Showing papers by "University of Texas Medical Branch published in 1998"

Exact and efficient analytical calculation of the accessible surface areas and their gradients for macromolecules

Abstract: A new method for exact analytical calculation of the accessible surface areas and their gradients with respect to atomic coordinates is described. The new surface routine, GETAREA, finds solvent-exposed vertices of intersecting atoms, and thereby avoids calculating buried vertices which are not needed to determine the accessible surface area by the Gauss)Bonnet theorem. The surface routine was implemented in FANTOM, a program for energy minimization and Monte Carlo simulation, and tested for accuracy and efficiency in extensive energy minimizations of Met-enkephalin, the a-amylase inhibitor . tendamistat, and avian pancreatic polypeptide APP . The CPU time for the exact calculation of the accessible surface areas and their gradients has been . . reduced by factors of 2.2 Met-enkephalin and 3.2 tendamistat compared with our previous approach. The efficiency of our exact method is similar to the recently described approximate methods MSEED and SASAD. The performance of several atomic solvation parameter sets was tested in searches for low energy conformations of APP among conformations near the native X-ray crystal structure and highly distorted structures. The protein solvation parameters from w . x

A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis

Abstract: The progressive familial intrahepatic cholestases (PFIC) are a group of inherited disorders with severe cholestatic liver disease from early infancy. A subgroup characterized by normal serum cholesterol and gamma-glutamyltranspeptidase (gammaGT) levels is genetically heterogeneous with loci on chromosomes 2q (PFIC2) and 18q. The phenotype of the PFIC2-linked group is consistent with defective bile acid transport at the hepatocyte canalicular membrane. The PFIC2 gene has now been identified by mutations in a positional candidate, BSEP, which encodes a liver-specific ATP-binding cassette (ABC) transporter, sister of p-glycoprotein (SPGP). The product of the orthologous rat gene has been shown to be an effective bile acid transporter in vitro. These data provide evidence that SPGP is the human bile salt export pump (BSEP).

Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia.

Abstract: Background Incidence rates have risen rapidly for esophageal adenocarcinoma and moderately for gastric cardia adenocarcinoma, while rates have remained stable for esophageal squamous cell carcinoma and have declined steadily for noncardia gastric adenocarcinoma. We examined anthropometric risk factors in a population-based case-control study of esophageal and gastric cancers in Connecticut, New Jersey, and western Washington. Methods Healthy control subjects (n = 695) and case patients with esophageal squamous cell carcinoma or noncardia gastric adenocarcinoma (n = 589) were frequency-matched to case patients with adenocarcinomas of esophagus or gastric cardia (n = 554) by 5-year age groups, sex, and race (New Jersey only). Classification of cases by tumor site of origin and histology was determined by review of pathology materials and hospital records. Data were collected using in-person structured interviews. Associations with obesity, measured by body mass index (BMI), were estimated by odds ratios (ORs). All ORs were adjusted for geographic location, age, sex, race, cigarette smoking, and proxy response status. Results The ORs for esophageal adenocarcinoma rose with increasing adult BMI. The magnitude of association with BMI was greater among the younger age groups and among nonsmokers. The ORs for gastric cardia adenocarcinoma rose moderately with increasing BMI. Adult BMI was not associated with risk of esophageal squamous cell carcinoma or noncardia gastric adenocarcinoma. Conclusions Increasing prevalence of obesity in the United States population may have contributed to the upward trends in esophageal and gastric cardia adenocarcinomas.

An Inverse Relation between cagA + Strains of Helicobacter pylori Infection and Risk of Esophageal and Gastric Cardia Adenocarcinoma

Abstract: Gastric colonization with Helicobacter pylori , especially cagA + strains, is a risk factor for noncardia gastric adenocarcinoma, but its relationship with gastric cardia adenocarcinoma is unclear. Although incidence rates for noncardia gastric adenocarcinoma have declined steadily, paralleling a decline in H. pylori prevalence, rates for adenocarcinomas of esophagus and gastric cardia have sharply increased in industrialized countries in recent decades. To clarify the role of H. pylori infection in these tumors with divergent incidence trends, we analyzed serum IgG antibodies to H. pylori and to a recombinant fragment of CagA by antigen-specific ELISA among 129 patients newly diagnosed with esophageal/gastric cardia adenocarcinoma, 67 patients with noncardia gastric adenocarcinoma, and 224 population controls. Cancer risks were estimated by odds ratios (OR) and 95% confidence intervals (CI) using logistic regression models. Infection with cagA + strains was not significantly related to risk for noncardia gastric cancers (OR, 1.4; CI, 0.7–2.8) but was significantly associated with a reduced risk for esophageal/cardia cancers (OR, 0.4; CI, 0.2–0.8). However, there was little association with cagA - strains of H. pylori for either cancer site (OR, 1.0 and 1.1, respectively). These findings suggest that the effects of H. pylori strains on tumor development vary by anatomical site. Further studies are needed to confirm these results and to assess whether the decreasing prevalence of H. pylori , especially cagA + strains, may be associated with the rising incidence of esophageal/gastric cardia adenocarcinomas in industrialized countries.

Fruits and vegetables that are sources for lutein and zeaxanthin: the macular pigment in human eyes

Abstract: Background—It has been suggested that eating green leafy vegetables, which are rich in lutein and zeaxanthin, may decrease the risk for age related macular degeneration. The goal of this study was to analyse various fruits and vegetables to establish which ones contain lutein and/or zeaxanthin and can serve as possible dietary supplements for these carotenoids. Methods—Homogenates of 33 fruits and vegetables, two fruit juices, and egg yolk were used for extraction of the carotenoids with hexane. Measurement of the different carotenoids and their isomers was carried out by high performance liquid chromatography using a single column with an isocratic run, and a diode array detector. Results—Egg yolk and maize (corn) contained the highest mole percentage (% of total) of lutein and zeaxanthin (more than 85% of the total carotenoids). Maize was the vegetable with the highest quantity of lutein (60% of total) and orange pepper was the vegetable with the highest amount of zeaxanthin (37% of total). Substantial amounts of lutein and zeaxanthin (30‐ 50%) were also present in kiwi fruit, grapes, spinach, orange juice, zucchini (or vegetable marrow), and diVerent kinds of squash. The results show that there are fruits and vegetables of various colours with a relatively high content of lutein and zeaxanthin.

Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer.

Abstract: Regular users of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are at reduced risk of colon cancer, but the evidence for protective effects of NSAIDs elsewhere in the digestive tract is scant. We investigated the association between the use of NSAIDs and risk of esophageal and gastric cancer, using data from a large population-based, case-control study. Cases were individuals, ages 30-79 years, diagnosed with esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261), or noncardia gastric adenocarcinoma (n = 368) in three areas with population-based tumor registries. Controls (n = 695) were selected by random digit dialing and through the rosters of the Health Care Financing Administration. After controlling for the major risk factors, we found that current users of aspirin were at decreased risk of esophageal adenocarcinoma [odds ratio (OR), 0.37; 95% confidence interval (CI), 0.24-0.58], esophageal squamous cell carcinoma (OR, 0.49; 95% CI, 0.28-0.87), and noncardia gastric adenocarcinoma (OR, 0.46; 95% CI, 0.31-0.68), but not of gastric cardia adenocarcinoma (OR, 0.80; 95% CI, 0.54-1.19), when compared to never users. Risk was similarly reduced among current users of nonaspirin NSAIDs. The associations with current NSAID use persisted when we excluded use within 2 or 5 years of reference date, which might have been affected by preclinical disease in cases, and when we restricted analyses to subjects reporting no history of chronic gastrointestinal symptoms. Our findings add to the growing evidence that the risk of cancers of the esophagus and stomach is reduced in users of NSAIDs, although whether the association is causal in nature is not clear.

Long-Term Dietary Strawberry, Spinach, or Vitamin E Supplementation Retards the Onset of Age-Related Neuronal Signal-Transduction and Cognitive Behavioral Deficits

Abstract: Recent research has indicated that increased vulnerability to oxidative stress may be the major factor involved in CNS functional declines in aging and age-related neurodegenerative diseases, and that antioxidants, e.g., vitamin E, may ameliorate or prevent these declines. Present studies examined whether long-term feeding of Fischer 344 rats, beginning when the rats were 6 months of age and continuing for 8 months, with diets supplemented with a fruit or vegetable extract identified as being high in antioxidant activity, could prevent the age-related induction of receptor-mediated signal transduction deficits that might have a behavioral component. Thus, the following parameters were examined: (1) oxotremorine-enhanced striatal dopamine release (OX-K+-ERDA), (2) cerebellar β receptor augmentation of GABA responding, (3) striatal synaptosomal45Ca2+ clearance, (4) carbachol-stimulated GTPase activity, and (5) Morris water maze performance. The rats were given control diets or those supplemented with strawberry extracts (SE), 9.5 gm/kg dried aqueous extract (DAE), spinach (SPN 6.4 gm/kg DAE), or vitamin E (500 IU/kg). Results indicated that SPN-fed rats demonstrated the greatest retardation of age-effects on all parameters except GTPase activity, on which SE had the greatest effect, whereas SE and vitamin E showed significant but equal protection against these age-induced deficits on the other parameters. For example, OX-K+-ERDA enhancement was four times greater in the SPN group than in controls. Thus, phytochemicals present in antioxidant-rich foods such as spinach may be beneficial in retarding functional age-related CNS and cognitive behavioral deficits and, perhaps, may have some benefit in neurodegenerative disease.

Apoptosis of CD8 + T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4

Abstract: CD8-positive T cells are thought to play an important role in the control of infection by human immunodeficiency virus (HIV) as a result of their cytotoxic activity and by releasing soluble factors. In AIDS patients, the absolute number of CD8+ T lymphocytes is decreased in peripheral blood and their turnover rate is increased, suggesting that there is more cell renewal and cell death occurring. Anti-retroviral therapy raises CD8+ T-cell counts in HIV-infected patients. Here we report that the death rate of CD8+ T cells by apoptosis increased markedly during HIV infection of peripheral blood mononuclear cells in vitro. Apoptosis is induced in a dose-dependent manner by recombinant envelope glycoprotein gp120 from HIV strain X4, or by stromal-derived factor-1 (SDF-1), the physiological ligand of the chemokine receptor CXCR4. Apoptosis is mediated by the interaction between tumour-necrosis factor-alpha bound to the membrane of macrophages (mbTNF) and a receptor on CD8+ T cells (TNF-receptor II, or TNFRII). The expression of both of these cell-surface proteins is upregulated by HIV infection or by treatment with recombinant gp120 or SDF-1. Apoptosis of CD8+ T cells isolated from HIV-infected patients is also mediated by macrophages through the interaction between mbTNF and TNFRII. These results indicate that the increased turnover of CD8+ T cells in HIV-infected subjects is mediated by the HIV envelope protein through the CXCR4 chemokine receptor.

Exogenous amino acids stimulate net muscle protein synthesis in the elderly.

Abstract: We have investigated the response of amino acid transport and protein synthesis in healthy elderly individuals (age 71+/-2 yr) to the stimulatory effect of increased amino acid availability. Muscle protein synthesis and breakdown, and amino acid transport were measured in the postabsorptive state and during the intravenous infusion of an amino acid mixture. Muscle-free amino acid kinetics were calculated by means of a three compartment model using data obtained by femoral arterio-venous catheterization and muscle biopsies from the vastus lateralis during the infusion of stable isotope tracers of amino acids. In addition, muscle protein fractional synthetic rate (FSR) was measured. Peripheral amino acid infusion significantly increased amino acid delivery to the leg, amino acid transport, and muscle protein synthesis when measured either with the three compartment model (P < 0.05) or with the traditional precursor-product approach (FSR increased from 0. 0474+/-0.0054 to 0.0940+/-0.0143%/h, P < 0.05). Because protein breakdown did not change during amino acid infusion, a positive net balance of amino acids across the muscle was achieved. We conclude that, although muscle mass is decreased in the elderly, muscle protein anabolism can nonetheless be stimulated by increased amino acid availability. We thus hypothesize that muscle mass could be better maintained with an increased intake of protein or amino acids.

Activation of apurinic/apyrimidinic endonuclease in human cells by reactive oxygen species and its correlation with their adaptive response to genotoxicity of free radicals.

Abstract: Apurinic/apyrimidinic (AP) endonuclease (APE; EC 4.2.99.18) plays a central role in repair of DNA damage due to reactive oxygen species (ROS) because its DNA 3′-phosphoesterase activity removes 3′ blocking groups in DNA that are generated by DNA glycosylase/AP-lyases during removal of oxidized bases and by direct ROS reaction with DNA. The major human APE (APE-1) gene is activated selectively by sublethal levels of a variety of ROS and ROS generators, including ionizing radiation, but not by other genotoxicants—e.g., UV light and alkylating agents. Increased expression of APE mRNA and protein was observed both in the HeLa S3 tumor line and in WI 38 primary fibroblasts, and it was accompanied by translocation of the endonuclease to the nucleus. ROS-treated cells showed a significant increase in resistance to the cytotoxicity of such ROS generators as H2O2 and bleomycin, but not to UV light. This “adaptive response” appears to result from enhanced repair of cytotoxic DNA lesions due to an increased activity of APE-1, which may be limiting in the base excision repair process for ROS-induced toxic lesions.

Enhanced Neocortical Neural Sprouting, Synaptogenesis, and Behavioral Recovery With d-Amphetamine Therapy After Neocortical Infarction in Rats

Abstract: Background and Purpose—d-Amphetamine administration increases behavioral recovery after various cortical lesions including cortical ablations, contusions, and focal ischemia in animals and after st...

Mohs Micrographic Surgery

Abstract: Mohs micrographic surgery (MMS) is a specialized type of minimal marginal surgery that offers cure rates superior to other options in the treatment of contiguous skin cancers in selected settings. Developed by Dr. Frederic E. Mohs, the technique originally required in situ tissue fixation before excision. Most Mohs micrographic surgeons now use the fresh tissue technique exclusively. Horizontal frozen histologic sections of the excised tumor permit more complete microscopic examination of the surgical margin than traditional methods. Residual tumor is graphically mapped and malignant extensions are pursued with staged excisions until the tumor is removed. Maximum sparing of tumor-free adjacent tissue is achieved with histologic mapping of the tumor boundaries, thus optimizing subsequent wound reconstruction. The history, techniques, indications, cure rates, and current controversies of MMS are reviewed.

Health-related quality of life in chronic disorders: a comparison across studies using the MOS SF-36.

Abstract: The purpose of this report is to examine health-related quality of life (HRQoL) as measured by the Medical Outcomes Study Short Form-36, across patient populations with chronic disorders and to compare quality of life (QoL) in these subjects with normative data on healthy persons. Six studies, within the Center for Research in Chronic Disorders at the University of Pittsburgh School of Nursing, in patients with urinary incontinence, prostate cancer, chronic obstructive pulmonary disease (COPD), acquired immune deficiency syndrome (AIDS), fibromyalgia and hyperlipidaemia provided the data for analysis. The results demonstrated that not only did the prostate cancer and hyperlipidaemia patients have the highest QoL across the chronic disorders, but their QoL was comparable to normative data on healthy persons. Homebound, elderly, incontinent patients had the lowest QoL for physical functioning, whereas patients hospitalized with AIDS had the lowest QoL in general health and social functioning. Patients with COPD had the lowest QoL in role-physical, role-emotional and mental health. Patients with fibromyalgia had the lowest QoL in bodily pain and vitality. Compared to normative data, patients with urinary incontinence, COPD, AIDS and fibromyalgia generally had lower QoL. Prostate cancer and hyperlipidaemia patients had QoL comparable to normative data. Compared to normative data, patients with urinary incontinence, COPD, AIDS and fibromyalgia had more variability for role-emotional. AIDS patients had more variability on physical functioning, bodily pain and social functioning compared to the normative data. These data suggest that patients with various chronic disorders may have QoL that is lower in most domains compared to a healthy population. However, there may be differences in the domains affected as well as the extent of variation across specific chronic disorders.

MutY catalytic core, mutant and bound adenine structures define specificity for DNA repair enzyme superfamily

Abstract: The DNA glycosylase MutY, which is a member of the Helix-hairpin-Helix (HhH) DNA glycosylase superfamily, excises adenine from mispairs with 8-oxoguanine and guanine. High-resolution crystal structures of the MutY catalytic core (cMutY), the complex with bound adenine, and designed mutants reveal the basis for adenine specificity and glycosyl bond cleavage chemistry. The two cMutY helical domains form a positively-charged groove with the adenine-specific pocket at their interface. The Watson-Crick hydrogen bond partners of the bound adenine are substituted by protein atoms, confirming a nucleotide flipping mechanism, and supporting a specific DNA binding orientation by MutY and structurally related DNA glycosylases.

Osmolyte-driven contraction of a random coil protein

Abstract: The Stokes radius characteristics of reduced and carboxamidated ribonuclease A (RCAM RNase) were determined for transfer of this “random coil” protein from water to 1 M concentrations of the naturally occurring protecting osmolytes trimethylamine N-oxide, sarcosine, sucrose, and proline and the nonprotecting osmolyte urea. The denatured ensemble of RCAM RNase expands in urea and contracts in protecting osmolytes to extents proportional to the transfer Gibbs energy of the protein from water to osmolyte. This proportionality suggests that the sum of the transfer Gibbs energies of individual parts of the protein is responsible for the dimensional changes in the denatured ensemble. The dominant term in the transfer Gibbs energy of RCAM RNase from water to protecting osmolytes is the unfavorable interaction of the osmolyte with the peptide backbone, whereas the favorable interaction of urea with the backbone dominates in RCAM RNase transfer to urea. The side chains collectively favor transfer to the osmolytes, with some protecting osmolytes solubilizing hydrophobic side chains as well as urea does, a result suggesting there is nothing special about the ability of urea to solubilize hydrophobic groups. Protecting osmolytes stabilize proteins by raising the chemical potential of the denatured ensemble, and the uniform thermodynamic force acting on the peptide backbone causes the collateral effect of contracting the denatured ensemble. The contraction decreases the conformational entropy of the denatured state while increasing the density of hydrophobic groups, two effects that also contribute to the ability of protecting osmolytes to force proteins to fold.

The many roles of c-Myc in apoptosis

Abstract: The proto-oncogene c-myc encodes a transcription factor c-Myc, which is of great importance in controlling cell growth and vitality. The quantity of c-Myc is carefully controlled by many mechanisms, and its actions to induce and repress genes are modulated by interactions with other regulatory proteins. Understanding the kinetic and quantitative relationships that determine how and what genes c-Myc regulates is essential to understanding how Myc is involved in apoptosis. Reduction of c-myc expression and its inappropriate expression can be associated with cellular apoptosis. This review outlines the nature and regulation of the c-myc gene and of c-Myc and presents the systems and conditions in which Myc-related apoptotic events occur. Hypotheses of the mechanisms by which expression and repression of c-myc lead to apoptosis are discussed.

Cell-Specific Expression of RANTES, MCP-1, and MIP-1α by Lower Airway Epithelial Cells and Eosinophils Infected with Respiratory Syncytial Virus

Abstract: Respiratory syncytial virus (RSV) is the major cause of acute bronchiolitis in infancy, a syndrome characterized by wheezing, respiratory distress, and the pathologic findings of peribronchial mononuclear cell infiltration and release of inflammatory mediators by basophil and eosinophil leukocytes. Composition and activation of this cellular response are thought to rely on the discrete target cell selectivity of C-C chemokines. We demonstrate that infection in vitro of human epithelial cells of the lower respiratory tract by RSV induced dose- and time-dependent increases in mRNA and protein secretion for RANTES (regulated upon activation, normal T-cell expressed and presumably secreted), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1α (MIP-1α). Production of MCP-1 and MIP-1α was selectively localized only in epithelial cells of the small airways and lung. Exposure of epithelial cells to gamma interferon (IFN-γ), in combination with RSV infection, induced a significant increase in RANTES production that was synergistic with respect to that obtained by RSV infection or IFN-γ treatment alone. Epithelial cell-derived chemokines exhibited a strong chemotactic activity for normal human blood eosinophils. Furthermore, eosinophils were susceptible to RSV and released RANTES and MIP-1α as a result of infection. Therefore, the inflammatory process in RSV-induced bronchiolitis appears to be triggered by the infection of epithelial cells and further amplified via mechanisms driven by IFN-γ and by the secretion of eosinophil chemokines.

A Randomized, Controlled, Molecular Study of Condylomata Acuminata Clearance during Treatment with Imiquimod

Abstract: Imiquimod, an immune response modifier, has been demonstrated to be safe and effective in the treatment of external genital and perianal warts caused by human papillomavirus (HPV). To identify the molecular mechanism(s) by which condylomata acuminata clear during topical treatment with imiquimod, wart skin biopsies were taken from patients before treatment, at treatment week 6, and at the end of treatment. Tissues were analyzed for HPV DNA and for mRNA of several cytokines and HPV gene products. Wart clearance was associated with evidence of tissue production of interferon-alpha, -beta, and -gamma and tumor necrosis factor-alpha. Regression of warts was strongly associated with a decrease in HPV DNA and in mRNA expression for both early and late viral proteins. Thus, topical imiquimod treatment of anogenital warts led to significant increases in local production of multiple interferon mRNAs and a significant reduction in virus load as measured by decreases in HPV DNA and mRNA for early HPV proteins.

Theoretical Justification of Wavelength Selection in PLS Calibration : Development of a New Algorithm

Abstract: The mathematical basis of improved calibration through selection of informative variables for partial least-squares calibration has been identified. A theoretical investigation of calibration slopes indicates that including uninformative wavelengths negatively affect calibrations by producing both large relative bias toward zero and small additive bias away from the origin. These theoretical results are found regardless of the noise distribution in the data. Studies are performed to confirm this result using a previously used selection method compared to a new method, which is designed to perform more appropriately when dealing with data having large outlying points by including estimates of spectral residuals. Three different data sets are tested with varying noise distributions. In the first data set, Gaussian and log-normal noise was added to simulated data which included a single peak. Second, near-infrared spectra of glucose in cell culture media taken with an FT-IR spectrometer were analyzed. Finally, dispersive Raman Stokes spectra of glucose dissolved in water were assessed. In every case considered here, improved prediction is produced through selection, but data with different noise characteristics showed varying degrees of improvement depending on the selection method used. The practical results showed that, indeed, including residuals into ranking criteria improves selection for data with noise distributions resulting in large outliers. It was concluded that careful design of a selection algorithm should include consideration of spectral noise distributions in the input data to increase the likelihood of successful and appropriate selection.

A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection

Abstract: Background: Painful sensory neuropathy is a common complication of HIV infection. Based on prior uncontrolled observations, we hypothesized that amitriptyline or mexiletine would improve the pain symptoms. Method: A randomized, double-blind, 10-week trial of 145 patients assigned equally to amitriptyline, mexiletine, or matching placebo. The primary outcome measure was the change in pain intensity between baseline and the final visit. Results: The improvement in amitriptyline group (0.31 ± 0.31 units [mean ± SD]) and mexiletine group (0.23 ± 0.41) was not significantly different from placebo (0.20 ± 0.30). Both interventions were generally well tolerated. Conclusions: Neither amitriptyline nor mexiletine provide significant pain relief in patients with HIV-associated painful sensory neuropathy.

Induction of p21WAF1/CIP1/SDI1 in kidney tubule cells affects the course of cisplatin-induced acute renal failure.

Abstract: The p21 protein is found in the nucleus of most cells at low levels and is induced to elevated levels after DNA damage, causing cell-cycle arrest. We have reported that p21 mRNA is rapidly induced to high levels in murine kidney after acute renal failure. The function(s) in the kidney of p21 induction in cisplatin-induced acute renal failure was studied with mice that are homozygous for a p21 gene deletion. After drug administration, as compared with their wild-type littermates, p21(-/-) mice display a more rapid onset of the physiologic signs of acute renal failure, develop more severe morphologic damage, and have a higher mortality. Therefore, the induction of p21 after cisplatin administration is a protective event for kidney cells. Using both bromodeoxyuridine incorporation and nuclear proliferating cell nuclear antigen detection, we found that cisplatin administration caused kidney cells to start entering the cell-cycle. However, cell-cycle progression is inhibited in wild-type mice, whereas kidney cells in the p21(-/-) mice progress into S-phase. We propose that p21 protects kidneys damaged by cisplatin by preventing DNA-damaged cells from entering the cell-cycle, which would otherwise result in death from either apoptosis or necrosis.

The anti-allodynic effects of amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain.

Abstract: The management of patients with neuropathic pain is challenging.There are only a few reports regarding the acute effects of the commonly used adjuvant drugs amitriptyline (AMI), gabapentin (GBP), and lidocaine (LDC) on neuropathic pain behaviors in animal models. Thus, the purpose of this study was

Systemic lupus erythematosus in three ethnic groups: I. The effects of HLA class II, C4, and CR1 alleles, socioeconomic factors, and ethnicity at disease onset

Abstract: Objective To study the relative impact of immunogenetic versus socioeconomic factors on systemic lupus erythematosus (SLE) at disease onset/presentation. Methods Medical records regarding SLE onset/presentation were abstracted on 229 SLE patients who were enrolled in a prospective lupus outcome study. Patients were grouped in equivalent proportions of Caucasians, African Americans, and Hispanics. HLA-DRB1, DQA1, and DQB1 oligotyping, as well as C4 and CR1 allotyping, were carried out by standard methods. In addition to these genetic factors, data on ethnicity, age at SLE onset, monthly income, level of education, and home ownership were entered into stepwise logistic or stepwise multiple linear regression models as independent variables, and each specific clinical feature (neurologic, renal, and cardiovascular disease due to SLE), as well as the total Systemic Lupus Activity Measure (SLAM) score and physician's global assessment of disease activity at disease onset, were entered as dependent variables. Results HLA-DRB1*0301 (DR3), DRB1*1503 (DR2), and DRB1*08 (DR8) alleles were more frequently found in Caucasians, African Americans, and Hispanics, respectively. Hispanics were more likely to have cardiac and renal disease, as well as a higher physician's global assessment of disease activity. African Americans were more likely to have neurologic disease, renal disease, and a higher SLAM score. Those with less education had a higher SLAM score. Patients with HLA-DRB1*01 had less renal disease and a lower SLAM score. Those with C4A*3 alleles had a higher SLAM score and a higher physician's global assessment of disease activity. Conclusion Both genetic and socioeconomic determinants, as well as other factors associated with Hispanic and African-American ethnicity, affect the presentation of SLE.

Ultrastructural analysis of NMDA, AMPA, and kainate receptors on unmyelinated and myelinated axons in the periphery.

Abstract: The present study determines the proportions of unmyelinated cutaneous axons at the dermal-epidermal junction in glabrous skin and of myelinated and unmyelinated axons in the sural and medial plantar nerves that immunostain for subunits of the ionotropic glutamate receptors. Approximately 20% of the unmyelinated cutaneous axon profiles at the dermal-epidermal junction immunostain for either N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or kainate receptor subunits. These findings are consistent with previous observations that NMDA and non-NMDA antagonists ameliorate nociceptive behaviors that result from noxious peripheral stimulation. In the sural nerve, where the large majority of myelinated fibers are sensory, approximately half of the myelinated axon profiles immunostain for the NMDA receptor 1 (R1) subunit, 28% immunostain for the glutamate receptor 1 (GluR1) AMPA subunit, and 11% for the GluR5,6,7 kainate subunits. Even higher proportions immunostain for these receptors in the medial plantar nerve, a mixed sensory and motor nerve. In the sural nerve, 20% of the unmyelinated axon profiles immunostain for NMDAR1 and only 7% label for GluR1 or GluR5,6,7. Because the sural nerve innervates hairy skin, these data suggest that glutamate will activate a higher proportion of unmyelinated axons in glabrous skin than in hairy skin. Measurements of fiber diameters indicate that all sizes of myelinated axon profiles, including Adelta and Abeta, are positively labeled for the ionotropic receptors. The presence of glutamate receptors on large-diameter myelinated axons suggests that these mechanosensitive receptors, presumably transducing touch and pressure, may also respond to local glutamate and thus be chemosensitive.