A recurrent homozygous LMNA missense variant p.Thr528Met causes atypical progeroid syndrome characterized by mandibuloacral dysostosis, severe muscular dystrophy, and skeletal deformities.

Atypical progeroid syndromes (APS) are premature aging syndromes caused by pathogenic LMNA missense variants, associated with unaltered expression levels of lamins A and C, without accumulation of wild-type or deleted prelamin A isoforms, as observed in Hutchinson-Gilford progeria syndrome (HGPS) or HGPS-like syndromes. A specific LMNA missense variant, (p.Thr528Met), was previously identified in a compound heterozygous state in patients affected by APS and severe familial partial lipodystrophy, whereas heterozygosity was recently identified in patients affected by Type 2 familial partial lipodystrophy. Here, we report four unrelated boys harboring homozygosity for the p.Thr528Met, variant who presented with strikingly homogeneous APS clinical features, including osteolysis of mandibles, distal clavicles and phalanges, congenital muscular dystrophy with elevated creatine kinase levels, and major skeletal deformities. Immunofluorescence analyses of patient-derived primary fibroblasts showed a high percentage of dysmorphic nuclei with nuclear blebs and typical honeycomb patterns devoid of lamin B1. Interestingly, in some protrusions emerin or LAP2α formed aberrant aggregates, suggesting pathophysiology-associated clues. These four cases further confirm that a specific LMNA variant can lead to the development of strikingly homogeneous clinical phenotypes, in these particular cases a premature aging phenotype with major musculoskeletal involvement linked to the homozygous p.Thr528Met variant.

Homozygous deletion of MYADML2 in cranial asymmetry, reduced bone maturation, multiple dislocations, lumbar lordosis, and prominent clavicles.

A null mutation in a patient can facilitate phenotype assignment and uncovers the function of that specific gene. We present five sibs of a consanguineous Pakistani family afflicted with a new syndrome with an unusual combination of skeletal anomalies including cranial asymmetry, fused sagittal sutures deviating from the medial axis, mandibular prognathia, maxillary hypoplasia, misaligned and crowded teeth, delayed bone age, multiple dislocations, hypoplastic and malpositioned patellae, humeral intracondylar fissures, scapular dyskinesis, long limbs, lumbar lordosis, protruding chest, prominent clavicles, short 5th digital rays, and ventral transverse digital creases plus features of cutis laxa. We mapped the disease gene locus to a 3.62-Mb region at 17q25.3 and identified a homozygous deletion of maximal 7.3 kb deduced to totally inactivate MYADML2 and downstream gene PYCR1, biallelic variants in which cause autosomal recessive cutis laxa (ARCL). All five affected sibs had the most common features of ARCL but not many of the less common ones. We attributed the anomalies not typical for ARCL to MYADML2 deficit, because no other genetic defect possibly a candidate to underlie the skeletal phenotype was found. MYADML2 is a gene of unknown function, has not been studied, and has not been associated with disease. Our findings present a possible phenotype for MYADML2 deficit that includes impaired bone patterning and maturation, definitely show that the gene is not essential for survival, and provide a start point for future studies on the function of MYADML2 protein. Detection of new patients is needed to confirm and delineate MYADML2-deficiency phenotype.

Differences in non-enzymatic glycation products in human dentine and clavicle: changes with aging.

In recent decades, several methods based on biochemical and molecular changes caused by aging have been proposed to improve the accuracy of forensic age estimation. The present study aimed to measure changes in furosine and pentosidine, two markers of non-enzymatic glycation of proteins (NEGs), in human dentine and clavicle with aging, and to identify possible differences between turnover rates in different mineralized tissues. Furosine and pentosidine were quantified in 32 dentine samples from living donors between 14 and 80 years of age, and in a second group of samples consisting of a tooth and a piece of clavicle collected from the same cadaver (15 individuals aged 18 to 85 years). Furosine concentration was much higher than pentosidine concentration in the same tissue, although they were strongly correlated in both dentine and bone. A close relationship between furosine and/or pentosidine content and chronological age was found in both tissues (r > 0.93). Moreover, age estimation was more accurate when furosine or pentosidine content was determined in dentine, with specificity values for the tests higher than 82% in all age groups. In clavicle, furosine concentration and pentosidine concentration were much lower (2.6-fold and 3.1-fold, respectively) than in dentine from the same individuals. In conclusion, although the results show strong correlations between chronological age and furosine or pentosidine concentrations determined in mineralized tissues, there is still a need for further research with larger data sets, including patients with diabetes.

Supraclavicular Brown Adipose Tissue 18F-FDG Uptake and Cardiovascular Disease.

UNLABELLED: Preclinical data suggest a negative correlation between brown adipose tissue (BAT) and the degree of coronary atherosclerosis. We sought to evaluate the relationship between (18)F-FDG uptake in supraclavicular BAT in relation to arterial inflammation and subsequent cardiovascular disease (CVD) events in humans. METHODS: Individuals who underwent (18)F-FDG PET/CT for clinical indications but who did not have either cancer or known atherosclerotic disease at the time of imaging were included. A radiologist masked to clinical data measured (18)F-FDG uptake within BAT (in the supraclavicular region) as well as in subcutaneous adipose tissues. Tissue density was evaluated using CT (Hounsfield units). Arterial inflammation was assessed by measuring arterial (18)F-FDG uptake and calculating target-to-background ratio. CVD events were independently adjudicated by masked cardiologists. Thereafter, the relationship between BAT activity and CVD events was evaluated. RESULTS: A total of 443 patients (age, 55 y [44-66 y]; 44% men; body mass index [BMI], 26 [range, 23-31]) were included, and 30 patients experienced a cardiovascular event during a median follow-up of 4 y. BAT activity negatively correlated with arterial inflammation (r = -0.178, P < 0.01), a relationship that persisted after correcting for age and BMI (r = -0.147, P < 0.01). When either high sensitivity or high accuracy thresholds (from receiver-operating curve analyses) were used to define elevated BAT, high BAT was associated with a reduced risk of CVD events (P = 0.048), even after correcting for age (P = 0.037). CONCLUSION: Our results suggest that increased supraclavicular BAT activity is inversely associated with arterial inflammation, independently of age and BMI. Additionally, increased BAT may be associated with fewer cardiovascular events.

Analgesia en el politraumatizado obeso. Utilidad de la ketamina intravenosa fuera de quirófano / Analgesia options for the morbidity obese with multiple trauma. Role of intravenous ketamine outside the operating theatre

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Infraclavicular sensor site: a new promising site for transcutaneous capnography.

BACKGROUND: Transcutaneous measurement of carbon dioxide is routinely done at the earlobe site. In patients receiving non invasive ventilation or in the intensive care setting with necklines, an alternate measurement site would be useful. We started to use the infraclavicular site for transcutaneous measurements of carbon dioxide using a new digital sensor. AIM: Comparison of transcutaneous carbon dioxide with arterial carbon dioxide at the infraclavicular site. METHODS: We retrospectively compared transcutaneous carbon dioxide at the infraclavicular site with arterial carbon dioxide in 50 samples. The Sentec Digital Monitoring System (Sentec AG, Therwil, Switzerland) was used. The V-Sign digital sensor was placed on the infraclavicular site at the medial two third and one third point from the sternoclavicular joint and acromioclavicular joint. RESULTS: When comparing P(c)CO(2) with P(a)CO(2) values, the Bland-Altman analysis revealed a bias of 0.02 kPa (95% CI: [- 0.1; 0.14]) with a precision of 0.42 kPa. Linear regression analysis describes the relationship between the two methods. The slope of the linear model was 0.85 ± 0.04 and the intercept was 0.77 ± 0.21 (RSE = 0.37, R(2) = 0.91). CONCLUSION: The measurement of transcutaneous carbon dioxide at the infraclavicular site is feasible with a digital sensor and has a good correlation with the carbon dioxide values obtained from the arterial blood gas. The findings of the current study form the basis for further clinical studies for its regular application in clinical use.

A pathological fracture and a solitary mass in the right clavicle: an unusual first presentation of HCC and the role of immunohistochemistry.

Hepatocellular carcinoma (HCC) is an aggressive malignant tumor that occurs throughout the world. Μetastases from hepatocellular carcinoma (HCC) were generally considered to be rare in the past, because the carcinoma had an aggressive clinical course. In our era, has been reported that extra-hepatic metastases occur in 13.5%-41.7% of HCC patients and this is considered as terminal-stage cancer. The prognosis for patients at this stage continues to be poor due to limited effective treatment. The common sites of extrahepatic metastases in patients with HCC are the lungs, regional lymph nodes, kidney, bone marrow and adrenals. We present here an extremely infrequent case of a patient, without known liver disease, in which the presenting symptom was a pathological-in retrospect-fracture of his right clavicle which wasn't properly evaluated, until he presented a bulky mass in the region 6 months later. For our patient, the added diagnostic difficulty alongside the unknown liver disease, has been that the clavicular metastases was the first presentation of any metastatic disease, rather than the more common sites of HCC spread to adjacent lung or lymph nodes.

Biomechanical comparison of fixation techniques in midshaft clavicular fractures.

OBJECTIVES: The purpose of this study is to evaluate the biomechanical properties and the stability among a locking clavicle plate (LCP), a dynamic compression plate (DCP) and an external fixator (Ex-fix) in an unstable displaced clavicle fracture model under torsional and three-point bending loading. MATERIALS AND METHODS: Forty-eight human adult formalin-fixed clavicles were paired according to their bone mineral density homogeneously into three groups: LCP, DCP, and Ex-fix. Each specimen was osteotomized at the midshaft. Torsional and three-point bending forces were performed for 1000 cycles with stiffness recorded at 10 cycles (initial) and then at 100-cycle intervals thereafter. Initial stiffness, failure loads, and the percentage of initial stiffness at the various intervals were compared using analysis of variance. RESULTS: The mean initial stiffness values (Nmm/deg) for torsion were 703.2 (LCP), 448.1 (DCP), and 365.2 (Ex-fix). The mean failure moments (Nmm) for torsion were 7671.7 (LCP), 4370.3 (DCP), and 2999.7 (Ex-fix). The mean initial stiffness (Nmm) for bending were 32.6 (LCP), 23.4 (DCP), and 20.6 (Ex-fix). The mean failure loads (N) for bending were 213.2 (LCP), 131.1 (DCP), and 102.7 (Ex-fix). For both torsion and bending, an overall significant difference among the three constructs in terms of failure loads and also a significant difference between the locking plate and the other two models only in terms of initial stiffness was seen. For torsion and bending, at all cyclic intervals, there was a significant difference between the locking plate and the other two models. After 700 cycles, a significant difference was also detected between the DCP and Ex-fix in torsion, but no difference was found between these groups at any cyclic interval in bending. CONCLUSIONS: The locking plate is significantly more stable than DCP and Ex-fix under torsional and bending cyclic loading in a displaced fracture clavicle model.

A Runx2 threshold for the cleidocranial dysplasia phenotype.

Cleidocranial dysplasia (CCD) in humans is an autosomal-dominant skeletal disease that results from mutations in the bone-specific transcription factor RUNX2 (CBFA1/AML3). However, distinct RUNX2 mutations in CCD do not correlate with the severity of the disease. Here we generated a new mouse model with a hypomorphic Runx2 mutant allele (Runx2(neo7)), in which only part of the transcript is processed to full-length (wild-type) Runx2 mRNA. Homozygous Runx2(neo7/neo7) mice express a reduced level of wild-type Runx2 mRNA (55-70%) and protein. This mouse model allowed us to establish the minimal requirement of functional Runx2 for normal bone development. Runx2(neo7/neo7) mice have grossly normal skeletons with no abnormalities observed in the growth plate, but do exhibit developmental defects in calvaria and clavicles that persist through post-natal growth. Clavicle defects are caused by disrupted endochondral bone formation during embryogenesis. These hypomorphic mice have altered calvarial bone volume, as observed by histology and microCT imaging, and decreased expression of osteoblast marker genes. The bone phenotype of the heterozygous mice, which have 79-84% of wild-type Runx2 mRNA, is normal. These results show there is a critical gene dosage requirement of functional Runx2 for the formation of intramembranous bone tissues during embryogenesis. A decrease to 70% of wild-type Runx2 levels results in the CCD syndrome, whereas levels >79% produce a normal skeleton. Our findings suggest that the range of bone phenotypes in CCD patients is attributable to quantitative reduction in the functional activity of RUNX2.