[Glutaric aciduria type I. Clinical, biochemical and molecular findings in six patients in Venezuela]. / Aciduria glutárica tipo I. Hallazgos clínicos, bioquímicos y moleculares en seis pacientes venezolanos.

INTRODUCTION: Glutaric aciduria type I is an autosomal recessive inborn error of metabolism that is due to a deficiency of the enzyme glutaryl-CoA dehydrogenase, which gives rise to an accumulation of glutaric and 3-hydroxyglutaric acids in biological fluids. Clinical features present as a sudden-onset severe neurological disorder, characterised by extrapyramidal signs (dystonia-dyskinesia), hypotonia, irritability, macrocephaly and degeneration of the basal ganglia; it may also manifest with unspecific symptoms, such as hypotonia and psychomotor retardation. AIMS: To describe the clinical, biochemical, neuroimaging and molecular aspects in six Venezuelan patients and to highlight the importance of an early diagnosis of glutaric aciduria type I so as to be able to establish early treatment and thus prevent the neurological damage produced by this disease. CASE REPORTS: Two patients were referred because of macrocephaly, hypotonia and psychomotor retardation, and four more following an encephalopathic crisis. In all of them, neuroimaging studies showed delays in myelination, bilateral frontotemporal hypoplasia and symmetric widening of the Sylvian fissures with poor opercularisation. Urinary organic acid analyses showed raised levels of glutaric and 3-hydroxyglutaric acids, and a molecular analysis confirmed the diagnosis. CONCLUSIONS: Organic acid analysis should be indicated in all patients who present macrocephaly, hypotonia, psychomotor retardation or an encephalopathic crisis of unknown causation. This study allowed us to determine the behaviour of the disease in Venezuela, since no epidemiological data exist in the country.

[In utero macrocephaly as clinical manifestation of glutaric aciduria type I. Report of a novel mutation]. / Macrocefalia in utero como manifestación clínica de aciduria glutárica tipo I. Informe de una nueva mutacion.

INTRODUCTION: Macrocephaly is a pivotal clinical sign, associated with multiple neurological diseases, particularly neurometabolical ones, such as the glutaric aciduria type I (GA I). This aciduria resulting from the genetical deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH). Is a relatively common cause of acute metabolic brain damage in early childhood. We report on one case of GA I, with early manifestations since fetal period and a novel mutation. CASE REPORT: Our patient was referred due macrocephaly in utero and occipitofrontal head circumference above the 98 percentile for chronologic age during first few months of life, hypotonia and development delay. The metabolic investigations of organic acids in urine and acylcarnitine profile in blood, the brain magnetic resonance and the molecular analyses of the glutaryl-CoA deshidrogenase gene, confirm the diagnosis. The molecular analysis allowed to identify one previously described mutation A293T and a novel mutation IVS5-2 A>G. CONCLUSION: It is important the recognition of in utero macrocephaly as a sign to early diagnosis of glutaric aciduria type I to initiate specific therapy to prevent the encephalopathic crises and minimize brain damage in patients who are already neurologically impaired.

HPV detection in oral carcinomas

Os autores buscaram verificar, neste estudo, a presença do papilomavírus humano (HPV) de baixo e de alto risco em carcinomas orais através do teste de captura híbrida Digene® (São Paulo-SP, Brasil) em amostras colhidas pela citologia esfoliativa bucal e, ainda, avaliar comparativamente as referidas leituras com alterações celulares indicativas deste vírus obtidas com a interpretação citológica óptica convencional (hematoxilina-eosina (HE)/Papanicolaou). Quarenta indivíduos concordaram, espontaneamente, através de assinatura do termo de consentimento livre e esclarecido, em participar da pesquisa, e seus dados clínicos foram analisados. Entre as 40 amostras provenientes da citologia esfoliativa 29 (72,5 por cento) mostraram-se negativas para presença de HPV-DNA de baixo e de alto risco; nove (22,5 por cento) foram positivas para o HPV-DNA de baixo e de alto risco; uma (2,5 por cento) foi positiva apenas para o HPV de baixo risco; e também uma (2,5 por cento) foi positiva apenas para o HPV de alto risco. Houve concordância entre todos os resultados positivos para presença de HPV-DNA nas amostras citológicas submetidas ao teste de captura híbrida Digene® e na leitura de esfregaço citológico ao microscópio óptico convencional. Desta forma, conclui-se que o vírus HPV pode comportar-se como mais um co-carcinógeno para o câncer de boca, à semelhança do carcinoma uterino.

Detecção do papilomavírus humano (HPV) pela captura híbrida (R) (tecnologia Digene) em lesões malignas da mucosa bucal / Human papillomavirus (HPV) detection by hybride (R) capture (digene tecnologie) in buccal malignant lesions

A pesquisa do Papilomavírus Humano (HPV) em mucosa bucal é relevante uma vez que, este vírus tem participação no desenvolvimento do câncer de colo uterino, que em muito se assemelha ao câncer bucal. Por isso buscamos verificar a presença do HPV de baixo e de alto risco, em lesões malignas da mucosa bucal, através do teste laboratorial de Captura Híbrida (R) (tecnologia DIGENE), em amostras colhidas pela citologia esfoliativa bucal, bem como pela biópsia e, ainda, avaliar comparativamente as referidas leituras com alterações celulares indicativas deste vírus obtidos com a interpretação citológica óptica convencional (H.E./Papanicolaou). A amostra final foi constituída por 40 indivíduos que concordaram, espontaneamente, através de assinatura do termo de consentimento livre e esclarecido, em particular da pesquisa e seus dados clínicos também foram analisados. Todas as 40 lesões clinicamente suspeitas de malignidade foram diagnosticadas com carcinomas de células escamosas. Com os resultados obtidos até o presente momento, porque esta pesquisa está em desenvolvimento, observou-se que dentre as amostras provenientes de citologia esfoliativa 29 (72,5 por cento) mostraram-se negativas na presença de HPV de baixo e alto risco; 09 (22,5 por cento) apresentaram resultado positivo para o HPV de baixo e de alto risco; 1 (2,5 por cento) foi positivo apenas para o HPV de baixo risco; e também 1 (2,5 por cento) foi positivo apenas para o HPV de alto risco. E dentre os 10 espécimes obtidos também por biópsia 04 (40 por cento) foram negativos para presença de HPV de baixo e de alto risco; 06 (60 por cento) apresentaram resultado positivo para a presença do HPV de baixo e de alto risco. Houve concordância entre todos os resultados positivos para presença de HPV de baixo e de alto risco tanto do material obtido pela citologia esfoliativa quanto pela biópsia, e ainda, a leitura do esfregaço citológico ao microscópio óptico convencional também apontou para a presença de coilócitos, ou seja, alterações indicativas da presença de HPV. Desta forma, concluímos que o vírus HPV pode comportar-se como mais um co-carcinógeno, como: o tabagismo, etilismo e ação solar, também presentes em nossa amostra, para o cêncer de boca, sendo válida a identificação do mesmo através de material obtido tanto pelo examente citológico esfoliativo da mucosa bucal, quanto pela biópsia; auxiliando na prevenção e diagnose precoce do câncer de boca à semalhança da prevenção ao carcinoma uterino...

Probable effect of photoperiod on seasonal variation in the nuclear volume of the adrenal cortex of viscacha (Lagostomus maximus maximus)

The neuroendocrine system regulates several organic functions such as reproduction, metabolism and adaptation to the environment. This system shows seasonal changes linked to the environment. The experimental model used in the present study was Lagostomus maximus maximus (viscacha). The reproduction of males of this species is photoperiod dependent. Twenty-four adult male viscachas were captured in their habitat at different times during one year. The adrenal glands were processed for light microscopy. Serial cuts were stained with hematoxylin-eosin for the morphometric study, and 100 nuclei of each zone of the adrenal cortex were counted per animal. Data were analyzed statistically by ANOVA and the Tukey test. The cells of the glomerulosa zone are arranged in a tube-shaped structure. The fasciculata zone has large cells with central nuclei and clearly visible nucleoli and with a vacuolar cytoplasm. In the reticularis zone there are two of types of cells, one with a nucleus of fine chromatin and a clearly visible nucleolus and the other with nuclear pycnosis. Morphometric analysis showed maximum nuclear volumes during the February-March period with values of 133 percet 7.3 µm3 for the glomerulosa, 286.4 percent 14.72 µm3 for the fasciculata, and 126.3 percent 9.49 µm3 for the reticularis. Minimum nuclear volumes were observed in August with values of 88.24 + or - 9.9 µm3 for the glomerulosa, 163.7 percent 7.78 µm3 for the fasciculata and 64.58 + or - 4.53 µm3 for the reticularis. The short winter photoperiod to which viscacha is subjected could inhibit the adrenal cortex through a melatonin increase which reduces the nuclear volume as well as the cellular activity

Probable effect of photoperiod on seasonal variation in the nuclear volume of the adrenal cortex of viscacha (Lagostomus maximus maximus).

The neuroendocrine system regulates several organic functions such as reproduction, metabolism and adaptation to the environment. This system shows seasonal changes linked to the environment. The experimental model used in the present study was Lagostomus maximus maximus (viscacha). The reproduction of males of this species is photoperiod dependent. Twenty-four adult male viscachas were captured in their habitat at different times during one year. The adrenal glands were processed for light microscopy. Serial cuts were stained with hematoxylin-eosin for the morphometric study, and 100 nuclei of each zone of the adrenal cortex were counted per animal. Data were analyzed statistically by ANOVA and the Tukey test. The cells of the glomerulosa zone are arranged in a tube-shaped structure. The fasciculata zone has large cells with central nuclei and clearly visible nucleoli and with a vacuolar cytoplasm. In the reticularis zone there are two of types of cells, one with a nucleus of fine chromatin and a clearly visible nucleolus and the other with nuclear pycnosis. Morphometric analysis showed maximum nuclear volumes during the February-March period with values of 133 +/- 7.3 microm3 for the glomerulosa, 286.4 +/- 14.72 microm3 for the fasciculata, and 126.3 +/- 9.49 microm3 for the reticularis. Minimum nuclear volumes were observed in August with values of 88.24 +/- 9.9 microm3 for the glomerulosa, 163.7 +/- 7.78 microm3 for the fasciculata and 64.58 +/- 4.53 microm3 for the reticularis. The short winter photoperiod to which viscacha is subjected could inhibit the adrenal cortex through a melatonin increase which reduces the nuclear volume as well as the cellular activity.

[Biochemical-histological study of the effects of lithium on various organs of vizcacha (Lagostomus maximus maximus)]. / Estudio bioquímico-histológico de los efectos de litio en algunos órganos de vizcacha (Lagostomus maximus maximus).

Considering that the vizcacha (Lagostomus maximus maximus) is a very Lithium sensitive rodent, we planned a biochemical-histological study injecting IP doses of 1 mEq/kg/day LiCl during one month to adult vizcachas, and they were divided into three lots: Lot I the optical microscopy revealed evident renal, gonadal, hyphophyseal and adrenal damages; the biochemical analysis showed that Li significantly decreased the female serum LH levels while testosterone and estradiol levels were not affected. The male Li serum values resulted to be significantly higher than those of female animals. The damage was greater in male specimens. Lott II: the tissue recovery from the damage observed in Lot I was the following: total in hyphophysis, partial in testis, the same in kidney and was enhanced in adrenal and ovary. The Li renal clearance was determined in Lot III verifying no changes in both sexs. According to our results, Li (1 mEq/kg/day during one month) produce modifications in different tissues probably the gonadal damage may be consequence of a direct Li effect and not for a hyphophysis alteration, since in male vizcacha the LH serum level was not changed. In regard to the selective effect in the suprarenal glomerulus structure, this Li effect is produced via hyphophysis. In conclusion, the selective effect of Li on adrenal and gonada organs of this rodent is a contribution in order to warm about the possible reproduction of such effects in human beings.

Estudio bioquímico-histológico de los efectos de litio en algunos organos de vizcacha (Lagostomus maximus maximus) / Biochemical-histological study of the effects of lithium in some organs of vizcacha (Lagostomus maximus maximus)

Considerando que la vizcacha (lagostomus maximus maximus) es un roedor muy sensible al Litio (Li), planificamos un estudio bioquímico-histológico inyectando cloruro de Li 1 mEq/Kg/día vía intraperitoneal durante un mes a vizcachas adultas de ambos sexos agrupadas en tres lotes. En el lote I se comprobó por técnicas de microscopía óptica un evidente dano renal, gonodal, hipofisario y adrenal; por métodos bioquímicos se comprobó que el Li disminuyó significativamente los niveles séricos de LH en hembra, el contenido de testosterona y estradiol no fue modificado. En machos el Li sérico resultó significativamente mayor (p<0.01, Prueba de t) que en hembras. El dano fue mayor en machos. en el Lote II se estudió a 30 días de la última administración el grado de recuperación tisular del dano comprobado en el Lote I. Se verificó una recuperación total en hipófisis, parcial en testículo, nula en rinón y se incrementó el dano en adrenal y ovario. Con respecto al efecto seletivo sobre la zona glomerulosa adrenal del Li sería producido via hipófisis. En conclusión el efecto selectivo de Li en adrenal y gónadas en este roedor es una contribución para alertar sobre la posible producción de estos efectos en humanos (AU)

Estudio bioquímico-histológico de los efectos de litio en algunos órganos de vizcacha (Lagostomus maximus maximus). / [Biochemical-histological study of the effects of lithium on various organs of vizcacha (Lagostomus maximus maximus)]

Considering that the vizcacha (Lagostomus maximus maximus) is a very Lithium sensitive rodent, we planned a biochemical-histological study injecting IP doses of 1 mEq/kg/day LiCl during one month to adult vizcachas, and they were divided into three lots: Lot I the optical microscopy revealed evident renal, gonadal, hyphophyseal and adrenal damages; the biochemical analysis showed that Li significantly decreased the female serum LH levels while testosterone and estradiol levels were not affected. The male Li serum values resulted to be significantly higher than those of female animals. The damage was greater in male specimens. Lott II: the tissue recovery from the damage observed in Lot I was the following: total in hyphophysis, partial in testis, the same in kidney and was enhanced in adrenal and ovary. The Li renal clearance was determined in Lot III verifying no changes in both sexs. According to our results, Li (1 mEq/kg/day during one month) produce modifications in different tissues probably the gonadal damage may be consequence of a direct Li effect and not for a hyphophysis alteration, since in male vizcacha the LH serum level was not changed. In regard to the selective effect in the suprarenal glomerulus structure, this Li effect is produced via hyphophysis. In conclusion, the selective effect of Li on adrenal and gonada organs of this rodent is a contribution in order to warm about the possible reproduction of such effects in human beings.

Estudio bioquímico-histológico de los efectos de litio en algunos organos de vizcacha (Lagostomus maximus maximus) / Biochemical-histological study of the effects of lithium in some organs of vizcacha (Lagostomus maximus maximus)

Considerando que la vizcacha (lagostomus maximus maximus) es un roedor muy sensible al Litio (Li), planificamos un estudio bioquímico-histológico inyectando cloruro de Li 1 mEq/Kg/día vía intraperitoneal durante un mes a vizcachas adultas de ambos sexos agrupadas en tres lotes. En el lote I se comprobó por técnicas de microscopía óptica un evidente dano renal, gonodal, hipofisario y adrenal; por métodos bioquímicos se comprobó que el Li disminuyó significativamente los niveles séricos de LH en hembra, el contenido de testosterona y estradiol no fue modificado. En machos el Li sérico resultó significativamente mayor (p<0.01, Prueba de t) que en hembras. El dano fue mayor en machos. en el Lote II se estudió a 30 días de la última administración el grado de recuperación tisular del dano comprobado en el Lote I. Se verificó una recuperación total en hipófisis, parcial en testículo, nula en rinón y se incrementó el dano en adrenal y ovario. Con respecto al efecto seletivo sobre la zona glomerulosa adrenal del Li sería producido via hipófisis. En conclusión el efecto selectivo de Li en adrenal y gónadas en este roedor es una contribución para alertar sobre la posible producción de estos efectos en humanos

Glutaric aciduria type I: unusual biochemical presentation.

We describe a patient with glutaryl-coenzyme A dehydrogenase deficiency, demonstrated by a residual enzyme activity of only 1% in cultured fibroblasts. Although the clinical presentation was typical of glutaric aciduria type I, the urine concentrations of glutaric, glutaconic, and 3-hydroxyglutaric acids remained normal, even during episodes of clinical decompensation. An increased free glutarate level was demonstrated only in cerebrospinal fluid.