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R Sood

Publications and source records attributed to R Sood.

At least 37 records · Page 2Linked to original sources
PubMed2000

A 6-Mb high-resolution physical and transcription map encompassing the hereditary prostate cancer 1 (HPC1) region.

Several hereditary disease loci have been genetically mapped to the chromosome 1q24-q31 interval, including the hereditary prostate cancer 1 (HPC1) locus. Here, we report the construction of a 20-Mb yeast artificial chromosome contig and a high-resolution 6-Mb sequence-ready bacterial artificial chromosome (BAC)/P1-derived artificial chromosome (PAC) contig of 1q25 by sequence and computational analysis, STS content mapping, and chromosome walking. One hundred thirty-six new STSs, including 10 novel simple sequence repeat polymorphisms that are being used for genetic refinement of multiple disease loci, have been generated from this contig and are shown to map to the 1q25 interval. The integrity of the 6-Mb BAC/PAC contig has been confirmed by restriction fingerprinting, and this contig is being used as a template for human chromosome 1 genome sequencing. A transcription mapping effort has resulted in the precise localization of 18 known genes and 31 ESTs by database searching, exon trapping, direct cDNA hybridization, and sample sequencing of BACs from the 1q25 contig. An additional 11 known genes and ESTs have been placed within the larger 1q24-q31 interval. These transcription units represent candidate genes for multiple hereditary diseases, including HPC1.

Base Sequence↗
PubMed2000

Isolation and characterization of the human homeobox gene HOX D1.

Homeobox genes, first identified in Drosophila, encode transcription factors that regulate embryonic development along the anteroposterior axis of an organism. Vertebrate homeobox genes are described on the basis of their homology to the genes found within the Drosophila Antennapedia and Bithorax homeotic gene complexes. Mammals possess four paralogous homeobox (HOX) gene clusters, HOX A, HOX B, HOX C and HOX D, each located on different chromosomes, consisting of 9 to 11 genes arranged in tandem. We report the characterization of the human HOX D1 gene. This gene consists of two exons, encoding a 328 amino acid protein, separated by an intron of 354 bp. The human HOX D1 protein is one amino acid longer (328 amino acids) than the mouse protein (327 amino acids) and is 82% identical to the mouse HOX D1 homolog. The DNA binding homeodomain region of the human protein exhibits a 97% and 80% identity between mouse Hoxd1 and Drosophila labial homeodomains, respectively. The exon/intron and intron/exon splice junctions are conserved in position between human and mouse genes. Determination of the human HOX D1 gene structure permits the use of PCR based analysis of this gene for the assessment of mutations, for diseases that link to the HOXD cluster (such as Duanes Retraction Syndrome (DRS)), or polymorphisms associated with human variation. Molecular characterization of the HOXD1 gene may also permit analysis of the functional role of this gene in human neurogenisis.

Amino Acid Sequence↗
PubMed2000

Hepatitis B, C and human immunodeficiency virus infections in multiply-injected kala-azar patients in Delhi.

Sera from 164 patients with parasitologically confirmed kala-azar and 100 patients with non-kala-azar Delhite in 2 Delhi hospitals were tested for anti-human immunodeficiency (anti-HIV) and anti-hepatitis C virus (anti-HCV) antibodies and hepatitis B surface antigens to determine which group is more likely to contract these infections. The mean age of the patients was 32.5 y (+/-6.5 y), (120 M, 44 F). Two patients were from Nepal and the others from the kala-azar endemic state of Bihar, India. As geographical controls, 50 serum samples from sex- and age-matched healthy Bihar residents were also tested for the blood-borne viral infections. All patients had been treated with injectable medicines by 1 or more local physicians before they were referred to the Delhi hospitals. The prevalence of hepatitis B virus (HBV) and HCV infection was significantly different between the 2 patient groups. While 2 kala-azar patients (1.21%) were found to be HIV-1 positive, 54 (32.9%) patients had anti-HCV antibodies detected by ELISA and 51 (31.1%) by RIBA test. The seroprevalence of HCV was only 2% in hospitalized non-kala-azar cases and 4% in the geographical controls (p < 0.001). The seroprevalence of HBV was 13.2% in hospitalized kala-azar cases, but only 1.75% in disease control cases and 1.6% in geographical control cases. The difference in infection rates between cases and controls was significant (p < 0.001). The results indicate that kala-azar patients treated locally in Bihar have a greater chance of contracting blood-borne infections. Interestingly, we found that HCV was more prevalent than HBV. These infections were most likely acquired through the re-use of needles by local medical and paramedical practitioners for administering anti-leishmanial drugs. This trend, if not checked immediately, may have drastic consequences in the horizontal transmission of HIV in Bihar.

Adolescent↗
PubMed2000

A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2alpha.

A family of protein kinases regulates translation in response to different cellular stresses by phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF-2alpha). In yeast, an eIF-2alpha kinase, GCN2, functions in translational control in response to amino acid starvation. It is thought that uncharged tRNA that accumulates during amino acid limitation binds to sequences in GCN2 homologous to histidyl-tRNA synthetase (HisRS) enzymes, leading to enhanced kinase catalytic activity. Given that starvation for amino acids also stimulates phosphorylation of eIF-2alpha in mammalian cells, we searched for and identified a GCN2 homologue in mice. We cloned three different cDNAs encoding mouse GCN2 isoforms, derived from a single gene, that vary in their amino-terminal sequences. Like their yeast counterpart, the mouse GCN2 isoforms contain HisRS-related sequences juxtaposed to the kinase catalytic domain. While GCN2 mRNA was found in all mouse tissues examined, the isoforms appear to be differentially expressed. Mouse GCN2 expressed in yeast was found to inhibit growth by hyperphosphorylation of eIF-2alpha, requiring both the kinase catalytic domain and the HisRS-related sequences. Additionally, lysates prepared from yeast expressing mGCN2 were found to phosphorylate recombinant eIF-2alpha substrate. Mouse GCN2 activity in both the in vivo and in vitro assays required the presence of serine-51, the known regulatory phosphorylation site in eIF-2alpha. Together, our studies identify a new mammalian eIF-2alpha kinase, GCN2, that can mediate translational control.

Amino Acid Sequence↗
PubMed1999

Modulation of TEL transcription activity by interaction with the ubiquitin-conjugating enzyme UBC9.

The E-26 transforming specific (ETS)-related gene TEL, also known as ETV6, is involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. The encoded protein contains two functional domains: a helix-loop-helix (HLH) domain (also known as pointed domain) located at the N terminus and a DNA-binding domain located at the C terminus. The HLH domain is involved in protein-protein interaction with itself and other members of the ETS family of transcription factors such as FLI1. TEL is a transcription factor, and we and others have shown that it is a repressor of gene expression. To understand further the role of TEL in the cell, we have used an in vivo interaction system to identify proteins that interact with TEL. We show that a protein, UBC9, interacts specifically with TEL in vitro and in vivo. UBC9 is a member of the family of ubiquitin-conjugating enzymes. These enzymes usually are involved in proteosome-mediated degradation; however, our data suggest that interaction of TEL with UBC9 does not lead to TEL degradation. Our studies show that UBC9 binds to TEL exclusively through the HLH domain of TEL. We also show that TEL expressed as fusion to the DNA-binding domain of Gal4 completely represses a Gal4-responsive promoter, but that the coexpression of UBC9 in the same system restores the activity of the promoter. Targeted point mutation of conserved amino acids in UBC9 essential for enzymatic ubiquitination of proteins does not affect interaction nor transcriptional activity. Based on our data, we conclude that UBC9 physically interacts with TEL through the HLH domain and that the interaction leads to modulation of the transcription activity of TEL.

DNA-Binding Proteins↗
PubMed1999

Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial.

CONTEXT: Insomnia is a prevalent health complaint in older adults. Behavioral and pharmacological treatments have their benefits and limitations, but no placebo-controlled study has compared their separate and combined effects for late-life insomnia. OBJECTIVE: To evaluate the clinical efficacy of behavioral and pharmacological therapies, singly and combined, for late-life insomnia. DESIGN AND SETTING: Randomized, placebo-controlled clinical trial, at a single academic medical center. Outpatient treatment lasted 8 weeks with follow-ups conducted at 3, 12, and 24 months. SUBJECTS: Seventy-eight adults (50 women, 28 men; mean age, 65 years) with chronic and primary insomnia. INTERVENTIONS: Cognitive-behavior therapy (stimulus control, sleep restriction, sleep hygiene, and cognitive therapy) (n = 18), pharmacotherapy (temazepam) (n = 20), or both (n = 20) compared with placebo (n = 20). MAIN OUTCOME MEASURES: Time awake after sleep onset and sleep efficiency as measured by sleep diaries and polysomnography; clinical ratings from subjects, significant others, and clinicians. RESULTS: The 3 active treatments were more effective than placebo at posttreatment assessment; there was a trend for the combined approach to improve sleep more than either of its 2 single components (shorter time awake after sleep onset by sleep diary and polysomnography). For example, the percentage reductions of time awake after sleep onset was highest for the combined condition (63.5%), followed by cognitive-behavior therapy (55%), pharmacotherapy (46.5%), and placebo (16.9%). Subjects treated with behavior therapy sustained their clinical gains at follow-up, whereas those treated with drug therapy alone did not. Long-term outcome of the combined intervention was more variable. Behavioral treatment, singly or combined, was rated by subjects, significant others, and clinicians as more effective than drug therapy alone. Subjects were also more satisfied with the behavioral approach. CONCLUSIONS: Behavioral and pharmacological approaches are effective for the short-term management of insomnia in late life; sleep improvements are better sustained over time with behavioral treatment.

Aged↗
PubMed1999

Identification and characterization of a zinc finger gene (ZNF213) from 16p13.3.

During our search for the familial Mediterranean fever (FMF) gene, we identified by cDNA selection a 1.2 kb cDNA fragment representing a novel human gene that is expressed in a wide variety of tissues. This gene spans approx. 8.0 kb genomic DNA and has seven exons. Its 3' untranslated region contains a long tandem repeat that gives rise to a polymorphism with two alleles of approx. 1.1 kb and 1.0 kb, with the 1.1 kb allele in strong linkage disequilibrium with FMF in patients of different ethnic backgrounds. However, both genetic and mutational analyses have excluded this gene as the one responsible for FMF. The predicted 424 amino acid protein, designated ZNF213, contains three C2H2 zinc fingers, a Kruppel associated A box and a leucine rich motif (LeR domain/SCAN box), strongly suggestive of a transcription factor.

Amino Acid Sequence↗
PubMed1999

Placenta percreta invading the bladder causing exsanguinating hemorrhage.

We report a case of placenta percreta invading the urinary bladder that presented as gross hematuria. The patient had normal cystoscopic findings initially and other radiological investigations were reported as normal. However, she had catastrophic second hemorrhage and in spite of bilateral internal iliac artery ligation, hysterectomy and bladder closure with resuscitative measures, she could not be saved.

Adult↗
PubMed1999

CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

Altered growth and function of synoviocytes, the intimal cells which line joint cavities and tendon sheaths, occur in a number of skeletal diseases. Hyperplasia of synoviocytes is found in both rheumatoid arthritis and osteoarthritis, despite differences in the underlying aetiologies of the two disorders. We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to synoviocyte hyperplasia, the principal pathological feature of this syndrome. Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP. The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor' and 'superficial zone protein', contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins. In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium. The similarity of CACP sequence to that of other protein families and the expression of CACP in non-skeletal tissues suggest it may have diverse biological activities.

Amino Acid Sequence↗
PubMed1999

MDS1/EVI1 enhances TGF-beta1 signaling and strengthens its growth-inhibitory effect but the leukemia-associated fusion protein AML1/MDS1/EVI1, product of the t(3;21), abrogates growth-inhibition in response to TGF-beta1.

MDS1/EVI1, located on chromosome 3 band q26, encodes a zinc-finger DNA-binding transcription activator not detected in normal hematopoietic cells but expressed in several normal tissues. MDS1/EVI1 is inappropriately activated in myeloid leukemias following chromosomal rearrangements involving band 3q26. The rearrangements lead either to gene truncation, and to expression of the transcription repressor EVI1, as seen in the t(3;3)(q21;q26) and inv(3)(q21q26), or to gene fusion, as seen in the t(3;21)(q26;q22) which results in the fusion protein AML1/MDS1/EVI1. This fusion protein contains the DNA-binding domain of the transcription factor AML1 fused in-frame to the entire MDS1/EVI1 with the exclusion of its first 12 amino acids. In this report, we have analyzed the response of the hematopoietic precursor cell line 32Dcl3, expressing either the normal protein MDS1/EVI1 or the fusion protein AML1/MDS1/EVI1, to factors that control cell differentiation or cell replication. The 32Dcl3 cells are IL-3-dependent for growth and they differentiate into granulocytes when exposed to G-CSF. They are growth-inhibited by TGF-beta1. We show that whereas the expression of MDS1/EVI1 has no effect on granulocytic differentiation induced by G-CSF, expression of AML1/MDS1/EVI1 blocks differentiation resulting in cell death. This effect is similar to that previously described by others for 32Dcl3 cells that express transgenic Evil. Furthermore, we show that whereas the expression of the fusion protein AML1/MDS1/EVI1 completely abrogates the growth-inhibitory effect of TGF-beta1 and allows 32Dcl3 cells to proliferate, expression of the normal protein MDS1/EVI1 has the opposite effect, and it strengthens the response of cells to the growth-inhibitory effect of TGF-beta1. By using the yeast two-hybrid system, we also show that EVI1 (contained in its entirety in MDS1/EVI1 and AML1/MDS1/EVI1) physically interacts with SMAD3, which is an intracellular mediator of TGF-beta1 signaling. Finally, we have correlated the response of the cells to G-CSF or TGF-beta1 with the ability of the normal and fusion proteins to activate or repress promoters which they can directly regulate by binding to the promoter site. We propose that mutations of MDS1/EVI1 either by gene truncation resulting in the transcription repressor EVI1 or by gene fusion to AML1 lead to an altered cellular response to growth and differentiation factors that could result in leukemic transformation. The different response of myeloid cells ectopically expressing the normal or the fusion protein to G-CSF and TGF-beta1 could depend on the different transactivation properties of these proteins resulting in divergent expression of downstream genes regulated by the two proteins.

Cell Differentiation↗
PubMed1999

Forced expression of the leukemia-associated gene EVI1 in ES cells: a model for myeloid leukemia with 3q26 rearrangements.

Chromosome band 3q26 is the locus of two genes, MDS1/EVI1 and EVI1. The proteins encoded by these genes are nuclear factors each containing two separate DNA-binding zinc finger domains. The proteins are identical, aside from the N-terminal extension of MDS1/EVI1, which is missing in EVI1. However, they have opposite functions as transcription factors. In contrast to MDS1/EVI1, EVI1 is often activated inappropriately by chromosomal rearrangements at 3q26 leading to inappropriate expression of the protein in hematopoietic cells and to myeloid leukemias, which are often characterized by abnormal megakaryopoiesis. We previously showed that the two proteins affect replication and differentiation of progenitor hematopoietic cell lines in opposite ways: whereas EVI1 inhibits the response of 32Dc13 cells to G-CSF and TGFbeta1, MDS1/EVI1 has no effect on the G-CSF-induced differentiation of the 32Dc13 cells, and it enhances the growth-inhibitory effect of TGFbeta1. In the present study, we analyzed the endogenous expression of the two genes during in vitro hematopoietic differentiation of murine embryonic stem (ES) cells and evaluated the effects of their forced expression on the ability of ES cells to produce differentiated hematopoietic colonies. We found that the expression of the two genes is independently and tightly controlled during differentiation. In addition, the forced expression of EVI1 led to a much higher rate of cell growth before and during differentiation, whereas the expression of MDS1/EVI1 repressed cell growth and strongly reduced the number of differentiated hematopoietic colonies. Finally, our study also found that the forced expression of EVI1 resulted in the differentiation of abnormally high numbers of megakaryocytic colonies, thus providing one of the first experimental models showing a clear correlation between inappropriate expression of EVI1 and abnormalities in megakaryopoiesis.

Animals↗
PubMed1999

An efficient, short synthesis and potent anti-hepatitis B viral activity of a novel ring-expanded purine nucleoside analogue containing a 5:7-fused, planar, aromatic, imidazo[4,5-e][1,3]diazepine ring system.

An efficient, short synthesis of a ring-expanded nucleoside analogue containing a novel 5:7-fused, planar, and potentially aromatic imidazo[4,5-e][1,3]diazepine heterocyclic ring system is reported. The target compound, 6-amino-8-hydroxy-4H-1-beta-D- ribofuranosylimidazo[4,5-e][1,3]diazepin-4-one (2) was synthesized in a single step in > or = 90% yield by condensation of guanidine with either methyl 1-beta-D-ribofuranosylimidazole-4,5- dicarboxylate(1a) or its 2',3',5'-tri-O-benzoyl derivative (1b). Compound 2 showed potent anti-hepatitis B virus (anti-HBV) activity with an EC50 value of 0.17 microM in the transfected hepatoma cell line 2.2.15, and a low cellular toxicity with a CC50 value of 2.4 mM (TI > 14,000).

Antiviral Agents↗
PubMed1999

Localization of a gene for Duane retraction syndrome to chromosome 2q31.

Duane retraction syndrome (DRS) is a congenital eye-movement disorder characterized by a failure of cranial nerve VI (the abducens nerve) to develop normally, resulting in restriction or absence of abduction, restricted adduction, and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. DRS has a prevalence of approximately 0.1% in the general population and accounts for 5% of all strabismus cases. Undiagnosed DRS in children can lead to amblyopia, a permanent uncorrectable loss of vision. A large family with autosomal dominant DRS was examined and tested for genetic linkage. After exclusion of candidate regions previously associated with DRS, a genomewide search with highly polymorphic microsatellite markers was performed, and significant evidence for linkage was obtained at chromosome 2q31 (D2S2314 maximum LOD score 11.73 at maximum recombination fraction. 0). Haplotype analysis places the affected gene in a 17.8-cM region between the markers D2S2330 and D2S364. No recombinants were seen with markers between these two loci. The linked region contains the homeobox D gene cluster. Three of the genes within this cluster, known to participate in hindbrain development, were sequenced in affected and control individuals. Coding sequences for these genes were normal or had genetic alterations unlikely to be responsible for the DRS phenotype. Identifying the gene responsible for DRS may lead to an improved understanding of early cranial-nerve development.

Amino Acid Substitution↗
PubMed1999

Lymphoscintigraphy with sentinel lymph node biopsy in cutaneous Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy characterized by an aggressive clinical behavior with high rates of locoregional and systemic recurrence. Regional disease and distant metastases are associated with poor prognosis. Despite a predisposition of MCC to spread via the lymphatics, prophylactic lymph node dissection in the absence of clinically apparent lymph node involvement is controversial. The value of lymphoscintigraphy in cutaneous melanoma is established in lesions with ambiguous lymphatic drainage patterns. When used with sentinel lymph node biopsy (SLNB), it can identify subjects with occult regional node metastasis. The authors present 2 patients with MCC who underwent regional node staging with lymphoscintigraphy-directed SLNB. Both patients had sentinel nodes that were positive for metastatic disease. In patients with MCC, minimally invasive regional node staging SLNB may be useful in limiting the sequelae of routine lymphadenectomies. Whether early identification and treatment of patients with occult regional node disease can influence survival in MCC is not known.

Aged↗
PubMed1999

Risk factors for predicting surgical salvage of sternal wound-healing complications.

A retrospective study was performed to determine whether clinical factors can predict which complicated poststernotomy wounds can be managed successfully by debridement and reclosure, and which wounds require a muscle flap for healing. Between January 1990 and December 1996, 3,435 median sternotomies were performed at Indiana University Medical Center and affiliated hospitals. A total of 91 patients (2.6%) were reoperated for sternal wound-healing complications. Seventy-six patients (83.5%) underwent debridement and rewiring, and 15 patients (16.5%) underwent primary flap coverage. Of the 76 patients who underwent initial rewiring, 45 (59%) healed and 31 (41%) required additional operative procedures. Of the 31 rewiring failures, 26 patients (84%) were healed with muscle flaps and 4 patients (13%) were managed with a second successful rewiring. The following clinical factors were correlated with operative procedure and outcome: history of smoking, chronic obstructive pulmonary disease, steroid use, previous sternotomy, age, diabetes, harvest of the left or right internal mammary artery (IMA), emergency operation, operation time, pump time, cross-clamp time, ischemic time, coronary artery bypass grafting alone versus combined with a valve replacement, positive wound cultures, positive blood cultures, elevated white blood cell count, and fever. When comparing patients with successful rewiring with those who had a failed rewiring, positive wound and blood cultures were significant risk factors (p < 0.05) on univariate analysis. Presence of a positive wound culture was significant on multivariate analysis. When comparing risk factors in patients who were rewired successfully versus all patients who had muscle flap coverage, the presence of a positive blood culture was significant on both univariate and multivariate analyses. We conclude patients most likely to fail rewiring and to require muscle flap closure are those with infected wounds, positive blood cultures, and possibly left IMA bypasses.

Adult↗