Endocultivation: the influence of delayed vs. simultaneous application of BMP-2 onto individually formed hydroxyapatite matrices for heterotopic bone induction.

When bone morphogenetic protein (BMP) is delivered to matrices in vivo may affect tissue engineered bone constructs for jaw reconstruction after cancer surgery. This study compared the effects of BMP application at different times after matrix implantation for heterotopic bone induction in a rat model. Hydroxyapatite blocks were implanted unilaterally onto the surface of the latissimus dorsi muscle. A second block was implanted onto the contralateral muscle after 1, 2 or 4 weeks and 200 µg rhBMP-2 was injected into the blocks on both sides. Bone formation and density inside the blocks was analysed by CT and histology. 8 weeks after BMP application increases in bone density within the scaffolds were most pronounced in the simultaneous application group (179 HU). Less pronounced increases were observed for the 1 (65 HU), 2 (58 HU) and 4 (31 HU; p<0.0001) week delay group. Homogeneous bone induction started from the central channel of the blocks. Capillaries and larger vessels were seen in all constructs, samples receiving delayed BMP treatment demonstrated significantly greater neovascularization. Delayed application of BMP was less effective for heterotopic bone formation than simultaneous application. A central channel allows homogeneous bone induction directly from the centre of the blocks.

Mirror, mirror on the wall : self-perception of facial beauty versus judgement by others.

In 1878, Margaret Wolfe Hungerford published a simple but insightful phrase in her novel 'Molly Bawn' that was to be quoted so often it has almost become cliché: "Beauty is in the eye of the beholder". While many questions regarding the perception and neural processing of facial attractiveness have been resolved, it became obvious to us that study designs have been principally based on either facial self-perception or perception by others. The relationship between these however, remains both crucial and unknown. Standardized images were taken of 141 subjects. These 141 subjects were asked to complete the adjective mood scale (AMS) and to rank specific issues related to their looks on a visual analogue scale. The images were then shown to independent judges to rank specific issues related to their looks on a visual analogue scale. Our results show proof for a strikingly simple observation: that individuals perceive their own beauty to be greater than that expressed in the opinions of others (p < 0.001). This observation provides insight into our basic behavioural patterns and suggests that there are strong psychological mechanisms in humans supporting self-identification and thereby encouraging the self-confidence and resilience necessary to maintain one's social standing. While the psychological basis of self-confidence is multifactorial, our finding provides critical objective insight. We prove here for the first time that nothing more than the beauty of the beholder is in the eyes of the latter.

Learning by doing virtually.

Selective reduction of bone without collateral damage (nerves, teeth) is essential in apicectomy. To test whether skills acquired on a virtual apicectomy simulator (VOXEL-MAN system with integrated force-feedback) are transferable from virtual to physical reality, two groups of trainees were compared. Group 1 received computer-based virtual surgical training before performing an apicectomy in a pig cadaver model. The probability of preserving vital neighboring structures was improved significantly, i.e. six-fold, after virtual surgical training (P<0.001). The average volume of the bony defects created by the trainees of Group 2 (mean: 0.47 ml) was significantly (P<0.001) larger than by the trainees of Group 1 (mean: 0.25 ml). Most importantly, the ability to objectively self-assess performance was significantly improved after virtual training. Training with a virtual apicectomy simulator appears to be effective, and the skills acquired are transferable to physical reality.

Extent, patterns, and burden of uncontrolled disease in severe or difficult-to-treat asthma.

BACKGROUND: Characterization of uncontrolled asthma burden in a natural treatment setting can influence treatment recommendations and clinical practice. The objective was to characterize and compare the economic burden of severe or difficult-to-treat asthma in uncontrolled and controlled patients. METHODS: Baseline patient data (age > or = 13 years; n = 3916) were obtained from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study. Disease control was assessed using two approaches: (i) applying criteria for control based on the Gaining Optimal Asthma Control study, and (ii) using the Asthma Therapy Assessment Questionnaire (ATAQ) to identify the number of asthma control problems. Assessments were performed at baseline, and at months 12 and 24. Monetary values were assigned to productivity loss and medical resource use. Direct and indirect costs were aggregated over 24 months and compared using Student's t-test for continuous measures and chi-squared for categorical variables. RESULTS: Throughout the study, most patients had uncontrolled asthma (83% uncontrolled; 16% inconsistent control; 1.3% controlled). Controlled patients experienced fewer work or school absences and less healthcare resource use than uncontrolled patients at all study time points. Using the multilevel ATAQ control score, asthma costs increased directly with the number of asthma control problems. Costs for uncontrolled patients were more than double those of controlled patients throughout the study (14,212 vs 6,452 US Dollars; adjusted to 2002 Dollars; P < 0.0001). CONCLUSIONS: This study demonstrated that few severe or difficult-to-treat asthma patients achieved control over a 2-year period and the economic consequence of uncontrolled disease is substantial.

Inhibition of nitric oxide and reactive oxygen species production improves the ability of a sunscreen to protect from sunburn, immunosuppression and photocarcinogenesis.

BACKGROUND: More effective strategies are required for the prevention of skin cancer, which is caused by ultraviolet (UV) radiation in sunlight. Sunscreens containing UV filters or reflectors offer some protection from sunlight. Pharmacologically active compounds that reduce UV damage offer considerable potential for improving sunscreen formulations. However, few studies have investigated whether the addition of such biological modifiers are an improvement. OBJECTIVES: In this study we supplemented a 2-ethyl hexyl methoxycinnamate-based sunscreen with the nitric oxide (NO) inhibitor NG-monomethyl-L-arginine acetate, the iron chelator 2,2'-dipyridyl, which reduces reactive oxygen species (ROS) production, or both. This was to determine whether inhibition of NO, ROS, or both could improve photoprotection by a sunscreen. METHODS: These sunscreens were compared for photoprotection from sunburn, immunosuppression and skin carcinogenesis in mice. To observe additional photoprotection by the NO and ROS inhibitors, UV doses were used that exceeded the protective capacity of the sunscreen. RESULTS: The combined inhibition of both NO and ROS production, but neither alone, increased sunscreen protection from sunburn and immunosuppression. Similarly, inhibition of both NO and ROS but neither alone reduced tumour multiplicity and incidence, therefore improving sunscreen protection from photocarcinogenesis. CONCLUSIONS: Whether NO and ROS inhibition were independently improving sunscreen photoprotection, with both being required for an observable effect, or whether inhibition of an interaction between NO and ROS was responsible for improved photoprotection by the sunscreen is unknown. These studies show that supplementation of a sunscreen with inhibitors of NO and ROS production improves the ability of the sunscreen to protect from sunburn, immunosuppression and photocarcinogenesis. Such an approach may be useful for reducing skin cancer incidence in humans.

Antibacterial essential oils in malodorous cancer patients: clinical observations in 30 patients.

Malodorous necrotic ulcers in cancer patients are of major concern as it leads to social isolation and poor quality of life. Current medications and topical therapies have proven inadequate in their ability to reduce foul smell to acceptable levels. We report the positive experience we have had in using antibacterial essential oils in patients with incurable head and neck cancer and associated malodorous necrotic ulcers. All patients received a standard course of therapy with oral or systemic antibiosis. In addition, we rinsed the ulcers with an antibacterial essential oil mix (mainly based on Eucalyptus oil) twice a day. All patients experienced complete resolution of the foul smell by only the third or fourth day of therapy. As a secondary effect we saw that besides smell reduction the oils had anti-inflammatory effects on neoplastic ulcers. In some patients ulcers started to heal and achieved complete re-epithiliazation. The patients experienced great personal relief upon resolution of their malodorous conditions. Quality of life improved significantly with the resulting reintroduction of social contact with friends and relatives.

Intraoral lesions associated with sebaceous nevus syndrome.

The sebaceous nevus syndrome describes the rare association of a sebaceous nevus with systemic features such as mental retardation, seizures and colobomas (among others). It is thought to be a cutaneous mosaic inherited as a paradominant trait. Three cases are provided illustrating the intraoral manifestations of the syndrome. The first histological comparison of contiguous mucosal and cutaneous lesions is provided. We also describe the possible association of SFM syndrome with a benign fibrous histiocytic lesion of the mandible. This and other mandibular tumors associated with the sebaceous nevus syndrome may have significant implications for patients. Awareness of the potential presence or development of significant intraoral lesions in association with the sebaceous nevus syndrome is important for those involved in the care of patients with this syndrome.

Innate immunity in human bone.

Bone has exceptional regenerative properties. Oral bone appears to be particularly resistant to infection despite exposure to oral flora, even in circumstances such as oral surgery where the thin mucosal layer covering the bone is disrupted. The goal of this study was to determine whether the innate immune system of antimicrobial peptides exists inside bone. Biopsies of non-infected and chronically infected mandibular bone were harvested from patients during maxillofacial surgical procedures. Bone biopsies from the iliac crest and fibula served as controls. Immunohistochemical staining was performed, directed against the human beta-defensin antimicrobial peptides (hBD) -1, -2 and -3. In addition, cultures of osteoblast-like cells were examined for the presence of each of the three beta-defensins and their mRNA transcripts. All three human beta-defensins were detected within the mineralized bone matrix of chronically infected mandibular bone in the vicinity of the endosteum and osteocytes. hBD-1, -2 and -3 were also found in the cytoplasm of osteocytes. Expression of all three beta-defensins was detected in each of the non-infected bone types including the controls, however, to a lesser degree than that found in the chronically infected mandibular bone. This may reflect upregulation of antimicrobial peptide expression in the presence of chronic infection. Cultures of non-infected osteoblast-like cells were found to express mRNA for each of hBD-1, -2 and -3. Immunohistochemical staining of the cultures was positive for hBD-1 and -2, but not for hBD-3. We provide the first evidence of a previously unrecognized innate immunological function of bone through the demonstration of the presence of the human beta-defensins hBD-1, -2 and -3 in bone.

Growth and transplantation of a custom vascularised bone graft in a man.

BACKGROUND: A major goal of research in bone transplantation is the ability to avoid creation of secondary bone defects. We aimed to repair an extended mandibular discontinuity defect by growth of a custom bone transplant inside the latissimus dorsi muscle of an adult male patient. METHODS: Three-dimensional computed tomography (CT) scanning and computer-aided design techniques were used to produce an ideal virtual replacement for the mandibular defect. These data were used to create a titanium mesh cage that was filled with bone mineral blocks and infiltrated with 7 mg recombinant human bone morphogenetic protein 7 and 20 mL of the patient's bone marrow. Thus prepared, the transplant was implanted into the latissimus dorsi muscle and 7 weeks later transplanted as a free bone-muscle flap to repair the mandibular defect. FINDINGS: In-vivo skeletal scintigraphy showed bone remodelling and mineralisation inside the mandibular transplant both before and after transplantation. CT provided radiological evidence of new bone formation. Postoperatively, the patient had an improved degree of mastication and was satisfied with the aesthetic outcome of the procedure. INTERPRETATION: Heterotopic bone induction to form a mandibular replacement inside the latissimus dorsi muscle in a human being is possible. This technique allows for a lower operative burden compared with conventional techniques by avoiding creation of a secondary bone defect. It also provides a good three-dimensional outcome.

Hospitalization and total medical costs for privately insured persons with schizophrenia.

This study used data from the 1991-1993 MarketScan files, a large database of private sector inpatient, outpatient, and prescription drug medical claims, to identify a sample of 665 patients with schizophrenia. Descriptive and multivariate analyses were conducted on the subsamples with hospitalizations (N = 185) and without hospitalizations (N = 480) in the 1-year period following the initial diagnosis for schizophrenia observed in the 1991-1993 time period. After controlling for patient demographic characteristics, medical co-morbidities, and other factors, the cost of hospitalization itself was found to be $15,805.

Tyrosinemia: a review.

Hypertyrosinemia encompasses several entities, of which tyrosinemia type I (or hepatorenal tyrosinemia, HT1) results in the most extensive clinical and pathological manifestations involving mainly the liver, kidney, and peripheral nerves. The clinical findings range from a severe hepatopathy of early infancy to chronic liver disease and rickets in the older child; gradual refinements in the diagnosis and medical management of this disorder have greatly altered its natural course, mirroring recent advances in the field of metabolic diseases in the past quarter century. Hepatorenal tyrosinemia is the inborn error with the highest incidence of progression to hepatocellular carcinoma, likely due to profound mutagenic effects and influences on the cell cycle by accumulated metabolites. The appropriate follow-up of patients with cirrhosis, the proper timing of liver transplantation in the prevention of carcinoma, and the long-term evolution of chronic renal disease remain important unresolved issues. The introduction of a new pharmacologic agent, NTBC, holds the hope of significantly alleviating some of the burdens of this disease. Mouse models of this disease have permitted the exploration of newer treatment modalities, such as gene therapy by viral vectors, including ex vivo and in utero methods. Finally, recent observations on spontaneous genetic reversion of the mutation in HT1 livers challenge conventional concepts in human genetics.

The economic burden of congestive heart failure in a managed care population.

OBJECTIVE: To examine the economic burden of and treatment patterns for congestive heart failure (CHF) in a managed care population. STUDY DESIGN: Retrospective review of medical and pharmacy claims. PATIENTS AND METHODS: We reviewed integrated medical and pharmacy claims data from 6 independent-practice-association model health maintenance organizations to identify patients diagnosed with CHF. Of the approximately 1.4 million people enrolled in these managed care plans during the study period (January through December 1994), a total of 2777 patients (mean age, 56.9 years) met the study criteria, which included diagnostic codes for CHF and claims eligibility of at least 1 year. We reviewed the charges incurred by patients diagnosed with CHF for the 6 months after the initial CHF medical claim. We also examined the treatment received by each of these patients. RESULTS: During the study period, 378 of the 2777 patients with CHF (14%) were admitted to the hospital at a cost of almost $3 million (an average of $7863 per hospitalized patient). Seventy-eight percent of the study population received prescription drugs, at an average per-patient cost of $942. The most commonly prescribed drug class was angiotensin-converting enzyme inhibitors, prescribed for 38% of patients. Calcium channel blockers were prescribed for 33% of patients, but beta-blockers were prescribed for only 18% of patients. Hospitalization accounted for 54% of the total cost for CHF treatment, with prescription drugs accounting for 38%. CONCLUSION: Congestive heart failure represents a significant financial burden within a non-elderly managed care population. Improved management of the condition is needed to reduce the morbidity and mortality, as well as the costs of treatment, associated with CHF. Considerable data indicate that drugs such as beta-blockers and angiotensin-converting enzyme inhibitors can significantly decrease the morbidity and mortality of CHF. Further investigation is needed into whether increased use of prescription pharmaceuticals may reduce hospitalization rates and overall costs for CHF in this setting.

Use of mental health services by persons with a mental illness in nursing facilities: initial impacts of OBRA87.

OBJECTIVE: To identify mental health service use patterns in nursing facilities subsequent to nursing home reforms in the Omnibus Budget Reconciliation Act of 1987. METHODS: The study involves a retrospective analysis of Medicare Part B claims for mental health care for persons in a nursing facility in 1992 (N = 692) using the Medicare Current Beneficiary Survey. Mental health service use was described and analyzed using logistic regression. RESULTS: Only 26% of nursing facility residents and 36% of residents with a mental illness had a mental health visit in 1992. Logistic regression confirms analyses prior to 1987 showing older residents and those in rural areas remain less likely to receive mental health visits. DISCUSSION: Claims data collected after the passage of The Nursing Home Reform Act (NHRA) of 1987 indicate continued low levels of mental health treatment in nursing homes.

Amplifications of DNA primase 1 (PRIM1) in human osteosarcoma.

We studied the involvement of PRIM1 in osteosarcoma by differential display, Northern and Southern hybridization, as well as fluorescence in situ hybridization (FISH) on interphase nuclei. In total, 22 pediatric oncology specimens were tested. PRIM1 was found to be amplified in 41% of the samples. PRIM1 is coamplified with the core 12q13 amplicon genes CDK4, SAS, and OS9, and was physically mapped very close to them. PRIM1 is therefore a new candidate for the role of a major target gene of 12q13 amplifications in human cancers. Genes Chromosomes Cancer 26:62-69, 1999.

Comparative analysis of serologic screening tests for the initial diagnosis of celiac disease.

OBJECTIVE: To prospectively evaluate and compare the sensitivity, specificity, and positive and negative predictive values of serum antigliadin (AGA) and antiendomysium antibodies (EMA) in predicting the initial diagnosis of celiac disease. DESIGN: Sera were tested prospectively for IgA and IgG AGA by enzymed-linked immunosorbent assay and IgA EMA by immunofluorescence techniques on monkey esophagus and human umbilical cord sections in 95 pediatric patients referred for duodenal biopsies. PATIENTS: Ninety-five pediatric patients were referred for duodenal biopsies, with a clinical suspicion of celiac disease; 24 of those patients had celiac disease by criteria of the European Society for Pediatric Gastroenterology and Nutrition. SETTING: A pediatric gastroenterology clinic of a tertiary care pediatric university hospital. RESULTS: EMA testing on human umbilical cords was the most specific but was also the least sensitive. All the patients with biopsy-proven celiac disease were identified by either one or both serologic tests (100% combined sensitivity). The combination of AGA and EMA on monkey esophagus resulted in a negative predictive value of 100% accuracy. CONCLUSIONS: A combination of AGA and EMA tests resulted in 100% sensitivity and 100% negative predictive value, useful in selecting patients for duodenal biopsy.

Autoimmune enteropathy.

Autoimmune enteropathy (AIE) is an entity reported primarily in infancy, resulting in intractable diarrhea and associated with small bowel villous atrophy and the presence of circulating anti-enterocyte (AEA) antibodies. It is a multisystem disorder with a response, in many cases, to immunosuppressive therapy.

Effect of inhibitors of oxygen radical and nitric oxide formation on UV radiation-induced erythema, immunosuppression and carcinogenesis.

We investigated whether supplementation of a sunscreen containing the UVB absorber 2-ethyl-hexyl-methoxycinnamate (cinnamate) with oxygen radical inhibitors (ORI) would improve protection from sunburn, immunosuppression and carcinogenesis. Mice were exposed to solar-simulated UV radiation (ssUV) containing a mixture of UVB and UVA. In initial studies, the ORI 2,2'-dipyridyl and N(G)-monomethyl-L-arginine acetate (L-NMMA) were shown to prevent UVA-induced suppression of contact sensitivity (CS) in mice. Addition of these inhibitors to the sunscreen did not affect the sun protection factor (SPF), but lowered the level of edema when mice were exposed to ssUV. Combination of both inhibitors with the sunscreen, however, increased the SPF from 5 to 5.5. The immune protection factor (IPF) of the sunscreen was only 1.18, but addition of neither dipyridyl nor L-NMMA singly or in combination measurably improved immune protection. However, the ORI improved the ability of the sunscreen to prevent carcinogenesis. The results indicate that reactive oxygen or nitrogen species produced in response to UV radiation are important for erythema, immunosuppression and carcinogenesis, and addition of inhibitors improves the protective capacity of sunscreens.

Ocular sequelae of BB injuries to the eye and surrounding adnexa.

BACKGROUND: BB injuries continue to be one of the most common causes of severe ocular injury among adolescent males. Extraocular and nonperforating anterior globe injuries most commonly result in favorable visual outcomes. The appropriate medical management of both perforating and nonperforating anterior globe injuries resulting from BB trauma and their potential ocular sequelae are reviewed. CASE REPORTS: Three cases illustrating typical as well as atypical anterior globe injuries caused by BBs are presented. Two cases involve nonperforating anterior globe injuries--one with intracranial and one with intraorbital involvement. The third involves a retained intraocular foreign body. The biomicroscopic and ophthalmoscopic features of these injuries are discussed, as are potential complications and management strategies associated with these types of trauma. CONCLUSIONS: Injuries associated with intraocular BBs often result in enucleation if functional vision is not salvageable. Sequelae to such injuries include endophthalmitis, traumatic hyphema, ocular siderosis, and sympathetic ophthalmia. Plain-film radiography and axial computed tomography are critical first steps in determination of the position of any intracranial or intraorbital metallic foreign body. Routine observation for the development of ocular sequelae resulting from retained intraocular, intracranial, and intraorbital BB injuries is recommended.