Central nervous system manifestations of LRBA deficiency: case report of two siblings and literature review.

BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency disease (PID) characterized by a regulatory T cell defect resulting in immune dysregulation and autoimmunity. We present two siblings born to consanguineous parents of North African descent with LRBA deficiency and central nervous system (CNS) manifestations. As no concise overview of these manifestations is available in literature, we compared our patient's presentation with a reviewed synthesis of the available literature. CASE PRESENTATIONS: The younger brother presented with enteropathy at age 1.5 years, and subsequently developed Evans syndrome and diabetes mellitus. These autoimmune manifestations led to the genetic diagnosis of LRBA deficiency through whole exome sequencing with PID gene panel. At 11 years old, he had two tonic-clonic seizures. Brain MRI showed multiple FLAIR-hyperintense lesions and a T2-hyperintense lesion of the cervical medulla.  His sister presented with immune cytopenia at age 9 years, and developed diffuse lymphadenopathy and interstitial lung disease. Genetic testing confirmed the same mutation as her brother. At age 13 years, a brain MRI showed multiple T2-FLAIR-hyperintense lesions. She received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) 3 months later. Follow-up MRI showed regression of these lesions. CONCLUSIONS: Neurological disease is documented in up to 25% of patients with LRBA deficiency. Manifestations range from cerebral granulomas to acute disseminating encephalomyelitis, but detailed descriptions of neurological and imaging phenotypes are lacking. LRBA deficiency amongst other PIDs should be part of the differential diagnosis in patients with inflammatory brain lesions. We strongly advocate for a more detailed description of CNS manifestations in patients with LRBA deficiency, when possible with MR imaging. This will aid clinical decision concerning both anti-infectious and anti-inflammatory therapy and in considering the indication for allo-HSCT.

Postoperative pain after ultrasonically and laser-activated irrigation during root canal treatment: a randomized clinical trial.

AIM: To compare the intensity of postoperative pain after primary root canal treatment of asymptomatic teeth when using ultrasonically (UAI) or laser-activated irrigation (LAI). METHODOLOGY: In this superiority randomized clinical trial (ClinicalTrials.gov ID: NCT03981237) with parallel design, fifty-six patients with an asymptomatic tooth in need of primary root canal treatment were enrolled. After chemo-mechanical canal preparation using rotary instruments and NaOCl irrigation, teeth were randomly assigned to two groups and patients were blinded to the final irrigation protocol. In the UAI group (n = 28), 60s activation with an Irrisafe tip was done per canal. In the LAI group (n = 28), NaOCl was activated with a pulsed Er:YAG (2940 nm) laser, equipped with a conical tip, with settings of 50 µs, 20 mJ at 15 Hz for 60 s. Patients recorded their pain intensity 6, 24, 48 and 72 h after treatment on a 100 mm visual analogue scale (VAS), as well as their analgesic consumption. Pain levels and incidence were compared across groups using the Mann-Whitney U-test and chi-square test. RESULTS: Overall, mean postoperative pain intensity was low, with the majority of patients having no or minimal pain 24 h postoperatively. At 6 h postoperatively, pain intensity and incidence were significantly higher in the UAI group compared to the LAI group (P < 0.05). For the other time intervals, no significant differences in postoperative pain incidence or intensity were found. The frequency of analgesic intake did not differ significantly between the two groups. Neither of the activation methods resulted in any adverse effects. CONCLUSIONS: Ultrasonically and laser-activated irrigation resulted in low and comparable levels of postoperative pain in asymptomatic patients receiving primary root canal treatment.

Endodontic performance by Flemish dentists: have they evolved?

AIM: To gather information on aspects of endodontic practice and referral behaviour by Flemish (Dutch-speaking Belgian) dentists and to compare the results with an earlier investigation. METHODOLOGY: A postal questionnaire was distributed to 4468 active Flemish dentists. It consisted of multiple-choice questions on endodontic practice and endodontic referral need. Basic information on age, gender, year of qualification and clinical specialty was also obtained. The questionnaire was free of charge to return. Data were imported in a database, subjected to descriptive and analytical statistics and compared to those of an earlier, comparable survey. RESULTS: The response rate was 18.5%. Of all respondents, 95% were general practitioners. More than half (56%) of the respondents never or seldom used rubber dam during endodontic treatment. The use of sodium hypochlorite as an irrigant was well established (80% of respondents using it), whereas the use of EDTA was limited. Female respondents were more likely to refer to an endodontist than male (70 versus 49%). Referrals for treatment of root canal obstruction (48%), perforations and root resorption (42%) and retreatment (39%) were rated 'very important'. Younger respondents more frequently made use of magnification, rotary instruments and rubber dam. Activation of irrigants was incorporated by a small number of respondents (50% never, 12.6% seldom). Cold lateral condensation was used by most GDPs (35.3% always, 19.5% frequently). CONCLUSIONS: Endodontic practice of general dentists in Flanders did not always comply with quality guidelines. However, when comparing the present data with those of a previous study, an obvious trend towards a more present-day treatment protocol is noticeable, as well as an increased appeal for endodontic referral.

Disruption of olfactory receptor neuron patterning in Scutoid mutant Drosophila.

Olfactory neurons show an extreme diversity of cell types with each cell usually expressing one member from a large family of 60 Odorant receptor (Or) genes in Drosophila. Little is known about the developmental processes and transcription factors that generate this stereotyped pattern of cellular diversity. Here we investigate the molecular and cellular basis of defects in olfactory system function in an unusual dominant mutant, Scutoid. We show that the defects map to olfactory neurons innervating a specific morphological class of sensilla on the antenna, large basiconics. Molecular analysis indicates defects in neurons expressing specific classes of receptor genes that map to large basiconic sensilla. Previous studies have shown that in Scutoid mutants the coding region of the transcriptional repressor snail is translocated near the no-ocelli promoter, leading to misexpression of snail in the developing eye-antenna disc. We show that ectopic expression of snail in developing olfactory neurons leads to severe defects in neurons of the antennal large basiconics, supporting the model that the dominant olfactory phenotype in Scutoid is caused by misexpression of snail.

Long-term sealing ability of Resilon apical root-end fillings.

AIM: To evaluate ex vivo the long-term sealing ability of the SE Resilon Epiphany system as an apical root-end filling material. METHODOLOGY: A total of 60 standardized horizontal bovine root sections were divided into three groups filled with either gutta-percha with AH 26, tooth-coloured mineral trioxide aggregate (MTA) or Resilon pellets with Epiphany SE, and submitted to capillary flow porometry at 48 h, 1 and 6 months to assess the minimum, mean flow and maximum pore diameters. Results of the different materials and results by material and time were analysed statistically using nonparametric tests; the level of significance was set at 0.05. RESULTS: Resilon had smaller pore diameters than gutta-percha and MTA at 48 h and smaller mean flow and maximum pore diameters than gutta-percha and MTA at 1 month. At 6 months Resilon had larger minimum pore diameters than gutta-percha. Although not always statistically significant, the minimum, mean flow and maximum pore diameters of gutta-percha and MTA diminished with time. This was not the case for Resilon, where the same parameters increased. CONCLUSIONS: All materials leaked at all times. Resilon performed better than gutta-percha and MTA in the short-term, but the seal of MTA and gutta-percha improved over time whereas the seal of Resilon deteriorated. It is critical to evaluate the performance of materials in the long-term contrary to most studies which are short-term.

Author Correction: A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation.

Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.

Odor coding in the Drosophila antenna.

Odor coding in the Drosophila antenna is examined by a functional analysis of individual olfactory receptor neurons (ORNs) in vivo. Sixteen distinct classes of ORNs, each with a unique response spectrum to a panel of 47 diverse odors, are identified by extracellular recordings. ORNs exhibit multiple modes of response dynamics: an individual neuron can show either excitatory or inhibitory responses, and can exhibit different modes of termination kinetics, when stimulated with different odors. The 16 ORN classes are combined in stereotyped configurations within seven functional types of basiconic sensilla. One sensillum type contains four ORNs and the others contain two neurons, combined according to a strict pairing rule. We provide a functional map of ORNs, showing that each ORN class is restricted to a particular spatial domain on the antennal surface.

The odor specificities of a subset of olfactory receptor neurons are governed by Acj6, a POU-domain transcription factor.

Little is known about how the odor specificities of olfactory neurons are generated, a process essential to olfactory coding. We have found that neuronal identity relies on the abnormal chemosensory jump 6 (acj6) gene, originally identified by a defect in olfactory behavior. Physiological analysis of individual olfactory neurons shows that in acj6 mutants, a subset of neurons acquires a different odorant response profile. Certain other neurons do not respond to any tested odors in acj6. Molecular analysis of acj6 shows that it encodes a POU-domain transcription factor expressed in olfactory neurons. Our data suggest that the odor response spectrum of an olfactory neuron, and perhaps the choice of receptor genes, is determined through a process requiring the action of Acj6.

Odor coding in a model olfactory organ: the Drosophila maxillary palp.

Odor coding relies on the activity of different classes of receptor neurons, each with distinct response characteristics. We have examined odor coding in a model olfactory organ, the maxillary palp of Drosophila. This organ contains only 120 olfactory receptor neurons, compartmentalized in sensory hairs called sensilla, and provides an opportunity to characterize all neurons in an entire olfactory organ. Extensive extracellular recordings from single sensilla reveal that the neurons fall into six functional classes. Each of the 60 sensilla houses two neurons, which observe a pairing rule: each sensillum combines neurons of two particular classes, thereby yielding three sensillum types. The sensillum types are intermingled on the surface of the palp, but their distribution is not random. The neurons exhibit diverse response characteristics, providing the basis for an olfactory code. A particular odor can excite one neuron and inhibit another, and a particular neuron can be excited by one odor and inhibited by another. Some excitatory responses continue beyond the end of odor delivery, but responses to most odors terminate abruptly after the end of odor delivery, with some followed by a period of poststimulus quiescence. The specificity of odor response is examined in detail for the neurons of one sensillum, which were found to differ in their relative responses to a homologous series of esters. Adaptation and cross-adaptation are documented, and cross-adaptation experiments demonstrate that the two neurons within one type of sensillum can function independently. The analysis of all neuronal types in this model olfactory organ is discussed in terms of its functional organization and the mechanisms by which it encodes olfactory information.

Dental and oral complications of lip and tongue piercings.

Piercing of the tongue and perioral regions is an increasingly popular expression of body art, with more patients coming in for a routine check-up with tongue and/or lip piercings. Several complications of oral piercing have been reported, some of which are life-threatening. In the present clinical survey the prevalence of both tongue and lip piercing complications in oral health was assessed in a group of 50 patients. The most common dental problem registered was chipping of the teeth, especially in association with tongue piercing. Gingival recession was seen as a result of lip piercing with studs. Post-procedural complications included oedema, haemorrhage and infection. Therefore, dentists and oral and maxillofacial surgeons should be given more authority to advise patients with oral and facial piercings or those who plan to acquire this type of body art.

Prolonged QT interval: a tricky diagnosis?

Prolonged heart-rate adjusted QT intervals on the electrocardiogram (ECG) are associated with an increased risk for coronary heart disease and sudden death. However, the diagnosis of the prolonged QT interval is hampered by lack of standards. We studied variations in the prevalence of prolonged QT, based on different common definitions, in a large nonhospitalized population, and compared our results with other studies applying the same definitions. The study population consisted of 2,200 men and 3,366 women participants of the Rotterdam Study, > or =55 years old. The QT interval was computed by our Modular ECG Analysis System (MEANS). Three different formulas to adjust QT for heart rate were used: Bazett's formula (QTc), a linear regression equation (QTlr), and the QT index (QTI). Prolonged QT occurred frequently in both men and women, and its prevalence increased with age. Women had longer heart-rate adjusted QT intervals than men (mean QTc 433 ms vs 422 ms), and mean values for QTlr were lower than for QTc (mean QTlr 422 ms in women and 412 ms in men). Prevalence was highest for prolonged QTlr (31% in men and 26% in women) and lowest for prolonged QTI (6% in men and 9% in women). Comparison with other studies applying the same correction formulas showed large discrepancies in prevalence estimates of prolonged QTc and QTlr, and to a lesser degree of prolonged QTI, possibly due to differences in measurement techniques. Future research is needed to relate QT interval to prognosis, to obtain measurement technique specific reference values of heart-rate adjusted QT measurements, and to obtain age- and sex-specific threshold values for prolonged QT. Such data are needed to use the QT interval with confidence.

Diagnostic interpretation of electrocardiograms in population-based research: computer program research physicians, or cardiologists?

We assessed the performance of diagnostic electrocardiogram (ECG) interpretation by the computer program MEANS and by research physicians, compared to cardiologists, in a physician-based study. To establish a strategy for ECG interpretation in health surveys, we also studied the diagnostic capacity of three scenarios: use of the computer program alone (A), computer program and cardiologist (B), and computer program, research physician, and cardiologist (C). A stratified random sample of 381 ECGs was drawn from ECGs collected in the Rotterdam Study (n = 3057), which were interpreted both by a trained research physician using a form for structured clinical evaluation and by MEANS. All ECGs were interpreted independently by two cardiologists; if they disagreed (n = 175) the ECG was judged by a third cardiologist. Five ECG diagnoses were considered: anterior and inferior myocardial infarction (MI), left and right bundle branch block (LBBB and RBBB), and left ventricular hypertrophy (LVH). Overall, sensitivities and specificities of MEANS and the research physicians were high. The sensitivity of MEANS ranged from 73.8% to 92.9% and of the research physician ranged from 71.8% to 96.9%. The specificity of MEANS ranged from 97.5% to 99.8% and of the research physician from 96.3% to 99.6%. To diagnose LVH, LBBB, and RBBB, use of the computer program alone gives satisfactory results. Preferably, all positive findings of anterior and inferior MI by the program should be verified by a cardiologist. We conclude that diagnostic ECG interpretation by computer can be very helpful in population-based research, being at least as good as ECG interpretation by a trained research physician, but much more efficient and therefore less expensive.

Factors associated with switching from oral hypoglycaemic agents to insulin therapy.

BACKGROUND: The aim of our study was to determine which factors are associated with switching from oral hypoglycaemic agents to insulin therapy in patients with type 2 diabetes mellitus in general practice. METHODS: Longitudinal, observational study in a Dutch general healthcare centre. All pharmacologically treated patients with type 2 diabetes mellitus were included (n = 152). Comorbidity, laboratory results and medication use were obtained from the general practitioners' files. RESULTS: A total of 31 (20.4%) patients switched from oral hypoglycaemic agents to insulin therapy; they were significantly younger at the onset of diabetes, 50.5 versus 57.7 years. Fasting blood glucose levels and HbA(1c) values were significantly higher after the switch compared with patients on oral treatment, 10.0 mmol/l versus 8.4 mmol/l and 8.8% versus 7.9%, respectively. Concerning comorbidity, they suffered more frequently from acute myocardial infarction, lipid disorders, depression, retinopathy and atrial fibrillation. Cardiovascular disease in general was more often present in patients who switched over to insulin, 77.4% versus 52.9% (OR 3.1; CI 1.2-7.6). CONCLUSIONS: Patients who switch over to insulin therapy are younger at diagnosis, suffer from more health problems besides diabetes, especially cardiovascular disease, and have worse metabolic control, compared with users of oral hypoglycaemic agents.

Hydrolysis of clonazepam, flunitrazepam and nitrazepam by hydrochloric acid. Identification of some additional products.

Several by-products in the hydrochloric acid hydrolysis of clonazepam, flunitrazepam and nitrazepam are isolated by a combination of TLC and HPLC. With mass and NMR spectroscopic methods the structures of the by-products are established. Some indications are given for possible modes of formation of the by-products.

[Cardiovascular risk factors. II. Signs of vascular damage: practical implications]. / Cardiovasculaire risicofactoren. II. Tekenen van vaatschade: praktische implicaties.

In recent years, an increasing amount of information has become available on new indicators of cardiovascular damage, their determinants and the value of these indicators in the prediction of the development of cardiovascular disease. These indicators include carotid intima-media thickness, ECG characteristics, endothelial function and the measurement of coronary calcium. These indicators are currently used predominantly in cardiovascular disease research. At present, only limited information is available as to whether these indicators are useful in clinical practice for estimating the absolute risk of cardiovascular disease in an individual. The relative value of these newer indicators compared to the routinely collected risk factor information such as medical history, lifestyle, anthropometric variables, blood pressure and lipids is also not yet well established. The recent Dutch guidelines for the initiation of treatment with blood pressure lowering and lipid lowering drugs as a function of the absolute risk of cardiovascular disease within 10 years for the individual patient point toward the urgent necessity for research in the area of new risk indicators of vascular damage.

[Hydrolysis of lorazepam with hydrochloric acid. Qualitative and quantitative analysis of byproducts of hydrolysis]. / Hydrolyse des Lorazepams mit Salzsäure. Qualitative und quantitative Analyse von Nebenprodukten der Hydrolyse.

Results of the identification of some additional products in the hydrochloric acid hydrolysis of lorazepam are reported, together with some quantitative results about the hydrolysis products under varying circumstances. It appeared that the amount of byproducts was reduced by applying hydrochloric acid of good quality and further on hydrolysis time had to be short.

[Cavity preparation using an Er:YAG laser in the adult dentition]. / La préparation de cavités à l'aide du laser Er:YAG dans la denture adulte.

Many lasers (i.e., different wavelengths) are available today for clinical applications. Not all lasers are to be used for cavity preparation and removal of carious tissues. Erbiumlasers (Er:YAG and Er,Cr:YSGG) are suitable for these purposes (the wavelengths coincide with the highest absorption peaks of water and hydroxyapatite). The advantages during cavity preparation and caries removal are smear layer free cavity walls, selective and localised removal of tooth substance, a restricted need or the absence of anaesthesia, and cavity walls with a higher acid resistance resulting in a better protection against secondary decay. Possible side effects of erbium lasers with water cooling and used with respect for correct power setting are minimal and can be compared with those of rotary instruments. Erbium laser tooth preparation is now one of the options in the minimal invasive approach. The needs for acid etching has been debated for long. At present it has become clear that acid etching is mandatory to obtain a good adhesion and retention with resin composites.

Odor detection in insects: volatile codes.

Insect olfactory systems present models to study interactions between animal genomes and the environment. They have evolved for fast processing of specific odorant blends and for general chemical monitoring. Here, we review molecular and physiological mechanisms in the context of the ecology of chemical signals. Different classes of olfactory receptor neurons (ORNs) detect volatile chemicals with various degrees of specialization. Their sensitivities are determined by an insect-specific family of receptor genes along with other accessory proteins. Whereas moth pheromones are detected by highly specialized neurons, many insects share sensitivities to chemical signals from microbial processes and plant secondary metabolism. We promote a more integrated research approach that links molecular physiology of receptor neurons to the ecology of odorants.