Hypercalcaemia with radiographic abnormalities in chronic myeloid leukaemia.
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Female↗
Biomedical subjects
S Varma
Publications and source records attributed to S Varma.
Fatal non-bacterial thrombotic endocarditis following viperine bite.
Non-bacterial thrombotic endocarditis (NBTE) commonly occurs in patients with wasting disease (e.g. malignancy) or with valves damaged following trauma due to intra-cardiac foreign body, scarring or marked turbulence. Although disseminated intravascular coagulation (DIC) is well documented following viperine bite and the underlying mechanism of NBTE is thought to be DIC, there is no report of NBTE in humans following snake bite. We report a young male who following viperine bite developed local swelling, superficial gangrene of tissues at the site of bite, and oliguria and died following multiple cerebral infarcts and acute renal failure. The post-mortem examination showed NBTE of the aortic valve, multiple embolic infarcts of brain, spleen and kidneys, acute tubular necrosis and features of DIC in the brain in the form of fibrin thrombi in the capillaries, perivascular hemorrhages and necrosis.
Adult↗
Hepatosplenic tuberculosis: a cause of persistent fever during recovery from prolonged neutropenia.
SETTING: Hepatosplenic abscesses in neutropenic patients, especially during the recovery phase, are almost always attributed to fungal infections. We report similar lesions due to Mycobacterium tuberculosis in neutropenic patients in a tertiary care centre in India. OBJECTIVE: To characterize the features of hepatosplenic tuberculosis in neutropenic patients. DESIGN: Retrospective comparison of disease pattern and response to treatment of hepatosplenic tuberculosis in febrile neutropenia patients (four of 30 with severe prolonged neutropenia) and in non neutropenic patients diagnosed during the same 12-month period (n = 4, control group). RESULTS: The disease in the neutropenic patients typically presented during the recovery phase of neutropenia, with ultrasonic abnormalities similar to those seen in hepatosplenic fungal infections. In contrast to the marked organomegaly and typical granulomatous response found in the control group, the disease in the neutropenic patients was characterised by an absence of organomegaly, non-involvement of other sites, poor inflammatory response and a high bacillary load. The initial response to therapy was satisfactory in both groups. CONCLUSION: Tuberculosis needs to be considered in the diagnostic work-up of hepatosplenic abscesses that occur during the recovery phase of neutropenia.
Abscess↗
In vivo determination of RNA structure-function relationships: analysis of the 790 loop in ribosomal RNA.
The 790 loop is a conserved hairpin located between positions 786 and 796 of Escherichia coli 16 S rRNA that is required for ribosome function. Using a novel genetic approach, all positions in the loop were simultaneously mutated and functional mutant sequences were selected in vivo. This "instant evolution" experiment revealed that approximately 190 of the 262,144 possible mutant sequences were functional. Analysis of functional mutant sequences allowed discrimination between nucleotides directly involved in protein synthesis and those involved primarily in loop structure. Among the functional mutant sequences, positions 789 and 791 were invariant and extensive covariation was observed among the nucleotides at the base of the loop at positions 787, 788, 794 and 795. NMR and thermodynamic analyses of model 790 hairpins in vitro revealed weak pairing interactions between positions 787 and 795 and between positions 788 and 794 consistent with the in vivo mutational analysis. Functional analysis of site-directed mutants containing all possible nucleotide combinations at positions 787 and 795 in vivo showed that stable base-pairs at these positions prevent subunit association.
Chloramphenicol↗
Patients from coronary care units should be given their electrocardiograms and carry them at all times.
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Coronary Care Units↗
Co-transactivation of the 3' erythropoietin hypoxia inducible enhancer by the HIF-1 protein.
Erythropoietin (Epo) is a glycoprotein hormone that is the primary regulator of red blood cell production. Epo production increases in response to tissue hypoxia. This increase occurs primarily at the transcriptional level. Hypoxia inducible factor (HIF-1) is a DNA binding protein that binds to a hypoxia inducible enhancer in the 3' flanking sequence of the Epo gene. HIF-1 is a heterodimer that consists of an alpha and beta subunit. HIF-1 DNA binding activity is induced in response to hypoxia. In order to determine if one or both HIF-1 subunits is capable of ligand binding, subsequently leading to Epo production we performed co-transactivation experiments. Transfections were performed in Hep 3B, an Epo producing human hepatoma cell line and Cos-7, a non-Epo producing monkey kidney cell line. Cells were co-transfected with the 38 bp Epo enhancer fragment bearing the HIF-1 binding motif, subcloned in the luciferase reporter plasmid and either the HIF-1alpha cDNA, HIF-1beta cDNA, HIF-1alpha and HIF-1beta cDNAs or pREP-4 respectively. Cells were incubated in an hypoxic (1%O2) or normoxic (21%O2) environment and assayed for luciferase activity. Epo levels were measured in the culture media from the transfected plates by an ELISA assay. Under hypoxic conditions Hep 3B cells transfected with the HIF-1alpha cDNA alone showed a 2.2 fold increase in luciferase activity, HIF-1beta showed a 3.4 fold increase and cells transfected with HIF-1 alpha and beta showed a 6. 9 fold increase in activity over cells transfected with pREP-4. The baseline luciferase activity in transfected 3B cells incubated in normoxia was very low. However, a similar fold increase in luciferase activity in cells transfected with both HIF-1alpha and beta was noted. Under normoxic or hypoxic conditions in Cos-7 cells, a 1.5 fold increase was obtained with the HIF-1alpha and beta constructs transfected independently and a 3.5 fold increase was noted in cells transfected with both constructs. Epo levels increased several fold in all Hep 3B cells that were incubated in hypoxic conditions. However, there was no additional increase in Epo levels in transfected Hep 3B cells. We therefore conclude that although the HIF-1alpha and beta subunits can independently co-transactivate the Epo enhancer, binding of both subunits and a hypoxic environment is necessary for maximal transactivation. Overexpression of the HIF-1 protein alone in normoxic or hypoxic conditions is insufficient for an increase in Epo secretion. Activation/inactivation and interaction of other tissue specific factors is necessary for an increase in Epo gene expression in response to hypoxia.
Cell Hypoxia↗
Del (X)(p21.2) in a mother and two daughters with variable ovarian function.
We report a family in which a woman with the mosaic karyotype 45,X/46,X,del(X)(p21.2) transmitted the deleted X chromosome to two daughters. The nature of the deletion was confirmed by fluorescent in situ hybridization (FISH). All three family members showed somatic Ullrich-Turner syndrome features, but only one daughter had ovarian failure. These observations have implications for the diagnosis of Ullrich-Turner syndrome and genotype/phenotype correlations of X chromosome deletions.
Abnormalities, Multiple↗
Experiences in religious psychotherapy.
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Cultural Diversity↗
High-dose methyl prednisolone for autoimmune thrombocytopenia in sarcoidosis.
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Adult↗
Histological and clinical evolution patterns of chronic myelocytic leukemia.
Trephine biopsies of 101 chronic myelocytic leukaemia (CML) patients were analysed to study the relationship between initial and subsequent histological features vis-a-vis clinical behaviour of the disease. The patients with blast crisis at presentation were excluded. At diagnosis 62 (61.4%) patients revealed granulocytic-megakaryocytic (gran-meg) proliferation whereas granulocytic (gran) proliferation was found in 39 (38.6%) patients. Gran pattern at diagnosis was associated with shorter survival and early evolution into blast crisis (36.8%) in 12 months, although the difference in the total incidence of blast crisis between the two histological groups was not statistically significant. Myelofibrosis was detected in more number of cases on follow up (89.1%) as compared to the initial biopsies (80.2%). However myelofibrosis did not correlate with initial cellular composition, overall survival or the phase of CML (P > 0.05). Transition from one histological type to another was observed in 15 out of 60 (25%) cases while remaining in the chronic phase.
Biopsy, Needle↗
Sterol dependent LDL-receptor gene transcription in lymphocytes from normal and CML patients.
Sterol regulatory element (SRE) has been recognized to regulate various key genes coding for especially low density lipoprotein (LDL)-receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and HMG-CoA synthase known to play a crucial role in the cholesterol feedback mechanism. The deranged cholesterol feedback mechanism has been widely recognised in initiation as well as progression of various types of cancers including chronic myeloid leukaemia (CML). Consequently, the present study was addressed to understand this phenomenon and revealed the existence of a unique 47 kDa protein factor having affinity for this SRE sequence in lymphocytes from normal subjects as well as its absence in lymphocytes from untreated CML patients. However, this factor appeared when the CML patients achieved complete haematological remission (CHR) through alpha-interferon therapy. Further, an inverse relationship was also observed between sterol modulated LDL-receptor gene transcription and the binding affinity of this 47 kDa factor to the SRE sequence. Based upon these results we propose that alpha-interferon through its receptor initiates phosphatidic acid dependent signalling which in turn regulates the affinity of 47 kDa sterol regulatory element binding factor as well as LDL-receptor gene transcription in lymphocytes from CML patients.
Bucladesine↗
Motivation for tattoo removal.
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Adolescent↗
Co-expression of two FAB-specific chromosome changes, t(15;17) and t(8;21), in a case of acute promyelocytic leukemia.
We describe a case of acute promyelocytic leukemia ANLL-M3 with association of t(15;17) and t(8;21) and various chromosomal aberrations. Clinically, immunologically, and morphologically, our patient fits the diagnosis of typical ANLL-M3. The co-existence of two specific FAB chromosomal translocations in a single leukemic clone is rare. The rarity of this association enhances the significance of this report.
Adult↗
Lymphocytes from CML patients lack a 47 kDa factor having affinity for a genomic sterol regulatory sequence.
Deranged cellular cholesterol homeostasis has been widely recognized in the initiation as well as progression of various types of cancers including chronic myeloid leukaemia (CML). Since the human genomic sterol regulatory element (SRE) has been shown to regulate various key genes involved in this phenomenon, the present study revealed the existence of a unique 47 kDa protein factor having affinity for this SRE sequence in lymphocytes from normal subjects, as well as its absence in lymphocytes from untreated CML patients. However, this factor appeared when these CML patients achieved complete haematological remission (CHR) through alpha-interferon therapy. Furthermore, an inverse relationship was also observed between the LDL receptor gene expression at the transcriptional level and the binding affinity of this 47 kDa protein factor to the SRE sequence. Based upon these results we propose that this factor may have a role in pathophysiology of chronic myeloid leukaemia.
Antineoplastic Agents↗
Quantification of PML-RAR alpha transcripts in acute promyelocytic leukaemia: explanation for the lack of sensitivity of RT-PCR for the detection of minimal residual disease and induction of the leukaemia-specific mRNA by alpha interferon.
The RT-PCR technique for the identification of the PML-RAR alpha fusion mRNA is widely used for the detection of minimal residual in acute promyelocytic leukaemia (APL). A positive result after remission induction is highly predictive of early relapse, but the vast majority of patients have no detectable disease by this technique after chemotherapy consolidation, despite the fact that many later relapse. We report a quantitative PCR technique for the PML-RAR alpha cDNA which was used to show that less than 1000 PML-RAR alpha molecules are obtained from 1 microgram of diagnostic bone marrow RNA derived from approximately 1 million APL blasts. The lack of sensitivity of currently employed RT-PCR methods may therefore be explained by their poor yield of PML-RAR alpha cDNA. Minor modifications to the reverse transcription procedure improved this yield 3 fold. Furthermore, expression of the leukaemia-specific transcript increased by approximately one order of magnitude after incubation of the patient's cells for 24 h in vitro with 100 iu/ml alpha interferon.
DNA, Neoplasm↗
Delayed diagnosis of psychological erectile dysfunction because of the presence of macroprolactinemia.
Idiopathic hyperprolactinemia can be found in men with either normal or low serum testosterone (T) levels. The explanation for the differing effects on T of similar PRL levels has not been found. Macroprolactinemia, as a clinical entity, has been reported mostly in women. These macromolecules are biologically less active and/or are transported less easily across the capillary bed than the 22-kDa molecules. Therefore, women with elevated PRL levels retain normal menses and fertility. We studied six men, aged 28-53 yr (mean, 45 yr), in whom hyperprolactinemia was initially considered to be the cause of their erectile dysfunction. PRL levels ranged from 25-92 ng/mL (normal, 2-15 ng/mL), but T and gonadotropin levels were normal, suggesting that PRL was not disrupting gonadotropin and gonadal steroid function. The results of magnetic resonance imaging studies of the pituitary gland were normal. Separation by Sephadex G-100 column chromatography showed a predominance (85-90%) of big (60 kDa) and big big ( > 150 kDa) PRL, in contrast to the predominance of 22-kDa PRL in normal subjects. Nocturnal tumescence testing was normal, supporting the diagnosis of psychogenic impotence in these subjects, and potency returned after counseling. Hence, the biologically inactive macroprolactinemia did not cause any organic derangement in erectile function. It further obscured and delayed the appropriate diagnosis and treatment of these individuals.
Adult↗
Growth hormone synthesized and secreted by human thymocytes acts via insulin-like growth factor I as an autocrine and paracrine growth factor.
There is increasing evidence that GH can influence immune function and that it is secreted by lymphocytes. In the present study we investigated the endogenous synthesis and secretion of GH and insulin-like growth factor I (IGF-I) from human thymocytes and evaluated the autocrine/paracrine effects of GH and IGF-I on T cell and thymic epithelial cell proliferation. First, the presence of thymic GH and IGF-I was detected by RIA of thymocyte extracts. Next, using a hormonal enzyme-linked immunoplaque assay, we found that thymocytes secreted GH and IGF-I. Further, we documented the endogenous synthesis of GH by human thymocytes using [35S]methionine labeling followed by immunoprecipitation, gel electrophoresis, and autoradiography. We then evaluated the physiological role of endogenously generated GH and IGF-I. Using an affinity-purified-GH polyclonal antibody, we observed a marked inhibition (P < 0.04) of phytohemagglutinin-stimulated thymocyte proliferation, suggesting an autocrine/paracrine role for the secreted GH. Further, we observed significant (P < 0.001) increases in thymocyte proliferation in cultures stimulated with varying doses of GH and IGF-I. Also, conditioned medium of human thymocytes (1 x 10(5) cells) stimulated with GH for 48 h contained a significant (P < 0.001) amount of IGF-I. Thymocyte proliferation stimulated by GH was significantly (P < 0.01) inhibited by monoclonal as well as polyclonal human IGF-I antisera. Finally, we studied the paracrine effect of thymocyte-secreted GH on human primary thymic epithelial cell (TEC) cultures. A significant (P < 0.05) increase in [3H]thymidine uptake in TEC cultures after GH addition was observed, which was abolished by GH antiserum. Polyclonal and monoclonal IGF-I antisera significantly (P < 0.05) inhibited GH-stimulated TEC proliferation. In summary, human thymocytes synthesize and secrete GH and IGF-I. Further, GH functions as an autocrine/paracrine growth factor in the human thymus via locally synthesized IGF-I.
Blotting, Western↗
Alteration of peripheral blood lymphocyte subsets in essential hypertension.
OBJECTIVE: To assess lymphocytic subpopulation by labelled monoclonal antibody technique in a small group of patients with untreated essential hypertension (EH) and to detect any alteration with control of blood pressure. DESIGN: Prospective study with phenotypic estimation of lymphocytes at presentation and a minimum of two weeks after the control of blood pressure. SETTING: Referral, tertiary care hospital. PATIENTS: Group 1, normotensive controls (n = 10); group 2, mild to moderate essential hypertension (n = 10); group 3, severe (accelerated/malignant) hypertension (n = 10). All the secondary causes of hypertension were ruled out by a thorough history, physical examination and appropriate radiological and biochemical investigations. TESTS: Venous blood samples, taken at entry and a minimum of two weeks after control of blood pressure, were analyzed by alkaline phosphatase antialkaline phosphatase (APAAP) antibody technique for CD4, CD3, CD8 and CD22. Peripheral lymphocytes were separated and cocultured with phytohemagglutinin (PHA) for 72 h and assayed for CD25 by the APAAP technique. MAIN RESULTS: In untreated patients with EH (groups 2 and 3), there was a significant down regulation of CD3, and CD4 lymphocytes whereas the proportion of mature CD22 cells increased. In group 3 there was a significant down regulation of CD25 with PHA stimulation. A negative correlation was observed between CD25 and diastolic pressure upon pooling the results of groups 2 and 3. No significant alteration in these parameters was observed following control of blood pressure with drugs for up to two weeks. CONCLUSION: In this small group of patients with untreated EH, a significant alteration in the lymphocytic repertoire was observed. Whether this will be found in large groups of hypertensives remains to be seen.
Adult↗