Contributors are a nuisance (parameter) for DNA mixture evidence evaluation.

Recently, a debate has arisen around the number of contributors postulated in hypotheses for the purpose of weight of evidence calculations on DNA mixture profiles. Specifically the issue at stake is whether or not one should have the same number of contributors under both hypotheses for which a likelihood ratio is calculated. In this paper we aim to clarify this issue. We take the general approach of considering the number of contributors as a nuisance parameter. Two central assumptions then determine the form of the overall likelihood ratio: whether the prior distributions of the nuisance parameter are equivalent given both hypotheses and whether they depend on the hypotheses. Examples are given for both scenarios where we have either independence or strong dependence between the prior distributions of the number of contributors and the hypotheses. Moreover, examples for different kinship scenarios are presented. In conclusion, the overall likelihood ratio does not only depend on likelihood ratios for fixed values of the nuisance parameter but may also vary considerably with different prior distributions.

Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus.

Objectives Low copy numbers and deletion of complement C4 genes are potent risk factors for systemic lupus erythematosus (SLE). However, it is not known whether this genetic association affects the clinical outcome. We investigated C4 copy number variation and its relationship to clinical and serological features in a Northern European lupus cohort. Methods We genotyped the C4 gene locus using polymerase chain reaction (PCR)-based TaqMan assays in 169 patients with SLE classified according to the 1997 revised American College of Rheumatology (ACR) criteria and in 520 matched controls. In the patient group the mean C4 serum protein concentrations nephelometrically measured during a 12-month period prior to genetic analysis were compared to C4 gene copy numbers. Severity of disease was classified according to the intensity of the immunosuppressive regimens applied and compared to C4 gene copy numbers, too. In addition, we performed a TaqMan based analysis of three lupus-associated single-nucleotide polymorphisms (SNPs) located inside the major histocompatibility complex (MHC) to investigate the independence of complement C4 in association with SLE. Results Homozygous deficiency of the C4A isotype was identified as the strongest risk factor for SLE (odds ratio (OR) = 5.329; p = 7.7 × 10-3) in the case-control comparison. Moreover, two copies of total C4 were associated with SLE (OR = 3.699; p = 6.8 × 10-3). C4 serum levels were strongly related to C4 gene copy numbers in patients, the mean concentration ranging from 0.110 g/l (two copies) to 0.256 g/l (five to six copies; p = 4.9 × 10-6). Two copies of total C4 and homozygous deletion of C4A were associated with a disease course requiring cyclophosphamide therapy (OR = 4.044; p = 0.040 and OR = 5.798; p = 0.034, respectively). Homozygous deletion of C4A was associated with earlier onset of SLE (median 24 vs. 34 years; p = 0.019) but not significant after correction for multiple testing. SNP analysis revealed a significant association of HLA-DRB1*0301 with SLE (OR = 2.231; p = 1.33 × 10-5). Conclusions Our findings confirm the important role of complement C4 genes in the development of SLE. Beyond the impact on the susceptibility for lupus, C4 copy numbers may be related to earlier onset and a more severe course of the disease. The association of homozygous deletion of C4A and SLE is accompanied by the presence of HLA-DRB1*0301 without a proven pathophysiological mechanism.

Implant placement under existing removable dental prostheses and its effect on masticatory performance.

OBJECTIVE: The aim of this within-subject study was to evaluate the outcome with implant-tooth-supported removable partial dental prostheses (RPDP group) and implant-supported removable complete dental prostheses (edentulous group) in terms of masticatory performance and self-assessment. MATERIALS AND METHODS: Thirty patients participated in this prospective clinical study (RPDP group: n = 12; edentulous group: n = 18). The prostheses were supported in strategically advantageous regions by placing implants with ball attachments and corresponding matrices in the existing dentures. The masticatory performance was evaluated with the Swallowing Threshold Test Index (STTI), the number of chewing strokes, and the time needed until swallowing at pre-treatment and 6 weeks after integration of ball attachments. Additionally, patients scored chewing satisfaction before and after implantation on a visual analogue scale. RESULTS: The STTI increased significantly (p ≤ 0.05) after implant therapy in the edentulous group but not in the RPDP group. Furthermore, the STTI was significantly higher (p ≤ 0.05) in the RPDP group than in the edentulous group at pre-treatment, however, not after therapy (P > 0.05). All patients were very satisfied after therapy concerning ability of speaking, chewing, and stability of their prosthesis. CONCLUSIONS: Patients of the edentulous group benefit more from strategically placed implants under the existing dentures than patients from the RPDP group. However, according to the subjective assessment, the chewing satisfaction generally increased for both groups after implant therapy. CLINICAL RELEVANCE: Patients with a strongly reduced dentition and edentulous patients benefit from strategically placed implants under the existing removable dentures.

SPAG7 is a candidate gene for the periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome.

Periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome is an auto-inflammatory disease for which a genetic basis has been postulated. Nevertheless, in contrast to the other periodic fever syndromes, no candidate genes have yet been identified. By cloning, following long insert size paired-end sequencing, of a de novo chromosomal translocation t(10;17)(q11.2;p13) in a patient with typical PFAPA syndrome lacking mutations in genes associated with other periodic fever syndromes we identified SPAG7 as a candidate gene for PFAPA. SPAG7 protein is expressed in tissues affected by PFAPA and has been functionally linked to antiviral and inflammatory responses. Haploinsufficiency of SPAG7 due to a microdeletion at the translocation breakpoint leading to loss of exons 2-7 from one allele was associated with PFAPA in the index. Sequence analyses of SPAG7 in additional patients with PFAPA point to genetic heterogeneity or alternative mechanisms of SPAG7 deregulation, such as somatic or epigenetic changes.

[Comparison of MRI and CT for assessment of childhood fractures: studies on a porcine model]. / Vergleich von MRT und CT bei Frakturen im Kindesalter: Untersuchungen an einem Schweinemodell.

BACKGROUND: The purpose of this study was to evaluate the capacity of MRI to achieve a diagnostic accuracy in pediatric fracture diagnosis comparable to CT. MATERIAL AND METHODS: In an ex vivo study design, simulating pediatric skeletal trauma, 248 limb bones of 9 dead young pigs with intact soft tissue were fractured. The samples were examined in a 1.5 T MRI with T1-weighted SE sequences. A standard scanning protocol was chosen for 64 multislice CT. CT results served as the reference standard. RESULTS: A total of 168 fractures were found. Seven fractures were missed by MRI, whereas another six ones were detected solely by MRI. The fracture type was the same in 137, partially the same in 12, and different in 6 cases. The dislocation was the same in 137, partially the same in 13, and different in 5 fractures. All differences were not statistically significant. CONCLUSION: MRI has a diagnostic accuracy in fracture diagnosis comparable to CT. Therefore, protocols of traumatology in infancy should be revised.

[Pediatric fracture diagnosis--ultra-low-dose CT with an effective dose equal to that of radiographs]. / Pädiatrische Frakturdiagnostik--Ultra-low-dose-CT mit der effektiven Dosis von Röntgenaufnahmen.

PURPOSE: Computed tomography (CT) plays an important role in trauma diagnosis in children, especially for complex fractures. The aim of this study was to examine the diagnostic value of ultra-low-dose-CT (ULD-CT) with an effective dose equal to that of radiographs in an experimental study and to compare its results with those of radiographs. MATERIALS AND METHODS: Limb bones of dead young pigs served as a model for pediatric bones. A total of 51 fractured and non-fractured bones were examined with a 64 multislice-CT with a standard dose protocol as gold standard, with two ultra-low-dose-protocols, and with standard radiographs with different exposures. RESULTS: In spite of high background noise the examinations of ULD-CT were not adequate only in 2 of 204 cases. ULD-CT was slightly superior to radiographs in detection of fractures. ULD-CT could significantly better characterize the fractures than radiographs. The overall result of ULD-CT was significantly better than that of radiographs with standard exposure. CONCLUSION: ULD-CT with the effective dose of radiographs is successfully applicable in pediatric fracture diagnosis, and its overall result is significantly better than that of radiographs.

Novel Tandem Duplication in Exon 1 of the SNURF/SNRPN Gene in a Child with Transient Excessive Eating Behaviour and Weight Gain.

A deletion in 15q11.2 involving the SNURF/SNRPN gene is the typical finding in patients with Prader-Willi syndrome. Apart from translocations disrupting this gene, no other mutation types have been described so far. We report a patient in whom a small duplication in exon 1 of the SNURF/SNRPN gene was diagnosed which is predicted to interrupt only SNURF expression. The patient was investigated due to overgrowth, increased appetite and developmental delay in childhood. This duplication was inherited from her father who carries the duplication on his paternal chromosome 15 and also had transient excessive eating behaviour as an adolescent. RNA studies showed that the duplication introduces a premature stop codon in SNURF.

A comparison of the Nexfin® and transcardiopulmonary thermodilution to estimate cardiac output during coronary artery surgery.

The newly introduced Nexfin(®) device allows analysis of the blood pressure trace produced by a non-invasive finger cuff. We compared the cardiac output derived from the Nexfin and PiCCO, using transcardiopulmonary thermodilution, during cardiac surgery. Forty patients with preserved left ventricular function undergoing elective coronary artery bypass graft surgery were studied after induction of general anaesthesia and until discharge to the intensive care unit. There was a significant correlation between Nexfin and PiCCO before (r(2) = 0.81, p < 0.001) and after (r(2) = 0.56, p < 0.001) cardiopulmonary bypass. Bland-Altman analysis demonstrated the mean bias of Nexfin to be -0.1 (95% limits of agreement -0.6 to +0.5, percentage error 23%) and -0.1 (-0.8 to +0.6, 26%) l.min(-1).m(-2), before and after cardiopulmonary bypass, respectively. After a passive leg-raise was performed, there was also good correlation between the two methods, both before (r(2) = 0.72, p < 0.001) and after (r(2) = 0.76, p < 0.001) cardiopulmonary bypass. We conclude that the Nexfin is a reliable method of measuring cardiac output during and after cardiac surgery.

Bladder exstrophy and extreme genital anomaly in a patient with pure terminal 1q deletion: expansion of phenotypic spectrum.

We describe a 5 2/12 years old male patient with a de novo deletion 1q43q44 of approximately 10.4 Mb in size. The boy presented with the classic features of chromosome 1q43q44 deletion syndrome including growth and psychomotor retardation, microcephaly, distinct facial features and various midline defects as agenesis of corpus callosum, cardiac and urogenital anomalies. Fronto-parietal simplified gyral pattern was an additional neuroimaging finding. The urogenital anomalies in our patient were remarkable in form of bladder exstrophy and severe hypogenitalism with a marked hypoplastic scrotum, small sized retractile testis and absent phallus. To the best of our knowledge, bladder exstrophy and absence phallus have not been previously reported in terminal deletion 1q43q44 syndrome. This report provides further evidence of phenotype-genotype correlation and expands the phenotypic spectrum of midline defects described with this syndrome.

Malignant melanoma and Wiedemann-Beckwith syndrome in childhood.

Patients with Wiedemann-Beckwith syndrome (WBS, MIM 130650), a congenital overgrowth syndrome, have a known increased tumor risk especially for embryonic tumors. WBS belongs to the "imprinting" syndromes caused by overexpression of IGF2 and/or loss of CDKN1C on chromosome 11p15.5. A 13-year-old boy with WBS developed a spitzoid malignant melanoma (Clark level V, Breslow index 4.8 mm) on the right cheek. Genetic analyses of the patient's blood showed hypermethylation at the H19 locus on chromosome 11p. The (epi)genetic changes of the WBS locus might have played a role in the pathogenesis of melanoma development.

[Is ultrasound equal to X-ray in pediatric fracture diagnosis?]. / Ist die Sonografie der Röntgendiagnostik in der pädiatrischen Frakturdiagnostik gleichwertig?

PURPOSE: Ultrasound is currently not established for the diagnosis of fractures. The aim of this study was to compare ultrasound and X-ray beyond their use solely for the identification of fractures, i. e., for the detection of fracture type and dislocation for pediatric fracture diagnosis. MATERIALS AND METHODS: Limb bones of dead young pigs served as a model for pediatric bones. The fractured bones were examined with ultrasound, X-ray, and CT, which served as the gold standard. RESULTS: 162 of 248 bones were fractured. 130 fractures were identified using ultrasound, and 148 using X-ray. There were some advantages of X-ray over ultrasound in the detection of fracture type (80 correct results using X-ray, 66 correct results using ultrasound). Ultrasound, however, was superior to X-ray for dislocation identification (41 correct results using X-ray, 51 correct results using ultrasound). Both findings were not statistically significant after adjustment for multiple testing. CONCLUSION: Ultrasound not only has comparable sensitivity to that of X-ray for the identification of limb fractures but is also equally effective for the diagnosis of fracture type and dislocation. Thus, ultrasound can be used as an adequate alternative method to X-ray for pediatric fracture diagnosis.

[Caudal regression syndrome - caudal agenesis]. / Kaudales Regressionssyndrom - kaudale Agenesie.

BACKGROUND: Neural tube defects are caused by complex genetic and environmental factors. The congenital anomaly most specific to pregnant women with diabetes mellitus is caudal regression syndrome. PATIENT: A 4-year-old boy with a history of mild delay in motor development presented with primary enuresis and encopresis. On physical examination, he had no sensory and motor deficits, but a short anal cleft. On questioning, the mother reported insulin-dependent diabetes mellitus during pregnancy. MRI of the spinal cord demonstrated a thoracic syringomyelia, a dysplastic conus medullaris, and an absence of coccyx and distal sacrum, called caudal regression syndrome or caudal agenesis. CONCLUSION: The caudal regression syndrome refers to sacral agenesis associated with spinal cord anomalies, e.g. syringomyelia. Sacral agenesis is marked by total absence of the coccyx and total or distal absence of the sacrum. An abnormal backside combined with a history of maternal diabetes mellitus in pregnancy is highly suggestive for the presence of caudal regression syndrome.

CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients.

It is currently not clear whether the concentration-time curves of the immunosuppressants differ with respect to the CYP3A5, MDR1, or MRP2 genotype in dose-adapted stable kidney transplant patients. Dose/trough concentration ratios were obtained in 134 tacrolimus and 20 sirolimus-treated patients, and plasma concentration-time profiles were obtained from 16 (tacrolimus) and 10 (sirolimus) patients. Genotyping was carried out for CYP3A5 6986A>G; ABCB1 2677G>T/A, 3435C>T and ABCC2 -24C>T; 1249G>A; 3972C>T. Dose/trough concentration ratios were 0.67+/-0.3 and 1.36+/-0.73 x 10(3) l (P<0.00001) for tacrolimus and 0.42+/-0.17 and 0.84+/-0.46 x 10(3) l (P=0.18) for sirolimus in CYP3A5 non-expressors and expressors. The unadjusted tacrolimus area under curve (AUC)(0-12) was 106.8+/-17.5 ng/ml x h compared with 133.3+/-42.2 ng/ml x h (P=0.37) without affecting serum creatinine. Mean unadjusted AUC(0-24) of sirolimus did not differ significantly either. Therefore, CYP3A5 expressor status and not transporter variants is a main determinant of oral clearance, particularly for tacrolimus. Dose adaptation according to trough levels, however, appears to be sufficient to maintain similar concentration-time profiles.

Open versus laparoscopic appendicectomy: a critical review.

BACKGROUND: The benefit of laparoscopic appendicectomy remains unclear. We have analysed available randomised studies comparing laparoscopic and open appendicectomy regarding their clinical pitfalls and statistical relevance. METHODS: Thirty eight studies were analysed in terms of the following aspects: A. clinical problems (e.g., expertise of the surgeons, pre- and postoperative antibiotic treatment, definition of complications, blinding of outcomes) and B. statistical problems (e.g., definition of primary and secondary outcomes, power and sample size, statistical methods, confidence intervals, comparability of groups and studies). RESULTS: Most of the studies have clinical and statistical pitfalls. The most important pitfalls are the uncertain expertise of the operating surgeons, blinding, and the exploratory nature of the studies. Our analysis aims at giving useful information for the appraisal of existing studies and the conduct of further studies. It also gives some preliminary results. CONCLUSIONS: More than twenty years after Semm performed the first laparoscopic appendicectomy, it is necessary to clarify the superiority of laparoscopic or open appendectomy with well-defined, carefully designed randomised studies.

Sigmoid diverticulitis in patients with Williams-Beuren syndrome: relatively high prevalence and high complication rate in young adults with the syndrome.

In a retrospective survey of 128 adults with Williams-Beuren syndrome (age range 18-62 years) sigmoid diverticulitis was reported in 10 patients (2 f, 8 m). The diagnosis of diverticulitis had been made between the ages of 17.1 and 39.6 years. An additional four patients (age range 23.5-32.2 years) had presented with sigmoid diverticulosis. In eight patients the course of the disease was complicated, some of them having to undergo multiple surgery. Conservative therapy was successful in only one female and one male patient with diverticulitis. Thus, we conclude that there is an increased prevalence of sigmoid diverticulitis in adult patients with Williams-Beuren syndrome (8% vs. 2% in the normal population in the age group below 40 years).

Phenotypical variation in cousins with the identical partial trisomy 9 (pter-q22.2) and 7 (q35-qter) at 16 and 23 weeks gestation.

From the study of numerical and structural chromosomal abnormalities, there is convincing evidence and accumulating information of a direct karyotype to phenotype correlation. Knowledge of phenotypic consequences of a specific chromosomal imbalance is important for genetic counseling and prenatal diagnosis. However, for unbalanced non-Robertsonian translocations a precise karyotype to phenotype correlation is difficult to predict for several reasons: (I) unbalanced non-Robertsonian translocations are rare, (II) the published case reports are often not age-matched, (III) varying breakpoints result in different lengths of the monosomic and trisomic segments and therefore the phenotype will depend on additional genes present or the loss of coding regions, and (IV) the combination of the same trisomy with different monosomies, or vice versa, can result in diverging phenotypes. Therefore, the study of the karyotype to phenotype correlation in affected relatives of the same age and the identical unbalanced translocation provides a good model to investigate phenotypic consequences of a specific genetic imbalance. We report of two second trimester fetuses with the identical major partial trisomy 9 (9pter-9q22.2) and minor partial trisomy 7 (q35-qter) resulting from a familial translocation (7;9)(q35;q22.2)mat. One fetus presented with a Dandy-Walker malformation, polymicrogyria, and mild dysmorphic features, whereas the other fetus showed unilateral cleft lip and palate without cerebral anomalies. Potential mechanisms for this different phenotypic expression of the same unbalanced translocation resulting in partial trisomy 9 and 7 in the two cousins and possible consequences for genetic counseling and prenatal diagnosis are discussed.

A new level detector for ion channel analysis.

The algorithm proposed here for automatic level detection in noisy time series of patch-clamp current is based on the detection of jump-free sections in the time series. The detector moves along the time series and uses a chi(2) test for the detection of jumps. When a jump is detected, the mean value, the variance and the length of the preceding jump-free section are stored. A Student's t-test was employed for the assignment of detected jump-free sections to discrete levels of the Markov model and for rejection of all sections with multiple assignments. The choice of the two significance levels is based on a 3-D diagram displaying the average number of detected levels from several time series vs. the significance levels of jump detection and of level assignment. The correct one is selected out of several plateaus with integer number of levels by means of the criterion of minimum scatter or other plausibility considerations. The test has been applied to simulated data obtained from a 2-state model and a 5-state aggregated Markov model, and the influences of SNR and of gating frequency are shown. Finally, the performance of the level detector is compared with a fit-by-eye and with a fit of the amplitude histogram by a sum of gaussians. At high noise, the fit of amplitude histograms failed, whereas the other two approaches were about equal.

[Molecular variants of fibrinogen]. / Molekulare Varianten des Fibrinogens.

In the final step of blood coagulation, fibrin monomers polymerize spontaneously and are covalently linked by factor XIIIa. Mutations in one of the three genes coding for the fibrinogen peptides may disturb this process and lead to diseases such as afibrinogenemia or dysfibrinogenemia, or may even cause hereditary renal amyloidosis. In the brief overview presented here we summarize some of the molecular aspects of these diseases.