Secondary biogenic amine deficiencies: genetic etiology,therapeutic interventions,and clinical effects

neurogenetics - Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that...     

The phosphatase PRL-3 affects intestinal homeostasis by altering the crypt cell composition

Expression of the phosphatase of regenerating liver-3 (PRL-3) is known to promote tumor growth in gastrointestinal adenocarcinomas, and the incidence of tumor formation upon inflammatory events correlates with PRL-3 levels in mouse models. These carcinomas and their onset are associated with the impairment of intestinal cell homeostasis, which is regulated by a balanced number of Paneth cells and Lgr5 expressing intestinal stem cells (Lgr5+ ISCs). Nevertheless, the consequences of PRL-3 overexpression on cellular homeostasis and ISC fitness in vivo are unexplored. Here, we employ a doxycycline-inducible PRL-3 mouse strain to show that aberrant PRL-3 expression within a non-cancerous background leads to the death of Lgr5+ ISCs and to Paneth cell expansion. A higher dose of PRL-3, resulting from homozygous expression, led to mice dying early. A primary 3D intestinal culture model obtained from these mice confirmed the loss of Lgr5+ ISCs upon PRL-3 expression. The impaired intestinal organoid formation was rescued by a PRL inhibitor, providing a functional link to the observed phenotypes. These results demonstrate that elevated PRL-3 phosphatase activity in healthy intestinal epithelium impairs intestinal cell homeostasis, which correlates this cellular mechanism of tumor onset with PRL-3-mediated higher susceptibility to tumor formation upon inflammatory or mutational events.

Key messages

? Transgenic mice homozygous for PRL-3 overexpression die early.

? PRL-3 heterozygous mice display disrupted intestinal self-renewal capacity.

? PRL-3 overexpression alone does not induce tumorigenesis in the mouse intestine.

? PRL-3 activity leads to the death of Lgr5+ ISCs and Paneth cell expansion.

? Impairment of cell homeostasis correlates PRL-3 action with tumor onset mechanisms.

     

TBX3 and TBX5 duplication: A family with an atypical overlapping Holt-Oram/ulnar-mammary syndrome phenotype

Holt-Oram syndrome (HOS) is a rare, autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. A wide spectrum of TBX5 mutations have been reported previously, most resulting in a null allele leading to haploinsufficiency. TBX5 gene duplications have been previously reported in association with typical and atypical HOS phenotypes. Ulnar-Mammary syndrome (UMS) is a distinct rare, autosomal dominant condition caused by mutations in the TBX3 gene. TBX5 and TBX3 are physically linked in cis on human chromosome 12 and contiguous chromosome 12q24 deletions comprising both TBX5 and TBX3 genes have been previously reported but to our knowledge, duplications have never been described. We report on a large German family with at least 17 affected individuals over 6 generations bearing a duplication at 12q24.21 identified on array-CGH comprising both TBX5 and TBX3 genes. Affected patients are presenting with HOS and UMS symptoms, consisting of variable limb anomalies involving the radial and the ulnar rays and cardiac findings such as congenital heart defects, persistent arterial duct or aortic stenosis, and non-classical symptoms, such as supernumerary nipples and cardiomyopathy. Fluorescence in situ hybridisation confirmed a tandem duplication at the 12q24.21 locus. This is the first report of a contiguous TBX3/TBX5 duplication associated with HOS/UMS phenotype.     

Novel Mutations Including Deletions of the Entire OFD1 Gene in 30 Families with Type 1 Orofaciodigital Syndrome: A Study of the Extensive Clinical Variability

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X‐linked condition with lethality in males. Mutations in OFD1 also cause X‐linked Joubert syndrome (JBTS10) and Simpson–Golabi–Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X‐inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.     

Treatment after inadequate immediate replantation of accidentally extracted immature mandibular premolar during primary molar extraction

During extraction of the primary mandibular right second molar in an 11‐year‐old girl, the unerupted second premolar was accidentally extracted. Clinical and radiographic examination showed that the immediately replanted immature premolar was not oriented and positioned correctly. Four hours later, treatment consisted of manual extrusion of the permanent tooth bud, rotation, and gentle repositioning into its original position. Adequate replantation was confirmed by a post‐operative radiograph. After 2 years and 4 months, clinical examination revealed normal, healthy appearance of the replanted tooth, no sensitivity to percussion, no tenderness to palpation, and a slight response to a cold pulp sensibility test. A radiograph showed completely developed root with closed apical foramen, slightly irregular root morphology and shorter root length, complete obliteration of the pulp, and no signs of periapical pathosis.     

Are There Differences in Arteriovenous Fistulae Created for Hemodialysis between Nephrologists and Vascular Surgeons?

ObjectiveMany studies have reported insufficient support from surgical services, resulting in nephrologists creating arteriovenous fistulas in many centers. The aim of this study was to compare risk factors of arteriovenous fistula dysfunction in patients whose fistulas were created by nephrologists versus vascular surgeons.MethodsThis was a retrospective, analytical study of interventions by nephrologists and vascular surgeons during a period of 15 years. Out of a total of 1,048 fistulas, 764 (72.9%) were created by nephrologists patients, while vascular surgeons were responsible for 284 (27.1%) fistulae. Laboratory, demographic, and clinical parameters which might affect functioning of these arteriovenous fistulae were analyzed.ResultsPatients whose arteriovenous fistula was formed by nephrologists differed significantly from those created by vascular surgeons in relation to the preventive character of the arteriovenous fistula (p = 0.011), lumen of the vein (p < 0.001) and systolic blood pressure (p = 0.047). Multivariate logistic regression of arteriovenous fistula dysfunction showed that risk factors were female gender (odds ratio [OR] = 1.56, 95% CI 1.16–2.07), whether the fistulae were created by vascular surgeons or nephrologists (OR = 1.38; 95% CI 1.01–1.89) and the site of the arteriovenous fistula (OR = 0.64; 95% CI 0.48–0.85).ConclusionsArteriovenous fistulae created by vascular surgeons, female gender, and the location are risk factors of dysfunction.     

Impairment of Left Atrial Mechanics Is an Early Sign of Myocardial Involvement in Systemic Sclerosis

Background

Left ventricular (LV) diastolic dysfunction is common in systemic sclerosis (SSc). Less is known, however, about left atrial (LA) mechanics in this context. The aim of this study was to investigate the correlation between LV diastolic function and LA mechanics in SSc patients with the use of volumetric and 2-dimensional speckle tracking–derived strain techniques and to compare the results with those obtained in healthy subjects.

Periodontal Disease and its Association with Angiographically Verified Coronary Artery Disease

Purpose

The aim of this research was to investigate the association of chronic and aggressive periodontitis with the severity of coronary artery disease which was angiographically verified.

Material and methods

Subjects were selected among the hospitalized patients at the University Hospital Centre Zagreb who had coronary angiography done because of the chest pain. Thorough clinical examination included periodontal indices and clinical and socio-demographic characteristics of participants. Subjects were divided in two test groups, acute coronary syndrome (ACS) and stable coronary artery disease (CAD), and the control group with no significant CAD. Data were analyzed using Kruskal-Wallis and Pearson’s Chi-Square test.

Results

From 106 subjects, 66 (62.3%) were hospitalized for ACS, 22 (20.7%) had stable CAD and only 18 (17.0%) had no significant CAD. Only 26 (24.5%) out of 106 patients were never smokers (p<0.05). Chronic periodontitis was the most common finding with 68.2% in ACS group and 54.5% in stable CAD group, while healthy patients without periodontitis (72.6%) were dominant in the control group (p<0.001). Stable CAD group had the highest mean probing depth (PD) 3.92±1.16, gingival recession (GR) 1.34±0.78, clinical attachment level (CAL) 4.60±1.41 and bleeding on probing (BOP) 45.98±26.19 values, whereas ACS group had mean PD value of 3.77±0.91, GR 1.11±0.66, CAL 4.32±1.08 and BOP 41.30±22.09, and no significant CAD group had mean PD value of 3.27±0.97, GR 0.69±0.37, CAL 3.62±1.04 and BOP 26.39±13.92 (p<0.05).

Conclusion

Periodontitis was shown to be associated with angiographically verified coronary artery disease. Physical inactivity, poor oral hygiene and periodontal inflammation were observed in patients with ACS and stable CAD.Key words: Periodontitis, Periodontal Index, Cardiovascular Diseases, Coronary Artery Disease, Coronary Angiography