man-made surfactant whose long half-life has led to bioaccumulation. This perfluorinated compound is ubiquitous in human body fluids. PFOS concentrations as high as 26µM in plasma have been reported in occupationally exposed populations, and high levels of PFOS in human follicular fluid have been associated with subfertility. However, the effect of PFOS on the maturation of oocytes in mammals has not been reported to date. The aim of this study was to determine the effects of PFOS during oocyte maturation. Results indicate that PFOS inhibits oocyte viability (Lethal Concentration50=32µM) and maturation (inhibition of maturation50=22µM) at physiologically relevant concentrations. In order to evaluate the mechanisms of oocyte maturation inhibition by PFOS, gap junctional intercellular communication (GJIC) between oocytes and granulosa cells was assessed. GJIC between granulosa cells and the oocyte was significantly affected during the first 8h of maturation. However, the inhibitory effect of PFOS on GJIC was not due to an alteration on the expression of connexin genes Cx43, Cx45 and Cx60. These findings suggest that occupationally exposed populations could be at risk, and that PFOS might affect oocyte maturation by interfering the GJIC in the cumulus-oocyte complexes during the first hours of maturation.