Capillary transit time heterogeneity inhibits cerebral oxygen metabolism in patients with reduced cerebrovascular reserve capacity from steno-occlusive disease

The healthy cerebral perfusion demonstrates a homogenous distribution of capillary transit times. A disruption of this homogeneity may inhibit the extraction of oxygen. A high degree of capillary transit time heterogeneity (CTH) describes that some capillaries have very low blood flows, while others have excessively high blood flows and consequently short transit times. Very short transit times could hinder the oxygen extraction due to insufficient time for diffusion of oxygen into the tissue. CTH could be a consequence of cerebral vessel disease. We examined whether patients with cerebral steno-occlusive vessel disease demonstrate high CTH and if elevation of cerebral blood flow (CBF) by administration of acetazolamide (ACZ) increases the cerebral metabolic rate of oxygen (CMRO₂), or if some patients demonstrate reduced CMRO₂ related to detrimental CTH. Thirty-four patients and thirty-one healthy controls participated. Global CBF and CMRO₂ were acquired using phase-contrast MRI. Regional brain maps of CTH were acquired using dynamic contrast-enhanced MRI. Patients with impaired cerebrovascular reserve capacity demonstrated elevated CTH and a significant reduction of CMRO₂ after administration of ACZ, which could be related to high CTH. Impaired oxygen extraction from CTH could be a contributing part of the declining brain health observed in patients with cerebral vessel disease.     

The survivors of gastroschisis

AIMS: To assess the long term morbidity and quality of life in survivors of gastroschisis. DESIGN: All babies born with gastroschisis between 1972 and 1984 and who survived more than one year were identified. Those who could be traced were questioned about their general health, growth, abdominal symptoms, cosmetic concerns, education, employment, and fertility. RESULTS: Of the 35 patients, two have died, seven could not be traced, and three declined to be interviewed. Twenty three subjects (70% of survivors) with a median age of 16 years (range 12-23 years) responded. Twenty two (96%) were in good health and overall growth was within normal limits. Eight subjects (35%) have had further surgery related to gastroschisis, including two for adhesive small bowel obstruction and three for scar complications. In 13 (57%), absence of an umbilicus caused distress during childhood. CONCLUSION: Most gastroschisis survivors can eventually expect normal growth and good health. Adhesive bowel obstruction is an uncommon, but potentially late, complication. The umbilicus should be conserved during gastroschisis repair.     

Prevalence of Asherman's syndrome after secondary removal of placental remnants or a repeat curettage for incomplete abortion

This prospective study assesses the prevalence of intrauterine adhesions among women undergoing secondary removal of placental remnants after delivery, or a repeat curettage for incomplete abortions, and evaluates risk factors associated with the presence of intrauterine adhesions. In 50 women, undergoing either a secondary removal of placental remnants more than 24 h after delivery, or a repeat curettage for incomplete abortions, ambulatory hysteroscopy was performed 3 months after the intervention. Intrauterine adhesions were found in 20 of the women (40%): five patients had Asherman's syndrome grade I, six had grade II, six had grade III and three had grade IV. In women with menstrual disorders a statistically significant 12-fold increased risk for Asherman's syndrome grade II-IV was found. Previous abortion as well as infection during surgery were associated with a mildly but non-significant increased risk. Based on our findings, hysteroscopy is recommended only in those patients who develop menstrual disorders, either after secondary intervention for placental remnants after delivery or after a repeat curettage.      

Altered glycosaminoglycan production by HL-60 cells treated with 4- methylumbelliferyl-beta-D-xyloside

Glycosaminoglycans, mainly chondroitin 4-sulfate, are located in the primary granules of human myeloid cells. These polyanionic carbohydrates are believed to play an important role in leukocyte maturation and function. To study the effect of altered chondroitin sulfate metabolism on human promyelocytic leukemia cells, we have treated HL-60 cells with 4-methylumbelliferyl-beta-D-xyloside. beta-D- Xylosides initiate the synthesis of free chondroitin sulfate chains. Cytochemical studies of treated cells demonstrated a marked increase in cytoplasmic granules stained with cationic dyes. This was confirmed by radiolabeled precursor incorporation studies that demonstrated a 344% increase in 35S-sulfate uptake into glycosaminoglycans associated with the cells and a 39% increase in incorporation into glycosaminoglycans released into the media. Chromatographic analyses of these glycosaminoglycans from treated cells demonstrated that the newly formed chondroitin sulfate chains were not attached to protein core and were of shorter length, but of greater charge density than chondroitin sulfate produced by control cells. Thus, beta-D-xyloside appears to alter the protein linkage, chain length, and sulfation of chondroitin sulfate produced by HL-60 cells, and these changes are morphologically evident. These biochemically altered cells may provide important information concerning the role of these macromolecules in myeloid development.     

A heparan sulfate-containing fraction of bone marrow stroma induces maturation of HL-60 cells in vitro

Constituents of the bone marrow microenvironment have the capacity to influence both normal and malignant hematopoietic cell behavior. For example, HL-60 human promyelocytic leukemia cells in vitro display a more mature phenotype when grown on a bone marrow stroma-derived matrix. To elucidate which component(s) of the stromal matrix is capable of modulating HL-60 cell phenotype, matrices were treated with a variety of chemicals and enzymes prior to being used in the differentiation assay. Treatment of matrices with collagenase, pronase, chondroitinase, or chloroform:methanol:ether could not abolish the differentiation-promoting activity of bone marrow stroma. In contrast, the activity was destroyed by alkali treatment (0.5 M NaOH for 18 h) or heparinase/heparitinase enzymes. Heparin added to cultures increased maturation of HL-60 cells as determined by esterase production, Fc rosette formation, and morphological appearance. Other stromal components such as laminin, fibronectin, collagen I, collagen IV, or chondroitin sulfate did not alter the HL-60 leukemia cell phenotype. Stroma-derived matrix material which labeled with [35S]sulfate and eluted on a DEAE ion-exchange column as a high ionic fraction in 1.5 M LiCl and 7.5% sodium dodecyl sulfate contained the active fraction. A heparan sulfate proteoglycan component isolated by polyacrylamide-agarose gel electrophoresis induced a more mature HL-60 phenotype, and digestion with heparinase/heparitinase in the presence of protease inhibitors abrogated the effects on HL-60 phenotype. We conclude that a heparan sulfate-associated fraction of the bone marrow matrix plays a key role in the regulation of leukemic cell maturation.     

Peripheral blood leukocyte counts in cytomegalovirus infected heart transplant patients: impact of acute disease versus subclinical infection

BACKGROUND: Cytomegalovirus (CMV)-associated leucopenia in heart transplant patients is poorly characterized. METHODS: We conducted a retrospective analysis of timing, degree, and type of leukopenia in four groups of patients: cases (n=20); controls (n=20); subclinical early infection (n=21), and subclinical late infection (n=22). In the cases, white blood cells (WBC) count at diagnosis was compared to prediagnosis; and cases were compared to controls. Subclinical cases (early and late) were identified by measurement of CMV DNA in peripheral blood mononucleocytes, and WBC was compared to those of the cases and controls. RESULTS: First, in human heart transplant recipients the total leukocyte count decreased prior to the time of diagnosis of CMV disease: cases: 5.4+/-2.1 x 10/microL vs. 3.7+/-2.1x10/muL (P<0.01); subclinical early: 8.1+/-4.1 x 10/microL vs. 6.9+/-1.6 x 10/microL (P<0.01). Second, the leukocyte populations most reduced during CMV disease are the neutrophils: 4.4 x 10/microL (78%) to 2.5 x 10/microL (69%) (P<0.05), and monocytes 0.6 x 10/microL (11%) to 0.3 x 10/microL (7.5%) (P<0.05). Third, the reduction in leukocyte count that occurs during CMV disease appears to be independent of immunosuppressive therapy (using cyclosporine A, mycophenolate mofetil, or azathioprine and prednisone). Finally, subclinical CMV infection in stable long-term heart transplant patients without disease is unassociated with a reduction in the leukocyte count. CONCLUSIONS: Aside from implications for early diagnosis, CMV-associated decrease in monocytes is important because viral infections like Epstein-Barr virus cause monocytosis. The absence of leucopenia in subclinical late infections is a new important finding.     

High-dose etoposide therapy for extensive small cell lung cancer: a Cancer and Leukemia Group B Study

Twenty-one previously untreated patients with extensive small cell lung cancer were treated with etoposide, 400 mg/m2/day for 3 consecutive days. Myelosuppression was severe, with a treatment-related death rate of 28%. Five partial responses were achieved. High-dose etoposide as given in this study produced unacceptable toxicity and no complete responses.     

Bone marrow matrix promotes differentiation and prolongs the cell cycle of U-937 cells.

The extracellular matrix influences the growth and differentiation of a variety of cell types. In this study, the effects of bone marrow extracellular matrix on U-937 cells, a human histiocytic lymphoma cell line, were assessed. Sixty percent of U-937 cells adhered to extracellular matrix, whereas only 1% adhered to uncoated plastic. U-937 cells grown on extracellular matrix released significantly more lysozyme into the medium (8.3 +/- 0.3 micrograms/10(6) cells) compared to those grown on plastic (4.2 +/- 0.5 micrograms/10(6) cells). FMLP (f-met-leu-phe) receptor expression was also enhanced suggesting a more mature phenotype in cells grown on matrix (2980 cpm/10(6) cells vs 230 cpm/10(6) cells on plastic). Furthermore, bone marrow extracellular matrix inhibited proliferation of U-937 cells. After four days in culture, there was a 65% inhibition of cell growth in matrix-coated flasks compared to uncoated flasks. Since an arrest in G0/G1 usually precedes mammalian cell differentiation, DNA histograms were performed on U-937 cells grown on matrix to detect such an arrest. However, the cell cycle distribution of U-937 cells grown on extracellular matrix or uncoated plastic for various time periods was similar. In contrast, bromodeoxyuridine pulse labeling revealed approximately a 5 hr prolongation in cycle length in cells grown on extracellular matrix. We conclude that bone marrow extracellular matrix induced macrophage-like differentiation and inhibited proliferation of U-937 cells with a prolongation of the cell cycle that was not G0/G1 phase specific.