Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies

The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1–0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1–2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.     

Perceiving nonverbal behavior: Neural correlates of processing movement fluency and contingency in dyadic interactions

Despite the fact that nonverbal dyadic social interactions are abundant in the environment, the neural mechanisms underlying their processing are not yet fully understood. Research in the field of social neuroscience has suggested that two neural networks appear to be involved in social understanding: (1) the action observation network (AON) and (2) the social neural network (SNN). The aim of this study was to determine the differential contributions of the AON and the SNN to the processing of nonverbal behavior as observed in dyadic social interactions. To this end, we used short computer animation sequences displaying dyadic social interactions between two virtual characters and systematically manipulated two key features of movement activity, which are known to influence the perception of meaning in nonverbal stimuli: (1) movement fluency and (2) contingency of movement patterns. A group of 21 male participants rated the “naturalness” of the observed scenes on a four‐point scale while undergoing fMRI. Behavioral results showed that both fluency and contingency significantly influenced the “naturalness” experience of the presented animations. Neurally, the AON was preferentially engaged when processing contingent movement patterns, but did not discriminate between different degrees of movement fluency. In contrast, regions of the SNN were engaged more strongly when observing dyads with disturbed movement fluency. In conclusion, while the AON is involved in the general processing of contingent social actions, irrespective of their kinematic properties, the SNN is preferentially recruited when atypical kinematic properties prompt inferences about the agents' intentions. Hum Brain Mapp 35:1362–1378, 2014. © 2013 Wiley Periodicals, Inc.     

Anterior loop of the mental nerve: a morphological and radiographic study

Treatment planning for dental implant patients is often complicated by the unknown extent of the anterior loop of the mental neurovascular bundle. The aim of this study was to determine the correlation between the visual interpretation of the panoramic radiographs and the anatomical dissection findings in a cadaveric sample. Panoramic radiographs of the 22 randomly selected coronally sectioned human head specimens were taken using the Scanora (Soridex, Orinon Corporation Ltd, Helsinki, Finland) radiographic unit jaw panorama (Programme 001, magnification 1.3) and dental panorama (Programme 003, magnification 1.7) and interpreted by two calibrated observers. Bilateral anatomical dissection was then performed on all specimens. The anterior loop of the mental canal was only identified in six panoramic radiographs (27%) (range 0.5-3 mm). There was a significant positive correlation between both observers of the radiographs and between the two radiographic programmes used. Anatomical measurements of the anterior loop of the mental neurovascular bundle revealed its presence in eight dissected specimens (range 0.11-3.31 mm; mean 1.20, +/-0.90). Fifty percent of the radiographically observed anterior loops of the mental canal were misinterpreted by observers with both radiographic programmes and 62% of the anatomically identified loops were not observed radiographically. Clinicians should not rely on panoramic radiographs for identifying the anterior loop of the mental nerve during implant treatment planning. However, a safe guideline of 4 mm, from the most anterior point of the mental foramen, is recommended for implant treatment planning, on the basis of our anatomical findings.     

Distal implants to modify the Kennedy classification of a removable partial denture: a clinical report

Dental implants or precision attachments can be used to resolve the bilateral distal extension removable partial denture (RPD) dilemma. This report describes the fabrication of a mandibular implant-supported chromium-cobalt RPD with a combination of bilateral single molar implants and metal ceramic crowns using the principles of the channel-shoulder-pin system. The maxillary arch was restored with splinted metal crowns and a conventional RPD retained by extracoronal precision attachments.     

Vascular thoracic outlet syndrome

Abstract The surgical treatment of 30 cases of vascular thoracic outlet syndrome (TOS) in 25 patients is presented. Patients included 17 women and 8 men with average age of 26.1 years. The causes of compression were cervical rib (n = 16), soft tissue anomalies (n = 12), and scar tissue after clavicle fracture (n = 2). Ten subclavian artery aneurysms containing intraluminal thrombus as well as one subclavian artery occlusion were found. All such cases had multiple distal arterial embolization. Presenting features of cases with arterial TOS included: hand ischemia (n = 11), transient ischemic attack (TIA) (n = 1), and claudication or vasomotor phenomena during the arm hyperabduction (n = 11). Two patients with venous TOS developed hand edema during arm hyperabduction, and five other patients had axillary-subclavian venous thrombosis. In all cases decompressive procedures using a combined supraclavicular and infraclavicular approach were performed. Decompression was achieved by cervical rib excision (n = 12), combined cervical and first rib excision (n = 4), and first rib excision (n = 14). In all cases division of all soft tissue elements was also accomplished. Associated vascular procedures included resection and replacement of 10 subclavian artery aneurysms, one subclavian-axillary and one axillary-brachial bypass, as well as nine brachial embolectomies. All five cases with axillary-subclavian vein thrombosis before decompression were treated with anticoagulant therapy. The mean follow-up period was 3 years and 2 months (range 1 to 6 years). Two pleural entry injuries and two transient brachial plexus injuries were noted. All reconstructed arteries were patent during the follow-up period. Complete resolution of symptoms with a return to full activity was noticed in all cases with arterial TOS and in two cases with venous TOS without axillary-subclavian vein thrombosis. In cases with axillary-subclavian vein thrombosis relief of symptoms was mild, and there were limitations on daily activity. Vascular TOS is seen less frequently than the neurogenic form; however, in most cases it requires surgical treatment. We prefer a combined supraclavicular and infraclavicular approach because it offers complete exposure of the subclavian artery, cervical and first ribs, and all soft tissue anomalies. Electronic Publication     

Genotype phenotype correlation in a pediatric population with antithrombin deficiency

Inherited antithrombin (AT) deficiency is a rare autosomal dominant disorder, caused by mutations in the AT gene (SERPINC1). Considering that the genotype phenotype relationship in AT deficiency patients remains unclear, especially in pediatric patients, the aim of our study was to evaluate genotype phenotype correlation in a Serbian pediatric population. A retrospective cohort study included 19 children younger than 18 years, from 15 Serbian families, with newly diagnosed AT deficiency. In 21% of the recruited families, mutations affecting exon 4, 5, and 6 of the SERPINC1 gene that causes type I AT deficiency were detected. In the remaining families, the mutation in exon 2 causing type II HBS (AT Budapest 3) was found. Thrombosis events were observed in 1 (33%) of those with type I, 11 (85%) of those with AT Budapest 3 in the homozygous respectively, and 1(33%) in the heterozygous form. Recurrent thrombosis was observed only in AT Budapest 3 in the homozygous form, in 27% during initial treatment of the first thrombotic event. Abdominal venous thrombosis and arterial ischemic stroke, observed in almost half of the children from the group with AT Budapest 3 in the homozygous form, were unprovoked in all cases.

Conclusion: Type II HBS (AT Budapest 3) in the homozygous form is a strong risk factor for arterial and venous thrombosis in pediatric patients.

Arterial ischemic stroke in a child with beta-thalassemia trait and methylentetrahydrofolate reductase mutation

Genetic and acquired disorders that foster a procoagulable state represent risk factors for stroke in childhood. Although an increased incidence of thromboembolic complications has been reported in patients with thalassemia, severe cerebral thromboembolism has rarely been observed in patients with beta-thalassemia minor. This article describes a case study of a 1-year-old boy who presented with left-sided hemiparesis, seizures, microcytic anemia, and recent infection with reactive thrombocytosis. Ischemic infarction in the territory of the right middle cerebral artery was confirmed by magnetic resonance imaging and magnetic resonance angiography. Genetic tests showed that the patient was heterozygous for the beta(degrees) -thalassemia IVS-I-1 mutation and homozygous for the methylentetrahydrofolate reductase C677T mutation. Based on these findings, it was concluded that the synergistic effects of multiple, genetic, and acquired prothrombotic risk factors brought about the hypercoagulable state that resulted in overt stroke in a thalassemic patient in early childhood.     

Low frequency of NRAS and KRAS2 gene mutations in childhood myelodysplastic syndromes

In children, myelodysplastic syndromes (MDS) represent less then 10% of all hematological malignancies; consequently, molecular genetic studies dealing with this group of patients are scarce. We have analyzed 35 archival bone marrow samples of children with MDS for the presence of mutations in the first and second exons of the NRAS and KRAS2 genes. Mutations were detected with single-strand conformation polymorphism analysis in three patients. One patient harbored a mutation in the second exon of NRAS and two patients in the second exon of KRAS2. Sequencing was performed in two samples and novel mutations were found in both. One patient had a missense mutation in codon 45 of NRAS; the other had a silent mutation in codon 53 and a missense mutation in codon 55 of KRAS2.