A novel mutation in the neonatal region of the fibrillin (FBN)1 gene associated with a classical phenotype of Marfan syndrome (MfS). Mutations in brief no. 163. Online

Marfan Syndrome (MfS) is an autosomal dominant inherited connective tissue disorder with variable phenotypic expression of cardiovascular, skeletal and ocular manifestations. Cardiovascular complications, such as aortic aneurysm and dissection drastically reduce life expectancy of individuals with MfS, whereas preventive surgery substantially improves the prognosis of these patients. A number of mutations in the fibrillin 1 (FBN1) gene associated with MfS have been identified to date, demonstrating considerable molecular heterogeneity. One region, however, located around exon 24, exhibits a striking clustering of mutations, which are associated with a severe, socalled neonatal form of MfS. Here we report the first mutation (G2950A) in exon 24 of the neonatal region of the FBN1 gene, associated with a classic MfS phenotype. The mutation leads to the subsitution of valin by isoleucin (V984I), both uncharged amino acids, which only differ in a single methyl group. This defect was identified in a proband with cardiovascular manifestations of MfS by SSCP analysis of PCR-amplified genomic DNA, direct PCR sequencing and RFLP analysis. The substitution was neither detected in the unaffected 4-year old daughter of the proband, nor in 3 of his healthy family members nor in 108 allels from control individuals, suggesting that this mutation is causative for MfS in the patient. Since no other family member of the proband is affected by MfS, the defect described is sporadic. In summary, we identified a novel defect in exon 24 of the neonatal region of the FBN1 gene in a patient with a classic phenotype of MfS, suggesting that conservative substitutions in this region may lead to a less severe phenotype of the disease. This finding further demonstrates the remarkable phenotypic heterogeneity associated with FBN1 mutations and stresses the significance of modifying genes and individual alterations in protein function for the pheontypic expression of the disease.     

Validation of low-cost models for minimal invasive surgery training of congenital diaphragmatic hernia and esophageal atresia

BackgroundMinimal invasive surgery (MIS) is increasingly used for the correction of congenital diaphragmatic hernia (CDH) and esophageal atresia (EA). It is important to master these complex procedures, preferably preclinically, to avoid complications. The aim of this study was to validate recently developed models to train these MIS procedures preclinically.MethodsTwo low cost, reproducible models (one for CDH and one for EA) were validated during several pediatric surgical conferences and training sessions (January 2017–December 2018), used in either the LaparoscopyBoxx or EoSim simulator. Participants used one or both models and completed a questionnaire regarding their opinion on realism (face validity) and didactic value (content validity), rated on a five-point-Likert scale.ResultsOf all 60 participants enrolled, 44 evaluated the EA model. All items were evaluated as significantly better than neutral, with means ranging from 3.7 to 4.1 (p < 0.001). The CDH model was evaluated by 48 participants. All items scored significantly better than neutral (means 3.5–3.9, p < 0.001), with exception of the haptics of the simulated diaphragm (mean 3.3, p = 0.054). Both models were considered a potent training tool (means 3.9).ConclusionThese readily available and low budget models are considered a valid and potent training tool by both experts and target group participants.Type of studyProspective study.Level of evidenceLevel II.     

The Lapidus Arthrodesis: Examining the Effect of the Metatarsal Base Transfixion Screw

The modified Lapidus bunionectomy is a useful and highly powerful procedure for correcting hallux abducto valgus. Traditionally reserved for “severe” deformities, this procedure has seen a recent resurgence in the podiatric community for its unique ability to achieve tri-planar correction of this challenging deformity. Although this procedure has been extensively studied in both biomechanical labs and the clinical arenas, no clear consensus has been achieved regarding optimal fixation for this thought-provoking procedure. The current study examined the differences in strength between commercially available 5-hole locking plates with interfragmentary compression vs a crossed-screw with a third “transfixation” screw construct in a controlled setting. Ten fresh-frozen cadaveric match pair limbs (20 total limbs) were used to complete this study. Ten limbs were randomly assigned to a 3-screw construct. The other 10 contralateral limbs were assigned to a commercially available 5-hole locking plate (5 stainless steel and 5 titanium alloy) with an interfragmentary lag screw construct. The first rays were then isolated and potted into a 4-point bending device. The specimens were loaded to failure in a servohydraulic load frame at a controlled rate. Failure was defined as catastrophic or 3 mm of plantar gapping at the arthrodesis site. The mean maximal load to failure was 310.9 ± 109.4 N for the 3-screw construct. The mean maximal load to failure for the locking plate constructs was 264.1 ± 100.9 N. This difference was not statistically significant (p = .328). These results suggest that a 3-screw construct for Lapidus arthrodesis is as strong as commercially available locking plate constructs.     

Long-term rates of bladder dysfunction after decompression in patients with cauda equina syndrome

BACKGROUND CONTEXTCauda equina syndrome (CES) occurs due to compression of the lumbar and sacral nerve roots and is considered a surgical emergency. Although the condition is relatively rare, the associated morbidity can be devastating to patients. While substantial research has been conducted on the timing of treatment, the literature regarding long-term rates of bladder dysfunction in CES patients is scarce.PURPOSEThe aim of this study was to identify long-term rates of bladder dysfunction in CES patients and to compare those rates to non-CES patients who underwent similar spinal decompression.STUDY DESIGN/SETTINGRetrospective database study.PATIENT SAMPLEThe CES cohort was comprised of 2,362 patients who underwent decompression surgery following CES diagnosis with a 5-year follow-up. These patients were matched to 9,448 non-CES control patients who underwent spinal decompression without a diagnosis of CES.OUTCOME MEASURESDiagnosis of bladder dysfunction, surgical procedure to address bladder dysfunctionMETHODSUsing the national insurance claims database, PearlDiver, CES patients who underwent decompression surgery were identified and 1:4 matched to non-CES patients who underwent similar spinal decompression surgery. The 1-year, 3-year, and 5-year rates of progression to a bladder dysfunction diagnosis and surgical intervention to manage bladder dysfunction were recorded. The CES and non-CES groups were compared with univariate testing, and an analysis of risk factors for bladder dysfunction was performed with multivariate logistic regression analysis.RESULTSA total of 2,362 CES patients who underwent decompression surgery were identified and matched to 9,448 non-CES control patients. After 5 years, CES patients had a 10%–12% increased absolute risk of continued bladder dysfunction and a 0.7%–0.9% increased absolute risk of undergoing a surgical procedure for bladder dysfunction, as compared to matched non-CES patients. Multivariate analysis controlling for age, sex, obesity, tobacco use, and diabetes, identified CES as independently associated with increased 5-year risk for bladder dysfunction diagnosis (odds ratio [OR]: 1.72; 95% confidence interaval [CI] 1.56–1.89; p<.001) and procedure (OR: 1.40; 95% CI 1.07–1.81; p=.012).CONCLUSIONSUnderstanding the long-term risk for bladder dysfunction in CES patients is important for the future care and counseling of patients. Compared to non-CES patients who underwent similar spinal decompression, CES patients were observed to have a significantly higher long-term likelihood for both bladder dysfunction diagnosis and urologic surgical procedure.     

Osteosarcomatosis

A review of the 690 cases of osteosarcoma in the radiographic file of the Armed Forces Institute of Pathology revealed 29 cases of "osteosarcomatosis" (multiple skeletal sites of osteosarcoma). Fifteen of these patients were 18 years old and under and manifested rapidly appearing, usually symmetric, sclerotic metaphyseal lesions. The remaining 14 patients were more than 18 years old and had fewer, asymmetric sclerotic lesions. In most patients (28 of 29), a radiographically dominant skeletal tumor was seen. Pulmonary metastases occurred in the majority of patients and were detected at the same time as the bone lesions. These 29 patients were studied with regard to demographic data and skeletal distribution and radiographic appearance of their lesions. As a result of the findings, a metastatic origin from a primary dominant osteosarcoma is favored over a multifocal origin as the basis for osteosarcomatosis. Osteosarcomatosis is more commonly encountered in the mature skeleton than has been previously recognized.     

Activation of benzylic alcohols to mutagens by human hepatic sulphotransferases

Four primary and five secondary benzylic alcohols derived frompolycyclic aromatic hydrocarbons were tested for mutagenicityin Salmonella typhimurium TA98 in the presence of 3'-phosphoadenosine-5'-phosphosulphate,the cofactor for sulphotransferases, and varying amounts ofhepatic cytosol from three or four different human subjects,a 3-year-old child, an adult female, an adult male and one unknown.All compounds except one, 4H-cyclopenta[def] phenanthren-4-ol,were activated to mutagens. The interindividual variation inthe activities was at most 3-fold and the individual activitiestowards the different substrates were correlated with each other.The same compounds had previously been tested in the presenceof hepatic cytosol from rats and all compounds activated inone species were also activated in the other species. However,there were marked quantitative differences, which were furthercomplicated by the observation of a substantial sex differencein the rat. Male and female rat liver cytosol showed highersulphotransferase activities towards 1-hydroxymethylpyrene,9-hydroxymethylanthracene, 7-hydroxymethyl-12-methylbenz[a]anthraceneand 4H-cyclopenta[def]chrysen-4-ol than human liver cytosol.The largest difference in activity was seen with 7-hydroxymethyl-12-methylbenz[a]anthracene,reaching a factor of     

Antigenic heterogeneity of the hepatitis C virus NS4 protein as modeled with synthetic peptides

The effect of sequence heterogeneity on the immunologic properties of two strong antigenic regions of the hepatitis C virus (HCV) NS4 protein was studied by using a set of 443 overlapping 20-mer synthetic peptides. One antigenic region comprising the cleavage site between NS4a and NS4b (region 5-1-1) was modeled with peptides derived from 73 different known sequences, representing HCV genotypes 1-6. The other antigenic region, designated region 59 and located at the C-terminus of the NS4b protein, was modeled with peptides from 7 known sequences representing genotypes 1-3. All peptides were tested for antigenic reactivity by enzyme immunoassay with a panel of anti-HCV-positive serum specimens representing genotypes 1-5. The data demonstrated that immunoreactive peptides fell into two groups. One group, represented by N-terminal peptides, demonstrated genotype-independent immunoreactivity; the other group, from the central part of region 5-1-1, showed strict genotype specificity. Nineteen peptides from the genotype-independent group strongly immunoreacted with a wide range of serum samples containing antibodies to all 5 HCV genotypes. Twenty-five peptides from the genotype-specific group were found to strongly react with serum containing antibodies only to the genotype from which the peptides were derived. Similar to the N-terminal part of region 5-1-1, peptides derived from region 59 did not show genotype-specific immunoreactivity. Some peptides derived from the central part of region 59 showed very strong and broad antigenic reactivity. Thus, after examining two antigenic regions of the NS4 protein, we identified short sequences that can be used for the efficient detection of either genotype-independent or genotype-specific HCV antibodies.