Nursing education: advocating for the dying.
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Education, Nursing↗
Biomedical subjects
L Schmidt
Publications and source records attributed to L Schmidt.
A novel germ line juxtamembrane Met mutation in human gastric cancer.
Activating mutations in the Met receptor tyrosine kinase, both germline and somatic, have been identified in human papillary renal cancer. Here we report a novel germline missense Met mutation, P1009S, in a patient with primary gastric cancer. The dosage of the mutant Met DNA was elevated in the tumor when compared to its matched normal DNA. Therefore, as with hereditary renal papillary cancer, the mutant Met allele may also be selectively duplicated in the tumor. Different from previously reported Met mutations, which occur in the tyrosine kinase domain, this missense mutation is located at the juxtamembrane domain, and is not constitutively activated. However, following treatment with HGF/SF, the P1009S mutant Met protein, expressed in NIH3T3 cells, displays increased and persistent tyrosine phosphorylation compared to the wild-type Met. Importantly, these cells also form colonies in soft agar, and are highly tumorigenic in athymic nude mice. A second nucleotide change in this region of Met, T1010I, was found in a breast cancer biopsy and a large cell lung cancer cell line. Although this previously reported 'polymorphism' did not stimulate NIH3T3 cell growth in soft agar, it was more active than the wild-type Met in the athymic nude mice tumorigenesis assay, suggesting that it may have effects on tumorigenesis. Met has been shown to be highly expressed in human gastric carcinoma cell lines, and our results raise the possibility that activating missense Met mutations could contribute to tumorigenesis of gastric cancer.
3T3 Cells↗
Tumorigenesis mediated by MET mutant M1268T is inhibited by dominant-negative Src.
We recently described germline and somatic mutations in the MET gene associated with papillary renal carcinoma type 1. MET mutation M1268T was located in a codon highly conserved among receptor tyrosine kinases, and homologous to the codon mutated in multiple endocrine neoplasia type 2B, and many cases of sporadic medullary carcinoma of the thyroid gland (Ret M918T). Ret M918T and MET M1268T have previously been shown to be highly active in mouse NIH3T3 transformation assays, and to change the substrate specificity of the kinase. We studied the mechanism of transformation mediated by MET M1268T by analysing a clone, F4, derived from NIH3T3 cells transformed by MET M1268T. In contrast to NIH3T3 cells, F4 cells grew in suspension in tissue culture, and rapidly formed tumors in nude mice. We found that c-Src was constitutively bound to MET proteins in F4 cells, and that Src kinase activity was elevated. Transfection of dominant negative Src constructs into F4 cells eliminated the ability of F4 cells to grow in suspension culture and retarded the growth of F4 cells in vivo. The ability of transfected dominant negative Src constructs to inhibit the growth of F4 cells correlated with the inhibition of phosphorylation of paxillin and focal adhesion kinase. Transfection of dominant negative Src constructs into F4 cells had no effect on Grb2 binding or PLC gamma phosphorylation. The results suggest that c-Src participates in the tumorigenic phenotype induced in NIH3T3 cells by MET M1268T by signaling through focal adhesion kinase and paxillin. Oncogene (2000).
3T3 Cells↗
Grazing incidence surface-induced dissociation of protonated peptides generated by matrix-assisted laser desorption/ionization.
The grazing incidence surface-induced dissociation (GI-SID) of various protonated peptides with typical kinetic energies of 350 eV was investigated. Peptide ions were generated by matrix-assisted laser desorption/ionization (MALDI) using delayed extraction. The collision target surfaces used were aluminum and a liquid film of perfluorinated hydrocarbons. All peptides studied in these experiments showed enhanced fragment ion yields at grazing incidence (GI-SID effect) as observed in our former experiments with other precursor ion types. In general the GI-SID spectra exhibit N-terminal a(1)-type fragment ions, immonium ions and side-chain fragment ions in the low mass-to-charge region. Fragment ion series of the peptide backbone were not observed, which are typical and abundant in the spectra of established fragmentation techniques like collision-induced dissociation, MALDI post-source decay or surface-induced dissociation at steeper angles. The potential of the GI-SID process to yield useful information for primary structure determination of peptides is indicated by the observed differences in the GI-SID spectra of the isomeric dipeptides LR and IR.
Algorithms↗
On the definition and measurement of nursing care.
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Humans↗
Mechanism(s) of butyrate transport in Caco-2 cells: role of monocarboxylate transporter 1.
The short-chain fatty acid butyrate was readily taken up by Caco-2 cells. Transport exhibited saturation kinetics, was enhanced by low extracellular pH, and was Na(+) independent. Butyrate uptake was unaffected by DIDS; however, alpha-cyano-4-hydroxycinnamate and the butyrate analogs propionate and L-lactate significantly inhibited uptake. These results suggest that butyrate transport by Caco-2 cells is mediated by a transporter belonging to the monocarboxylate transporter family. We identified five isoforms of this transporter, MCT1, MCT3, MCT4, MCT5, and MCT6, in Caco-2 cells by PCR, and MCT1 was found to be the most abundant isoform by RNase protection assay. Transient transfection of MCT1, in the antisense orientation, resulted in significant inhibition of butyrate uptake. The cells fully recovered from this inhibition by 5 days after transfection. In conclusion, our data showed that the MCT1 transporter may play a major role in the transport of butyrate into Caco-2 cells.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Superior mesenteric artery syndrome: an uncommon cause of intestinal obstruction.
Superior mesenteric artery (SMA) syndrome is an atypical cause of high intestinal obstruction, most frequently occurring in patients who have had rapid weight loss. Identification of this syndrome can be a diagnostic dilemma and is frequently made by exclusion. The most characteristic symptoms are postprandial epigastric pain, eructation, fullness, and voluminous vomiting. The symptoms are caused by compression of the third portion of the duodenum against the posterior structures by a narrow-angled SMA. When nonsurgical management is not possible or the problem is refractory, surgical intervention is necessary. We report a case of SMA syndrome in a patient without a history of rapid weight loss. The patient complained of early satiety, nausea, and vomiting of partially digested food worsening over 2 years. Diagnostic evaluation revealed compression of the third portion of the duodenum by the SMA with resultant proximal dilatation. The patient successfully had duodenojejunal anastomosis.
Duodenal Diseases↗
New directions in alcohol and drug treatment under managed care.
OBJECTIVE: To examine the potential effects of the introduction and expansion of managed care on the financing and organization of public and private alcohol and drug abuse treatment systems by reviewing studies on managed care and substance abuse. STUDY DESIGN: Spending on treatment for alcohol and drug abuse, the organization of treatment, treatment workforce composition, provision of services, and their implications for access and treatment outcome were examined by review of the treatment literature. RESULTS: Managed care has had major effects on the organization of service delivery, the workforce, and the provision of services. Most of the changes have occurred without the benefit of clinical or policy research. Although managed care has the potential ability to address longstanding problems associated with alcohol and drug treatment, it also presents additional barriers to access and improving treatment outcome. CONCLUSIONS: The review suggests that organizational approaches, particularly the settings in which treatment is placed, will differ in their impact on ties between treatment agencies and the medical community, and ties with other health and social service agencies. Also of importance is a new emphasis on accountability of treatment through the mechanisms of outcomes monitoring and performance indicators. It remains to be seen whether these innovations will be meaningfully linked with outcomes research. It is incumbent on researchers and clinicians to explore these issues.
Alcoholism↗
Novel mutations of the MET proto-oncogene in papillary renal carcinomas.
Hereditary papillary renal carcinoma (HPRC) is characterized by multiple, bilateral papillary renal carcinomas. Previously, we demonstrated missense mutations in the tyrosine kinase domain of the MET proto-oncogene in HPRC and a subset of sporadic papillary renal carcinomas. In this study, we screened a large panel of sporadic papillary renal carcinomas and various solid tumors for mutations in the MET proto-oncogene. Summarizing these and previous results, mutations of the MET proto-oncogene were detected in 17/129 sporadic papillary renal carcinomas but not in other solid tumors. We detected five novel missense mutations; three of five mutations were located in the ATP-binding region of the tyrosine kinase domain of MET. One novel mutation in MET, V1110I, was located at a codon homologous to an activating mutation in the c-erbB proto-oncogene. These mutations caused constitutive phosphorylation of MET when transfected into NIH3T3 cells. Molecular modeling studies suggest that these activating mutations interfere with the intrasteric mechanism of tyrosine kinase autoinhibition and facilitate transition to the active form of the MET kinase. The low frequency of MET mutations in noninherited papillary renal carcinomas (PRC) suggests that noninherited PRC may develop by a different mechanism than hereditary papillary renal carcinoma.
3T3 Cells↗
Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas.
The MET protooncogene encodes a transmembrane tyrosine kinase identified as the receptor of a polypeptide known as hepatocyte growth factor/scatter factor. We performed PCR-based single-strand conformational polymorphism and sequencing analysis of the tyrosine kinase domain of the MET gene (exon 15-19) in 75 primary liver cancers. Three missense mutations were detected exclusively in 10 childhood hepatocellular carcinomas (HCCs), while no mutations were detected in 16 adult HCCs, 21 cholangiocarcinomas, or 28 hepatoblastomas. The extremely short incubation period from hepatitis B virus infection to the genesis of childhood HCC as compared with the adult HCC suggests that there may be an additional mechanism that accelerates the carcinogenesis of childhood HCC. Our results indicate that mutations of the tyrosine kinase domain of the MET gene may be involved in the acceleration of the carcinogenesis in childhood HCC.
Adolescent↗
Fragmentation of polyatomic molecules by grazing incidence surface-induced dissociation (GI-SID).
The grazing incidence surface-induced dissociation (GI-SID) of n-hexadecylpyridinium and verapamil ions generated by fission fragment desorption was studied. These molecules show the effect of enhanced surface-induced dissociation at grazing incidence as it was observed in former experiments with metal organic ions. A liquid film of perfluorinated polyether is used as collision surface. Small hydrocarbon fragment ions predominate in the GI-SID spectra. Pyridine ions appear as specific fragment ions in the GI-SID spectrum of n-hexadecylpyridinium. The GI-SID conversion efficiency varies in the range 40-70%. The experimental results are discussed within the scope of a quantum mechanical model which is based on the accumulation of internal molecular energy by resonant excitation of collective vibrational states and energy transfer to a trap bond due to dipole-dipole interactions. In this context the GI-SID spectra of n-hexadecylpyridinium and verapamil ions are compared with the fragmentation occurring in regular (252)Cf plasma desorption mass spectrometry.
Cetylpyridinium↗
The quality of life of African American women with breast cancer.
The objectives of this study were to describe the quality of life of African American women with breast cancer and test a model of factors that may affect their quality of life. A stress-coping framework that included person (demographics, current concerns, and optimism), social resources (family functioning), and illness-related factors (symptom distress, medical characteristics), as well as appraisal of illness and quality of life, was used to guide this exploratory, cross-sectional study. Participants included 98 African American women who were approximately 4 years postdiagnosis. The women reported a fairly high quality of life, were generally optimistic, and had effective family functioning. Although symptom distress was generally low, a sizable number of women reported problems with energy loss, sleep disturbances, and pain. The model explained 75% of the variance in quality of life, with appraisal, family functioning, symptom distress, and recurrence status each explaining a significant amount of the variance. Current concerns had an indirect effect on quality of life that was mediated by appraisal. These findings underscore the importance of helping women foster a positive appraisal of their illness, manage current concerns, maintain family functioning, and reduce symptom distress, because each of these factors indirectly or directly affects their quality of life.
Adaptation, Psychological↗
Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype.
Germline mutations of c-met oncogene at 7q31 have been detected in patients with hereditary papillary renal cell carcinoma. In addition, c-met mutations were shown to play a role in 13% of patients with papillary renal cell carcinoma and no family history of renal tumors. The histopathology of papillary renal cell carcinoma with c-met mutations has not been previously described. We analyzed the histopathology of 103 bilateral archival papillary renal cell carcinomas and 4 metastases in 29 patients from 6 hereditary papillary renal cell carcinoma families with germline c-met mutations and 6 papillary renal cell carcinomas with c-met mutations from 5 patients with no family history of renal tumors. Twenty-five sporadic renal tumors with prominent papillary architecture and without somatic c-met mutations were evaluated for comparison. All papillary renal cell carcinomas with c-met mutations were 75 to 100% papillary/tubulopapillary in architecture and showed chromophil basophilic, papillary renal cell carcinoma type 1 histology. Fuhrman nuclear grade 1-2 was seen in tumors from 23 patients, and nuclear grade 3 was observed focally in 8 patients. Seventeen patients had multiple papillary adenomas and microscopic papillary lesions in the surrounding renal parenchyma. Clear cells with intracytoplasmic lipid and glycogen were focally present in tumors of 94% papillary renal cell carcinoma patients. Clear cells of papillary renal cell carcinoma had small basophilic nuclei, and clear cell areas lacked a fine vascular network characteristic of conventional (clear) cell renal cell carcinoma. We conclude that papillary renal cell carcinoma patients with c-met mutations develop multiple, bilateral, papillary macroscopic and microscopic renal lesions. Renal tumors with c-met genotype show a distinctive papillary renal cell carcinoma type 1 phenotype and are genetically and histologically different from renal tumors seen in other hereditary renal syndromes and most sporadic renal tumors with papillary architecture. Although all hereditary and sporadic papillary renal cell carcinomas with c-met mutations share papillary renal cell carcinoma type 1 histology, not all type 1 sporadic papillary renal cell carcinomas harbor c-met mutations.
Adenoma↗
Molecular cloning, tissue distribution, and functional expression of the human Na(+)/H(+) exchanger NHE2.
In the present report, we describe the cloning of a human colonic cDNA that describes the full-length Na(+)/H(+) exchanger (NHE) 2 coding region. The human NHE2 (hNHE2) cDNA encodes for a polypeptide of 812 amino acids with a 90% overall identity to both rabbit and rat NHE2 isoforms. In comparison with SLC9A2, recently reported as the human NHE2, the hNHE2 polypeptide is 115 amino acids longer in the NH(2)-terminal end and shows only an 84% DNA nucleotide sequence identity. Northern blot analysis revealed that hNHE2 message has an uneven tissue distribution, with high levels in the skeletal muscle, colon, and kidney and lower levels in the testis, prostate, ovary, and small intestine. Protein expression studies with hNHE2 clone showed that a 75-kDa protein was expressed. Stable expression of transfected full-length hNHE2 cDNA in Na(+)/H(+) exchange-deficient LAP1 cells exhibited Na(+)-dependent pH recovery after an acid prepulse that was inhibited by 0.1 mM amiloride. These data indicate that this cDNA is the true human NHE2 cDNA and that the encoded protein is capable of catalyzing Na(+)/H(+) exchange activity.
Amino Acid Sequence↗
Hereditary papillary renal carcinoma: pathology and pathogenesis.
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Alleles↗
Cross-cultural applicability in international classifications and research on alcohol dependence.
OBJECTIVE: Underlying cultural differences in the meaning of alcohol problems and dependence symptoms can lead people from different societies to systematically vary in their responses to a diagnostic interview, in ways that may be difficult for researchers to quantify or control. We identify four different ways that cultures can vary in their accounts of dependence symptoms, potentially leading to problems with the cross-cultural applicability of diagnostic criteria: (1) in terms of thresholds of symptom severity, or the point at which respondents from different societies recognize a symptom of dependence as something serious; (2) in the problematization of drinking-related states, or whether the symptoms described in official nomenclature on addiction even count as alcohol problems in all cultures; (3) in causal assumptions about how alcohol-related problems arise; and (4) in the extent to which there exist culture-specific manifestations of symptoms not adequately captured by official disease nomenclature. METHOD: Comparable data on the meaning of alcohol dependence criteria were collected from key informants in nine sites worldwide under the auspices of the WHO/NIH Cross-Cultural Applicability Research Project. Qualitative analysis compares and contrasts descriptions of ICD-10 dependence criteria across sites along the above four dimensions of cultural variation. RESULTS: While descriptions of dependence symptoms were quite similar among key informants from sites that share norms around drinking and drunkenness, they varied significantly in comparisons between sites with markedly different drinking cultures. Contrary to expectation, descriptions of physical dependence criteria appeared to vary across sites as much as the more subjective symptoms of psychological dependence. CONCLUSIONS: Problems with the cultural applicability of international nomenclature warrant careful consideration in future comparative research on addiction, although comparisons of dependence made across some cultural boundaries are likely to be much more problematic than comparisons made across others. Findings on dependence should be interpreted in light of what is known about the drinking cultures and norms of the societies involved. Future nosologies and diagnostic interview schedules should take into account a broad base of cultural experiences in conceptualizing alcohol dependence, in developing criteria and operationalizations and in determining the diagnostic significance of these.
Adolescent↗
Validation studies of an immunochromatographic 1-step test for the forensic identification of human blood.
An immunochromatographic 1-step test for the detection of fecal occult blood was evaluated for applicability for the forensic identification of human blood in stained material. The following experiments were conducted: 1) determination of the sensitivity and specificity of the assay; 2) evaluation of different extraction media for bloodstains (sterile water, Tris buffer pH 7.5 provided in the test kit, 5% ammonia); 3) analysis of biological samples subjected to a variety of environmental insults; and 4) evaluation of casework samples. This immunochromatographic 1-step occult blood test is specific for human (primate) hemoglobin and is at least an order of magnitude more sensitive than previous methods for detecting human hemoglobin in bloodstains. The antigen is insensitive to a variety of environmental insults, except for exposure to certain detergents and household bleaches and prolonged exposure to certain preparations of luminol. The entire assay can be conducted in field testing conditions within minutes. When in the laboratory the supernatant from a DNA extraction is used for the assay, there is essentially no consumption of DNA for determining the presence of human hemoglobin in a forensic sample. The data demonstrate that this test is robust and suitable for forensic analyses.
Animals↗
Genetics in obstetricians' offices: a survey study.
OBJECTIVE: To investigate obstetricians' genetic knowledge base and practice trends. METHODS: A questionnaire survey was sent to 1003 ACOG Fellows, 554 (55%) of whom responded. Results from the 446 respondents practicing obstetrics are reported. RESULTS: The majority of obstetricians surveyed (85.6%) reported completing standardized genetic-history forms for prenatal patients, and about half (48%) performed their own invasive diagnostic procedures. Most (87%) had access to genetic counselors. For aneuploidy risks associated with advanced maternal age, up to 69% of respondents provided at least some patient counseling in their offices. Physician knowledge of risk assessment and diagnostic testing in the areas of aneuploidy and neural tube defects was very good; however, for single-gene disorders such as cystic fibrosis, Tay-Sachs disease, and sickle cell disease, correct risk assessment or appropriate test selection presented difficulties for at least half of the respondents. Respondents cited the rapidity of changes in genetic testing as the greatest obstacle to providing genetic information to patients. CONCLUSION: Obstetricians' knowledge of inheritance and test selection pertaining to single-gene disorders was more limited than that for aneuploidy and neural tube defects. Comparable deficits were noted in patient-education efforts for single-gene disorders.
Congenital Abnormalities↗