Genome-wide association study identifies novel risk loci for apical periodontitis.

Apical periodontitis (AP) is a common consequence of root canal infection leading to periapical bone resorption. Microbial and host genetic factors, and their interactions, have been shown to play a role in AP development and progression. Variations in a few genes have been reported in association with AP, however, the lack of genome-wide studies has hindered progress in understanding the mechanisms involved in AP. Here, we report the first genome-wide association study of AP in a well-characterized population. Male and female adults (n=932) presenting with deep caries with AP (cases) or without AP (controls) were included. Genotyping was performed using the Illumina Expanded Multi-Ethnic Genotyping Array. Single-variant association testing was performed adjusting for sex and five principal components. Subphenotype association testing, analyses of genetically regulated gene expression, polygenic risk score and phenome-wide association (PheWAS) analyses were also performed. Eight loci reached near-genome-wide significant association with AP (p < 5 x 10-6); gene-focused analyses replicated three previously reported associations (p < 8.9 x 10-5). Sex-specific and subphenotype analyses revealed additional significant associations with variants genome-wide. Functionally oriented gene-based analyses revealed eight genes significantly associated with AP (p < 5 x 10-5), and PheWAS analysis revealed 33 phecodes associated with AP risk score (p < 3.08 x 10-5). This study identified novel genes/loci contributing to AP and revealed specific contributions to AP risk in males and females. Importantly, we identified additional systemic conditions significantly associated with AP risk. Our findings provide strong evidence for host-mediated effects on AP susceptibility.

Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

Cardiac toxoplasmosis after heart transplantation diagnosed by endomyocardial biopsy.

We describe a case of cardiac toxoplasmosis diagnosed by routine endomyocardial biopsy in a patient with trimethoprim-sulfamethoxazole (TMP-SMX) intolerance on atovaquone prophylaxis. Data are not available on the efficacy of atovaquone as Toxoplasma gondii prophylaxis after heart transplantation. In heart transplant patients in whom TMP-SMX is not an option, other strategies may be considered, including the addition of pyrimethamine to atovaquone.

Nineteen eating disorder scales: Comparison by focus, ease, response format, and readability.

Eating scales vary enormously in focus, ease, response format, and readability. As part of a larger study related to ethnicity and eating scales, we examined differences in eating scales to determine whether some scales may be more global and culture free in application than others. Ease of readability is related to the educational and cultural background of those to whom the scales are administered. Thus, 30 years of psychological literature (1968-1997) was reviewed; 40 eating disorder scales were found and requested from their authors. Using those who responded, 19 major scales were compared by focus, response format, validity, length, structure, reading level, and reading complexity. As expected, scales vary enormously in focus, length, content, and response format. Readability (as grade level) ranged from a high of 10.6 to a low of 1.1; 70% of the rated scales were rated as "highly readable."

Clonal analysis of the late flowering fca mutant of Arabidopsis thaliana: cell fate and cell autonomy.

Plants that are homozygous for the fca mutation bolt and flower later than wild-type (FCA) plants. The mutation has little or no effect on the fate map of the dry seed, except that the central cells give rise to further rosette leaves instead of the bolting stem, cauling leaves and inflorescence. The large and variable sectors affecting the late rosette leaves of fca plants were used to generate an abstract frequency-distance fate map of vegetative growth. The map relates the initiation of leaves in the plant apex to their final arrangements. The map was found to be a shallow dome with phyllotaxy superimposed on its surface. X-irradiation was used to provoke loss of the FCA allele from cells in heterozygous seeds. The resulting fca sectors had no effect on the plant phenotype. Even when L2 and L3 cells at the centre of the meristem could not produce the FCA gene product, bolting and flowering was unaffected. The genotypically fca mutant tissue was incorporated into phenotypically normal stems, cauline leaves and flowers. Possible reasons for the non-autonomous behaviour of the trait are discussed.

Comprehensive surgical radiation oncology.

Surgical radiation oncology uses surgical procedures to deliver or assist in the delivery of radiation to a tumor or tumor bed after resection. Intraoperative radiation therapy (IORT) bypasses radiosensitive skin and superficial structures and allows radiation to be delivered directly to the surgically exposed tumor. Removable brachytherapy places radioactive material inside or close to a tumor through hollow catheters positioned inside the tumor. Permanent brachytherapy inserts encapsulated radioactive seeds through needles attached to a mechanical gun directly into the tumor during surgery. This article discusses radiation precautions associated with each type of therapy and describes the nursing care needed by patients undergoing liver transplant radiation therapy.

Dissociative states and disordered eating.

To investigate the relationship between eating problems and dissociation, 142 college women completed the Eating Disorders Inventory, the Bulimia Test, the Dissociative Experiences Scale, the Perceptual Alteration Scale, and a demographic information worksheet. The two eating-disorder inventories were strongly correlated (rs = .71). The two dissociation scales, however, were only moderately correlated (rs = .32), suggesting they are measuring different underlying experiences. The pattern of the correlations of the subscales of the dissociation scales with the eating disorder scales suggested that cognitive distortions were not as important in the relationship with eating disorders (all correlations were less than .21) as were dissociation of feelings and loss of control (the correlations for eating related subscales ranged as high as .51). These results were interpreted to suggest that dissociation of feelings might underlie eating problems. These results indicate the value of the use of hypnotherapy in working with eating-disordered clients.

Role of carcinoembryonic antigen in predicting resectability of recurrent colorectal cancer.

The reported low resectability rate for patients with recurrent colorectal cancer who have carcinoembryonic antigen (CEA) levels > 11 has led us to perform this study. One hundred twenty-four patients who underwent Radioimmunoguided Surgery (RIGS) procedures for recurrent colorectal cancer from 1986 to the present were studied. In surgery, all patients underwent a traditional exploration followed by survey with a hand-held, gamma-detecting probe to detect preinjected radiolabeled monoclonal antibodies attached to cancer cells. Sites of metastases included: 72 liver (58.1 percent), 23 pelvis (18.5 percent), 15 distant lymph nodes (12.1 percent), 2 anastomotic (1.6 percent), and 12 other sites (9.7 percent). The resectability rate was 43.5 percent (54 patients). The mean preoperative CEA level for patients with resectable disease was significantly lower than for patients with unresectable disease (P = 0.017): unresectable--mean, 87.1; SD, 141.0; minimum, 0.3; maximum, 501; resectable--mean, 36.6; SD, 59.3; minimum, 0.3; maximum, 329. The CEA level for patients with liver metastasis did not vary significantly from those patients without metastasis: 70 vs. 58.2 (P = 0.58). Those patients with resectable liver tumors had lower mean CEA levels than those with unresectable liver, approaching significance: 41.6 vs. 91.9 (P = 0.065). Other metastatic sites had a mean CEA level of: pelvic, 72.6; distant lymph nodes, 47.8; anastomotic, 2.7; and other sites, 53.8. These data suggest that there is a significant difference between the preoperative CEA level of the resectable and unresectable recurrent colorectal cancer patients, but the large standard deviation does not justify abandonment of exploration for any CEA level.

Anesthetic management of a patient with moyamoya disease: a case report.

A previously healthy 4-year-old female presented with an 18-month history of frequent headaches and seizures. Magnetic resonance imaging (MRI) and angiography revealed severe stenosis of the left proximal intracranial carotid artery, with bilateral development of moyamoya vessels, left greater than right. A diagnosis of moyamoya disease was made, and the patient was scheduled for surgical correction consisting of an encephalo-duro-arterio-synangiosis. Moyamoya disease is a rare, occlusive cerebrovascular disorder characterized by bilateral stenosis of the internal carotid arteries and their branches. While its etiology is currently uncertain, recent studies indicate that focal arteritis, secondary to an antigen-antibody reaction, leads to the development of the stenosis. Anesthetic management of patients with moyamoya disease focuses on maintenance of adequate cerebral blood flow, normalization of intracranial pressure, and avoidance of both cerebral vasoconstriction and vasodilation. Several anesthetic techniques have been successfully employed; one such method is presented.

Radioimmunoguided radical prostatectomy and lymphadenectomy.

BACKGROUND: The feasibility of using radioimmunoguided surgery (RIGS) (Neoprobe Corp., Columbus, OH) for intraoperative detection of prostate cancer was examined in a pre-Phase I clinical study involving 10 patients having radical prostatectomy and lymphadenectomy. METHODS: Patients were injected with iodine 125-radiolabeled B72.3 monoclonal antibody, which has been shown previously to bind to TAG-72, a pancarcinoma and oncofetal antigen. At a mean of 26 days after injection, RIGS was performed with a specially designed intraoperative gamma-detecting probe. RESULTS: By comparing probe counts with counts of appropriate background tissues, the RIGS system successfully localized tumor to the prostate of all 10 patients. Clinically occult and histologically confirmed bilateral intraprostatic tumor was identified in three patients. One additional patient had bilateral positive intraprostatic probe count ratios with the RIGS technique; on histologic examination, tumor was identified unilaterally, and extensive high-grade prostatic intraepithelial neoplasia was found on the contralateral side. Probe count ratios were positive in the lymph nodes of three patients; two had tumor confirmed histologically. CONCLUSIONS: The current investigation supports the feasibility of the RIGS technique and the need for additional studies.

Intraoperative detection of colorectal cancer with radioimmunoguided surgery and CC49, a second-generation monoclonal antibody.

Radioimmunoguided surgery (RIGS) has been employed intraoperatively in cases of colorectal cancer to assess the extent of local tumor spread and metastatic disease. This technique uses radiolabeled monoclonal antibodies (MAbs) directed against tumor-associated antigens, and a hand-held gamma-detection probe to detect the radiolabel fixed to tumor tissue. Recently introduced is an MAb directed against tumor-associated glycoprotein (anti-TAG), CC49. Sixty patients were entered into the initial study. Eighteen of 21 (86%) primary tumors were localized by the CC49 MAb and the gamma-detecting probe. Twenty-nine of 30 (97%) recurrent tumors were localized. Antibody dose did not affect localization. Specimens were divided into tissue types I through IV, based on antibody localization and hematoxylin and eosin (H&E) staining: type I, RIGS (-) and histologically (-); type II, RIGS (-) and histologically (+); type III, RIGS (+) and histologically (-); type IV, RIGS (+) and histologically (+). Type IV tissue were further classified by whether they were grossly apparent, IVa, or grossly inapparent, IVb (occult). Occult tumor found by RIGS and confirmed by H&E staining (type IV) had localization ratios similar to RIGS-positive, histology-negative tissue (type III). Traditionally found cancer (type IV) had significantly higher ratios. In 12 of 24 patients (50%) with primary tumors and 14 of 30 patients (47%) with recurrent tumors, RIGS with CC49 altered the planned operative procedure. Radioimmunoguided surgery with CC49 provides useful, immediate intraoperative information not available by other techniques.

Hypertension and vascular dementia.

Postmortem surveys on patients treated for chronic hypertension often fail to demonstrate significant vessel changes. Nevertheless, hypertensive alterations in the brain can include infarcts and hemorrhages. Autopsies in a primary care hospital have shown that hypertension can affect arteries, arterioles, and capillaries in various patterns and degrees in the brain. These vascular lesions may be associated with large and small infarcts and hemorrhages in isolated or diffuse patterns. Widespread cerebral edema can occur with rapidly progressive hypertension. Atherosclerosis, arterial and arteriolar fibrinoid necrosis, and micro-aneurysms may be observed. Chronic hypertensive encephalopathy causes vascular dementia and can be associated with subcortical arterial and arteriolar leukoencephalopathy, leukoaraiosis and/or Binswanger's disease. Epidemiologic evaluations based on complete autopsy studies need to be correlated with compliance of therapy, appropriate diagnosis of hypertension, and its long-term effects on the nervous system. Although persistent poorly controlled hypertension is known to damage the brain both acutely and chronically, the effects of intermittent hypertension remain to be defined.

Preoperative 3D rendering of MR imaging in liver metastases.

In 15 patients who were to undergo resection of hepatic metastases, three-dimensional (3D) images of the liver were rendered from axial T2-weighted MR images by a dedicated 3D workstation. This report assesses the utility of these images in preoperative planning and intraoperative guidance. In three patients, the preoperative 3D images convinced the surgeon of resectability. All patients had laparotomies and in 12 patients, in whom the liver lesions were evaluated, there was good to excellent spatial correlation. Intraoperatively, the 3D images aided the surgeon by allowing early detection of unresectability, by showing relationships of lesions to major vessels, and by directing the surgeon to lesions otherwise difficult to find. In two patients, the original MR images failed to show multiple small lesions, thus limiting the usefulness of the 3D images.

The dexamethasone suppression test in depressed, dysthymic, and nondepressed children.

Dexamethasone suppression tests were given to seven children with major depression, six dysthymic children, and 17 children without affective disorders. The test showed sensitivity for major depressive disorder (87%) but a low specificity (53%).

Autistic children who become schizophrenic.

Infantile autism and schizophrenia have been regarded as unrelated and distinct disorders. There is, however, some evidence in the literature that supports a relationship between the two disorders in that there may be a subgroup of autistic children in whom schizophrenia develops. The diagnostic criteria used in the literature to describe infantile autism and schizophrenia in childhood has not been uniform. The three cases in this report, diagnosed on the basis of current criteria and detailed clinical descriptions, clearly point to an initial diagnosis of infantile autism followed by the development of schizophrenia.