Development of angiogenic cell and gene therapy by transplantation of umbilical cord blood with vascular endothelial growth factor gene.

Endothelial progenitor cells (EPCs) are present in the mononuclear cells (MNCs) of umbilical cord blood and peripheral blood. To establish the efficiency of angiogenic cell and gene therapies, we transfected the human vascular endothelial growth factor (hVEGF) gene into cord blood MNCs to enhance endothelialization. MNCs from cord blood and peripheral blood were isolated and transfected with pCR3 expressing hVEGF165 or GFP by the Hemagglutinating Virus of Japan (HVJ)-envelope and the cells were cultured in endothelium basal medium-2. The number of attached cells from cord blood was higher than that from peripheral blood. Attached cells expressed Flk-1, VE-cadherin, PECAM-1, CD34, and Tie-2. The increase in the number of attached cells was transient with the transfection of vascular endothelial growth factor (VEGF) gene early in the experimental period. Flt-1 mRNA was not expressed early in the culture period, but was expressed at 2 weeks after separation. VEGF gene transfer into MNCs at 12 days after separation, i.e., when Flt-1 mRNA was expressed continuously, increased the number of attached cells. We evaluated the effects of the transplantation of cord blood MNCs expressing the hVEGF gene on regional blood flow in an ischemic area in a rat model of chronic hindlimb ischemia. Blood flow was significantly improved in nude rats that received transplanted control MNCs. Transplantation of cord blood MNCs transfected with the hVEGF gene yielded greater improvements in blood flow. These results indicate that the hVEGF gene enhances endothelialization of EPCs, and that the transplantation of cord blood MNCs transfected with the VEGF gene may be feasible for the treatment of ischemic diseases as a type of angiogenic cell and gene therapy.     

Effects of a low dose of indapamide, a diuretic, given daily or every-other-day on blood pressure and metabolic parameters.

To investigate the effects of the diuretic, indapamide, on blood pressure (BP) and metabolic parameters, thirty hypertensive patients were treated with 1 mg of indapamide either every day or every other day. BP, fasting plasma glucose, lipids, serum potassium and uric acid were determined at baseline and after 3 months of a stable regimen of the drug. At the termination of the study, 48-h ambulatory blood pressure monitoring (ABPM) was performed. Three patients received only indapamide, while other patients were treated in combination with additional antihypertensive medications. Patients treated with daily indapamide showed a BP reduction from 162 +/- 2.9/85 +/- 2.4 mmHg to 134 +/- 2.4/71 +/-2.6 mmHg (p < 0.001). The BP reduction was similar in those patients receiving the drug every other day (137 +/- 3.4/71 +/- 3.6 mmHg). While plasma lipids and serum potassium did not differ significantly with the intervention, uric acid increased significantly with daily treatment and normalized with every-other-day treatment. Glycosylated hemoglobin A1c (HbA1c) was not altered (5.6 +/- 0.1% vs. 5.4 +/- 0.2%), and did not differ between patients with and without diabetes mellitus. ABPM revealed an average 24-h BP of 134 +/- 3.3/75 +/- 1.7 mmHg on days in which patients received the medication and 139 +/- 4.9/78 +/- 2.6 mmHg on the intervening day without indapamide (no significant difference). These results suggest that a low dose of indapamide given every day or every other day is effective in lowering BP and does not result in metabolic derangements.     

Differential diagnosis of benign versus malignant nonfunctioning islet cell tumors of the pancreas: the roles of EUS and ERCP.

BACKGROUND: Differentiation between benign and malignant nonfunctioning islet cell tumors of the pancreas before surgery is often difficult. The roles of EUS and ERCP were evaluated in the differential diagnosis of these tumors. METHODS: Seven patients with histologically confirmed nonfunctioning islet cell tumors (4 benign, 3 malignant) underwent EUS and ERCP. OBSERVATIONS: EUS demonstrated a homogeneous hypoechoic mass or a hypoechoic mass with a regular central echogenic area in the 4 cases of benign tumor, and a hypoechoic mass with an irregular central echogenic area in all 3 cases of malignant tumor. The irregular central echogenic area corresponded to severe hemorrhage, necrosis, or fibrosis with hyalinosis (hyaline degeneration) on pathologic examination. ERCP demonstrated displacement or complete obstruction (because of ductal invasion) of the main pancreatic duct in 2 patients with malignant tumors and no abnormalities in the other 5 cases. CONCLUSIONS: In patients with nonfunctioning islet cell tumors, a hypoechoic mass with an irregular central echogenic area on EUS or complete obstruction of the main pancreatic duct on ERCP suggests malignancy.     

Infection mechanism of biofilm‐forming Staphylococcus aureus on indwelling foreign materials in mice

Indwelling foreign‐body infections are a critical medical problem, especially in immunocompromised patients. To examine the pathogenicity of biofilm‐forming bacteria settling on foreign materials, mice implanted with plastic discs were infected with Staphylococcus aureus. After opening a wide subcutaneous pocket on the dorsal side of mice with or without temporal leukocytopenia, a plastic sheet was placed in the left subcutaneous space; subsequently, bacteria in a planktonic state were dispersed over the subcutaneous space. Bacterial numbers were examined 7 days after inoculation. In subcutaneous tissue on the right, S. aureus was found only in leukocytopenic mice. Meanwhile, bacteria were detected on the plastic and neighbouring tissue in both leukocytopenic and normal mice; however, colony‐forming analysis indicated that leukocytopenic mice possessed significantly more bacteria. Tissue reaction against bacteria was pathologically examined. Invading S. aureus induced severe inflammation. In transient leukocytopenic mice, bacterial microcolonies formed on the plastic as well as in the developed necrotic tissue – both of which were shielded from inflammatory cell infiltration – result in bacteraemia. These results indicate that biofilm‐forming S. aureus settling on indwelling foreign material are tolerant against host immunity and assault neighbouring tissue, which may lead to chronic wound infection.     

Maternal overweight/obesity characteristics and child anthropometric status in Jos,Nigeria

Objective:

This study is to determine the pattern of overweight and obesity and its relationship with childhood anthropometric status in Nigeria.

Materials and Methods:

This cross-sectional study was conducted in Jos, Nigeria. Interviewer administered questionnaire was used in data collection. Maternal and child anthropometric measurements were obtained using standard WHO methods. Child anthropometric Z scores were obtained from WHO Anthroplus while BMI of mothers were also determined. Totally, 262 mother-child pairs were recruited.

Results:

Mean maternal age and mean child age were 30.8 ± 6.3 yrs (15-47 yrs) and 22.3 ± 18.7 months (3-72 months). Prevalence of maternal underweight, overweight and obesity was 4.2% (11/262), 29.4% (77/262) and 25.9% (68/262), respectively. Child overweight/obesity was 5.4% (14/262), severe under-nutrition 5.7% (15/262). Mean maternal BMI was higher in the older, more educated and higher socioeconomic status (SES). Child mean birth-weight, weight-for-age Z-score and BMI-for-age Z-score (BAZ) were higher among mothers with BMI ≥ 25 kg/m². All large-for-age babies were in mothers with maternal BMI ≥ 25 kg/m². Childhood over-nutrition was more common in maternal BMI of ≥25 kg/m². Overall, BAZ was directly related with maternal BMI, maternal age and birth-weight, although it was inversely related with maternal BM I ≥ 25 kg/m².

Conclusion:

Higher BMI is seen in educated and higher SES mothers and this impact on childhood anthropometry.     

Lidocaine‐Propitocain Cream,a Eutectic Mixture of Local Anesthetics,Effectively Relieves Pain Associated With Vascular Access Intervention Therapy in Patients Undergoing Hemodialysis: A Placebo‐Controlled,Double‐Blind,Crossover Study

Vascular access intervention therapy (VAIVT) is necessary to maintain vascular access in patients undergoing hemodialysis. VAIVT‐associated vasodilatation is painful. However, few reports have focused on effective pain relief at the time of VAIVT. The present study was performed to determine whether lidocaine‐propitocain cream, a eutectic mixture of local anesthetics (EMLA), effectively reduces VAIVT‐associated pain in patients undergoing hemodialysis. This placebo‐controlled, double‐blind, crossover study was conducted in a single center. Among 210 patients who underwent a total of 437 VAIVT procedures from August 2017 to June 2018, 30 patients were randomly allocated to either the EMLA–placebo arm or placebo–EMLA arm at the time of VAIVT. EMLA application significantly reduced the visual analog scale score compared with placebo (47.0 ± 21.1 vs. 68.6 ± 20.7 mm, respectively; P < 0.05). EMLA is a safe and effective treatment for relief of VAIVT‐associated pain in patients undergoing hemodialysis.     

Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development

The immune system is influenced by the vital zinc (Zn) status, and Zn deficiency triggers lymphopenia; however, the mechanisms underlying Zn-mediated lymphocyte maintenance remain elusive. Here we investigated ZIP10, a Zn transporter expressed in the early B-cell developmental process. Genetic ablation of Zip10 in early B-cell stages resulted in significant reductions in B-cell populations, and the inducible deletion of Zip10 in pro-B cells increased the caspase activity in parallel with a decrease in intracellular Zn levels. Similarly, the depletion of intracellular Zn by a chemical chelator resulted in spontaneous caspase activation leading to cell death. Collectively, these findings indicated that ZIP10-mediated Zn homeostasis is essential for early B-cell survival. Moreover, we found that ZIP10 expression was regulated by JAK-STAT pathways, and its expression was correlated with STAT activation in human B-cell lymphoma, indicating that the JAK-STAT-ZIP10-Zn signaling axis influences the B-cell homeostasis. Our results establish a role of ZIP10 in cell survival during early B-cell development, and underscore the importance of Zn homeostasis in immune system maintenance.Zinc (Zn) has wide-ranging effects on immunity. Zn deficiency has uncovered the importance of Zn homeostasis in immune cell maintenance and function (1). Dramatic effects of Zn on immunity have been observed in several immune and allergy-related cells, including lymphocytes such as B cells (2–6). B cells develop in the bone marrow (BM); the initial commitment to pro-B cells is followed by their differentiation into pre-B cells, and subsequently into immature B cells, which express the B-cell receptor on their surface (7). The immature B cells reach the spleen as transitional B cells, further differentiating into follicular or marginal zone mature B cells (7). Although the perturbation of Zn homeostasis causes splenic atrophy associated with lymphocyte reduction, and compromises cellular and humoral immune responses (6), the mechanisms underlying how Zn controls immune cell function, and in particular, the impact on early B-cell development, have been largely unknown.Zn homeostasis is tightly controlled by Zn transporter family members, Zrt- and Irt-like proteins (ZIPs, Zn importers) and zinc transporters (ZnTs, Zn exporters) (8), and recent studies revealed that alterations in Zn homeostasis mediated by specific Zn transporters play indispensable roles in a variety of cellular events (9). The intestinal Zn transporter ZIP4 is important for the initial absorption of dietary Zn, and patients with mutations in the SLC39A4/ZIP4 gene suffer from the inherited disorder acrodermatitis enteropathica (10, 11). ZIP13 controls the formation of bone, teeth, and connective tissues by modulating BMP/TGF-β signaling (12), and its loss-of-function mutation causes spondylocheiro dysplastic Ehlers-Danlos syndrome in humans (12, 13). ZIP14 controls systemic growth by regulating G protein-coupled receptor (GPCR) signaling (14), and ZIP8 is involved in osteoarthritis (15) and negatively manipulates NF-κB activation (16). In addition, ZnT5 regulates cytokine production by controlling the activation of protein kinase C upon antigen exposure in mast cells (17). Thus, Zn homeostasis mediated by Zn transporters is linked to a wide variety of biological and regulatory functions, and the disruption of a Zn transporter-Zn axis can lead to various symptoms in the absence of redundant machinery (18).Here we demonstrate a definitive role of ZIP10 in early B-cell development. We found that a loss of ZIP10 during an early B-cell stage specifically abrogated cell survival, resulting in the absence of mature B cells, which led to splenoatrophy and reduced Ig levels. The inducible deletion of Zip10 in pro-B cells increased the caspase activity because of the reduced intracellular Zn level, leading to cell death. This phenomenon was mimicked by the intracellular chelation of Zn. These findings indicated that Zn homeostasis via ZIP10 plays an indispensable role in early B-cell survival. We also demonstrated that the ZIP10 expression levels were regulated by STAT3/STAT5 activation, and that ZIP10 was highly expressed in human B-cell lymphoma samples in which both STAT proteins were activated, indicating that the JAK-STAT-ZIP10-Zn signaling axis is important for B-cell maintenance. Our results establish a functional link between ZIP10 and the survival of early stages of B cells, revealing a molecular mechanism underlying the requirement of Zn for maintenance of the immune system.