Genetic determinants of micronucleus formation in vivo.

Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.

Injury Risk Functions for the Midsized Male Wrist and Elbow as a Result of Behind Shield Blunt Trauma.

Ballistic shields protect users from a variety of threats, including projectiles. Shield back-face deformation (BFD) is the result of the shield deflecting or absorbing a projectile and deforming toward the user. Back-face deformation can result in localized blunt loading to the upper extremity, where the shield is supported by the user. Two vulnerable locations along the upper extremity were investigated-the wrist and elbow-on eight postmortem human subjects (PMHS) using a pneumatic impacting apparatus for investigating the fracture threshold as a result of behind shield blunt trauma (BSBT). Impacting parameters were established by subjecting an augmented WorldSID anthropomorphic test device (ATD) positioned behind a ballistic shield to ballistic impacts. These data were used to form the impact parameters applied to PMHS, where the wrist most frequently fractured at the distal radius and the elbow most frequently fractured at the radial head. The fracture threshold for the wrist was 5663±1386 N (mean±standard deviation), higher than the elbow at 4765±894 N (though not significantly, p = 0.15). The failure impact velocity for wrist impacts was 17.7±2.1 m/s, while for the elbow, the failure impact velocity was 19.5±0.9 m/s. An approximate 10% risk of fracture threshold was identified on the modified WorldSID ATD (no flesh analogue included) to inform future protective standards.

[Diagnosing neuropathic orofacial pain in the general dental practice]. / Diagnosticeren van neuropathische orofaciale pijn in de algemene tandartspraktijk.

Dental pain is a common reason for patients to visit the dentist. This type of pain is usually easy to diagnose and treat. However, diagnosing and treating other forms of orofacial pain remains complicated. One of the most challenging types of orofacial pain to diagnose and treat is neuropathic orofacial pain: pain resulting from damage to nerve tissue. Recognizing this type of pain in a timely manner can prevent unnecessary invasive dental treatments and disappointment for patients who seek help for this type of pain. There are relatively simple tools for dentists to distinguish neuropathic pain from other types of orofacial pain. The treatment of neuropathic pain is primarily focused on symptom relief through medication.

[Dental rehabilitation in a young patient with glycogen storage disease type 1B]. / Dentale rehabilitatie bij jonge patiënt met glycogeenstapelingsziekte type 1B.

A young woman, known to have glycogen storage disease type 1B (GSD1B) presents with severe periodontitis. GDS1B causes decreased hepatic and renal glucose production and in many cases neutropenia and neutrophil dysfunction leading to recurrent infections. It was decided to treat the patient by extraction of the most affected teeth and retention of the remaining teeth through periodontal treatment, both with antibiotic prophylaxis. After a follow-up period of 1.5 years, during which there was no visible improvement, it was decided to do a full dental extraction and fabricate complete dentures. Due to subsequent bone resorption in both jaws, the dentures were not functional. After consulting the internist and the oral and maxillofacial surgeon, the decision was then made to place dental implants in both the upper and lower jaw for implant-supported prosthetics. After successful treatment and an osseointegration period, the prosthetics were placed. 1 year after placement, there is a stable implantological situation, without pockets or apparent bone loss. The start of SGLT2 medication may have played a significant role in this.

[Cosmetic injectables in dental practice: legal aspects in the Netherlands]. / Cosmetische injectables in de tandheelkundige praktijk: juridische aspecten in Nederland.

A recent survey indicates 49% of this journal's subscribers endorse the administration of cosmetic injectables by properly trained dentists. Given the surging demand for cosmetic treatments, it's essential to establish clear guidelines and conventions defining the roles of the various healthcare professionals in various situations. There is, however, considerable discussion still and from a legal standpoint, the role of dentists within cosmetic medicine remains ambiguous. Under the Dutch Individual Healthcare Professions Act (Wet BIG), dentists are authorized to administer cosmetic injectables exclusively for dental purposes. However, based on the content of current dental training, one might argue that dentists' authorization could be extended to include facial injectable treatments in the entire face, in future. Presently, it is prudent for general practice dentists to abstain from cosmetic procedures with cosmetic injectables without a specific (aesthetic) dental objective.

[Patient-specific joint prothesis for ankylotic temporomandibular joints]. / Individueel vervaardigde prothesen voor ankylotische kaakgewrichten.

A 49-year-old woman who suffered from severe obstructive sleep apnea (OSA) was referred to the department of Oral-, Maxillofacial Surgery department due to progressive limitation of the mouth opening and chronic pain in both temporomandibular joints. Based on clinical and radiological examinations, the patient was diagnosed with recurrent ankylosis of the temporomandibular joints. The patient was treated with 2 patient-specific implants of the temporomandibular joint combined with a Le Fort I osteotomy, and a genioplasty including a genioglossus advancement. This treatment may have advantages for the patient such as a lower recurrence rate of ankylosis, improved maximal mouth opening, pain reduction and improved aesthetic results.

[Intra-oral Perineurioma, a case report]. / Perineurioma: een zeldzame intraorale wekedelentumor.

A 48 year old woman was referred by her general practitioner to an oral and maxillofacial surgeon because of an asymptomatic, slow growing intra-oral tumor since three years. There were no sensory and motor symptoms. A well-defined tumor of 5 cm in diameter was located in the right cheek between the zygomaticus arch and the labial commissure. The skin and the intra-oral mucosa were intact without any change in colour or texture. The MRI showed a solitary mass with benign characteristics. A transoral radical excisional biopsy was performed under general anesthesia. Histopathological examination revealed a rare soft tissue perineurioma tumor.

A stepwise titration protocol for oral appliance therapy in positional obstructive sleep apnea patients: proof of concept.

PURPOSE: In patients with positional obstructive sleep apnea (POSA), oral appliance therapy (OAT) is among the first-line treatments. The aim of this study was to evaluate the effects of a new standardized stepwise titration protocol for OAT in a group of patients with POSA. METHODS: This was an observational intervention trial. Patients who were previously randomized to the OAT intervention arm of a comparison study comprised the subjects for this study. These patients, who had mild to moderate POSA, were assessed after 3 and 12 months for treatment efficacy, objective adherence by temperature microsensor, and side effects. The titration of OAT was performed using a standardized stepwise titration protocol including advancement levels of 60%, 75%, and 90% of the maximum mandibular protrusion. The optimal advancement level per individual was based on a weighted compromise between efficacy and side effects. RESULTS: In total, 36 patients were included and all completed the titration protocol after 3 months. At baseline, the OAT was set at 60% of the maximal mandibular protrusion position. At a 3-month evaluation, the advancement remained at 60% in 16 patients (44%) and reached 75% advancement in 20 patients (56%). Mean apnea-hypopnea index decreased from 12.9 events per hour (9.1-16.7) to 6.9 (3.7-10.3) (P < 0.001), and median objective adherence was 97.4 (61.4-100.00) after 3 months. The 12-month analysis showed consistent results and good OAT tolerance. Six patients (16.7%) terminated OAT and one patient (2.8%) was lost to follow-up. CONCLUSIONS: This standardized stepwise titration protocol for OAT showed good efficacy, good OAT tolerance, and good objective adherence in patients with mild to moderate POSA. Therefore, the protocol is recommended in research projects to improve standardization of methods between studies and in clinical practice for its practical feasibility.

[Maxillary osteonecrosis after denosumab treatment]. / Verlies van de bovenkaak door denosumab.

A 58-year-old patient with a history of intravenous use of denosumab was referred to the department of oral and maxillofacial surgery with inadequate recovery after a series of extractions. During physical and radiological examination, several sites of exposed necrotic bone with purulent discharge were seen, and the maxilla appeared fractured at the level of Le Fort 1. Treatment consisted of intravenous administration of antibiotics with consecutive sequestrectomy of the maxilla under general anaesthesia. While Medication Related Osteonecrosis of the Jaw (MRONJ) is most commonly seen in patients treated with bisphosphonates, in the past decade, it has become apparent that other types of medication, most notably denosumab, can cause comparable disorders. Treatment of MRONJ strongly depends on the stage the disease is in. In patients with a history of denosumab or bisphosphonate use (administered either intravenously or orally in combination with corticosteroids), abnormal radiological findings, or developing osteonecrosis, referral to a department of oral and maxillofacial surgery is recommended.

[An (un)conventional autogenous tooth transplantation]. / Een (on)conventionele autotransplantatie.

A 15-year-old boy was referred to an Oral and Maxillofacial Surgery department because of a persistent tooth 85 and a malposition of tooth 45. Following additional examination, it was concluded that the root formation of tooth 45 was already completed. Furthermore, it was horizontally impacted against the inferior border of the mandible. The decision was made to extract tooth 85 and to autotransplant tooth 45. Post-operatively, tooth 45 was fixed to the orthodontic equipment already in place and later treated endodontically. The success rate of this kind of autotransplantation of teeth with already closed apices (94%) is comparable in the literature to the success rate of autotransplantation of teeth with open apices (98%). Autotransplantation should be considered, especially in patients who are still growing and for whom dental implants do not (yet) offer a solution.

Oral appliance therapy versus nasal continuous positive airway pressure in obstructive sleep apnoea syndrome: a randomised, placebo-controlled trial on self-reported symptoms of common sleep disorders and sleep-related problems.

Obstructive sleep apnoea syndrome (OSAS) is associated with several sleep disorders and sleep-related problems. Therefore, the aim of this study was to compare the effects of a mandibular advancement device (MAD) with those of nasal continuous positive airway pressure (nCPAP) on self-reported symptoms of common sleep disorders and sleep-related problems in mild and moderate OSAS patients. In this randomised placebo-controlled trial, sixty-four OSAS patients (52·0 ± 9·6 years) were randomly assigned to an MAD, nCPAP or an intra-oral placebo appliance in a parallel design. All participants filled out the validated Dutch Sleep Disorders Questionnaire (SDQ) twice: one before treatment and one after six months of treatment. With 88 questions, thirteen scales were constructed, representing common sleep disorders and sleep-related problems. Linear mixed model analyses were performed to study differences between the groups for the different SDQ scales over time. The MAD group showed significant improvements over time in symptoms corresponding with 'insomnia', 'excessive daytime sleepiness', 'psychiatric sleep disorder', 'periodic limb movements', 'sleep apnoea', 'sleep paralysis', 'daytime dysfunction', 'hypnagogic hallucinations/dreaming', 'restless sleep', 'negative conditioning' and 'automatic behaviour' (range of P values: 0·000-0·014). These improvements in symptoms were, however, not significantly different from the improvements in symptoms observed in the nCPAP and placebo groups (range of P values: 0·090-0·897). It can be concluded that there is no significant difference between MAD and nCPAP in their positive effects on self-reported symptoms of common sleep disorders and sleep-related problems in mild and moderate OSAS patients. These beneficial effects may be a result of placebo effects.

[Non-invasive brain stimulation in schizophrenia: hallucinations and negative symptoms]. / Non-invasieve hersenstimulatie bij schizofrenie, gericht op hallucinaties en negatieve symptomen.

BACKGROUND: New approaches are needed in the treatment of characteristic symptoms of schizophrenia such as hallucinations and negative symptoms. Non-invasive brain stimulation can make a useful contribution.
AIM: To discuss the published evidence regarding efficacy and safety of repetitive transcranial magnetic stimulation (rtms) and transcranial direct current stimulation (tdcs) when used in the treatment of auditory verbal hallucinations and negative symptoms.
METHOD: We review and discuss recent meta-analyses and we analyse relevant factors.
RESULTS: On average, when compared to sham-stimulation, rtms was found to have a significant effect on hallucinations and negative symptoms. Nevertheless, the results of some studies were variable and some studies did not report any improvement. There are indications that some factors such as age and distance between scalp and cortex may influence efficiency. There were only a few studies relating to the use of tdcs and none of these reported a clear effect.
CONCLUSION: There is reasonable evidence that rtms is an efficient treatment for hallucinations and negative symptoms, although some variable results have been reported. There is insufficient evidence for conclusions to be drawn about the efficacy of tdcs for the treatment of hallucinations and negative symptoms. However, both simulation methods are safe and largely without side-effects.

[Ocular complications of local anaesthesia in dentistry]. / Oculaire bijwerkingen van lokale anesthesie in de tandheelkunde.

An estimated 1 in 1,000 local anaesthetic injections in the maxilla or the mandible lead to unwanted effects on the ipsilateral eye. We have seen a case with diplopia and lateral rectus palsy following bimaxillary anaesthesia. A systematic literature review of reports on this type of complication resulted in a total of 144 documented cases published between 1936 and 2016. The most frequently reported symptoms included diplopia (72%), partial or full ophthalmoplegia (26%), ptosis (22%), mydriasis (18%), amaurosis (13%) and orbital pain (12%). This type of complication is best understood by pathophysiological hypotheses that include intra-arterial injection, intravenous injection, autonomic dysregulation, or deep injection and diffusion. If ocular symptoms appear after local intraoral anaesthesia, the patient should be reassured. In the case of diplopia, the eye should be covered with a gauze dressing, and the patient should be instructed about associated safety risks. If symptoms persist or when vision deteriorates, referral to an ophthalmologist is advisable.

Positional OSA part 2: retrospective cohort analysis with a new classification system (APOC).

BACKGROUND: In Part 1 of this two-part article, the Amsterdam Positional Obstructive Sleep Apnoea Classification (APOC) was recently introduced, a classification system aimed at facilitating the identification of suitable candidates for positional therapy (PT): patients who will benefit from a clinically significant improvement of their obstructive sleep apnoea (OSA) with PT. APOC was developed with new generation PT devices in mind rather than conventional PT (tennis ball technique). New generation PT can be defined as a well-tolerated device which prevents a patient from adopting the worst sleeping position (WSP) without negatively influencing sleep efficiency, as objectified by a full night polysomnography (PSG). PT is rapidly gaining momentum in the scope of OSA treatment. The objective of this manuscript is to measure the prevalence of position-dependent obstructive sleep apnoea (POSA) according to the APOC, in a consecutive series of patients referred for PSG as well as an investigation of associations between POSA and certain patient characteristics. METHODS: We performed a retrospective, single-centre cohort study including a consecutive series of patients who underwent a PSG during the period of April 2010 until October 2010. RESULTS: Within this OSA-cohort (n = 253), a prevalence of POSA of 69 % when applying APOC is measured, compared to 64 % when applying Cartwright's classification. An inverse relation between POSA and BMI was observed, likewise between POSA and apnoea hypopnoea index (AHI). CONCLUSION: We are of opinion that APOC is a suitable tool to identify patients who will or will not benefit from PT, thus resulting in more cost-efficient treatment.

[Endodontic re-treatment or apical surgery, is an evidence-based choice possible?]. / Endodontische herbehandeling of apexresectie: is een evidencebased keuze mogelijk?

Treatment of a recurrence after an initial endodontic treatment can consist of endodontic re-treatment or apical surgery. The literature reports comparable success rates for these two options. However, randomised controlled trials that are truly comparable to each other are unavailable as a result of which comparison and an informed choice are not really possible. In addition to the treatment outcome, consideration also has to be given to cost-effectiveness and other patient-related factors, such as pain, swelling and medication. Regarding these considerations, too, little reliable information can be found in the literature. Moreover, factors relating to insurance play an important role in the Netherlands, where only apical surgery is covered by the basic healthcare insurance. In conclusion, all of these factors should be carefully considered before proceeding to an individual treatment strategy.

Efficacy of bilateral repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: results of a multicenter double-blind randomized controlled trial.

BACKGROUND: Few studies have investigated the efficacy of repetitive transcranial magnetic stimulation (rTMS) treatment for negative symptoms of schizophrenia, reporting inconsistent results. We aimed to investigate whether 10 Hz stimulation of the bilateral dorsolateral prefrontal cortex during 3 weeks enhances treatment effects. METHOD: A multicenter double-blind randomized controlled trial was performed in 32 patients with schizophrenia or schizo-affective disorder, and moderate to severe negative symptoms [Positive and Negative Syndrome Scale (PANSS) negative subscale ⩾15]. Patients were randomized to a 3-week course of active or sham rTMS. Primary outcome was severity of negative symptoms as measured with the Scale for the Assessment of Negative Symptoms (SANS) and the PANSS negative symptom score. Secondary outcome measures included cognition, insight, quality of life and mood. Subjects were followed up at 4 weeks and at 3 months. For analysis of the data a mixed-effects linear model was used. RESULTS: A significant improvement of the SANS in the active group compared with sham up to 3 months follow-up (p = 0.03) was found. The PANSS negative symptom scores did not show a significant change (p = 0.19). Of the cognitive tests, only one showed a significant improvement after rTMS as compared with sham. Finally, a significant change of insight was found with better scores in the treatment group. CONCLUSIONS: Bilateral 10 Hz prefrontal rTMS reduced negative symptoms, as measured with the SANS. More studies are needed to investigate optimal parameters for rTMS, the cognitive effects and the neural basis.

Positional OSA part 1: Towards a clinical classification system for position-dependent obstructive sleep apnoea.

BACKGROUND: In 1984, Cartwright suggested that physicians should differentiate between patients with either positional obstructive sleep apnoea (POSA) or non-positional OSA. Treatment of POSA has advanced dramatically recently with the introduction of a new generation of positional therapy (PT), a small device attached to either the neck or chest which corrects the patient from adopting the supine position through a vibrating stimulus. Encouraging data have been published suggesting that this simple therapy successfully prevents patients with POSA from adopting the supine position without negatively influencing sleep efficiency, as well as allowing for good adherence. Unfortunately, evaluating the efficacy of PT and comparing results are hindered by the fact that there are no universally used POSA criteria. In 1984, Cartwright introduced the arbitrary cut-off point of a difference of 50% or more in apnoea index between supine and non-supine positions. INTRODUCTION: The aim of this project was to introduce a new classification system, which ideally should identify suitable candidates for PT: patients that will benefit from a clinically significant improvement of their OSA with PT. The shared use of this classification can facilitate collection of data across multiple centres and comparison of results across studies. We report on the development and process that resulted in the Amsterdam Positional OSA Classification (APOC). METHOD: A panel of three field experts were instructed to independently assign the diagnosis POSA to 100 randomly selected patients they considered likely to benefit from a clinically significant improvement of their OSA with PT. In a group setting, the completed lists were compared. Discrepancies were discussed until consensus was met. This resulted in the consensus standard used to calibrate the new classification. Using the nominal group technique, the APOC was developed. RESULTS: The APOC criteria evolve around the percentage of total sleep time spent in either the worst sleeping position (WSP) or the best sleeping position (BSP) and the apnoea-hypopnoea index (AHI) in BSP. On applying APOC, one discriminates between the true positional patient, the non-positional patient and the multifactorial patient, whose OSA severity is influenced in part by sleep position. APOC has an increased sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) compared to previously applied POSA criteria in identifying patients that will benefit from positional therapy.

[Mandibular advancement: bilateral sagittal split versus -distraction osteogenesis]. / Verlenging van de onderkaak: bilaterale sagittale splijtingsosteotomie versus distractieosteogenese.

In the 1990s intra-oral distraction osteogenesis (DO) became available as an alternative for bilateral sagittal splitosteotomy (BSSO) for advancement of the mandible. It was thought that DO would lead to more stability in the results and fewer neurosensory disturbances of the inferior alveolar nerve. However, there was no scientific evidence for this assumption. This article describes a number of recently published, prospective studies that demonstrate that BSSO is not inferior to DO with respect to stability and neurosensory disturbances of the inferior alveolar nerve. They also demonstrate that BSSO leads to less pain in patients and to lower total costs. It can be concluded that BSSO should be considered the standard therapy for mandibular advancement up to 10 mm in non-syndromal patients.

Oral complications in hematopoietic stem cell recipients: the role of inflammation.

Hematopoietic stem cell transplantation (HSCT) is widely used as a potentially curative treatment for patients with various hematological malignancies, bone marrow failure syndromes, and congenital immune deficiencies. The prevalence of oral complications in both autologous and allogeneic HSCT recipients remains high, despite advances in transplant medicine and in supportive care. Frequently encountered oral complications include mucositis, infections, oral dryness, taste changes, and graft versus host disease in allogeneic HSCT. Oral complications are associated with substantial morbidity and in some cases with increased mortality and may significantly affect quality of life, even many years after HSCT. Inflammatory processes are key in the pathobiology of most oral complications in HSCT recipients. This review article will discuss frequently encountered oral complications associated with HSCT focusing on the inflammatory pathways and inflammatory mediators involved in their pathogenesis.

[Throat ache ans swelling of the neck: first symptoms of Lemierre's syndrome]. / Keelpijn en zwelling van de hals: eerste symptomen van het syndroom van Lemierre.

Lemierre's syndrome, a thrombophlebitis of the internal jugular vein, is a rare disorder, usually caused by the microorganism Fusobacterium necrophorum. Throat ache and swelling of the neck are often the first symptoms. Without adequate treatment, Lemierre's syndrome may result in thrombosis of the internal jugular vein and metastatic lung abscesses, with a mortality rate of 18%. On the basis of 2 cases, Lemierre's syndrome is described here. In cases where Lemierre's syndrome is suspected, hospitalization often follows, with the administration of intravenous antibiotics and drainage of the abscesses. One should be on the alert for Lemierre's syndrome when a patient is presented with swelling in the neck following an oropharyngeal infection.