Estimating hypoxic status in human tumors: a simulation using Eppendorf oxygen probe data in cervical cancer patients

PURPOSE: To define the minimal number of pO(2) measurements, with 90% sensitivity and 90% specificity, needed to categorize cervical tumors as either hypoxic or oxic. METHODS AND MATERIALS: Using Eppendorf oxygen probe data from our ongoing prospective trial, we simulated the measurement of tumor oxygenation with a smaller number of data points in 135 patients with cervical cancer. The hypoxic proportion, defined as the percentage of pO(2) values <5 mm Hg (HP5), was calculated for each tumor. Hypoxic tumors were defined as those with a median HP5 >50%, and tumors with normal oxygen levels as those with a median HP5 < or =50%. A small number of pO(2) measurements were randomly selected from the Eppendorf measurements in each tumor, or per Eppendorf track, and used to define the tumor as hypoxic or oxic. The sensitivity and specificity were calculated, considering the classification as given by the complete set of Eppendorf measurements as the reference standard. RESULTS: The probability of falsely classifying the tumor decreased as the selected number of pO(2) measurements per tumor increased, and at 16 measurements was approximately 10%. Adding additional measurements per tumor beyond 24 improved the ability to classify the tumor accurately only slightly. The probability of falsely classifying the tumor decreased as the pO(2) measurements per track increased. At five measurements per track, the probability of falsely classifying the tumor was approximately 9%. CONCLUSION: Approximately 20 measurements per tumor, or five measurements per track, using the Eppendorf pO(2) histograph, are sufficient to categorize cervical tumors as hypoxic or oxic. The results of this study will serve as a guide for research clinicians in the use of this and other systems in the assessment of tumor oxygenation in humans.     

Calcium hydroxide in restorative dentistry

This paper reviews the various calcium hydroxide preparations available for use in restorative dentistry and their constituents. The significance of individual constituents in relation to the properties of such materials and their mode of therapeutic action with respect to the dentine pulpal response and antibacterial activity is discussed. Applications of calcium hydroxide in restorative dentistry are also reviewed.     

Does Alzheimer's disease begin in the brainstem?

Although substantial evidence indicates that the progression of pathological changes of the neuronal cytoskeleton is crucial in determining the severity of dementia in Alzheimer's disease (AD), the exact causes and evolution of these changes, the initial site at which they begin, and the neuronal susceptibility levels for their development are poorly understood. The current clinical criteria for diagnosis of AD are focused mostly on cognitive deficits produced by dysfunction of hippocampal and high‐order neocortical areas, whereas noncognitive, behavioural and psychological symptoms of dementia such as disturbances in mood, emotion, appetite, and wake–sleep cycle, confusion, agitation and depression have been less considered. The early occurrence of these symptoms suggests brainstem involvement, and more specifically of the serotonergic nuclei. In spite of the fact that the Braak and Braak staging system and National Institutes of Aging – Reagan Institute (NIA‐RI) criteria do not include their evaluation, several recent reports drew attention to the possibility of selective and early involvement of raphe nuclei, particularly the dorsal raphe nucleus (DRN), in the pathogenesis of AD. Based on these findings of differential susceptibility and anatomical connectivity, a novel pathogenetic scheme of AD progression was proposed. Although the precise mechanisms of neurofibrillary degeneration still await elucidation, we speculated that cumulative oxidative damage may be the main cause of DRN alterations, as the age is the main risk factor for sporadic AD. Within such a framework, β‐amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD‐related neuropathological changes.     

Hysteroscopic endometrial resection and high-dose-rate brachytherapy: treatment of endometrial cancer in a medically compromised patient.

OBJECTIVE: The use of a combined treatment option for endometrial cancer in a medically compromised patient is outlined. METHODS/RESULTS: A case of a 49-year-old severely medically compromised patient with endometrial cancer is described. A complete hysteroscopic endometrial resection with insertion and suturing in place of an endocervical cannula allowed weekly outpatient delivery of high-dose-rate intracavitary radiation without anesthetic or repeat dilatation of the endocervical canal. CONCLUSION: The use of hysteroscopic endometrial resection with adjuvant high-dose-rate radiation therapy is a feasible treatment option for patients with endometrial cancer in whom surgery is contraindicated.     

Inducible nitric oxide synthase does not mediate brain damage after transient focal cerebral ischemia in mice.

Nitric oxide produced by the inducible nitric oxide synthase (iNOS) is believed to participate in the pathogenic events after cerebral ischemia. In this study, we examined the expression of iNOS in the brain after transient focal cerebral ischemia in mice. We detected differential expression of exons 2 and 3 of iNOS mRNA (16-fold upregulation at 24 to 72 h after middle cerebral artery occlusion, MCAO) compared with exons 6 to 8, 12 to 14, 21 to 22, and 26 to 27 (2- to 5-fold upregulation after 72 and 96 h), which would be compatible with alternative splicing. Expression levels of iNOS mRNA were too low for detection by the Northern blot analysis. Using specific antibodies, we did not detect any iNOS immunoreactivity in the mouse brain 1 to 5 days after MCAO, although we detected iNOS immunoreactivity in the lungs of mice with stroke-associated pneumonia, and in mouse and rat dura mater after lipopolysaccharide administration. In chimeric iNOS-deficient mice transplanted with wild-type bone marrow (BM) cells expressing the green fluorescent protein (GFP) or in wild-type mice transplanted with GFP(+) iNOS-deficient BM cells, no expression of iNOS was detected in GFP(+) leukocytes invading the ischemic brain or in resident brain cells. Moreover, both experimental groups did not show any differences in infarct size. Analysis of three different strains of iNOS-deficient mice and wild-type controls confirmed that infarct size was independent of iNOS deletion, but strongly confounded by the genetic background of mouse strains. In conclusion, our data suggest that iNOS is not a universal mediator of brain damage after cerebral ischemia.     

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire

PurposeThis paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib).MethodsThis is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe.ResultsClinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction–related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals.ConclusionEmpagliflozin has a favorable effect on neutropenia/neutrophil dysfunction–related symptoms and safety profile in individuals with GSD Ib.     

Future Directions for Research on Early Intervention for Young Children at Risk for Social Anxiety

Anxiety disorders are common among young children, with earlier onset typically associated with greater severity and persistence. A stable behaviorally inhibited (BI) temperament and subsequent shyness and social withdrawal (SW) place children at increased risk of developing anxiety disorders, particularly social anxiety. In this Future Directions article, we briefly review developmental and clinical research and theory that point to parenting and peer interactions as key moderators of both the stability of BI/SW and risk for later anxiety, and we describe existing interventions that address early BI/SW and/or anxiety disorders in young children. We recommend that future research on early intervention to disrupt the trajectory of anxiety in children at risk (a) be informed by both developmental science and clinical research, (b) incorporate multiple levels of analysis (including both individual and contextual factors), (c) examine mediators that move us closer to understanding how and why treatments work, (d) be developed with the end goal of dissemination, (e) examine moderators of outcome toward the goal of treatment efficiency, (f) consider transdiagnostic or modular approaches, (g) integrate technology, and (h) consider cultural norms regarding BI/SW/anxiety and parenting.