Bacterial colonization dynamics associated with respiratory syncytial virus during early childhood

Respiratory syncytial virus (RSV) is an important cause of early life acute respiratory infections. Potentially pathogenic respiratory bacteria, including Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae are frequently detected during RSV infections and associated with increased illness severity. However, the temporal dynamics of bacterial colonization associated with RSV infection remain unclear. We used weekly nasal swab data from a prospective longitudinal birth cohort in Brisbane, Australia, to investigate bacterial colonization patterns within children aged less than 2 years in the 4‐week period before and after an RSV infection. During 54 RSV infection episodes recorded in 47 children, both S. pneumoniae and M. catarrhalis were detected frequently (in 33 [61.1%] and 26 [48.1%] RSV infections, respectively). In most cases, S. pneumoniae and M. catarrhalis colonization preceded the viral infection, with the nasal load of each increasing during RSV infection. Generally, the dominant serotype of S. pneumoniae remained consistent in the 1 to 2 weeks immediately before and after RSV infection. Little evidence was found to indicate that prior colonization with either bacteria predisposed participants to developing RSV infection during the annual seasonal epidemic. Possible coacquisition events, where the bacteria species was first detected with RSV and not in the preceding 4 weeks, were observed in approximately 20% of RSV/S. pneumoniae and RSV/M. catarrhalis codetections. Taken together our results indicate that RSV generally triggered an outgrowth, rather than a new acquisition, of S. pneumoniae and M. catarrhalis from the resident microbial community.     

Occurrence of the t(2;5)(p23;q35) in non-Hodgkin's lymphoma

Primary CD30(Ki-1)-positive anaplastic large-cell lymphoma (ALCL) is considered by some to be a distinct clinicopathologic entity associated with the t(2;5) (p23;q35). However, the specificity of t(2;5) for ALCL has not been carefully studied. Therefore, we performed a detailed analysis of all cases of ALCL with abnormal cytogenetics results in the Nebraska Lymphoma Study Group registry, as well as all other cases of non-Hodgkin's lymphoma with t(2;5) in the registry. We found the t(2;5) in only five of 10 cases of ALCL, four of whom were young patients. However, we also found the t(2;5) in 11 other cases of nonanaplastic lymphoma, including eight children with typical peripheral T-cell lymphomas of various types. The t(2;5) was also found in three older adults with B-cell lymphomas of various types. Thus, the t(2;5) was not specific for CD30+ ALCL. However, t(2;5) may define a clinicopathologic entity in children and young adults characterized by variable morphologies with a T-cell or indeterminate phenotype, CD30-positivity, nodal disease with frequent extranodal involvement, advanced stage, and an excellent response to therapy, including bone marrow transplantation for relapsed disease. The clinical relevance of the t(2;5) in older patients requires further study.     

Severe viral respiratory infections in infants with cystic fibrosis

Limited data in children with cystic fibrosis (CF) suggest that respiratory viral infections during infancy result in substantial morbidity. Eighty of 101 (79%) infants with CF diagnosed by neonatal screening during 1991–1996 were recruited into a prospective, multiple-birth cohort study. We aimed to perform an initial, then annual bronchoalveolar lavage (BAL) for bacterial and viral culture, cytology, IL-8, and elastolytic activity over the following 2 years. When possible, BAL was also performed during any hospitalization for a pulmonary exacerbation, and additional specimens for viral culture were collected by nasopharyngeal aspiration. Thirteen infants undergoing bronchoscopy for congenital stridor served as disease controls. During infancy, 31 children (39%) were hospitalized for respiratory disease and 20 (65%) cases had an etiologic agent identified. Respiratory viruses were detected in 16/31 (52%) cases, including four with simultaneous bacterial infection. Another four were infected with Staphylococcus aureus. Respiratory syncytial virus predominated and was found in seven infants. In the absence of bacteria, those with viral infections had acute onset of respiratory distress, were not treated with antibiotics, and had an uncomplicated hospital course. Compared to noninfected CF subjects and controls, infected infants had elevated BAL inflammatory indices (P < 0.01). Eleven of 31 (35%) hospitalized infants followed for 12–60 months acquired Pseudomonas aeruginosa, compared with only three of 49 (6%) subjects not hospitalized for respiratory symptoms during infancy (risk ratio 5.8, CI 1.9, 24). We conclude that respiratory viruses are important causes of hospitalization in CF infants. While viral infections were self-limited, they were accompanied by airway inflammatory changes, and admission to hospital was associated with early acquisition of Pseudomonas aeruginosa and persistent respiratory symptoms. Pediatr Pulmonol. 1998; 26:371–379. © 1998 Wiley-Liss, Inc.     

4-Amido-2-carboxytetrahydroquinolines. Structure-activity relationships for antagonism at the glycine site of the NMDA receptor.

trans-2-Carboxy-5,7-dichloro-4-amidotetrahydroquinolines, evolved from the lead 5,7-dichlorokynurenic acid, have been synthesized and tested for in vitro antagonist activity at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Optimization of the 4-substituent has provided antagonists having nanomolar affinity, including the urea trans-2-carboxy-5,7-dichloro-4[[(phenylamino)carbonyl]amino]-1,2,3, 4-tetrahydroquinoline (35; IC50 = 7.4 nM vs [3H]glycine binding; Kb = 130 nM for block of NMDA responses in the rat cortical slice), which is one of the most potent NMDA antagonists yet found. The absolute stereochemical requirements for binding were found to be 2S,4R, showing that, in common with other glycine-site NMDA receptor ligands, the unnatural configuration at the alpha-amino acid center is required. The preferred conformation of the trans-2,4-disubstituted tetrahydroquinoline system, as shown by X-ray crystallography and 1H NMR studies, places the 2-carboxyl pseudoequatorial and the 4-substituent pseudoaxial. Modifications of the 4-amide show that bulky substituents are tolerated and reveal the critical importance for activity of correct positioning of the carbonyl group. The high affinity of trans-2-carboxy-5,7-dichloro-4-[1-(3-phenyl-2-oxoimidazolidinyl)]- 1,2,3,4-tetrahydroquinoline (55; IC50 = 6 nM) suggests that the Z,Z conformer of the phenyl urea moiety in 35 is recognized by the receptor. Molecular modeling studies show that the 4-carbonyl groups of the kynurenic acids, the tetrahydroquinolines, and related antagonists based on N-(chlorophenyl)glycine, can interact with a single putative H-bond donor on the receptor. The results allow the establishment of a three-dimensional pharmacophore of the glycine receptor antagonist site, incorporating a newly defined bulk tolerance/hydrophobic region.     

Rotavirus vaccines: opportunities and challenges

Each year rotavirus gastroenteritis episodes in young children cause more than 500,000 deaths and 2.4 million hospital admissions worldwide. Vaccine development became a priority when improved personal hygiene and living standards failed to significantly reduce this disease burden. Rotavirus vaccines were developed mimicking natural immunity by protecting against severe gastroenteritis in young children, which would otherwise lead to health-care attendance, hospitalization or even death. Licensed rotavirus vaccines appear safe and are well-tolerated. In high and middle-income countries they provide 80-100% protection against severe disease and 70-80% protection against rotavirus gastroenteritis of any severity, depending upon the population studied. However, rotavirus vaccines remain to be fully evaluated in low-income countries where reduced immunogenicity of oral vaccines, greater strain diversity and difficulties reaching target populations might decrease immunization program performance. Nevertheless, if these challenges are met, rotavirus vaccines should help reduce the 5% of all childhood deaths attributable to rotavirus gastroenteritis.     

Patients with enteric adenovirus gastroenteritis admitted to an Australian pediatric teaching hospital from 1981 to 1992.

During the period 1981 to 1992, 4,473 fecal specimens collected from children hospitalized with acute gastroenteritis at the Royal Children's Hospital, Melbourne, Australia, were examined by electron microscopy. A monoclonal antibody enzyme immunoassay for enteric adenovirus (EAd) types 40 (Ad40) and 41 (Ad41) was used when adenoviruses were visualized. Fecal samples were positive for adenovirus by both electron microscopy and enzyme immunoassay in 138 patients (3.1%). Ad40 was identified in 19 children (14%), and Ad41 was identified in 119 children (86%). These EAd were identified during each of the 12 years surveyed. EAd were present year-round, but the annual number of hospitalizations was not constant. Yearly prevalence varied from 0.7% (1981) to 6.5% (1985). This was associated with monthly fluctuations in Ad41 activity, with overall peak monthly prevalence in May (late autumn). By contrast, Ad40 numbers remained low and constant year-round. The frequency of Ad41 relative to Ad40 increased from 25% in 1981 to exceed 75% after 1983. Children admitted with EAd infection were more likely to have diarrhea for more than 5 days (P < 0.001) but less likely to be febrile or dehydrated (P < 0.05) than children with rotavirus infection. EAd are responsible for enteric symptoms of only a fraction of hospitalized children with infectious diarrhea but result in a more-protracted illness than rotavirus. Their relationship to persistent diarrhea requires further investigation.     

Quality of life (QOL) assessment of MIP (mitomycin, ifosfamide and cisplatin) chemotherapy in advanced non-small cell lung cancers (NSCLC)

BACKGROUND: Quality of life (QOL) assessment has emerged to measure and quantify the balance between treatment benefit and toxicity, and has a value in predicting response and overall survival in cancer patients. METHODS: From July 1995 to February 1997, 38 symptomatic patients with advanced non-small cell lung cancer (NSCLC) were treated with MIP chemotherapy (mitomycin 6 mg/m2, ifosfamide 3000 mg/m2 and cisplatin 50 mg/m2 on day 1 every 3 weeks). Patients were assessed for QOL including physical well-being, general symptoms and lung cancer-specific symptoms, as well as objective response. RESULTS: The overall response rate was 38.9% (14/36, all were partial response) and the median duration of response was 3.5 months [95% confidence interval (CI) 2.0-4.0]. The median duration of overall survival was 7 months (95% CI 5.9-8.5). The overall improvement of QOL was 58.3% with 21 patients feeling better on treatment. The toxicity of chemotherapy was mild, mainly nausea/vomiting and minimal alopecia. Using multiple clinical predictors of survival (age, histology, stage, performance status), only change of QOL emerged significantly (P = 0.0007). CONCLUSIONS: MIP had an endurable response and low toxicity profile, and provided good QOL. Integral QOL data in our study provided the strong prediction of survival in advanced NSCLC. Further experienced QOL study will provide greatly enhanced outcome data in clinical trials.      

Duration of action of a broad range of selective κ-opioid receptor antagonists is positively correlated with c-Jun N-terminal kinase-1 activation

The κ-opioid receptor is a widely expressed G-protein-coupled receptor that has been implicated in biological responses to pain, stress, anxiety, and depression, and its potential as a therapeutic target in these syndromes is becoming increasingly apparent. However, the prototypical selective κ-opioid antagonists have very long durations of action that have been attributed to c-Jun N-terminal kinase (JNK) 1 activation in vivo. To test generality of this proposed noncompetitive mechanism, we used C57BL/6 wild type mice to determine the durations of antagonist action of novel κ-opioid receptor ligands and examined their efficacies for JNK1 activation compared with conventional competitive antagonists. Of the 12 compounds tested, 5 had long durations of action that positively correlated with JNK activation: RTI-5989-97 [(3S)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-(2-methylpropyl]-2-methyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide], RTI-5989-194 [(3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-(2-methylbutyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide], RTI-5989-241 [(3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide)], nor-binaltorphimine (nor-BNI); and (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic). Seven had short durations of action and did not increase phospho-JNK-ir: RTI-5989-212[(3R)-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-(2-methylpropyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide], RTI-5989-240 [(3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl]-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide], JSPA0658 [(S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide], JSPA071B [(S)-3-fluoro-4-(4-((2-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide]. PF-4455242 [2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine], PF-4455242 [2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine], FP3FBZ [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide], and naloxone. After long-acting antagonist treatment, pJNK-ir did not increase in mice lacking the κ-opioid receptor; increased pJNK-ir returned to baseline by 48 h after treatment; and a second challenge with nor-BNI 72 h after the first did not increase pJNK-ir. Long-lasting antagonism and increased phospho-JNK-ir were not seen in animals lacking the JNK1 isoform. These results support the hypothesis that the duration of action of small molecule κ-opioid receptor antagonists in vivo is determined by their efficacy in activating JNK1 and that persistent inactivation of the κ-receptor does not require sustained JNK activation.