Transdiscal instrumentation in single-level lumbosacral fusion for high-grade isthmic pediatric spondylolisthesis: Technical note and review of the literature.

Pediatric spondylolisthesis is a common cause of back pain in children, typically managed conservatively with bracing and non-steroidal anti-inflammatory drugs. When posterolateral fusion is performed for refractory pain, pseudarthrosis and implant failure may occur, necessitating reoperation. To improve patient outcomes, there is a need for alternative surgical techniques to effectively manage high-grade isthmic slips. Here, the authors report the case of a child with Meyerding grade III anterolisthesis of L5 on S1 who was treated with a single-level, instrumented fusion using bilateral S1-L5 transdiscal screws, supported with L5-S1 posterolateral instrumentation and arthrodesis. Postoperatively, there was improvement in the patient's symptoms with good clinical and radiographic outcomes. The patient continues to be symptom free with radiographic evidence of hardware stability and bony fusion across the segment. The authors detail a novel surgical technique in children as well as a review of lumbosacral transdiscal screw fixation. Further evidence is required to definitively establish the safety, outcomes, and biomechanical strength of this technique.

Roundabout model with on-ramp queues: Exact results and scaling approximations.

This paper introduces a general model of a single-lane roundabout, represented as a circular lattice that consists of L cells, with Markovian traffic dynamics. Vehicles enter the roundabout via on-ramp queues that have stochastic arrival processes, remain on the roundabout a random number of cells, and depart via off-ramps. Importantly, the model does not oversimplify the dynamics of traffic on roundabouts, while various performance-related quantities (such as delay and queue length) allow an analytical characterization. In particular, we present an explicit expression for the marginal stationary distribution of each cell on the lattice. Moreover, we derive results that give insight on the dependencies between parts of the roundabout, and on the queue distribution. Finally, we find scaling limits that allow, for every partition of the roundabout in segments, to approximate (i) the joint distribution of the occupation of these segments by a multivariate Gaussian distribution, and (ii) the joint distribution of their total queue lengths by a collection of independent Poisson random variables. To verify the scaling limit statements, we develop a way to empirically assess convergence in distribution of random variables.

Risk of brainstem necrosis in pediatric patients with central nervous system malignancies after pencil beam scanning proton therapy.

Background: Radiation therapy (RT) plays an important role in management of pediatric central nervous system (CNS) malignancies. Centers are increasingly utilizing pencil beam scanning proton therapy (PBS-PT). However, the risk of brainstem necrosis has not yet been reported. In this study, we evaluate the rate of brainstem necrosis in pediatric patients with CNS malignancies treated with PBS-PT.Material and methods: Pediatric patients with non-hematologic CNS malignancies treated with PBS-PT who received dose to the brainstem were included. All procedures were approved by the institutional review board. Brainstem necrosis was defined as symptomatic toxicity. The actuarial rate was analyzed by the Kaplan Meier method.Results: One hundred and sixty-six consecutive patients were reviewed. Median age was 10 years (range 0.5-21 years). Four patients (2.4%) had prior radiation. Median maximum brainstem dose in the treated course was 55.4 Gy[RBE] (range 0.15-61.4 Gy[RBE]). In patients with prior RT, cumulative median maximum brainstem dose was 98.0 Gy [RBE] (range 17.0-111.0 Gy [RBE]). Median follow up was 19.6 months (range, 2.0-63.0). One patient who had previously been treated with twice-daily radiation therapy and intrathecal (IT) methotrexate experienced brainstem necrosis. The actuarial incidence of brainstem necrosis was 0.7% at 24 months (95% CI 0.1-5.1%).Conclusion: The rate of symptomatic brainstem necrosis was extremely low after treatment with PBS-PT in this study. Further work to clarify clinical and dosimetric parameters associated with risk of brainstem necrosis after PBS-PT is needed.

CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles.

Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with 'paradox breaker' RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions.

Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA).

BACKGROUND: A family history of diabetes (FHD) is a strong predictor of diabetes risk, yet has rarely been investigated in latent autoimmune diabetes in adults (LADA). This study therefore investigated the risk of LADA and type 2 diabetes (T2D) in relation to FHD, taking into account the type of diabetes in relatives. METHODS: Data from a population-based study were used, including incident cases of LADA [glutamic acid decarboxylase antibody (GADA)-positive, n=378] and T2D (GADA-negative, n=1199), and their matched controls (n=1484). First-degree relatives with disease onset at age<40 years and taking insulin treatment were classified as type 1 diabetes (T1D) or, if otherwise, as T2D. Odds ratios (ORs) were adjusted for age, gender, BMI, education and smoking. Cases were genotyped for high- and low-risk HLA genotypes. RESULTS: Both FHD-T1D (OR: 5.8; 95% CI: 3.2-10.3) and FHD-T2D (OR: 1.9; 95% CI: 1.5-2.5) were associated with an increased risk of LADA, whereas the risk of T2D was associated with FHD-T2D (OR: 2.7; 95% CI: 2.2-3.3), but not FHD-T1D. In LADA patients, FHD-T1D vs FHD-T2D was associated with higher GADA but lower C-peptide levels, lower prevalence of low-risk HLA genotypes (5.0% vs 28.6%, respectively; P=0.038) and a tendency for higher prevalence of high-risk genotypes (90.0% vs 69.1%, respectively; P=0.0576). CONCLUSION: The risk of LADA is substantially increased with FHD-T1D but also, albeit significantly less so, with FHD-T2D. This supports the idea of LADA as a mix of both T1D and T2D, but suggests that the genes related to T1D have greater impact. LADA patients with FHD-T1D had more T1D-like features, emphasizing the heterogeneity of LADA.

Use of Swedish smokeless tobacco (snus) and the risk of Type 2 diabetes and latent autoimmune diabetes of adulthood (LADA).

AIMS: It has been suggested that moist snuff (snus), a smokeless tobacco product that is high in nicotine and widespread in Scandinavia, increases the risk of Type 2 diabetes. Previous studies are however few, contradictory and, with regard to autoimmune diabetes, lacking. Our aim was to study the association between snus use and the risk of Type 2 diabetes and latent autoimmune diabetes of adulthood (LADA). METHOD: Analyses were based on incident cases (Type 2 diabetes, n = 724; LADA, n = 200) and population-based controls (n = 699) from a Swedish case-control study. Additional analyses were performed on cross-sectional data from the Norwegian HUNT study (n = 21 473) with 829 prevalent cases of Type 2 diabetes. Odds ratios (OR) were estimated adjusted for age, BMI family history of diabetes and smoking. Only men were included. RESULTS: No association between snus use and Type 2 diabetes or LADA was seen in the Swedish data. For Type 2 diabetes, the OR for > 10 box-years was 1.00 [95% confidence interval (CI), 0.47 to 2.11] and for LADA 1.01 (95% CI, 0.45 to 2.29). Similarly, in HUNT, the OR for Type 2 diabetes in ever-users was estimated at 0.91 (95% CI, 0.75 to 1.10) and in heavy users at 0.92 (95% CI, 0.46 to 1.83). CONCLUSION: The risk of Type 2 diabetes and LADA is unrelated to the use of snus, despite its high nicotine content. This opens the possibility of the increased risk of Type 2 diabetes seen in smokers may not be attributed to nicotine, but to other substances in tobacco smoke.

Characterization of resident lymphocytes in human pancreatic islets.

The current view of type 1 diabetes (T1D) is that it is an immune-mediated disease where lymphocytes infiltrate the pancreatic islets, promote killing of beta cells and cause overt diabetes. Although tissue resident immune cells have been demonstrated in several organs, the composition of lymphocytes in human healthy pancreatic islets have been scarcely studied. Here we aimed to investigate the phenotype of immune cells associated with human islets of non-diabetic organ donors. A flow cytometry analysis of isolated islets from perfused pancreases (n = 38) was employed to identify alpha, beta, T, natural killer (NK) and B cells. Moreover, the expression of insulin and glucagon transcripts was evaluated by RNA sequencing. Up to 80% of the lymphocytes were CD3+ T cells with a remarkable bias towards CD8+ cells. Central memory and effector memory phenotypes dominated within the CD8+ and CD4+ T cells and most CD8+ T cells were positive for CD69 and up to 50-70% for CD103, both markers of resident memory cells. The frequency of B and NK cells was low in most islet preparations (12 and 3% of CD45+ cells, respectively), and the frequency of alpha and beta cells varied between donors and correlated clearly with insulin and glucagon mRNA expression. In conclusion, we demonstrated the predominance of canonical tissue resident memory CD8+ T cells associated with human islets. We believe that these results are important to understand more clearly the immunobiology of human islets and the disease-related phenotypes observed in diabetes.

Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer.

Cartilage oligomeric matrix protein (COMP) is a soluble pentameric protein expressed in cartilage and involved in collagen organization. Tissue microarrays derived from two cohorts of patients with breast cancer (n=122 and n=498) were immunostained, revealing varying expression of COMP, both in the tumor cells and surrounding stroma. High levels of COMP in tumor cells correlated, independently of other variables, with poor survival and decreased recurrence-free survival. Breast cancer cells, MDA-MB-231, stably expressing COMP were injected into the mammary fat pad of SCID (CB-17/Icr-Prkdcscid/Rj) mice. Tumors expressing COMP were significantly larger and were more prone to metastasize as compared with control, mock-transfected, tumors. In vitro experiments confirmed that COMP-expressing cells had a more invasive phenotype, which could in part be attributed to an upregulation of matrix metalloprotease-9. Furthermore, microarray analyses of gene expression in tumors formed in vivo showed that COMP expression induced higher expression of genes protecting against endoplasmic reticulum stress. This observation was confirmed in vitro as COMP-expressing cells showed better survival as well as a higher rate of protein synthesis when treated with brefeldin A, compared with control cells. Further, COMP-expressing cells appeared to undergo a metabolic switch, that is, a Warburg effect. Thus, in vitro measurement of cell respiration indicated decreased mitochondrial metabolism. In conclusion, COMP is a novel biomarker in breast cancer, which contributes to the severity of the disease by metabolic switching and increasing invasiveness and tumor cell viability, leading to reduced survival in animal models and human patients.

Altered serotonin (5-HT) 1D and 2A receptor expression may contribute to defective insulin and glucagon secretion in human type 2 diabetes.

Islet produced 5-hydroxy tryptamine (5-HT) is suggested to regulate islet hormone secretion in a paracrine and autocrine manner in rodents. Hitherto, no studies demonstrate a role for this amine in human islet function, nor is it known if 5-HT signaling is involved in the development of beta cell dysfunction in type 2 diabetes (T2D). To clarify this, we performed a complete transcriptional mapping of 5-HT receptors and processing enzymes in human islets and investigated differential expression of these genes in non-diabetic and T2D human islet donors. We show the expression of fourteen 5-HT receptors as well as processing enzymes involved in the biosynthesis of 5-HT at the mRNA level in human islets. Two 5-HT receptors (HTR1D and HTR2A) were over-expressed in T2D islet donors. Both receptors (5-HT1d and 5-HT2a) were localized to human alpha, beta and delta cells. 5-HT inhibited both insulin and glucagon secretion in non-diabetic islet donors. In islets isolated from T2D donors the amine significantly increased release of insulin in response to glucose. Our results suggest that 5-HT signaling participates in regulation of overall islet hormone secretion in non- diabetic individuals and over-expression of HTR1D and HTR2A may either contribute to islet dysfunction in T2D or arise as a consequence of an already dysfunctional islet.

Reconstructive challenges in the extended endoscopic transclival approach.

OBJECTIVE: We wanted to present our experience with the extended endoscopic approach to clival pathology, focusing on cerebrospinal fluid leak and reconstruction challenges. METHODS: We examined a consecutive series of 37 patients undergoing the extended endoscopic approach for skull base tumours, 9 patients with clival pathology. Patients were examined for the incidence of post-operative cerebrospinal fluid leak in relation to tumour pathology, location, size, reconstruction and lumbar drain. RESULTS: The overall incidence of post-operative cerebrospinal fluid leak was 10.8 per cent. Seventy-five per cent of patients who had a post-operative cerebrospinal fluid leak underwent a transclival approach (p < 0.05). All patients with clival pathology who underwent an intradural dissection had a post-operative cerebrospinal fluid leak (p < 0.05). CONCLUSION: Post-operative cerebrospinal fluid leak rates after the extended endoscopic approach have improved significantly after advancements including the vascularised nasoseptal flap. Despite this, transclival approaches continue to pose much difficulty. Further investigation is necessary to develop technical improvements that can meet the unique challenges associated with this region.

Coffee consumption and the risk of latent autoimmune diabetes in adults--results from a Swedish case-control study.

AIMS: Coffee consumption is associated with a reduced risk of Type 2 diabetes. Our aim was to investigate if coffee intake may also reduce the risk of latent autoimmune diabetes in adults, an autoimmune form of diabetes with features of Type 2 diabetes. METHODS: We used data from a population-based case-control study with incident cases of adult onset (≥ 35 years) diabetes, including 245 cases of latent autoimmune diabetes in adults (glutamic acid decarboxylase antibody positive), 759 cases of Type 2 diabetes (glutamic acid decarboxylase antibody negative), together with 990 control subjects without diabetes, randomly selected from the population. Using questionnaire information on coffee consumption, we estimated the odds ratio of latent autoimmune diabetes in adults and Type 2 diabetes adjusted for age, sex, BMI, smoking, physical activity, alcohol, education and family history of diabetes. RESULTS: Coffee intake was inversely associated with Type 2 diabetes (odds ratio 0.92, 95% CI 0.87-0.98 per cup/day). With regard to latent autoimmune diabetes in adults, the general trend was weak (odds ratio 1.04, 95% CI 0.96-1.13), but stratification by degree of autoimmunity (median glutamic acid decarboxylase antibody levels) suggested that coffee intake may be associated with an increased risk of high glutamic acid decarboxylase antibody latent autoimmune diabetes in adults (odds ratio 1.11, 95% CI 1.00-1.23 per cup/day). Furthermore, for every additional cup of coffee consumed per day, there was a 15.2% (P = 0.0268) increase in glutamic acid decarboxylase antibody levels. CONCLUSIONS: Our findings confirm that coffee consumption is associated with a reduced risk of Type 2 diabetes. Interestingly, the findings suggest that coffee may be associated with development of autoimmunity and possibly an increased risk of more Type 1-like latent autoimmune diabetes in adults.

IFNγ and perforin cooperate to control infection and prevent fatal pathology during persistent gammaherpesvirus infection in mice.

Infection with murine gammaherpesvirus 68 has become an accepted model for studying the virus/host interactions with regard to gammaherpesvirus infections. Previous studies using gene-deficient mice have revealed that neither IFNγ nor perforin is essential in controlling the outcome of infection or the virus load during chronic infection in C57BL/6 mice. However, pronounced multiorgan fibrosis and splenic atrophy are observed in mice lacking IFNγ or the IFNγ receptor. To study the interplay between perforin and IFNγ in controlling the virus-induced pathology and the viral load during chronic gammaherpesvirus infection, we infected IFNγ/perforin double-deficient C57BL/6 mice and followed the course of infection. While absence of perforin prevented the splenic atrophy in IFNγ-deficient mice, fibrosis did not disappear. Moreover, double-deficient mice developed extreme splenomegaly, were unable to control the viral load and displayed chronic immune activation. Thus, IFNγ and perforin act in concert to minimize pathology and control the viral load in mice chronically infected with MHV68. Furthermore, while certain aspect of the virus-induced pathology in IFNγ-deficient mice may be alleviated in double-deficient mice, other aspects are exaggerated, and the normal architecture of the spleen is completely destroyed. We believe that these findings add to the understanding of the virus/host interaction during chronic gammaherpes virus infection.

Diagnostic accuracy of CBCT for periodontal lesions.

OBJECTIVES: The present study compares the diagnostic value of periodontal bone defect images using conventional two-dimensional single-tooth radiographs and three-dimensional cone beam computed tomography (CBCT) images. MATERIALS AND METHODS: Classified periodontal bone defects were prepared on pig mandibles and presented radiographically. Fifteen dentists were instructed to make a diagnosis based on these x-rays, regarding the type and the extent of the bone defects. Subsequently, the results were evaluated and compared to the morphology of the surgically prepared defects as the gold standard. RESULTS: On average, the diagnosis of infrabony defects were 21 %, dehiscence 25 %, and fenestration 33 % more accurate using the three-dimensional projection than with the single-tooth radiograph. Furthermore, the CBCT allows grade II furcation to be captured more accurately. CONCLUSIONS: The results of this study indicate that a considerably more precise analysis of periodontal defects is possible due to the third dimension. Particularly, in the oro-vestibular orientation, defects could be detected significantly more accurate. CLINICAL RELEVANCE: CBCT images offer an advantageous alternative to the conventional single-tooth radiograph while taking the higher exposure of radiation into account.

Influence of platform switching on bone-level alterations: a three-year randomized clinical trial.

The concept of platform switching has been introduced to implant dentistry based on clinical observations of reduced peri-implant crestal bone loss. However, published data are controversial, and most studies are limited to 12 months. The aim of the present randomized clinical trial was to test the hypothesis that platform switching has a positive impact on crestal bone-level changes after 3 years. Two implants with a diameter of 4 mm were inserted crestally in the posterior mandible of 25 patients. The intraindividual allocation of platform switching (3.3-mm platform) and the standard implant (4-mm platform) was randomized. After 3 months of submerged healing, single-tooth crowns were cemented. Patients were followed up at short intervals for monitoring of healing and oral hygiene. Statistical analysis for the influence of time and platform type on bone levels employed the Brunner-Langer model. At 3 years, the mean radiographic peri-implant bone loss was 0.69 ± 0.43 mm (platform switching) and 0.74 ± 0.57 mm (standard platform). The mean intraindividual difference was 0.05 ± 0.58 mm (95% confidence interval: -0.19, 0.29). Crestal bone-level alteration depended on time (p < .001) but not on platform type (p = .363). The present randomized clinical trial could not confirm the hypothesis of a reduced peri-implant crestal bone loss, when implants had been restored according to the concept of platform switching.

Conserved features of cancer cells define their sensitivity to HAMLET-induced death; c-Myc and glycolysis.

HAMLET is the first member of a new family of tumoricidal protein-lipid complexes that kill cancer cells broadly, while sparing healthy, differentiated cells. Many and diverse tumor cell types are sensitive to the lethal effect, suggesting that HAMLET identifies and activates conserved death pathways in cancer cells. Here, we investigated the molecular basis for the difference in sensitivity between cancer cells and healthy cells. Using a combination of small-hairpin RNA (shRNA) inhibition, proteomic and metabolomic technology, we identified the c-Myc oncogene as one essential determinant of HAMLET sensitivity. Increased c-Myc expression levels promoted sensitivity to HAMLET and shRNA knockdown of c-Myc suppressed the lethal response, suggesting that oncogenic transformation with c-Myc creates a HAMLET-sensitive phenotype. Furthermore, HAMLET sensitivity was modified by the glycolytic state of tumor cells. Glucose deprivation sensitized tumor cells to HAMLET-induced cell death and in the shRNA screen, hexokinase 1 (HK1), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 and hypoxia-inducible factor 1α modified HAMLET sensitivity. HK1 was shown to bind HAMLET in a protein array containing ∼8000 targets, and HK activity decreased within 15 min of HAMLET treatment, before morphological signs of tumor cell death. In parallel, HAMLET triggered rapid metabolic paralysis in carcinoma cells. Tumor cells were also shown to contain large amounts of oleic acid and its derivatives already after 15 min. The results identify HAMLET as a novel anti-cancer agent that kills tumor cells by exploiting unifying features of cancer cells such as oncogene addiction or the Warburg effect.

Long-term persistence after acute Q fever of non-infective Coxiella burnetii cell components, including antigens.

BACKGROUND: Previous studies of inciting factors for a prolonged post-infection fatigue syndrome after Q fever (variously termed QFS or Q fever associated CFS/ME in the literature) showed that after the acute infection a high proportion of asymptomatic and QFS patients had Q fever antibody and also low levels in PBMC and bone marrow of Coxiella burnetii (C.b.) DNA with PCR assays directed against three different target sequences in different parts of the coxiella genome. Attempts to isolate a strain of C.b. in A/J mice, and cell culture from PCR positive PBMC and bone marrow were consistently negative. The detailed composition of the persisting coxiella residues remains to be defined. AIM: To retest and provide detailed results on selected PCR positive samples from the Birmingham Q fever outbreak patients tested by a highly sensitive method to detect viable organisms and to determine the nature of the residual coxiella cell components. DESIGN: Laboratory case study. METHODS: NOD/SCID mice were inoculated with samples from the 1989 Q fever outbreak in Birmingham and followed for evidence of infection and the presence of coxiella DNA and specific antigens in spleen and liver macrophages. A significant, unexpected finding of specific antigen was followed by assessment of its ability to provoke production of inflammatory and non-inflammatory cytokines in mice, in THP-1 human macrophage cell cultures and to induce inflammatory lesions in the skin of guinea pigs hyperimmunized against Q fever vaccine. RESULTS: Culture of samples from 10 Birmingham Q fever patients in NOD/SCID mice, 12 years from infection did not yield viable Coxiella burnetii, as shown earlier. However complexes of material with coxiella antigens were found in mouse spleens in all cases but in significantly greater amounts in samples from those with post Q fever fatigue syndrome. The antigenic complexes [now designated 'immunomodulatory complexes' (IMC)] were shown to stimulate cytokine release in the mice and in the THP-1 macrophages and to provoke an inflammatory reaction on intradermal injection into the skin of Q fever hyperimmunized guinea pigs. CONCLUSION: The study identifies a non-infective complex of C.b. antigens able to survive in the host and provoke aberrant humoral and cell medicated immunity responses - a possible pathogenic link between initial infection and a subsequent long-term post Q fever fatigue syndrome.

NOD1 gene polymorphisms in relation to aggressive periodontitis.

BACKGROUND: NOD proteins are part of innate immunity mechanisms. They play a role in epithelial barrier functions and inflammatory responses to bacteria. Single nucleotide polymorphisms (SNPs) in the NOD1 gene have proven to be associated with inflammatory bowel disease (IBD) and asthma. OBJECTIVE: To investigate SNPs in the NOD1 gene in relation to aggressive periodontitis (AgP), a multifactorial, inflammatory disease of the supporting tissues of the teeth. MATERIALS AND METHODS: Five SNPs in the NOD1 gene (4 intronic and 1 exonic) were tested for association in a total of 415 AgP patients and 874 controls both of Northern European ancestry. RESULTS: The frequencies of the rare SNP alleles ranged between 21% and 26% among cases, and 20-27% among controls, and were not statistically different between cases and controls. Two SNPs were in strong linkage disequilibrium (r(2) = 0.97 in cases and 0.94 in controls). The overall haplotype distributions did not differ between cases and controls. We observed 8 haplotypes with a frequency of >or=1% among cases and/or controls, but none of these haplotype frequencies differed significantly among cases and controls. Logistic regression analyses with adjustment for gender and smoking status did not reveal significant associations with AgP for any of the 5 SNPs. This study had a power of >or=95% to detect associations with variants carrying relative risks of >or=1.5 for heterozygote carriers and >or=2.25 for homozygote carriers. CONCLUSIONS: Although SNPs in the NOD1 gene have been strongly associated with cases of IBD, the current study failed to show an association of NOD1 SNPs with AgP.

Q fever: persistence of antigenic non-viable cell residues of Coxiella burnetii in the host--implications for post Q fever infection fatigue syndrome and other chronic sequelae.

BACKGROUND: Our previous studies of persistence of Coxiella burnetii in humans after an initial acute Q fever infection revealed raised, maintained antibody levels and low levels of coxiella genomic DNA at the age of 5 years from onset in Australian patients and at 12 years in patients in the 1989 Birmingham UK Q fever outbreak. Attempts to isolate the coxiella in standard cell culture and susceptible mice by serial passage of PCR positive PBMC and bone marrow were negative. AIM: To retest PCR positive patient samples by more sensitive methods for viable coxiellas and for the coxiella cell components of antigen and specific lipopolysaccharide (LPS). To re-interpret the previous results in the light of the new information. To review the pertinent literature for a concept of an immuno-modulatory complex generated by the current studies. DESIGN: Laboratory case study. METHODS: Stored patient samples were inoculated into SCID mice that were followed for 60 days. Mouse spleen and liver samples were then examined by PCR assay for targets in the COM1 and IS1111a sequences and for antigens by IFA with a polyclonal rabbit antiserum to C. burnetii Phase 1 and a monoclonal antiserum to Phase 1 LPS (details; O. Sukocheva et al., unpublished data). RESULTS: All specimens, including a recently excised heart valve from a Birmingham patient with late developing endocarditis, were infection negative in SCID mice. Dilutions of SCID mouse spleen and liver homogenates titrated in PCR assays were negative at dilutions attained by control mice inoculated with an endpoint dilution of a viable prototype strain of C. burnetii. Sections of the spleens from all specimens showed a complex of coxiella antigen-LPS by IFA. DISCUSSION/REVIEW: We advance a concept of long-term persistence of a non-infective, non-biodegraded complex of coxiella cell components with its antigens and specific LPS [so called Immunomodulatory complex (IMC)] associated with traces of genomic DNA that signalled its presence in our earlier studies. The IMC's survival in patients for at least 12 years, and in one patient for 70 years implies a capacity for serial passage in macrophages with effective down-regulation of their biodegrading functions. The review assesses the compatibility of the IMC concept in relation to cogent literature on C. burnetii interactions with macrophage and cell-mediated immunity. Some remaining gaps in our knowledge of the organ sites and duration of carriage of viable coxiellas after initial infection are also identified.

Clinical outcomes after treatment of intra-bony defects with an EMD/synthetic bone graft or EMD alone: a multicentre randomized-controlled clinical trial.

OBJECTIVES: Comparison of the outcomes of a combination of an enamel matrix derivative and a synthetic bone graft (EMD/SBC) with EMD alone in wide intra-bony defects. MATERIAL AND METHODS: Seventy-three patients with chronic periodontitis were recruited in five centres in Germany. All patients had one wide intra-bony defect of >/=4 mm. Surgical procedures involved microsurgical technique and the modified papilla preservation flap. After debridement, defects were randomly assigned to EMD/SBC (test) or EMD (control). Assessments at baseline and after 6 months included bone sounding, attachment levels, probing pocket depths, bleeding on probing and recessions. Early wound-healing, adverse effects and patients' perceptions were also recorded. RESULTS: Both treatment modalities led to significant clinical improvements. Change in bone fill 6 months after surgery was 2.0 mm (+/- 2.1) in the test group and 2.1 mm (+/- 1.2) in the control group. A gain in clinical attachment of 1.3 mm (+/- 1.8) in the test group and 1.8 mm (+/- 1.6) in the control group was observed. One week after surgery, primary closure was maintained in 95% of the test sites and 100% of the control sites. No differences in patients' perceptions were found. CONCLUSION: The results of the present study showed similar clinical outcomes following both treatment modalities.