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Biomedical subjects

P Rajan

Publications and source records attributed to P Rajan.

At least 19 recordsLinked to original sources
PubMed2006

Delta-aminolevulinic acid dehydratase polymorphism and the relation between low level lead exposure and the Mini-Mental Status Examination in older men: the Normative Aging Study.

OBJECTIVE: To determine whether a polymorphism the in delta-aminolevulinic acid dehydratase (ALAD) gene modifies the neurotoxicity of lead in older adults. METHODS: The authors studied men participating in the Department of Veterans Affairs' Normative Aging Study, assessing their recent exposure to lead by measuring blood lead (n = 915) at each triennial clinic visit, and, beginning in 1991, assessing their cumulative exposure by measuring lead levels in tibia (n = 722) and patella (n = 720), using K-shell x ray fluorescence. Starting in 1993 and again at each triennial visit, the authors administered the Mini-Mental State Examination (MMSE) to assess their cognitive functioning. The relation of the lead biomarkers to MMSE score was evaluated and this association was compared among men who carried the variant allele, ALAD-2, versus men without the allele. RESULTS: Sixteen per cent of men carried the ALAD-2 allele. Median tibia and patella lead levels (first-third quartile) were 19 (13-28) and 27 (18-39) microg/g. Blood lead levels were consistent with non-occupational exposure: only 6% of men had levels > or =10 microg/dl. In multivariable adjusted analyses, higher levels of blood lead were associated with poorer performance on the MMSE. This association was most pronounced among ALAD-2 carriers, among whom a 3 microg/dl increment in blood lead (the interquartile range) was associated with a 0.26 point lower mean MMSE score (95% CI -0.54 to 0.01), compared with a 0.04 point lower score (95% CI -0.16 to 0.07) among non-carriers. The modest 0.22 point difference in these associations did not attain statistical significance, however (p(interaction) = 0.13). The associations between bone lead levels and MMSE score did not vary by ALAD-2 status. CONCLUSIONS: Although not statistically significant, these findings suggest that ALAD genotype may modify blood lead's adverse association with cognition among older men who had community exposures to lead. However, despite a relatively large sample size and the use of sensitive methods for measuring lead burden, the evidence overall was fairly weak.

Adult↗
PubMed2006

Adrenal cortical carcinoma metastatic to the breast.

A 56 year old woman was diagnosed with adrenal cortical carcinoma in May 2003, for which she underwent left radical adrenalectomy. Eight months later, in January 2004, she presented with a solitary, well delineated, left breast mass with central pleomorphic calcifications on mammographic examination. A diagnosis of metastatic adrenal cortical carcinoma was made on core biopsy. Subsequently, the patient underwent a lumpectomy of the mass, which confirmed the diagnosis. To our knowledge, this is the first case report of adrenal cortical carcinoma metastatic to the breast.

Adrenal Cortex Neoplasms↗
PubMed2005

Sentinel node biopsy can replace four-node-sampling in staging early breast cancer.

AIM: Four-node axillary sampling for breast cancer is an established method of staging the axilla in the United Kingdom. We report the sensitivity of sentinel node (SN) biopsy and compare it with that of four-node sampling. METHODS: SN identification was attempted in 234 consecutive patients with unifocal breast cancers up to 25 mm in diameter on pre-operative ultrasound. A combination of isotope-labelled nanocolloid and patent blue dye techniques were used and SN were identified in 221 (94.5%). All patients underwent back-up four-node sampling and those with positive sentinel nodes on frozen section (FS) underwent immediate full axillary clearance. RESULTS: Among those patients who had SN successfully identified, an average of 1.38 SN were identified per patient. Histological examination of the SN alone would have identified all node-positive patients that the four-node sample identified. CONCLUSION: In patients who have SN identified, four-node axillary sampling does not provide any additional information.

Axilla↗
PubMed2005

High frequency of isolation of antibiotic-resistant oral Viridans streptococci from children in Kuwait.

Antimicrobial resistance among the Viridans group of streptococci (VGS) has emerged as a hindrance to effective antibiotic therapy. Our objective was to evaluate the prevalence of antibiotic-resistant VGS in healthy children. Plaque samples were collected from tooth and tongue surfaces of 102 healthy subjects. Serially diluted samples were inoculated onto BHI agar plates and Mitis Salivarius Agar (MSA) plates and incubated as appropriate. Representative colonies were identified to species level by standard methods. Susceptibility of the VGS was performed by determining the minimum inhibitory concentrations (MICs) of 11 antibiotics using Etest. Of the 540 VGS isolates from both sites, 58% were from the tooth surfaces and 42% from the tongue. The most prevalent were S. salivarius (21.5%) and S. sanguis (16.3%). Imipenem and vancomycin had excellent activities. Resistance rates to trimethoprim, amoxicillin, piperacillin, erythromycin, cefuroxime and cephalothin, were 60.7, 40.8, 34.7, 32.6, 27.5 and 25.3%, respectively. Resistance rates to penicillin and clindamycin were 15.9% and 15.4%, respectively. The majority of the erythromycin-resistant isolates were from the tongue; 41% versus 29%. At the species level, 26% and 23% of S. salivarius and 23% and 14% of S. mutans from the tooth and tongue, respectively were resistant to penicillin. The data show species-related and site-related variations in the susceptibility pattern and an emerging high prevalence of antibiotic-resistant VGS. The difference in the susceptibilities between the species underscores the importance of accurate-identification and the need for surveillance of antimicrobial resistance among clinical isolates in our hospitals.

Anti-Bacterial Agents↗
PubMed2003

Core biopsy versus FNAC for palpable breast cancers. Is image guidance necessary?

The aim of this study was to assess the efficacy of free-hand percutaneous core biopsy (FHCB) and to determine the role of fine needle aspiration cytology (FNAC) as diagnostic tools for palpable radiologically-suspicious breast lumps. This retrospective study was based on reviewing the clinical records of all patients diagnosed as having breast cancer between January 1999 and December 2000 and patients who had benign lesions, but suspicious breast imaging at triple assessment. Absolute sensitivity of FHCB for diagnosing cancer in palpable lesions was 98.7% compared with 51.3% for FNAC. The difference in the sensitivity of FHCB and FNAC was statistically significant (P<0.005, Wilcoxon matched pair test). Since 94.8% of radiologically-suspicious lumps were shown to be cancers, we advocate FHCB for all patients presenting with radiologically suspicious palpable lumps to our breast clinic. We also conclude that the sensitivity of FHCB for the diagnosis of malignancy in palpable radiologically-suspicious breast lesions is so high that image-guidance is unnecessary.

Biopsy, Needle↗
PubMed2001

A monkey model for enterohemorrhagic Escherichia coli infection.

Adult Macaca radiata (n=22) were infected intragastrically with 10(12) Escherichia coli O157:H7 strain 84-01, which produces Shiga toxins 1 and 2. Clinical symptoms and bacterial excretion were documented in each monkey for a specified time period before they were killed. At necropsy, samples were obtained for culture and histologic and ultrastructural examination. Seventeen monkeys had diarrhea: E. coli O157 was isolated from postinfection stool samples from all monkeys and from autopsy cultures for 14 of 22 monkeys. Histologic examination showed attaching-effacing lesions, which appeared at 12 h and persisted for 7 days, in 12 monkeys. Widening of the intercellular spaces, degeneration and vacuolization of the epithelial cells, epithelial tufting, extrusion of epithelial cells, and neutrophilic infiltration were characteristic features seen in 20 of the 22 infected monkeys but not in 4 control monkeys. This monkey model closely parallels the early stages of the disease produced by E. coli O157:H7 and would be useful in the further study of pathogenic mechanisms and prevention methods in enterohemorrhagic E. coli infections.

Animals↗
PubMed2001

Neuronal cyclin-dependent kinase 5 activity is critical for survival.

Cyclin-dependent kinase 5 (Cdk5) null mice exhibit a unique phenotype characterized by perinatal mortality, disrupted cerebral cortical layering attributable to abnormal neuronal migration, lack of cerebellar foliation, and chromatolytic changes of neurons in the brainstem and the spinal cord. Because Cdk5 is expressed in both neurons and astrocytes, it has been unclear whether this phenotype is primarily attributable to defects in neurons or in astrocytes. Herein we report reconstitution of Cdk5 expression in neurons in Cdk5 null mice and its effect on the null phenotype. Unlike the Cdk5 null mice, the reconstituted Cdk5 null mice that express the Cdk5 transgene under the p35 promoter (TgKO mice) were viable and fertile. Because Cdk5 expression is mainly limited to neurons in these mice and rescues the defects in the nervous system of the Cdk5 null phenotype, it clearly demonstrates that Cdk5 activity is necessary for normal development and survival of p35-expressing neurons.

Animals↗
PubMed2001

Varicella zoster virus. Recent advances in management.

OBJECTIVE: To provide an update on strategies for managing varicella zoster virus (VZV) and for preventing and treating established postherpetic neuralgia (PHN). QUALITY OF EVIDENCE: Treatment guidelines are based on randomized clinical trials. Recommendations concerning other aspects of VZV management (e.g., vaccination) are based mainly on expert opinion. MAIN MESSAGE: Varicella and herpes zoster caused by VZV can give rise to serious morbidity and mortality and should be treated. For preventing chickenpox, safe and effective immunization is widely recommended. Treating varicella-exposed seronegative pregnant women requires special attention because the virus can harm expectant mothers, fetuses, and newborns. The antiviral drugs, acyclovir, valacyclovir, and famciclovir, have been approved for treating herpes zoster and have a role in reducing the duration of PHN. Established PHN can be managed with analgesics, tricyclic antidepressants, and other agents. CONCLUSION: Vaccination and antiviral and other systemic agents can substantially reduce the morbidity associated with VZV infection.

Antiviral Agents↗
PubMed1998

Leukemia inhibitory factor and NGF regulate signal transducers and activators of transcription activation in sympathetic ganglia: convergence of cytokine- and neurotrophin-signaling pathways.

We have used the response of the superior cervical ganglia (SCG) to axotomy to investigate interactions between neuropoietic cytokines and neurotrophins. Postganglionic sympathetic axotomy leads to a prolonged leukemia inhibitory factor (LIF)-dependent activation of signal transducers and activators of transcription (STAT) factors. To study regulation of LIF-dependent activation of STAT proteins and to mimic the loss of target-derived NGF resulting from postganglionic axotomy in vivo, SCG were explanted into media lacking NGF and activation of STAT proteins was assessed by electrophoretic mobility shift assay. Like postganglionic axotomy in vivo. STAT proteins were activated for up to 8 days after explantation of SCG in vitro. SCG cultured in the presence of NGF showed decreased STAT binding when compared to ganglia cultured in NGF-free media. This inhibition of STAT activation by NGF was only present in ganglia cultured for more than 5 days and was mimicked by brain-derived neurotrophic factor (BDNF). The serine kinase inhibitor H7 augmented the increase of STAT binding produced by explantation, suggesting the presence of a labile repressor of STAT activation in the SCG. These data indicated that the neuropoietic cytokine-signaling pathway interacts with neurotrophin and H7-sensitive-signaling pathways to regulate activation of STAT proteins in sympathetic neurons. Moreover, these data suggest that one of the mechanisms leading to prolonged activation of STAT proteins after postganglionic axotomy in vivo is loss of target-derived neurotrophins.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

Structure-activity requirements for flavone cytotoxicity and binding to tubulin.

A series of 79 flavones related to centaureidin (3,6,4'-trimethoxy-5, 7,3'-trihydroxyflavone, 1) was screened for cytotoxicity in the NCI in vitro 60-cell line human tumor screen. The resulting cytotoxicity profiles of these flavones were compared for degree of similarity to the profile of 1. Selected compounds were further evaluated with in vitro assays of tubulin polymerization and [3H]colchicine binding to tubulin. Maximum potencies for tubulin interaction and production of differential cytotoxicity profiles characteristic of 1 were observed only with compounds containing hydroxyl substituents at C-3' and C-5 and methoxyl groups at C-3 and C-4'.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Multiple routes to astrocytic differentiation in the CNS.

Ciliary neurotrophic factor (CNTF) acts instructively to switch multipotent stem cells of the CNS to an astrocytic fate. Here we show that CNTF causes activation of janus kinase-signal transducers and activators of transcription and mitogen-activated protein kinase (MAPK) pathways with differential kinetics in these cells. Inhibition studies indicate that activation of the MAPK pathway is required early in the differentiation process, whereas activation of signal transducer and activator of transcription (STAT) proteins is required for commitment to an astrocytic fate. Bone morphogenetic proteins have also been shown to cause astrocytic differentiation but do not cause STAT activation or astrocytic differentiation in fibroblast growth factor 2-expanded fetal stem cells used here. These results show that there are two distinct routes to initiate astrocytic commitment in multipotent CNS precursors.

Animals↗
PubMed1998

BRCA-associated breast cancer: absence of a characteristic immunophenotype.

To characterize the biological features of breast cancer associated with germ-line mutations in BRCA1 and BRCA2, invasive tumors were studied from 58 Jewish women ascertained through studies of early-onset breast cancer. All women were tested for the BRCA1 founder mutations 187delAG (commonly known as 185delAG) and 5385insC (commonly known as 5382insC) and the BRCA2 founder mutation 6174delT. Mutations were detected in 17 of 58 (29.3%) women. Comparing BRCA-associated breast cancers (BABCs) to cases arising in women without founder mutations, no differences were noted in tumor size, tumor stage, or frequency of axillary nodal involvement. Infiltrating ductal carcinoma was the predominant histological type in both groups. BABCs were significantly more likely to be of histological grade III (100 versus 63%; P = 0.04), estrogen receptor negative (75 versus 35%; P = 0.004), and HER2/neu negative (87 versus 58%; P = 0.04). An associated intraductal component was present in 59% of BABCs and 76% of cancers not associated with mutations (P = not significant). A high Ki-67 labeling index was more commonly observed in BABCs than in cases without mutations (83 versus 48%; P = 0.09). There were no differences between the two groups in the frequency of expression of epidermal growth factor receptor, cathepsin D, bcl-2, p27, p53, or cyclin D. There were no significant differences in relapse-free or overall survival. These observations suggest that breast cancers arising in Jewish women with germ-line BRCA founder mutations have a greater proliferative potential than cancers in women without such mutations. Additional studies of BABC are required to determine the nature and implications of additional genetic abnormalities occurring in these tumors.

Adult↗
PubMed1998

BRCA-associated breast cancer in young women.

PURPOSE: To delineate the clinical characteristics and outcomes of breast cancer that arises in the setting of a germline BRCA mutation and to compare BRCA-associated breast cancers (BABC) with those that arise in women without mutations. PATIENTS AND METHODS: We reviewed the clinical records of 91 Ashkenazi Jewish women ascertained during studies of the genetics of early-onset breast cancer. All women underwent testing for the BRCA1 mutations 185delAG and 5382insC. After the discovery of BRCA2, 79 women were also tested for the BRCA2 mutation 6174delT. RESULTS: Mutations were identified in 30 women (33%). BABC were less likely to present with stage I disease than cases in women without mutations (27% v 46%), more likely to have axillary nodal involvement (54% v46%), and more likely to have extensive axillary involvement (25% v 17%). These differences were not statistically significant. BABC were significantly more likely to be histologic grade III (100% v 59%, P=.04) and to be estrogen receptor-negative (70% v 34%, P=.04). In the entire cohort, there were no significant differences between BABC and non-BRCA-associated cancers in 5-year relapse-free survival (65% v 69%, P=not significant [NS]), 5-year event-free survival (57% v 68%, P=NS), or 5-year overall survival. However, among cases diagnosed within 2 years of study entry, there was a trend toward shorter event-free survival in BRCA heterozygotes, but not relapse-free survival. Women with germline BRCA mutations were significantly more likely to develop contralateral breast cancer at 5 years (31% v 4%, P=.0007). CONCLUSION: BABC present with adverse clinical and histopathologic features when compared with cases not associated with BRCA mutations. However, the prognosis of BABC appears to be similar to that of nonassociated cancer. Further studies of incident cases are necessary to define the independent prognostic significance of germline BRCA mutations.

Adult↗
PubMed1996

Simian virus 40 large-T bypasses the translational block imposed by the phosphorylation of elF-2 alpha.

One of the cellular defense mechanisms against virus infection is mediated by activating the interferon-induced, double-stranded-RNA-activated protein kinase, PKR. Upon activation, PKR phosphorylates and thereby inactivates the protein synthesis initiation factor, elF-2, leading to cessation of protein synthesis. Viruses have evolved diverse strategies to counteract this cellular antiviral response. A majority of these strategies target PKR to prevent its activation. Recently, we showed that simian virus 40 (SV40) large-T antigen reverses PKR-mediated translational inhibition at a step downstream of PKR activation (Rajan et al., J. Virol. 69, 785--795, 1995). In this paper, we present evidence showing that SV40 can restore efficient translation in cells despite the elevated levels of phosphorylated elF-2 alpha resulting from PKR activation. Thus, SV40 large-T-mediated translational rescue occurs at a step downstream of elF-2 alpha phosphorylation.

Animals↗