A novel gene delivery method transduces porcine pancreatic duct epithelial cells.

Gene therapy offers the possibility to treat pancreatic disease in cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene; however, gene transfer to the pancreas is untested in humans. The pancreatic disease phenotype is very similar between humans and pigs with CF; thus, CF pigs create an excellent opportunity to study gene transfer to the pancreas. There are no studies showing efficient transduction of pig pancreas with gene-transfer vectors. Our objective is to develop a safe and efficient method to transduce wild-type (WT) porcine pancreatic ducts that express CFTR. We catheterized the umbilical artery of WT newborn pigs and delivered an adeno-associated virus serotype 9 vector expressing green-fluorescent protein (AAV9CMV.sceGFP) or vehicle to the celiac artery, the vessel that supplies major branches to the pancreas. This technique resulted in stable and dose-dependent transduction of pancreatic duct epithelial cells that expressed CFTR. Intravenous (IV) injection of AAV9CMV.sceGFP did not transduce the pancreas. Our technique offers an opportunity to deliver the CFTR gene to the pancreas of CF pigs. The celiac artery can be accessed via the umbilical artery in newborns and via the femoral artery at older ages--delivery approaches that can be translated to humans.

Lipofuscin in human glaucomatous optic nerves.

Lipofuscin accumulation has been observed in a number of neurodegenerative diseases. We recently found that autofluorescent particles also occur in the aged human optic nerve. In this study we sought to determine the nature of these particles and their correlation with aging, age-related macular degeneration (AMD) and primary open angle glaucoma (POAG). Groups of eight optic nerves from patients diagnosed with primary open angle glaucoma, age-related macular degeneration, age-matched controls and four optic nerves derived from controls younger than 42 years were used for the study. All samples were fixed in paraformaldehyde and frozen frontal sections were prepared. Sections were analyzed with fluorescence microscopy, bright field microscopy, Sudan black staining and spectrofluorometry using a confocal laser scanning microscope. Sections were photographed and analyzed to establish the distribution, quantity, and size of the autofluorescent particles. Additionally, transmission electron microscopy was used to determine the ultrastructural location of the granules. On unstained sections under light microscopy granules are detectable as pale brown inclusions and are easily stained with oil-soluble dyes, such as Sudan black. Granules fluoresce when excited at all tested wavelengths but lose their fluorescence after staining with Sudan black. These particles are distributed throughout the axonal columns, but not in the septa, and appear to be located within the glia ensheathing optic nerve axons. The histologic properties of the granules seen in the optic nerve sections correspond to lipofuscin aggregates, a result of incomplete degradation of oxidized proteins. Our morphometric analyses indicate that overall the optic nerves from control, glaucoma, and AMD donors contain similar amounts of lipofuscin. However, optic nerves derived from donors with glaucoma contain lipofuscin particles that are larger than those observed in the age-matched control and AMD groups. Furthermore optic nerves from glaucoma donors display a smaller diameter than those from age-matched controls resulting in a higher concentration of lipofuscin in glaucomatous optic nerves.

[Study and treatment of heart failure require new approaches. Natriuretic peptides can be safe and simple diagnostic and outcome measures]. / Utredning och behandling av hjärtsvikt söker nya vägar. Natriuretiska peptider kan bli säkert och enkelt mått i diagnostik och behandling.

Analysis of plasma natriuretic peptides and related propeptide fragments may be a cost-effective aid to diagnostic evaluation and treatment follow-up in cases of heart failure. In diagnostic potential such variables may constitute first-line measures of high negative predictive value, allowing further examination, e.g. by echocardiography, in cases where values are above the respective cut-off levels. However, in many cases evaluation of published reports is rendered difficult by their omission of information on such pre-analytical variables as blood sampling and storage, and drug therapy. Moreover, different analytical methods may yield widely divergent results. Thus, before such assays are introduced in general use, their long-term validity needs to be ensured, for instance by consistency in calibration, and measurements need to be made in representative series of unselected patients for the determination of appropriate cut-off levels.

Brain natriuretic peptide in an elderly population.

OBJECTIVES: To study the relationship of brain natriuretic peptide concentrations to ageing, and whether brain natriuretic peptide could reflect current disease states in the general elderly population. DESIGN: Brain natriuretic peptide was measured in two population samples from the general population. SUBJECTS: Five hundred forty-five 85-year-old subjects from the longitudinal population study '70-year-old people in Gothenburg, Sweden' were investigated in respect to cardiovascular, renal and metabolic disease, and 191 subjects from the 40-year-old male population were examined. MAIN OUTCOME MEASURES: To study the influence of ageing on circulating brain natriuretic peptide and the association between concentrations of brain natriuretic peptide and common disease states in the elderly. RESULTS: Brain natriuretic peptide concentrations were significantly increased in relation to ageing (P < 0.001). Brain natriuretic peptide concentrations were significantly increased in elderly with congestive heart failure (P < 0.001), ischaemic heart disease (P < 0.001), atrial fibrillation (P < 0.001) and renal dysfunction (P < 0.001) but not in hypertension. In multivariate analysis, brain natriuretic peptide concentrations were predictive for ischaemic heart disease (P < 0.001), atrial fibrillation (P < 0.01), renal dysfunction (P < 0.01), congestive heart failure (P < 0.05) and treatment with beta-adrenergic blockers (P < 0.05). CONCLUSIONS: Plasma concentrations of brain natriuretic peptide are increased in healthy elderly compared to middle-aged individuals. In the elderly, measurements of brain natriuretic peptide may provide prognostic information, due to the augmented secretion in cardiovascular diseases commonly seen in this population. It remains to be determined whether routine measurements of circulating brain natriuretic peptide will be of value in predicting current cardiovascular disease for the individual patient.

Atrial natriuretic peptides predict mortality in the elderly.

OBJECTIVES: To ascertain whether atrial natriuretic peptides could be used as prospective and independent predictors of total mortality in an elderly population. DESIGN: Atrial natriuretic peptides, ANP(1-98) and ANP(99-126), were measured in 541 subjects from the 85-year-old population of Gothenburg, Sweden. Before the study cardiovascular disorders such as congestive heart failure, ischaemic heart disease, hypertension and atrial fibrillation were defined. Total mortality was recorded during the prospective 60-month follow-up period. SETTING: Individuals aged 85 years from the population of Gothenburg, Sweden, were visited once at home and made one visit to Vasa Hospital. MAIN OUTCOME MEASURES: Sixty-month mortality in relation to circulating concentrations of atrial natriuretic peptides. RESULTS: Circulating concentrations of ANP(1-98) and ANP(99-126) were significantly correlated with 60-month mortality in the total study population (ANP(1-98), P < 0.001: ANP(99-126), P < 0.01). In subjects with cardiovascular disorders, 60-month mortality was significantly correlated with increased concentrations of ANP(1-98) (P < 0.01) and ANP(99-126) (P < 0.05). In subjects with no defined cardiovascular disorder, 60-month mortality was significantly correlated with increased ANP(1-98) concentrations (P < 0.01). CONCLUSIONS: In the elderly population, atrial peptides predict mortality in subjects with defined cardiovascular disorders as well as in the total population and may predict future cardiovascular disorder.

Brain natriuretic peptide predicts mortality in the elderly.

OBJECTIVE: To study whether prospective measurements of circulating concentrations of brain natriuretic peptide (BNP) could predict mortality in the general elderly population. DESIGN AND SETTING: Circulating BNP was measured in a cohort of 85 year olds from the general population who were followed up prospectively for five years as part of a longitudinal population study, "70 year old people in Gothenburg, Sweden". PATIENTS: 541 subjects from the 85 year old population in Gothenburg. All subjects were investigated for the presence or absence of cardiovascular disorder such as congestive heart failure, ischaemic heart disease, hypertension, and atrial fibrillation. Venous plasma samples were obtained for BNP analysis. MAIN OUTCOME MEASURE: Overall mortality during the prospective follow up period. RESULTS: Circulating concentrations of BNP predicted five-year mortality in the total population (P < 0.001). In subjects with a known cardiovascular disorder, five-year mortality was correlated with increased BNP concentrations (P < 0.01). Increased BNP concentrations predicted five-year mortality in subjects without a defined cardiovascular disorder (P < 0.05). CONCLUSIONS: In an elderly population, measurements of BNP may add valuable prognostic information and may be used to predict mortality in the total population as well as in patients with known cardiovascular disorders. In subjects without any known cardiovascular disorder, BNP was a strong and independent predictor of total mortality.

Atrial peptides, ANP(1-98) and ANP(99-126) in health and disease in an elderly population.

Circulating immunoreactive atrial natriuretic peptide, IrANP(99-126) and the N-terminal fragment of the prohormone, IrANP(1-98) were measured in two population samples from the general population of Gothenburg, Sweden. A group of 85-year olds (974 subjects) and a group of 40-year olds (191 subjects) were investigated in respect of cardiovascular, renal and metabolic disease. IrANP(99-126) and IrANP(1-98) were significantly higher in the 85-year olds compared to the 40-year olds, and were significantly increased in subjects with congestive heart failure, ischaemic heart disease, atrial fibrillation and renal dysfunction but not in subjects with hypertension. Eighty-five-year-old subjects who were on treatment with digitalis, beta-adrenergic-blockers, nitrates and diuretics had significantly increased IrANP(99-126) and IrANP(1-98). In multivariate analysis IrANP(99-126) concentrations were predictive for congestive heart failure, ischaemic heart disease, atrial fibrillation and treatment with beta-blockers and anti-depressant drugs. IrANP(1-98) was predictive for congestive heart failure, ischaemic heart disease, atrial fibrillation, diabetes mellitus, renal failure and drug treatment with beta-blockers and neuroleptics. We conclude that measurements of circulating concentrations of IrANP(99-126) and/or IrANP(1-98) may add valuable information in the diagnosis of congestive heart failure and ischaemic heart disease in an elderly population. It remains to be determined whether routine measurements of circulating IrANP (99-126) and IrANP(1-98) may be of value in predicting current cardiovascular disease for the individual patient.

Linear and rotational changes in large mandibular advancements using three or four fixation screws.

Forty-one patients who underwent bilateral sagittal ramus osteotomy for large mandibular advancements were evaluated by retrospective cephalometric analysis for rotational and linear stability of the proximal and distal segments of the mandible. The patients were grouped by the number of screws used in fixation (three versus four 2-mm bicortical screws) and matched for the amount of advancement measured from changes in mandibular body length. The group with four fixation screws did receive significantly larger advancements relative to the cranial base than did the group with three screws. However, the pattern of postoperative change was similar for the two groups. There was no higher rate of relapse seen in those patients with high mandibular plane angles, genioplasties, mandibular constriction with a symphyseal osteotomy, or open bites preoperatively, nor did the number of screws used in fixation affect changes seen in those patients. Factors associated with both relapse and continued postoperative movement in the direction of advancement independent of the screw fixation group were identified.

Stability of mandibular constriction with a symphyseal osteotomy.

The purposes of this study are to determine the stability of surgical mandibular constriction with a midline osteotomy and to evaluate the periodontal and temporomandibular joint responses. A symphyseal osteotomy to facilitate mandibular construction was performed in 15 patients to correct transverse discrepancies. At the same time a surgical anterior or posterior repositioning of the mandible was done by using a bilateral sagittal osteotomy of the vertical ramus. Tomograms in the coronal plane including the mandibular second molars were taken preoperatively (T1), immediately postoperatively (T2) and 8 weeks postoperatively (T3). Linear measurements between the cortical borders of the mandible were assessed from the tomograms at each time period. Median surgical and postoperative changes in mandibular width were determined. When evaluating the entire group no statistically significant change in the surgical constriction was found postoperatively (T2 and T3), although there was some individual variability. An examination of the periodontal response at the osteotomy site revealed no statistically significant change between the initial and the 5-month postoperative examinations. No changes in joint noise were detected postoperatively, and all mandibular joint movements returned to preoperative values except for excursive movements. Mandibular constriction with a midline osteotomy on conjunction with a bilateral sagittal osteotomy was found to be a stable modality for correcting transverse disharmonies.

Case report MM. Surgical-orthodontic correction of bilateral buccal crossbite (Brodie syndrome)

A surgical approach to treatment was required for this 35-year-old patient to correct a malocclusion characterized by a bilateral buccal crossbite. Surgical procedures included a LeFort 1 osteotomy to reduce maxillary width and correct the vertical asymmetry. The mandible was lengthened with a bilateral sagittal split osteotomy. Treatment options for the nongrowing patient are limited in the correction of severe skeletal disharmonies.

Stability of mandibular advancement osteotomy using rigid internal fixation.

Forty-three patients who underwent surgical lengthening of the mandible using an inverted L osteotomy, bone grafting, and rigid internal fixation between the mandibular segments were evaluated by retrospective cephalometric analysis for longitudinal skeletal and dental changes. Postoperative response (means = 1 year 9 months) was found to demonstrate a high level of stability with some individual variability. No propensity for relapse was observed in any postoperative time interval. Condylar repositioning postoperatively appeared to be an important factor in those patients who exhibited any relapse tendency. Overall postoperative stability of this surgical/fixation technique appears to be significantly improved compared with previously documented techniques.

Perceptions of facial profile and their influence on the decision to undergo orthognathic surgery.

Eighty patients, who had previously been evaluated by an oral surgeon and an orthodontist as requiring orthognathic surgery, completed questionnaires rating their perceptions of their own profiles. Half of the patients had decided to undergo surgical correction of their jaw deformities, while the other half had decided against surgical treatment. In addition, booklets containing pretreatment photographs of all 80 patients were mailed to 37 oral surgeons, 46 orthodontists, and 43 lay persons. These three groups of evaluators rated the patients' profiles, using the same rating scales that the patients had used. Cephalometrically, the two patient groups were statistically the same in all skeletal and soft-tissue measures except for ANB (mean difference = 1.8 degrees) and soft-tissue AN-pogonion (mean difference = 2.4 degrees). Differences in these dimensions were considered in subsequent data analyses. Results of this study support the following conclusions: In spite of the fact that surgical treatment may be recommended by dental specialists and indicated by cephalometric measurements, self-perceptions of profile are more important in the patient's decision to elect surgical correction; the perception by others that the profiles of patients deciding against surgery are closer to ideal may have some influence on their decision against surgical correction of their jaw deformities; oral surgeons and orthodontists evaluate facial profiles similarly, but surgeons are more likely to recommend surgical correction; lay persons are more likely to rate an individual's profile as being normal than are dental specialists in orthodontics and oral surgery; in contrast, individuals perceive their own profiles differently than orthodontists, oral surgeons, and lay persons, particularly with respect to the mandibular and dentoalveolar dimensions.

Anterior open-bite malocclusion: a longitudinal 10-year postretention evaluation of orthodontically treated patients.

Long-term response of the anterior open-bite malocclusion was evaluated in forty-one white subjects who had undergone orthodontic treatment and were out of retention a minimum of 9 years 6 months. The purpose of the study was threefold: (1) to make cephalometric comparisons between a sample of open-bite patients and a sample with normal cephalometric standards, (2) to evaluate treatment and posttreatment changes that occurred in treated open-bite patients, and (3) to search for predictors and associations of value. Changes occurring across time in the open-bite patients were analyzed by computer means using pretreatment, posttreatment, and long-term cephalometric radiographs and dental casts. An analysis of subgroups was reviewed to compare dentoalveolar and skeletal relationships of both stable and relapse groups. More than 35% of the treated open-bite patients demonstrated a postretention open bite of 3 mm or more, with the relapse subgroup demonstrating across-time, less mandibular anterior dental height, less upper anterior facial height, greater lower anterior facial height, and less posterior facial height. Neither the magnitude of pretreatment open bite, mandibular plane angle, nor any other single parameter of dentofacial form proved to be a reliable predictor of posttreatment stability.

Stability and relapse of mandibular anterior alignment-first premolar extraction cases treated by traditional edgewise orthodontics.

Assessment at least 10 years postretention of sixty-five cases previously treated in the permanent-dentition stage with first-premolar extractions, traditional edgewise mechanics, and retention revealed considerable variation among patients. The long-term response to mandibular anterior alignment was unpredictable; no variables, such as degree of initial crowding, age, sex, Angle classification, etc., were useful in establishing a prognosis. Typically, arch width and length decreased after retention, regardless of treatment expansion or constriction. Two thirds of the patients had unsatisfactory lower anterior alignment after retention. Cases that were minimally crowded before treatment usually became more crowded, while initially severe crowding cases usually moderated.