RESUMEN
Chlorpyrifos (CPF), an organophosphate pesticide inhibits acetylcholinesterase (AChE) and causes neuromuscular incoordination among children and elderly. The objectives of the present study were to compare the neurotoxic effects of dermal application of CPF on the cerebellum in the parameters of glial fibrillary acidic protein (GFAP) expression in young and adult mice and to correlate with the changes in acetylcholinesterase levels. Male Balb/c mice, 150 days old (adult) and 18 days old (young) were dermally applied with ½ LD(50) of CPF over the tails for 14 days. Serum AChE concentration was estimated and GFAP immunostaining was performed on sagittal paraffin sections through the vermis of cerebellum. Although reduced in both age-groups exposed to CPF, percentage of reduction in serum AChE was more in adult compared to the young. Under GFAP immunostaining, brown colour fibres and glial cells were observed in cerebellar cortex and medulla in both the experimental groups. The mean GFAP-positive glial cell count in cerebellar medulla per mm(2) of section was significantly (p < 0.05) increased in adult mice exposed to CPF when compared with age-matched control. In conclusion, this study confirmed that dermal exposure of CPF was able to exert neurotoxic effect in both young and adult mice. However, the quantitative results revealed that adult mice showed more GFAP expression in cerebellum when compared with the young, when exposed to CPF.
Asunto(s)
Cerebelo/efectos de los fármacos , Cloropirifos/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Insecticidas/toxicidad , Acetilcolinesterasa/sangre , Administración Cutánea , Factores de Edad , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Cerebelo/metabolismo , Cloropirifos/administración & dosificación , Inhibidores de la Colinesterasa/administración & dosificación , Proteína Ácida Fibrilar de la Glía/metabolismo , Insecticidas/administración & dosificación , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
The alteration of craniofacial structures has been associated with obstructive sleep apnoea (OSA). We hypothesised that: 1) a smaller mandible is a risk factor for OSA; and 2) the previously observed inferiorly positioned hyoid bone in apnoeics is associated with enlarged tongue volume. This is a case-control study using three-dimensional magnetic resonance imaging cephalometry. 55 apneics and 55 controls were matched for age, sex and race. The analysis was stratified by sex and controlled for age, race, height, neck visceral fat, skeletal type and tongue volume. We found that a 1-sd increase in mandibular length and depth were associated with decreased risk of sleep apnoea (OR 0.52, 95% CI 0.28-0.99 and OR 0.46, 95% CI 0.23-0.91, respectively) in males but not in females. Greater hyoid-to-nasion (OR 2.64, 95% CI 1.19-5.89 in males and OR 5.01, 95% CI 2.00-12.52 in females) and supramentale-to-hyoid (OR 2.39, 95% CI 1.12-5.14) in males and OR 3.38, 95% CI 1.49-7.68 in females) distances were associated with increased risk of OSA. The difference for hyoid position between apnoeics and controls was lost after controlling for tongue volume. Enlargement of tongue is likely to be the pathogenic factor for inferior-posterior positioning of hyoid. A small and shallow mandible is an independent risk factor for OSA in males but not in females.
Asunto(s)
Anomalías Craneofaciales/complicaciones , Apnea Obstructiva del Sueño/etiología , Adulto , Estudios de Casos y Controles , Cefalometría/métodos , Anomalías Craneofaciales/fisiopatología , Femenino , Humanos , Hueso Hioides/anomalías , Hueso Hioides/fisiopatología , Imagen por Resonancia Magnética , Masculino , Mandíbula/anomalías , Mandíbula/fisiopatología , Persona de Mediana Edad , Tamaño de los Órganos , Faringe/anomalías , Faringe/fisiopatología , Factores de Riesgo , Factores Sexuales , Apnea Obstructiva del Sueño/fisiopatología , Lengua/anomalías , Lengua/fisiopatologíaRESUMEN
Atopic dermatitis (AD) is a common immune-medicated skin disease. Previous studies have explored the relationship between Human Leukocyte Antigen (HLA) allelic variation and AD with conflicting results. The aim was to examine HLA Class I genetic variation, specifically peptide binding groove variation, and associations with AD. A case-control study was designed to evaluate HLA class I allelic variation and binding pocket polymorphisms, using next generation sequencing on 464 subjects with AD and 388 without AD. Logistic regression was used to evaluate associations with AD by estimating odds ratios (95% confidence intervals). Significant associations were noted with susceptibility to AD (B*53:01) and protection from AD (A*01:01, A*02:01, B*07:02 and C*07:02). Evaluation of polymorphic residues in Class I binding pockets revealed six amino acid residues conferring protection against AD: A9F (HLA-A, position 9, phenylalanine) [pocket B/C], A97I [pocket C/E], A152V [pocket E], A156R [pocket D/E], B163E [pocket A] and C116S [pocket F]. These findings demonstrate that specific HLA class I components are associated with susceptibility or protection from AD. Individual amino acid residues are relevant to protection from AD and set the foundation for evaluating potential HLA Class I molecules in complex with peptides/antigens that may initiate or interfere with T-cell responses.
Asunto(s)
Dermatitis Atópica/genética , Predisposición Genética a la Enfermedad , Variación Genética , Antígenos de Histocompatibilidad Clase I/genética , Alelos , Estudios de Casos y Controles , Dermatitis Atópica/diagnóstico , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Antígenos de Histocompatibilidad Clase I/química , Humanos , Modelos Moleculares , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Conformación Proteica , Análisis de Secuencia de ADN , Relación Estructura-ActividadRESUMEN
The specificity and implementation of current MRI-based diagnostic criteria for multiple sclerosis (MS) are imperfect. Approximately 1 in 5 of individuals diagnosed with MS are eventually determined not to have the disease, with overreliance on MRI findings a major cause of MS misdiagnosis. The central vein sign (CVS), a proposed MRI biomarker for MS lesions, has been extensively studied in numerous cross sectional studies and may increase diagnostic specificity for MS. CVS has desirable analytical, measurement, and scalability properties. "Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)" is an NIH-supported, 2-year, prospective, international, multicenter study conducted by the North American Imaging in MS Cooperative (NAIMS) to evaluate CVS as a diagnostic biomarker for immediate translation into clinical care. Study objectives include determining the concordance of CVS and McDonald Criteria to diagnose MS, the sensitivity of CVS to detect MS in those with typical presentations, and the specificity of CVS among those with atypical presentations. The study will recruit a total of 400 participants (200 with typical and 200 with atypical presentations) across 11 sites. T2*-weighted, high-isotropic-resolution, segmented echo-planar MRI will be acquired at baseline and 24 months on 3-tesla scanners, and FLAIR* images (combination of FLAIR and T2*) will be generated for evaluating CVS. Data will be processed on a cloud-based platform that contains clinical and CVS rating modules. Imaging quality control will be conducted by automated methods and neuroradiologist review. CVS will be determined by Select6* and Select3* lesion methods following published criteria at each site and by central readers, including neurologists and neuroradiologists. Automated CVS detection and algorithms for incorporation of CVS into McDonald Criteria will be tested. Diagnosis will be adjudicated by three neurologists who served on the 2017 International Panel on the Diagnosis of MS. The CAVS-MS study aims to definitively establish CVS as a diagnostic biomarker that can be applied broadly to individuals presenting for evaluation of the diagnosis of MS.
Asunto(s)
Esclerosis Múltiple , Biomarcadores , Estudios Transversales , Humanos , Imagen por Resonancia Magnética , Estudios Multicéntricos como Asunto , Esclerosis Múltiple/diagnóstico por imagen , Estudios ProspectivosRESUMEN
INTRODUCTION: Sepsis is the leading cause of infectious morbidity and mortality among hospitalized neonates. In high-resource pediatric and adult intensive care units, use of aqueous chlorhexidine (CHG) solution has been associated with reduced risk of bloodstream infections (BSI). OBJECTIVES: To assess the impact of bathing of neonates with 2% CHG on BSI, suspected sepsis, and mortality in a low-income country neonatal care unit. METHODS: We conducted a secondary analysis of data from the Sepsis Prevention in Neonates in Zambia (SPINZ) study, a prospective observational cohort study performed at a large public referral hospital in Lusaka, Zambia. The SPINZ study assessed the impact of an infection control bundle (consisting of alcohol hand rub, SMS hygiene reminders, enhanced environmental cleaning, and CHG baths for babies ≥1.5 kg) on sepsis, BSI, and all-cause mortality. Episodic shortages in study staffing resulted in some enrolled babies not receiving a CHG bath. Using Longitudinal Targeted Maximum Likelihood Estimation and Cox proportional hazards regression to adjust for observed confounding, we estimated the causal effect of receiving a CHG bath within the first 3 days of life on suspected sepsis, BSI, and death among inborn babies enrolled during the study implementation and intervention phases. RESULTS: The majority of inborn, enrolled babies ≥1.5 kg received a CHG bath within 3 days of NICU admission (864 of 1233, 70%). We found that CHG bathing reduced the hazard rate of BSI among inborn babies ≥1.5 kg by a factor of 0.58 (p = 0.10, 95% CI: 0.31, 1.11), corresponding to an absolute risk reduction of 9.6 percentage points within a week of admission (p = 0.002, 95% CI: 3.4-15.7 percentage points). We did not find a statistically significant effect of CHG bathing on culture-negative sepsis (p = 0.54) or death (p = 0.85). CONCLUSION: In our single center study, CHG bathing at admission was associated with a reduced risk of BSI due to a pathogenic organism after adjusting for potential confounding. Our results suggest that CHG may be an effective intervention for preventing neonatal sepsis in high-risk, low-income country settings.
Asunto(s)
Clorhexidina , Control de Infecciones , Sepsis/prevención & control , Baños , Estudios de Cohortes , Femenino , Mortalidad Hospitalaria , Humanos , Higiene , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Masculino , Estudios Prospectivos , ZambiaRESUMEN
Naphthoquinones have been investigated as potential therapeutic molecules for neurodegenerative disorders, which is largely based on their anti-oxidative potential. However, a theoretical framework for the pleiotropic protective effects of naphthoquinone derivatives is largely missing. We synthesized a library of novel short chain 2,3-disubstituted naphthoquinone derivatives and measured their redox characteristics to identify a potential connection with their biological activity. Using two cell lines with different reducing potential, the compounds were tested for their inherent toxicity, acute rescue of ATP levels and cytoprotective activity. For the first time, a structure-activity-relationship for naphthoquinones has been established. Our results clearly demonstrate that it is the group on the alkyl side chain and not solely the redox characteristics of the naphthoquinone unit or lipophilicity that determines the extent of cytoprotection by individual compounds. From this, we developed a number of amide containing naphthoquinones with superior activity in ATP rescue and cell viability models compared to the clinically used benzoquinone idebenone.
RESUMEN
F9 embryonal carcinoma cells treated with 1 microM retinoic acid undergo irreversible differentiation and simultaneously lose their tumorigenicity. Described here are the isolation and characterization of an F9 variant clone (5C), which undergoes partial differentiation in retinoic acid. The behavior of 5C cells indicates that retinoic acid successfully initiates the differentiation pathway but that complete differentiation is not achieved due to a subsequent block in the pathway. The fact that 5C cells do not undergo complete differentiation, or lose their tumorigenicity in response to retinoic acid, indicates that the lesion affects an element involved in the regulation of both these events. Therefore, further genetic and biochemical characterization of this variant should provide information concerning the relationship between the regulation of differentiation and tumorigenicity. Furthermore, the isolation of this variant establishes the feasibility of genetically dissecting the various steps of the differentiation pathway.
Asunto(s)
Teratoma/patología , Tretinoina/farmacología , Fosfatasa Alcalina/análisis , Animales , Antígenos de Superficie/análisis , Proteínas Portadoras/análisis , Diferenciación Celular/efectos de los fármacos , Línea Celular , Fibronectinas/análisis , Cariotipificación , Laminina/análisis , Ratones , Fenotipo , Receptores de Ácido Retinoico , Teratoma/análisis , Teratoma/microbiologíaRESUMEN
Legume lectins family of proteins, despite having the same 'jelly roll' tertiary structural fold at monomeric level, exhibit considerable variation in their quaternary structure arising out of small changes in their sequence. Nevertheless, their folding behavior and stability correlates very well with their patterns of assembly into dimers and tetramers. A conservation of their fold during evolution, its wide distribution in many protein families together with the availability of structural information on them make them interesting as proteins to explore the effect of inter- versus intra-subunit interactions in the stability of multimeric proteins. Additionally, as 'natural mutants' of quaternary association, proteins of legume lectin family provide interesting paradigms for studies addressing the effect of subunit oligomerization on the stability, folding and function as well as the evolution of multimeric structures.
Asunto(s)
Fabaceae/química , Lectinas/química , Plantas Medicinales , Secuencia de Aminoácidos , Rastreo Diferencial de Calorimetría , Dimerización , Modelos Moleculares , Datos de Secuencia Molecular , Lectinas de Plantas , Desnaturalización Proteica , Pliegue de Proteína , Alineación de SecuenciaRESUMEN
The three-dimensional structure of the recombinant form of Erythrina corallodendron lectin, complexed with lactose, has been elucidated by X-ray crystallography at 2.55 A resolution. Comparison of this non-glycosylated structure with that of the native glycosylated lectin reveals that the tertiary and quaternary structures are identical in the two forms, with local changes observed at one of the glycosylation sites (Asn17). These changes take place in such a way that hydrogen bonds with the neighboring protein molecules in rECorL compensate those made by the glycan with the protein in ECorL. Contrary to an earlier report, this study demonstrates that the glycan attached to the lectin does not influence the oligomeric state of the lectin. Identical interactions between the lectin and the non-covalently bound lactose in the two forms indicate, in line with earlier reports, that glycosylation does not affect the carbohydrate specificity of the lectin. The present study, the first of its kind involving a glycosylated protein with a well-defined glycan and the corresponding deglycosylated form, provides insights into the structural aspects of protein glycosylation.
Asunto(s)
Lectinas de Plantas/química , Lectinas de Plantas/metabolismo , Sitios de Unión , Metabolismo de los Hidratos de Carbono , Cristalografía por Rayos X , Glicosilación , Lactosa/química , Lactosa/metabolismo , Lectinas/química , Lectinas/metabolismo , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMEN
RNase S consists of two proteolytic fragments of RNase A, residues 1-20 (S20) and residues 21-124 (S pro). A 15-mer peptide (S15p) with high affinity for S pro was selected from a phage display library. Peptide residues that are buried in the structure of the wild type complex are conserved in S15p though there are several changes at other positions. Isothermal titration calorimetry studies show that the affinity of S15p is comparable to that of the wild type peptide at 25 degrees C. However, the magnitudes of DeltaH(o) and DeltaC(p) are lower for S15p, suggesting that the thermal stability of the complex is enhanced. In agreement with this prediction, at pH 6, the T(m) of the S15p complex was found to be 10 degrees C higher than that of the wild type complex. This suggests that for proteins where fragment complementation systems exist, phage display can be used to find mutations that increase protein thermal stability.
Asunto(s)
Ribonucleasas/química , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Calorimetría , Secuencia Conservada , Cartilla de ADN/genética , Estabilidad de Enzimas , Humanos , Técnicas In Vitro , Datos de Secuencia Molecular , Mutación , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Biblioteca de Péptidos , Desnaturalización Proteica , Ribonucleasa Pancreática/química , Ribonucleasa Pancreática/genética , Ribonucleasa Pancreática/metabolismo , Ribonucleasas/genética , Ribonucleasas/metabolismo , Homología de Secuencia de Aminoácido , Especificidad por Sustrato , TermodinámicaRESUMEN
It has been known for many years that caffeine reduces or eliminates the G2-phase cell cycle delay normally seen in human HeLa cells or Chinese hamster ovary (CHO) cells after exposure to X or gamma rays. In light of our recent demonstration of a consistent difference between human normal and tumor cells in a G2-phase checkpoint response in the presence of microtubule-active drugs, we examined the effect of caffeine on the G2-phase delays after exposure to gamma rays for cells of three human normal cell lines (GM2149, GM4626, AG1522) and three human tumor cell lines (HeLa, MCF7, OVGI). The G2-phase delays after a dose of 1 Gy were similar for all six cell lines. In agreement with the above-mentioned reports for HeLa and CHO cells, we also observed that the G2-phase delays were eliminated by caffeine in the tumor cell lines. In sharp contrast, caffeine did not eliminate or even reduce the gamma-ray-induced G2-phase delays in any of the human normal cell lines. Since caffeine has several effects in cells, including the inhibition of cAMP and cGMP phosphodiesterases, as well as causing a release of Ca(++) from intracellular stores, we evaluated the effects of other drugs affecting these processes on radiation-induced G2-phase delays in the tumor cell lines. Drugs that inhibit cAMP or cGMP phosphodiesterases did not eliminate the radiation-induced G2-phase delay either separately or in combination. The ability of caffeine to eliminate radiation-induced G2-phase delay was, however, partially reduced by ryanodine and eliminated by thapsigargin, both of which can modulate intracellular calcium, but by different mechanisms. To determine if caffeine was acting through the release of calcium from intracellular stores, calcium was monitored in living cells using a fluorescent calcium indicator, furaII, before and after the addition of caffeine. No calcium release was seen after the addition of caffeine in either OVGI tumor cells or GM2149 normal cells, even though a large calcium release was measured in parallel experiments with ciliary neurons. Thus it is likely that caffeine is eliminating the radiation-induced G2-phase delay through a Ca(++)-independent mechanism, such as the inhibition of a cell cycle-regulating kinase.
Asunto(s)
Cafeína/farmacología , Fase G2/efectos de los fármacos , Rayos gamma/efectos adversos , Células Madre Neoplásicas/efectos de los fármacos , 3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , 3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , 4-(3-Butoxi-4-metoxibencil)-2-imidazolidinona/farmacología , Animales , Neoplasias de la Mama/patología , Bloqueadores de los Canales de Calcio/farmacología , Señalización del Calcio/efectos de los fármacos , Carcinoma/patología , Pollos , Demecolcina/farmacología , Resistencia a Medicamentos , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/efectos de la radiación , Fase G2/efectos de la radiación , Células HeLa/citología , Células HeLa/efectos de los fármacos , Células HeLa/efectos de la radiación , Humanos , Mitosis/efectos de los fármacos , Mitosis/efectos de la radiación , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/efectos de la radiación , Neuronas/efectos de los fármacos , Neoplasias Ováricas/patología , Inhibidores de Fosfodiesterasa/farmacología , Quinazolinas/farmacología , Tolerancia a Radiación/efectos de los fármacos , Rianodina/farmacología , Canal Liberador de Calcio Receptor de Rianodina/efectos de los fármacos , Tapsigargina/farmacología , Células Tumorales Cultivadas/citología , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/efectos de la radiaciónRESUMEN
OBJECTIVES: Recent studies have shown that Exisulind, a sulfone metabolite of the nonsteroidal anti-inflammatory drug (NSAID) sulindac, has inhibitory activity in vitro with cultured human prostate cancer cells. To determine whether this effect might be pharmacologically relevant in vivo, we tested whether Exisulind therapy could suppress the growth of human prostate cancer cells in a nude mouse xenograft model. METHODS: Thirty athymic nude mice were injected subcutaneously in the flank with 1 x 10(7) LNCaP human prostate tumor cells. All mice received a control diet for 21 days. One group of mice was continued on this control diet for an additional 4 weeks, a second group was switched to a diet supplemented with 0.05% Exisulind (40% of maximal tolerated dose [MTD]), and a third group was switched to a diet supplemented with 0.1% Exisulind (80% MTD) for the additional 4 weeks. Tumor growth was measured through the 4-week test period, and subsequently tissue sections from the various groups were tested for apoptotic and dividing cells by quantified use of the TUNEL assay and a bromodeoxyuridine (BrdU) incorporation immunoassay. RESULTS: Tumors grew by 158%, 24%, and 18% for the control and 0.05% and 0.1% Exisulind groups, respectively (P = 0.02) during the 4-week test period. Immunohistochemical studies on excised tumors showed an increased number of apoptotic bodies in the treated groups versus the control group (P<0.0001) but no change in the number of BrdU positive cells. CONCLUSIONS: This is the first study to show a direct in vivo effect of an NSAID-derived drug, lacking cyclooxygenase inhibitory activity, in a xenograft model of prostate cancer. Clinical studies to evaluate the effects of Exisulind against prostate cancer in humans are warranted.
Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Sulindac/análogos & derivados , Animales , División Celular , Humanos , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias de la Próstata/patología , Sulindac/uso terapéuticoRESUMEN
Studies were performed to bring out a serotoninergic involvement in physostigmine tremor, hitherto known to be working via the cholinergic system. 5-Hydroxytryptamine (5-HT) was estimated fluorimetrically after isolation on Sephadex G-10 and acetylcholinesterase (AChE) was assayed spectrophotometrically. The dose-dependent tremor was quantified by a double-blind study. No correlation (r = 0.01) existed between tremor and AChE inhibition since the non-tremoring dose of physostigmine caused the same degree of enzyme inhibition. An increase of 5-HT was found to be correlated (r = 0.59) with the duration and intensity of tremor. Cholinergic antagonists atropine (2 and 5 mg/kg, i.p.), scopolamine (0.5, 1.0, 2.0 mg/kg, i.p.) and mecamylamine (1 mg/kg, i.p.) failed to block the tremor while the 5-HT antagonists methysergide (5 mg/kg, i.v.) and cyproheptadine (10 and 30 mg/kg, s.c.) could afford more than 60% protection. These results suggest a serotoninergic rather than a cholinergic component in the genesis of physostigmine tremor.
Asunto(s)
Acetilcolinesterasa/metabolismo , Núcleo Caudado/enzimología , Mesencéfalo/enzimología , Fisostigmina/análogos & derivados , Putamen/enzimología , Serotonina/fisiología , Temblor/fisiopatología , Animales , Atropina/farmacología , Núcleo Caudado/efectos de los fármacos , Ciproheptadina/farmacología , Mecamilamina/farmacología , Mesencéfalo/efectos de los fármacos , Metisergida/farmacología , Ratones , Ratones Endogámicos BALB C , Fisostigmina/farmacología , Putamen/efectos de los fármacos , Escopolamina/farmacología , Temblor/inducido químicamenteRESUMEN
Behavioural and neurochemical effects of acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in mice have been studied in order to determine the change in the neurotransmitter profile of the following areas of the brain: substantia nigra (SN), nucleus caudatus putamen (NCP), limbic system (LS; tuberculum olfactorium and nucleus accumbens), medulla oblongata (MO) and cerebellum (CER). Subcutaneous administration of MPTP (40 mg/kg) caused behavioural syndromes including restlessness, straub tail, hindlimb abduction, tremor, jumping, bradykinesia and akinesia in Balb/c mice. There existed a well-defined biphasic profile of motor activity comprising of an initial excitatory phase followed by an inhibitory phase lasting about two and a half and five hours, respectively. A significant rise in 5-hydroxytryptamine (5-HT) content together with a decreased 5-HT utilization as evidenced by lower 5-hydroxyindole acetic acid (5-HIAA) to 5-HT ratio in the above brain areas demarcated the excitatory phase, whereas the inhibitory phase was distinguished by a significant decrease in dopamine (DA) content along with an increased turnover of the amine as shown by a higher homovanillic acid (HVA) to DA ratio in the functionally important nuclei of the extrapyramidal system like SN, NCP and LS. Methysergide, a nonspecific 5-HT receptor blocker, but not ketanserin, a specific 5-HT2 antagonist, prevented the occurrence of the initial excitatory phase without affecting the depressive phase. Administration of apomorphine, a dopamine agonist, 30 minutes prior to MPTP was ineffective, whereas its application 90 minutes after MPTP prevented the occurrence of bradykinesia and akinesia. Interestingly, treatment with haloperidol, the dopamine (D1/D2) antagonist, before and after MPTP administration caused an early onset and prolongation of the inhibitory phase without affecting the initial hyperexcitement. The results provide direct evidence for the involvement of serotoninergic and dopaminergic mechanisms in the genesis of the early and late syndromes of acute MPTP poisoning respectively.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Química Encefálica/efectos de los fármacos , Dopamina/fisiología , Serotonina/fisiología , Animales , Conducta Animal/efectos de los fármacos , Dopaminérgicos/farmacología , Ratones , Ratones Endogámicos BALB C , Actividad Motora/efectos de los fármacos , Neurotransmisores/metabolismoRESUMEN
A child of first-cousin Puerto Rican parents had global developmental delay, failure to thrive, and hypotonia since early infancy. At 1 1/2 years of age, she developed clinical and electrophysiologic evidence of progressive motor and sensory neuropathy. At 2 1/2 years, she developed visual impairment and optic atrophy followed by gradual involvement of the 7th, 9th, 10th, and 12th cranial nerves. Uncontrollable myoclonic seizures began at 4 years and she died at 6 years of age. Motor nerve conduction velocities were initially normal and later became markedly slowed. Sensory distal latency responses were absent. Lysosomal enzyme activities in leukocytes and fibroblasts were normal. Sural nerve and two muscle biopsies showed only nondiagnostic abnormalities. Electron microscopy of lymphocytes, skin, and fibroblasts showed cytoplasmic inclusions. Light microscopy of frontal cortex biopsy showed neuronal storage material staining positively with Luxol fast blue, and electron microscopy showed cytoplasmic membranous bodies in neurons, suggesting an accumulation of a ganglioside. At autopsy, all organs were small but otherwise normal and without abnormal storage cells in the liver, spleen, or bone marrow. Anterior spinal nerve roots showed loss of large myelinated axons. The brain was small and atrophic; cortical neurons showed widespread accumulation of storage material, most marked in the pyramidal cell layer of the hippocampus. Subcortical white matter was gliotic with loss of axons and myelin sheaths. In cortical gray matter there was a 35% elevation of total gangliosides, with a 16-fold increase in GM3, a three- to four-fold increase in GM2 gangliosides, and a 15-fold elevation of lactosyl ceramide. GM3 sialidase activity was normal in gray matter at 3.1 nmols/mg protein per hour and lactosyl ceraminidase I and II activities were 70% to 80% of normal. In white matter, total myelin was reduced by 50% but its composition was normal. Phospholipid distribution and sphingomyelin content were normal in gray matter, white matter, and in the liver. These biochemical findings were interpreted as nonspecific abnormalities. The nature of the neuronal storage substance remains to be determined.
Asunto(s)
Fibroblastos/ultraestructura , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Cuerpos de Inclusión/ultraestructura , Enfermedades por Almacenamiento Lisosomal/genética , Atrofia/complicaciones , Atrofia/patología , Biopsia , Encéfalo/patología , Preescolar , Cromatografía en Capa Delgada/métodos , Enfermedades Desmielinizantes/patología , Diagnóstico Diferencial , Progresión de la Enfermedad , Epilepsias Mioclónicas/complicaciones , Resultado Fatal , Femenino , Gangliósidos/metabolismo , Neuropatías Hereditarias Sensoriales y Autónomas/complicaciones , Humanos , Neuronas/ultraestructura , Atrofia Óptica/complicacionesRESUMEN
A case is presented of incontinentia pigmenti with severe neurological handicaps and unusual features such as single umbilical artery, pigmented lesion at birth, and biochemical changes including elevated alkaline phosphatase and immunoglobulin M.
Asunto(s)
Anomalías Múltiples , Trastornos de la Pigmentación/congénito , Fosfatasa Alcalina/sangre , Preescolar , Femenino , Humanos , Inmunoglobulina M/análisis , Nevo Pigmentado/congénito , Trastornos de la Pigmentación/metabolismo , Síndrome , Arterias Umbilicales/anomalíasRESUMEN
Effect of chronic intake of alcohol and its subsequent withdrawal was studied in albino mice on the layers of neurons of the iso-cortex. Neuronal density per mm2 of section in different layers of iso-cortex was counted and compared in 3 groups of animals (control, ethanol fed and withdrawal). Qualitative changes on nissl granules of neurons and myelinated fibres were also studied. Mice fed with 10% ethanol v/v ad libitum for 6 months showed loss of nissl granules and nucleolus and discontinuity of nuclear membrane. Quantitatively, significant reduction in neuronal density (P<0.001) was observed in layers II+III IV and V neurons of iso-cortex. Withdrawal of ethanol for 2 months showed continued reduction of counts of neuronal density in layers II+III and V only whereas reversal of count was found significantly (P<0.001) in layer IV of iso-cortex. Qualitatively, only few neurons showed prominent nissl granules after withdrawal of ethanol. More afferent synaptic connection in layer IV may be suggested as probable factor helping relative replenishment of neuronal count after withdrawal of alcohol.
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Depresores del Sistema Nervioso Central/toxicidad , Corteza Cerebral/efectos de los fármacos , Etanol/toxicidad , Neuronas/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/patología , Animales , Corteza Cerebral/patología , Femenino , Masculino , Ratones , Neuronas/patologíaRESUMEN
Microemulsification of vegetable oils (ricebran, saffola, soyabean, sesame, palm and linseed) with water using aerosol-OT and cinnamic alcohol as mixed amphiphiles was studied. The biological microemulsions formed covered on the average approximately 27% of single phase area in the triangular phase diagram. The multiphasic zone for saffola was studied in detail, two- and three-phase zones were identified with patches of thick gel. The effect of temperature on the multiphase formation in the range 29-55 degrees C was also studied. The formation of multiphase and their proportions found to depend on the type of oil. The biological microemulsions at reasonable water/AOT mole ratio showed moderate increase in conductance with temperature. The viscosity of the microemulsions was high. Of the studied systems (sesame, saffola and ricebran) the viscosity of the first two decreased with the rate of shear whereas that of ricebran increased. When cinnamic alcohol was used as the oil, the trend of viscosity was similar to that of sesame and saffola.
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Ácido Dioctil Sulfosuccínico , Emulsiones , Aceites de Plantas/química , Propanoles , Tensoactivos , Cinética , Termodinámica , Viscosidad , AguaRESUMEN
The mixing behaviour of plant oils (ricebran, saffola and clove) with water in presence of amphiphiles (Triton X-100, Tween-60, Aerosol OT, Igepal, Na-oleate, ethanol and cinnamic alcohol) in various ternary and quaternary combinations has been studied. The phase behaviour at different mass proportions and temperature has been investigated in the absence and presence of additives such as NaCl, glucose, urea and cholesterol. Of all the combinations studied, those with ethanol plus sodium oleate as amphiphile have shown maximum extent of single phase microemulsion formation. The presence of urea in the aqueous medium has further increased the monophasic extent whereas NaCl has decreased it. Cholesterol in oil and glucose in water have apparently shown inert effects. The effects of the additives on the formation of biphasic or triphasic formulations, on the other hand, have been found to be distinct and well-dependent on [H2O]/[amphiphile] mole ratio and temperature. Spectral measurements of I3- in the aqueous micropool in microemulsion of clove oil/(ethanol + Na-oleate)/water have shown the microenvironment to be physicochemically different from bulk water.
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Emulsiones , Aceites de Plantas , Tensoactivos , Agua , Soluciones , Espectrofotometría , Relación Estructura-Actividad , TermodinámicaRESUMEN
Effect of malnutrition was studied on placentas of eighty-five malnourished mothers, taking the placentas of sixty-five well nourished mothers as control. Nutritional status of mothers were studied by estimation of haemoglobin, total R.B.C. count and serum protein. Mothers of the malnourished group, showed anaemia of normocytic, microcytic, a few macrocytic type and hypoproteinaemia. Their placentas were of lower weights and sizes than those of control group. Placentas of both the groups showed infarction, degenerative, calcification, fibrinoid necrosis of villi, intervillous fibrin deposition, villous fibrosis, syncytial knotting of villi and proliferation of Langhan's cell of the villi. But the extent and degree of these changes were much more in malnourished group than control group. Activities of the enzyme such as alkaline phosphatase and Glucose-6-phosphatase in placental villi were increased in malnourished group than those in control group. So it appears that placentas of malnourished mothers become underdeveloped having pathological changes greater in extent and degree than control group resulting in inadequate supply of nutrients from mother's blood to foetus blood.