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Biomedical subjects

H Rosen

Publications and source records attributed to H Rosen.

At least 37 records · Page 2Linked to original sources
PubMed1999

Prevalence of upper and lower gastrointestinal tract findings in liver transplant candidates undergoing screening endoscopic evaluation.

OBJECTIVE: The incidence of esophageal and gastric varices and portal hypertensive gastropathy (PHG) has been well studied in cirrhotic patients. Because little is known of the prevalence of other upper and lower gastrointestinal tract pathology in pre-liver transplant candidates, we retrospectively studied the prevalence of and factors associated with these findings. METHODS: One hundred and twenty pre-liver transplant candidates underwent esophagogastroduodenoscopy to evaluate for varices, and 71 of them also underwent flexible sigmoidoscopy to screen for colorectal carcinoma. The association of upper and lower GI tract pathology with Child-Pugh Class, etiology of cirrhosis, and signs of portal hypertension, including presence and size of esophageal varices, presence of gastric varices, PHG, ascites, and splenomegaly, was analyzed using univariate and multivariate analysis. RESULTS: Etiology of cirrhosis among 87 men and 33 women (mean age, 52 yr) included 25% hepatitis C, 27% hepatitis C/alcohol, 15% alcohol, 10% primary sclerosing cholangitis/primary biliary cirrhosis, 9% cryptogenic, 8% metabolic, and 6% hepatitis B. Prevalence of Child-Pugh Classes A, B, and C were 34%, 49%, and 17%, respectively; 73% of patients had esophageal varices (23% were large), 62% PHG (23% were severe), and 16% gastric varices. Excluding varices and PHG, endoscopic findings in the upper GI tract (n = 120) included: 13% esophagitis/ulcers, 7.5% gastritis, 8% duodenitis, 2% Barrett's esophagus, 3% duodenal ulcers, and 2% gastric ulcers. Findings in the lower gastrointestinal tract (n = 71) included 21% adenomatous polyps, 21% internal hemorrhoids, 15% diverticulosis, 7% rectal varices, 3% colopathy, and 3% vascular ectasias. Univariate analysis revealed that there was a significant association between rectal varices and severe PHG (p < 0.05). This association was not maintained when multivariate analysis was performed. CONCLUSIONS: Among all the findings, only rectal varices and colopathy were of higher prevalence in the pre-liver transplant population than that reported for the general population. No significant associations were found between these gastrointestinal tract lesions and patient characteristics.

Colorectal Neoplasms↗
PubMed1999

In vitro activities of the potent, broad-spectrum carbapenem MK-0826 (L-749,345) against broad-spectrum beta-lactamase-and extended-spectrum beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli clinical isolates.

An important mechanism of bacterial resistance to beta-lactam antibiotics is inactivation by beta-lactam-hydrolyzing enzymes (beta-lactamases). The evolution of the extended-spectrum beta-lactamases (ESBLs) is associated with extensive use of beta-lactam antibiotics, particularly cephalosporins, and is a serious threat to therapeutic efficacy. ESBLs and broad-spectrum beta-lactamases (BDSBLs) are plasmid-mediated class A enzymes produced by gram-negative pathogens, principally Escherichia coli and Klebsiella pneumoniae. MK-0826 was highly potent against all ESBL- and BDSBL-producing K. pneumoniae and E. coli clinical isolates tested (MIC range, 0.008 to 0.12 microgram/ml). In E. coli, this activity was associated with high-affinity binding to penicillin-binding proteins 2 and 3. When the inoculum level was increased 10-fold, increasing the amount of beta-lactamase present, the MK-0826 MIC range increased to 0.008 to 1 microgram/ml. By comparison, similar observations were made with meropenem while imipenem MICs were usually less affected. Not surprisingly, MIC increases with noncarbapenem beta-lactams were generally substantially greater, resulting in resistance in many cases. E. coli strains that produce chromosomal (Bush group 1) beta-lactamase served as controls. All three carbapenems were subject to an inoculum effect with the majority of the BDSBL- and ESBL-producers but not the Bush group 1 strains, implying some effect of the plasmid-borne enzymes on potency. Importantly, MK-0826 MICs remained at or below 1 microgram/ml under all test conditions.

Carbapenems↗
PubMed1999

[Stomach carcinoma. Optimizing therapy by neoadjuvant or adjuvant therapy?].

Despite the decreasing frequency of gastric cancer in most Western countries prognosis could not be improved by surgery alone in the past. Advanced tumor stage due to late diagnosis is one of the reasons for this observation. Contrary to breast and colorectal cancer, postoperative chemotherapy failed to improve prognosis in gastric cancer. Small number of patients in Western studies, insufficient surgical procedures and the high frequency of locoregional relapse may be attributed for this observation. Intraperitoneal, adjuvant chemotherapy showed a positive impact on survival in Asian studies only, but was also used successfully as a part of a multimodality approach in Western phase II trials. Since neoadjuvant therapy proved to create downstaging of tumor size in some patients with advanced gastric cancer some working groups tried to influence prognosis of potentially resectable tumors by preoperative chemotherapy, surgical resection and postoperative, adjuvant therapy in the recent past. However, the efficacy of this therapeutic approach has to be reconfirmed in a controlled, phase III fashion.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Myeloperoxidase and horseradish peroxidase catalyze tyrosine nitration in proteins from nitrite and hydrogen peroxide.

Nitration of tyrosine residues in proteins occurs in a wide range of inflammatory diseases involving neutrophil and macrophage activation. We report that both myeloperoxidase (MPO) and horseradish peroxidase (HRP) utilize nitrite (NO2-) and hydrogen peroxide (H2O2) as substrates to catalyze tyrosine nitration in proteins. MPO was approximately 10 times more effective than HRP as a nitration catalyst of bovine serum albumin (BSA). Nitration of BSA by MPO did not require chloride as a cofactor. Physiologic levels of chloride did not significantly inhibit nitration by MPO. Oxidation of chloride to hypochlorous acid (HOCl) is catalyzed by MPO but not by HRP, yet HRP also catalyzed nitration from hydrogen peroxide plus nitrite. Therefore, HOCl formation was not obligatory for tyrosine nitration. Although HOCl plus nitrite can nitrate the amino acid tyrosine in simple solutions, protein nitration by HOCl plus nitrite was not observed in heart homogenates, probably due to the presence of multiple alternative targets of both HOCl and HOCl plus nitrite. In contrast, MPO catalyzed nitration of many proteins in rat heart homogenates using NO2- plus H2O2, suggesting that peroxidase-catalyzed nitration of tyrosine could occur in the presence of competing substrates in vivo. HOCl could substitute for H2O2 as the oxidizing substrate for nitration of either BSA or tissue homogenates catalyzed by either peroxidase. Activated neutrophils may generate nitrotyrosine by several mechanisms, including peroxynitrite, HOCl plus nitrite, and a chloride-independent mechanism involving MPO, nitrite, and hydrogen peroxide.

Animals↗
PubMed1998

Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene.

Sterol 27-hydroxylase is important for the degradation of the steroid side chain in conversion of cholesterol into bile acids and has been ascribed a regulatory role in cholesterol homeostasis. Its deficiency causes the autosomal recessive disease cerebrotendinous xanthomatosis (CTX), characterized by progressive dementia, xanthomatosis, and accelerated atherosclerosis. Mice with a disrupted cyp27 (cyp27(-/-)) had normal plasma levels of cholesterol, retinol, tocopherol, and 1,25-dihydroxyvitamin D. Excretion of fecal bile acids was decreased (<20% of normal), and formation of bile acids from tritium-labeled 7alpha-hydroxycholesterol was less than 15% of normal. Compensatory up-regulation of hepatic cholesterol 7alpha-hydroxylase and hydroxymethylglutaryl-CoA reductase (9- and 2-3-fold increases in mRNA levels, respectively) was found. No CTX-related pathological abnormalities were observed. In CTX, there is an increased formation of 25-hydroxylated bile alcohols and cholestanol. In bile and feces of the cyp27(-/-) mice only traces of bile alcohols were found, and there was no cholestanol accumulation. It is evident that sterol 27-hydroxylase is more important for bile acid synthesis in mice than in humans. The results do not support the contention that 27-hydroxylated steroids are critical for maintenance of cholesterol homeostasis or levels of vitamin D metabolites in the circulation.

Animals↗
PubMed1998

Dissolution of cement, root caries, fracture, and retrofit of post and cores.

Fixed partial denture abutments severely damaged by dental caries or fracture present a challenge to the dentist. The fixed partial denture may need to be removed for endodontic treatment with post and core fabrication. Frequently, the existing fixed partial denture can be recycled as a provisional restoration. Retrofitting the post and core greatly improves the stabilization of the interim as well as the remake of the definitive fixed partial denture. This article describes a chair side procedure for retrofitting posts and cores and, at the same appointment, converting the original fixed partial denture to an effective provisional restoration.

Dental Abutments↗
PubMed1998

Comparison of immunohistochemical and biochemical measurement of steroid receptors in primary breast cancer: evaluation of discordant findings.

Tumor samples of 240 patients with primary breast cancer were biochemically and immunohistochemically investigated for estrogen receptors (ER) and, in 130 of the samples, for progesterone-receptors (PgR) in order to examine reasons for discordant findings. The biochemical (DCCA) and immunohistochemical assays (ICA) yielded positivity in 71% for ER, and in 44% for PgR. Concordant ER-DCCA and ER-ICA results were obtained in 84%; two thirds of the discordant ER-findings manifested as DCCA-neg/ICA-pos. Concordance in the case of PgR amounted to 72%, and of the discordances 60% were DCCA-neg/ICA-pos. Significant association with postmenopausal status existed only for ER positivity in ICA (p = 0.01), whereas ER-DCCA, PgR-DCCA and PgR-ICA were all more or less independent of the menopausal status. The frequency of discordances was independent of menopausal status. Discordance for ER-assays increased significantly near the respective cut-off point; this was not unequivocally true for PgR-assays. The correlation of tumor types of sparse cellularity, as well as prominent stroma content ('scirrhous carcinoma') with increased frequency of the constellation DCCA-neg/ICA-pos was of borderline significance for PgR (p = 0.06), but not for ER. The percentage of discordant ER-findings, figuring as DCCA-neg/ICA-pos, was statistically significantly increased in locally advanced breast cancer (p = 0.03). Fibrocystic disease in peritumoral breast tissue had no impact on receptor-assay discordance. In any case, the models derived from theoretical thought, laboratory data and singular observations can only in part explain the discordance in steroid receptor values measured with different methods.

Adult↗
PubMed1998

Milk thistle (Silybum marianum) for the therapy of liver disease.

Silymarin, derived from the milk thistle plant, Silybum marianum, has been used for centuries as a natural remedy for diseases of the liver and biliary tract. As interest in alternative therapy has emerged in the United States, gastroenterologists have encountered increasing numbers of patients taking silymarin with little understanding of its purported properties. Silymarin and its active constituent, silybin, have been reported to work as antioxidants scavenging free radicals and inhibiting lipid peroxidation. Studies also suggest that they protect against genomic injury, increase hepatocyte protein synthesis, decrease the activity of tumor promoters, stabilize mast cells, chelate iron, and slow calcium metabolism. In this article we review silymarin's history, pharmacology, and properties, and the clinical trials pertaining to patients with acute and chronic liver disease.

Humans↗
PubMed1998

In vivo activity and pharmacokinetic evaluation of a novel long-acting carbapenem antibiotic, MK-826 (L-749,345).

MK-826 (formerly L-749,345), is a potent 1-beta-methyl carbapenem with a long half-life and broad spectrum of activity. This compound is presently in phase-II clinical trials. Its activity against a number of gram-positive and gram-negative organisms was compared to those of imipenem (IPM) and eight other beta-lactam agents in two in vivo murine infection models. The distribution in tissue and pharmacokinetic properties of MK-826 and ceftriaxone (CTRX) were also evaluated in CD-1 mice following a single intraperitoneal dose (10 mg/kg of body weight). In addition, concentrations in plasma as well as biliary and urinary recovery of MK-826 were compared to that of CTRX in a cannulated rat model. In a localized murine thigh infection model, MK-826 and IPM were superior to a variety of beta-lactam antibiotics in reduction of Staphylococcus aureus CFU compared with results from nontreated controls (eliminating >/=4 log10 CFU). Similar activities of IPM and MK-826 were observed in a gram-positive bacterial murine systemic infection model. While IPM demonstrated greater efficacy than MK-826 against Enterobacter cloacae (50% effective doses [ED50s] of 0.062 and 0.227 mg/kg, respectively) and Pseudomonas aeruginosa (ED50s of 0.142 and 3.0 mg/kg, respectively) systemic infections, MK-826 was 8- to 350-fold more efficacious than IPM against all other gram-negative organisms in this infection model. In mice, MK-826 demonstrated a higher peak concentration in serum (62.8 versus 42.6 microg/ml) and a larger area under the curve (AUC) (150.8 versus 90.0 microg . hr/ml) than CTRX. The concentrations of MK-826 and CTRX in serum declined slowly, with levels of 3.6 and 2.0 microg/ml remaining, respectively, at 6 h posttreatment. The rat pharmacokinetic model showed the average AUC of MK-826 to be greater than that of CTRX (284 versus 142 microg . hr/ml) following a single 10-mg/kg dose. Also, a half-life of MK-826 longer than that of CTRX (3.2 versus 2.3 h) was observed in this species. The total amount of drug excreted in the bile in 8 h was greater for CTRX (55 to 64% of the dose) than for MK-826 (6 to 12.5% of the dose). Urinary recovery was similar for both antibiotics, with 16 to 18% of the dose recovered over an 8-h period. This excellent broad-spectrum in vivo efficacy of MK-826, together with advantageous pharmacokinetics, supports the argument for its further clinical development.

Animals↗
PubMed1998

Differential effects of myeloperoxidase-derived oxidants on Escherichia coli DNA replication.

The microbicidal myeloperoxidase (MPO)-H2O2-chloride system strongly inhibits Escherichia coli DNA synthesis. Also, cell envelopes from MPO-treated E. coli cells lose their ability to interact with hemimethylated DNA sequences of oriC, the chromosomal origin of replication, raising the prospect that suppression of DNA synthesis involves impairment of oriC-related functions (H. Rosen, et al. Proc. Natl. Acad. Sci. USA, 87:10048-10052, 1990). To evaluate whether origin-specific DNA sequences play a role in the MPO effect on E. coli DNA synthesis, plasmid DNA replication was compared to total (chromosomal) DNA replication for six plasmids with three distinct origins of replication. Plasmid pCM700 replication, replicating from oriC, was as sensitive to MPO-mediated inhibition as was total (chromosomal) DNA replication. A regression line describing this relationship had a slope of 0.90, and the r2 was 0.89. In contrast, the replication activities of three of four non-oriC plasmids, pUC19, pACYC184, and pSC101, demonstrated significant early resistance to inhibition by MPO-derived oxidants. The exception to this resistance pattern was plasmid pSP102, which has an origin derived from P1 phage. pSP102 replication declined similarly to that of total DNA synthesis. The regression line for pSP102 replication versus total DNA synthesis had a slope of 0.95, and the r2 was 0.92. The biochemical requirements for P1-mediated replication are strikingly similar to those for oriC-mediated replication. It is proposed that one of these requirements, common to oriC and the P1 origin but not critical to the replication of the other non-oriC plasmids, is an important target for MPO-mediated oxidations that mediate the initial decline in E. coli chromosomal DNA synthesis.

Chromosomes, Bacterial↗
PubMed1998

Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin.

Recent studies suggest that fracture risk is associated with increased undercarboxylated osteocalcin. Methods use differences in binding of undercarboxylated and fully carboxylated osteocalcin to hydroxyapatite or barium sulfate. We evaluated these methods and found that results varied with the amount and preparation of the salts. Furthermore, patient samples with differing amounts of total osteocalcin could not be directly compared. Errors in the determination of undercarboxylated osteocalcin were minimized by expressing data as the percent of the total osteocalcin in the sample, and correcting for the basal level of osteocalcin using a polynomial equation derived from multiple binding curves. Errors from 5-15% in estimation of undercarboxylated osteocalcin were observed without both of these corrections. When differing types of assays were employed (RIA, intact, N-terminal), results also were affected. In normal adults and children and in patients on long-term warfarin therapy, the percent osteocalcin not bound to hydroxyapatite was lower when measured with an intact assay than by a polyclonal RIA. Differences were related to the amount of N-terminal osteocalcin fragments, which had low affinity for hydroxyapatite and resulted in variable overestimation of undercarboxylated osteocalcin. In a kit specific for uncarboxylated osteocalcin, we found good discrimination between carboxylated and uncarboxylated intact osteocalcin. However, the assay detected large osteocalcin fragments and overestimated their concentration by up to 350%. Values for uncarboxylated osteocalcin were not different in patients on coumadin compared with normal adults with this kit, but when normalized to the total intact osteocalcin, percent uncarboxylated osteocalcin was greater in patients on coumadin than in controls, as would be expected. Kit values for uncarboxylated osteocalcin in normal children were higher than intact values in the same subject, because of the increased reactivity of the kit toward circulating fragments that were elevated in children. Thus, for estimation of undercarboxylated osteocalcin, care must be taken to standardize the hydroxyapatite or barium sulfite used for binding, to correct for the basal level of osteocalcin in the sample, to use immunoassays that do not detect small fragments, and to express the results as the percent of the total osteocalcin in the sample. Without these precautions, the assessment of undercarboxylated osteocalcin is not reliable.

Adult↗
PubMed1998

Restriction digest PCR (RD-PCR) for the analysis of gene mutations. Application to Ki-ras.

The Kirsten-ras (onco)gene codes for a GTP-binding membrane protein that is involved in signal transduction. Activated ras triggers a cascade of protein-phosphorylations that ultimately lead to cell proliferation. Ras-mutations are the main cause for adenocarcinomas of the pancreas besides some mutations in the tumor suppressor gene p53 and the c-erbB-2 oncogene. The site of ras mutations in pancreatic cancer is restricted to codon 12 that normally encodes a glycine. For analysis of codon-12 mutations, DNA is extracted from cells in pancreatic fluid and amplified by PCR. Because most of these cells originate from normal tissue with only a few tumor cells in the fluid, "enrichment PCR" must be utilized: In a first round of the PCR, ras sequences from all cells are amplified. By utilizing an appropriate restriction enzyme, wild-type sequences can be digested and the remaining fragments containing mutated sequences be amplified again. An artificial restriction site must be introduced by the 5'primer (...GGA CCT GGT...) for an enzyme (BstNI) (5'CC!WGG 3') to differentiate between wild-type sequence (...GGA GCT GGT...) (during amplification, the G is replaced by a C) and mutated sequences (_...GGA GCT (GTT), (CGT), (CCT), etc.). The necessary manipulations pose a considerable risk for contamination for the second round of the PCR procedure. Therefore, we considered whether it would be feasible to perform the restriction digest simultaneously with the first PCR reaction, and avoiding the second round altogether. The results of our experiments demonstrate that one tumor cell in 1000 normal cells can be determined readily, paralleling the results with the original two step-assay. The restriction enzyme used to enrich mutated sequences is stable long enough to be included into the PCR procedure. By this, wild-type sequence amplicons are digested while they are formed and mutated sequences can be enriched selectively.

Base Sequence↗
PubMed1998

Victims no more: preventing home care aide abuse.

Home care aides are especially susceptible to abuse because of their unique workplace situation. It's up to their employers--the home care agencies--to take deliberate steps to prevent on-the-job abuse. The aides, nurses, and supervisors of the home care team also play an important role in keeping care situations safe for all involved.

Contract Services↗
PubMed1998

Nitric oxide and septic shock. From bench to bedside.

Refractory hypotension with end-organ hypoperfusion is an ominous feature of inflammatory shock. In the past fifteen years, nitric oxide (a diffusible, short-lived product of arginine metabolism) has been found to be an important regulatory molecule in several areas of metabolism, including vascular tone control. Vascular endothelial cells constitutively produce low levels of nitric oxide that regulate blood pressure by mediating adjacent smooth-muscle relaxation. In an inflammatory shock state, cytokines, like interleukin-1 and tumor necrosis factor-alpha, induce a separate, high-output form of the enzyme that synthesizes nitric oxide in both endothelial and smooth-muscle cells. The ensuing high rates of nitric oxide formation result in extensive smooth-muscle relaxation, pressor refractory vasodilation, and--ultimately--shock. The concept of the pathogenesis of inflammatory shock explains many limitations of current therapies and may foster the development of new interventions to mitigate the effects of nitric oxide overproduction in this syndrome.

Aged↗
PubMed1997

Cutaneous injection of RANTES causes eosinophil recruitment: comparison of nonallergic and allergic human subjects.

RANTES, a member of the C-C chemokine family, is a potent chemoattractant for T lymphocytes and eosinophils, but not neutrophils. To determine the effect of RANTES on cell recruitment in vivo, we injected up to 4 microg of RANTES intradermally into both allergic and nonallergic subjects and obtained biopsies 30 min, 6 h, and 24 h later. A dose- and time-dependent recruitment of eosinophils, CD45RO+ cells, and CD3+ cells was observed, with no effect seen on polymononuclear, cutaneous lymphocyte Ag+, CD68+, or tryptase+ cells. Eosinophil recruitment occurred more rapidly in allergic subjects than in nonallergic subjects. No eosinophil infiltrate was observed in nonallergic biopsies at 30 min and 6 h, whereas significant eosinophil recruitment was observed in allergic subjects by 30 min, reaching near-maximum levels by 6 h. The peak responses at 24 h were similar in both groups (nonallergic, 110 +/- 24 eosinophils/mm2; allergic, 113 +/- 38 eosinophils/mm2). The two groups had comparable numbers of circulating eosinophils. Major basic protein staining demonstrated eosinophil degranulation in both allergic and nonallergic groups. RANTES injection resulted in activation of endothelial E-selectin expression at 24 h. Incubation of cultured HUVECs with RANTES had no effect on adhesion molecule expression, suggesting that the in vivo effect may have been indirect. Our studies demonstrate that RANTES is a potent chemoattractant for eosinophils, CD3+ cells, and CD45RO+ cells in human skin. The accelerated eosinophil recruitment in allergic subjects provides support for the hypothesis that eosinophils from these subjects are primed in vivo.

Administration, Cutaneous↗
PubMed1997

HLA-DR-mediated signals for hematopoiesis and induction of apoptosis involve but are not limited to a nitric oxide pathway.

Cross-linking of major histocompatibility complex (MHC) class II antigens by anti-HLA-DR monoclonal antibody (MoAb; H81.9; IgG2a) results in inhibition of hematopoiesis in canine and human models. Inhibition of hematopoiesis is associated with apoptosis in a proportion of marrow cells. Since in murine macrophages class II cross-linking triggers nitric oxide (NO) production, and NO is thought to affect regulation of hematopoiesis, we investigated whether NO was involved in our models. In murine J774 monocytes/macrophages, MoAb H81.9 did induce NO. NO production was blocked by N(G)-monomethyl-L-arginine (NMMA), an inhibitor of NO synthase (NOS), and by the antioxidant N-acetylcysteine (NAC). In human and canine long-term marrow cultures (LTMCs) and in enriched marrow monocytes, however, no measurable increase in NO production was noted after H81.9 exposure. Nevertheless, NAC protected LTMCs against H81.9 induced inhibition of hematopoiesis. Therefore, we determined the effect of an exogenous NO donator, sin-1 (3-morpholinosydnonimine), on canine and human LTMCs and on apoptosis. Sin-1 at concentrations > or =100 microg/mL inhibited LTMCs and induced apoptosis; at low concentrations (1 microg/mL), however, sin-1 stimulated the generation of colony-forming unit granulocyte-macrophage. Combined treatment with sin-1 at 100 microg/mL and MoAb H81.9 resulted in profound inhibition of hematopoiesis in both canine and human LTMCs, and had an additive effect on apoptosis. At 1 microg/mL sin-1 counteracted the effect of H81.9 on hematopoiesis. The effect of sin-1 on apoptosis and hematopoiesis in LTMC was largely prevented by NAC. These results are consistent with the hypothesis that HLA-DR mediated apoptosis and inhibition of hematopoiesis involve oxidative stress. However, the biphasic response of hematopoiesis to sin-1 suggests a complex regulatory network possibly related to differences in NO sensitivity of distinct subpopulations of cells. Signals in addition to NO appear to be involved in the effect of anti-HLA-DR MoAb on hematopoiesis.

Animals↗