Low rate of nasopharyngeal carriage and high rate of ampicillin resistance for Haemophilus influenzae among healthy children younger than 5 years old in northern Taiwan.

BACKGROUND AND PURPOSE: Surveillance data of colonization by Haemophilus influenzae in Taiwan are lacking. This study aimed to define the nasopharyngeal carriage rate of H. influenzae among children younger than 5 years in northern Taiwan, and to determine the antibiotic susceptibility, serotype and the clonal relationship of these isolates. METHODS: Nasopharyngeal specimens were obtained from 511 healthy children younger than 5 years. All H. influenzae isolates were serotyped. The minimal inhibitory concentrations for various antibiotics were determined. Pulsed-field gel electrophoresis (PFGE) was used for clonal analysis. RESULTS: Among 511 children, 269 (52.6%) had been vaccinated with at least one dose of H. influenzae type b (Hib) conjugate vaccine, 236 (46.2%) were unvaccinated and 6 (1.2%) had no vaccination records available. Twenty six H. influenzae strains were isolated. There were three Hib isolates and the others were nontypeable H. influenzae (NTHi). The carriage rate for Hib was 0.6% (3/511) and of NTHi was 5% (23/511). Three (1.27%) of the 236 unvaccinated children were carriers of Hib, whereas none of the 269 vaccinated children carried Hib. Two out of the three Hib isolates and 14 (60.9%) of 23 NTHi isolates were ampicillin-resistant. Multidrug resistance was found in 7 (26.9%) of the isolates. Among the isolates, 61.5% were beta-lactamase producers; there were no beta-lactamase-negative ampicillin-resistant isolates. The PFGE restriction patterns showed a wide diversity of genotypes. CONCLUSIONS: There is very low nasopharyngeal carriage of Hib among children younger than 5 years in northern Taiwan. This may explain why the incidence of invasive Hib disease is also low in Taiwan. In addition, we found a high prevalence of beta-lactamase-positive ampicillin-resistant nasopharyngeal H. influenzae isolates.     

Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer.

PURPOSE: ErbB receptor signaling pathways are important regulators of cell fate, and their dysregulation, through (epi)genetic alterations, plays an etiologic role in multiple cancers. ErbB ligands are synthesized as membrane-bound precursors that are cleaved by members of the ADAM family of zinc-dependent metalloproteases. This processing, termed ectodomain shedding, is essential for the functional activation of ErbB ligands. Recent studies suggest that elevated levels of ErbB ligands may circumvent the effectiveness of ErbB-targeted therapeutics. Here, we describe the discovery and preclinical development of potent, selective inhibitors of ErbB ligand shedding. EXPERIMENTAL DESIGN: A series of biochemical and cell-based assays were established to identify selective inhibitors of ErbB ligand shedding. The therapeutic potential of these compounds was assessed in multiple in vivo models of cancer and matrix metalloprotease-related toxicity. RESULTS: INCB3619 was identified as a representative selective, potent, orally bioavailable small-molecule inhibitor of a subset of ADAM proteases that block shedding of ErbB ligands. Administration of INCB3619 to tumor-bearing mice reduced ErbB ligand shedding in vivo and inhibited ErbB pathway signaling (e.g., phosphorylation of Akt), tumor cell proliferation, and survival. Further, INCB3619 synergized with clinically relevant cancer therapeutics and showed no overt or compounding toxicities, including fibroplasia, the dose-limiting toxicity associated with broad-spectrum matrix metalloprotease inhibitors. CONCLUSIONS: Inhibition of ErbB ligand shedding offers a potentially novel and well-tolerated therapeutic strategy for the treatment of human cancers and is currently being evaluated in the clinic.     

Neutrophil inhibitory factor abrogates neutrophil adhesion by blockade of CD11a and CD11b beta(2) integrins.

We studied the basis of inhibition of polymorphonuclear leukocyte (PMN) adhesion induced by neutrophil inhibitory factor (NIF), a 41-kDa CD11/CD18 beta(2) integrin-binding protein isolated from the canine hookworm (Ancylostoma caninum). NIF blocked PMN adhesion in a concentration-dependent manner with complete blockade occurring at approximately 10 nM NIF. Because CD11a and CD11b beta(2) integrins are functionally active on stimulated PMNs, and yet NIF is postulated to inhibit only CD11b integrin by binding to its I domain, we evaluated the contributions of CD11a and CD11b beta(2) integrins in the mechanism of inhibition of PMN adhesion to endothelial cells. We observed an additive inhibitory effect (>90% inhibition) of PMN adhesion to endothelial cells when NIF was used in combination with anti-CD11b monoclonal antibodies, which alone at saturating concentrations reduced PMN adhesion by only 50%. NIF also prevented aggregation of phorbol ester-stimulated JY lymphoblastoid cells that expressed only the functionally active CD11a, suggesting that NIF also can inhibit CD11a-dependent response. We transduced the NIF cDNA into human dermal microvessel endothelial cells in which NIF synthesis and release prevented PMN adhesion to the transduced human dermal microvessel endothelial cells. These data indicated that the potent antiadhesive effect of NIF may be the result of inhibition of CD11a and CD11b beta(2) integrins on PMNs. Moreover, the strategy of NIF release from transduced endothelial cells suggests the feasibility of blocking the CD11a- and CD11b beta(2) integrin-dependent PMN adhesion and PMN migration responses specifically at sites of endothelial cell activation.     

Polydeoxyribonucleotide stimulates angiogenesis and wound healing in the genetically diabetic mouse

Healing of diabetic wounds still remains a critical medical problem. Polydeoxyribonucleotide (PDRN), a compound having a mixture of deoxyribonucleotide polymers, stimulates the A2 purinergic receptor with no toxic or adverse effect. We studied the effects of PDRN in diabetes‐related healing defect using an incisional skin‐wound model produced on the back of female diabetic mice (db+/db+) and their normal littermates (db+/+m). Animals were treated daily for 12 days with PDRN (8 mg/kg/ip) or its vehicle (100 μL 0.9%NaCl). Mice were killed 3, 6, and 12 days after skin injury to measure vascular endothelial growth factor (VEGF) mRNA expression and protein synthesis, to assay angiogenesis and tissue remodeling through histological evaluation, and to study CD31, Angiopoietin‐1 and Transglutaminase‐II. Furthermore, we measured wound breaking strength at day 12. PDRN injection in diabetic mice resulted in an increased VEGF message (vehicle=1.0±0.2 n‐fold vs. β‐actin; PDRN=1.5±0.09 n‐fold vs. β‐actin) and protein wound content on day 6 (vehicle=0.3±0.07 pg/wound; PDRN=0.9±0.1 pg/wound). PDRN injection improved the impaired wound healing and increased the wound‐breaking strength in diabetic mice. PDRN also caused a marked increase in CD31 immunostaining and induced Transglutaminase‐II and Angiopoietin‐1 expression. Furthermore, the concomitant administration of 3,7‐dimethyl‐1‐propargilxanthine, a selective adenosine A2A receptor antagonist, abolished PDRN positive effects on healing. However, 3,7‐dimethyl‐1‐propargilxanthine alone did not affect wound healing in both diabetic mice and normal littermates. These results suggest that PDRN might be useful in wound disorders associated with diabetes.     

Effects of aminophylline on respiratory drive and neuromuscular coupling in normal man and in patients with chronic airflow obstruction

Summary In order to evaluate the separate effects of aminophylline on the neural and muscular components of the respiratory control system, assessed by electromyographic activity of the diaphragm (EMGd) and mouth occlusion pressure (P_0.1), respectively, 6 normal subjects and 14 patients with mild or moderate chronic airflow obstruction (8 asthmatics and 6 COPD) were studied during CO₂ rebreathing, before and after administration of a therapeutic dose of aminophylline 5.6 mg/kg.Compared to normal subjects, before aminophylline administration both asthmatic and COPD patients exhibited a significantly greater value in EMGd response slope to CO₂. In no group did aminophylline modify P_0.1 or EMGd activity response slope to CO₂, nor did it significantly affect neuromuscular coupling, assessed by plotting change in P_0.1 against change in EMGd activity with increasing CO₂.The data appear to indicate that aminophylline in therapeutic concentrations does not modify respiratory drive or neuromuscular coupling in normal subjects, or in patients with mild or moderate chronic airflow obstruction.     

Immunophenotypic analysis of non-Hodgkin's lymphomas in Chinese. A study of 75 cases in Hong Kong

The cell surface markers of 75 cases of non-Hodgkin's lymphoma were studied on cryostat sections using a panel of monoclonal antibodies. Forty-nine cases (65.3%) were found to express a B-cell phenotype, 23 cases (30.7%) a T-cell phenotype, 1 case (1.3%) a histiocytic phenotype and 2 cases (2.7%) no demonstrable surface markers. Follicular lymphoma accounted for only 10.7% of the cases. Most B-cell lymphomas expressed IgM-lambda or IgM-IgD-lambda, but a few failed to express surface immunoglobulin. Among the 23 cases of T-cell lymphoma, 22 were of peripheral T-cell type; most were of helper-cell (T4) phenotype and a significant number expressed J5 (CALLA) and I2 (HLA-DR). The present study shows that the percentage of T-cell lymphoma in Chinese is higher than in Caucasians, but lower than in Japanese. However, when the age-adjusted incidence of non-Hodgkin's lymphoma is considered, the incidence rates of T-cell lymphoma in Hong Kong Chinese and Japanese in areas non-endemic for adult T-cell lymphoma/leukemia are similar; the incidence in Americans is similar or slightly lower. The major difference between the races is that B-cell lymphoma, particularly the follicular type, is much rarer in Asians than Americans.