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Biomedical subjects

M Kramer

Publications and source records attributed to M Kramer.

At least 19 recordsLinked to original sources
PubMed1992

Effective activation of the proenzyme form of the urokinase-type plasminogen activator (pro-uPA) by the cysteine protease cathepsin L.

Increased levels of both the cysteine protease, cathepsin L, and the serine protease, uPA (urokinase-type plasminogen activator), are present in solid tumors and are correlated with malignancy. uPA is released by tumor cells as an inactive single-chain proenzyme (pro-uPA) which has to be activated by proteolytic cleavage. We analyzed in detail the action of the cysteine protease, cathepsin L, on recombinant human pro-uPA. Enzymatic assays, SDS-PAGE and Western blot analysis revealed that cathepsin L is a potent activator of pro-uPA. As determined by N-terminal amino acid sequence analysis, activation of pro-uPA by cathepsin L is achieved by cleavage of the Lys158-Ile159 peptide bond, a common activation site of serine proteases such as plasmin and kallikrein. Similar to cathepsin B (Kobayashi et al., J. Biol. Chem. (1991) 266, 5147-5152) cleavage of pro-uPA by cathepsin L was most effective at acidic pH (molar ratio of cathepsin L to pro-uPA of 1:2,000). Nevertheless, even at pH 7.0, pro-uPA was activated by cathepsin L, although a 10-fold higher concentration of cathepsin L was required. As tumor cells may produce both pro-uPA and cathepsin L, implications for the activation of tumor cell-derived pro-uPA by cathepsin L may be considered. Different pathways of activation of pro-uPA in tumor tissues may coexist: (i) autocatalytic intrinsic activation of pro-uPA; (ii) activation by serine proteases (plasmin, kallikrein, Factor XIIa); and (iii) activation by cysteine proteases (cathepsin B and L).

Amino Acid Sequence↗
PubMed1992

cis and trans elements differ among mouse strains with high and low extrahepatic complement factor B gene expression.

Factor B (Bf), an enzyme of the alternative pathway of complement activation, is one of four major histocompatibility complex (MHC) class III genes. To ascertain the genetic mechanism for tissue-specific constitutive and regulated expression of Bf, we sequenced the regulatory regions 5' of the gene from mice of different H-2 MHC haplotypes and assessed trans-acting factors, specific DNA binding nucleoproteins, in liver and kidney. Striking tissue-specific differences in constitutive expression of Bf were demonstrated in mice of H-2f or H-2z haplotypes when compared with H-2d or H-2u (kidney and intestinal Bf in H-2d or H-2u much greater than H-2f or H-2z). These differences correlated with a point nucleotide substitution 3 bp downstream of the upstream Bf initiation site that affects interaction with a DNA binding protein. This and additional cis differences localize the sequence substitutions responsible for previously identified restriction fragment length polymorphisms among inbred mouse strains and also reveal two previously unrecognized polymorphisms generated by SmaI and HinfI digestion. Evidence for differences in trans was found in a comparison of DNA binding nucleoproteins from kidney, but not liver, of B10.PL when compared with B10.M. These data, together with the high degree of sequence homology between human and mouse Bf 5' flanking regions, should prompt a search for polymorphic restriction sites and cis binding elements in the Bf promoter that could serve as markers of human MHC-associated renal pathology and variants in local MHC class III gene expression.

Animals↗
PubMed1992

Cardiac function after domino-donor heart transplantation.

A major limitation in cardiac transplantation is donor availability. A possible way to increase the supply of donor hearts is to use explanted hearts from patients undergoing heart-lung transplantation for primary lung disease. One potential advantage of this approach, termed domino-donor transplantation, is the existence of a donor right ventricle already adapted to pulmonary hypertension, which would therefore theoretically decrease the likelihood of acute donor right heart failure in recipients with preexisting elevation of pulmonary vascular resistance. Potential disadvantages include graft failure secondary to chronic effects of pulmonary hypertension on the right ventricle, arrhythmia and infections. Seven domino-donor transplants were performed at Stanford University Hospital; graft and patient survival to date are 100% at a mean follow-up of 20 months (range 1 to 26). Infection and rejection rates have been comparable to those of the current Stanford experience for conventional orthotopic transplantation. Right ventricular function and size have either improved or remained unchanged in all patients after transplantation. Transient early postoperative donor right ventricular dilation, a characteristic adaptive response seen in nondomino transplants, occurred in 4 patients with pulmonary hypertension before surgery. These data indicate that, with adequate assessment before surgery, domino-donor cardiac transplantation is an appropriate means of augmenting the donor pool.

Actuarial Analysis↗
PubMed1992

Reduction in the incidence of Clostridium difficile-associated diarrhea in an acute care hospital and a skilled nursing facility following replacement of electronic thermometers with single-use disposables.

OBJECTIVE: To determine if the spread of Clostridium difficile-associated diarrhea is related to the use of electronic thermometers in an acute hospital and a chronic healthcare facility. DESIGN: After finding that a significant percentage (20.8%) of electronic rectal thermometer handles were contaminated with C difficile, all electronic thermometers were replaced with disposables. A before/after trial was conducted to determine if the change to disposable thermometers would reduce the incidence of C difficile-associated diarrhea. SETTING: The study took place in a 343-bed acute hospital and a 538-bed skilled nursing facility. PATIENTS: All patients who underwent routine microbiological evaluation for nosocomially acquired diarrhea over a 1-year period were included in the study. Nosocomial diarrhea was defined as 3 or more loose stools per day for 2 consecutive days and/or abdominal findings such as pain, distension, and ileus occurring 3 or more days after admission. RESULTS: During the 6-month postintervention period, the incidence of C difficile-associated diarrhea was reduced from 2.71/1,000 patient days to 1.76/1,000 patient days in the acute hospital and from 0.41/1,000 patient days to 0.11/1,000 patient days in the skilled nursing facility. The protective effect of the intervention was statistically significant for both facilities. CONCLUSIONS: Replacement of electronic thermometers with single-use disposables significantly reduced the incidence of C difficile-associated diarrhea in both acute care and skilled nursing care facilities. Data suggest that the rectal route may be important in the transmission of C difficile in these settings.

Aged↗
PubMed1992

Pulmonary involvement as the major manifestation of chronic lymphocytic leukemia.

Respiratory symptoms and abnormal findings on chest X-ray are frequently noted in patients with chronic lymphocytic leukemia (CLL). However, most of these represent pulmonary infections or mediastinal lymphadenopathy, and leukemic involvement of the lung is seldom diagnosed during life. In this report we describe three patients with non-progressive, responsive CLL who developed biopsy proven pulmonary infiltration with CLL. In one case, pulmonary involvement was the sole manifestation of recurrent disease and a second case had little disease elsewhere with minimal CLL in the blood at the time pulmonary involvement appeared. In all three cases, transbronchial biopsy and bronchoalveolar lavage performed during fibreoptic bronchoscopy provided adequate tissue for diagnosis. We conclude that CLL may involve the lung even in the presence of a low peripheral white blood cell count with responsive disease elsewhere, and can readily be diagnosed by transbronchial biopsy and bronchoalveolar lavage.

Adult↗
PubMed1992

[The exposure of the population to toxic substances in the interior of motor vehicles--the example of benzene].

The exposure of the population to benzene is caused in the first place by emissions of the motor-vehicle traffic. The air pollution concentrations in main traffic routes and in the sphere of influence of industrial plants amount to 5-30 micrograms Benzene/m3 in the course of the year. In indoor air about 6-12 micrograms/m3 are detectable, in the interior of motor-vehicles between 50 and 200 micrograms/m3. Smoking raises the individual burden significantly; in contrast food and drinking water amount only for a small part of the total intake of benzene. In rural areas with low outdoor-air concentrations the main source of burden can be the intake of benzene during the use of motor-vehicles. Despite the relatively low carcinogenic potency of benzene but because of the unfavourable exposure conditions and the comparatively high concentrations measures for the reduction of benzene in fuel should be taken immediately.

Air Pollutants↗
PubMed1992

[Case study of a Legionella epidemic in a rehabilitation clinic].

A series of nosocomial Legionella infections in a rehabilitation center is reported. In a three months period a total of 10 pneumonias with 3 deaths occurred (8 patients, 1 companion, 1 staff member). Serologic analysis proved additional Legionella infections within the nursing staff. The warm-water system was proved to be the source of infection by isolating Legionella pneumophila serogroup 1 subtype Pontiac both in warm-water and patients samples. The air conditioning system could not be ruled out as another (secondary) route of exposure because of shortcomings in construction. Conclusions about prevention and the course of the disease are discussed and standards for warm-water and air conditioning systems are proposed.

Adult↗
PubMed1991

Cathepsin B efficiently activates the soluble and the tumor cell receptor-bound form of the proenzyme urokinase-type plasminogen activator (Pro-uPA).

Action of purified human cathepsin B on recombinant single-chain urokinase-type plasminogen activator (pro-uPA) generated enzymatically active two-chain uPA (HMW-uPA), which was indistinguishable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot from plasmin-generated HMW-uPA and from elastase- or thrombin-generated inactive two-chain urokinase-type plasminogen activator. Preincubation of cathepsin B with E-64 (transepoxysuccinyl-L-leucylamino- (4-guanidino)butane, a potent inhibitor for cathepsin B) prior to the addition of pro-uPA prevented the activation of pro-uPA. The cleavage site within the cathepsin B-treated urokinase-type plasminogen activator (uPA) molecule, determined by N-terminal amino acid sequence analysis, is located between Lys158 and Ile159. Pro-uPA is cleaved by cathepsin B at the same peptide bond that is cleaved by plasmin or kallikrein. Binding of cathepsin B-activated pro-uPA to the uPA receptor on U937 cells did not differ from that of enzymatically inactive pro-uPA, indicating an intact receptor-binding region within the growth factor-like domain of the cathepsin B-treated uPA molecule. Not only soluble but also tumor cell receptor-bound pro-uPA could be efficiently cleaved by cathepsin B to generate enzymatically active two-chain uPA. Thus, cathepsin B can substitute for plasmin in the proteolytic activation of pro-uPA to enzymatically active HMW-uPA. In contrast, no significant activation of pro-uPA by cathepsin D was observed. As tumor cells may produce both pro-uPA and cathepsin B, implications for the activation of tumor cell-derived pro-uPA by cellular proteases may be considered.

Blotting, Western↗
PubMed1991

The influence of birth setting on the father's behavior toward his partner and infant.

As part of a controlled, clinical trial conducted to compare medical and psychological outcomes of a birth room and a conventional hospital setting, we examined the behavior of fathers toward their partners and infants. One hundred fourteen couples were systematically assigned to either locale by strict alternation. They learned about this allocation on arrival at the hospital in labor. Observations of fathers' behavior were made at midlabor and during home visits at three months and one year. During labor, fathers assigned to the conventional setting were more involved in helping and encouraging their partners. Parenting behavior was not influenced by the birth setting. Unexpectedly, fathers were more involved with their infants when the mothers had expressed less satisfaction with childbirth. Compensation behavior may explain these results, which can be seen as appropriately adaptive in the face of perceived environmental deficiencies affecting the laboring woman and the infant.

Adult↗
PubMed1991

The "natural history" of the transplanted lung: rates of pulmonary functional change in long-term survivors of heart-lung transplantation.

Long-term pulmonary function in HLT is well preserved with no evidence of functional decline as a result of transplant "aging," providing the allografts remain free of complications. Long-term survivors with OB appear to be able to maintain adequate oxygenation despite the marked alterations of pulmonary function. The ability to preserve gas exchange at reasonable levels of oxygenation may be the factors permitting extended survival with OB for mean periods of 36.0 months or greater. Preliminary studies suggest that a declining FEF50/FVC, at a time when pulmonary function is normal, may be an index of impending airway disease. Physiologically, from a long-term point of view, HLT remains a viable option for selected patients with end-stage cardiopulmonary disease.

Bronchiolitis Obliterans↗
PubMed1990

Racial congruity as a contextual correlate of mental disorder.

The effects of exposure to racially dissonant residential environments on depressive psychopathology are explored. Epidemiological survey data are shown to support the hypothesis that an inverse relationship exists between racial congruity and depression. Limitations of the analysis are discussed, as are the social implications of the findings.

Adjustment Disorders↗
PubMed1990

Role of instability in the cis action of the insertion sequence IS903 transposase.

An unusual subset of DNA-binding proteins, termed cis-acting proteins, has been shown to act preferentially at their site of synthesis; the transposases of several bacterial insertion sequences (ISs) fall into this class. The transposase of IS903 exhibits a strong preference for action in cis: complementation of defective transposons in trans occurs at less than 1%. Furthermore, transposition mediated by transposase acting in cis is extremely sensitive to the distance between the 3' end of the transposase gene and the nearest transposon inverted repeat; we find that an insertion of 1 kilobase of DNA reduces transposition to 1-2% of control levels. Here we show that there is a strong correlation between the stability of transposase and its ability to act in trans. We found that the wild-type transposase is a very unstable protein with a physical half-life of about 3 min. However, a transposase-beta-galactosidase fusion protein has a much greater half-life and can act equally well in cis or in trans. In addition, the native transposase is stabilized in lon- strains of Escherichia coli, and, in these protease-deficient strains, trans action of transposase is increased 10- to 100-fold. These results suggest that instability of the IS903 transposase is a major determinant of its cis action and that the La protease, product of the lon gene, is an important determinant of transposase instability.

DNA Transposable Elements↗