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.

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.

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.

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.

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.

Kleptomania: making sense of the nonsensical.

OBJECTIVE: Kleptomania, or the irresistible impulse to steal unneeded objects, is a poorly understood disorder. The objectives of this paper are to critically review and integrate existing data and to make suggestions for further research. DATA COLLECTION: Information was gathered by reviewing the English-language literature on kleptomania. Cases were chosen for review that approximated the diagnosis as defined in DSM-III-R. These cases were analyzed in terms of their relationship to previous theories about the disorder, and larger relevant studies were examined. Using the data organized into a table, the author explores areas of convergence and disagreement and discusses the methodological difficulties of the different studies. FINDINGS: Kleptomania is more common than previously thought. The "typical" individual with kleptomania is a 35-year-old woman who began to steal when she was 20 years old. Her thefts bring both relief and guilt. She probably has not sought treatment on her own but suffers from a necessary, pervasive, repetitive, and self-destructive act. She may have a history of sexual dysfunction or sexual preoccupation and may be unhappily married to an emotionally unsupportive husband. She has been labile and dysphoric for many years and may have a personality disorder. She has probably had a tumultuous, stressful childhood and may dissociate. CONCLUSIONS: The author proposes a biopsychosocial model of the etiology of kleptomania based on data from the literature. This model emphasizes possible childhood abuse as a precipitating factor in later development of kleptomania. More complete research is needed in the study of kleptomania.

Regulation of genes for enzymes involved in fatty acid synthesis.

The levels of malic enzyme and fatty acid synthase are increased by feeding and decreased by starvation in liver in vivo and are increased by triiodothyronine and decreased by glucagon in hepatocytes in culture. Cloned malic enzyme and fatty acid synthase cDNAs are being used to analyze regulation of these unique genes. Dietary regulation of both enzymes occurs at pretranslational steps. Increased transcription and increased mRNA stability contribute about equally to a 20-fold increase in malic enzyme mRNA level when starved ducklings are refed. In contrast, a 10-fold increase in the level of fatty acid synthase mRNA is largely accounted for by increased transcription of this gene. In chick-embryo hepatocytes incubated in serum-free medium containing insulin, triiodothyronine causes a greater than 10-fold increase in levels of both malic enzyme and fatty acid synthase mRNAs. Kinetic and inhibitor experiments suggest a protein intermediate in the increases of malic enzyme and fatty acid synthase mRNAs caused by triiodothyronine. For malic enzyme, the stimulation by triiodothyronine is predominantly posttranscriptional. Glucagon decreases the level of malic enzyme mRNA by 90 to 95%, with regulation occurring at a posttranscriptional step. Inhibitor experiments suggest that stimulation of the degradation of malic enzyme mRNA is partially responsible. Glucagon inhibited fatty acid synthase mRNA level by less than 50%; the inhibited step has not been identified. Thus, the coordinated regulation of malic enzyme and fatty acid synthase proteins by nutritional state may involve different hormones regulating at different points. A surprisingly large component of the regulation is posttranscriptional.

Aortic arch digital arteriography: an alternative technique to digital venous angiography and routine arteriography in the evaluation of cerebrovascular insufficiency.

Digital arch arteriography is a technique in which the cervicocerebral vasculature is studied by injecting small amounts of contrast material (20 ml or less of diatrizoate meglumine 60%) into the aortic arch. It was used as the initial phase of arteriography in 100 patients with cerebrovascular disease. Five to ten series were obtained in various projections to evaluate the cerebrovascular system. Because suboptimal studies may be repeated, only 3% of carotid bifurcations were suboptimally visualized by digital arch arteriography as compared with 17% by film arch angiography. Intracranial vascular pathology was identified less reliably than with selective angiography. Digital arch arteriography yielded excellent studies in cases when digital venous angiography was suboptimal (20%). Digital arch arteriography may be preferable to digital venous angiography as a screening test in patients with significant cardiac or renal dysfunction because of the lower contrast load.

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.

Human lymphocyte antigen haplotype and resistance to periodontitis.

Certain human lymphocyte antigen (HLA) haplotypes have been correlated with the presence of certain diseases. To date no significant relationship between periodontitis and HLA haplotype has been demonstrated. The purpose of this study was to determine the frequency of HLA-A, HLA-B and HLA-C haplotypes in patients resistant to chronic periodontitis and to determine if there is any association between specific HLA genes and periodontal health. Twenty-five healthy individuals who demonstrated a high resistance to periodontal disease (mean age 49.9 years) were matched to 25 subjects with chronic periodontitis and to a periodontally undiagnosed population of 22,000 individuals. Peripheral blood was taken and HLA specificity was determined by the microlymphocytotoxicity test. The results indicated a statistically significant increase in the occurrence of HLA-B5 (P = 0.0059) and a trend in the occurrence of HLA-A28 (P = 0.0565) in those patients resistant to periodontal disease when compared to the matched controls. When compared to the large random control group, a significant correlation was observed for HLA-A28 (P less than 0.01) in blacks and HLA-B5 (P less than 0.01) in whites. It is possible that the HLA-A28 and the HLA-B5 individual may have the ability to resist the progression of chronic periodontitis.

Effect of periodontal therapy on patients maintained for 15 years or longer. A retrospective study.

A retrospective study of tooth loss in 211 patients who were treated for periodontal disease in private practice and maintained for 15 to 34 years on 3- to 6-month recall schedules is reported. The average age of the patients was 42 years, and the average length of time in maintenance was 22 years. On the basis of response to therapy, the patients were classified as Well-Maintained (62%), Downhill (28%) and Extreme Downhill (10%). Seven hundred and seventy-one (771) teeth were lost (13.4%) due to all causes. Molar teeth are the most prone to loss and the mandibular cuspid is the most resistant. The importance of maintenance therapy is emphasized.

An objective appraisal of the role of computed tomographic (CT) guided drainage of intra-abdominal abscesses.

Computed tomographic (CT) guided drainage is an important tool in the treatment of intra-abdominal abscess. Its most important role is in the treatment of small, unilocular, well-placed abscesses. Success rates in our experience diminish considerably in abscesses involving necrotic tumors or those infected with yeast. As is frequently characteristic of new technologic procedures, the initial evaluation of the success rate of the procedure is overly optimistic. The procedure carries a considerable complication rate (13%) and mortality rate (15%). Most importantly, success is usually evident early; within the first 24 to 48 hours. After this length of time, careful evaluation to consider further treatment should be contemplated.

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.

Detection of postcardiotomy bacterial pericarditis with gallium-67 citrate.

A 46-year-old man who had undergone apical cardiac aneurysmectomy with a ventriculotomy graft and implanted automatic cardioverter-defibrillator electrodes, presented with fever, left-sided pleuritic chest pain, and a draining sinus. A Ga-67 scan was performed to aid in determining whether the infection was limited to the chest wall or if it had penetrated deeper to the cardiac structures. Uptake of gallium within the cardiac region, in association with minimal rib uptake of Tc-99m MDP, strongly supported the existence of infection within the pericardium. CT scan demonstrated a pericardial collection which under CT-guided aspiration proved to be purulent. Definitive surgical drainage was performed, and the patient was discharged 4 weeks postoperatively. Ga-67 imaging can provide an accurate and relatively rapid means of localizing infection in the postcardiotomy patient. A thorough bibliography of pericardial gallium uptake is provided.

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.

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.