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Biomedical subjects

A Rosen

Publications and source records attributed to A Rosen.

At least 91 records · Page 5Linked to original sources
PubMed1999

Autoantigens as substrates for apoptotic proteases: implications for the pathogenesis of systemic autoimmune disease.

Systemic autoimmune diseases are a genetically complex, heterogeneous group of diseases in which the immune system targets a diverse, but highly specific group of intracellular autoantigens. The clustering and marked concentration of these molecules in the surface blebs of apoptotic cells, and their modification by apoptosis-specific proteolytic cleavage and/or phosphorylation at these sites, has focused attention on a unique apoptotic setting as the potential initiating stimulus for systemic autoimmunity. This apoptotic event is likely to (i) occur in a microenvironment containing high concentrations of the targeted antigens, (ii) be pro-immune in nature (e.g. viral infection), and (iii) allow suprathreshold concentrations of antigen with non-tolerized structure (either novel fragments, post-translational modifications, or complexes) to enter the class II processing pathway and initiate a primary immune response. Defective clearance or reduced anti-inflammatory consequences of apoptotic material may be important susceptibility factors in this group of diseases. Once the primary immune response to apoptotic antigens has been initiated, other apoptotic events (occurring in the course of homeostasis or damage) may stimulate the secondary immune response with less stringency, resulting in flares.

Apoptosis↗
PubMed1999

Influence of cigarette-smoking on the result of the triple test.

The aim was to establish whether the risk of trisomy 21 in women smokers undergoing triple test differs to women nonsmokers, whether increased smoking changes the hormonal values, and if the cessation of smoking at the beginning of pregnancy has any influence on the triple test. 1,854 pregnant women were interviewed regarding their smoking habits at the time of the triple test. They were divided into 5 groups: (a) nonsmokers; (b) smokers before pregnancy; (c) 1-5 cigarettes; (d) 6-10; (e) 11 or more. MOM values of AFP, E3 and beta-HCG and Down risk calculated by the triple test were compared within the 5 groups. Increasing smoking was associated with a reduction in MOM values of beta-HCG. Smokers were significantly less likely to be counseled for karyotyping (cut-off level 1:250) than nonsmokers. The values of women who stopped smoking at the beginning of pregnancy were not different to nonsmokers. The results suggest the benefits of inclusion of smoking habits for the calculation of the triple test.

Adult↗
PubMed1999

Prenatal diagnosis of unilateral megalencephaly by 2D and 3D ultrasound: a case report.

Unilateral megalencephaly is a rare malformation of the central nervous system characterized by an overgrowth of one cerebral hemisphere due to an anomaly of neuronal cell migration. It shows macroscopic and histological alterations of the central nervous tissue. We report on a case of this malformation detected prenatally with the support of 3D ultrasonography.

Abortion, Induced↗
PubMed1999

Analysis of radiographic measurements as prognostic indicators of treatment success in patients with developmental dysplasia of the hip.

Measurements were taken and statistically analyzed from the initial radiographs, the 1-year follow-up radiographs, and the most recent radiographs of 81 patients (103 hips) to determine which measurements could predict the success of treatment. The average follow-up was 49 months (range, 12-139 months), and the average age of the patients at the last follow-up was 65 months (range, 15-190 months). Analysis of the data showed that the measurement with statistically significant predictive value was the Tonnis grade of dislocation determined from the initial radiograph. A single unit increase in the Tonnis grade was associated with a doubling of the odds of failure in patients treated with a Pavlik harness (P < 0.04, odds ratio = 2.2) or a closed reduction (odds ratio = 2.0).

Adolescent↗
PubMed1999

Kidney transplantation at the University of Miami.

Of the 1,679 renal allografts performed at the University of Miami between January 1, 1979 and October 31, 1999, 1,154 were from cadaver donors (CAD), 515 were from living-related donors (LRD), and 10 were from living-unrelated donors. The 3 ethnic groups: Black Caribbean-African-American, Hispanic, and others were almost equally represented among recipients. Recipient ages ranged between 1-83 years. In the CAD group, HLA matching was emphasized so that no patient received a kidney with less than one DR match, and for the entire series a mean of 2.59 of 6 HLA antigens were matched between donors and recipients. Overall actuarial 20-year patient and graft survival rates were 65.3% and 30.7%, respectively, with 69.2% patient and 38.5% graft survival rates for LRD, and 65.6% patient and 29.0% graft survival rates for CAD recipients. Several factors adversely affected long-term graft outcome. African-Americans had an overall 20-year graft survival rate of 13.6% compared with 34% for non African-Americans (p < 0.001) (not dependent on patient survival). Diabetic patients had an overall 20-year graft survival rate of 13.5% versus 34.2% for non-diabetics (primarily dependent on patient survival). In the category of non African-American, non-diabetic patients under age 36 (n = 412), the 20-year patient survival rates in the LRD and CAD groups were 85.0% and 79.3%, respectively, and the graft survival rates were 55.7% and 46.5%, respectively. This differed markedly from the results for the entire series.

Adolescent↗
PubMed1998

Impaired liver regeneration in inducible nitric oxide synthasedeficient mice.

The mechanisms that permit adult tissues to regenerate when injured are not well understood. Initiation of liver regeneration requires the injury-related cytokines, tumor necrosis factor (TNF) alpha and interleukin (IL) 6, and involves the activation of cytokine-regulated transcription factors such as NF-kappabeta and STAT3. During regeneration, TNFalpha and IL-6 promote hepatocyte viability, as well as proliferation, because interventions that inhibit either cytokine not only block hepatocyte DNA synthesis, but also increase liver cell death. These observations suggest that the cytokines induce hepatoprotective factors in the regenerating liver. Given evidence that nitric oxide can prevent TNF-mediated activation of the pro-apoptotic protease caspase 3 and protect hepatocytes from cytokine-mediated death, cytokine-inducible nitric oxide synthase (iNOS) may be an important hepatoprotective factor in the regenerating liver. In support of this hypothesis we report that the hepatocyte proliferative response to partial liver resection is severely inhibited in transgenic mice with targeted disruption of the iNOS gene. Instead, partial hepatectomy is followed by increased caspase 3 activity, hepatocyte death, and liver failure, despite preserved induction of TNFalpha, IL-6, NF-kappabeta, and STAT3. These results suggest that during successful tissue regeneration, injury-related cytokines induce factors, such as iNOS and its product, NO, that protect surviving cells from cytokine-mediated death.

Animals↗
PubMed1998

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Journal Article↗
PubMed1998

The caspase-3 precursor has a cytosolic and mitochondrial distribution: implications for apoptotic signaling.

Caspase-3-mediated proteolysis is a critical element of the apoptotic process. Recent studies have demonstrated a central role for mitochondrial proteins (e.g., Bcl-2 and cytochrome c) in the activation of caspase-3, by a process that involves interaction of several protein molecules. Using antibodies that specifically recognize the precursor form of caspase-3, we demonstrate that the caspase-3 proenzyme has a mitochondrial and cytosolic distribution in nonapoptotic cells. The mitochondrial caspase-3 precursor is contained in the intermembrane space. Delivery of a variety of apoptotic stimuli is accompanied by loss of mitochondrial caspase-3 precursor staining and appearance of caspase-3 proteolytic activity. We propose that the mitochondrial subpopulation of caspase-3 precursor molecules is coupled to a distinct subset of apoptotic signaling pathways that are Bcl-2 sensitive and that are transduced through multiple mitochondrion-specific protein interactions.

Apoptosis↗
PubMed1998

Caspase-mediated proteolysis during apoptosis: insights from apoptotic neutrophils.

Apoptosis is initiated by activation of caspases (interleukin 1beta-converting enzyme homologues), which cause coordinated cleavage of several death substrates that function in structural or homeostatic pathways. The relationship between substrate cleavage and apoptosis is not yet known, nor is it clear whether cleavage of specific substrates is a critical requirement for apoptosis. The human neutrophil provides novel insights into the roles of proteolysis of specific substrates during apoptosis, since only a subset of caspase substrates are present in mature neutrophils. Of the death substrates we screened, PARP, the nuclear mitotic apparatus protein (NuMA), the 70 kDa subunit of the U1 small ribonucleoprotein (U1-70kDa) and the catalytic subunit of DNA-dependent protein kinase (DNA-PK(CS)) were not detected in non-apoptotic neutrophils; in contrast, lamin B and fodrin were present in amounts similar to those found in other cells. Caspase-3 activity was absent in freshly isolated neutrophils, but was detected when neutrophils were aged in vitro, coincident with the onset of morphologic and biochemical apoptosis. The absence of PARP, NuMA, U1-70kDa and DNA-PK(CS) in non-apoptotic neutrophils suggests that these are not critical anti-apoptotic proteins, and that their fragments are not required components of the neutrophil apoptotic pathway. These studies highlight the conserved role of caspase activation in the apoptotic mechanism, and focus attention on several conserved structural substrates as potential transducers of the proteolytic signal in apoptosis.

Apoptosis↗
PubMed1998

Group B streptococci during pregnancy: a comparison of two screening and treatment protocols.

OBJECTIVE: The objective was to evaluate whether the rate of neonatal group B streptococcal infection could be reduced by screening for group B streptococci during the third trimester of pregnancy. STUDY DESIGN: Two periods in which different screening and treatment protocols were applied were compared. In period A all mothers showing high-risk factors were given peripartal antibiotic coverage. In period B vaginal and rectal smears were routinely obtained in gestational week 34 and cultured for group B streptococci. If culture results were positive, the woman received peripartal antibiotics. The incidence of group B streptococcal infections and the number of peripartal antibiotic doses were established by comparing 3700 neonates (3623 mothers) in period A with 3648 neonates (3569 mothers) in period B. RESULTS: In period A, 20 group B streptococcal infections were recorded. Of these, 5 were severe to life-threatening. In period B, 4 group B streptococcal infections were observed. Two were severe and occurred in neonates born before the mothers could be screened. Another 2 were mild and occurred in neonates whose mothers had negative screening test results. The reduction was significant by the chi2 test (chi2 = 9.19, Yates' corrected P = .0024). The rates of peripartal antibiotic treatment were 11.9% in period A and 14.5% in period B. CONCLUSION: Although no neonate died of group B streptococcal sepsis in either of the 2 periods, the protocol used in period B clearly reduced the incidence of group B streptococcal infection. The number of peripartal antibiotic doses required was not much higher than in period A. Screening for group B streptococci in week 34 seems to be a valuable contribution to further improvement of neonatal outcome.

Anti-Bacterial Agents↗
PubMed1998

Rheumatoid arthritis of the wrist and hand.

A complete assessment of the entire patient along with a clear understanding of the progression of rheumatoid deformities is the key to success when contemplating surgical intervention for rheumatoid arthritis of the hand. The decision to perform surgery must be made following careful evaluation of the patient's signs and symptoms weighed against the potential benefits likely to be gained. The surgical plan will vary from patient to patient and should be tailored accordingly. Early in the disease process, conservative measures including pharmacologic intervention, steroid injections, and hand therapy, including splinting and wrist use modification, are indicated. Surgical intervention, however, should not be avoided for so long that the benefit of successful intervention is diminished. Hand surgery has proven to be effective in correcting deformity and maintaining or increasing function in patients with rheumatoid arthritis. The indications for synovectomy, tenosynovectomy, tendon repair or realignment, arthroplasty, and arthrodesis have been well established. Superior results are possible when surgical reconstruction is performed before tendon rupture, severe fixed contractures, subluxation, or dislocation.

Arthritis, Rheumatoid↗
PubMed1998

Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis.

Caspase-mediated proteolysis of downstream substrates is a critical element of the execution pathway common to all forms of apoptosis studied to date. While this caspase-dependent pathway is activated during cytotoxic lymphocyte granule-induced cell death, recent studies have also provided evidence for caspase-independent pathways. However, the mechanisms mediating these additional pathways have not been defined. The current study demonstrates that DNA-PKcs and NuMA are directly and efficiently cleaved by granzyme B in vitro and in vivo, generating unique substrate fragments not observed during other forms of apoptosis. This direct, caspase-independent ability of granzyme B to cleave downstream death substrates constitutes an apoptotic effector mechanism that is insensitive to inhibitors of the signaling or execution components of the endogenous apoptotic cascade.

Antigens, Nuclear↗