A Novel Operation Technique for Forearm Deformities in Patients with Brachial Plexus Birth Injury: Retrospective Analysis of 14 Patients.

Background: We aimed to evaluate the effectiveness of our novel operation technique that included radial shaft shortening plus supination producing osteotomy and transfer of the biceps brachii tendon to the brachialis tendon in patients with chronic radial head dislocation secondary to brachial plexus birth injury (BPBI). Methods: Fourteen patients with chronic radial head dislocation resulting from BPBI were included in this study, with a minimum 1-year postoperative follow-up period. All patients underwent the same surgical procedure. The range of motion of affected elbow was measured with a standard goniometer. The Mayo Elbow Performance Score (MEPS) was used to measure for evaluation of functional result of these patients. The affected elbow radiograph also obtained in the last visit for evaluation of compatibility of the radiocapitellar joint. Results: Fourteen patients (10 males and 4 females) were included in the study. The average age at the time of surgery was 7.2 (5-8) years and average follow-up was 73.2 ± 19 (36-131) months. Although the forearm active-passive pronation decreased, active-passive supination significantly improved postoperatively (p < 0.001). Ten patients had excellent MEPS results (90 and above), two patients with good results (75 and 80), one patient with fair (65) and one patient with poor result (55). Radiocapitellar reduction was achieved in 78.5% (11/14) of the patients. Conclusions: The novel surgical techniques that included radial shaft shortening plus supination producing osteotomy and transfer of the biceps brachii tendon to the brachialis tendon improved the functional outcomes of patients with chronic radial head dislocation secondary to BPBI. Level of Evidence: Level IV (Therapeutic).

ADAM19 cleaves the PTH receptor and associates with brachydactyly type E.

Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons. Since we had shown earlier that the extracellular domain of the parathyroid hormone receptor (PTHR1) is subject to an unidentified metalloproteinase cleavage, we tested the hypothesis that ADAM19 is a sheddase for PTHR1. WT ADAM19 cleaved PTHR1, while mutated ADAM-19 did not. We mapped the cleavage site that we verified with mass spectrometry between amino acids 64-65. ADAM-19 cleavage increased Gq and decreased Gs activation. Moreover, perturbed PTHR1 cleavage by ADAM19 increased ß-arrestin2 recruitment, while cAMP accumulation was not altered. We suggest that ADAM19 serves as a regulatory element for PTHR1 and could be responsible for BDE. This sheddase may affect other PTHrP or PTH-related functions.

An unusual cause of posterior interosseous nerve palsy and contribution of ultrasonography to electromyography in a patient with neurofibroma.

Neurofibroma, a benign peripheral nerve sheath tumor, represents a rare cause of posterior interosseous nerve syndrome. Electrodiagnostic studies may not identify the exact site of nerve compression, a possible lesion that compresses the nerve and do not provide information about the morphological changes. Ultrasound is a cost-effective, practical modality that provides the opportunity for dynamic tracking in the peripheral nerves, and it is widely considered as the initial imaging modality for peripheral nerves. Herein, we report a case of posterior interosseous nerve palsy in a 13-year-old boy with neurofibroma of posterior interosseous nerve diagnosed with ultrasound. The benefit of ultrasound in localizing and determining the etiology of the posterior interosseous nerve palsy is emphasized in this case report. A meticulous ultrasound examination is recommended in suspected peripheral nerve lesions, regardless of the results of electrophysiological and imaging modalities.

The effect of botulinum toxin application on latissimus dorsi and teres major muscles in patients with brachial plexus birth palsy: An electron microscopic and clinical study.

BACKGROUND: In brachial plexus birth palsy (BPBP), botulinum toxin may be utilized to prevent glenohumeral dysplasia and to maintain the stable growth of the glenohumeral joint. Repeated injections may cause muscular atrophy and their functional effects are uncertain. The aim of this study was to compare the microstructure and the function of the muscles that received two injections before transfer with the muscles that were not injected. METHODS: BPBP patients that were operated between January 2013 and December 2015 were included in the study. Latissimus dorsi and teres major muscles were transferred to humerus in standard fashion. Patients were divided in two groups according to bo-tulinum toxin status. Group 1 was toxin negative whereas Group 2 was toxin positive. For each patient, mean latissimus dorsi myocyte thickness (LDMT) was measured with electron microscopy and pre-operative and post-operative active shoulder abduction, flexion, external and internal rotation, and Mallet scores were evaluated with goniometry. RESULTS: Fourteen patients (seven patients per group) were evaluated. Five patients were female whereas nine were male. Mean LDMT was not affected significantly (p>0.05). The operation improved shoulder abduction, flexion, and external rotation significantly (p<0.05), independent of the toxin status. The internal rotation decreased significantly only in Group 2 (p<0.05). The Mallet score increased in both groups, but it was not significant (p>0.05), independent of the toxin status. CONCLUSION: Botulinum toxin that was applied twice prevented glenohumeral dysplasia and it did not cause permanent latissimus dorsi muscle atropy and function loss in late period. It augmented upper extremity functions by alleviating internal rotation contracture.

Quality of upper extremity skills and disability inventory via manual ability classification in children with neonatal brachial plexus palsy.

PURPOSE: The aim of study was to investigate the relationship between upper extremity skill quality and disability inventory according to manual ability classification system in children with neonatal brachial plexus palsy (NBPP). MATERIALS AND METHODS: Children with NBPP were included between the ages of 4-7.5 years. Children were classified in Manual Ability Classification System (MACS). Upper extremity skill quality was evaluated with Quality of Upper Extremity Skills Test (QUEST), disability status was assessed with Pediatric Evaluation of Disability Inventory (PEDI). RESULTS: Total of 63 children (girls:31/boys:32), and mean age was 6.32 ± 1.73 years. 37 (58.73%) of children were at MACS Level-2. According to MACS classification, significant differences were noted in PEDI scores (p = 0.001), dissociated movements (p = 0.016) and grasp (p = 0.002) domains of QUEST. However, no significant differences between QUEST total scores (p = 0.079). PEDI (ROC; AuC = 0.762) and QUEST total score (ROC; AuC = 0.714) were sensitive to difference between groups across MACS in children with NBPP. CONCLUSION: The PEDI and QUEST are sensitive in distinguishing the disability of children with NBPP at different MACS levels. Assessment of children with NBPP is not limited to functionality, disability, and quality of movement, it is multidimensional. Outcomes measures studies of movement's quality in children with NBPP are needed.

Functionality evaluation in children with neonatal brachial plexus palsy is multidimensional.Appropriate assessment of functionality in children with neonatal brachial plexus palsy provides accurate information about daily living activities and disability levels.We propose using Quality of Upper Extremity Skills Test (QUEST) and Pediatric Evaluation of Disability Inventory (PEDI) to evaluate the relationship between the quality of upper extremity movements and disability in school-aged children with neonatal brachial plexus palsy at different Manual Ability Classification System (MACS) levels.

Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage.

BACKGROUND: Phosphodiesterase 3A (PDE3A) gain-of-function mutations cause hypertension with brachydactyly (HTNB) and lead to stroke. Increased peripheral vascular resistance, rather than salt retention, is responsible. It is surprising that the few patients with HTNB examined so far did not develop cardiac hypertrophy or heart failure. We hypothesized that, in the heart, PDE3A mutations could be protective. METHODS: We studied new patients. CRISPR-Cas9-engineered rat HTNB models were phenotyped by telemetric blood pressure measurements, echocardiography, microcomputed tomography, RNA-sequencing, and single nuclei RNA-sequencing. Human induced pluripotent stem cells carrying PDE3A mutations were established, differentiated to cardiomyocytes, and analyzed by Ca2+ imaging. We used Förster resonance energy transfer and biochemical assays. RESULTS: We identified a new PDE3A mutation in a family with HTNB. It maps to exon 13 encoding the enzyme's catalytic domain. All hitherto identified HTNB PDE3A mutations cluster in exon 4 encoding a region N-terminally from the catalytic domain of the enzyme. The mutations were recapitulated in rat models. Both exon 4 and 13 mutations led to aberrant phosphorylation, hyperactivity, and increased PDE3A enzyme self-assembly. The left ventricles of our patients with HTNB and the rat models were normal despite preexisting hypertension. A catecholamine challenge elicited cardiac hypertrophy in HTNB rats only to the level of wild-type rats and improved the contractility of the mutant hearts, compared with wild-type rats. The ß-adrenergic system, phosphodiesterase activity, and cAMP levels in the mutant hearts resembled wild-type hearts, whereas phospholamban phosphorylation was decreased in the mutants. In our induced pluripotent stem cell cardiomyocyte models, the PDE3A mutations caused adaptive changes of Ca2+ cycling. RNA-sequencing and single nuclei RNA-sequencing identified differences in mRNA expression between wild-type and mutants, affecting, among others, metabolism and protein folding. CONCLUSIONS: Although in vascular smooth muscle, PDE3A mutations cause hypertension, they confer protection against hypertension-induced cardiac damage in hearts. Nonselective PDE3A inhibition is a final, short-term option in heart failure treatment to increase cardiac cAMP and improve contractility. Our data argue that mimicking the effect of PDE3A mutations in the heart rather than nonselective PDE3 inhibition is cardioprotective in the long term. Our findings could facilitate the search for new treatments to prevent hypertension-induced cardiac damage.

Microwave assisted synthesis, experimental and theoretical characterization and antibacterial activity screening of novel azomethine compounds containing thiophene and aminophenol functionality.

Eight new azomethine compounds (3a-3h) containing thiophene and aminophenol functionality were synthesized in excellent yields by using conventional heating and microwave assisted synthesis methods. The structures of newly synthesized compounds were characterized by spectroscopic techniques such as UV-Vis, FTIR, 1H and 13C NMR and elemental analysis. UV-Vis and 1H NMR results show that all compounds prefer the phenol-imine tautomer form in solvent media. The chemical structure of 3a, 3b and 3g was also confirmed by single crystal X-ray diffraction method. The molecular conformations of 3a, 3b and 3g are stabilized by an N+-H⋯O- type intramolecular hydrogen bond in zwitterionic form in the crystalline solid state. The optimized molecular structures, 1H and 13C NMR chemical shift values, UV-Vis spectroscopic parameters, HOMO-LUMO energies, Mulliken (MPA) and natural (NBO) atomic charges, Natural bond orbitals (NBO), molecular electrostatic potential (MEP) maps and solvent accessible surfaces (SASs) for 3a-3h were calculated by using DFT/B3LYP/6-311G(2d,p) approach. The theoretical spectroscopic features obtained by DFT calculations show a very good agreement with the experimental data. In addition, the synthesized compounds (3a-3h) were screened for their antibacterial activities against Bacillus cereus (NRRL-B3711), Bacillus subtilis (NRRL-B4378), Escherichia coli (NRRL B-3008), Staphylococcus aureus (ATCC-6538) and Salmonella typhimurium (ATCC-13311). The results show that investigated compounds have either moderately active, slightly active or inactive among the tested microorganisms. 3a exhibited the stronger antibacterial activity against all test bacteria than other compounds. It also has been observed that compounds with relatively low HOMO-LUMO energy gaps exhibit better antibacterial effects.

Phosphodiesterase 3A and Arterial Hypertension.

BACKGROUND: High blood pressure is the primary risk factor for cardiovascular death worldwide. Autosomal dominant hypertension with brachydactyly clinically resembles salt-resistant essential hypertension and causes death by stroke before 50 years of age. We recently implicated the gene encoding phosphodiesterase 3A (PDE3A); however, in vivo modeling of the genetic defect and thus showing an involvement of mutant PDE3A is lacking. METHODS: We used genetic mapping, sequencing, transgenic technology, CRISPR-Cas9 gene editing, immunoblotting, and fluorescence resonance energy transfer. We identified new patients, performed extensive animal phenotyping, and explored new signaling pathways. RESULTS: We describe a novel mutation within a 15 base pair (bp) region of the PDE3A gene and define this segment as a mutational hotspot in hypertension with brachydactyly. The mutations cause an increase in enzyme activity. A CRISPR/Cas9-generated rat model, with a 9-bp deletion within the hotspot analogous to a human deletion, recapitulates hypertension with brachydactyly. In mice, mutant transgenic PDE3A overexpression in smooth muscle cells confirmed that mutant PDE3A causes hypertension. The mutant PDE3A enzymes display consistent changes in their phosphorylation and an increased interaction with the 14-3-3θ adaptor protein. This aberrant signaling is associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function. CONCLUSIONS: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance causing hypertension. We present 2 new animal models that will serve to elucidate the underlying mechanisms further. Our findings could facilitate the search for new antihypertensive treatments.

Reliability and validity of the Brachial Plexus Outcome Measure in children with obstetric brachial plexus palsy.

STUDY DESIGN: Clinical measurement and cross-sectional study. INTRODUCTION: Numerous scales have been developed to examine activities of daily living and function in children with brachial plexus palsy. The Brachial Plexus Outcome Measure (BPOM) scale was developed in 2012 by Emily S. Ho and contains 14 items that measure activity and self-evaluation. PURPOSE OF THE STUDY: The aim of the study was to cross-culturally translate the BPOM scale into Turkish and test its measurement properties in children with brachial plexus palsy. METHODS: The scale was translated into Turkish using standard cross-cultural translation procedures. Forty-eight children with obstetric brachial plexus palsy (OBPP) were included in psychometric evaluations. Internal structure consistency and test-retest reliability were measured for reliability analyses. For each item on the scale, Cronbach alpha coefficient and item-total score correlations for all subscales were calculated. The scale was administered at baseline and 1 week later by 2 different physiotherapists to evaluate test-retest reliability. Concurrent construct validity was assessed using Pearson correlations between the OBPP and the Mallet classification system. RESULTS: Eighteen (37.5%) girls and 30 (62%) boys, in total 48 children, whose mean age was 8.7 ± 2.4 (minimum-maximum = 5-14) years were included in the study; 9 (18.9%) have a history of both early microsurgery and tendon transfers and 39 (81.3%) have a history of only tendon transfer. Cronbach alpha ranged from 0.89 to 0.96, and for the whole scale, it was calculated as 0.938. DISCUSSION: Test-retest reliability was high. Moderate correlations were observed between the measures. CONCLUSION: The Turkish BPOM scale is a valid and reliable measurement for assessing function in children with OBPP in the Turkish population.

Reorganization of inter-chromosomal interactions in the 2q37-deletion syndrome.

Chromosomes occupy distinct interphase territories in the three-dimensional nucleus. However, how these chromosome territories are arranged relative to one another is poorly understood. Here, we investigated the inter-chromosomal interactions between chromosomes 2q, 12, and 17 in human mesenchymal stem cells (MSCs) and MSC-derived cell types by DNA-FISH We compared our findings in normal karyotypes with a three-generation family harboring a 2q37-deletion syndrome, featuring a heterozygous partial deletion of histone deacetylase 4 (HDAC4) on chr2q37. In normal karyotypes, we detected stable, recurring arrangements and interactions between the three chromosomal territories with a tissue-specific interaction bias at certain loci. These inter-chromosomal interactions were confirmed by Hi-C. Interestingly, the disease-related HDAC4 deletion resulted in displaced inter-chromosomal arrangements and altered interactions between the deletion-affected chromosome 2 and chromosome 12 and/or 17 in 2q37-deletion syndrome patients. Our findings provide evidence for a direct link between a structural chromosomal aberration and altered interphase architecture that results in a nuclear configuration, supporting a possible molecular pathogenesis.

Distally based subcutaneous veins for venous insufficiency of the reverse posterior interosseous artery flap.

BACKGROUND: The reverse posterior interosseous artery flap (PIAF) provides soft, thin, and pliable tissue for upper extremity reconstruction without sacrificing any major arteries of the hand. The authors performed a new technique that included one extra distally based subcutaneous vein within the pedicle to diminish venous insufficiency and they aimed to present the results of reconstruction with this technique. PATIENTS AND METHODS: Twelve patients with a mean age of 30 years (range 5-52 years) underwent reverse PIAF surgery. The defects were located on the hand and wrist, with a mean area of 57.8 cm2 (range 20-99 cm2) . After the skin between the distal edge and the pivot point of the flap was elevated, the most reliable subcutaneous vein was chosen, chased, and included within the flap. RESULTS: The average size of the PIAF was 6 × 5 cm to 12 × 9 cm (mean area: 64.4 cm2 ) and the median follow-up time was 13 months (range 4-16 months). The mean quick Disabilities of the Arm, Shoulder and Hand (DASH) score was 21.4, indicating a low degree of disability. Of the 12 patients, ten were very satisfied and two were satisfied with the result of the reconstruction. All but one flap survived completely. One flap was nearly totally lost due to arterial insufficiency after hemodialysis. We observed no venous congestion or insufficiency in the patients. CONCLUSIONS: Subcutaneous veins may be reliable and useful for overcoming major drawbacks associated with reverse flow posterior interosseous artery flap and for diminishing flap loss due to venous insufficiency. © 2016 Wiley Periodicals, Inc. Microsurgery 36:384-390, 2016.

Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly.

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population.

PDE3A mutations cause autosomal dominant hypertension with brachydactyly.

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.

Digital artery perforator flaps: an easy and reliable choice for fingertip amputation reconstruction.

OBJECTIVE: The aim of this study was to evaluate the use and efficacy of digital artery perforator (DAP) flaps in fingertip reconstruction. METHODS: From 2007 to 2011, 7 fingers of 5 patients (4 male, 1 female) underwent fingertip reconstruction with extended DAP flaps following traumatic fingertip amputation. Average flap size was 4.25 cm². RESULTS: All flaps survived except one case in which partial skin necrosis was observed and treated with wet-dressing. Donor sites were closed with full-thickness skin grafting in 5 and primarily in 2 fingers. We did not observe hypersensitivity or cold intolerance in repaired fingers. CONCLUSION: The DAP flap is a reliable, free-style perforator flap that can be used for all types of fingertip injuries.

Cosmetic closure of pilonidal sinus defects with bilateral transpositional adipofascial flaps.

The optimal treatment of the pilonidal sinus has not currently been defined. This study described the use of a modified bilateral transpositional adipofascial flap technique that effectively serves to flatten the deep natal cleft while keeping the scar limited to the intergluteal fold for good cosmesis. Between June 2007 and September 2011, 83 patients (61 men, 22 women) were included in the study. Duration of pilonidal sinus symptoms ranged from 1-15 (median 5) years; 15 patients had recurrent disease. Before the operation, perforating branches of the four pairs of lateral sacral arteries were identified with a Doppler audioscope. After complete excision of the sinus cavity and adequate undermining of the skin, bilateral adipofascial flaps were raised in order to realise a Yin-Yang pattern, with the lateral sacral artery perforators at the base of each flap. Complementary flaps were then transposed into the defect and inset to completely obliterate dead space. Skin was closed primarily in two layers. The median (range) defect size after total excision of the sinus cavity was 38 (19-60) cm2. All flaps survived. There was no wound infection or dehiscense. Median (range) follow-up was 26 (6-52) months. No recurrences were observed. Extensive scarring or asymmetry in the gluteal prominences was not observed. Transient paraesthesia over the flap donor region occurred in 14 cases (16%) and resolved completely within 6 months. The bilateral adipofascial transpositional flap method is an alternative to previously described treatment options in pilonidal sinus surgery. It is a safe, reliable, and easily applicable method, which provides cosmetically acceptable coverage of pilonidal sinus defects of moderate size.

Psychological adjustment, maternal distress, and family functioning in children with obstetrical brachial plexus palsy.

PURPOSE: To examine emotional and behavioral characteristics of children with obstetrical brachial plexus palsy (OBPP), psychological distress of their mothers and their family functioning, and compare them with healthy peers. METHODS: Participants included 42 children with OBPP (22 boys, 20 girls; age range, 4-16 y; mean, 7 y 0 mo; SD, 3 y 3 mo) and 43 healthy controls (24 boys, 19 girls; age range, 4-15 y; mean, 8 y 0 m; SD, 3 y 0 mo). Childhood Behavior Checklist, Symptom Checklist 90, and Family Assessment Device were filled in by the mothers. RESULTS: Participants with OBPP displayed higher problem scores than the comparison children in most of the domains, including internalizing and externalizing problems. Maternal distress was higher in the OBPP group, and few differences in family functioning were noted. Maternal distress and having the diagnosis of OBPP were the strongest predictors of children's total problem scores and explained 26% of the variance when the effect of age, sex, and family functioning were controlled. CONCLUSIONS: Children with OBPP and their mothers are at increased risk for a variety of psychological problems. Professionals should be aware of these children's and their caregivers' psychological adjustment and refer them for further psychological support when needed. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

A misplaced lncRNA causes brachydactyly in humans.

Translocations are chromosomal rearrangements that are frequently associated with a variety of disease states and developmental disorders. We identified 2 families with brachydactyly type E (BDE) resulting from different translocations affecting chromosome 12p. Both translocations caused downregulation of the parathyroid hormone-like hormone (PTHLH) gene by disrupting the cis-regulatory landscape. Using chromosome conformation capturing, we identified a regulator on chromosome 12q that interacts in cis with PTHLH over a 24.4-megabase distance and in trans with the sex-determining region Y-box 9 (SOX9) gene on chromosome 17q. The element also harbored a long noncoding RNA (lncRNA). Silencing of the lncRNA, PTHLH, or SOX9 revealed a feedback mechanism involving an expression-dependent network in humans. In the BDE patients, the human lncRNA was upregulated by the disrupted chromosomal association. Moreover, the lncRNA occupancy at the PTHLH locus was reduced. Our results document what we believe to be a novel in cis- and in trans-acting DNA and lncRNA regulatory feedback element that is reciprocally regulated by coding genes. Furthermore, our findings provide a systematic and combinatorial view of how enhancers encoding lncRNAs may affect gene expression in normal development.