A clinico-radiological review of chronic non-bacterial osteomyelitis in paediatrics, adolescents, and adults: demystifying a forgotten differential.

Chronic non-bacterial osteomyelitis (CNO), also known as non-bacterial osteitis, is a chronic autoinflammatory disease of unknown aetiology that primarily occurs in the paediatric population, although rare cases of adult-onset disease also exist. CNO has non-specific clinical and radiological presentations, and the affected population often present with bone pain of insidious onset secondary to sterile bony inflammation that can be associated with swelling, focal tenderness, and warmth at the affected sites. The pattern of bony involvement appears to be dependent on the age of onset, with adults frequently having axial skeletal lesions and children and adolescents often being affected in the appendicular skeletal sites. CNO is a diagnosis of exclusion, and imaging is heavily relied on to identify and characterise the bony lesions in addition to exclude diseases that can mimic CNO. Magnetic resonance imaging is often the reference standard with biochemical and histopathological findings being complementary. Although combining imaging methods can be used to facilitate the diagnosis, a single technique could be adequate depending on the clinical picture. Given the relatively rare incidence of CNO, limited awareness of the disease among care providers, and its similarity in clinical and radiological presentation to various bony diseases, there are often long delays in diagnosis, with adults being unfavourably affected compared to paediatrics and adolescents. This review of CNO will describe the condition, overview its clinical presentation, highlight the radiological features, and emphasise clinical pearls that can aid in diagnosis and ruling out the mimics.

PORTABILITY OF GWAS RESULTS BETWEEN ETHNIC POPULATIONS: GENETIC MARKERS FOR POLYCYSTIC OVARY SYNDROME (PCOS) IN MEDITERRANEAN AREA.

Genome Wide Association Studies (GWAS) are excellent opportunities to define culprit genes in complex disorders such as the polycystic ovary syndrome (PCOS). PCOS is a prevalent disorder characterized by anovulation, hyperandrogenism and polycystic ovaries, which benefitted from several GWASs in Asians and Europeans revealing more than 20 potential culprit genes near associated single nucleotide variations (SNV). Translation of these findings into the clinical practice raises difficulties since positive hits are surrogate SNVs linked with causative mutations by linkage disequilibrium (LD). Studies in Mediterranean populations (e.g. Southern Europe and North Africa) raise supplementary problems because of a different LD-pattern, which may disrupt the link with causative mutations. Our experience in MEDIGENE program between Tunisia and France enforces the necessity of genetic anthropology studies before translating GWAS data. Tunisians are a heterogeneous population with ancestral Berbers, European, Arab and Sub-Saharan African components while South Europeans display a high level of genetic diversity, partially explained by gene flow from North Africa. Human diversity studies require sampling from Middle East and North Africa (MENA) region that will help to understand genetic factors in complex diseases.

BRANCHED CHAIN AMINO ACIDS AT THE EDGE BETWEEN MENDELIAN AND COMPLEX DISORDERS.

Branched chained amino acids (BCAA) are essential components of the human diet and important nutrient signals, which regain particular interest in recent years with the avenue of metabolomics studies suggesting their potential role as biomarkers. There is now compelling evidence for predictive role of BCAA in progression of diabetes, but causality relationship is still debated concerning insulin resistance and genetic versus non-genetic pathogenesis. Mendelian randomization studies in large cohorts of diabetes indicated pathogenic role of PPM1K (protein phosphatase Mg2+/Mn2+ dependent 1K) on Chr 4q22.1 gene, encoding for a phosphatase that activates BCKDH (branched chain keto acid dehydrogenase) complex. Recent studies indicated that insulin rapidly and dose-dependently regulates gene expression of the same complex, but the relationship with systemic insulin resistance and glucose levels is complex. Rare genetic syndromes due to Mendelian mutations in key genes in BCAA catabolism may be good models to understand potential role of gene of BCAA catabolism. However, in studying complex disorders geneticists are faced to complete new aspects of metabolic regulation complicating understanding genetics of obesity, diabetes or metabolic syndrome. A review of genetic syndromes of BCAA metabolism suggests that insulin resistance is not present, except rare cases of methylmalonic aciduria due to MUT (methylmalonyl-coA mutase) gene on Chr 6p12.3. Another aspect that complicates understanding is the new role of central nervous system (CNS) in insulin resistance. For a long time the hypothalamic hunger/satiety neuronal system was considered a key site of nutrient regulation. Genes may also affect the brain rewarding system (BRS) that would regulate food intake by modulating the motivation to obtain food and considering hedonic properties. Nutrigenomic and nutrigenetic investigations taking into account concurrently BCAA intake, metabolic regulation and gene variation have large perspectives to merge genetic and nutritional understanding in complex disorders.

Nephritogenic mAb 5-1-6 is directed at the extracellular domain of rat nephrin.

mAb 5-1-6 identifies an antigen on rat podocyte slit-diaphragms and induces severe proteinuria when injected into rats. Nephrin, an Ig-like transmembrane protein that is mutated in congenital nephrotic syndrome of the Finnish type, has been localized to the slit-diaphragm on human podocytes. Here we document that the mAb 5-1-6 antigen is rat nephrin. After incubation of rat glomeruli with this mAb, the antibody/antigen complex was chemically cross-linked, extracted, and immunoprecipitated, prior to Western analysis. By mass spectrometry and 2D gel electrophoresis, we identified several peptides with complete identity to human nephrin. In addition, the 185-kDa protein immunoprecipitated by mAb 5-1-6 from rat glomerular extracts reacts with a rabbit anti-mouse nephrin antibody. Finally, nephrin and the mAb 5-1-6 antigen have identical glomerular localization patterns on immunofluorescence of rat kidney. These results demonstrate that the nephritogenic mAb 5-1-6 identifies the extracellular domain of nephrin, thereby documenting the importance of the slit-diaphragm and its component, nephrin, in the regulation of glomerular permselectivity.

A potential mechanism of vasodilation after warm heart surgery. The temperature-dependent release of cytokines.

Peripheral vasodilation is a common feature of warm heart surgery and creates clinical concerns when pressor agents become necessary because of the potential for some of these drugs to adversely affect flow through newly engrafted arterial and venous bypass conduits. The possible role of a temperature-dependent production of cytokines in the pathogenesis of this vasodilation was investigated in a two-part study. In part I, lipopolysaccharide-activated peritoneal rabbit macrophages (5 x 10(6)/ml) were incubated at 30 degrees or 37 degrees C up to 9 hours and the concentration of tumor necrosis factor released in the supernatant was serially measured by a bioassay. Tumor necrosis factor production was found to increase over time for each of the two temperatures of incubation but was significantly higher throughout the observation period in normothermic experiments than in those done at 30 degrees C. Part II was a prospective clinical study involving 30 patients who underwent either cold (core temperature 28 degrees to 30 degrees C, n = 15) or warm (37 degrees C, n = 15) cardiopulmonary bypass and in whom serum levels of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 were measured by enzyme-linked immunosorbent assays at 2, 4, 10, and 24 hours after bypass. Cytokine levels were found to be consistently higher in patients having normothermic bypass. Differences between the two groups were significant 2 hours after bypass for tumor necrosis factor alpha and interleukin-6 (p < 0.02 and p = 0.0001, respectively) and 4 and 10 hours after bypass for interleukin-1 beta (p < 0.01 and p < 0.04, respectively). The incidence of vasodilation necessitating vasopressor support was twofold higher in the normothermic group (six patients versus three in the hypothermic group). Taken as a whole, patients supported by pressor agents had significantly higher cytokine levels after bypass than those who did not require pressor therapy. Our results suggest that vasodilation occurring with warm heart operation is, at least partly, mediated by a temperature-dependent release of cytokines. Vasodilation might therefore be mitigated by simply allowing the core temperature to drift during bypass. Our recent clinical experience suggests that this "tepid" heart surgery (32 degrees to 34 degrees C) effectively blunts most of the vasodilatory response to strictly normothermic bypass without compromising maintenance of myocardial aerobiosis during arrest.

Long-term outcome, survival analysis, and risk stratification of dynamic cardiomyoplasty.

METHODS: To analyze the long-term outcome of dynamic cardiomyoplasty, we retrospectively studied 127 consecutive patients who underwent this procedure in Paris, France (n = 76), São Paulo, Brazil (n = 37), and Portland, Oregon (n = 14). Preoperative data were collected for patients operated on between January 1985 and June 1994 and examined with respect to effect on long-term survival. Patients had a mean age of 50 +/- 13 years and were predominantly male (82%). In 46% the cause of disease was ischemic. Concomitant operations were performed in 22 patients. RESULTS: Operative mortality was 12% (15/127). Kaplan-Meier survival +/- standard error at 1 through 5 years was 73% +/- 4%, 57% +/- 5%, 49% +/- 6%, 44% +/- 6%, and 40% +/- 7%, respectively. There was a distinct improvement at 6 months in New York Heart Association functional class (3.2 +/- 0.05 vs 1.7 +/- 0.07, p < 0.0001) and a small but significant increase in left ventricular ejection fraction (20% +/- 0.8% vs 23% +/- 1.5%, p = 0.04). Ninety-day mortality was associated with low right ventricular ejection fraction, a blunted hemodynamic response to exercise testing, and requirement for an intraaortic balloon pump at the time of the operation. Using a stepwise Cox regression method of multivariable survival analysis (n = 101), we determined that atrial fibrillation, New York Heart Association class IV, high pulmonary capillary wedge pressure, and balloon pump use were independent variables simultaneously associated with poor overall survival. When metabolic testing variables were added to this model, peak oxygen consumption eliminated both pulmonary capillary wedge pressure and functional class from the model, albeit with fewer (n = 74) patients. CONCLUSION: Dynamic cardiomyoplasty is an evolving therapy for symptomatic congestive heart failure, the results of which may be enhanced by intelligent, risk-sensitive patient selection.

Normothermic cardioplegia: is aortic cross-clamping still synonymous with myocardial ischemia?

The enthusiastic clinical reports on normothermic blood cardioplegia contrast with the paucity of data on the myocardial metabolic effects of this technique. The present study was therefore designed to assess whether normothermic blood cardioplegia really provides an aerobic environment during aortic cross-clamping. Thirty-one patients undergoing coronary (16 patients), valve (13 patients), and transplantation (2 patients) procedures were given continuous normothermic blood cardioplegia through the coronary sinus. Myocardial metabolism was assessed either immediately before aortic unclamping (16 patients) by collecting blood simultaneously from the cardioplegia infusion line and the aortic effluent or during reperfusion (15 patients) by collecting blood simultaneously from the radial artery and the coronary sinus. All samples were assayed for markers of anaerobiosis (blood gases, lactates), leukocyte activation (elastase), and lipid peroxidation (malondialdehyde, vitamin E). At the end of arrest, oxygen extraction was low, whereas the production of lactates was small, thereby suggesting the efficacy of normothermic blood cardioplegia in maintaining a predominantly aerobic metabolism. This was confirmed by postarrest data, as oxygen extraction measured immediately after cross-clamp removal was unchanged from prearrest values, whereas lactate metabolism yielded transient and limited production followed by prompt recovery of normal extraction patterns. There was no release of elastase from the myocardium, which suggests adequate protection of the coronary endothelium from ischemic injury and the related increase in leukocyte activation. Likewise, postarrest coronary sinus concentrations of malondialdehyde and vitamin E were identical to the respective arterial concentrations, thereby ruling out the occurrence of intramyocardial lipid peroxidation at the time of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Delayed tooth formation in low birthweight African-American children.

Low birthweight (LBW) infants are susceptible to several developmental problems (e.g., pulmonary diseases, hyperbilirubinemia, hypocalcemia) with potentially long-lasting effects that slow growth during infancy and childhood. Dental age (DA), judged from stages of permanent tooth mineralization, was scored in 4- to 7-year-old LBW African-American children (N = 66; x = 5.5 years) to test whether they were delayed due to LBW and its consequences. Data were matched in a case-control fashion to African-American children with normal birth-weights (N = 76). Only the early-forming teeth (incisors, first molars) were delayed significantly in their formation. Children with the lowest height-for-age centiles were the most delayed dentally which suggests that height status would improve as dental age caught up with chronological age (CA). Older children were more delayed because there is a proportionately greater opportunity for DA to diverge from CA as children grow older. Since only those teeth undergoing rapid differentiation neonatally were affected systematically, it was speculated that perinatal insults may have an enduring impact on developing primordia, while leaving later-forming teeth unaffected.

Post-retention results of spring-loaded posterior bite-block therapy.

In this study, ten patients who were treated with spring-loaded posterior bite blocks (SLPBB), were evaluated over a period of two years in order to test the effects of the appliance and the incidence of relapse. Successful treatment with SLPBB was achieved in skeletal and dental open bite cases. However, the use of acrylic bite blocks for retention during the post-treatment growth period, did not prevent relapse.

Space maintainer effects on intercanine arch width and length.

In order to investigate the effects of space maintainers in intercanine arch width and length, twenty cases, characterized with the early loss of mandibular primary molars were selected and divided into two groups. The treatment group used removable space maintainers, while the other ten cases served as the control group. The first dental casts of the treatment and control groups were obtained when the primary canines were in the mouth. After the eruption of permanent canines second dental casts were obtained in both groups. Six measurements were made on the dental casts of each patient. No parameter was found to be statistically significant in the treatment group. In the control group the increase in intercanine arch width and perimeter were found to be statistically significant. Also the increase at the buccal and lingual bone measurements were found to be statistically significant. These results showed that space maintainers might cease the increase in intercanine arch width and length during the transition period between the primary and permanent canines.

Comparison of Jones jig molar distalization appliance with extraoral traction.

In this study, 20 patients were evaluated. Ten were treated with intraoral distalization followed by fixed appliance therapy, and 10 were treated with extra oral traction followed by fixed appliance therapy. Molar relationship correction was achieved in 2.5 months with intraoral distalization and in 10.7 months with extraoral distalization. A significant anterior movement of the anchorage unit (P <.001) was observed with the intraoral distalization and a significant distal drift of premolars was observed in the headgear group (P <.05). Palatal plane was found to tip downward significantly in the headgear group (P <.05). Total outcome of the 2 methods were discussed evaluating the advantages and disadvantages of the 2 distalization methods.

Effects of spring-loaded posterior bite-block appliance on masticatory muscles.

The effects of spring-loaded posterior bite-blocks on masticatory muscles were investigated to evaluate the correlation between masticatory muscles and craniofacial form in long-faced children. The appliance was used in 10 subjects (6 girls and 4 boys) with a chronological mean age of 10.40 +/- 1.12 years for the treatment of skeletal anterior open bite. Electromyographic activity of the anterior and posterior temporal and masseter muscles was recorded before and after treatment during postural position, maximal biting, chewing, swallowing, postural position with the appliance in the mouth, and maximal biting with the appliance in the mouth. After treatment, increases in SNB and overbite (P <.05, P <.001, respectively) and decreases in ANB, SNGoAr, and overjet parameters were found to be statistically significant (P <.05, P <.01). When the measurements related to muscle activity were examined, increases in anterior temporal postural (P <.05), anterior temporal chewing (P <.01), masseter chewing (P <.05), posterior temporal chewing (P <. 05), and masseter swallowing (P <.01) were found to be statistically significant. A positive correlation was found between ANB and anterior temporal postural and a negative correlation between SNGoAr and masseter swallowing. The increase in muscle activities was considered to occur as a result of the appliance used.

The effects of cervical headgear on dentofacial structures.

A study was made on the effects of cervical headgear on dentofacial structures, especially non-erupted teeth, in the early and late mixed dentition periods. Pretreatment and post-treatment cephalometric evaluation was done on 8 patients in the early mixed dentition period and 10 patients in the late mixed dentition period. The results showed that any reference line passing through Ptm point should not be used to evaluate the efficiency of cervical headgear, and that such headgear is more effective on non-erupted teeth in early mixed dentition.

Complement-mediated injury reversibly disrupts glomerular epithelial cell actin microfilaments and focal adhesions.

BACKGROUND: Foot process effacement and condensation of the glomerular epithelial cell (GEC) cytoskeleton are manifestations of passive Heymann nephritis, a model of complement-mediated membranous nephropathy. METHODS: To study the effects of complement on the actin cytoskeleton in this model, we have used an in vitro system in which GECs are sublethally injured using a combination of complement-fixing anti-Fx1A IgG and human serum as a source of complement. We examined the effects of this injury on the organization of the cytoskeleton and focal contacts using immunohistology and immunochemistry. RESULTS: By immunofluorescence, sublethal complement-mediated injury was accompanied by a loss of actin stress fibers and focal contacts but retention of matrix-associated integrins. Full recovery was seen after 18 hours. Western blot analysis showed no change in the cellular content of the focal contact proteins. Inhibition of the calcium-dependent protease calpain did not prevent injury. In addition, cycloheximide during recovery did not inhibit the reassembly of stress fibers or focal contacts. Injury was associated with a reduction in tyrosine phosphorylation of paxillin and a currently unidentified 200 kDa protein, but inhibition of tyrosine phosphatase activity with sodium vanadate did not prevent injury. Cellular adenosine triphosphate content was significantly reduced in injured cells. CONCLUSION: These results document reversible, complement-dependent disruption of actin microfilaments and focal contacts leading to the dissociation of the cytoskeleton from matrix-attached integrins. This may explain the altered cell-matrix relationship accompanying podocyte effacement in membranous nephropathy.

Synthesis and antitumor activities of 5-methyl-1- and 2-[[2-dimethylaminoethyl]amino]-aza-thiopyranoindazoles.

The synthesis of 1- and 2-substituted aza-benzothiopyranoindazoles has been accomplished. The comparisons of the in vitro antitumor activities of the 2-substituted analogues with the benzothiopyranoindazole chemotypes indicate that the positioning of the nitrogen atom at C-9 (9-aza analogue 4d) leads to a substrate with potent antitumor activity. The 1-substituted aza-benzothiopyranoindazoles, in comparison with the corresponding 2-substituted analogues, exhibit a much lower potency.

Aminopeptidase A: a nephritogenic target antigen of nephrotoxic serum.

BACKGROUND: We investigated potential targets of antibody-mediated glomerular injury induced with a noncomplement binding fraction of sheep anti-rat nephrotoxic serum (NTS). This model is characterized by severe complement- and leukocyte-independent proteinuria within 24 hours of NTS injection into rats. METHODS: NTS-reactive glomerular cell and matrix proteins were identified by immunoprecipitation, Western blot analysis, protein sequencing, cDNA library screening, and enzyme-linked immunosorbent assay. Proteinuria was measured in rats injected with NTS from which reactivity against type IV collagen had been removed by immunoadsorption, and antibodies were eluted from the glomeruli of proteinuric rats that had been injected with unabsorbed NTS. Having identified aminopeptidase A (APA) as a major target of NTS, we studied the effect of NTS and anti-APA on mouse glomerular epithelial cells in culture. RESULTS: NTS identified several podocyte and matrix proteins; however, APA was the only cell surface protein reactive with antibodies eluted from the glomeruli of rats injected with NTS. Although the eluate also contained reactivity to the noncollagenous domains of alpha1 and alpha3 chains of type IV collagen, immunodepletion of these antibodies did not diminish the ability of NTS to cause proteinuria. We also documented the surface expression of APA on mouse glomerular epithelial cells in culture, and found that NTS and specific anti-APA antibodies induce a time- and temperature-dependent redistribution of the antigen. CONCLUSIONS: APA, a type II integral membrane metallopeptidase, is a major target of NTS in vivo and is known to be present on the surface of podocytes. NTS-induced proteinuria is independent of reactivity to known nephritogenic matrix proteins. These findings, in combination with previous studies showing that monoclonal anti-APA antibodies induce severe proteinuria in mice, suggest that anti-APA antibodies are responsible for complement-independent proteinuria in this model.