Selection of criteria for assessment of occlusal acceptability

There is no general agreement on criteria that could be applied to distinguish between orthodontically acceptable and non-acceptable occlusions after the completion of dental development. The aim of the present study was to analyse morphological and functional features that could be used as an index to define an acceptable occlusion in young adults. Three expert panels representing specialists in orthodontics and stomatognathic physiology participated in a modified Delphi method. Each panel responded to a questionnaire concerning the usefulness of various occlusal features, and a set of characteristics was selected on the basis of the responses; thereafter, applicability of the chosen characteristics and their cut-offs for an acceptable non-acceptable dichotomy was tested clinically. To obtain a consensus level of 100%, the last panel session was completed with a group discussion. Assessments made using the morphological criteria were compared with those made with the dental health component of the Index of Orthodontic Treatment Need. The selected morphological characteristics consisted of overjet, overbite, canine relationship, crossbite, scissors bite and midline deviation. The functional evaluation comprised assessments of discrepancy between the centric relation and the intercuspal position, working- and non-working-side contacts and protrusion contacts. The dental health component and our morphological criteria showed different sensitivity to contact point displacements, interdigitation in buccal segments and increased overbite. This study provides a set of morphological and functional indicators reflecting the current consensus opinion of Finnish professionals. Further studies are needed to analyse the reproducibility of assessment of the characteristics included.     

Expression of claudin‐11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38δ

The incidence of cutaneous squamous cell carcinoma (cSCC) is rapidly increasing, and the prognosis of patients with metastatic disease is poor. There is an emerging need to identify molecular markers for predicting aggressive behaviour of cSCC. Here, we have examined the role of tight junction (TJ) components in the progression of cSCC. The expression pattern of mRNAs for TJ components was determined with RNA sequencing and oligonucleotide array‐based expression analysis from cSCC cell lines (n=8) and normal human epidermal keratinocytes (NHEK, n=5). The expression of CLDN11 was specifically elevated in primary cSCC cell lines (n=5), but low or absent in metastatic cSCC cell lines (n=3) and NHEKs. Claudin‐11 was detected in cell‐cell contacts of primary cSCC cells in culture by indirect immunofluorescence analysis. Analysis of a large panel of tissue samples from sporadic UV‐induced cSCC (n=65), cSCC in situ (n=56), actinic keratoses (n=31), seborrhoeic keratoses (n=7) and normal skin (n=16) by immunohistochemistry showed specific staining for claudin‐11 in intercellular junctions of keratinizing tumor cells in well and moderately differentiated cSCCs, whereas no staining for claudin‐11 was detected in poorly differentiated tumors. The expression of claudin‐11 in cSCC cells was dependent on the activity of p38δ MAPK and knock‐down of claudin‐11 enhanced cSCC cell invasion. These findings provide evidence for the role of claudin‐11 in regulation of cSCC invasion and suggest loss of claudin‐11 expression in tumor cells as a biomarker for advanced stage of cSCC.     

Mortality‐risk‐based apnea–hypopnea index thresholds for diagnostics of obstructive sleep apnea

The severity of obstructive sleep apnea is clinically assessed mainly using the apnea–hypopnea index. Based on the apnea–hypopnea index, patients are classified into four severity groups: non‐obstructive sleep apnea (apnea–hypopnea index < 5); mild (5 ≤ apnea–hypopnea index < 15); moderate (15 ≤ apnea–hypopnea index < 30); and severe obstructive sleep apnea (apnea–hypopnea index ≥ 30). However, these thresholds lack solid clinical and scientific evidence. We hypothesize that the current apnea–hypopnea index thresholds are not optimal despite their global use, and aim to assess this clinical shortcoming by optimizing the thresholds with respect to the risk of all‐cause mortality. We analysed ambulatory polygraphic recordings of 1,783 patients with suspected obstructive sleep apnea (mean follow‐up 18.3 years). We simulated 79,079 different threshold combinations in 100 randomized subgroups of the population and studied the relative risk of all‐cause mortality corresponding to each combination and randomization. The optimal thresholds were chosen according to three criteria: (a) the hazard ratios increase linearly between severity groups towards more severe obstructive sleep apnea; (b) each group includes at least 15% of the study population; (c) group sizes decrease with increasing obstructive sleep apnea severity. The risk of all‐cause mortality varied greatly across simulations; the threshold defining non‐obstructive sleep apnea group having the largest effect on the hazard ratios. The apnea–hypopnea index threshold combination of 3‐9‐24 was optimal in most of the subgroups. In conclusion, the assessment of obstructive sleep apnea severity based on the current apnea–hypopnea index thresholds is not optimal. Our novel approach provides methods for optimizing apnea–hypopnea index‐based severity classification, and the revised thresholds better differentiate patients into severity groups, ensuring that an increase in the severity corresponds to an increase in the risk of all‐cause mortality.     

Impaired negative chronotropic response to adenosine in patients with inappropriate sinus tachycardia

INTRODUCTION: Adenosine is an endogenous nucleoside that has an important role in the diagnosis and treatment of several cardiac arrhythmias. However, its effects on inappropriate sinus tachycardia (IST) are not well established. METHODS AND RESULTS: In this study, the response to intravenous adenosine (0.1 to 0.15 mg/kg) was studied in 18 patients (age 46+/-15 years) with IST. In a subset of patients (n = 5), the direct effects of adenosine were assessed during pharmacologic beta-adrenergic and cholinergic blockade. Atrial cycle length (ACL) was measured before adenosine injection, at the time of the greatest cycle length prolongation, and during the maximum rebound acceleration of heart rate. Eighteen subjects (age 46+/-11 years) with normal sinus rhythm undergoing clinically indicated electrophysiologic study served as controls. Adenosine did not terminate IST in any patient. The maximum dose of adenosine prolonged the sinus interval significantly, from 780+/-128 msec to 985+/-225 msec (P < 0.001) in the control subjects. In contrast, adenosine caused no significant lengthening of atrial cycle length (527+/-69 msec vs 590+/-148 msec; P = NS) in the patients with IST. Similar difference in the response to adenosine was seen during the pharmacologic autonomic blockade. The reflex increase of the sinus rate (rebound effect) was greater in the control subjects than in the patients with IST (21.2%+/-9.7% vs 8.5%+/-8.8%; P < 0.001). CONCLUSION: The usual negative chronotropic effect of adenosine was impaired in the patients with IST. This may have important diagnostic implications and provide new insight into the mechanism(s) of IST.     

Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy

Background

The purpose of this study was to identify early features of lamin A/C gene mutation related dilated cardiomyopathy (DCM) with cardiovascular magnetic resonance (CMR). We characterise myocardial and functional findings in carriers of lamin A/C mutation to facilitate the recognition of these patients using this method. We also investigated the connection between myocardial fibrosis and conduction abnormalities.

Methods

Seventeen lamin A/C mutation carriers underwent CMR. Late gadolinium enhancement (LGE) and cine images were performed to evaluate myocardial fibrosis, regional wall motion, longitudinal myocardial function, global function and volumetry of both ventricles. The location, pattern and extent of enhancement in the left ventricle (LV) myocardium were visually estimated.

Results

Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities. Sixty-nine percent of our asymptomatic or mildly symptomatic patients showed mild ventricular dilatation, systolic failure or both in global ventricular analysis. Decreased longitudinal systolic LV function was observed in 53% of patients.

Conclusions

Cardiac conduction abnormalities, mildly dilated LV and depressed systolic dysfunction are common in DCM caused by a lamin A/C gene mutation. However, other cardiac diseases may produce similar symptoms. CMR is an accurate tool to determine the typical cardiac involvement in lamin A/C cardiomyopathy and may help to initiate early treatment in this malignant familiar form of DCM.     

Immunohistochemical Study of Colorectal Tumors for Expression of a Novel Transmembrane Carbonic Anhydrase, MN/CA IX, with Potential Value as a Marker of Cell Proliferation

Carbonic anhydrase isoenzyme IX, MN/CA IX, is a recently discovered member of the carbonic anhydrase (CA) gene family with a suggested function in acid-base balance, intercellular communication, and cell proliferation. Increased expression of MN/CA IX has been observed with certain epithelial tumors. We investigated the expression of MN/CA IX in 69 colorectal neoplasms, consisting of 1 juvenile polyp, 8 hyperplastic polyps, 39 adenomatous lesions, 21 carcinomas, and 7 metastases. Tissue sections were immunostained with a monoclonal antibody specific to MN/CA IX. The proliferative activity of the tumor cells was evaluated by Ki-67 antigen immunoreactivity. The hyperplastic polyps showed a weak or moderate reaction for MN/CA IX only in the cryptal epithelium, as did the normal intestinal mucosa. The adenomas showed immunoreactivity mainly in the superficial part of the mucosa, whereas the distribution in the carcinomas and metastases was more diffuse. Comparative immunostaining of serial sections for Ki-67, a well established marker of cell proliferation, confirmed that MN/CA IX is expressed in areas with high proliferative capacity. Our results show abnormal MN/CA IX expression in colorectal neoplasms, suggesting its involvement in their pathogenesis. The co-occurrence of MN/CA IX and Ki-67 in the same tumor cells indicates its potential for use as a marker of increased proliferation in the colorectal mucosa.     

Human ROBO1 regulates interaural interaction in auditory pathways

In rodents, the Robo1 gene regulates midline crossing of major nerve tracts, a fundamental property of the mammalian CNS. However, the neurodevelopmental function of the human ROBO1 gene remains unknown, apart from a suggested role in dyslexia. We therefore studied axonal crossing with a functional approach, based on magnetoencephalography, in 10 dyslexic individuals who all share the same rare, weakly expressing haplotype of the ROBO1 gene. Auditory-cortex responses were recorded separately to left- and right-ear sounds that were amplitude modulated at different frequencies. We found impaired interaural interaction that depended on the ROBO1 in a dose-dependent manner. Our results indicate that normal crossing of the auditory pathways requires an adequate ROBO1 expression level.     

Selective changes in the levels of nicotinic acetylcholine receptor protein and of corresponding mRNA species in the brains of patients with Parkinson's disease

Reductions in the number of neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to occur in connection with Parkinson's disease (PD), but it is still unclear which subtype of this receptor is affected. In the present study we examined various nAChR subtypes employing ligand binding, as well as levels of subunit protein and mRNA in the brains of PD patients and age-matched controls. Binding of [3H]epibatidine and levels of alpha3 mRNA in the caudate nucleus and temporal cortex, but not in the hippocampus were significantly decreased in the PD brain. The level of the alpha3 protein subunit was significantly reduced in all these brain regions but there was no change in the level of alpha4. The level of the beta2 protein subunit in the temporal cortex and hippocampus and the beta2 mRNA in the temporal cortex was lowered. Both the levels of the alpha7 subunit protein and [125I]alpha-bungarotoxin binding were significantly increased in the temporal cortex of PD patients whereas the alpha7 mRNA level was unchanged. These findings reveal selective losses of the alpha3- and beta2-containing nAChRs and an increase in the alpha7 nAChRs that might be related to the pathogenesis of PD.