Effects of endocrine disorders on maxillary and mandibular growth in Colombian children and adolescents: a cross-sectional study.

OBJECTIVE: To establish the influence of overweight/obesity, medicated hypothyroidism, and medicated non-syndromic hypogrowth on maxillary and mandibular growth. MATERIALS AND METHODS: The relation between 10 craniofacial anthropometric measurements and hypothyroidism (n = 216), overweight/obesity (n = 108), and non-syndromic hypogrowth (n = 250) were evaluated in patients aged 1-19 years and a control group of healthy patients (n = 587). A subgroup analysis was performed at the peak growth in all groups. RESULTS: Patients with overweight/obesity and hypothyroidism showed increased craniofacial growth, while hypogrowth patients showed differences in zygomatic width and nasal base growth. Females with hypothyroidism and non-syndromic hypogrowth showed decreased head circumference at peak growth. Several anthropometric measurements were increased in patients with overweight/obesity, including head circumference. When all age groups were analyzed, overweight/obese and hypothyroidism patients showed increased zygomatic width while decreased hypogrowth. Overall, most craniofacial anthropometric measurements in overweight/obese patients were increased. Finally, the peak growth in males with hypothyroidism and subjects with non-syndromic hypogrowth was delayed compared to the control group (p < 0.05). CONCLUSIONS: Children and adolescents with overweight/obesity and endocrine disorders showed alterations in craniofacial growth. Clinicians must be aware that the growth peak in these patients may be delayed when planning maxillary and mandibular orthopedic treatment.

Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder.

Huntington disease (HD) is a neurodegenerative disorder produced by an expansion of CAG repeats in the HTT gene. Patients of HD show involuntary movements, cognitive decline and psychiatric impairment. People carrying abnormally long expansions of CAGs (more than 35 CAG repeats) produce mutant huntingtin (mHtt), which encodes tracks of polyglutamines (polyQs). These polyQs make the protein prone to aggregate and cause it to acquire a toxic gain of function. Principally affecting the frontal cortex and the striatum, mHtt disrupts many cellular functions. In addition, this protein is expressed ubiquitously, and some reports show that many other cell types are affected by the toxicity of mHtt. Several studies reported that metformin, a widely-used anti-diabetic drug, is neuroprotective in models of HD. Here, we provide a review of the benefits of this substance to treat HD. Metformin is a pleiotropic drug, modulating different targets such as AMPK, insulin signalling and many others. These molecules regulate autophagy, chaperone expression, and more, which in turn reduce mHtt toxicity. Moreover, metformin alters gut microbiome and its metabolic processes. The study of potential targets, interactions between the drug, host and microbiome, or genomic and pharmacogenomic approaches may allow us to design personalised medicine to treat HD.

Synergistic activation of AMPK prevents from polyglutamine-induced toxicity in Caenorhabditis elegans.

Expression of abnormally long polyglutamine (polyQ) tracks is the source of a range of dominant neurodegenerative diseases, such as Huntington disease. Currently, there is no treatment for this devastating disease, although some chemicals, e.g., metformin, have been proposed as therapeutic solutions. In this work, we show that metformin, together with salicylate, can synergistically reduce the number of aggregates produced after polyQ expression in Caenorhabditis elegans. Moreover, we demonstrate that incubation polyQ-stressed worms with low doses of both chemicals restores neuronal functionality. Both substances are pleitotropic and may activate a range of different targets. However, we demonstrate in this report that the beneficial effect induced by the combination of these drugs depends entirely on the catalytic action of AMPK, since loss of function mutants of aak-2/AMPKα2 do not respond to the treatment. To further investigate the mechanism of the synergetic activity of metformin/salicylate, we used CRISPR to generate mutant alleles of the scaffolding subunit of AMPK, aakb-1/AMPKß1. In addition, we used an RNAi strategy to silence the expression of the second AMPKß subunit in worms, namely aakb-2/AMPKß2. In this work, we demonstrated that both regulatory subunits of AMPK are modulators of protein homeostasis. Interestingly, only aakb-2/AMPKß2 is required for the synergistic action of metformin/salicylate to reduce polyQ aggregation. Finally, we showed that autophagy acts downstream of metformin/salicylate-related AMPK activation to promote healthy protein homeostasis in worms.

Extended phenotype and clinical subgroups in unilateral Meniere disease: A cross-sectional study with cluster analysis.

OBJECTIVES: To define clinical subgroups by cluster analysis in patients with unilateral Meniere disease (MD) and to compare them with the clinical subgroups found in bilateral MD. DESIGN: A cross-sectional study with a two-step cluster analysis. SETTINGS: A tertiary referral multicenter study. PARTICIPANTS: Nine hundred and eighty-eight adult patients with unilateral MD. MAIN OUTCOME MEASURES: best predictors to define clinical subgroups with potential different aetiologies. RESULTS: We established five clusters in unilateral MD. Group 1 is the most frequently found, includes 53% of patients, and it is defined as the sporadic, classic MD without migraine and without autoimmune disorder (AD). Group 2 is found in 8% of patients, and it is defined by hearing loss, which antedates the vertigo episodes by months or years (delayed MD), without migraine or AD in most of cases. Group 3 involves 13% of patients, and it is considered familial MD, while group 4, which includes 15% of patients, is linked to the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by a comorbid AD. We found significant differences in the distribution of AD in clusters 3, 4 and 5 between patients with uni- and bilateral MD. CONCLUSIONS: Cluster analysis defines clinical subgroups in MD, and it extends the phenotype beyond audiovestibular symptoms. This classification will help to improve the phenotyping in MD and facilitate the selection of patients for randomised clinical trials.

Ophthalmic features of Friedreich ataxia.

PURPOSE: To describe ocular abnormalities in patients with Friedreich ataxia (FRDA). METHODS: Patients diagnosed with FRDA by genetic analysis were invited to participate in a prospective cohort. The patients included underwent an extensive ophthalmologic examination, including low-contrast Sloan letter charts test and retinal nerve fiber layer (RNFL) thickness analysis by optical coherence tomography (OCT). RESULTS: Twenty-three patients agreed to participate. In all, 19 patients (83%) had a visual acuity of at least 0.8 in both eyes. Fundus examination showed diffuse optic nerve pallor in four patients. However, OCT showed a decreased mean peripapillary RNFL thickness in all but three adult cases and one teenager. The RNFL thickness was found to have a positive correlation with visual acuity (P=0.001) and contrast sensitivity (P=0.001) and a negative correlation with time elapsed from diagnosis (P=0.001). CONCLUSIONS: OCT and low contrast test sensitivity show that the visual pathway is affected in FRDA. However, in most patients there is no significant visual impairment. In a small proportion of patients visual acuity declines with disease progression. This study provides a better understanding of the ophthalmic features of FRDA.

Estudio fitoquímico y farmacológico de 4 Plantas con efecto hipoglicemiante / Phytochemical and pharmacological studies in four plants with hypoglycemic effect

Se realizó el estudio de la acción hipoglicemiante de Ocimum sanctus (Albahaca morada), Notholaena nivea (Cuti-Cuti), Geranuim lechleri (Pasuchaca) y Smallantus sonchifolius (Yacón), frente a la hiperglicemia aloxánica, tanto de los extractos atomizados, como del pool de alcaloides, de cada una de las plantas. Igualmente, se determinó la DL50 del extracto atomizado y de los alcaloides de las cuatro plantas evaluadas. La toxicidad aguda se determinó en ratones albinos, cepa nihs, cuyos pesos oscilaron entre 25 y 30 g. La acción hipoglicemiante, fue evaluada en ratas albinas cepa holtzman, de 200 a 250 g de peso. Tanto los extractos atomizados, como los alcaloides de Cuti-Cuti, Pasuchaca y hojas de Yacón, mostraron un excelente efecto hipoglicemiante, frente a la hiperglicemia inducida por aloxano. Las tres plantas poseen escasa toxicidad aguda, y según los criterios de Williams podrían considerarse como plantas prácticamente atóxicas. Sin embargo, solamente el pool de alcaloides de Albahaca a la dosis de 250 mg/ kg de peso, mostró una escasa acción hipoglicemiante, no mostrando eficacia la dosis de 500mg/kg, del pool de alcaloides, ni el atomizado de la planta, a la dosis de 1000 mg/kg de peso.

The study of the hypoglicemic action of Ocimum sanctum (Albahaca morada), Notholaena nivea (Cuti-Cuti), Geranuim lechleri (Pasuchaca) and Smallantus sonchifolius (Yacón), was performed on alloxan-induced hyperglicemic rats. In addition, atomized extracts and the pool of alkaloids, of the different plants were studied. To evaluate acute toxicity, DL50 of the atomized extract and of the alkaloids on the four plants were determined using albino mice, whose weights oscillated between 25 and 30 g. The hypoglycemic action, was evaluated in Holtzman albino rats, of 200 to 250 g of weight. The atomized extracts, as well as the alkaloids of Cuti-Cuti, Pasuchaca and leaves of Yacón, showed an excellent hypoglicemic effect in the hyperglicemic alloxaninduced rats. These three plants have little acute toxicity and according to the Williams` criteria they could be considered as practically non toxic. On the other hand only the pool of alkaloids of Albahaca, at the dose of 250 mg/kg showed little hypoglicemic action. No hypoglicemic effect was observed with the albahaca alkaloids at the dose of 500mg/kg nor with the atomized extract of the plant at the dose of 1000 mg/kg.

Efectos metabólicos de Lepidium meyenii Walpers, “MACA” y Lupinus mutabilis Sweet, “CHOCHO”en ratas / Metabolic effects of lipidium meyenii walpers “MACA” and lupinus mutabilis sweet, “CHOCHO” in rats

El Lepidium meyenii, “Maca” y el Lupinus Mutabilis S, “Chocho”, pertenecen al grupo de plantas conocidas como nutracáticas. El uso de la Maca, se remonta al siglo 7 AC. En la época de la conquista fue el producto más importante del agro peruano; pertenece a la familia de las Cruciferaceae (Brasicaceae). Ambas plantas son usadas, desde tiempos precolombinos, como medicinales y/o alimenticias. En el presente trabajo, evaluamos el efecto de Maca y de Lupinus, en ratas hembras Sprague Dawley, con peso corporal entre 120 y 170g, sobre los valores de hematocrito, hemoglobina, glucosa, colesterol, trigliceridos, HDL, LDL, proteínas totales, albúmina, TGO, TGP y peso corporal, después de 15 y 30 días de tratamiento. Utilizamos 60 ratas albinas distribuidas en 3 grupos de 20 animales cada uno. Al primer grupo se le administró, por 30 días, suero fisiológico (GRUPO CONTROL). Al segundo grupo se le administró cocimiento acuoso de harina de maca, a la dosis de 500 mg/Kg y al tercer grupo, cocimiento acuoso de harina de semillas de chocho, desamargado y descascarado, a las dosis de 500 mg/Kg, durante 30 días. Nuestros resultados, indican un aumento de los niveles de triglicéridos en sangre, por efecto de Lupinus (de 45.9 a 76.55 mg), a los 30 días, con respecto al control, que varió de 43.5 a 61.8 mg. Con maca, las variaciones fueron de 43,5 a 56.7 mg: asimismo, apreciamos un ligero aumento del hematocrito y la hemoglobina, a los 15 días de tratamiento, con maca. Los an lisis estadísticos entre el grupo control y los tratados, con Maca y Lupinus, no fueron significativos.

Lepidium meyenii, “Maca” and the Lupinus mutabilis S, “Chocho” belong to the group of plants known as nutraceutic plants. Maca has been used since the seventh century BC and it was the most important crop in Peruvian agriculture during the sisxteenth century, around the time when the Spanierds arrived to our territory. This plant belongs to the Cruciferaceae (Brasicaceae) family. Both plants (Maca and Chocho) were used in Peru, since pre Columbian times as part of the diet as well as for their medicinal properties. In these issue, we evaluated the effects of Maca and Lupinus on female Sprague Dawley rats (weight between 120 and 170 g), and we tested Hemoglobin, hematocrit, total proteins, albumin, TGO, TGP and corporal weight values after 15 and 30 days of trestment.We used 60 albino rats, distributed in three groups of twenty animals each one. The first group was the control and re ceived 0, 9% saline solution for 30 days. The second group received Maca flour watery solution at 500 mg/kg doses and the third group received Lupinus, watery solution at 500 mg/kg doses for thirty days.Our results showed an increase of the serum levels of triglycerides due to Lupinus (from 45.9 to 76.55mg) after 30 days in relation to the control that varied from 43.5 to 61.8mg. With Maca variations were from 43.5 to 56.7 mg. We also appeciated a slight increase of hematocrit and haemoglobin after 15 days of treatment with Maca in relation to the control group. Analyses between control and treated groups showed no statistical differences.

Estudio de la actividad analgésica de extractos metanólicos de Maytenus krukovii (chuchahuasi), Alchornea castaneifolia (hiporuro), Sambucus nigra (saúco) y Aristeguietia discolor (pulmonaria) en ratones frente el Ibuprofeno / Study of the analgesic activity of methanolic extracts of Maytenus krukovii (chuchahuasi) castaneifolia Alchornea (hiporuro), Sambucus nigra (elderberries) and Aristeguietia discolor (pulmonary) in mice versus Ibuprofen

Al evaluar el efecto analgésico se encontró actividad positiva del extracto metanólico de Maytenus krukovii (chuchahuasi), Alchornea castaneifolia (Hiporuro), Sambucus nigra (Saúco) y Aristeguietia discolor (Pulmonaria) a las dosis de 100 mg/kg, 250 mg/kg, 250mg/kg y 750 mg/kg, respectivamente, por vía oral; luego de una hora de administración se encontró que el efecto analgésico de Chuchuhuasi y Pulmonaria eran comparables al Ibuprofeno. Asimismo, apreciamos, en todos los extractos, una prolongación del período de latencia con respecto al control.

We evaluated the analgesic effect of four different plants, and this effect was positive for thr metanolic extracts of Maytenus krukovii (Chuchuhuasi), Alchornea castaneifolia (Hiporuro), Sambucus nigra (Saúco) y Aristeguietia discolor (Pulmonaria) in the doses of 1000 mg/g, 250 mg/kg, and 750 mg/kg, respectively administered orally to mice. After one hour of administration the analgesic effect of Chuchuhuasi and Pulmonaria were comparable to that Ibuprofene. It was also noted that all extracts delayed the latency time regarding to the control sample.

Renal failure as a determinant of mortality after cardiac transplantation.

INTRODUCTION: Patients with heart failure frequently develop renal failure, which increases the mortality rate among patients undergoing cardiac transplantation. PURPOSE: To determine whether preoperative renal function influenced postoperative mortality in cardiac transplantation recipients. MATERIALS AND METHODS: The measurements of plasma urea, plasma creatinine, and 24-hour creatinine clearance in patients who underwent cardiac transplantation were correlated with mortality at 30, 90, and 365 days after the procedure, using Student t test for continuous variables and the chi-square test for categorical variables. RESULTS: All variables correlated with mortality, particularly plasma creatinine at 30, 90, and 365 days (P =.029,.003, and.0029, respectively). CONCLUSION: Preoperative renal failure is a mortality indicator in cardiac transplantation recipients.

Genotype and phenotype analysis of Friedreich's ataxia compound heterozygous patients.

Friedreich's ataxia is caused by mutations in the FRDA gene that encodes frataxin, a nuclear-encoded mitochondrial protein. Most patients are homozygous for the expansion of a GAA triplet repeat within the FRDA gene, but a few patients show compound heterozygosity for a point mutation and the GAA-repeat expansion. We analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. Patients heterozygous for the GAA expansion were screened for point mutations within the FRDA coding region. Molecular analyses included the single-strand conformation polymorphism analysis, direct sequencing, and linkage analysis with FRDA locus flanking markers. Seven compound heterozygous patients were identified. In four patients, a point mutation that predicts a truncated frataxin was detected. Three of them associated classic early-onset Friedreich's ataxia with an expanded GAA allele greater than 800 repeats. The other patient associated late-onset disease at the age of 29 years with a 350-GAA repeat expansion. In two patients manifesting the classical phenotype, no changes were observed by single-strand conformation polymorphism (SSCP) analysis. Linkage analysis in a family with two children affected by an ataxic syndrome, one of them showing heterozygosity for the GAA expansion, confirmed no linkage to the FRDA locus. Most point mutations in compound heterozygous Friedreich's ataxia patients are null mutations. In the present patients, clinical phenotype seems to be related to the GAA repeat number in the expanded allele. Complete molecular definition in these patients is required for clinical diagnosis and genetic counseling.

Evolution of gypsy endogenous retrovirus in the Drosophila obscura species group.

The Ty3/gypsy family of retroelements is closely related to retroviruses, and some of their members have an open reading frame resembling the retroviral gene env. Sequences homologous to the gypsy element from Drosophila melanogaster are widely distributed among Drosophila species. In this work, we report a phylogenetic study based mainly on the analysis of the 5' region of the env gene from several species of the obscura group, and also from sequences already reported of D. melanogaster, Drosophila virilis, and Drosophila hydei. Our results indicate that the gypsy elements from species of the obscura group constitute a monophyletic group which has strongly diverged from the prototypic D. melanogaster gypsy element. Phylogenetic relationships between gypsy sequences from the obscura group are consistent with those of their hosts, indicating vertical transmission. However, D. hydei and D. virilis gypsy sequences are closely related to those of the affinis subgroup, which could be indicative of horizontal transmission.

Terapia nutricional em transplante cardíaco / Nutritional therapy in heart transplantation

Os casos graves de miocardiopatias com indicaçäo cirúrgica de transplante cardíaco necessitam de rigoroso cuidado nutricional. A avaliaçäo desses pacientes, baseada em parâmetros clínicos, laboratoriais e exames especializados, constitui a base do sucesso da dietoterapia aplicada. Na formulaçäo dietética, configura-se a necessidade de rigoroso aporte protéico, controle glicídio baseado nos parâmetros clínicos e laboratoriais e restriçäo lipídica relativa. O acompanhamento requer a interaçäo multiprissional que atua nas decisöes e orientaçöes no pós-transplante imediato e ambulatorial.

Terapia imunossupressora no transplante cardíaco / Immunotherapy in heart transplantation

A terapia imunossupressora tem por finalidade a diminuiçäo da resposta fisiológica do organismo contra o enxerto, aumentando sua vida útil. A partir da identificaçäo dos mecanismos envolvidos na compatibilidade e resposta imunológica (celular e humoral), tenta-se controlá-los adequadamente, minimizando ou eliminando a rejeiçäo a curto, médio e longo prazos. Säo descritos esquemas terapêuticos, com associaçäo de drogas com mecanismos de açäo complementares, nas doses mais baixas possíveis, visando eito imunossupressor adequado, para manutençäo da vitalidade do enxerto, ao mesmo tempo que se tentam eveitar efeitos colaterais, potencialmente muito deletérios.

Comparaçäo entre a dosagem de ciclosporina-A em amostras de sangue coletadas em papel de filtro e pela técnica habitual / Comparison between the dosage of cyclosporin-A in blood samples collected on filter paper and by the ordinary technique

A monitorizaçäo dos níveis sanguíneos da ciclosporina A (CsA) é fundamental para o uso racional deste medicamento. No Brasil, poucos laboratórios realizam dosagem de CsA, embora haja muitos centros de transplante. Desta forma, surgiu o problema de fazer chegar a amostra de sangue ao laboratório. A coleta de sangue em papel de filtro é técnica já empregada, em situaçöes especiais, há muito tempo. OBJETIVOS. Correlacionar a fidedignidade da dosagem de CsAem amostras de sangue coletadas em papel de filtro com as técnicas habituais de coleta. MÉTODOS. Foram estudados 20 pacientes transplantados com rim de cadáver em uso de CsA, associada à azatioprina e à prednisona. Noventa e cinco amostras de sangue foram coletadas em EDTA e subdivididas em duas alíquotas. Uma delas foi encaminhada, da forma habitual, para o laboratório clínico para dosagem sanguínea de CsA. Da outra alíquota foram pipetados 20 microlitros sobre papel de filtro que, após secagem, foram enviados, pelo correio, para outro laboratório, onde, após eluiçäo, foi feita a dosagem de CsA. Nos dois casos a técnica de dosagem foi a mesma, usando-se o radioimunoen-saio com anticorpo policlonal anti-CsA. RESULTADOS. A correlaçäo linear entre ambas as dosagens resultou r = 0,81, näo havendo diferença significativa. CONCLUSÖES. Este método se presta, portanto, para ser usado na prática clínica, o que, em país de dimensöes continentais como o Brasil, pode ser muito útil

[Comparison of the determination of cyclosporin-A in blood samples collected on filter paper and by the ordinary technique]. / Comparação entre a dosagem de ciclosporina-A em amostras de sangue coletadas em papel de filtro e pela técnica habitual.

Monitoring cyclosporin-A (CsA) blood levels is of utmost importance for the rational use of this drug. Although many centers perform transplants, in Brazil there are few laboratories able to measure CsA blood levels. Therefore making blood samples reach the laboratory emerged as a problem. Collection of blood on filter paper has been a technique used for a long time in special cases. PURPOSE--To confirm the usefulness of measuring CsA blood levels in blood samples collected on filter paper and in the usual way. METHOD--We studied twenty renal cadaver kidney recipients who were receiving CsA, azathioprine and prednisone. Ninety five blood samples were collected and divided into two aliquots. One of them was sent routinely to one laboratory to perform whole blood CsA measurements. From the other aliquot, 20 microliters were pipetted on filter paper. When dried they were mailed to the other laboratory, where, after elution, CsA was measured. In both cases radioimmunoassay with polyclonal antibody was used. RESULTS--Linear correlation between both measurements revealed r = 0.81 with no statistical difference. CONCLUSION--The technique showed to be useful in clinical practice. In countries with continental size, as Brazil, it may be very helpful.

Changes in plasma levels of 17 beta-estradiol after administration of an analogue of luteinizing hormone releasing hormone (LHRH-A) and pimozide in Diplectrum formosum (Teleostei: Serranidae).

Gonadotropin secretion in teleosts is known to be stimulated by gonadotropin hormone releasing hormone (GnRH) and inhibited by dopamine. This study has investigated the effects of administration of pimozide (PIM) alone or in combination with an analogue of GnRH on plasma 17 beta-estradiol (17 beta-E) levels and the gonadosomatic index. Adult Diplectrum formosum were treated with a gonadotropin-releasing hormone analogue [des-Gly10 D-Ala6 Pro9 N-ethylamide (LHRH-A); 50, 70, and 100 ng/g body wt] alone or in combination with pimozide (PIM), a dopamine antagonist (0.5, 1.0, and 5.0 micrograms/g body wt). LHRH-A alone caused a dose-dependent increase in plasma 17 beta-E levels. A single injection of PIM (0.5 or 5.0 micrograms/g) 12 hr previous to a single injection of 100 ng/g body wt of LHRH-A increased 17 beta-E concentrations compared with fish receiving PIM alone; however, 1 microgram/g PIM did not change 17 beta-E plasma levels. Simultaneous administration of PIM (0.5, 1.0, and 5.0 micrograms/g body wt) and 100 ng/g body wt of LHRH-A at an interval of 12 hr (30% of the total dose of both PIM and LHRH-A was administered in the first injection and 70% in the second injection) significantly increased plasma 17 beta-E concentrations. The magnitude of this increase was at least threefold higher than those of fish receiving a single injection of PIM, 12 hr before a single injection of LHRH-A. LHRH-A or PIM alone or combined was ineffective in causing ovulation.