Heterogeneity of B cell involvement in acute nonlymphocytic leukemia

In order to study the pattern of B cell involvement in acute nonlymphocytic leukemia (ANLL), multiple B lymphoid cell lines were established by Epstein-Barr virus transformation of peripheral blood mononuclear cells from two patients with the disease who were heterozygous for the X chromosome-linked glucose-6-phosphate dehydrogenase (G6PD). In one patient, the progenitor cells involved by the leukemia exhibited multipotent differentiative expression, whereas in the other patient the cells showed differentiative expression restricted to the granulocytic pathway. In the patient whose abnormal clone showed multipotent expression, the ratio of B-A G6PD in B lymphoid cell lines was skewed in the direction of type B (the enzyme characteristic of the leukemia clone) and significantly different from the 1:1 ratio expected. It is, therefore, likely that the neoplastic event occurred in a stem cell common to the lymphoid series as well as to the myeloid series. In contrast, evidence for B cell involvement was not detected in the patient whose ANLL progenitor cells exhibited restricted differentiative expression. These findings underscore the heterogeneity of ANLL. Clinically and morphologically similar malignancies in these two patients originated in progenitors with different patterns of stem cell differentiative expression. This difference may reflect differences in cause and pathogenesis.     

Dietary acculturation of Hispanic immigrants in Mississippi

OBJECTIVE: Assisting Hispanic immigrants in making culturally acceptable food choices may affect their health for generations. As a relatively new enclave of Hispanics, Scott County, Mississippi, was chosen to study dietary acculturation and health concerns of immigrants. MATERIAL AND METHODS: The research method consisted of interviews with community representatives (N=11), a focus group (N=6), and interviews with Hispanic immigrants (N=18). RESULTS: Community representatives mentioned availability influenced immigrants' food choices and suggested promoting cultural awareness and offering nutrition classes on local ingredients. Food cost, health concepts, food selection, and eating habits of children were salient themes from the focus group and interviews with Hispanics. Hispanic participants mentioned long work hours affect food selection and that U.S. produce lacks freshness and flavor. CONCLUSIONS: Results indicate that an intervention must be formulated that preserves healthful dietary practices and minimizes the negative health aspects of acculturation to the "American diet"     

The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation

Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) is a potentially lethal complication during the first 6 months after allogeneic bone marrow transplantation (BMT). To determine whether deficiencies of EBV-specific cellular immunity contribute to EBV-LPD susceptibility and distinguish patients at risk, we performed limiting dilution analysis to quantify anti-EBV cytotoxic T-lymphocyte precursor (CTLp) frequencies in 26 recipients of unmodified or T-cell-depleted (TCD) grafts from EBV-seropositive donors. At 3 months post-BMT (n = 26), only five patients had EBV CTLp frequencies in the range of seropositive normal controls, irrespective of the type of transplant administered. By 6 months post-BMT, 9 of 13 patients tested had EBV CTLp frequencies within the normal range. The time period in which these patients had deficient cellular immunity to EBV corresponds to the period in which we have observed EBV-LPD in most prior patients. One patient with a low EBV CTLp frequency at 4 months post-BMT developed an EBV-LPD. Within 2 weeks of receiving an infusion of donor peripheral blood mononuclear cells (PBMC) providing less than 1,200 EBV- specific cytotoxic T-cell precursors, populations of EBV-specific CTL in the circulation were restored to levels detected in normal seropositive adults. Concurrently, the patient achieved a regression of the EBV-LPD, which has been sustained without further therapy. These studies indicate that recipients of both unmodified and TCD marrow grafts have profound deficiencies of EBV-specific T cell-mediated immunity early posttransplant, and that the period of risk for EBV-LPD closely corresponds to this interval of severe deficiency. Treatment of one patient with EBV-LPD with marrow donor-derived PBMC induced a rapid expansion of EBV-specific cytotoxic T-cell populations that occurred contemporaneously with the clinical regression of disease.     

The factor V B-domain provides two functions to facilitate thrombin cleavage and release of the light chain

Blood coagulation factors V and VIII are homologous proteins that have the domain organization A1-A2-B-A3-C1-C2. Upon thrombin activation, the B-domains of both molecules are released. Previous studies on factor VIII showed that the B-domain was not required for thrombin cleavage or activity. In contrast, deletion of the factor V B-domain (residues 709 to 1545) yielded a molecule with sevenfold reduced procoagulant activity that was not cleaved by thrombin. However, this factor V B- domain deletion molecule was activated by factor Xa, although the fold- activation was 85% that of wild-type factor V. Thrombin cleavage of factor V occurs initially after residue 709 and subsequently after residues 1018 and 1545. The requirement for thrombin cleavage within the B-domain at residue 1018 was evaluated by mutagenesis of Arg1018 to Ile. In the resultant R1018I mutant, the rate of thrombin activation and appearance of maximal cofactor activity was delayed and was consistent with delayed cleavage of the light chain at residue 1545. In contrast, the rate of factor Xa activation in the R1018I mutant was not altered. This finding suggests that thrombin cleavage at 1018 facilitates subsequent thrombin cleavage at 1545. Further mutagenesis was used to study the requirement for sequences within the factor V B- domain for thrombin cleavage at residue 1545. Whereas the factor V deletion molecule removing residues 709 to 1545 was not cleaved by thrombin, a smaller B-domain deletion molecule (residues 709 to 1476) containing an acidic amino acid-rich region (residues 1490 to 1520) was effectively cleaved by thrombin. These results show that residues 1476 to 1545, which contain an acidic amino acid-rich region, were required for thrombin cleavage of the light chain. Introduction of an acidic amino acid-rich region from factor VIII (residues 337 to 372) into the factor V 709 to 1545 deletion also restored thrombin cleavage of the light chain. In contrast, similar replacement with the acidic region from the factor VIII light chain (residues 1649 to 1689) was significantly less effective in promoting thrombin cleavage of the light chain. This finding suggests that the different acidic regions in factors V and VIII are not functionally equivalent in their interaction with thrombin.(ABSTRACT TRUNCATED AT 400 WORDS)     

Organization of the gene for human platelet/endothelial cell adhesion molecule-1 shows alternatively spliced isoforms and a functionally complex cytoplasmic domain

Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a cell-cell adhesion molecule that is expressed on circulating platelets, on leukocytes, and at the intercellular junctions of vascular endothelial cells and mediates the interactions of these cells during the process of transendothelial cell migration. The cDNA for PECAM-1 encodes an open reading frame of 738 amino acids (aa) that is organized into a 27- aa signal peptide, a 574-aa extracellular domain composed of 6 Ig homology units, and a relatively long cytoplasmic tail of 118 aa containing multiple sites for posttranslational modification and postreceptor signal transduction. To provide a molecular basis for the precise evaluation of the structure and function of this transmembrane glycoprotein, we have determined the organization of the human PECAM-1 gene. The PECAM-1 gene, which has been localized to human chromosome 17, is a single-copy gene of approximately 65 kb in length and is broken into 16 exons by introns ranging in size from 86 to greater than 12,000 bp in length. Typical of other members of the Ig superfamily, each of the extracellular Ig homology domains is encoded by a separate exon, consistent with PECAM-1 having arisen by gene duplication and exon shuffling of ancestral Ig superfamily genes. However, the cytoplasmic domain was found to be surprisingly complex, being encoded by seven short exons that may represent discrete functional entities. Alternative splicing of the cytoplasmic tail appears to generate multiple PECAM-1 isoforms that may regulate phosphorylation, cytoskeletal association, and affinity modulation of the mature protein. Finally, a processed pseudogene having 76% identity with PECAM- 1 cDNA was identified and localized to human chromosome 3. These findings should have important implications for structure/function analysis of PECAM-1 and its role in vascular adhesive interactions.     

Novel PEGylated Basal Insulin LY2605541 Has a Preferential Hepatic Effect on Glucose Metabolism

The impact of the novel basal insulin LY2605541 (LY) on hepatic and nonhepatic glucose uptake (non-HGU) was evaluated. Conscious dogs underwent euglycemic clamps with tracer and hepatic balance measurements. Clamp period infusions were peripheral venous regular insulin (0.1 nmol ⋅ kg⁻¹ ⋅ h⁻¹ [control], n = 6) or LY (bolus [nmol/kg], continuous [nmol ⋅ kg⁻¹ ⋅ h⁻¹]: 0.5, 0.5 [n = 6]; 0.375, 0.375 [n = 5]; 0.25, 0.25 [n = 4]), somatostatin, and glucose, as well as intraportal glucagon (basal). During the clamp, the dogs switched from net hepatic glucose output to uptake (rates reached 2.1 ± 1.2, 0.9 ± 2.1, 8.6 ± 2.3, and 6.0 ± 1.1 µmol ⋅ kg⁻¹ ⋅ min⁻¹ within 5 h in control, LY_0.25, LY_0.375, and LY_0.5, respectively). Non-HGU in LY increased less than in control; the ratio of change from basal in non-HGU to change in net hepatic glucose balance, calculated when glucose infusion rates (GIRs) were ~20 µmol ⋅ kg^-1 ⋅ min⁻¹ in all groups, was higher in control (1.17 ± 0.38) versus LY_0.25 (0.39 ± 0.33), LY_0.375 (−0.01 ± 0.13), and LY_0.5 (−0.09 ± 0.07). Likewise, the change from baseline in glucose R_d-to-R_a ratio was greatest in control (1.4 ± 0.3 vs. 0.6 ± 0.4, 0.5 ± 0.2, and 0.6 ± 0.2 in LY_0.25, LY_0.375, and LY_0.5, respectively). In contrast to exogenously administered human insulin, LY demonstrated preferential hepatic effects, similar to endogenously secreted insulin. Therefore, the analog might reduce complications associated with current insulin therapy.     

Mobile health and cardiac rehabilitation in older adults

With the ubiquity of mobile devices, the availability of mobile health (mHealth) applications for cardiovascular disease (CVD) has markedly increased in recent years. Older adults represent a population with a high CVD burden and therefore have the potential to benefit considerably from interventions that utilize mHealth. Traditional facility-based cardiac rehabilitation represents one intervention that is currently underutilized for CVD patients and, because of the unique barriers that older adults face, represents an attractive target for mHealth interventions. Despite potential barriers to mHealth adoption in older populations, there is also evidence that older patients may be willing to adopt these technologies. In this review, we highlight the potential for mHealth uptake for older adults with CVD, with a particular focus on mHealth cardiac rehabilitation (mHealth-CR) and evidence being generated in this field.     

Orofacial neuralgia associated with a middle cerebral artery aneurysm

Chronic orofacial pain of neuropathic origin can present diagnostic and management dilemmas to dental practitioners and also affects the patient's quality of life. Intracranial aneurysms are a potential cause of stroke (e.g. sub‐arachnoid haemorrhage) that is usually associated with, high rates of mortality and morbidity. A patient who had been previously managed for symptoms of temporomandibular joint disorder (TMD) presented with sharp, shooting pain of moderate intensity. It was precipitated by swallowing, and radiated to the right throat, posterior border of the mandible, ear and temporomandibular joint. Clinical and radiological investigations ruled out odontogenic pain, TMD and other more common types of facial pain. Magnetic resonance imaging revealed a 7 × 6 mm aneurysm in the right middle cerebral artery (MCA) which was subsequently surgically clipped. Interestingly, the facial pain resolved after this procedure. Compression of the insular region of the brain innervated by the trigeminal, glossopharyngeal and vagus nerves provides a plausible explanation for the pain reported. To our knowledge, this is the first case of facial neuralgia associated with an aneurysm in the MCA which emphasizes the importance of a multidisciplinary approach in the diagnosis and management of unusual cases of chronic orofacial pain.