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Supplementary Figure 1 from Caffeine-Mediated Inhibition of Calcium Release Channel Inositol 1,4,5-Trisphosphate Receptor Subtype 3 Blocks Glioblastoma Invasion and Extends Survival

Supplementary Figure 4 from Caffeine-Mediated Inhibition of Calcium Release Channel Inositol 1,4,5-Trisphosphate Receptor Subtype 3 Blocks Glioblastoma Invasion and Extends Survival

Supplementary Figure 2 from Caffeine-Mediated Inhibition of Calcium Release Channel Inositol 1,4,5-Trisphosphate Receptor Subtype 3 Blocks Glioblastoma Invasion and Extends Survival

Supplementary Methods from Caffeine-Mediated Inhibition of Calcium Release Channel Inositol 1,4,5-Trisphosphate Receptor Subtype 3 Blocks Glioblastoma Invasion and Extends Survival

Diabetes is prevalent, and it imposes a substantial public health burden globally and in the Asia-Pacific (APAC) region. The cornerstone for optimizing diabetes management and treatment outcomes is glucose monitoring, the techniques of which have evolved from self-monitoring of blood glucose (SMBG) to glycated hemoglobin (HbA1c), and to continuous glucose monitoring (CGM). Contextual differences with Western populations and limited regionally generated clinical evidence warrant regional standards of diabetes care, including glucose monitoring in APAC. Hence, the APAC Diabetes Care Advisory Board convened to gather insights into clinician-reported CGM utilization for optimized glucose monitoring and diabetes management in the region. We discuss the findings from a pre-meeting survey and an expert panel meeting regarding glucose monitoring patterns and influencing factors, patient profiles for CGM initiation and continuation, CGM benefits, and CGM optimization challenges and potential solutions in APAC. While CGM is becoming the new standard of care and a useful adjunct to HbA1c and SMBG globally, glucose monitoring type, timing, and frequency should be individualized according to local and patient-specific contexts. The results of this APAC survey guide methods for the formulation of future APAC-specific consensus guidelines for the application of CGM in people living with diabetes.

Background The role of mobile health care (mHealth) in glycemic control has been investigated, but its impact on self-management skills and its psychological aspects have not been studied. Objective We evaluated the efficacy of mHealth-based diabetes self-management education and the effect of voluntary participation on its effects. Methods This study was a randomized controlled open-label trial conducted for 6 months at Kangbuk Samsung Hospital. Participants in the control group (n=31) maintained their previous diabetes management strategies. Participants in the intervention group (n=41) additionally received mHealth-based diabetes self-management education through a mobile app and regular individualized feedback from health care professionals. The primary outcome was change in glycated hemoglobin (HbA1c) level over 6 months between the 2 groups (intervention versus control) and within each group (at 6 months versus baseline). The secondary outcomes were changes in body mass index, blood pressure, lipid profile, and questionnaire scores (the Korean version of the Summary of Diabetes Self-Care Activities Questionnaire, an Audit of Diabetes Dependent Quality of Life, the Appraisal of Diabetes Scale, and Problem Areas in Diabetes) over 6 months between groups and within each group. Results A total of 66 participants completed this study. HbA1c (P=.04), total cholesterol level (P=.04), and Problem Areas in Diabetes scores (P=.02) significantly decreased; total diet (P=.03) and self-monitoring of blood glucose level scores (P=.01), based on the Summary of Diabetes Self-Care Activities Questionnaire, markedly increased within the intervention group. These significant changes were observed in self-motivated participants who were recruited voluntarily via advertisements. Conclusions mHealth-based diabetes self-management education was effective at improving glycemic control and diabetes self-management skills and lowering diabetes-related distress in voluntary participants. Trial Registration ClinicalTrials.gov NCT03468283; http://clinicaltrials.gov/ct2/show/NCT03468283

t-PA has a widespread neuroendocrine distribution including prominent expression in chromaffin cells of the sympathoadrenal system. Chromaffin cell t-PA is sorted into catecholamine storage vesicles and co-released with catecholamines in response to sympathoadrenal activation, suggesting that catecholamine storage vesicles may serve as a reservoir for the rapid release of t-PA. Chromogranin A (CgA), a major core protein in secretory vesicles throughout the neuroendocrine system, may play a crucial role in targeting proteins into the regulated secretory pathway, by forming aggregated "granin" complexes to which other proteins destined for the regulated secretory vesicle bind and become separated from constitutively secreted proteins in the trans-Golgi network (TGN). Formation of such complexes is facilitated by conditions of the TGN (low pH, high Ca(+2)). We tested the hypothesis that t-PA interacts specifically with CgA and that this interaction is enhanced under conditions of the TGN. Immobilized t-PA was incubated with (125)I-CgA. t-PA interacted specifically and saturably with CgA and the interaction was domain-specific, mediated by the EGF/finger and kringle 1 domains of t-PA and by a specific internal hydrophilic domain within CgA (KERTHQQKKHSSYEDELSEVL) as assessed by antibody and peptide competition studies. The interaction of t-PA with aggregated CgA complexes may play a role in the targeting of t-PA and its release from neurosecretory cells. These results may have broad implications for the regulation of local neurosecretory cell plasminogen activation under both normal physiological conditions and pathological conditions including cerebral ischemia.

BACKGROUND The role of mobile health care (mHealth) in glycemic control has been investigated, but its impact on self-management skills and its psychological aspects have not been studied. OBJECTIVE We evaluated the efficacy of mHealth-based diabetes self-management education and the effect of voluntary participation on its effects. METHODS This study was a randomized controlled open-label trial conducted for 6 months at Kangbuk Samsung Hospital. Participants in the control group (n=31) maintained their previous diabetes management strategies. Participants in the intervention group (n=41) additionally received mHealth-based diabetes self-management education through a mobile app and regular individualized feedback from health care professionals. The primary outcome was change in glycated hemoglobin (HbA1c) level over 6 months between the 2 groups (intervention versus control) and within each group (at 6 months versus baseline). The secondary outcomes were changes in body mass index, blood pressure, lipid profile, and questionnaire scores (the Korean version of the Summary of Diabetes Self-Care Activities Questionnaire, an Audit of Diabetes Dependent Quality of Life, the Appraisal of Diabetes Scale, and Problem Areas in Diabetes) over 6 months between groups and within each group. RESULTS A total of 66 participants completed this study. HbA1c (P=.04), total cholesterol level (P=.04), and Problem Areas in Diabetes scores (P=.02) significantly decreased; total diet (P=.03) and self-monitoring of blood glucose level scores (P=.01), based on the Summary of Diabetes Self-Care Activities Questionnaire, markedly increased within the intervention group. These significant changes were observed in self-motivated participants who were recruited voluntarily via advertisements. CONCLUSIONS mHealth-based diabetes self-management education was effective at improving glycemic control and diabetes self-management skills and lowering diabetes-related distress in voluntary participants. CLINICALTRIAL ClinicalTrials.gov NCT03468283; http://clinicaltrials.gov/ct2/show/NCT03468283

Background Microfracture is a surgical technique that involves creating multiple holes of 3–4 mm depth in the subchondral bone to recruit stem cells in the bone marrow to the lesion, inducing fibrocartilage repair and knee cartilage regeneration. Recently, it has been reported that increasing the exposed area of the lower cartilaginous bone (drilling a lot of holes) increases the outflow of stem cells, which is expected to affect the physical properties of the subchondral bone when the exposed area is large. The purpose of this study was to analyse the effect of the distance between the holes in the microfracture procedure on the structural stability of the osteochondral bone using a finite element method. Methods In this study, lateral aspects of the femoral knee, which were removed during total knee arthroplasty were photographed using microtomography. The model was implemented using a solitary walks program, which is a three-dimensional simplified geometric representation based on the basic microtomography data. A microfracture model was created by drilling 4 mm-deep holes at 1, 1.5, 2, 2.5, 3, 4, and 5 mm intervals in a simplified three-dimensional (3D) geometric femoral model. The structural stability of these models was analysed with the ABAQUS program. We compared the finite element model (FEM) based on the microtomography image and the simplified geometric finite element model. Results Von Mises stress of the subchondral bone plate barely increased, even when the distance between holes was set to 1 mm. Altering the distance between the holes had little impact on the structural stability of the subchondral bone plate. Safety factors were all below 1. Conclusions Although we did not confirm an optimal distance between holes, this study does provide reference data and an epidemiological basis for determining the optimal distance between the holes used in the microfracture procedure.

This study aimed to investigate the effect of patient engagement in self-monitoring with a telemonitoring device on glycemic control among patients with type 2 diabetes. We conducted a subanalysis of the telemonitoring device study in Kaiser Permanente Northern California members. We divided the telemonitoring group into 53 frequent and 54 infrequent users based on self-monitoring of blood glucose (SMBG) frequency of the first 6 weeks. The frequency of SMBG transmitted from the telemonitoring device was examined over 24 weeks. Clinic and laboratory tests were collected at baseline, 6 weeks and 6 months. There was no significant difference in baseline HbA1c level between the two groups. After 6 months, change in HbA1c was −2.4 ± 1.6% among frequent users and −1.5 ± 1.5% among infrequent users (p = 0.003). The proportion of patients achieving target HbA1C level at 6 months was significantly higher among frequent users than among infrequent users. An increased frequency of SMBG was significantly correlated with a reduction in HbA1c at 6 months. In conclusion, initial active engagement in self-monitoring with a telemonitoring device could provide incremental improvement of glycemic control over 6 months.

Recently, mobile health care has been applied to manage diabetes requiring self-management. Health care by mobile applications (apps) has a great advantage when applied to patients with diabetes; the adherence to self-management activities for diabetes can be improved through mobile apps. The Food and Drug Administration (FDA) has cleared and approved the use of some mobile apps as medical devices for the management of diabetes since 2010. However, mobile apps may not be effective for all patients. We here report the effect of use of mobile-based diabetes care app (Healthy-note app) for 2 patients with diabetes, and discuss issues and strategies for effective mobile intervention. Further study is needed on improving patient's participation to increase the effect of management via a mobile app.

Limited information is available on the optimal cement thickness of monolithic zirconia crowns. This study was designed to evaluate the stress distribution in the posterior monolithic zirconia crowns with different cement thicknesses under masticatory force and maximum bite force using three-dimensional finite element analysis. The prepared and unprepared mandibular right first molar models were scanned and exported to the computer-aided design system. Solid models of monolithic zirconia crowns, which were cemented on prepared teeth were generated. Four models were fabricated applying different cement thicknesses (100 µm, 200 µm, 400 µm, and 600 µm). The solid models were imported into the finite element analysis software and meshed into tetrahedral elements. Four three-dimensional finite element models were simulated under masticatory force and maximum bite force: vertical (axial), angular (45°) and horizontal loads of 280 N at 5 points; vertical load of 700 N at 8 points were loaded, respectively. The stress distribution varied with the different cement thicknesses and directions of applied loads. The monolithic zirconia crowns with cement thicknesses exceeding 200 µm had wider distributions of peak maximum principal stress under the same loading conditions. Monolithic zirconia crowns have more stress concentrations on the occlusal surfaces, while the cement layers have more stress concentrations on the cervical areas. Thicker cement layers were associated with more concentrated stresses on the buccal and lingual cervical areas. The test results show that the cement thickness plays an essential role in the success of monolithic zirconia restorations in terms of reducing cement wash-out. Cement thickness of 100 µm is recommended for monolithic zirconia crowns.

The purpose of this study was to evaluate the effects of coping designs on the stress distributions in posterior zirconia crowns by non-linear three-dimensional finite element analysis. Three-dimensional finite element models of a mandibular right first molar with layers of veneering porcelain, zirconia coping, cement, and abutment tooth were designed by computer software (HyperWorks 10.0). Ten zirconia crowns with different designs were produced according to various shoulder positions and heights. The shoulders (1-mm width) exhibited incremental height increases of 1 mm, 2 mm, and 3 mm on the buccal, lingual, and proximal sides, respectively. An axial compressive dynamic load simulating the progressive load was applied until a stainless steel ball model (7 mm in diameter) deepened the veneer surface to 0.7 mm in depth. Loads were placed on the inner inclines of the mesiobuccal, distobuccal, and mesiolingual cusps. Residual maximum principal stresses (MPSs) at the veneer and coping under progressive loading were determined for each zirconia crown. Reinforcements with the shoulders on the buccal, lingual, and proximal axial walls resulted in lower MPSs in the veneering porcelain but higher MPSs in the zirconia coping. As the shoulder height increased, the tensile stresses decreased, while the compressive stresses increased in the veneering porcelains. It can be concluded that the shoulder height and position in the zirconia coping will affect the MPSs of the crown. Our findings conclusively reveal the critical role of the shoulder design of the coping in preventing veneer fracture on posterior zirconia restorations by reducing tensile stresses in veneering porcelain.

An analytical study has been carried out to investigate the effect of piezoelectricity and spontaneous polarization on the critical thickness for misfit dislocation formation at the interface of InGaN/GaN layers. Two representative critical thickness prediction formulations given by Matthews (1974) and Freund (1987) have been generalized to include piezoelectricity and spontaneous polarization. Critical thicknesses have been calculated by using the generalized methods and presented for both c-plane and a-plane deposition in hexagonal crystal lattice. Numerical results of the critical thickness for an InGaN epitaxial film on a GaN substrate has been presented and discussed in terms of the indium concentration in the epitaxial layer, the line charge associated with the dislocation core, the spontaneous polarization along c-axis, and the piezoelectric constants of the In x Ga ( 1 - x ) N film. Here, x stands for indium concentration. The indium concentration determines the misfit strain due to lattice mismatch between the InGaN film and GaN substrate. It is shown that the piezoelectricity and spontaneous polarizations have negligible effect on the critical thickness for the case of InGaN/GaN. Parametric studies were carried out by increasing the piezoelectric properties of the In x Ga ( 1 - x ) N ten folds. It has been found that the enhanced piezoelectricity reduces the critical thickness so that it becomes easier to form the misfit dislocation. We have investigated the reason for the decrease in the critical thickness due to piezoelectricity by investigating the state of stress and internal energy of the film. Our study shows that the enhanced piezoelectric properties give rise to stiffening of the film which increases its elastic energy. This makes it favorable to form misfit dislocations by increasing the available energy for dislocation formation. It is also shown that spontaneous polarization along c-axis in the InGaN film decreases the critical thickness for c-growth orientation while it increases the critical thickness along a-growth orientation. This occurs because the internal energy of the film increases due to spontaneous polarization for c-growth orientation while it decreases for a-growth orientation. However, the increase or decrease in the critical thickness due to spontaneous polarization is very marginal. A line charge associated with dangling bonds along the dislocation core increases the critical thickness because it increases the required energy to form the dislocation.

A misfitted spherical inclusion embedded in an infinite matrix under far-field triaxial mechanical and uniform thermal loads is analyzed in three-dimensional linear elasticity. Closed-form expressions for each loading case have been obtained separately utilizing proper continuity and far-field loading conditions. The principle of superposition has been utilized to obtain the complete solution from these three individual solutions. The solutions are discussed in terms of stress distribution, magnitude and locations of stress concentrations. Closed-form expressions for energy release rates have been derived based on the stress and strain solutions by employing the path-independent integrals, J, L and M considering the inclusion as a defect. The measure of self-similar expansion energy release rate provided by the M-integral brings some interesting insight which can be applicable to many practical cases such as phase transformations in metals and nanoscale defects. The fundamental work presented here will help to better understand the behavior of materials with a misfitted inclusion subjected to various loading environments.

The corrosion behavior of mild steel was studied in 1 M HCl solution containing varying amounts of triazine derivatives having amine groups and alkyl carboxylic acid groups. The synthesized triazine derivatives were characterized by Fourier transform infrared (FT-IR) spectroscopy, NMR, mass spectroscopy, and elemental analysis (EA), and their corrosion inhibition properties were determined by potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) techniques. We found that the triazine derivatives acted as mixed-type inhibitors by their adsorption on the metal surface. We also proposed that the Langmuir adsorption isotherm model could be used to explain the adsorption of triazine derivatives. In addition, when the alkyl chain length of the triazine derivative was relatively long, we also obtained a high-adsorption equilibrium constant and low Gibbs free energy of adsorption. Thus, we conclude that the alkyl chain length plays an important role in the corrosion inhibition properties of triazine derivatives.

Background On September 27, 2012, at 3:43 pm, a hydrogen fluoride spill occurred in a manufacturing plant located at the 4th complex of the Gumi National Industrial Complex in Gumi City, South Korea. The present study aimed to evaluate the psychological effects of the hydrogen fluoride spill on the members of the community and to investigate their relationships with physical symptoms and changes in psychological effects occurring as time passed after the accident. Methods The 1st phase involved a survey of 1359 individuals that was conducted 1 month after the spill, and the 2nd phase involved a survey of 711 individuals that was conducted 7 months after the accident. The questionnaires included items for assessing demographic characteristics, hydrogen fluoride exposure level, physical symptoms, and psychological status. Physical symptoms were assessed to determine the persistence of irritations. Psychological status was assessed to investigate the impact of event level using the Impact of Event Scale – Revised Korean version (IES-R-K), and the anxiety level was assessed using the Beck Anxiety Inventory (BAI). Results As the hydrogen fluoride exposure level increased, the impact of event and anxiety levels increased significantly both 1 and 7 months after the accident (p

Secretory granules have been demonstrated to be the major inositol 1,4,5-trisphosphate (IP3)-sensitive intracellular Ca2+ stores in secretory cells, primarily due to the presence of high concentrations of the Ca2+ storage proteins chromogranins and the IP3 receptor (IP3R)/Ca2+ channels in addition to 40 mM Ca2+. Among the many extraordinary features of secretory granules is the coupling to the IP3R/Ca2+ channels and the channel-modulatory roles of chromogranins, increasing the open probability and the mean open time of the channels multiple-fold. Particularly noteworthy is that most conserved regions of chromogranins A (CGA) and B (CGB) and of the IP3Rs, i.e., the near amino (N)-terminal region of chromogranins A and B and the last intraluminal loop (L3-2 loop) of the IP3Rs, participate in the coupling. Given that the two regions which participate in the coupling are highly conserved in the biokingdom, the coupling between chromogranins and the IP3R/Ca2+ channels appears to be a very ancient molecular design forming the IP3-dependent Ca2+ signaling systems of organisms. Although the coupling is uncovered in secretory cells, similar molecular arrangements which involve the IP3R/Ca2+ channels and some type of Ca2+ storage and/or Ca2+ channel-modulatory proteins that are functionally equivalent to chromogranins in secretory cells will also exist in nonsecretory cells.

The effects of crystal orientation on the optical gain characteristics of blue AlInGaN/InGaN quantum-well (QW) structures with a reduced internal field were investigated by using the non-Markovian model with many-body effects. The AlInGaN/InGaN system has a larger matrix element than the conventional InGaN/GaN system because the former has a smaller internal field than the latter for relatively small crystal angles. As a result, for QW structures with a relatively small crystal angle (θ = 30°), the AlInGaN/InGaN system is shown to have a much larger optical gain than the conventional InGaN/GaN system. On the other hand, in the case of QW structures with a large crystal angle (θ = 90°), the AlInGaN/InGaN system is shown to have a smaller optical gain than the conventional InGaN/GaN system. Hence, we expect that we can obtain high-efficiency optoelectronic devices by using quaternary AlInGaN QW for relatively small crystal angles.

Phosphatidylinositol (PI) kinases are key molecules that participate in the phosphoinositide signaling in the cytoplasm. Despite the accumulating evidence that supports the existence and operation of independent PI signaling system in the nucleus, the exact location of the PI kinases inside the nucleus is not well defined. Here we show that PI4-kinases IIα and IIβ, which play central roles in PI(4,5)P2 synthesis and PI signaling, are localized in numerous small nucleoplasmic vesicles that function as inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)-sensitive Ca(2+) stores. This is in accord with the past results that showed the localization of PI4(P)5-kinases that are essential in PI(4,5)P2 production and PI(4,5)P2 in nuclear matrix. Along with PI(4,5)P2 that also exists on the nucleoplasmic vesicle membranes, the localization of PI4-kinases IIα and IIβ in the nucleoplasmic vesicles strongly implicates the vesicles to the PI signaling as well as the Ins(1,4,5)P3-depenent Ca(2+) signaling in the nucleus. Accordingly, the nucleoplasmic vesicles indeed release Ca(2+) rapidly in response to Ins(1,4,5)P3. Further, the Ins(1,4,5)P3-induced Ca(2+) release studies suggest that PI4KIIα and IIβ are localized near the Ins(1,4,5)P3 receptor (Ins(1,4,5)P3R)/Ca(2+) channels on the Ca(2+) store vesicle membranes. In view of the widespread presence of the Ins(1,4,5)P3-dependent Ca(2+) store vesicles and the need to fine-control the nuclear Ca(2+) concentrations at multiple sites along the chromatin fibers in the nucleus, the existence of the key PI enzymes in the Ins(1,4,5)P3-dependent nucleoplasmic Ca(2+) store vesicles appears to be in perfect harmony with the physiological roles of the PI kinases in the nucleus.

Although early detection and successful gastrectomy have improved the survival of patients with gastric cancer, long-term health problems remain troubling. We evaluated the prevalence of osteoporosis and its risk factors in long-term survivors of gastric cancer after gastrectomy. We reviewed the medical records of a tertiary hospital between 2007 and 2014 to identify survivors of gastric cancer who had visited our center at around 5 years after gastrectomy. We evaluated their health status, including bone mineral density (BMD). Dual-energy X-ray absorptiometry was used to measure the BMD of the lumbar spine and femur (total and neck area). The prevalence of osteoporosis, defined by a BMD T score

In the present work, the corrosion inhibition properties of three amino acid compounds, glycine (Gly), 2,2′-azanediyldiacetic acid (IDA), 5-aminopentanoic acid (5-APA), and two triazine (Tris) derivatives containing Gly or IDA units were investigated. It was found that the amino acids and their triazine derivatives behaved like mixed-type corrosion inhibitors that reduced oxidative dissolution and retarded a hydrogen emission reaction. In the case of the three amino acids, it was found that the increase in the length and the number carboxylic acid groups of the molecules enhanced the corrosion inhibition properties. It was also observed that the presence of triazine ring enhanced the corrosion inhibition properties significantly. It was suggested that the adsorption of triazine derivatives on a metal surface was the Langmuir isotherm adsorption and mainly physisorption. In the case of Tris-IDA, the six acetic acid moieties emanating from the triazine ring led to partial negative charges on the outer layer...

PURPOSE The purpose of this study was to evaluate various core designs on stress distribution within zirconia crowns. MATERIALS AND METHODS Three-dimensional finite element models, representing mandibular molars, comprising a prepared tooth, cement layer, zirconia core, and veneer porcelain were designed by computer software. The shoulder (1 mm in width) variations in core were incremental increases of 1 mm, 2 mm and 3 mm in proximal and lingual height, and buccal height respectively. To simulate masticatory force, loads of 280 N were applied from three directions (vertical, at a 45° angle, and horizontal). To simulate maximum bite force, a load of 700 N was applied vertically to the crowns. Maximum principal stress (MPS) was determined for each model, loading condition, and position. RESULTS In the maximum bite force simulation test, the MPSs on all crowns observed around the shoulder region and loading points. The compressive stresses were located in the shoulder region of the veneer-zirconia interface and at the occlusal region. In the test simulating masticatory force, the MPS was concentrated around the loading points, and the compressive stresses were located at the 3 mm height lingual shoulder region, when the load was applied horizontally. MPS increased in the shoulder region as the shoulder height increased. CONCLUSION This study suggested that reinforced shoulder play an essential role in the success of the zirconia restoration, and veneer fracture due to occlusal loading can be prevented by proper core design, such as shoulder.

Introduction The aim of this study was to improve the quality of diabetes control and evaluate the efficacy of an Internet-based integrated healthcare system for diabetes management and safety. Methods We conducted a large-scale, multi-centre, randomized clinical trial involving 484 patients. Patients in the intervention group ( n = 244) were treated with the Internet-based system for six months, while the control group ( n = 240) received the usual outpatient management over the same period. HbA1c, blood chemistries, anthropometric parameters, and adverse events were assessed at the beginning of the study, after three months, and the end of the study. Results There were no initial significant differences between the groups with respect to demographics and clinical parameters. Upon six-month follow-up, HbA1c levels were significantly decreased from 7.86 ± 0.69% to 7.55 ± 0.86% within the intervention group ( p Discussion This e-healthcare system was effective for glucose control and body composition improvement without associated adverse events in a multi-centre trial. This system may be effective in improving diabetes control in the general population.

It is well known that the energy release rate associated with translation, rotation and self-similar expansion of defects in solids are expressed by the path-independent integrals J, L, and M, respectively. It is shown that these integrals for a crack or a circular hole may be obtained by first considering an elliptical cavity and then performing a limiting process. This obviates dealing with singularities at the crack tip. The energy release rates for these defects under various mechanical, thermal and electromechanical loading conditions are calculated.