Multiple hematopoietic defects and delayed globin switching in Ikaros null mice

We have previously reported the structure of a chromatin remodeling complex (PYR complex) with Ikaros as its DNA binding subunit that is specifically present in adult murine and human hematopoietic cells. We now show that homozygous Ikaros "knockout" (null) mice lack the PYR complex, demonstrating the requirement for Ikaros in the formation of the complex on DNA. Heterozygous Ikaros null mice have about half as much PYR complex, indicating a dosage effect for both Ikaros and PYR complex. We also show that Ikaros null mice have multiple hematopoietic cell defects including anemia and megakaryocytic abnormalities, in addition to previously reported lymphoid and stem cell defects. The null mice also have a delay in murine embryonic to adult beta-globin switching and a delay in human gamma to beta switching, consistent with a previously suggested role for PYR complex in this process. Lastly, cDNA array analyses indicate that several hematopoietic cell-specific genes in all blood lineages are either up- or down-regulated in 14-day embryos from Ikaros null as compared with wild-type mice. These results indicate that Ikaros and PYR complex function together in vivo at many adult hematopoietic cell-specific genes and at intergenic sites, affecting their expression and leading to pleiotropic hematopoietic defects.     

Immediate IgA precursor cells in rabbit intestinal lamina propria.

Immunofluorscence studies have shown that injection of lymphocytes from either the intestinal lamina propria (LP) or from the Peyer's patches (PP) into irradiated (1000-1250 rad) allogeneic rabbits leads to the differentiation and proliferation of IgA containing cells in the spleen, mesenteric lymph node (MLN) and intestine by day 6 and to a lesser extent by day 4. In contrast, few IgA containing cells were seen in irradiated animals not given lymphocytes or given popliteal lymph node cells. Transfer of PP lymphocytes resulted in statistically greater numbers of IgA containing cells in the recipient MLN or spleen than did transfer of LP lymphocytes. In the PP of recipient rabbits given either LP or PP lymphocytes, intercellular IgA was abundant and more IgA containing cells were seen near the PP than in sites distant from PP. These results show that IgA precursor cells are present in the intestinal LP as well as in the PP. The nature and distribution of the IgA precursor and the characteristics of the IgA repopulation are discussed.     

Human leucocyte antigen class II associations in chronic idiopathic urticaria

The major histocompatibility complex (MHC) acts as a marker for self during T-cell ontogeny and is associated with the pathogenesis of many autoimmune diseases. Recent investigations have shown about 30% of patients with chronic idiopathic urticaria (CIU) have IgG autoantibodies against the high-affinity IgE receptor, FcepsilonRI, or IgE. A link between MHC class II alleles and CIU has not been reported previously. DNA was extracted from blood of 100 Caucasian patients with CIU, and the MHC class II type determined using the polymerase chain reaction with sequence-specific primers, testing for DRB and DQB1 alleles. The frequency of alleles in CIU patients was compared with that found in 603 controls. Further human leucocyte antigen (HLA) typing on patient subsets, classified by the patients' responses to intradermal injection of autologous serum and their serum-induced histamine release from basophil leucocytes of healthy donors, was undertaken. HLA DRB1*04 (DR4) and its associated allele, DQB1*0302 (DQ8), are raised in CIU patients compared with a control population (P = 2 x 10-5 and P = 2 x 10-4, respectively). HLA DRB1*15 (DR15) and its associated allele, DQB1*06 (DQ6), are significantly less frequently associated with CIU. The HLA DRB1*04 association is particularly strong (corrected P = 3.6 x 10-6) for patients whose serum has in vivo and in vitro histamine-releasing activity. HLA class II typing is consistent with the concept that CIU is a heterogeneous disease, and supports an autoimmune pathogenesis in a subset of patients.     

Protection from Lyme Neuroborreliosis in Nonhuman Primates with a Multiantigenic Vaccine

In an effort to develop an effective and safe vaccine for lyme disease, rhesus macaques were injected with a multiantigenic preparation of Borrelia burgdorferi, strain N40. One month later animals were boosted before intradermal challenge with infectious B. burgdorferi. Challenges were performed at 1 and again at 5 months after the booster vaccination. Vaccinated and control nonvaccinated animals were monitored for development of systemic infection by measurement of serum anti-spirochetal antibodies by ELISA and Western blotting, and neurological involvement was monitored by testing of cerebrospinal fluid (CSF) and PCR analysis of central nervous system (CNS) tissue obtained at necropsy. Two control nonhuman primates (NHPs), given saline injections instead of vaccine and then challenged with B. burgdorferi, developed CSF pleocytosis, PCR positivity of the brain, and high levels of specific anti-B. burgdorferi antibody in the serum and CSF. Necropsy studies revealed widespread invasion of the CNS of one of these animals by the spirochete. In contrast, none of the four vaccinated animals developed evidence of invasion of the CNS after either of two challenge inoculations with infectious B. burgdorferi. In addition to resisting infection, no vaccinated animal demonstrated any untoward consequence of vaccination. These data demonstrate that a multiantigenic vaccine is effective in preventing systemic infection and lyme neuroboreliosis in NHPs and suggest that a successful vaccine could be developed in humans which would prevent lyme disease.     

Investigating the relationship between the practice of pharmaceutical care, construed external image, organizational identification, and job turnover intention of community pharmacists

BACKGROUND: Pharmacy employers are being challenged to recruit and retain qualified employees. OBJECTIVES: Our study hypothesized that pharmacists who practice pharmaceutical care have an attractive construed external image (how employees think outsiders view their organization), which strengthens their organizational identification (perceptions of oneness with or belongingness to the organization) and decreases job turnover intention (thoughts of quitting/searching for another job). METHODS: A 7-page questionnaire was mailed to the homes of a random sample of 759 licensed pharmacists practicing in the United States. Participants had the option of returning the completed survey via postal mail or a Web site. The study variables were measured with previously validated scales. Structural equation modeling with latent variables evaluated the hypothesized relationships. Several demographic variables were included. RESULTS: Responses were received from 252 subjects (33%); 121 were community pharmacists. As hypothesized, organizational identification and job turnover intention were significantly related (B=-0.24) as well as construed external image and organizational identification (B=0.41). The practice of pharmaceutical care and construed external image were not significantly correlated (B=0.10). Although not hypothesized, construed external image was directly related to job turnover intention (B=-0.25). The effects of the practice of pharmaceutical care on job turnover intention were mediated through organizational identification. Position had significant effects. CONCLUSIONS: One additional benefit to the practice of pharmaceutical care may be strengthened organizational identification. Pharmacists' perception of the image of their employer may increase organizational identification and decrease job turnover intention. An understanding of the organizational identification of pharmacists would be useful in decreasing job turnover intention. Given the current demand for pharmacists, this is a worthwhile endeavor. Future research should focus on other predictors of construed external image and ways to enhance organizational identification. Encouraging the practice of pharmaceutical care may be 1 such way.     

Effect of inhibiting HMG-CoA reductase on 7α-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis: contrasting findings in patients with and without prior up-regulation of the latter pathway

BACKGROUND: Atorvastatin is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, but its effect on bile acid synthesis is unknown. The objectives of the study were to determine the effect of atorvastatin on bile acid synthesis in patients in whom this process had not been or had been previously up-regulated by pharmacological or surgical means. MATERIALS AND METHODS: Four patients with heterozygous familial hypercholesterolaemia (FH) and partial ileal bypass (PIB) and 19 FH heterozygotes without PIB were treated with placebo, atorvastatin 10 mg and atorvastatin 40 mg daily, each regimen for 4 weeks. The non-PIB group was subsequently treated with bile acid (BA) sequestrant 8-16 g daily followed by co-administration of atorvastatin 10 mg, each for 4 weeks. Plasma 7 alpha-hydroxy-4-cholesten-3-one (7 alpha-HCO), a well-validated marker of BA synthesis was measured using high-performance liquid chromatography with UV detection. RESULTS: The plasma 7 alpha-HCO concentration was tenfold higher with placebo in the PIB than in the non-PIB group (418.5 ng mL-1 vs. 39.6 ng mL-1 p = 0.0001). Levels decreased in PIB patients treated with atorvastatin 10 mg and 40 mg daily (350.1 ng mL-1 and 174.0 ng mL-1, P = 0.007 respectively) but did not change significantly in the non-PIB group (44.7 ng mL-1 and 28.3 ng mL-1 respectively). Administration of BA sequestrant to non-PIB patients increased 7 alpha-HCO to 197.4 ng mL-1; this decreased to 106.0 ng mL-1 during co-administration of atorvastatin 10 mg daily (P = 0.0001). CONCLUSION: Atorvastatin decreases the rate of BA synthesis only if the latter is up-regulated by PIB or BA sequestrants, presumably by limiting the supply of newly synthesized free cholesterol.     

Tissue compensator fabrication using a simple photographic technique

A simple method of fabricating photon beam tissue compensators is described. A plaster cast of the patient's surface contours is partially immersed in a mixture of India ink and water to obtain a topographic map relative to a reference plane which is perpendicular to the photon beam. The contours are photographed, and successive contours corresponding to different missing tissue thicknesses are used to fabricate a compensator from lead sheets cut to the same shape with the proper magnification.     

Necrotizing enterocolitis in the newborn: operative indications.

Fifty-two premature, low birth weight infants presented mainly in the first week of life with sudden manifestations of intestinal ileus and an x-ray picture of pneumatosis intestinalis. Twenty-two of 32 patients treated with gastric decompression, antibiotics, intensive supportive therapy and intravenous hyperalimentation survived. Twenty other patients had progression of their disease and required operation. Twelve of these patients survived. Review of this material indicated that some medically treated patients might have survived if they had been operated upon. Indications for operation included free perforation and clinical signs of deterioration. Abdominal physical findings and x-rays were not reliable except as signs of far advanced pathology. Confirmation of ascites by paracentesis and gram stain of fluid was helpful when present. If patients were adequately treated and then developed sudden hyponatremia or progressive acidosis, they invariably had gangrenous bowel and required operation. The most striking finding was that a sudden, profound drop in the platelet count to levels below 100,000 reliably predicted the presence of gangrenous bowel and the need for operation. Other clotting studies indicated that disseminated intravascular coagulation is an important accompaniment of NNE with the complication of bowel gangrene prior to perforation. Gastrostomy and resection of involved bowel with staged anastomosis proved to be the most successful form of surgical management. Overall suvival was 66 per cent.