[21 hydroxylase deficiency: new strategies emerging from molecular studies].
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Adrenal Hyperplasia, Congenital↗
Biomedical subjects
M David
Publications and source records attributed to M David.
[Four case reports of Biermer's anemia in West Africa].
The purpose of this report is to describe 4 cases of Biermer's anemia observed in West Africa over a 7-year period. Severe asthenia was the main clinical manifestation. Laboratory tests consistently demonstrated macrocytic anemia usually with a deep drop in hemoglobin levels ranging from 40 to 84 g/l associated with various degrees of thrombocytopenia or leukopenia. Other consistent findings were bone marrow megaloblastosis, serum vitamin B12 deficiency, and intrinsic factor antibodies. In most cases diagnosis was established on the basis of therapeutic tests with subsequent confirmation. Treatment using vitamin B12 therapy was successful in all cases. The authors recommend iron deficiency testing during the course of the disease and gastric biopsy during fibroscopy of upper digestive tract even if no macroscopic lesions are found.
Africa, Western↗
Endovascular treatment as first choice in chronic intestinal ischemia.
The purpose of this study was to define the place of endovascular treatment in chronic intestinal ischemia (CII). We report here a series of 19 consecutive patients treated with percutaneous angioplasty of the intestinal arteries. We excluded patients with acute ischemia, from the study. From January 1, 1989 to December 31, 2001, 19 patients with symptomatic CII were treated by endovascular techniques. This study group included 11 men and 8 women with a mean age of 59 years (range 30 to 90 years). The clinical presentation included postprandial pain in 16 patients, weight loss in 14 patients, with a mean weight loss of 7.4 kg (range 0 to 30 kg); and gastroparesis in 2 patients. Stenoses were significant in the single superior mesenteric artery (SMA) in 2 patients and in two arteries in 17 patients, including the celiac artery (CA) and SMA (n = 13), CA and inferior mesenteric artery (IMA) (n = 1), and SMA and IMA (n = 3). Balloon angioplasty was performed in only one of the arteries in each patient, 15 times in the SMA and 4 times in the CA. In 7 patients, angioplasty required stenting because of recoil (n = 5) or dissection (n = 1). In one patient the lesion was stented primarily, because of adjacent thrombus on the stenosis. Our results showed that initial treatment of CII can be endovascular. Focus on one artery only, seems to be reasonable and efficient in the short and long term.
Adult↗
Anti-D (WinRho SD) treatment of children with chronic autoimmune thrombocytopenic purpura stimulates transient cytokine/chemokine production.
Intravenous anti-D is often used in the treatment of autoimmune thrombocytopenic purpura (AITP), but little is known about its mechanisms of action. To investigate anti-D's potential in vivo mechanism(s) of action, a small group (N = 7) of children with chronic AITP was studied. The children initially received either 25 or 50 microg/kg of WinRho-SD in a four-cycle cross-over trial, and peripheral blood samples from the first and third cycles were assessed for cytokine levels at pre-treatment, 3 hr, 1 day, and 8 days post-treatment. Results showed that platelet counts significantly increased in all the children by day 8 post-treatment. Analysis of serum by ELISA showed that there was a significant but transient rise in both pro- and anti-inflammatory cytokine/chemokine levels (e.g., IL1RA, IL6, GM-CSF, MCP-1 alpha, TNF-alpha and MCP-1) by 3 hr post-treatment in both cycles which returned to baseline levels by 8 days post-treatment. These results suggest that anti-D administration may initially activate the RES in the form of cytokine/chemokine secretion, which is subsequently followed by an increase in platelet counts. It is possible that the induced cytokine/chemokine storm may have an effect on several physiological processes such as those mediating either adverse effects or potentially RES phagocytic activity.
Chemokines↗
Fatal cardiovascular complications in a patient with Ehlers-Danlos syndrome type IV and dextrocardia.
A report is presented of a 31 year female patient with Ehlers-Danlos syndrome type IV who presented a bilateral renal artery dissection and a hematoma of the ascending aorta simultaneously. She had had an uneventful delivery six months before. We also discovered a situs solitus with dextrocardia in this patient. These complications were managed conservatively. Unfortunately the patient died of a pulmonary infection and a multi-organ failure syndrome several days after her admission.
Adult↗
Pigmented contact dermatitis from topical minoxidil 5%.
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Administration, Topical↗
Cosmetics patch tests: first report from Israel.
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Adolescent↗
[Importance of routine examinations in patients with obstructive sleep apnea syndrome].
BACKGROUND AND OBJECTIVE: In patients with obstructive sleep apnea syndrome (OSAS) there is an increased comorbidity of internal diseases such as hypertension, coronary heart disease, chronic obstructive pulmonary disease and endocrine diseases. We analyzed prospectively frequency and consequences of pathological results in routine examinations of internal medicine in sleep laboratory. METHODS: 250 patients with OSAS underwent routine bodyplethysmography, blood- gas analysis, electrocardiogram and laboratory studies after anamnesis and clinical examination. Prior to this we indicated, whether we based on history and physical examination deemed any of these examinations necessary. Frequency and kind of pathological results as well as the consequences were analyzed. RESULTS: 129 results of bodyplethysmography and blood-gas analysis were pathological (51.6 % of all investigations), most frequently hypoxemia (22 %) and obstructive pattern (16.4 %). Further steps were necessary in 19 patients (7.6 %); the indication was seen before in 13 patients, therefore 6 results with consequences (2.4 %) were not expected. Laboratory studies were abnormal in 133 patients (53.2 % of all investigations), most of them hyperglycaemia (26.8 %) and elevated liver enzymes (20.4 %). 29 results (11.6 %) had consequences, of which 16 (6.4 %) were not expected. 82 electrocardiograms were pathological (32.8 % of all investigations), presenting most frequently as coronary heart disease (21.2 %). Further steps were necessary in 5 patients (2 %), while that was not expected in 3 patients (1.2 %). CONCLUSIONS: Routine examinations of internal medicine in patients with OSAS frequently present pathological results, which seldom have further consequences. As most of the important results can be predicted by history and clinical investigation, pathological by chance diagnoses are rare. With the exception of blood sugar tests routine examinations for patients with OSAS should be considered critically.
Blood Gas Analysis↗
[Four years followup of complicated Cockett syndrome treated by iliac vein endoprosthesis].
The purpose of this study was to check the long-term patency of the left common iliac vein endoprosthesis in Cockett syndrome and to confirm this appropriate etiological treatment in complicated cases. Three patients had respectively a pulmonary embolism, left common iliac vein occlusion with protein S deficiency, and venous claudication (Paget-von Schroetter syndrome) as complications of the Cockett syndrome. Treatment with endoprosthesis was performed. A mean follow-up of 48.6 months (31-61 months) revealed a clinical improvement without any recurrence of complications. The patency of the left common iliac vein flow was maintained. Indications on this treatment are being discussed.
Adolescent↗
[Hemoglobin anomalies at the university hospital center in Lome, Togo].
Togo is a sub-Saharan African nation with a number of public health problems including endemic tropical disease. The country is also located in the Lehmann sickle cell belt characterized by a high incidence of genetic red blood cell disorders. The purpose of this study was to identify the main hemoglobin variants, evaluate their incidence and discuss diagnostic pitfalls. Data on 5604 subjects was compiled from the 3 studies, i.e., a 405-case prospective study conducted in a rheumatology department, a 5028-case retrospective study using electrophoresis and a 171-case transversal study in newborns. Diagnosis of hemoglobinopathy was based on alkaline electrophoresis. Rare hemoglobins were identified in the Biochemistry Laboratory of the Henri Mondor Hospital in Paris, France. Diagnosis of alpha-thalassemia was checked by PCR. The main abnormal hemoglobins were the S and C variants with respective incidence ranges of 15.8 to 16.7% for the AS trait and 12.1 to 15.8% for AC trait. SS sickle cell disease was observed in 1.2 to 2% of subjects and SC sickle disease in 2.3 to 4.2%. Rare hemoglobulinopathies involved the fast hemoglobulin variant, hemoglobin D, and hereditary persistence of hemoglobin F. Alpha-thalassemia was detected in 47% of the 171 newborns studied with a predominance of the heterozygous form (36.8%), followed by the homozygous form (8%). The incidence of alpha gene triplication in the newborns was about 2.4%. Hemoglobin Barts was not a consistent finding in association with diagnosis of alpha-thalassemia since it was present in 15 newborns with normal alpha genotype (8.8%) and absent in 10 newborns with heterozygous alpha genotype (5.9%). This study demonstrates that molecular biology is the best method for the detection of the alpha-globin gene abnormalities.
Cross-Sectional Studies↗
Regulation of STAT protein synthesis by c-Cbl.
Many cytokines and growth factors induce transcription of immediate early response genes by activating members of the Signal Transducers and Activators of Transcription (STAT) family. Although significant progress has been made in understanding the events that lead to the activation of STAT proteins, less is known about the regulation of their expression. Here we report that murine embryonic fibroblasts derived from c-Cbl-deficient mice display significantly increased levels of STAT1 and STAT5 protein. In contrast, STAT2 and STAT3 expression, as well as the levels of the tyrosine kinases Jak1 and Tyk2, appear to be regulated independently of c-Cbl. Interestingly, the half-life of STAT1 was unaffected by the presence of c-Cbl, indicating that c-Cbl acts independently of STAT1 degradation. Further analysis revealed similar levels of STAT1 mRNA, however, a dramatically increased rate of STAT1 protein synthesis was observed in c-Cbl-deficient cells. Thus, our findings demonstrate an additional control mechanism over STAT1 function, and also provide a novel biological effect of the Cbl protein family.
Animals↗
Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer.
PURPOSE: To compare 6% miltefosine solution (Miltex; Asta Medica, Frankfurt, Germany), a new topical cytostatic drug, with placebo as palliative treatment for cutaneous metastases from breast cancer. PATIENTS AND METHODS: In a double-blind, placebo-controlled, multicenter phase III study, a total of 52 patients with inoperable progressive skin lesions from histologically or cytologically confirmed breast cancer, not manageable by radiotherapy or systemic treatment, with superficial or flat skin lesions (estimated depth of invasion < or = 1 cm) were randomized to receive either 6% miltefosine solution or placebo. The solution was applied at the dose of 2 drops/10 cm(2), once daily during the first week and twice daily thereafter until treatment failure. RESULTS: Treatment groups were well balanced for patient characteristics at study entry except for a small difference in age. Time to treatment failure (TTF), the primary parameter of this study, showed miltefosine solution to be significantly superior to placebo (P = .007); the median TTF in the miltefosine solution group was nearly three times longer than that in the placebo group (56 days v 21 days). The rate of response based on intention to treat patients was 33.3% for miltefosine solution compared with 3.7% for placebo (P = .006). Cutaneous reactions were seen mainly in the miltefosine group, with the type and frequency similar to those observed in previous studies. CONCLUSION: 6% Miltefosine solution is confirmed as an effective palliative treatment option for cutaneous metastases from breast cancer. Skin reactions, when present, are well tolerated and only occasionally require cessation of treatment.
Administration, Topical↗
Induction of the IL-13 receptor alpha2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways.
IL-4 and IL-13 are related cytokines which induce both pro- and anti-inflammatory effects depending on the cell type they act upon and the nature of the receptors expressed. The type I receptor complex is composed of the IL-4Ralpha and gammac and only binds IL-4, whereas, in the type II receptor, IL-4Ralpha dimerizes with IL-13Ralpha1 upon either IL-4 or IL-13 binding. Another ligand binding chain potentially implicated in the IL-4/IL-13 receptor has been described, the IL-13Ralpha2, but the regulation of its expression and its role in IL-4/IL-13 transduction is poorly understood. In this study we report that IL-4 and IL-13 upregulate IL-13Ralpha2 at both the mRNA and protein levels in the keratinocyte cell line HaCaT. In these cells, IL-4 or IL-13 were shown to activate the Janus Kinases JAK1 and JAK2, the transcription factor STAT6, and the ERK and p38 mitogen-activated protein kinases. We show that IL-4 or IL-13-induced IL-13Ralpha2 mRNA expression was inhibited by the ERK inhibitor U0126, the JAK inhibitor AG490 and, to a lesser extent, the p38 MAPK inhibitor SB203580. Moreover, expression of a constitutive active mutant of STAT6 alone did not modify IL-13Ralpha2 mRNA expression, but potentiated the effects of IL-4 or IL-13 on IL-13Ralpha2 expression. The constitutive active mutants of MEK1 or MKK6 increased the level of expression of IL-13Ralpha2 mRNA even in absence of stimulation. Our findings demonstrate, for the first time, that IL-4 and IL-13 can induce IL-13Ralpha2 expression in keratinocytes, and that the ERK and p38 MAPK together with JAK2 and STAT6 play a critical role in this process.
Antineoplastic Agents↗
Cerebral sinovenous thrombosis in children.
BACKGROUND: Cerebral sinovenous thrombosis in children is a serious disorder, and information is needed about its prevention and treatment. METHODS: The Canadian Pediatric Ischemic Stroke Registry was initiated in 1992 at the 16 pediatric tertiary care centers in Canada. Children (newborn to 18 years of age) with symptoms and radiographic confirmation of sinovenous thrombosis were included. RESULTS: During the first six years of the registry, 160 consecutive children with sinovenous thrombosis were enrolled, and the incidence of the disorder was 0.67 cases per 100,000 children per year. Neonates were most commonly affected. Fifty-eight percent of the children had seizures, 76 percent had diffuse neurologic signs, and 42 percent had focal neurologic signs. Risk factors included head and neck disorders (in 29 percent), acute systemic illnesses (in 54 percent), chronic systemic diseases (in 36 percent), and prothrombotic states (in 41 percent). Venous infarcts occurred in 41 percent of the children. Fifty-three percent of the children received antithrombotic agents. Neurologic deficits were present in 38 percent of the children, and 8 percent died; half the deaths were due to sinovenous thrombosis. Predictors of adverse neurologic outcomes were seizures at presentation and venous infarcts. CONCLUSIONS: Sinovenous thrombosis in children affects primarily neonates and results in neurologic impairment or death in approximately half the cases. The occurrence of venous infarcts or seizures portends a poor outcome.
Adolescent↗
Analysis of protein arginine methylation and protein arginine-methyltransferase activity.
Posttranslational modification of proteins allows cells to adapt and react quickly to their environment beyond the boundaries set forth by genetic code. Arginine methylation, a protein modification discovered almost 30 years ago, has recently experienced a renewed interest as several new arginine methyltransferases have been identified and numerous proteins were found to be regulated by methylation on arginine residues. Until recently, the detection of arginine methylation required the use of chromatography and mass-spectrometrical analysis. The following protocol provides guidelines for the straightforward identification of arginine-methylated proteins, made possible by the availability of novel, commercially available reagents.
Animals↗
Allergy in coronary in-stent restenosis.
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Coronary Disease↗
Arginine methylation of STAT1 modulates IFNalpha/beta-induced transcription.
Transcriptional induction by interferons requires the tyrosine and serine phosphorylation of STAT transcription factors. The N-terminal region is highly homologous among the STAT proteins and surrounds a completely conserved arginine residue. Here we demonstrate arginine methylation of STAT1 by the protein arginine methyl-transferase PRMT1 as a novel requirement for IFNalpha/beta-induced transcription. Methyl-thioadenosine, a methyl-transferase inhibitor that accumulates in many transformed cells, inhibits STAT1-mediated IFN responses. This inhibition arises from impaired STAT1-DNA binding due to an increased association of the STAT inhibitor PIAS1 with phosphorylated STAT1 dimers in the absence of arginine methylation. Thus, arginine methylation of STAT1 is an additional posttranslational modification regulating transcription factor function, and alteration of arginine methylation might be responsible for the lack of interferon responsiveness observed in many malignancies.
Amino Acid Sequence↗
Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus.
Acquired activated protein C resistance (APCR) has been hypothesized as a possible mechanism by which antiphospholipid antibodies (APLAs) cause thrombotic events (TEs). However, available evidence for an association of acquired APCR with APLAs is limited. More importantly, an association of acquired APCR with TEs has not been demonstrated. The objective of the study was to determine, in pediatric patients with systemic lupus erythematosus (SLE), whether (1) acquired APCR is associated with the presence of APLAs, (2) APCR is associated with TEs, and (3) there is an interaction between APCR and APLAs in association with TEs. A cross-sectional cohort study of 59 consecutive, nonselected children with SLE was conducted. Primary clinical outcomes were symptomatic TEs, confirmed by objective radiographic tests. Laboratory testing included lupus anticoagulants (LAs), anticardiolipin antibodies (ACLAs), APC ratio, protein S, protein C, and factor V Leiden. The results revealed that TEs occurred in 10 (17%) of 59 patients. Acquired APCR was present in 18 (31%) of 58 patients. Acquired APCR was significantly associated with the presence of LAs but not ACLAs. Acquired APCR was also significantly associated with TEs. There was significant interaction between APCR and LAs in the association with TEs. Presence of both APCR and LAs was associated with the highest risk of a TE. Protein S and protein C concentrations were not associated with the presence of APLAs, APCR, or TEs. Presence of acquired APCR is a marker identifying LA-positive patients at high risk of TEs. Acquired APCR may reflect interference of LAs with the protein C pathway that may represent a mechanism of LA-associated TEs. (Blood. 2001;97:844-849)
Activated Protein C Resistance↗