Role of neuroinflammation in the pathophysiology of CDKL5 deficiency disorder

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), a rare neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene, is characterized by early-onset epilepsy, intellectual disability, and autistic features. To date, little is known about the etiology of CDD and no therapies are available. When overactivated in response to neuronal damage and genetic or environmental factors, microglia – the brain macrophages – cause damage to neighboring neurons by producing neurotoxic factors and pro-inflammatory molecules. Importantly, overactivated microglia have been described in several neurodegenerative and neurodevelopmental disorders, suggesting that active neuroinflammation may account for the compromised neuronal survival and/or brain development observed in these pathologies. Recent evidence shows a subclinical chronic inflammatory status in plasma from CDD patients. However, it is unknown whether a similar inflammatory status is present in the brain of CDD patients and, if so, whether it plays a causative or exacerbating role in the pathophysiology of CDD. Here, we show evidence of a chronic microglia overactivation status in the brain of Cdkl5 KO mice, characterized by alterations in microglial cell number/morphology and increased pro-inflammatory gene expression. We found that the neuroinflammatory process is already present in the postnatal period in Cdkl5 KO mice and worsens during aging. Remarkably, by restoring microglia alterations, treatment with luteolin, a natural anti-inflammatory flavonoid, promotes neuronal survival in the brain of Cdkl5 KO mice since it counteracts hippocampal neuron cell death and protects neurons from NMDA-induced excitotoxic damage. In addition, through the restoration of microglia alterations, luteolin treatment also increases hippocampal neurogenesis and restores dendritic spine maturation and dendritic arborization of hippocampal and cortical pyramidal neurons in Cdkl5 KO mice, leading to improved behavioral performance. These findings highlight new insights into the CDD pathophysiology and provide the first evidence that therapeutic approaches aimed at counteracting neuroinflammation could be beneficial in CDD.

Estudos sobre o «vermelhão» do algodoeiro (III)

In several cotton crops areas of the State of S. Paulo it was observed, during the years of 1948, 1949, and 1951, the appearance of a purple color of the leaves; the color appears in the opening of the bolls and was correlated with a decrease of production. The opinions concerning the cause of such abnormality were very different and sometimes contradictory; certain investigators attributed the disease to insect attack, others to bad climatic conditions whereas others to a potassium deficiency now called "fome de potássio" (potash hunger); our ideas on the subject is another one. We think that the disease is caused by lack of a suitable supply of magnesium. This opinion is largely based on the syntomatology found in the literature. To study the problem, several experiments were carried out, namely: 1. pot experiments using soil collected in areas where the disorder had appeared; 2. pot experiments controlling the water supply; 3. sand culture experiments omitting either potassium or magnesium; 4. leaf analysis of plant matrial collected troughout the Piracicaba County; 5. plot experiments with the varieties Texas, Express, and I.A. 817 Campinas. The first four experiments were discussed elsewhere. To study the point 5 an experiment was carried out, with the following treatments : 1 - NPKCaMg (no K added) - Mg supplied as MgSO4 (a soluble form); 2 -NPKCa (no Mg added); 3 -NPKCaMg (complete) - Mg supplied as MgSO4; 4 - NPKCaMg (complete) - Mg supplied as dolomitic limestone (a slightly soluble form) as a rate 2.5 higher than in the treatment 1 and 3. Organic matter as cottonseed meal was applied in the proportion of 500 kg per hectare. The experimental design was randomized blocks with 4 replications and the results can be summarized as follows: 1 the I.A 817 variety was the most strongly affected by the physiological disorder, with severe decrease in yield; 2. the disease occurred more frequently in the minus magnesium treatment; 3. dolomitic limestone is so effective as magnesium sulfate in the control of the disease as well in the raising of the yield; 4. in the minus K treatment it was observed a marked occurrence of the typical symptoms of potassium deficiency (cotton rust); 5. magnesium was actually, in the experimental conditions the responsible for the purple color (vermelhão) of the cotton leaves.

Contribuição ao estudo do «vermelhão» do algodoeiro (Gossipium herbaceum)

During the years 1948, 1949 and 1951 a disease occurred in the cotton crops of the state of S. Paulo Brazil (S. Am.), which caused a severe drop in yields. The abnormality was characterized by a typical reddish - purple color of the leaves, being by this reason, called "vermelhão", that is, reddening of the cotton plant. The disease was associated with a dry season. Among the several hypotheses raised to explain the causes of the disease were: insect attack, potassium deficiency - where from the name "potash hunger" was also given -, and magnesium deficiency: In order to study the problem the Department of Agricultural Chemistry of the College of Agriculture of the University of São Paulo, at Piracicaba, carried out a series of experiments as follows: 1. pot experiments in which soil of one of the affected regions was used ("terra roxa", a red-brownish soil derived from basalt); 2. pot-soil experiments varying the moisture supplied; 3. sand culture experiments omitting certain elements from the nutrient solutions; 4. field plot experiments, conducted on a sandy soil; three different varieties were employed: Texas, Express, and I.A. 817; magnesium was applied either as sulfate or dolomitic limestone. All the experiments were completed with suitable chemical analyses. The results can be summarized as follows: 1. in the first trial, the not properly manured pots (minus Mg), symptoms were registered which were similar to the symptoms observed in the field; it was possible to establish some differences among three different types of reddening: due to lack of K in the mixed fertilizers used, the characteristic cotton rust made its appearance, the red color in the leaves of the minus Mg plants was all alike that described in the current literature as a symptom of Mg-deficiency; in all the treatments ocurred a yellow-reddish color in the leaves associated with the latest stages of maturity; 2. in the second experiment it was verified that when the plants in the pots with soil were kept 75 per cent of the water holding capacity, no symptom of deficiency showed up; was true even for the plants not receiving neither K nor Mg; however, plants supplied with only 25 per cent of the water holding capacity showed, respectively, cotton rust in the minus K treatment and the red purplish color in the minus Mg series; 3. the sand culture experiment confirmed lack of Mg as the cause of "vermelhão", being potash deficiency the responsible for cotton rust; 4. in the field experiment, variety LA. 817 revealed to be the most sensitive to "vermelhão" when Mg was omitted from the fertilizers; symptoms of K deficiency appeared when no K was supplied; both magnesium sulfate and dolomitic limestone proved to be equally effective in the control of "vermelhão"; 5. the analyses of material collected both in the field as well in the pots revealed that leaf petiole in the most reliable part to indicate the K and Mg status of the plant; the variation in Mg content suffered by the plants showing different stages of "vermelhão was, quantitatively, at least as large as that in K content, however when one deals with K deficient plants, that is, plants showing the typical rust, no variation occurred in the Mg content, whereas K in the dry mater dropped from more than 1 per cent to less than half per cent. Then, the following general conclusions can be drawn: 1. Mg deficiency is the cause of "vermelhão" of cotton crops; 2. K deficiency also occurred, but in a lesser degree; 3. the climate conditions - especially the lack of rain influenced the soil dynamic of K, and especially Mg, bringing a severe reduction in their assimilability; 4. the "vermelhão" disease can be easily controlled upon additions either of magnesium sulfate or dolomitic limestone.

Omissão de macronutrientes no crescimento e no estado nutricional de plantas de repolho cultivado em solução nutritiva

Given the importance of heart, especially among the high brassica consumption, coupled with the scarcity of studies that report symptoms of nutritional disorders in the culture, the work was carried out to evaluate the effect of the omission of macronutrients in the development and nutritional status of cabbage, and describe visual symptoms of nutritional deficiency. The experiment was conducted under greenhouse conditions in the UNESP, Jaboticabal, SP. The experiment was arranged in completely randomized design with three replications and seven treatments, corresponding to complete nutritive solution (macro and micronutrients) and individual N, P, K, Ca, Mg and S omission. Plant height, number of leaves, leaf area, shoot, root and whole plant dry mass and macronutrient levels were determined and nutritional deficiency symptoms were described. Individual omissions of N, P, K or Ca were limiting for cabbage growth, considerably reducing plant height, number of leaves, and shoot, root and whole plant dry mass. Nutritional deficiency symptoms were observed for each element. Shoot macronutrient levels in control and nutrient omission treatments were, respectively: N = 31.0-11.9; P = 5.3-0.60; K = 63.5-4.8; Ca = 25.9-4.8; Mg = 5.2-0.5; S = 10.3-1.4 g kg(-1).

Nutrição mineral do mamoeiro (Carica papaya L.): III - sintomatologia de carências nutricionais

Objetivando caracterizar as deficiências de N, P, K, Ca, Mg e S em mamoeiro (Carica papaya L.) em condições de casa de vegetação e soluções nutritivas, desenvolveu-se o presente trabalho. Os autores descrevem os sintomas de carência dos macronutrientes, com exceção do enxofre, cujas plantas que receberam o tratamento deficiente neste nutriente, não mostraram sintomas, provavelmente por contaminação externa. Os níveis analíticos encontrados em folhas sadias e desnutridas, expressos em função da matéria seca foram: N-4,24% e 3,61%; P-0,52% e 0,14%; K-3,81% e 1,36%; Ca-1,29% e 0,28%; Mg-0,65 e 0,17%.

Deficiências de macronutrientes em plantas de soja cv. BRSMG 68 (Vencedora) cultivada em solução nutritive

Soybean is a crop of great importance for Brazil, and knowledge of their nutritional status allows production and high quality products. Thus, the present work aimed to evaluate the culture of the soybean cv. BRSMG 68 (Vencedora), submitted to macronutrients omission on the development, nutritional status and the visual symptomatology of nutrient deficiency. The design used was completely randomized, with seven treatments that corresponded to the complete (macro and micronutrients) solution and the individual omission of N, P, K, Ca, Mg and S. The treatments were applied two weeks after the emergency of the soybean. The nutrient solution was constantly oxygenated and replaced weekly, and the pH monitored daily remained around 5. After six weeks of application of the treatments, the height of the plants, number of leaves, stem diameter was evaluated, matter dry accumulated in the roots, it leaves aerial and the nutritional state and the characterization of the visual symptoms. The macronutrient deficiency promoted a decrease in production of root and shoot dry mass of soybean cultivar BRSMG 68 (Vencedora) in nutrient solution, for the full treatment. The most limiting nutrient for dry matter production of soybean compared to complete treatment were N, S and K, with decreases of 90, 76 and 73%, respectively. Individual omissions resulted in morphological changes, which were translated by characteristic visual symptoms of nutritional deficiency of the respective nutrient.

Caracterização de sintomas visuais de deficiência de macronutrientes em alface

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Estado nutricional de couve-flor ‘Verona’ submetida à omissão de macronutrientes

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Sintomas de deficiências de macronutrientes em pimentão

Pós-graduação em Agronomia (Ciência do Solo) - FCAV

Absorção e mobilidade do boro em plantas de repolho e de couve-flor

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Sintomas de deficiências de macronutrientes em pepineiro

Pós-graduação em Agronomia (Produção Vegetal) - FCAV

EMAS position statement: Testosterone replacement therapy in the aging male‏.

INTRODUCTION Late-onset hypogonadism (LOH) represents a common clinical entity in aging males, characterized by the presence of symptoms (most usually of a sexual nature, such as decreased libido, decreased spontaneous erections and erectile dysfunction) and signs, in combination with low serum testosterone concentrations. Whether testosterone replacement therapy (TRT) should be offered to those individuals is still under extensive debate. AIMS The aim of this position statement is to provide and critically appraise evidence on TRT in the aging male, focusing on pathophysiology and characteristics of LOH, indications for TRT, available therapeutic agents, monitoring and treatment-associated risks. MATERIALS AND METHODS Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS Diagnosis and treatment of LOH is justified, if a combination of symptoms of testosterone deficiency and low testosterone is present. Patients receiving TRT could profit with regard to obesity, metabolic syndrome, type 2 diabetes mellitus, sexual function and osteoporosis and should undergo scheduled testing for adverse events regularly. Potential adverse effects of TRT on cardiovascular disease, prostate cancer and sleep apnea are as yet unclear and remain to be investigated in large-scale prospective studies. Management of aging men with LOH should include individual evaluation of co-morbidities and careful risk versus benefit assessment.

A critical comparison of the external and internal boron requirements for contrasting species in boron-buffered solution culture

Despite reports that boron (B) requirements differ among plant species there is a shortage of critical evidence to demonstrate unequivocally whether species differ in internal or external B requirements or both. The present research was conducted to establish the external and internal B requirements of three contrasting species, a woody dicot (marri), an herbaceous dicot (sunflower) and a monocot (wheat) using B-buffered solution culture. Boron-buffered solution culture provided satisfactory control of external B concentrations ranging from 0.04 to 30 muM throughout the 20- (sunflower and wheat) or 40-day (marri) growth period. At low external B concentrations (less than or equal to 0.13 muM), the growth of marri and sunflower was severely depressed but by contrast the vegetative growth of wheat plants was satisfactory and free of B deficiency symptoms. Marri and sunflower plants achieved total maximum shoot growth at greater than or equal to1.2 muM B in solutions while wheat plants did so at greater than or equal to 0.6 muM B. The critical B concentrations (mg kg(-1) dry matter) in the youngest open leaf blades of marri, sunflower and wheat plants were 17.9, 19.7 and 1.2 on 20, 10 and 10 days after transplanting (DAT), respectively. Lower internal and external B requirements of wheat were matched by a lower uptake rate of B compared to marri and sunflower.

Reversible congestive heart failure associated with primary carnitin deficiency: report of a case and review of the literature.

A 5-year-old previously healthy boy was admitted for abdominal pain and vomiting. Physical examination showed tachypnoe (32/min), hepatomegaly and painful palpation of the upper right abdominal quadrant. Laboratory tests were normal except for elevated ammonium (202mcmol/l). Chest X-ray was performed, showing cardiomegaly and interstitial edema. Transthoracic echocardiography revealed dilated left cavities and LV hypertrophy together with a diffuse hypokinesia and LVEF of 30-40%. Diuretics and ACE-inhibitors were introduced. At that time, the differential diagnosis for the DCM included myocarditis, congenital or genetic, metabolic or autoimmune disease. The next day, the boy underwent cardiac magnetic resonance (CMR) examination, showing a severe dilatation of the LV with an end-diastolic diameter of 50mm and a volume of 150ml. LVEF was 20% with diffuse LV hypokinesia (Fig. 1). No late enhancement was present after Gadolinium injection, ruling out myocarditis. Further laboratory metabolic analysis indicated severely decreased total and free carnitin levels and low renal carnitin reabsorption, corroborating the diagnosis of primary carnitin deficiency (PCD). Carnitin substitution was initiated. The clinical condition rapidly improved. No symptoms of heart failure were present anymore. A follow-up CMR performed 9 months later confirmed the recovery. LV end-diastolic volume decreased from 150ml to 66ml, LVEF increased from 20% to 55% (Fig. 2). Late enhancement was absent after Gadolinum injection (Fig. 3).Carnitin is required for the transport of fatty acids from the cytosol into mitochondria during lipid breakdown. 75% of carnitin is obtained from food, 25% is endogenously synthesized. PCD is an autosomal recessive disorder resulting from impairment of a transporter activity, caused by mutation of the SLC22A5 gene. Incidence is about 1 in 40'000 newborns. Diagnosis is usually made at age 1 to 7. Three forms of PCD are described. In the form associated with cardiomyopathy, the disease is progressive and patient die from heart failure if not treated. Substitution of L-Carnitin leads to a dramatic improvement of disease course.This case underlines the crucial role of etiologic diagnostics in this reversible form of DCM. Early diagnostics and therapy are critical for the prognosis of the patient. This is furthermore an example of a role played by CMR in the diagnostic work-up of heart failure and its follow-up under therapy.

Acute life-threatening presentation of vitamin d deficiency rickets.

Context: Clinical manifestations of vitamin D deficiency rickets are widely described; however cardiorespiratory arrest is an extremely rare presentation. Objective: The aim of this paper is to present the symptoms of severe vitamin D deficiency rickets and to highlight the importance of vitamin D prophylaxis in infants. Results: We report a case of a 16-month-old infant who presented to emergency room with a stridor that evolved into a full cardiorespiratory arrest secondary to hypocalcemia. Medical history revealed that the infant was exclusively breastfed without vitamin D supplementation until the age of 10 months. Due to cultural habits, his diet was also grossly deficient in dairy products. Physical exam revealed clinical signs of rickets. Laboratory test showed severe hypocalcemia, elevated alkaline phosphatase, normal serum phosphorous, decreased 25(OH) cholecalciferol, increased intact parathyroid hormone level, and normal urine calcium excretion. The radiography of the wrist showed evidence of cupping, fraying, metaphyseal widening, and demineralization of the distal radial and ulnar metaphyses. The bone mineral density of the lumbar spine measured by dual x-ray absorptiometry showed a Z-score below -2 SD. His cardiorespiratory arrest secondary to hypocalcemia was therefore attributed to severe nutritional rickets. Conclusion: Vitamin D deficiency rickets can be life threatening. Vitamin D supplementation is therefore crucial, especially in breastfed infants and some ethnic minorities (dark-skinned people, poor sun exposure), more at risk for developing severe rickets if not supplemented.