Are women more susceptible than men to iatrogenic inferior alveolar nerve injury in dental implant surgery?

An over-representation of women in dental implant-related inferior alveolar nerve injuries (IANIs) is recognized in the literature but has not been investigated. Therefore, a nationwide retrospective register study was conducted to analyse how IANIs compare with other implant-related complications (infection, implant malposition, lack of bone at implant site, mechanical damage, or failed osseointegration) separately in women and men. Financially compensated malpractice claims related to dental implant surgery were collected from the Finnish Patient Insurance Centre for the years 1997-2013, while the total number of nationally placed implants was ascertained from the implant register held by the Finnish Institute for Health and Welfare. In the 242 complications, the following were analysed: age of subject, absolute risk for complication, and aetiological factor of IANI. Statistical tests applied include Mann-Whitney U-test, Chi-squared test, and Fisher's exact test. Women sustaining IANI were more likely older than those having infection, mechanical damage, or failed osseointegration (P<0.05), while no significant differences emerged in men. Women were more likely at risk for IANI (P<0.01) or implant malposition (P<0.05) than men. The results support earlier propositions that women are more vulnerable than men to iatrogenic IANI.

MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction.

Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA (mtDNA) mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias. Here we show that elevated mtDNA mutagenesis in mice with a proof-reading deficient mtDNA polymerase (PolG) leads to incomplete mitochondrial clearance, with asynchronized iron loading in erythroid precursors, and increased total and free cellular iron content. The resulting Fenton chemistry leads to oxidative damage and premature destruction of erythrocytes by splenic macrophages. Our data indicate that mitochondria actively contribute to their own elimination in reticulocytes and modulate iron loading. Asynchrony of this sequence of events causes severe mitochondrial anaemia by depleting the organism of red blood cells and the bone marrow of iron. Our findings account for the anaemia development in a progeroid mouse model and may have direct relevance to the anemias associated with human mitochondrial disease and ageing.

Justification and good practice in using handheld portable dental X-ray equipment: a position paper prepared by the European Academy of DentoMaxilloFacial Radiology (EADMFR).

Handheld portable X-ray devices are increasingly used for intraoral radiography. This development introduces new challenges to staff and patient safety, for which new or revised risk assessments must be made and acted upon prior to use. Major issues might be: difficulties in using rectangular collimation with beam aiming devices, more complex matching of exposure settings to the X-ray receptor used (e.g. longer exposure times), movements owing to the units' weight, protection of the operator and third persons, and the use in uncontrolled environments. These problems may result in violation of the "as low as reasonably achievable'', that is, ALARA principle by an increase in (re)exposures compared with the other available intraoral X-ray devices. Hence, the use of handheld portable X-ray devices should be considered only after careful and documented evaluation (which might be performed based on medical physics support), when there is evidence that handheld operation has benefits over traditional modalities and when no new risks to the operators and/or third parties are caused. It is expected that the use of handheld portable X-ray devices will be very exceptional, and for justified situations only. Special attention should be drawn to beam-aiming devices, rectangular collimation, the section of the X-ray receptor, focus-skin distance, and backscatter shielding, and that the unit delivers reproducible dose over the full set of environmental conditions (e.g. battery status and temperature).

Adipocyte morphology and implications for metabolic derangements in acquired obesity.

BACKGROUND: Adipocyte size and number have been suggested to predict the development of metabolic complications in obesity. However, the genetic and environmental determinants behind this phenomenon remain unclear. METHODS: We studied this question in rare-weight discordant (intra-pair difference (Δ) body mass index (BMI) 3-10 kg m(-2), n=15) and concordant (ΔBMI 0-2 kg m(-)(2), n=5) young adult (22-35 years) monozygotic twin pairs identified from 10 birth cohorts of Finnish twins (n=5 500 pairs). Subcutaneous abdominal adipocyte size from surgical biopsies was measured under a light microscope. Adipocyte number was calculated from cell size and total body fat (D × A). RESULTS: The concordant pairs were remarkably similar for adipocyte size and number (intra-class correlations 0.91-0.92, P<0.01), suggesting a strong genetic control of these measures. In the discordant pairs, the obese co-twins (BMI 30.6 ± 0.9 kg m(-2)) had significantly larger adipocytes (volume 547 ± 59 pl), than the lean co-twins (24.9 ± 0.9 kg m(-)(2); 356 ± 34 pl, P<0.001). In 8/15 pairs, the obese co-twins had less adipocytes than their co-twins. These hypoplastic obese twins had significantly higher liver fat (spectroscopy), homeostatic model assessment-index, C-reactive protein and low-density lipoprotein cholesterol than their lean co-twins. Hyperplastic obesity was observed in the rest (7/15) of the pairs, obese and lean co-twins having similar metabolic measures. In all pairs, Δadipocyte volume correlated positively and Δcell number correlated negatively with Δhomeostatic model assessment-index and Δlow-density lipoprotein, independent of Δbody fat. Transcripts most significantly correlating with Δadipocyte volume were related to a reduced mitochondrial function, membrane modifications, to DNA damage and cell death. CONCLUSIONS: Together, hypertrophy and hypoplasia in acquired obesity are related to metabolic dysfunction, possibly through disturbances in mitochondrial function and increased cell death within the adipose tissue.

Next-generation sequencing for mitochondrial disorders.

A great deal of our understanding of mitochondrial function has come from studies of inherited mitochondrial diseases, but still majority of the patients lack molecular diagnosis. Furthermore, effective treatments for mitochondrial disorders do not exist. Development of therapies has been complicated by the fact that the diseases are extremely heterogeneous, and collecting large enough cohorts of similarly affected individuals to assess new therapies properly has been difficult. Next-generation sequencing technologies have in the last few years been shown to be an effective method for the genetic diagnosis of inherited mitochondrial diseases. Here we review the strategies and findings from studies applying next-generation sequencing methods for the genetic diagnosis of mitochondrial disorders. Detailed knowledge of molecular causes also enables collection of homogenous cohorts of patients for therapy trials, and therefore boosts development of intervention.

Characterising metabolically healthy obesity in weight-discordant monozygotic twins.

AIMS/HYPOTHESIS: Not all obese individuals display the metabolic disturbances commonly associated with excess fat accumulation. Mechanisms maintaining this 'metabolically healthy obesity' (MHO) are as yet unknown. We aimed to study different fat depots and transcriptional pathways in subcutaneous adipose tissue (SAT) as related to the MHO phenomenon. METHODS: Sixteen rare young adult obesity-discordant monozygotic (MZ) twin pairs (intra-pair difference (∆) in BMI ≥ 3 kg/m(2)), aged 22.8-35.8 years, were examined for detailed characteristics of metabolic health (subcutaneous, intra-abdominal and liver fat [magnetic resonance imaging/spectroscopy]), OGTT, lipids, adipokines and C-reactive protein (CRP). Affymetrix U133 Plus 2.0 chips were used to analyse transcriptomics pathways related to mitochondrial function and inflammation in SAT. RESULTS: Based on liver fat accumulation, two metabolically different subgroups emerged. In half (8/16) of the pairs (∆weight 17.1 ± 2.0 kg), the obese co-twin had significantly higher liver fat (∆718%), 78% increase in AUC insulin during OGTT and CRP, significantly more disturbance in the lipid profile and greater tendency for hypertension compared with the lean co-twin. In these obese co-twins, SAT expression of mitochondrial oxidative phosphorylation, branched-chain amino acid catabolism, fatty acid oxidation and adipocyte differentiation pathways were downregulated and chronic inflammation upregulated. In the other eight pairs (∆weight 17.4 ± 2.8 kg), the obese co-twin did not differ from the non-obese co-twin in liver fat (∆8%), insulin sensitivity, CRP, lipids, blood pressure or SAT transcriptomics. CONCLUSIONS/INTERPRETATION: Our results suggest that maintenance of high mitochondrial transcription and lack of inflammation in SAT are associated with low liver fat and MHO.

Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.

Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism.

CT findings of necrotizing sialometaplasia.

An otherwise healthy 56-year-old Caucasian female was referred to the radiology department because of an ulceration of her palatal mucosa. Clinically the lesion was suspected to be malignant and a multislice CT examination of the head and neck region was performed. This revealed an ulcer-like cavity with no tumour-like contrast enhancement. No relevant bone changes or suspicious lymph nodes of the neck were detected. Based on the multislice CT findings, necrotizing sialometaplasia was suspected and the diagnosis was verified histopathologically. This report describes the CT findings of necrotizing sialometaplasia at the ulceration stage.

Parental smoking, nasal resistance and rhinitis in children.

AIM: To determine whether parent-reported perennial rhinitis or objectively measured nasal resistance is more common in children from smoking families. To assess tonsillar size, nasopharyngeal airway and upper airway surgery frequency in children with smoking and non-smoking parents. METHODS: Ninety-five children (age 3-6 years, median 68 months) participated in this prospective cross-sectional clinical study. History of nasal symptoms was obtained, and all underwent an ear-nose-throat examination, anterior rhinomanometry and a lateral cephalogram. Regular smoking by either parent and their child's snoring was inquired about with a parental questionnaire. We compared children with a parental smoker and children without a parental smoker in the family. RESULTS: Smoking in the family led to increased risk for perennial rhinitis in the children up to 2.76-fold (aOR, 95%CI 1.00-7.67), but with no difference in nasal resistance between children from smoking and non-smoking households. Neither tonsillar size, nasopharyngeal airway nor upper airway surgery was associated with parental smoking. CONCLUSIONS: Parental smoking is associated with symptoms of perennial rhinitis in children. The possible role of environmental tobacco smoke should be taken into account in parent counselling and in evaluation of children being treated for symptoms of rhinitis and nasal obstruction.

POLG1 manifestations in childhood.

OBJECTIVE: Mitochondrial DNA polymerase γ (POLG1) mutations in children often manifest as Alpers syndrome, whereas in adults, a common manifestation is mitochondrial recessive ataxia syndrome (MIRAS) with severe epilepsy. Because some patients with MIRAS have presented with ataxia or epilepsy already in childhood, we searched for POLG1 mutations in neurologic manifestations in childhood. METHODS: We investigated POLG1 in 136 children, all clinically suspected to have mitochondrial disease, with one or more of the following: ataxia, axonal neuropathy, severe epilepsy without known epilepsy syndrome, epileptic encephalopathy, encephalohepatopathy, or neuropathologically verified Alpers syndrome. RESULTS: Seven patients had POLG1 mutations, and all of them had severe encephalopathy with intractable epilepsy. Four patients had died after exposure to sodium valproate. Brain MRI showed parieto-occipital or thalamic hyperintense lesions, white matter abnormality, and atrophy. Muscle histology and mitochondrial biochemistry results were normal in all. CONCLUSIONS: POLG1 analysis should belong to the first-line DNA diagnostic tests for children with an encephalitis-like presentation evolving into epileptic encephalopathy with liver involvement (Alpers syndrome), even if brain MRI and morphology, respiratory chain activities, and the amount of mitochondrial DNA in the skeletal muscle are normal. POLG1 analysis should precede valproate therapy in pediatric patients with a typical phenotype. However, POLG1 is not a common cause of isolated epilepsy or ataxia in childhood.

DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis.

BACKGROUND: Leucoencephalopathy with brain stem and spinal cord involvement and high brain lactate (LBSL) was first defined by characteristic magnetic resonance imaging and spectroscopic findings. The clinical features include childhood or juvenile onset slowly progressive ataxia, spasticity, and dorsal column dysfunction, occasionally accompanied by learning difficulties. Mutations in DARS2, encoding mitochondrial aspartyl-tRNA synthetase, were recently shown to cause LBSL. The signs and symptoms show some overlap with the most common leucoencephalopathy of young adults, multiple sclerosis (MS). OBJECTIVE: To clarify the molecular background of LBSL patients in Finland, and to look for DARS2 mutations in a group of MS patients. METHODS: Clinical evaluation of LBSL patients, DARS2 sequencing and haplotype analysis, and carrier frequency determination in Finland. RESULTS: All eight LBSL patients were compound heterozygotes for DARS2 mutations: all carried R76SfsX5 change, seven had M134_K165del, and one had C152F change. Axonal neuropathy was found in five of the eight patients. The carrier frequencies of the R76SfsX5 and M134_K165del mutations were 1:95 and 1:380, respectively. All patients shared common European haplotypes, suggestive of common European LBSL ancestors. No enrichment of the two common DARS2 mutations was found in 321 MS patients. CONCLUSION: All LBSL patients were compound heterozygotes, which suggests that DARS2 mutation homozygosity may be lethal or manifest as a different phenotype. The authors show here that despite identical mutations the clinical picture was quite variable in the patients. Axonal neuropathy was an important feature of LBSL. DARS2 mutations cause childhood-to-adolescence onset leucoencephalopathy, but they do not seem to be associated with MS.

Dosimetry and image quality of four dental cone beam computed tomography scanners compared with multislice computed tomography scanners.

OBJECTIVES: The aim of this study was to evaluate the radiation dose and image quality of four dental cone beam CT (CBCT) scanners, and to compare them with those of two multislice CT (MSCT) scanners. METHODS: Tissue doses were measured using a tissue-equivalent anthropomorphic RANDO Head Phantom((R)) with thermoluminescence dosemeters (TLD). An RSVP Head Phantom(TM) with a specially designed cylindrical insert was used for comparison of image quality and absorbed dose. Image quality was evaluated in the form of contrast-to-noise ratio (CNR) and modulation transfer function (MTF). RESULTS: Using standard imaging parameters, the effective doses varied between 14 microSv and 269 microSv (International Commission on Radiation Protection (ICRP) 1990) and 27 microSv and 674 microSv (ICRP 2008) with the CBCT scanners, and between 350 microSv and 742 microSv (ICRP 1990) and 685 microSv and 1410 microSv (ICRP 2008) with the MSCT scanners. The CNR of the CBCT and MSCT scanners were 8.2-18.8 and 13.6-20.7, respectively. Low-dose MSCT protocols provided CNRs comparable with those from CBCT scanners. The 10% MTF of the CBCT scanners varied between 0.1 mm(-1) and 0.8 mm(-1), and was 0.5 mm(-1) for all the MSCT protocols examined. CONCLUSIONS: CBCT scanners provide adequate image quality for dentomaxillofacial examinations while delivering considerably smaller effective doses to the patient. Large variations in patient dose and image quality emphasize the importance of optimizing imaging parameters in both CBCT and MSCT examinations.

Cone-beam computed tomography: a new method for imaging of the temporal bone.

BACKGROUND: Clinical cone-beam computed tomography (CBCT), used in diagnostics of dental and maxillofacial radiology for almost 10 years, allows three-dimensional (3D) imaging of a focused area, with reasonable radiation dose. PURPOSE: To clarify the applicability of CBCT in imaging of the temporal bone. MATERIAL AND METHODS: We imaged cadaver temporal bones, one non-operated and five postmortem operated, with CBCT to evaluate the accuracy of this method in showing clinically important landmarks and the positions of middle-ear implants. In addition, to clarify the imaging protocols for the best possible result, we conducted a contrast-to-noise ratio (CNR) analysis by imaging a specially built phantom insert with different protocols. RESULTS: For all the temporal bones, image quality was good and of diagnostic value, and the surgical landmarks as well as positions and details of the implants could be accurately observed. Based on measurements conducted with the phantom, the best possible clarity of the images with the machine used (3D Accuitomo; Morita Co., Kyoto, Japan) was achieved with a tube voltage of 80 kVp and a current of 4 mA. CONCLUSION: Cone-beam CT is a promising new method for otologic imaging, based on its accuracy and relatively low radiation exposure per investigation.

Simple bone cyst: a radiological dilemma.

An asymptomatic cystic lesion in the corpus region on the right side of the mandible was detected in a panoramic radiograph of a 13-year-old girl, taken for orthodontic reasons. MR examination revealed a cavity filled with fluid and thin-rim peripheral contrast enhancement of the lesion similar to an odontogenic cyst lined with epithelium. The clinical and histological diagnosis of the lesion was a simple bone cyst. This report demonstrates the confounding similarity of the MR findings of a simple bone cyst to an odontogenic cyst.

Downregulation of SRF-FOS-JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas.

Defects of metabolic enzymes result in a variety of manifestations not logically explained by the primary metabolic function. Dominant defects of fumarate hydratase (FH) result in predisposition to cutaneous and uterine leiomyomas, and renal cell cancer. FH is a metabolic enzyme of the tricarboxylic acid cycle, and its tumor-suppressor mechanism is not fully understood. We compared the consequences of FH deficiency and respiratory chain (RC) deficiency using global expression pattern of diploid primary fibroblasts. This approach utilized the information that RC defects do not seem to predispose to tumorigenesis, and the aim was to identify FH-specific signaling effects that might have relevance to tumor formation. These results were then compared to global expression patterns of FH-deficient and sporadic uterine leiomyoma data sets. We show here that FH-deficient fibroblasts share a common transcriptional fingerprint with FH-deficient and sporadic leiomyomas, highlighting the downregulation of serum response factor (SRF)-regulated transcripts, particularly the FOS-JUNB pathway. We confirmed the downregulation of this pathway at transcriptional and protein level. SRF has a fundamental function in the differentiation of smooth muscle progenitor cells, and its downregulation both in diploid FH-deficient primary fibroblasts and in leiomyomas suggests an early function in the mechanism of uterine leiomyoma formation in FH deficiency. Concordantly, the phosphorylated form of SRF, known to activate transcription, is undetectable in leiomyomas whereas clearly detected in several nuclei in the differentiated myometrium. A similar transcriptional SRF-pathway fingerprint in FH-deficient and sporadic leiomyomas emphasizes the potential importance of this pathway in primary events leading to leiomyomatosis.

Accuracy of linear measurements using dental cone beam and conventional multislice computed tomography.

OBJECTIVES: The aim of this study was to evaluate the accuracy of linear measurements obtained with dental cone beam CT (CBCT) and multislice CT (MSCT) by altering radiation doses using pre-operative planning of the placement of oral implants as a model. METHODS: A human cadaver mandible was examined in two edentulous areas and one dentate area using CBCT and MSCT. The mandible was examined both dry and immersed in sucrose solution isointense with soft tissue. Two readers measured four linear distances twice from each section. The mandible was cut into 4 mm thick slices at three marked places. These slices were microradiographed and used as the gold standard for measurements from each section. RESULTS: The intraclass correlations between the intra- and interobserver readings obtained with the different methods showed almost perfect matches. The measurement error (ME) showed significant differences between the methods studied (P = 0.022): the mean ME was 4.7% for CBCT and 8.8% for MSCT of the dry mandible, 2.3% and 6.6%, respectively, for the mandible immersed in sucrose solution and 5.4% for low-dose MSCT. Lowering the MSCT radiation dose to less than a quarter of its conventional original value did not significantly affect the ME. CONCLUSIONS: CBCT is a reliable tool for implant-planning measurements when compared with MSCT. In this study, a considerable radiation dose reduction could be achieved with low-dose MSCT examinations without a major loss of measurement accuracy.

Do carriers of POLG mutation W748S have disease manifestations?

Mitochondrial recessive ataxia syndrome (MIRAS) is a common cause of autosomal recessive juvenile- or adult-onset ataxia, at least in Scandinavia. MIRAS patients are homozygous or compound heterozygous for POLG mutations W748S and A467T. Because many first-degree relatives of MIRAS patients in the studied families have reported neurological symptoms and some recent studies have suggested dominant negative effect of these mutations, a careful family study of heterozygotes was needed. We investigated all available members of the original large MIRAS family with W748S mutation. Neurological symptoms and signs were present in a number of carriers, but clearly defined neurological diseases did not segregate consistently with the mutation. Sensory polyneuropathy as a subclinical finding was observed in the majority of carriers examined. By positron emission tomography, cerebral glucose metabolism was moderately reduced in two out of four heterozygotes compared with severe reduction in one MIRAS patient. In conclusion, W748S heterozygotes showed no clinically manifesting phenotype.

Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease.

OBJECTIVE: Dysfunction of mitochondrial DNA polymerase gamma (POLG) has been recently recognized as an important cause of inherited neurodegenerative diseases. We have reported dominant and recessive inheritance of parkinsonism, mitochondrial myopathy, and premature amenorrhea in five ethnically distinct families with POLG1 mutations. This prompted us to carry out a detailed analysis of the coding region and intron-exon boundaries of POLG1 in Finnish patients with idiopathic sporadic Parkinson disease (PD) and in nonparkinsonian controls. METHODS: The coding region of POLG1 was analyzed in 140 Finnish patients with PD and their 127 spouses as age- and ethnically matched controls. Further, we analyzed the intragenic CAG-repeat region of POLG1 in 126 additional patients with nonparkinsonian neurologic disorders and in 516 Finnish population controls. RESULTS: We found clustering of rare variants of the POLG1 CAG-repeat, encoding a polyglutamine tract, in Finnish patients with idiopathic PD as compared to their spouses (p = 0.003; OR 3.01, 95% CI 1.35 to 6.71), population controls (p = 0.001; OR 2.45, 95% CI 1.45 to 4.14), and patients with nonparkinsonian neurologic disorders (p = 0.05, OR 1.98, 95% CI 0.97 to 4.05). We found several amino acid substitutions, none of them associating with PD. These included a previously parkinsonism-associated POLG variant Y831C, found in one patient with PD, but also in five controls, suggesting that it is a neutral amino acid polymorphism. CONCLUSIONS: Our results suggest that POLG polyglutamine tract variants should be considered as a predisposing genetic factor in idiopathic sporadic Parkinson disease.