Effect of exchange exocrine pancreatic insufficiency on small intestine in the mouse.

A genetically conditioned mouse model of exocrine pancreatic insufficiency (epi) has been used to study the effect of the absence of lumenal proteases on small intestinal mucosal proteins. The small bowel was divided into eight equal segments. Enzyme activity was increased only in the first three segments in the case of maltase, sucrase, and lactase (all mol wt above 200,000). Alkaline phosphatase (mol wt 145,000), trehalase (mol wt 95,000), and peptidase (mol wt 175,000) activities were unaffected in proximal segments from epi mice. Proximal brush border proteins were identified and measured quantitatively by sodium dodecyl sulfate acrylamide gel electrophoresis. Those enzymes with increased activity were associated with increased amounts of protein in epi mice. Double labeled studies of protein turnover revealed a longer half-life for large brush border proteins (mol wt above 175,000) in epi mice than in normal mice. Enterokinase activity (a marker for duodenal mucosa) was nearly absent from the duodenum of epi mice. Receptors for the intrinsic factor-vitamin B12 complex (markers for ileal mucosal) were present in the ileum equally in normal and in epi mice. Enterokinase activity can be induced in epi mice by feeding its substrate trypsinogen, but not by trypsin or chymotrypsinogen. Epi mice thus retain the ability to synthesize enterokinase. Pancreatic proteases play an important role in the turnover of certain large mucosal proteins and in the induction of enterokinase.     

Telomere-mediated mitotic disturbances in immortalized ovarian epithelial cells reproduce chromosomal losses and breakpoints from ovarian carcinoma

Ovarian carcinomas (OCs) often exhibit highly complex cytogenetic changes. Abnormal chromosome segregation at mitosis is one potential mechanism for genomic rearrangements in tumors. In this study, OCs were demonstrated to have dysfunctional short telomeres, anaphase bridging, and multipolar mitoses with supernumerary centrosomes. When normal human ovarian surface epithelial (HOSE) cells were transfected with human papilloma virus 16 e6/e7 genes and subsequently driven into telomere crisis, the same set of mitotic disturbances occurred in a distinct sequence, initiated by telomere dysfunction, followed by anaphase bridging, and then supernumerary centrosomes and multipolar mitoses. The anaphase bridges resolved either by kinetochore-spindle detachment, corresponding to whole-chromosome losses in the HOSE karyotypes, or by extensive fragmentation of intercentromeric DNA sequences, corresponding to a high frequency of pericentromeric rearrangements. At later passages, the high degree of instability at telomere crisis was moderated by telomerase expression and centrosome coalescence, ultimately leading to a level of mitotic instability that was highly similar to that in OC cell lines and to complex karyotypes that were similar to those observed in high-grade OCs. This suggests that a significant proportion of the structural chromosome changes and genomic losses in OC are caused by a specific sequence of mitotic disturbances triggered by telomere crisis. That the model did not produce any of the whole-chromosome gains observed in OC indicates that these changes develop through a different mechanism.     

School absenteeism in children with asthma in a Los Angeles inner city school

OBJECTIVE: To investigate the pattern of school absenteeism in asthmatic children within a Los Angeles inner city school. STUDY DESIGN: Five hundred twenty-eight students of predominant Hispanic ethnicity, from a Los Angeles inner city school were divided into 3 groups: known asthma, high probability of asthma, and low probability of asthma using a previously validated instrument. Attendance records of these students were analyzed to determine total and respiratory absences over a year. School records were compared to the corresponding answers on 513 surveys to determine the accuracy of parental responses in regard to their children's absenteeism. RESULTS: Children with known asthma missed on average 2 more days of school than children with low probability of asthma and high probability of asthma. This was only significant in the younger age groups. Survey responses were found to have a 45.6% agreement with school attendance records. Underestimation occurred more often when school-recorded absentee rates were highest. Overestimation occurred more by parents of children with known asthma or a high probability of asthma. CONCLUSION: In a Los Angeles inner city population, younger children with known asthma miss more days of school than those with no asthma. Survey-reported absenteeism is less accurate than school attendance records.     

Therapy-related acute myeloid leukemia after single-agent treatment with fludarabine for chronic lymphocytic leukemia

A 70-year-old man with B-cell chronic lymphocytic leukemia (CLL) received single-agent treatment with the purine analogue fludarabine, which led to complete remission. After 8 years, he presented with pancytopenia. Marrow examination showed acute myeloid leukemia (AML) with trilineage myelodysplasia (MDS). Cytogenetic analysis showed an unbalanced der(1;7)(p10;q10) that resulted effectively in deletion 7q; confirming the diagnosis of therapy-related AML (t-AML). No residual CLL was present. Together with previous reports of secondary cancers after fludarabine treatment and the association of monosomy 7/7q- with another purine analogue azathioprine, results suggest that t-AML might develop after fludarabine therapy.     

Temporal profiling of gene expression during neurogenesis and remodeling in the olfactory epithelium at short intervals after target ablation

Neurogenesis in the olfactory epithelium (OE) is induced by olfactory bulbectomy (OBX), which effectively axotomizes olfactory sensory neurons (OSNs) and removes their synaptic targets, resulting in apoptosis. We used Affymetrix high-density oligonucleotide arrays to investigate changes in gene expression during initiation of signaling in pathways that regulate apoptosis and neurogenesis in the murine OE at 2, 8, 16, and 48 hr after bilateral OBX compared to that in sham-operated controls. We focused on regulation of a defined set of genes associated with apoptosis, stem/progenitor cell regulation, and cell cycle progression because of the activation of these processes in OE degeneration and remodeling after OBX. After data scrubbing and categorical analysis, one-way analysis of variance identified 72 genes (4.9% of the present known genes) as being regulated significantly (P < 0.05) at one or more points; 50 were defined as regulated differentially with the false discovery rate at 10%. Significant changes in gene expression occurred in all categories as early as 2 hr post-OBX, with the greatest number of differentially regulated genes at 16 and 48 hr. Hierarchical cluster analysis and correlation coefficients were used to identify similarities in patterns of gene expression changes within and across categories. Validation was carried out with SuperArray macroarrays and real-time RT-PCR. Our results confirmed the participation of many genes in known signaling pathways and identified changes in the expression of 42 genes not identified previously as participating in apoptosis and neurogenesis in the OE. Additionally, our analyses indicated the early involvement of genes regulating cytoskeletal reorganization and angiogenesis in the response to OBX. These studies are an important first step in defining early time-dependent changes in gene expression after target ablation that lead to neurogenesis in the olfactory sensory epithelium.     

Support for Barker hypothesis upheld in rat model of maternal undernutrition during the preimplantation period: application of integrated 'random effects' statistical model

In response to a recent paper published in Reproductive BioMedicine Online by Walters and Edwards (2003), this study reports the application of a random effects regression analysis for evaluation of integrated data involving maternal and embryo/offspring components. Using this method, it is possible to confirm the conclusions of an earlier study that rat maternal undernutrition during the preimplantation period results in blastocyst cell number reduction and post-natal outcomes, including altered growth rates and elevated blood pressure.     

Neuroanatomy of adult strabismus: a voxel-based morphometric analysis of magnetic resonance structural scans

Cerebral deficit has been implicated in the genesis of strabismus and in the mechanisms adopted to compensate for the visual disorder. Voxel-based morphometry (VBM) was applied to magnetic resonance images of strabismic adults to detect any abnormal brain anatomy, which could not be easily identified by simple inspection. The gray matter volume in strabismic adults was smaller than that in normal subjects at the areas consistent with the occipital eye field (OEF) and parietal eye field (PEF). However, greater gray matter volume was found in strabismic adults relative to normal controls at the areas consistent with the frontal eye field (FEF), the supplementary eye field (SEF), the prefrontal cortex (PFC), and subcortical regions such as the thalamus and the basal ganglia. These opposite gray matter changes in the visual and the oculomotor processing areas are compatible with a hypothesis of plasticity in the oculomotor regions to compensate for the cortical deficits in the visual processing areas.     

Triamcinolone suppresses human tenocyte cellular activity and collagen synthesis

Glucocorticoid injection is widely used in tendon disorders. Despite previous studies on the histologic and biomechanical changes in tendons after glucocorticoid injections, the role of glucocorticoid in tendon rupture still is controversial. It was hypothesized that glucocorticoid has a direct deleterious effect on human tenocytes, suppressing its cellular activity and collagen production. Primary cultures of human tenocytes were obtained from explants of healthy patellar tendon harvested during anterior cruciate ligament reconstructions. The effects on cell viability and cell proliferation were measured by [3-(4,5-demethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and 5-bromo-deoxyuridine incorporations. The effect on collagen synthesis was measured by H-proline incorporation assay. Triamcinolone acetonide at 10 to 10 mol/L decreased human tenocyte viability to 45% to 88% of control in a dose-dependent manner. Cell proliferation was suppressed to 87% +/- 8% at all doses. Treatment with 1 micromol/L triamcinolone acetonide reduced the amount of collagen synthesis as measured by H-proline incorporation from 40 +/- 2 cpm/1000 cells to 27 +/- 4 cpm/1000 cells. The suppressed human tenocyte cellular activity and reduced collagen production may lead to disturbed tendon structure and predispose the tendon to subsequent spontaneous rupture.