Evolution of models to support community and policy action with science: Balancing pastoral livelihoods and wildlife conservation in savannas of East Africa.

We developed a "continual engagement" model to better integrate knowledge from policy makers, communities, and researchers with the goal of promoting more effective action to balance poverty alleviation and wildlife conservation in 4 pastoral ecosystems of East Africa. The model involved the creation of a core boundary-spanning team, including community facilitators, a policy facilitator, and transdisciplinary researchers, responsible for linking with a wide range of actors from local to global scales. Collaborative researcher-facilitator community teams integrated local and scientific knowledge to help communities and policy makers improve herd quality and health, expand biodiversity payment schemes, develop land-use plans, and fully engage together in pastoral and wildlife policy development. This model focused on the creation of hybrid scientific-local knowledge highly relevant to community and policy maker needs. The facilitation team learned to be more effective by focusing on noncontroversial livelihood issues before addressing more difficult wildlife issues, using strategic and periodic engagement with most partners instead of continual engagement, and reducing costs by providing new scientific information only when deemed essential. We conclude by examining the role of facilitation in redressing asymmetries in power in researcher-community-policy maker teams, the role of individual values and character in establishing trust, and how to sustain knowledge-action links when project funding ends.

The dental network: the interrelationships of specialists and general dentists.

There is an unsubstantiated belief that patients are referred only to dental specialists and not from specialist to general dentist. For the most part, a high percentage of new patients to oral surgeons, periodontists and endodontists are generated from general practices. These specialists, in turn, could be a source of new patients to the general practitioner. Often the specialists have information about which dentists may be selling their practices or looking for an associate. This would be valuable if a dentist wanted to expand or merge a practice, or for a dentist just beginning to practice. A specialist can influence the patient to accept a restorative treatment plan, or perhaps recommend treatment that the patient requires. The GP should make an effort to attend study clubs, dental society meetings, and to meet the local specialists. It is just as important for the GP to be known by specialists as it is for specialists to be known by the GP.

A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis.

A third-generation adenoviral vector containing recombinant human cystic fibrosis transmembrane conductance regulator (CFTR) gene was delivered by bronchoscope in escalating doses to the conducting airway of 11 volunteers with cystic fibrosis. Assessments of dose-limiting toxicity (DLT), efficiency of gene transfer, and cell-mediated and humoral immune responses to vector administration were performed. DLT, manifest by flulike symptoms and transient radiographic infiltrates, was seen at 2.1 x 10(11) total viral particles. A highly specific assay for gene transfer was developed using in situ hybridization with an oligoprobe against unique vector sequence. Detectable gene transfer was observed in harvested bronchial epithelial cells (<1%) 4 days after vector instillation, which diminished to undetectable levels by day 43. Adenovirus-specific cell-mediated T cells were induced in most subjects, although only mild increases in systemic humoral immune response were observed. These results demonstrate that gene transfer to epithelium of the lower respiratory tract can be achieved in humans with adenoviral vectors but that efficiency is low and of short duration in the native CF airway.

A prospective, population-based study of the demographics, epidemiology, management, and outcome of out-of-hospital pediatric cardiopulmonary arrest.

STUDY OBJECTIVES: To perform a population-based study addressing the demography, epidemiology, management, and outcome of out-of-hospital pediatric cardiopulmonary arrest (PCPA). METHODS: Prospective, population-based study of all children (17 years of age or younger) in a large urban municipality who were treated by EMS personnel for apneic, pulseless conditions. Data were collected prospectively for 3(1/2) years using a comprehensive data collection tool and on-line computerized database. Each child received standard pediatric advanced cardiac life support. RESULTS: During the 3(1/2)-year period, 300 children presented with PCPA (annual incidence of 19. 7/100,000 at risk). Of these, 60% (n=181) were male (P =.0003), and 54% (n=161) were patients 12 months of age or younger (152,500 at risk). Compared with the population at risk (32% black patients, 36% Hispanic patients, 26% white patients), a disproportionate number of arrests occurred in black children (51.6% versus 26.6% in Hispanics, and 17% in white children; P <.0001). Over 60% of all cases (n=181) occurred in the home with family members present, and yet those family members initiated basic CPR in only 31 (17%) of such cases. Only 33 (11%) of the total 300 PCPA cases had a return of spontaneous circulation, and 5 of the 6 discharged survivors had significant neurologic sequelae. Only 1 factor, endotracheal intubation, was correlated positively with return of spontaneous circulation (P =.032). CONCLUSION: This population-based study underscores the need to investigate new therapeutic interventions for PCPA, as well as innovative strategies for improving the frequency of basic CPR for children.

Mouse beta-defensin 1 is a salt-sensitive antimicrobial peptide present in epithelia of the lung and urogenital tract.

One component of host defense at mucosal surfaces appears to be epithelium-derived peptides with antimicrobial activity called defensins. Human beta-defensin 1 (hBD-1) represents the first member of the beta-defensin family isolated from humans and has been implicated in the pathogenesis of cystic fibrosis. We describe in this report the isolation and characterization of a murine homolog of hBD-1 called mouse beta-defensin 1 (mBD-1). The predicted amino acid sequence shows the hallmark features of other known epithelial beta-defensins, including the ordered array of six cysteine residues. Analysis of a genomic clone of mBD-1 revealed two exons separated by a 15-kb intron. By use of fluorescence in situ hybridization, the mBD-1 gene was localized at the proximal portion of chromosome 8, the site where mouse alpha-defensins are found. Lysates from cells transfected with the mBD-1 cDNA showed antibacterial activity against gram-positive and gram-negative bacteria. mBD-1 transcripts were found in kidney, liver, and female reproductive organ tissues. In the airways, mBD-1 is expressed diffusely throughout the epithelial cells of the large proximal airways with less expression in the small distal airways and no expression in alveolar cells. The present study demonstrates that a beta-defensin potentially homologous to human beta-defensin 1 is present in the respiratory system and other mucosal surfaces in mice.

Sodium bicarbonate to correct widened QRS in a case of flecainide overdose.

A 16-yr-old male attempted suicide by ingesting approximately 4000 mg of flecainide. He developed coma, hypotension, and ventricular tachycardia. In addition to supportive care and antidysrhythmics, he received intravenous sodium bicarbonate for the wide complex dysrhythmia. Animal studies and anecdotal human experience have suggested that increasing the extracellular sodium improves cardiac conduction in flecainide toxicity. The patient's QRS narrowed immediately following sodium bicarbonate infusion. Sodium bicarbonate may be useful in the treatment of widened QRS and ventricular ectopy resulting from flecainide toxicity.

Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis.

A human bronchial xenograft model was used to characterize the molecular basis for the previously described defect in bacterial killing that is present in the cystic fibrosis (CF) lung. Airway surface fluid from CF grafts contained abnormally high NaCl and failed to kill bacteria, defects that were corrected with adenoviral vectors. A full-length clone for the only known human beta-defensin (i.e., hBD-1) was isolated. This gene is expressed throughout the respiratory epithelia of non-CF and CF lungs, and its protein product shows salt-dependent antimicrobial activity to P. aeruginosa. Antisense oligonucleotides to hBD-1 ablated the antimicrobial activity in airway surface fluid from non-CF grafts. These data suggest that hBD-1 plays an important role in innate immunity that is compromised in CF by its salt-dependent inactivation.

Lentiviral vectors for gene therapy of cystic fibrosis.

A replication-defective vector based on human immunodeficiency virus (HIV) was evaluated for gene transfer directed to the lung. The tropism of this vector has been expanded through the incorporation of the vesticular stomatitis virus G protein into its envelope. The HIV vector effectively transduced nondividing airway epithelial cells in vitro whereas a murine-based retroviral vector did not. Experiments in a human bronchial xenograft model demonstrated high-level gene transduction with a cystic fibrosis transmembrane conductance regulator (CFTR) HIV vector into undifferentiated, cystic fibrosis (CF)-derived cells of the xenograft. CFTR expression was stable and capable of functional correction of the CF defect after the graft matured. The HIV vector did not effectively transduce cells of the xenograft when instilled after the epithelium had differentiated. This block to transduction appears to be at the level of entry, although post entry restrictions cannot be ruled out. Further development of this vector system for CF gene therapy should focus on a better understanding of potential entry and post entry blocks.

Expression of alpha v beta 5 integrin is necessary for efficient adenovirus-mediated gene transfer in the human airway.

Recombinant adenoviruses are being evaluated for gene therapy of cystic fibrosis lung disease with the goal of reconstituting the expression of the cystic fibrosis transmembrane conductance regulator in pulmonary epithelia by direct administration of the virus into the airway. The therapeutic potential of recombinant adenoviruses is limited in part by the relative inefficiency by which gene transfer occurs. This study uses a human bronchial xenograft model to study adenovirus infection in the human airway in an attempt to define the molecular events that limit gene transfer. Our studies of the human airway confirm previous observations of cell lines that have indicated a two-step process for adenovirus entry, which begins with the binding of the virus to the cell through the fiber protein and continues with internalization via interactions among cellular integrins and an RGD motif (Arg-Gly-Asp) in the penton base. Furthermore, the level of maturity of the epithelia in xenografts has a major impact on gene transfer. Undifferentiated epithelia express high levels of alpha v beta 5 integrins and are easily infected with recombinant adenoviruses; gene transfer is completely inhibited with excess fiber and partially inhibited with RGD peptide and alpha v beta 5 integrin antibody. Pseudostratified epithelia do not express alpha v beta 5 integrin in differentiated columnar cells and are relatively resistant to adenovirus-mediated gene transfer; what little gene transfer occurs is inhibited by fiber but not by RGD peptide or alpha v beta 5 integrin antibody. These studies suggest that the expression of integrins in human airway epithelia limits the efficiency of gene transfer with recombinant adenoviruses. However, low-level gene transfer can occur in fully mature epithelia through alpha v beta 5 integrin-independent pathways.

Transfer of the CFTR gene to the lung of nonhuman primates with E1-deleted, E2a-defective recombinant adenoviruses: a preclinical toxicology study.

This paper describes a preclinical toxicology study designed to investigate the biological efficacy and safety profile of second-generation adenovirus for CFTR gene transfer into the baboon lung. This second-generation virus is deleted of E1 and contains a temperature-sensitive mutation in the E2a gene, which encodes a defective DNA-binding protein. Two distinct projects were undertaken. Group A animals received a first-generation adenovirus (i.e., deleted of E1) in an upper lobe at the time a second-generation virus was instilled into the contralateral upper lobe. The goal of study A was to compare the biology of each construct directly and to determine if an immune response to the first-generation virus affected the performance of the second-generation virus. Group B animals received a lacZ second-generation virus in an upper lobe at the same time the CFTR second-generation virus was instilled in the other upper lobe. Necropsies were performed 4 or 21 days after gene transfer and tissues were evaluated for recombinant gene expression and histopathology. Using a second-generation adenovirus, recombinant gene stability was prolonged and associated with a diminished level of perivascular inflammation as compared to first-generation vectors. Markedly diminished levels of hexon protein were present in tissues infected with second-generation as compared to first-generation virus. No evidence of viral shedding was evident. Furthermore, coadministration of first- and second-generation adenovirus did not affect the stability of transgene expression from the second-generation virus. These data suggest that second-generation adenoviral vectors provide an improved gene delivery vehicle, and thus may be useful in gene therapy for cystic fibrosis.

Gene therapy in a xenograft model of cystic fibrosis lung corrects chloride transport more effectively than the sodium defect.

We have developed a model of gene therapy for cystic fibrosis (CF) lung disease, based on growth of human CF bronchial xenografts in nu/nu mice. We now report an evaluation of the primary abnormalities in CF lung epithelia--defective Cl secretion and Na hyperabsorption--in xenografts following adenovirus-mediated gene transfer. In vivo infection of CF xenografts with a cystic fibrosis transmembrane regulator (CFTR) recombinant adenovirus, at a multiplicity of infection equal to 100, was sufficient to reconstitute near normal levels of cAMP-stimulated Cl transport, despite transducing only 5% of cells in the pseudostratified epithelium. Correction in sodium hyperabsorption was partial and variable. These experiments define aspects of adenovirus-mediated gene therapy relevant to CF protocols based on intrapulmonary genetic reconstitution.

Mucogingival orthodontic and periodontal problems.

The absence of keratinized gingiva alone is not an indication for a periodontal surgical procedure. However, if recession increases during orthodontic treatment, then a gingival graft may be indicated. Orthodontic therapy and removal of a mandibular incisor where excessive gingival recession is present may be the indicated treatment.

The misperceived duty to report patients' past crimes.

A questionnaire survey revealed that a number of mental health professionals believed that they had a duty to report a hypothetical patient's past criminal act. The authors examine the legal context of this misperceived reporting duty and discuss its implications for training and practice.

Adverse ocular effects of anticonvulsants.

With increasing recognition of the interface between neurology and psychiatry, the use of anticonvulsants to treat the signs and symptoms of many psychiatric disturbances is becoming commonplace. Although rare adverse reactions, such as those in the hepatic and hematological systems, have attracted considerable concern, for many anticonvulsants it is the ocular reactions that are among the most common. This article reviews the major ocular reactions to anticonvulsants and suggests guidelines for their use. It also underscores the importance of including adverse ocular effects as part of the informed consent process.

The dissolution of the dyad in psychiatry: implications for the understanding of patient-therapist sexual misconduct.

Psychiatry has undergone multiple changes in this century. Some twenty years ago, Kubie describe a move away from patients, particularly in those practitioners involved in academic psychiatry. His concern was warranted; such a trend appears to have involved much of psychiatry. There has been a markedly decreased emphasis in viewing the operative unit of psychiatric inquiry as a dyad of the physician and patient, in which the parties inescapably influence each other. Newer treatments tend to employ the physician as a more independent entity that applies necessary treatment to the patient. Concomitantly, we have seen a trend toward a diminishing focus on sexuality as a primary motivating force in all areas of human endeavor. Freud proposed that libidinal impulses dominated much of our behavior; later psychoanalytic theorists and founders of other modalities of treatment have focused on other sources of motivation. Within the context of a psychiatry less focused on the physician and patient in a dyadic sense, and less focused on sexuality as a universal source of motivation, we have witnessed a marked increase in interest in the sexual misconduct of psychiatrists. Comprehension of this disturbing issue in the service of prevention rests upon reversing these trends. We must attend to the dyad as a bipersonal field serving as the arena for misconduct. We must also parallel our strident disapproval of misconduct with an objective exploration of the dynamics of both parties and the human commonality of sexual feelings. This special section represents such an exploratory effort.

Bone regeneration around a failing implant using guided tissue regeneration. A case report.

An implant was determined to be clinically and radiographically failing. The implant was treated as if it were a natural tooth with periodontal disease. The defect around the implant was degranulated and a polytetrafluoroethylene periodontal membrane placed over the implant to cover the defect. The membrane was removed 6 weeks later. A 5-month re-entry found new bone around the implant and the implant could then be used as a prosthetic abutment. Further case studies may prove this to be a predictable procedure to save failing implants.