Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption

Objectives

Primary failure of tooth eruption (PFE) is a rare autosomal-dominant disease characterized by severe lateral open bite as a consequence of incomplete eruption of posterior teeth. Heterozygous mutations in the parathyroid hormone 1 receptor (PTH1R) gene have been shown to cause PFE likely due to protein haploinsufficiency. To further expand on the mutational spectrum of PFE-associated mutations, we report here on the sequencing results of the PTH1R gene in 70 index PFE cases.

Materials and methods

Sanger sequencing of the PTH1R coding exons and their immediate flanking intronic sequences was performed with DNA samples from 70 index PFE cases.

Results

We identified a total of 30 unique variants, of which 12 were classified as pathogenic based on their deleterious consequences on PTH1R protein while 16 changes were characterized as unclassified variants with as yet unknown effects on disease pathology. The remaining two variants represent common polymorphisms.

Conclusions

Our data significantly increase the number of presently known unique PFE-causing PTH1R mutations and provide a series of variants with unclear pathogenicity which will require further in vitro assaying to determine their effects on protein structure and function.

Clinical relevance

Management of PTH1R-associated PFE is problematic, in particular when teeth are exposed to orthodontic force. Therefore, upon clinical suspicion of PFE, molecular DNA testing is indicated to support decision making for further treatment options.     

Photodynamic therapy of melanoma with new,structurally similar,NIR-absorbing ruthenium (II) complexes promotes tumor growth control via distinct hallmarks of immunogenic cell death

Cancer therapies that generate T cell-based anti-cancer immune responses are critical for clinical success and are favored over traditional therapies. One way to elicit T cell immune responses and generate long-lasting anti-cancer immunity is through induction of immunogenic cell death (ICD), a form of regulated cell death that promotes antigenicity and adjuvanticity within dying cells. Therefore, research in the last decade has focused on developing cancer therapies which stimulate ICD. Herein, we report novel photodynamic therapy (PDT) compounds with immunomodulatory and ICD inducing properties. PDT is a clinically approved, minimally invasive anti-cancer treatment option and has been extensively investigated for its tumor-destroying properties, lower side effects, and immune activation capabilities. In this study, we explore two structurally related ruthenium compounds, ML19B01 and ML19B02, that can be activated with near infrared light to elicit superior cytotoxic properties. In addition to its direct cell killing abilities, we investigated the effect of our PSs on immunological pathways upon activation. PDT treatment with ML19B01 and ML19B02 induced differential expression of reactive oxygen species, proinflammatory response-mediating genes, and heat shock proteins. Dying melanoma cells induced by ML19B01-PDT and ML19B02-PDT contained ICD hallmarks such as calreticulin, ATP, and HMGB1, initiated activation of antigen presenting cells, and were efficiently phagocytosed by bone marrow-derived dendritic cells. Most importantly, despite the distinct profiles of ICD hallmark inducing capacities, vaccination with both PDT-induced dying cancer cells established anti-tumor immunity that protected mice against subsequent challenge with melanoma cells.     

What's in it for the community? Public academic liaison and local mental health agencies

This paper reviews a triangular relationship in which a state mental health administration, a university, and a local mental health authority (and by extension, community mental health programs) co-exist. The relationship is based on mutual trust and interdependence, both of which are reinforced when certain key positions are developed such that individuals can work in two or more of the three arenas. It is essential that representatives of each group be encouraged to recognize the needs and assets of the other two groups. Specific examples of the benefits of this arrangement are described based on experiences in the state of Oregon.This work is supported in part by NIMH grant number P50 MH43458 to the Western Mental Health Research Center at Oregon Health Sciences University. Dr. McFarland is Burroughs-Wellcome Scholar in Pharamacoepidemiology.     

Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria"

New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.     

Spatial organization of human perioral reflexes

Reflex responses recorded from the upper and lower divisions of the human orbicularis oris muscle were studied as a function of the site of stimulation. Stimuli were applied to 11 sites, ranging from the glabrous skin of the upper and lower lip vermilion borders to the hairy skin of the cheek. Highly localized, innocuous mechanical stimuli were created by displacing a servo-controlled probe over the surface of the perioral skin. Reflex response amplitude was strongly dependent on the site of stimulation. Stimulation of some sites, for example the ipsilateral corner of the mouth, the chin, and cheek, produced no responses, whereas stimulation of other sites, particularly the ipsilateral vermilion borders, produced large reflex responses. Changes in response amplitude as a function of stimulation site were the same for the upper lip and lower lip muscle recordings, with the largest responses at both recording sites produced by stimulation of the ipsilateral upper lip vermilion border. These results suggest that the upper and lower divisions of orbicularis oris share common synaptic drive, at least from inputs generated via reflex pathways, and that the upper vermilion border may be more densely innervated with mechanoreceptors than the lower. The latter hypothesis was supported by an additional experiment examining two-point discrimination thresholds for the glabrous skin of the upper and lower lips. Two-point thresholds were significantly smaller for the upper compared with the lower lip vermilion border.     

Efficacy of propranolol therapy after acute myocardial infarction related to coronary arterial anatomy and left ventricular function

The effect of the beta-adrenergic blocking agent propranolol on morbidity and mortality risk after acute myocardial infarction was studied relative to coronary anatomy and left ventricular (LV) ejection fraction in a subset of 406 patients participating in a randomized study of 3,837 patients in the Beta Blocker Heart Attack Trial (BHAT). Median follow-up for this subset of patients was 28 months. The mortality rate was 2% (2 of 100) in patients with 2- and 3-vessel coronary artery disease taking propranolol and 10% (12 of 126) in those taking placebo (p less than 0.02). In patients with 2- and 3-vessel coronary artery disease with decreased LV function (defined as ejection fraction less than 50%), no patient taking propranolol died, whereas 17% (7 of 42) taking placebo died (p less than 0.04). The salutary effect of propranolol on mortality in the larger BHAT after acute myocardial infarction also was evident in this population studied in regard to their coronary and LV anatomy and function.     

An EEG-based brain-computer interface for cursor control.

This study began development of a new communication and control modality for individuals with severe motor deficits. We trained normal subjects to use the 8-12 Hz mu rhythm recorded from the scalp over the central sulcus of one hemisphere to move a cursor from the center of a video screen to a target located at the top or bottom edge. Mu rhythm amplitude was assessed by on-line frequency analysis and translated into cursor movement: larger amplitudes moved the cursor up and smaller amplitudes moved it down. Over several weeks, subjects learned to change mu rhythm amplitude quickly and accurately, so that the cursor typically reached the target in 3 sec. The parameters that translated mu rhythm amplitudes into cursor movements were derived from evaluation of the distributions of amplitudes in response to top and bottom targets. The use of these distributions was a distinctive feature of this study and the key factor in its success. Refinements in training procedures and in the distribution-based method used to translate mu rhythm amplitudes into cursor movements should further improve this 1-dimensional control. Achievement of 2-dimensional control is under study. The mu rhythm may provide a significant new communication and control option for disabled individuals.     

Violence,mental health,and physical symptoms in an academic internal medicine practice

OBJECTIVE: To assess how physical and/or sexual intimate partner violence (IPV), child abuse, and community violence relate to long-term mental and physical problems; to examine the overlap between different forms of violence and the impact of experiencing multiple forms of violence. DESIGN: Cross-sectional survey. SETTING: Three general internal medicine practices affiliated with an academic medical center. PARTICIPANTS: English-speaking women aged 25 to 60. MEASUREMENTS: Telephone or in-person interview and chart review. RESULTS: One hundred seventy-four women completed interviews. A majority of participants experienced more than one form of violence. In separate multivariate analyses, each form of violence was associated with depressive symptoms or with at least 6 chronic physical symptoms, after adjustment for demographic factors and substance abuse. The degree of association with health outcomes was similar for each form of violence (odds ratio [OR], 2.4 to 3.9; P < .003). The association with chronic physical symptoms remained significant for IPV (OR, 3.3; P < .002) and community violence (OR, 3.4; P < .003), even after adjustment for depression and posttraumatic stress disorder. There were dose-response relationships between the number of forms of violence experienced and the odds of depressive symptoms and the odds of multiple chronic physical symptoms. CONCLUSIONS: Multiple types of victimizations may contribute to patients' current mental health and physical problems. Research or clinical protocols that only focus on one form of violence may underestimate the complexity of women's experiences and needs.