Interferon alpha plus intermittent oral Ara-C ocfosfate (YNK-01) in chronic myeloid leukemia primarily resistant or with minimal cytogenetic response to interferon.

BACKGROUND AND OBJECTIVES: Subcutaneous Ara-C plus interferon (IFN) produces more cytogenetic responses than IFN in chronic myeloid leukemia (CML) but a greater toxicity. The objective of this study was to determine the efficacy and tolerance of IFN plus oral Ara-C ocfosfate (YNK-01) in IFN-resistant CML patients. DESIGN AND METHODS: A phase II pilot study was conducted in 19 CML patients primarily resistant or with minimal cytogenetic response to IFN. Patients were scheduled to receive 6 monthly 14-day cycles of YNK-01 (500 mg/day), with progressive escalation if tolerated, in addition to IFN. Cytogenetic assessment was performed thereafter. RESULTS: Of the first 7 patients, 5 had severe hematologic and 5 moderate gastrointestinal toxicity; IFN was reduced in 6, YNK-01 in 5, and treatment discontinued in 2; hematologic response was achieved in 2 of the 5 evaluable patients. In the following 4 patients the Ara-C was reduced to 300 mg: 2 had severe hematologic and 2 moderate gastrointestinal toxicity; IFN and Ara-C were reduced in 2 patients and treatment discontinued in 2 due to progression or toxicity; the other 2 achieved a minor cytogenetic response, progressing in one to a major response after 6 more cycles. In 8 patients the starting Ara-C dose was 200 mg: 5 had moderate-severe hematologic and 5 mild gastrointestinal toxicity; IFN was reduced in 5, Ara-C in 1, and treatment discontinued in 1; Ara-C was increased in 7 cases; hematologic response was obtained in 4 patients, 2 of whom attained a minor and 1 a major cytogenetic response. INTERPRETATION AND CONCLUSIONS: These results provide background for future studies aimed at ascertaining the role of oral Ara-C combined with IFN or STI571 in newly diagnosed CML.

Correlations between motor persistence and plasma levels in methylphenidate-treated boys with ADHD.

Following a 0.9 mg/kg methylphenidate loading dose, serial plasma level determinations, self-scored mood ratings, and measures of motor persistence were gathered on eight previously unmedicated boys with attention deficit disorder with hyperactivity (ADHD) during a 9-h period. The measures were repeated using the same loading dose after 6 months of maintenance treatment with methylphenidate (1.3 mg/kg x d). Kinetic-dynamic modelling suggests inverse correlative relationships between motor performance errors and plasma levels. Pharmacokinetic parameters did not change between acute and maintenance drug treatment phases, and there was no evidence of long-term tolerance.

[Genetic counseling in profound deafness]. / Consejo genético a los sordos profundos.

One of the responsibilities of cochlear implant centers is to counsel deaf patients regarding the potential for transmitting deafness of their children. Diagnostic studies should be made to determine if deafness is an isolated event or part of a syndrome. We report the criteria used in our center for genetic counseling of the deaf.

[Identification of Arg-135-Leu mutation in the rhodopsin gene in a family with autosomal dominant retinitis pigmentosa]. / Identificación de la mutación Arg-135-Leu en el gen de la rodopsina en una familia con retinosis pigmentaria autosómica dominante.

Mutations in the rhodopsin gene have been sought in a family with autosomal dominant retinitis pigmentosa. Screening for mutations in the rhodopsin gene was carried out by polimerase chain reaction and denaturant gradient gel electrophoresis. Direct DNA sequencing was performed for the characterization of punctual mutations. A base substitution in the exon 2 of the rhodopsin gene was detected. Direct DNA sequencing revealed a CGC to CTG change in codon 135, that substitutes arginine for leucine residue in rhodopsin. The mutation segregates with the disease phenotype in the family. The mutation Arg-135-Leu causes the retinitis pigmentosa phenotype in the family, where the disease is inherited following an autosomal dominant pattern.

Corticotropin-releasing hormone challenge in prepubertal major depression.

This study investigates cortisol and ACTH (corticotropin) responses to an infusion of human CRH (corticotropin-releasing hormone) in prepubertal children with major depressive disorder (MDD). Following a period of 24 hours of adaptation to the laboratory environment with an intravenous catheter in place, 34 children with MDD and 22 healthy controls received 1 microgram/kg of human CRH at 5:00 PM. Blood samples for cortisol and ACTH were measured at baseline and post-CRH. Overall, there were no significant differences between the MDD and the normal controls in baseline or post CRH stimulation values of either cortisol or ACTH. Melancholic (n = 4) patients had significantly higher baseline cortisol levels than nonmelancholic (n = 24) patients. Compared with the outpatients and the nonmelancholics, the inpatients (n = 10) and the melancholics showed significantly lower total ACTH secretion (effect size: 0.9 and 1.4, respectively) after CRH infusion. These results are consistent with a broad literature suggesting that the HPA axis abnormalities occur less frequently in early-onset depression than reported in adult studies. The pattern of results in the subgroups of inpatients and in melancholic children, however, raise questions about possible continuities with adult studies.

A case-control family history study of depression in adolescents.

OBJECTIVE: To examine whether depression aggregates in the families of depressed adolescents and to determine whether clinical features and/or comorbid syndromes in the depressed adolescents change the risk of psychopathology in relatives. METHOD: Lifetime prevalence rates of psychopathology in the first-degree (n = 228) and second-degree (n = 736) relatives of 76 adolescents with major depressive disorder (MDD) and the first-degree (n = 107) and second-degree (n = 323) relatives of 34 normal control adolescents were assessed by the Family History-Research Diagnostic Criteria (FH-RDC) method using the parent/guardian as the family informant. RESULTS: Compared with the first-degree relatives of normal controls, the relatives of depressed adolescents had significantly higher lifetime rates of MDD (25% versus 13%) and "any" of the FH-RDC psychiatric disorders (53% versus 36%). The second-degree relatives of adolescents with MDD had significantly higher lifetime rates of FH-RDC "other" psychiatric disorder (12% versus 7%) and "any" of the FH-RDC psychiatric disorders (22% versus 15%) but not MDD (5% versus 6%) compared with the relatives of normal controls. The first-degree relatives of depressed adolescents who were also suicidal had increased lifetime rates of suicidal behavior which significantly cosegregated with MDD. Comorbid conduct disorder in the depressed adolescent was associated with increased rates of antisocial personality disorder in the first-degree relatives and also tended to cosegregate with MDD. CONCLUSIONS: The current study provides further evidence for the familial aggregation of depression in adolescent-onset MDD. This study also suggests that the familial aggregation of nonaffective psychiatric disorders depends on the clinical features and comorbid syndromes present in the depressed adolescent proband.

Schinzel-Giedion syndrome: report of two sibs.

We report on two further cases, a sister and a brother, with Schinzel-Giedion syndrome. Both presented the following manifestations: "coarse face" with midface retraction, agenesis of corpus callosum, bilateral hydronephrosis, and typical skeletal anomalies. Patient 1 had a malignant sacrococcygeal teratoma. This is the third case of malignancy in this syndrome. Patient 2 died shortly after birth.

Consejería genética a los sordos profundos / Genetic counselling to profound deaf

Uno de los problemas que debemos ayudar a resolver a los pacientes con hipoacusias graves, es la posibilidad de transmitir su sordera a sus descendientes, asi como el saber que tipo de exámenes diagnosticos han de realizarse para conocer si su sordera es un hecho aislado o forma parte de un sindrome. El proposito de este articulo es el de exponer los criterios geneticos que en nuestro Centro de Implantes Cocleares damos a los pacientes afectos de sordera profunda

A point mutation in the RDS-peripherin gene in a Spanish family with central areolar choroidal dystrophy.

The RDS-peripherin gene encodes a photoreceptor-specific protein that is localized in the outer segment disc membranes of both rods and cones. We screened a Spanish family with central areolar choroidal dystrophy for mutations in candidate genes. A base substitution was identified in the RDS-peripherin gene of one patient and DNA sequencing revealed a C-to-T transition in codon 172, arginine being substituted by tryptophan. The mutation was also detected in two asymptomatic family members who showed irregular pigmentation in the retinal pigment epithelium (RPE). The phenotype is similar to other macular dystrophies caused by mutation in the RDS-peripherin gene.

Identification of a novel rhodopsin mutation (Met-44-Thr) in a simplex case of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a group of genetically heterogeneous retinal degenerations that can be autosomal dominant (ADRP), autosomal recessive (ARRP), or X-linked. Approximately 30% of ADRP patients show point mutations or small deletions in the rhodopsin gene. However, over 50% of the RP patients are simplex cases (sporadic). Screening for mutations in the rhodopsin gene of 33 patients with simplex RP by denaturing gradient gel electrophoresis (DGGE) was carried out. One patient, with D-type (diffuse) RP and consanguineous parents, showed an altered electrophoretic pattern for the 5' half of exon 1. Direct sequencing revealed a new mutation ATG to ACG in codon 44; this predicts a change of Met-44-Thr in rhodopsin. The position and amino acid substitution suggest that this mutation causes the RP phenotype. Implications for genetic counselling are discussed.

Stimulatory tests of growth hormone secretion in prepubertal major depression: depressed versus normal children.

OBJECTIVE: Blunted stimulation of growth hormone (GH) secretion after pharmacological stimuli has been linked to depressive and anxiety disorders throughout the life span. This study sought to better characterize this dysregulation in prepubertal depression. METHOD: GH regulation was compared in 38 medically healthy prepubertal children with current major depressive disorder and 19 control children who were medically and psychiatrically healthy. The study evaluated GH stimulatory responses to three pharmacological challenge agents: (1) insulin-induced hypoglycemia, using 0.1 IU/kg intravenous regular insulin; (2) 1.3 micrograms/kg intravenous clonidine; and (3) 1.0 microgram/kg intravenous human growth hormone-releasing hormone (GHRH). RESULTS: The results provide replication and extension of earlier findings. GH responses to insulin-induced hypoglycemia and to GHRH stimulation were blunted in depressed children compared to the normal controls. Clonidine stimulation results yielded a similar picture but did not reach statistical significance. CONCLUSIONS: Overall these results further strengthen the evidence showing GH dysregulation in childhood depression. However, the blunted GH response seen with GHRH (which reflects pituitary hyporesponsivity) was in contrast to our original hypothesis and has implications regarding the site (or sites) of dysregulation.

The 24-hour pattern of prolactin secretion in depressed and normal adolescents.

Plasma prolactin concentrations were measured at 20-min intervals over a 24-hr period in 49 adolescents with major depressive disorder (MDD) and 39 normal control adolescents. Neither the pattern nor the amount of prolactin secretion was significantly different between these two groups. There were significant gender differences, with girls secreting more prolactin than boys, but no significant gender-by-diagnosis interactions were found. With the possible exception of psychosis, dividing the MDD sample based on clinical characteristics failed to reveal differences. These findings are discussed in the context of changes in prolactin in childhood depression using a serotonergic challenge study, as well as in relation to baseline prolactin studies in adult depression.

Cholinergic REM induction test with arecoline in depressed children.

Children with major depressive disorder often fail to exhibit electroencephalographic (EEG) sleep abnormalities similar to those reported in depressed adults. It was hypothesized that a cholinergic rapid eye movement (REM) induction test would contribute to the identification of EEG sleep abnormalities in depressed children. To test this hypothesis, prepubertal children meeting research diagnostic criteria for major depressive disorder (n = 33) and carefully screened healthy control children (n = 15) were enrolled in a 4-day psychobiologic protocol that included 1 night with infusion of arecoline (0.5 mg) during the first non-REM sleep period. Although there had been no significant group differences in baseline sleep measures, results on the arecoline night revealed significantly shorter REM latency in the group of depressed children compared with the control children (mean +/- SD = 105 +/- 51 minutes vs. 140 +/- 46 minutes). The design of the protocol (with an interval break immediately preceding the arecoline night) prevented a direct estimation of arecoline effects within subjects; however, these data provide promising preliminary results regarding cholinergic REM induction tests in childhood depression.

Blood transfusion has no effect on colorectal cancer survival. A population-based study.

This study was conducted to evaluate the impact on survival of perioperative blood transfusion in a series of 698 colorectal cancer patients undergoing radical surgery. Patients were identified, and follow-up was carried out by the local population-based cancer registry. Data on blood transfusion was obtained by record linkage with the files of the blood banks operating in the area covered by the registry. Prognostic factors were age, Dukes stage and topography of the primary tumour. Relative risk (RR) for Dukes B patients was 1.53 [95% confidence interval (CI) 0.94-2.50] and for Dukes C, 3.57 (95% CI 2.22-5.75) when compared with Dukes A patients. For the left colon, RR was 0.96 (0.61-1.52) and for the rectum 1.87 (1.22-2.86) when compared with the right colon. When adjusting for these factors and excluding operative mortality, RR for transfused patients was 1.16 (95% CI 0.87-1.55). It is concluded that blood transfusion does not adversely affect survival in colorectal cancer patients.

The psychosocial functioning and family environment of depressed adolescents.

OBJECTIVE: This study examined measures of functional impairment and family relations in a sample of 62 adolescents with major depressive disorder (MDD) and 38 normal controls with no history of psychiatric illness. METHOD: Ratings of the following domains were obtained: mother-child relations, father-child relations, spousal relations, sibling relations, peer relations, and school performance. Ratings of each domain for the 3-month period preceding the assessment were derived from information obtained using a semistructured interview administered independently to the adolescents and one of their parents. RESULTS: Adolescents with MDD were found to have severe difficulties in all areas. Ninety percent of the depressed adolescents had scores greater than 2 SD above the mean of the normal controls on one or more of the domain ratings. In addition, adolescents with difficulties in parent-child relations were more likely than those adolescents without problems in family relations to have difficulties in peer relations and school performance. CONCLUSIONS: The authors discuss the importance of systematically examining psychosocial variables in future studies of the etiology, course, and treatment of MDD in adolescents.

Neural tube defect and amniotic band sequence.

A 28-years-old pregnant woman was examined by fetal ultrasonography at 18 weeks' gestation. Anencephaly was diagnosed, followed by prostaglandin induced abortion and fetotomy. Fetal fragments showed a very small head, bilateral anophthalmy, absence of nasal structures and calvarium, intact cranial skin and a very small cranial cavity. The right lower limb was reduced to a few toes covered by a large amniotic adhesion. The left lower limb showed an amniotic band from sole to thigh. The abdominal wall was absent. The diagnoses were amniotic adhesion syndrome and cephalic pole induction failure. The pathogenesis of these defects has been the subject of controversy. Vascular disruption and secondary reduction of the paraaxial mesodermal cells can explain the anomalies observed in this case.