Asociación de polimorfismos de simple nucleótido (SNP) de CD28 (IVS3+17T/C) Y CTLA-4 (+49A/G) con autoinmunidad tiroidea (AIT) / Association of single nucleotide polymorphism (SND) of CD28 (IVS3+17+K) and CTLA-4 (+49 A/G) with thyroid autoimmunity AIT)

La enfermedad tiroidea autoinmune es la patología autoinmune más prevalente y afecta hasta el 5% de la población general. Su desarrollo está dado por la interacción entre susceptibilidad genética y otros factores. Una característica es la temprana producción de anticuerpos antiperoxidasa tiroidea (aTPO) que a menudo predicen el desarrollo clínico de la enfermedad. La susceptibilidad genética para AIT es generada por genes del HLA y por otros candidatos del cromosoma 2q33. Esta región contiene los genes CTLA-4 y CD 28, y sus polimorfismos estarían asociados. Objetivo: Analizar y comparar la distribución de los polimorfismos de simple nucleótido (SNP) de CD28 (IVS3+17 T/C) y CTLA-4 (+49 A/G) en pacientes con aTPO >10 IU/ml (AIT) comparados con un grupo control aTPO ≤ 10 IU/ml sin AIT. Sujetos y métodos: Estudiamos 69 pacientes y 36 sujetos considerados controles. Para determinar aTPO se utilizó IMMULITE 1000 y muestra sérica. Para el estudio de los SNP se extrajo ADN de sangre periférica. La amplificación de los genes se realizó por PCR. Las diferencias entre grupos fueron comparadas usando el test de Chi Cuadrado. Resultados: Observamos diferencia significativa en el genotipo CD28 C/T entre AIT y controles (p=0.026). Analizando los genotipos de los polimorfismos CTLA-4 no observamos diferencia significativa entre AIT y controles. Del análisis de asociación de genotipos CD28 C/T y CTLA-4 A/A o A/G, observamos diferencia significativa comparando AIT vs. controles (p=0,013). Conclusión: Encontramos una posible asociación significativa del genotipo CD28 C/T en individuos con AIT, y estos portadores tendrían un riesgo tres veces mayor de adquirir AIT. La combinación de los genotipos CD28 C/T y CTLA-4 A/A o A/G incrementaría cuatro veces el riesgo de adquirir AIT. Estos resultados permitirían llevar a cabo un diagnóstico precoz, con la adecuada caracterización de una posible enfermedad tiroidea autoinmune en pacientes con AIT.

The autoimmune thyroid disease is the most prevalent autoimmune affection and affects until 5% of the general population; its development is given by the interaction between genetic susceptibility and other factors. One particularity is the early production of thyroid autoantibodies against thyroid peroxidase (aTPO) which often predicts the clinical development of the disease. The genetic susceptibility for the thyroid autoimmunity (AIT) is generated by genes of the HLA and by other genes candidates of the chromosome 2q33. This region contains the genes: CTLA-4 and CD 28. Several polymorphisms of both would be associated according to previous studies. Objective: To analyze and to compare the simple nucleotide polymorphism distribution (SNP) of CD28 (IVS3+17 T/C) and CTLA-4 (+ 49 A/G) in patients with aTPO> 10 IU/ml (AIT) compared to a control group aTPO ≤ 10 IU/ml with no AIT. Subjects and Methods: We have studied 69 patients with AIT and 36 control subjects. Serum aTPO were measured by using chemiluminescence immunoassay (IMMULITE1000, Siemens). Genomic DNA was prepared from peripheral white blood cells. The amplification of the genes was carry out by polymerase chain reaction (PCR). Statistical analyses : the differences between groups were made using the chisquare test. P less than 0.05 was considered statistically significant. Results: There was a significant difference of genotype CD 28 C/T in patients with AIT compared with controls (p=0.026). The genotypes of CTLA-4 was analyzed and there was no significant difference between AIT and controls. Analysis of genotypes association CD 28 C/T and CTLA-4 A/A or A/G, revealed significant difference comparing AIT versus controls (p= 0.013). Conclusions: We found a possible association of genotype CD 28 C/T in individuals with AIT, since carriers of genotype C/T would have a risk three times higher to acquire AIT. The combination of genotypes CD 28 C/T and CTLA-4 A/A or A/G would increase the risk of acquiring AIT four times. These results could be useful in order to make a premature diagnosis, with adequate characterization of a possible autoimmune thyroid disease in patients with AIT.

Neoadjuvant chemotherapy with ifosfamide, cisplatin, and vinorelbine in advanced squamous cell carcinoma of the cervix.

A phase II trial was performed to assess the efficacy and toxicity of a combination of ifosfamide (IFX), cisplatin (CDDP), and vinorelbine (VNB) as neoadjuvant chemotherapy (NAC) for untreated advanced cervical carcinoma (ACC). Between October 1995 and February 1998, 40 patients were entered in this study. Their median age was 43 years (range: 23-74 years). International Federation of Gynecology and Obstetrics stages were: IIB, 23; IIIB, 13; and IVA, 4. Therapy consisted of: IFX 2,000 mg/m2 1-hour (H) IV infusion days 1 to 3; 2-mercaptoethanesulfonic acid sodium salt (mesna) 400 mg/m2 IV bolus H 0 and 4, and 800 mg/m2 by mouth H 8, days 1 to 3; VNB 25 mg/m2 20-minute IV infusion days 1 and 8; and CDDP 75 mg/m2 IV day 3. Cycles were repeated every 28 days for a total of three courses. Both staging and response (R) assessment were performed by a multidisciplinary team. An objective response (OR) was observed in 24 of 40 patients (60%; 95% confidence interval, 45-75%). Four patients achieved complete response (CR) (10%); 20 partial response (50%); 12 patients stable disease (30%); and 4 progressive disease (10%). Eight of 24 patients (33%) with OR underwent radical surgery, and histologic CRs were recorded in 2 of them. The remaining patients received definitive radiotherapy after NAC. The dose-limiting toxicity was myelosuppression. Leukopenia occurred in 32 patients (80%) and was grade III or IV in 14 patients (36%). Peripheral neuropathy occurred in 9 patients (22%), whereas myalgias occurred in 10 (25%). Constipation was observed in 9 patients (23%); emesis occurred in 35 patients (88%). There were no therapy-related deaths. These results indicate that IFX/CDDP/VNB is an active combination for ACC with moderate toxicity. Implementation of this regimen in a multimodal therapy protocol deserves further study.

[Frontal lobe dysfunction in patients with epilepsy and chronic psychosis]. / Disfunción del lóbulo frontal en pacientes con epilepsia y psicosis crónica.

PATIENTS AND METHODS: Fifty patients diagnosed as having epileptic crises were given neuropsychological tests including the Wechsler Adult Intelligence Scale or WAIS, Luria's neuropsychological test and a quantitative EEG examination. Multivariate analysis was done of the following variables: presence or absence of inter-octal psychosis, onset of crises before the age of 10 years, frequency of crises or status epilepticus greater than 100, known cause or otherwise of epilepsy, and the presence of more than one type of crisis in a particular patient. The working hypothesis was to show that the association of epilepsy and psychosis causes alterations in superior psychic functions (SPF) particularly of the frontal lobes. The WAIS test, intelligence, verbal and executive quotients and the 11 subtests were evaluated using multivariate analysis (ANOVA) conditioned by the different variables studied. The broad band spectral measurements of the quantitative EEG (BBSM) were studied using a statistical programme (COMPARA) by which the groups of individuals were compared with a standard group, using the Student t and Fisher tests. The different BBSM variables studied were: absolute power, relative power and total dominant frequency. RESULTS: Amongst the most important results were: reduction in the performance scale of epileptics with chronic psychosis, alterations on the verbal scale in epileptics with more than one type of crisis, presence of frontal and fronto-temporal dysfunction in epileptics with chronic psychosis and negative signs of schizophrenia. On the quantitative EEG in epileptics with psychosis there was abnormally slow activity predominantly in the frontal lobes. CONCLUSIONS: From the overall results we may conclude that in patients with epilepsy and chronic psychosis there is cortical dysfunction of the frontal lobe.

Biochemical modulation of 5-fluorouracil by methotrexate in patients with advanced gastric carcinoma.

A phase II trial was conducted to evaluate the efficacy and toxicity of a modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) (with leucovorin (LV) rescue) as first-line chemotherapy in patients with locally advanced (inoperable) or metastatic gastric carcinoma. From July 1993 through August 1996, 36 patients with advanced gastric carcinoma received a regimen that consisted of: MTX 200 mg/m2 diluted in 250 ml normal saline by intravenous infusion over 20 minutes at hour 0; 5-FU 1,200 mg/m2 intravenous push injection at hour 20. Beginning 24 hours after MTX administration all patients received LV 15 mg/m2 intramuscularly every 6 hours for six doses. Cycles were repeated every 15 days. One patient was not assessable for response. Objective regression was observed in 15 of 37 patients (43%; 95% confidence interval, 26%-60%). One patient (3%) achieved complete response and 14 (40%) achieved partial response. No change was recorded in 14 patients (40%) and progressive disease was noted in six patients (17%). The median time to treatment failure was 7 months and the median survival was 12 months. Toxicity was within acceptable limits but one therapy-related death resulting from severe leukopenia occurred. The dose-limiting toxicity was mucositis. Five episodes of grade 3 or 4 stomatitis were observed and caused dosage modifications of MTX and 5-FU. Biochemical modulation of 5-FU by MTX appears as an attractive modality in patients with advanced gastric cancer. Further investigation both in experimental and clinical fields is needed to clearly define its role and to design the best modulatory strategy.

Inyección accidental intrarterial de penicilina benzatínica / Accidental intraarterial injection of benzathine penicillin

La inyección intramuscular de penicilina benzatínica puede ocasionar complicaciones graves por lesión del nervio ciático o inyección accidental intraarterial. Se presentan 3 pacientes con lesiones isquémicas graves en miembros inferiores que provocaron amputaciones distales en todos, sumándose en el tercero mielitis transversa. Los hallazgos histopatológicos en 2 de ellos fueron compatibles con lesiones en vasos y arterias de pequeño tamaño. Se recomienda no utilizar las inyecciones intramusculares de penicilina benzatínica en menores de 2 años, en especial desnutridos o prematuros

Inyección accidental intrarterial de penicilina benzatínica / Accidental intraarterial injection of benzathine penicillin

La inyección intramuscular de penicilina benzatínica puede ocasionar complicaciones graves por lesión del nervio ciático o inyección accidental intraarterial. Se presentan 3 pacientes con lesiones isquémicas graves en miembros inferiores que provocaron amputaciones distales en todos, sumándose en el tercero mielitis transversa. Los hallazgos histopatológicos en 2 de ellos fueron compatibles con lesiones en vasos y arterias de pequeño tamaño. Se recomienda no utilizar las inyecciones intramusculares de penicilina benzatínica en menores de 2 años, en especial desnutridos o prematuros (AU)