Urinary deoxypyridinoline, serum osteocalcin and bone mineral density in girls with Turner's syndrome.
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Adolescent↗
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Hypomelanosis of Ito and precocious adrenarche in a girl.
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Abnormalities, Multiple↗
Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity.
The purine nucleoside analogs (PNA) form an important group of cytotoxic drugs active in the treatment of neoplastic and autoimmune diseases. Three of them, fludarabine (FA), cladribine (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (2'-deoxycoformycin, DCF) have established clinical activity in hematological malignancies and have been approved by FDA. These drugs are also investigated in some autoimmune diosorders. Recently four novel PNA: clofarabine (CAFdA), nelarabine, immucillin H (BCX-1777, forodesine) and 8-chloroadenosine (8-Cl-Ado) have been synthesized and introduced into clinical trials. All these drugs have chemical structure similar to adenosine or guanosine, however, the mechanism of their action is different. FA, 2-CdA and CAFdA mainly require phosphorylation by deoxynucleoside salvage pathways. The cytotoxic effect exerts the triphosphate metabolites, which are incorporated into DNA, and finally lead to programmed cell death. In contrast, DCF does not need to be phosphorylated and results in an increase of plasma deoxyadenosine (dAdo) levels and intracellular deoxyadenosine triphosphate (dATP). Nelarabine is an arabinosylguanine (ara-G) prodrug, which after conversion to ara-G is phosphorylated to ara-G triphosphate (ara-GTP). Accumulation of ara-GTP finally leads to apoptosis. Forodesine is a purine nucleoside phosphatase (PNP) inhibitor which blocks intracellular deoxyguanine (dGuo) cleaving to guanine (Guo), but instead converts it to deoxyguanosine triphosphate (dGTP), and similarly to other PNA resulting in apoptosis. 8-chloroadenosine (8-Cl-Ado) is a ribonucleoside analog. The mechanism of its action is quite different from other PNA and remains poorly understood. However, it is known that the drug inhibits RNA synthesis, but not DNA. These agents have significant cytotoxic activity against lymphoid and myeloid malignant cells. Moreover, they have deleterious effects on the normal resting lymphocytes. They result in prolonged lymphocyte depletion especially in the CD4 subset of T-cells. Several clinical trials have demonstrated that PNA used alone or in combination with other cytotoxic drugs or monoclonal antibodies shows good efficacy and acceptable toxicity profile in the treatment of lymphoid malignancies. 2-CdA and DCF are drugs of choice in the treatment of hairy cell leukemia. FA and 2-CdA have significant clinical activity in low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. 2-CdA exhibits some activity in progressive multiple sclerosis and other autoimmune disorders. This review will summarize current knowledge concerning the mechanism of action, pharmacological properties, clinical activity and toxicity of PNA accepted for use in clinical practice as well as new agents available for clinical trials.
Antineoplastic Agents↗
Heterozygosity of CDAN II (HEMPAS) gene may be detected by the analysis of erythrocyte membrane glycoconjugates from healthy carriers.
BACKGROUND AND OBJECTIVES: Congenital dyserythropoietic anemia (CDA) type I, II, and III, is associated with abnormalities of erythrocyte membrane glycoconjugates that are most pronounced in type II CDA or hereditary erythroblastic multinuclearity with a positive acidified-serum test (HEMPAS). The abnormalities consist in hypoglycosylation of polylactoaminoglycans linked to proteins (as in band 3 glycoprotein) and ceramides (known under the name of polyglycosylceramides) as well as in accumulation of some oligoglycosylceramides: lactotriaosylceramide, neolactotetraosylceramide, and sometimes globotetraosylceramide. Glycophorin A is partially unglycosylated with respect to O-linked glycans. Types I and II of the disease are inherited in an autosomal recessive fashion. The aim of the present study was to investigate a possibility that heterozygosity with respect to CDAN2 gene in healthy carriers could be detected by analysis of erythrocyte membrane glycoconjugates. DESIGN AND METHODS: We examined a family which consisted of heterozygous parents and their two sons, one of whom was afflicted with CDA II (proband) while the other was healthy. In all family members the glycosylation status of band 3 glycoprotein, polyglycosylceramides and glycophorin A was evaluated from their carbohydrate molar composition. In addition we determined erythrocyte membrane contents of oligo- and polyglycosylceramides, and agglutinability of erythrocytes by anti-i antibody. RESULTS: We found that the heterozygous parents showed, but about 50% less pronounced, most of the typical abnormalities of erythrocyte membrane glycoconjugates that were present in the proband. These abnormalities included: hypoglycosylation of band 3, accumulation and hypoglycosylation of polyglycosylceramides, and accumulation of lactotriaosylceramide. The level of neolactotetraosylceramide in the erythrocyte membranes of the parents was, however, normal. Globotetraosylceramide content was elevated in erythrocytes from the proband and, surprisingly, even more so in the parents. Glycophorin A in the proband was only slightly abnormal. Erythrocytes from both the parents and the proband expressed increased agglutinability with anti-i antibody. All glycoconjugates examined were normal in erythrocytes from the healthy son. INTERPRETATION AND CONCLUSIONS: Individuals heterozygous with respect to CDAN2 gene can be identified through determination of the carbohydrate molar composition of band 3 and polyglycosylceramides as well as by an elevated erythrocyte content of polyglycosylceramides. In the parents these abnormalities show dosage effects. Determination of the carbohydrate molar composition of glycophorin A and of oligoglycosylceramides seems to be less promising. These findings indicate that the analysis of erythrocyte membrane glycoconjugates may be a valuable addition to the repertoire of methods used in studies on the genetics of CDA.
Adult↗
[Spirometry evaluation of montelukast treatment in children with bronchial asthma].
Difficulties associated with the management of asthma were the cause of using the leukotriene antagonists. There was performed a randomised group of 31 children aged 6-18 y (mean 12 yrs., 10 girls and 21 boys) with persistent asthma and poor asthma control. Montelukast was administered once daily, 5-10 mg depended of the age of the patients. This treatment was conducted for three months. Montelukast significantly improved pulmonary lung function (as measured by spirometry). Another effect of montelukast treatment was possibility the reduction beta 2-agonist use and the required dose of inhaled corticosteroids.
Acetates↗
[Vertebral canal abscess as a complication of congenital sacral sinus in a two year old girl].
Vertebral canal abscess is rather an uncommon disease. Since 1830, when the first report that spinal of abscess was published. Till to 2000, no more than 20 cases as a result of dermal sinus infection were reported. Dermal sinus results from an incomplete separation of the cutaneus ectoderm from the neural ectoderm between the 4 and 6 weeks of fetal development. Surgical excision of the sinus is the treatment of choice for prevention of infection. The authors describes a 2-year-old girl with that abscess secondary to dorsal dermal sinus in sacral region. The patient presented with fever, since two weeks, flaccid paraparesis mainly in the right lower extremity, urinary and bowel incontinence. The child was initially treated conservatively, and after limitation of inflammatory process the dermal sinus and dermoid cyst containing a large quantity of pus were excised. The authors reviewed the literature of spinal cord abscesses secondary to congenital dermal sinus. The diagnostic and therapeutic methods presented in the literature are discussed in comparison with our case.
Abscess↗
[Cutaneous larva migrans--an unusual case].
Cutaneous larva migrans is the result of human skin infestation by nematode larvae, which penetrate through the epidermis. The case of 21-year-old woman with serpiginous, erythematosus, and linear stripes was reported. The skin lesions lasted for five months. The diagnosis of cutaneous larva migrans was established based on the typical clinical picture of infestation. Thus, it is important for infestation to be recognized clinically, so that effective treatment may be instituted. Various therapeutic modalities, including cryotherapy, topical and systemic chemotherapy, can be used in the treatment of cutaneous larva migrans. It was demonstrated, that cryosurgery is a fast and effective method in the therapy of cutaneous larva migrans infestation.
Adult↗
Active lymphocytic myocarditis treated with murine OKT3 monoclonal antibody in a patient presenting with intractable ventricular tachycardia.
This report describes the case of a 33-year-old woman with biopsy-proven, active lymphocytic myocarditis manifested by intractable ventricular tachycardia, nonspecific intraventricular block, and myocardial dysfunction. We treated hersuccessfully with OKT3 monoclonal antibody and antiarrhythmic agents. Immunosuppression is not recommended in patients with infectious or postinfectious myocarditis. However, it may have an important role in autoimmune myocarditis. In the few reports in the medical literature that we were able to find, OKT3 monoclonal antibody was administered early in the setting of acute, fulminant autoimmune myocarditis. Our patient received OKT3 therapy in a later phase of the disease, when inflammatory infiltrates were accompanied by extensive fibrosis and severe damage of cardiomyocytes. Our patient had concomitant Helicobacter pylori infection and a strong positive family history of gastric cancer, a disease often associated with H. pylori. We discuss the possibility of a causal relationship between H. pylori infection and autoimmune myocarditis.
Adult↗
[Chemotherapy of advanced non-small cell lung cancer with the combination of gemcitabine and cisplatin].
The aim of the study was to assess the efficacy of a combination of gemcitabine and cisplatin in advanced non-small cell lung cancer. Twenty-five patients were included (13--IIIB, and 12--IV stage). Gemcitabine--1000 mg/m2 was given intravenously on days 1, 8, and 15, and cisplatin--100 mg/m2 on day 2. In 13 patients partial remission was obtained, in 8--stabilisation, and in 4--progression. Median survival was 12 months (range: 1.5-32 months). Mean time to progression was 6 months. Toxicity was tolerable and included mainly thrombocytopenia, neutropenia and anemia. In 11 patients pain relief was obtained. Furthermore cough, dyspnoea and hemoptysis disappeared in a proportion of patients. These results indicate the efficacy of the combination of gemcitabine and cisplatin regimen in advanced non-small cell lung cancer, and its acceptable toxicity.
Adult↗
Plasmin/alpha2-antiplasmin complexes (PAP) in lung cancer patients: effects of radiotherapy.
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Dose-Response Relationship, Radiation↗
[Yeast-like fungi as etiologic agents of blood infections in patients hospitalized in 1998-1999].
The aim of the study was the analysis of frequency of yeast-like fungi as etiological agents of fungemias in patients hospitalized in operative and conservative wards of Medical Academy Central Clinical Hospital in Warsaw in 1998-1999. Peripheral blood samples and collected from vascular catheters were incubated in BacT/Alert system(Organon Teknika, USA). Positive blood samples were inoculated on Sabouraud medium with chloramphenicol (bioMerieux, France) (the time of cultivation from 48 h to 7 days at 30 C) and on chromogenic medium BBL CHROMagar Candida (Becton Dickinson, USA). Fungal strains were identified by standard mycological procedures using ID 32 C strips (ATB system, bioMerieux, France) and tests of Sanofi Diagnostics Pasteur (France). The total number of positive blood cultures was 1724. Fifty eight fungal strains were isolated from blood samples (3.36%). Strains belonged to 4 genera: Candida (55), Trichosporon (1), Saccharomyces (1) and Pichia (1). Thirty eight fungal strains were isolated from peripheral blood samples. Forty seven fungal strains were cultured from patients hospitalized in operative wards. Among fungi isolated from peripheral blood samples C. albicans (10), C. glabrata (9) and C. parapsilosis (5) strains dominated. From blood samples collected from vascular catheters most often C. albicans (7), C. glabrata (4) and C. parapsilosis (3) were isolated.
Blood↗
[MELAS--mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome--two cases confirmed by biochemical and molecular investigations. Differential diagnosis of stroke causes].
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS) is a maternally inherited multisystem disease caused by mutations of the mitochondrial DNA. The characteristic clinical features are: encephalopathy manifesting as dementia and seizures, stroke-like episodes at young age (usually < 40), lactic acidosis and myopathy with ragged-red fibres. Other frequent manifestations include: sensorineural deafness, diabetes, hypoparathyroidism, peripheral neuropathy and cardiomyopathy. We present two patients with MELAS who were diagnosed 4 and 9 years respectively following the onset of the disease despite the characteristic clinical pictures. The differential diagnostics of inborn and acquired disorders causing stroke is included. We regard that mitochondrial diseases are still insufficiently known and are frequently misdiagnosed. The knowledge is indispensable for establishing diagnosis and accurate genetic counselling. Although there is no specific therapy for mitochondrial diseases to date, coenzyme Q and various vitamins as well as moderate degree exercise might be recommended.
Adolescent↗
Germline mutations in the BRCA1 gene predisposing to breast and ovarian cancers in Upper Silesia population.
Germline mutations in the BRCA1 or BRCA2 genes predispose their carriers to breast or/and ovary cancers during their lifetime. The most frequent mutations: 5382insC, 185delAG, C61G and 4153delA in BRCA1, and 6174delT and 9631delC in BRCA2 were studied in a group of 148 probands admitted for genetic counseling, using allele-specific amplification (ASA) PCR test. Fifteen carriers of three different mutations: 5382insC, 185delAG and C61G in BRCA1 were found. Two families carried the 185delAG mutation and additional two C61G in BRCA1. Nobody carried the mutation 4153delA in BRCA1 nor 6174delT or 9631delC in BRCA2. Most of the carriers of a germline mutation were observed among the patients who developed bilateral breast cancer (17%). The lowest frequency of the germline mutations was found in the healthy persons who had two or more relatives affected with breast or ovarian cancer.
Breast Neoplasms↗
The cGMP synthesis and PKG1 expression in murine lymphoid organs.
Numerous reports indicate that cyclic 3',5' guanosine monophosphate (cGMP) is involved in the regulation of immune processes. However, the mechanisms responsible for the synthesis of this nucleotide and its signaling pathways in immune cells are still not well recognized. The aim of our studies was to establish: 1) which form of guanylyl cyclase (GC) synthesizes cGMP in murine lymphoid organs and 2) whether the same organs express the isoforms PKG1alpha and/or PKG1beta of protein kinase G, known as possible target for synthesized cGMP. Cells isolated from thymus, lymph nodes, and spleen were treated with activators (SNP, ANP, CNP, STa) of soluble or particulate cyclases. Sodium nitroprusside (SNP) elevated intracellular cGMP 2-fold in thymic and lymph node cells and about 10-fold in spleen cells. Atrial natriuretic peptide (ANP) caused modest but statistically significant increases of cGMP in cells of all three organs. Additionally, spleen cells elevated their cGMP content about 2-fold in response to C-type natriuretic protein (CNP). In cellular homogenates of the all analyzed organs, the antibody anti-PKG1beta stained the 78 kDa band corresponding to the molecular mass of PKG1. Only homogenates of spleen cells were stained by the antibody recognizing PKG1alpha. Our results indicate that in the investigated organs cGMP may be synthesized mainly by soluble GC in response to nitric oxide. The modest increase of cGMP upon stimulation by ANP suggests that in all these organs either exists only a small subpopulation of cells that express particulate cyclase GC-A or GC-A is expressed at very low level. In spleen cells, however, cyclase GC-B appears to be the more active enzyme. Elevated cGMP concentration may in turn activate PKG1beta in thymus, lymph node, and spleen cells and also PKG1alpha in spleen cells.
Animals↗
KCNQ1 gene mutations and the respective genotype-phenotype correlations in the long QT syndrome.
KCNQ1 (formerly called KVLQT1) is a Shaker-like voltage-gated potassium channel gene responsible for the LQT1 sub-type of LQTS. In general, heterozygous mutations in KCNQ1 cause Romano-Ward syndrome (LQT1 only), while homozygous mutations cause JLNS (LQT1 and deafness). To date, more than 100 families with mutations in this gene have been reported, most with their own novel 'private' mutations. The majority of these mutations are missense. However, other types of mutations, such as deletions, frame-shifts and splice-donor errors have also been reported. There is one frequently reported mutated region (the 'hot-spot'). KCNQ1 is now believed to be the most commonly mutated gene in LQTS. The combination of normal and mutant KCNQ1 alpha-subunits has been found to form abnormal IKS channels, hence mutations associated with the KCNQ1 gene are also believed to act mainly through a dominant-negative mechanism (the mutant form interferes with the function of the normal wild-type form through a 'poison pill' type mechanism) or loss of function mechanism. Even in the case of carriers of the same mutation, it is currently unknown why there are significant clinical phenotype variations in LQT1 patients. This question could be answered by increasing the number of patient genotypes studied. LQT1 patients experience a majority of their cardiac events (62%) during exercise, and only 3% occur during rest or sleep. Of the patients who experienced cardiac events while swimming, 99% were LQT1. Auditory stimuli are rare and occur in only 2% of patients. However, both lethal and non-lethal events follow the same pattern.
Electrocardiography↗
[The erythrocyte sodium-proton exchanger activity in patient with primary hypertension].
A sodium-proton exchanger (NHE) is a membrane transport system taking part in intracellular sodium homeostasis. An increased NHE activity was observed in erythrocytes of primary hypertension (NTP) patients. Study group consisted of 25 NTP patients and 24 control (K). NTP patients were significantly heavier (p < 0.01) than control group (BMI 26.0 +/- 2.9 vs. 23.1 +/- 2.7, respectively). They also had significantly higher systolic, diastolic and mean arterial pressure than K (SBP 167 +/- 24.6 vs. 120 +/- 10.5; DBP 98 +/- 16.7 vs. 76 +/- 6.4; MAP 118.6 +/- 17.9 vs. 89 +/- 6.4, respectively). There was positive correlation between MAP and BMI (p < 0.02) in NTP patients. Mean NHE activity was significantly higher in NTP than in K group (9.6 +/- 3.6 vs. 8.2 +/- 2.6 mmol/L RBC/h) p = 0.05. A bimodal distribution of NHE activity in NTP group was observed. There was no correlation between NHE activity and BMI, MAP, SBP, DBP, age or positive family history of hypertension in NTP or K groups.
Adult↗
Diversity of clinical symptoms in A3243G mitochondrial DNA mutation (MELAS syndrome mutation).
BACKGROUND: MELAS (mitochondrial myopathy, lactic acidosis and stroke-like episodes) is one of the most common mitochondrial encephalomyopathies. MATERIAL/METHODS: We present four children with A3243G MELAS mtDNA mutation and give a summary of clinical MELAS symptoms reported in the literature. Serum lactate elevation, mosaic pattern of COX deficit and decreased activity of complex I and IV in the muscle biopsy were found in all cases. RRFs were recognized in three out of four. RESULTS: The main features seen in all our patients were poor growth and fatigability with muscle weakness. All presented epileptic jerks of various character, some deformation features (recurrent pretibial and peritarsal edema, large swollen-looking hands and feet, hypertelorism and protruding ears) and some cutaneous lesions (atopic dermatitis, local melanoderma, asymmetric vascular dilatation). Stroke-like episodes, multihormonal hypopituitarism, sensorineural hypoacusis, pigmentary retinal degeneration, intracranial calcification, heart involvement, recurrent vomiting or abdominal pain were seen only in individual cases. The homonymous hemianopia frequently reported in the literature was not a feature of our patients. One of them suffered from nonspecific sialoadenitis never mentioned in the literature. CONCLUSIONS: Morphological, enzymatic and molecular investigations of a muscle biopsy sample should be undertaken to improve early MELAS detection in patients with any multiorgan disease associated with serum lactate elevation.
Age of Onset↗
[Pyoderma gangrenosum--positive effect of cyclosporin A therapy ].
Although pyoderma gangrenosum is a disorder known since over 70 years, it still remains a diagnostic and therapeutic problem. We describe three subjects with pyoderma gangrenosum; two were females, one was male, one case was associated with colitis ulcerosa, two were without any related disorders. Histopathologic examinations supported the diagnosis in all cases. In spite of intensive topical and systemic treatment with corticosteroids, Dapsone, Clofazimine, no sufficient effects were achieved. Cyclosporin A introduced in the dose of 5 mg/kg/d resulted in dramatic response and complete remission. Serum CyA levels, biochemical parameters of liver and kidney function, blood pressure were monitored during the therapy. No adverse events due to Cyclosporin A were observed.
Administration, Topical↗