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M Sherman

Publications and source records attributed to M Sherman.

At least 73 records · Page 4Linked to original sources
PubMed1996

Effects of sex hormones on mesangial cell proliferation and collagen synthesis.

In a variety of renal diseases, males progress at a more rapid rate and have a more fulminant course than females. This gender difference may be related to the direct effects of sex hormones on the cells of the kidney. To evaluate this hypothesis, we studied the effects of estrogens and testosterone on mesangial cell proliferation and collagen synthesis. At 48 hours, estradiol at 10 nM and 100 nM had a modest proliferative effect on cultured mesangial cells, as measured by 3H thymidine incorporation into DNA and direct cell counting. This estradiol effect was fully reversed by Tamoxifen (1 microM). Estradiol had no effect on cellular proliferation at 1 microM concentrations, but suppressed proliferation at 10 microM doses. Testosterone had a modest but statistically insignificant effect on proliferation at 10 nM and 100 nM concentrations but no effect at 1 microM or 10 microM. Neither estradiol nor testosterone at 10 microM affected total cellular protein accumulation. Estradiol at 1 microM and 10 microM, markedly suppressed total collagen synthesis as measured by 3H proline incorporation, and specifically suppressed the synthesis of collagen types I and IV, as measured by immunoprecipitation and gel electrophoresis. Testosterone did not affect collagen synthesis. Estradiol also reduced the steady state message for the alpha 2 chain of type I collagen, while testosterone had no effect. Neither estradiol nor testosterone affected the steady state message for TGF beta or EGF. The direct effects of estradiol on mesangial cell collagen generation may help explain the slower development of glomerulosclerosis in women and therefore the "protective" effect of female gender on the progression of renal disease.

Animals↗
PubMed1996

Lipiodol accumulation in hepatic hemangioma. Detection with osmium postfixation.

Lipiodol has been used to increase the detectability of small primary neoplasms in the liver. We report a patient who was found to have lipiodol deposits in the liver one month after intra-arterial injection. The region was resected, under ultrasound control, because of the impression that the lesion was malignant. The specimen contained two small hemangiomas as well as many small dysplastic nodules (adenomatous hyperplasia) in a noncirrhotic parenchyma. To locate the lipiodol deposit in this case, the tissue was radiographed, postfixed in osmium tetroxide, and embedded in paraffin. Black osmium-stained deposits were found within the cavities of the hemangiomas but not in the dysplastic nodules. Most of the deposits were extracellular multivesiculated bodies with a small focus of lipid droplets engulfed by multinucleated foreign-body type giant cells. This report reinforces that hepatic lipiodol retention is not specific for hepatocellular carcinoma. We present, for the first time, the histologic appearance of lipiodol accumulation in an hemangioma. The value of osmium tetroxide postfixation for the detection of lipiodol is also demonstrated.

Adult↗
PubMed1996

Rapid identification of patient specimens with microsatellite DNA markers.

Despite the use of standardized clerical and processing procedures in surgical pathology, questions might arise regarding the proper identification of specimens with respect to patient source. Genotypic analysis of microsatellite DNA polymorphisms was used to identify the patient source of two surgical pathology specimens showing carcinoma. Four highly polymorphic microsatellite loci were evaluated in DNA extracted from various formalin-fixed, paraffin-embedded tissues. Using this technique, we determined that the diagnosis of poorly differentiated adenocarcinoma arising from a background of colitis had been assigned to the correct patient, despite the fact that multiple repeat endoscopic examinations, with biopsy specimens, were negative. In the second case, a suspected processing error involving the exchange of specimen accession numbers was resolved when a lymph node containing a microscopic focus of metastatic carcinoma was assigned to the appropriate patient. A multitude (approximately 50,000 to 100,000) of microsatellite loci are distributed throughout the human genome, and many are highly polymorphic. Hence, genotypic analysis using microsatellite loci has a significantly higher power of discrimination than other commonly used methods. The technique is rapid and is particularly well suited to the analysis of small, fixed-tissue specimens.

Adenocarcinoma↗
PubMed1996

Some permutation tests for survival data.

We introduce two new classes of tests for censored data. The first tests for association between survival and a covariate and the second tests for equality of survival distributions between K groups. Both tests are permutation tests based on nonparametric test statistics and, unlike the Wald test in the proportional hazards model or the log rank test, can detect alternatives of the "crossed hazards" type. The tests are simple to implement and require no theoretical analysis by the user nor an appeal to asymptotic distribution theory. Simulation results show that the tests are competitive with their classical counterparts under proportional hazards and superior under certain nonproportional hazards alternatives in both the continuous and K-sample cases. The tests are applied to data from the British Medical Research Council's fourth myelomatosis trial and from a Danish study of malignant melanoma.

Biometry↗
PubMed1995

Trigger factor is involved in GroEL-dependent protein degradation in Escherichia coli and promotes binding of GroEL to unfolded proteins.

In Escherichia coli, the molecular chaperones of hsp60/hsp10 (GroEL/GroES) families are required not only for protein folding but also for the rapid degradation of certain abnormal proteins. The rate-limiting step in the degradation of the fusion protein CRAG by protease ClpP appears to be the formation of a complex with GroEL. We have isolated these complexes and found that each GroEL 14mer contained a short-lived fragment of CRAG plus a 50 kDa polypeptide, which we identified by sequencing and immunological methods as Trigger Factor (TF). Upon ATP addition, GroEL and TF dissociated together from CRAG but remained tightly associated with each other even upon gel filtration. TF was originally proposed to function in protein translocation across membranes but altering cellular content of TF did not affect this process in vivo. By contrast, low levels of TF expression markedly reduced CRAG degradation, while an overproduction of TF greatly stimulated this process. Furthermore, in extracts of cells expressing high levels of TF, the capacity of GroEL to bind to CRAG is greatly increased. Overproduction of TF also stimulated GroEL's ability to bind to other unfolded proteins (fetuin and histone). Thus, TF is a rate-limiting factor for CRAG degradation; it appears to regulate GroEL function and to promote the formation of TF-GroEL-CRAG complexes which are critical for proteolysis.

Adenosine Triphosphatases↗
PubMed1995

Sequence of human tryptophan 2,3-dioxygenase (TDO2): presence of a glucocorticoid response-like element composed of a GTT repeat and an intronic CCCCT repeat.

Abnormalities in serotonin levels have been implicated in a wide range of psychiatric disorders. Tryptophan 2,3-dioxygenase is the rate-limiting enzyme in the catabolism of tryptophan, the precursor of serotonin. As such it is a potential major candidate gene in psychiatric genetics. The regulatory, intron, and exon regions of the human TDO2 gene have been sequenced. Twelve exons were identified. The amino acid sequence of the enzyme was 88% homologous to that of the rat. Compared to the rat, the regulatory region of the human TDO2 gene had an insertion of approximately 1064 bp of random DNA beginning at -293 bp and extending to -1357 bp. This displaced the glucocorticoid response element (GRE) occurring at -1174 bp in the rat to -1500 in the human. The proximal GRE at -419 in the rat was missing in the human. However, within the DNA insert there was a GRE-like microsatellite region containing multiple GTT repeats plus additional GT(n) sequences. This could produce several staggered regions of the sequence TGTTGTnnnTGTTGT similar to a GRE consensus sequence of TGTTCAnnnTGTTCT. The intron regions 5' and 3' to each exon were sequenced This showed a HIS --> Val mutation polymorphism in exon 7. Three introns, 1,5, and 6, were completely sequenced and examined for polymorphism. This identified two polymorphisms consisting of G -- >T and G --> A mutations 2 bp apart in intron 6. The 3' end of intron 5 showed an extensive CCCT pentanucleotide repeat that was markedly polymorphic. These polymorphisms allow the TDO2 gene to be examined for a possible role in psychiatric disorders.

Amino Acid Sequence↗
PubMed1995

Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group.

BACKGROUND: Epidemiologic studies have shown that the association of genital human papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. There are more than 20 different cancer-associated HPV types, but little is known about their geographic variation. PURPOSE: Our aim was to determine whether the association between HPV infection and cervical cancer is consistent worldwide and to investigate geographic variation in the distribution of HPV types. METHODS: More than 1000 specimens from sequential patients with invasive cervical cancer were collected and stored frozen at 32 hospitals in 22 countries. Slides from all patients were submitted for central histologic review to confirm the diagnosis and to assess histologic characteristics. We used polymerase chain reaction-based assays capable of detecting more than 25 different HPV types. A generalized linear Poisson model was fitted to the data on viral type and geographic region to assess geographic heterogeneity. RESULTS: HPV DNA was detected in 93% of the tumors, with no significant variation in HPV positivity among countries. HPV 16 was present in 50% of the specimens, HPV 18 in 14%, HPV 45 in 8%, and HPV 31 in 5%. HPV 16 was the predominant type in all countries except Indonesia, where HPV 18 was more common. There was significant geographic variation in the prevalence of some less common virus types. A clustering of HPV 45 was apparent in western Africa, while HPV 39 and HPV 59 were almost entirely confined to Central and South America. In squamous cell tumors, HPV 16 predominated (51% of such specimens), but HPV 18 predominated in adenocarcinomas (56% of such tumors) and adenosquamous tumors (39% of such tumors). CONCLUSIONS: Our results confirm the role of genital HPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide. They also suggest that most genital HPVs are associated with cancer, at least occasionally. IMPLICATION: The demonstration that more than 20 different genital HPV types are associated with cervical cancer has important implications for cervical cancer-prevention strategies that include the development of vaccines targeted to genital HPVs.

Adult↗
PubMed1995

Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in cirrhosis and refractory ascites.

OBJECTIVE: To assess the effects of transjugular intrahepatic portosystemic shunt (TIPS) on systemic and renal hemodynamics, neurohumoral factors, and sodium homeostasis in patients with cirrhosis and refractory ascites. DESIGN: Prospective study with 1-year follow-up. SETTING: Tertiary referral center and university-affiliated hospital. PATIENTS: 7 patients with cirrhosis and refractory ascites had metabolic studies done while receiving a 22 mmol/d sodium, 1 L/d fluid diet. INTERVENTION: TIPS insertion. MEASUREMENTS: Urinary sodium excretion, systemic and renal hemodynamics, hormonal profile, and central blood volume were measured before, at day 1 after, and at 1 month after TIPS insertion. RESULTS: Immediately after TIPS insertion, mean corrected sinusoid pressure decreased from 18.2 +/- 2.2 mm Hg to 7.7 +/- 1.3 mm Hg (P < 0.001); mean cardiac output increased from 6.83 +/- 0.68 L/min to 8.62 L/min (P = 0.005); and mean systemic vascular resistance decreased from 1018 +/- 103 dyne.s.cm-5 to 762 +/- 46 dyne.s.cm-5 (P = 0.011). Mean plasma renin activity, serum aldosterone levels, and 24-hour urinary sodium excretion (5.8 +/- 0.7 mmol/d before TIPS insertion compared with 6.0 +/- 1.8 mmol/d 1 day after insertion) were unchanged; mean elevated plasma norepinephrine levels significantly increased. By 1 month after insertion, mean proximal tubular reabsorption of sodium had decreased, and this had led to a mean natriuresis of 15.1 +/- 3.1 mmol/d (P = 0.02 compared with baseline), which was associated with a decrease in plasma renin activity and aldosterone levels to within the normal range. CONCLUSIONS: Our results suggest that natriuresis associated with TIPS is delayed and occurs in the presence of increased systemic vasodilatation at 1 month after insertion and that TIPS insertion should not be done in any patients with refractory ascites without careful attention to cardiac and renal status. However, in carefully selected patients, TIPS is a safe and effective means of managing refractory ascites.

Adult↗
PubMed1995

Interferon alfa treatment of chronic hepatitis B: randomized trial in a predominantly homosexual male population.

BACKGROUND/AIMS: It has been suggested that human immunodeficiency virus (HIV) coinfection and male homosexuality predict poor response to interferon alfa therapy of chronic hepatitis B. The aim of this study was to examine the effect of HIV coinfection on the response of chronic hepatitis B virus (HBV) infection to interferon alfa therapy in a predominantly homosexual male population. METHODS: Fifty patients (82% male homosexuals, 50% HIV positive) with evidence of chronic HBV infection were randomized, stratified by HIV status, to undergo either treatment with interferon alfa (10 MU/m2 three times weekly for 12 weeks) or no treatment. Response was predefined as loss of serum HBV DNA, loss of hepatitis B e antigen, and the appearance of antibody to hepatitis B e antigen. HIV status and the interferon alfa-associated enzyme, 2',5'-oligoadenylate synthetase, were evaluated as potential predictors of response to therapy. RESULTS: Six treated patients responded with development of antibodies to hepatitis B e antigen (P < 0.05). HIV-positive patients were about one-fifth as likely to respond to interferon alfa therapy (relative risk, 0.22; 95% confidence interval, 0.03-1.78). Pretreatment alanine aminotransferase levels were significantly higher in responders than in nonresponders (P = 0.0005). Pretreatment 2',5'-oligoadenylate synthetase levels did not predict response. CONCLUSIONS: Interferon alfa, 10 MU/m2 three times weekly for 12 weeks, is effective in eradicating HBV replication in a predominantly homosexual male population not coinfected with HIV.

2',5'-Oligoadenylate Synthetase↗
PubMed1995

Hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is among the 10 most common tumors in the world. However, incidence is not evenly distributed across the world. In many instances, the proximate cause for the tumor can be identified. Chronic hepatitis B infection is probably the most common cause, followed by chronic hepatitis C. Other important causes are alcoholic liver disease, hemochromatosis, alpha 1-antitrypsin deficiency, and other chronic liver diseases. Although proximate causes may be identifiable, pathogenesis remains uncertain. Factors that may be important include the presence of Aflatoxin B1 in food, genetic changes induced by the hepatitis B virus, and repeated rounds of necrosis and regeneration, also induced by hepatitis viruses. The genes involved and the mutations necessary for hepatic carcinogenesis are unknown, with the sole exception of the p53 gene, which is probably a late phenomenon. Screening for HCC is widely practiced despite the lack of evidence of improved survival. The screening tests used include alphafetoprotein levels and ultrasonography. Screening can identify small tumors; however, survival may not be improved, because the presence of cirrhosis may limit the number of patients who can undergo resections; recurrences or second primary tumors are common; and the presence of chronic liver disease means that survival may be limited anyway. There are many different forms of therapy available; unfortunately, most have not been compared in randomized controlled trials. Surgery remains the therapy of choice if feasible. All other therapy is palliative, including chemotherapy, chemoembolization, hepatic artery embolization, various forms of radiotherapy, and various forms of ablative therapy.

Carcinoma, Hepatocellular↗
PubMed1995

Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population.

OBJECTIVE: To prospectively determine the prevalence and annual incidence of hepatocellular carcinoma in hepatitis B carriers in a heterogeneous urban North American population and to assess the diagnostic accuracy of tests used for screening for this cancer. DESIGN: Prospective cohort study of 1,069 chronic carriers of hepatitis B virus using screening with alpha-fetoprotein alone or in combination with ultrasonography every 6 months. RESULTS: The mean age of the cohort was 39 +/- 12 years (+/- SD), 65% were men, 71% were Asians. At the first screening visit, serum alpha-fetoprotein was > or = 20 micrograms/L in 4%. In those subjects who were also screened by ultrasonography during the first visit, 9% were found to have focal lesions. Only 3 subjects were found to have hepatocellular carcinoma at the first screening, giving a prevalence of 281/100,000 chronic carriers of hepatitis B virus. The cohort was followed for 2,340 person-years (mean, 26 months follow-up, with a range from 6 to 60 months). During this period, 11 more subjects, 10 men and 1 woman, were diagnosed to have hepatocellular carcinoma (annual incidence, 470/100,000). In men only, the annual incidence was 657/100,000. During the study, 5 subjects died from hepatocellular carcinoma (annual mortality rate, 214/100,000). Sensitivity and specificity of serum alpha-fetoprotein > 20 micrograms/L were 64.3% and 91.4%, respectively. For ultrasonography, sensitivity was 78.8% and specificity 93.8%. CONCLUSIONS: These data suggest that the incidence and prevalence of hepatocellular carcinoma in hepatitis B carriers in our area, an urban North American setting, are as high as in countries where hepatitis B is endemic. Current screening tests have significant false-positive and false-negative rates raising questions about the cost-benefit of screening for hepatocellular carcinoma in our study population.

Adult↗
PubMed1995

Patients > or = age 40 years undergoing autologous or allogeneic BMT have regimen-related mortality rates and event-free survivals comparable to patients < age 40 years.

To evaluate the safety and efficacy of marrow transplantation for older adults, the regimen-related mortality and event-free survival for patients > or = 40 years were compared with those for patients < 40 years. Of 148 consecutive patients receiving autotransplants for lymphoma or Hodgkin's disease, 70 were < 40 years and 78 were > or = 40 years at the time of transplant, including 40 who were > or = 50 years and 12 who were > or = 60 years. Eleven patients (16%) in the younger age group died from transplant-related complications compared with 4 (5%) in the older age group. The 4-year actuarial event-free survivals (EFS) for the younger and older age groups were 43% and 48%, respectively. After adjustment for covariates with prognostic significance, older age was marginally associated with improved event-free survival (P = 0.08). Of 92 consecutive patients undergoing allogeneic BMT during the same period, 62 patients were < 40 years and 30 patients were > or = 40 years, including 8 patients > or = 50 years, and 1 patient > 60 years. Non-relapse mortality (including deaths from GVHD) occurred in 28 of the younger patients (45%) and 9 of the older patients (30%). The 3-year actuarial EFS for the younger patients was 26% vs. 56% for the patients > or = 40 years (P = 0.057). However, this difference was mainly due to the higher proportion of patients with CML and early-stage leukemia in the older age group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Heat shock-induced phosphorylation of GroEL alters its binding and dissociation from unfolded proteins.

During heat shock of Escherichia coli, the expression of the major molecular chaperone, GroEL, increases; in addition, a small fraction of the GroEL becomes phosphorylated (Sherman, M. Yu., and Goldberg, A. L. (1992) Nature 367, 166-1692). This heat shock-induced phosphorylation was found to enhance 50-100-fold the capacity of GroEL to bind to several denatured proteins, including casein and fetuin. The phosphorylated species in the cell extract bound quantitatively to affinity columns containing these ligands, and treatment of the extract with alkaline phosphatase markedly reduced this binding. Like heat shock (42 degrees C), overproduction of GroEL (5-10-fold) from the multicopy plasmid at low temperature (25 degrees C) increased the phosphorylated fraction, which bound strongly to denatured fetuin. Heat shock of these cells further enhanced phosphorylation, and about 15% of the induced level of GroEL could bind tightly to the fetuin column. The predominant form of the GroEL that bound to the denatured protein columns appeared to contain at least one phosphate on each of its subunits, although multiple phosphorylated subunits were also observed. With fetuin and casein as affinity ligands, only the phosphorylated species bound, and this material dissociated quantitatively upon addition of ATP-Mg2+. With CRAG and histone as the ligands, some unphosphorylated GroEL also bound, but this species (unlike the phosphorylated form) was not released by ATP alone; its release required the addition of the cofactor GroES together with ATP. Thus, the phosphorylation of GroEL during heat shock greatly enhances its ability to bind to certain denatured proteins and stimulates its ATP-dependent dissociation in the absence of GroES. Presumably, these alterations in the properties of a fraction of GroEL aid in the refolding or the degradation of specific damaged polypeptides.

Adenosine Triphosphate↗
PubMed1994

Rapid degradation of an abnormal protein in Escherichia coli involves the chaperones GroEL and GroES.

In Escherichia coli, the molecular chaperones (DnaK, DnaJ, and GrpE) are essential for the rapid degradation of certain proteins. To see if chaperones are involved more generally in proteolysis, we studied the degradation of a short-lived fusion protein, CRAG, which associates with DnaK and GroEL in vivo. Its rapid degradation requires ATP and ClpP, the proteolytic subunit of protease Ti (Clp). However, this process is not reduced in strains lacking the complementary ATPase subunit, ClpA, or its homologs, ClpB and ClpX. At 37 degrees C, but not at 42 degrees C, protease La also contributes partially to CRAG degradation. Nevertheless, CRAG is not degraded in cell-free extracts or upon incubation with ClpP or protease La. We tested whether the chaperones associated with CRAG might be involved in its degradation. CRAG breakdown was accelerated 2-3-fold in strains with high levels of heat-shock proteins (hsps), i.e. in those that overproduce the hsp transcription factor (sigma 32) or carry a dnaK deletion. A similar stimulation of proteolysis was observed in cells overproducing GroEL or both GroEL and GroES; in these cells, more CRAG was associated with GroEL than in the wild type. In a temperature-sensitive groEL44 mutant at the nonpermissive temperature, CRAG breakdown was accelerated, and more CRAG was found complexed with GroEL. However, in a temperature-sensitive groES mutant, CRAG was completely stable at the nonpermissive temperature and accumulated bound to GroEL. These findings indicate that the association of CRAG with GroEL is a rate-limiting step in CRAG degradation, which also requires a subsequent action of GroES. We propose that if the hsp60/hsp10 chaperonins fail to catalyze the proper folding of a protein, they can facilitate its rapid degradation.

ATP-Dependent Proteases↗
PubMed1994

Unit-based shared governance can work!

The Nurse Executive Council at a 540-bed community teaching health center planned and implemented Shared Governance in a 10-bed Medical Intensive Care Unit (MICU). Paid time was provided for nurses to take part in one of four councils. After a pilot year resulting in satisfaction with job autonomy and input into decision-making, staff reaffirmed their commitment to shared governance as a permanent "way of life" in the MICU. During the second year, patient care assistants and unit clerks were integrated into the Councils and staff began serving as consultants to other units and institutions.

Decision Making, Organizational↗
PubMed1993

Small encapsulated hepatocellular carcinoma of the liver. Provisional analysis of pathogenetic mechanisms.

BACKGROUND: Small hepatocellular carcinomas frequently were found incidentally during routine pathologic examinations of adult livers removed at liver transplant. METHODS: Sixty-nine carcinomas of all sizes were found in 25 patients; 39 of the tumors were smaller than 1 cm in diameter, and 18 of the carcinomas in five patients were not clinically suspected. These small incidental carcinomas lend themselves to analysis of the morphologic basis of human hepatocellular carcinogenesis. RESULTS: All of these tumors arose in cirrhotic livers. Most of the small carcinomas were multilobulated and subdivided by pre-existing fibrous septa. The surrounding capsule usually was not a true capsule. They were all well differentiated, most formed bile, Mallory bodies, or showed alpha-1-antitrypsin (A1AT) positivity. Transition from cirrhotic nodular parenchyma to areas of hyperplasia or atypical hyperplasia to well-differentiated carcinoma were common. Large cell dysplasia also was common. CONCLUSIONS: These morphologic transitions closely parallel changes seen in experimental chemical carcinogenesis. They also strongly suggest a multicentric origin of the tumors. In addition, in every instance, the lesions were multiple in the liver and involved both lobes. This latter finding has possible implications for recurrence after local surgical excision of small hepatocellular carcinomas.

Adult↗