Godanti bhasma (anhydrous CaSO4) induces massive cytoplasmic vacuolation in mammalian cells: A model for phagocytosis assay.

Phagocytosis is an essential physiological mechanism; its impairment is associated with many diseases. A highly smart particle is required for understanding detailed sequential cellular events in phagocytosis. Recently, we identified an Indian traditional medicine named Godanti Bhasma (GB), a bioactive calcium sulfate particle prepared by thermo-transformation ofgypsum. Thermal processing of the gypsum transforms its native physicochemical properties by removing water molecules into the anhydrous GB, which was confirmed by Raman and FT-IR spectroscopy. GB particle showed a 0.5-5 µm size range and a neutral surface charge. Exposure of mammalian cells to GB particles showed a rapid cellular uptake through phagocytosis and induced massive cytoplasmic vacuolation in cells. Interestingly, no cellular uptake and cytoplasmic vacuolation were observed with the parent gypsum particle. The presence of the GB particles in intra-vacuolar space was confirmed using FESEM coupled with EDX. Flow cytometry analysis and live tracking of GB-treated cells showed particle internalization, vacuole formation, particle dissolution, and later vacuolar turnover. Quantification of GB-induced vacuolation was done using neutral red uptake assay in cells. Treatment of lysosomal inhibitors (BFA1 or CQ) with GB could not induce vacuolation, suggesting the requirement of an acidic environment for the vacuolation. In the mimicking experiment, GB particle dissolution in acidic cell-free solution suggested that degradation of GB occurs by acidic pH inside the cell vacuole. Vacuole formation generally accompanies with cell death, whereas GB-induced massive vacuolation does not cause cell death. Moreover, the cell divides and proliferates with the vacuolar process, intra-vacuolar cargo degradation, and eventually vacuolar turnover. Taken together, the sequential cellular events in this study suggest that GB can be used as a smart particle for phagocytosis assay development in animal cells.

Clinico-pathological profiling of peripheral ossifying fibroma of the oral cavity.

POF represents a separate entity with diverse histological presentation. Considerable overlapping of clinical and histological features are present among different reactive gingival lesions, which warrant a meticulous review for the diagnosis of POF.

Association Between Self-Reported Dyspnea and Depressive Symptoms in New Mexico Uranium Workers.

New Mexico has the largest number of former uranium workers, mostly racial/ethnic minorities. Uranium workers are at risk for dyspnea secondary to mine dust exposure. The association between dyspnea and depressive symptoms has not been well examined in occupational minority cohorts. This study evaluated the associations between dyspnea (measured by the modified Medical Research Council Questionnaire) and depressive symptoms (measured by the Patient Health Questionnaire-2) in former uranium workers screened by the New Mexico Radiation Exposure Screening & Education Program. The subjects were mostly elderly, rural-residing, minority males. Dyspnea was commonly reported; however, depressive symptoms were uncommon. At baseline, former workers experiencing higher levels of dyspnea were more than 3 times likely to endorse depressive symptoms than those with no or mild dyspnea. Longitudinal analysis failed to determine an association between change in dyspnea and concomitant change in depressive symptoms. Dyspnea and depressive symptoms were associated cross-sectionally in former uranium workers.

Association between Spirometric Parameters and Depressive Symptoms in New Mexico Uranium Workers.

BACKGROUND: Uranium workers are at risk of developing lung disease, characterized by low forced expiratory volume in one second (FEV1) and/or forced vital capacity (FVC). Previous studies have found an association between decreased lung function and depressive symptoms in patients with pulmonary pathologies, but this association has not been well examined in occupational cohorts, especially uranium workers. METHODS: This cross-sectional study evaluated the association between spirometric measures and depressive symptoms in a sample of elderly former uranium workers screened by the New Mexico Radiation Exposure Screening & Education Program (NM-RESEP). Race- and ethnicity-specific reference equations were used to determine predicted spirometric indices (predictor variable). At least one depressive symptom [depressed mood and/or anhedonia, as determined by a modified Patient Health Questionnaire-2 (PHQ-2)], was the outcome variables. Chi-square tests and multivariable logistic regression models were used for statistical analyses. RESULTS: At least one depressive symptom was self-reported by 7.6% of uranium workers. Depressed mood was reported over twice as much as anhedonia (7.2% versus 3.3%). Abnormal FVC was associated with at least one depressive symptom after adjustment for covariates. There was no significant interaction between race/ethnicity and spirometric indices on depressive symptoms. CONCLUSIONS: Although depressive symptoms are uncommonly reported in uranium workers, they are an important comorbidity due to their overall clinical impact. Abnormal FVC was associated with depressive symptoms. Race/ethnicity was not found to be an effect modifier for the association between abnormal FVC and depressive symptoms. To better understand the mechanism underlying this association and determine if a causal relationship exists between spirometric indices and depressive symptoms in occupational populations at risk for developing lung disease, larger longitudinal studies are required. We recommend screening for depressive symptoms for current and former uranium workers as part of routine health surveillance of this occupational cohort. Such screening may help overcome workers' reluctance to self-report and seek treatment for depression and may avoid negative consequences to health and safety from missed diagnoses.

Higher Prevalence of Metabolic Syndrome in Child-adolescent Patients with Bipolar Disorder.

OBJECTIVE: Previous studies have indicated a convergent and bidirectional relationship between metabolic syndrome (MetS) and bipolar disorder (BD). As most of these studies focused mainly on adults diagnosed with BD, our study aims to investigate and characterize metabolic disturbances in child-adolescents diagnosed with BD. METHODS: We retrospectively examined the medical records of psychiatric hospitalizations with admitting diagnosis of BD in child-adolescents (age ＜ 18 years). Body mass index (BMI), lipid profile, fasting blood glucose, and blood pressure were primary variables. National Cholesterol Education Program criteria were used to define MetS. Reference group data was obtained from the National Health and Nutrition Examination Survey study. Statistical analyses included t tests, chi-square tests, and Fisher's exact tests. RESULTS: We identified 140 child-adolescent patients with BD (mean age = 15.12 ± 1.70 years, 53% male). MetS was significantly more common in BD compared to the reference group: 14% (95% confidence interval [95% CI] 8-20) vs. 6.7% (95% CI 4.1-9.2), p = 0.001 with no significant difference by sex. MetS components were higher in the BD group, particularly BMI ≥ 95% (25% vs. 11.8%, p ＜ 0.001) and high blood pressure (17% vs. 8%, p = 0.05). Moreover, female patients had lower odds of high blood pressure (odds ratio = 0.24 [95% CI 0.08-0.69], p = 0.005). CONCLUSION: Compared with the general child-adolescent population, the prevalence of MetS was significantly higher in patients with BD of same age. This reiterates the notion of an increased risk of MetS in patients diagnosed with BD; and thus, further exploration is warranted.

Methamphetamine Abuse Trends in Psychiatric Emergency Services: A Retrospective Analysis Using Big Data.

OBJECTIVE: This exploratory retrospective study assessed demographic and hospital utilization characteristics of patients presenting with methamphetamine use to an urban psychiatric emergency service in New Mexico. METHODS: De-identified data from patients presenting to PES from 2011 to 2015 were extracted from our health system. Descriptive statistics were used to characterize the study population. We employed bivariate analyses to assess the relationship between methamphetamine use and patient demographics. RESULTS: Methamphetamine use increased faster than any other drug tested during the study's time period. Compared to non-methamphetamine patients, methamphetamine use was associated with a shorter PES stay when the patient was in the PES more than 12 h. CONCLUSIONS: Patients with methamphetamine use are increasingly seeking emergency psychiatric evaluations. Methamphetamine use may impact certain racial, ethnic, and socioeconomic classes disproportionately. Further health service delivery studies are needed to develop clear, evidence-based interventions and policy recommendations to address the methamphetamine crisis in the United States.

The role of online social networking on deliberate self-harm and suicidality in adolescents: A systematized review of literature.

Social media use by minors has significantly increased and has been linked to depression and suicidality. Simultaneously, age-adjusted suicide rates have steadily increased over the past decade in the United States with suicide being the second most common cause of death in youth. Hence, the increase in suicide rate parallels the simultaneous increase in social media use. In addition, the rate of nonsuicidal self-injury ranges between 14% and 21% among young people. Evidence suggests that self-harming youth is more active on online social networks than youth who do not engage in self-harm behavior. The role of online social networking on deliberates self-harm and suicidality in adolescents with a focus on negative influence was assessed by conducting a systematized literature review. A literature search on "PubMed" and "Ovid Medline" using a combination of MeSH terms yielded nine articles for data extraction satisfying predefined inclusion/exclusion criteria. It was found that social networking websites are utilized by suicidal and self-harming youth as a medium to communicate with and to seek social support from other users. Online social networking also leads to increased exposure to and engagement in self-harm behavior due to users receiving negative messages promoting self-harm, emulating self-injurious behavior of others, and adopting self-harm practices from shared videos. Greater time spent on social networking websites led to higher psychological distress, an unmet need for mental health support, poor self-rated mental health, and increased suicidal ideation. In conclusion, greater time spent on online social networking promotes self-harm behavior and suicidal ideation in vulnerable adolescents.

Lower circulating levels of angiotensin-converting enzyme (ACE) in patients with schizophrenia.

This study aimed at evaluating changes in the renin-angiotensin system (RAS) in patients with schizophrenia in comparison with controls. Plasma levels of angiotensin-converting enzyme (ACE), ACE2, angiotensin (Ang)-(1-7) and Ang II were assessed in 25 patients with schizophrenia and 20 controls. Patients with schizophrenia presented decreased levels of ACE compared to controls [median (25th-75th percentiles) = 434.79 (341.15-524.02) vs. 508.49 (396.34-608.72); p < 0.05]. No significant differences were found regarding ACE2, Ang-(1-7) and Ang II levels. There were no associations between the measured molecules and clinical parameters. Our results corroborate the hypothesis that the RAS is involved in the pathophysiology of schizophrenia.

Protamine coated proliposomes of recombinant human insulin encased in Eudragit S100 coated capsule offered improved peptide delivery and permeation across Caco-2 cells.

In present investigation, recombinant human insulin loaded proliposomes and protamine sulphate coated proliposomes (rh insulin-proliposomes and Pt-rh insulin proliposomes) were encased in Eudragit S100 coated capsule to offer peptide release in simulated intestinal conditions. The particle size and zeta potential of Pt-rh insulin proliposomes were measured to be 583.2±10.2nm/+28.3±3.7mV significantly (P<0.05) higher than 569.7±14.9nm/-37.9±4.3mV and 534.6±24.6nm/-42.7±2.8mV of rh insulin proliposomes and proliposomes, respectively. Next, shape and surface morphology analysis pointed out the successful transformation of proliposomes in to spherical shaped liposomes. Furthermore, in vitro release study specified that free rh insulin solution encapsulated in uncoated gelatine capsule released 97.8% of peptide within 1h in SGF (pH~1.2). On other hand, rh insulin-proliposomes and Pt-rh insulin proliposomes encased in Eudragit S100 coated capsule released 93.2% and 81.6% of peptide, up to 24 h in SIF (pH~7.2). SDS-PAGE and circular dichroism (CD) ascertained the stability and intactness of isolated rh insulin from tailored dosage forms. In last, cellular uptake in Caco-2 cells indicating the superiority of Pt-rh insulin proliposomes in comparison to rh-insulin proliposomes and free rh insulin solution, respectively. In conclusion, Pt-rh insulin proliposomes displayed promising results and may be considered for further investigations.

Minimally invasive, maximal outcomes in breast surgery.

The contemporary treatment of breast cancer has evolved in response to numerous randomised control trials which have aided in the development of guidelines for effective treatment. Breast cancer surgery has progressed thanks in part to the advances made in chemotherapy, radiation therapy and early detection. As these advances continue the field of surgery needs to progress in tandem to maximise survival outcomes but to also minimise morbidity.

The fate of chemoresistance in triple negative breast cancer (TNBC).

BACKGROUND: Treatment options for women presenting with triple negative breast cancer (TNBC) are limited due to the lack of a therapeutic target and as a result, are managed with standard chemotherapy such as paclitaxel (Taxol®). Following chemotherapy, the ideal tumour response is apoptotic cell death. Post-chemotherapy, cells can maintain viability by undergoing viable cellular responses such as cellular senescence, generating secretomes which can directly enhance the malignant phenotype. SCOPE OF REVIEW: How tumour cells retain viability in response to chemotherapeutic engagement is discussed. In addition we discuss the implications of this retained tumour cell viability in the context of the development of recurrent and metastatic TNBC disease. Current adjuvant and neo-adjuvant treatments available and the novel potential therapies that are being researched are also reviewed. MAJOR CONCLUSIONS: Cellular senescence and cytoprotective autophagy are potential mechanisms of chemoresistance in TNBC. These two non-apoptotic outcomes in response to chemotherapy are inextricably linked and are neglected outcomes of investigation in the chemotherapeutic arena. Cellular fate assessments may therefore have the potential to predict TNBC patient outcome. GENERAL SIGNIFICANCE: Focusing on the fact that cancer cells can bypass the desired cellular apoptotic response to chemotherapy through cellular senescence and cytoprotective autophagy will highlight the importance of targeting non-apoptotic survival pathways to enhance chemotherapeutic efficacy.

An overview of triple negative breast cancer for surgical oncologists.

Triple negative breast cancers (TNBCs) represent a distinct subgroup of breast cancers with an immunohistochemical phenotype that is negative for oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). The aim of this article is to provide a broad overview of recent developments in the diagnosis and management of TNBC for surgical oncologists. This overview discusses the subtypes of TNBC and the relationship between this type of breast cancer and the BRCA1 gene. In addition, the article explores recent advances in the treatment of TNBC from a surgical, radiation, and medical oncology point of view. Lastly, evolving therapeutic strategies that have potential to enhance outcomes for patients with TNBC are also discussed.

Correction of pulmonary arteriovenous malformation using image-based surgical planning.

The objectives of this study were to develop an image-based surgical planning framework that 1) allows for in-depth analysis of pre-operative hemodynamics by the use of cardiac magnetic resonance and 2) enables surgeons to determine the optimum surgical scenarios before the operation. This framework is tailored for applications in which post-operative hemodynamics are important. In particular, it is exemplified here for a Fontan patient with severe left pulmonary arteriovenous malformations due to abnormal hepatic flow distribution to the lungs. Patients first undergo cardiac magnetic resonance for 3-dimensional anatomy and flow reconstruction. After analysis of the pre-operative flow fields, the 3-dimensional anatomy is imported into an interactive surgical planning interface for the surgeon to virtually perform multiple surgical scenarios. Associated hemodynamics are predicted by the use of a fully validated computational fluid dynamic solver. Finally, efficiency metrics (e.g., pressure decrease and hepatic flow distribution) are weighted against surgical feasibility to determine the optimal surgical option.

Fontan hemodynamics: importance of pulmonary artery diameter.

OBJECTIVE: We quantify the geometric and hemodynamic characteristics of extracardiac and lateral tunnel Fontan surgical options and correlate certain anatomic characteristics with their hemodynamic efficiency and patient cardiac index. METHODS AND RESULTS: The study was conducted retrospectively on 22 patients undergoing Fontan operations (11 extracardiac and 11 lateral tunnel operations). Total cavopulmonary connection geometric parameters such as vessel areas, curvature, and offsets were quantified using a skeletonization method. Energy loss at the total cavopulmonary connection junction was available from previous in vitro experiments and computational fluid dynamic simulations for 5 and 9 patients, respectively. Cardiac index data were available for all patients. There was no significant difference in the mean and minimum cross-sectional vessel areas of the pulmonary artery between the extracardiac and lateral tunnel groups. The indexed energy dissipation within the total cavopulmonary connection was strongly correlated to minimum cross-sectional area of the pulmonary arteries (R(2) value of 0.90 and P < .0002), whereas all other geometric features, including shape characteristics, had no significant correlation. Finally, cardiac index significantly correlated with the minimum pulmonary artery area (P = .006), suggesting that total cavopulmonary connection energy losses significantly affect resting cardiac output. CONCLUSIONS: The minimum outlet size of the total cavopulmonary connection (ie, minimum cross section of pulmonary artery) governs the energy loss characteristics of the total cavopulmonary connection more strongly than variations in the shapes corresponding to extracardiac and lateral tunnel configurations. Differences in pulmonary artery sizes must be accounted for when comparing energy losses between extracardiac and lateral tunnel geometries.

The total cavopulmonary connection resistance: a significant impact on single ventricle hemodynamics at rest and exercise.

Little is known about the impact of the total cavopulmonary connection (TCPC) on resting and exercise hemodynamics in a single ventricle (SV) circulation. The aim of this study was to elucidate this mechanism using a lumped parameter model of the SV circulation. Pulmonary vascular resistance (1.96+/-0.80 WU) and systemic vascular resistances (18.4+/-7.2 WU) were obtained from catheterization data on 40 patients with a TCPC. TCPC resistances (0.39+/-0.26 WU) were established using computational fluid dynamic simulations conducted on anatomically accurate three-dimensional models reconstructed from MRI (n=16). These parameters were used in a lumped parameter model of the SV circulation to investigate the impact of TCPC resistance on SV hemodynamics under resting and exercise conditions. A biventricular model was used for comparison. For a biventricular circulation, the cardiac output (CO) dependence on TCPC resistance was negligible (sensitivity=-0.064 l.min(-1).WU(-1)) but not for the SV circulation (sensitivity=-0.88 l.min(-1).WU(-1)). The capacity to increase CO with heart rate was also severely reduced for the SV. At a simulated heart rate of 150 beats/min, the SV patient with the highest resistance (1.08 WU) had a significantly lower increase in CO (20.5%) compared with the SV patient with the lowest resistance (50%) and normal circulation (119%). This was due to the increased afterload (+35%) and decreased preload (-12%) associated with the SV circulation. In conclusion, TCPC resistance has a significant impact on resting hemodynamics and the exercise capacity of patients with a SV physiology.

Patient-specific surgical planning and hemodynamic computational fluid dynamics optimization through free-form haptic anatomy editing tool (SURGEM).

The first version of an anatomy editing/surgical planning tool (SURGEM) targeting anatomical complexity and patient-specific computational fluid dynamics (CFD) analysis is presented. Novel three-dimensional (3D) shape editing concepts and human-shape interaction technologies have been integrated to facilitate interactive surgical morphology alterations, grid generation and CFD analysis. In order to implement "manual hemodynamic optimization" at the surgery planning phase for patients with congenital heart defects, these tools are applied to design and evaluate possible modifications of patient-specific anatomies. In this context, anatomies involve complex geometric topologies and tortuous 3D blood flow pathways with multiple inlets and outlets. These tools make it possible to freely deform the lumen surface and to bend and position baffles through real-time, direct manipulation of the 3D models with both hands, thus eliminating the tedious and time-consuming phase of entering the desired geometry using traditional computer-aided design (CAD) systems. The 3D models of the modified anatomies are seamlessly exported and meshed for patient-specific CFD analysis. Free-formed anatomical modifications are quantified using an in-house skeletization based cross-sectional geometry analysis tool. Hemodynamic performance of the systematically modified anatomies is compared with the original anatomy using CFD. CFD results showed the relative importance of the various surgically created features such as pouch size, vena cave to pulmonary artery (PA) flare and PA stenosis. An interactive surgical-patch size estimator is also introduced. The combined design/analysis cycle time is used for comparing and optimizing surgical plans and improvements are tabulated. The reduced cost of patient-specific shape design and analysis process, made it possible to envision large clinical studies to assess the validity of predictive patient-specific CFD simulations. In this paper, model anatomical design studies are performed on a total of eight different complex patient specific anatomies. Using SURGEM, more than 30 new anatomical designs (or candidate configurations) are created, and the corresponding user times presented. CFD performances for eight of these candidate configurations are also presented.

Quantitative analysis of extracardiac versus intraatrial Fontan anatomic geometries.

BACKGROUND: There exists large geometric variability among total cavopulmonary connections (TCPC) because of the patient-specific anatomies and the chosen surgical procedure. In this study we present quantitative comparison of the geometric characteristics of the extracardiac and intraatrial Fontan anatomies, the two commonly used TCPC procedures. METHODS: A method of centerline approximation of the three-dimensional geometries (skeletonization) was used to quantify the TCPC geometric parameters such as vessel areas, curvature, and collinearity. The TCPC anatomies of 26 patients, 13 extracardiac and 13 intraatrial, were analyzed in this study. RESULTS: There was no significant difference in the vessel dimensions between extracardiac and intraatrial TCPCs, with the overall magnitudes agreeing well with that seen in normal children except for the inferior vena cava. Intraatrial baffles had significant fluctuations in cross-sectional area along the length of the baffle as opposed to extracardiacs (p < 0.05). Patients with hypoplastic left heart syndrome had significant narrowing of the left pulmonary artery (p < 0.05), suggesting a possible physical constriction from the reconstructed aorta. CONCLUSIONS: This study benchmarks the anatomic variability of patient-specific TCPCs. Intraatrial Fontan geometries have significant difference in the area variations across the vessel length compared with the extracardiac geometry. Also, patients with hypoplastic left heart are at a higher risk of left pulmonary artery narrowing.

Introduction of a new optimized total cavopulmonary connection.

BACKGROUND: Several variations of the total cavopulmonary connection (TCPC) have been investigated for favorable fluid mechanics and flow distribution. This study presents a hemodynamically optimized TCPC configuration code-named "OptiFlo." Featuring bifurcated vena cava (superior venacava to inferior vena cava SVC/IVC), it was designed to lower the fluid mechanical power losses in the connection and to ensure proper hepatic blood perfusion to both lungs. METHODS: A rapid prototype model of the OptiFlo TCPC was built and in vitro control volume flow analysis was performed to evaluate the fluid mechanical power loss performance of the model. Furthermore, computational fluid dynamics simulations were used to investigate the flow patterns in the model, which were compared with those in the planar one-diameter offset TCPC with flared anastomosis sites, the best known TCPC configuration to date. RESULTS: Compared with the one-diameter offset reference model, the OptiFlo showed lower power losses: -26%, -31%, and -42% for increasing cardiac outputs of 2, 4, and 6 L/minute, respectively. No statistically significant differences were found in power loss between 40:60 and 50:50 SVC/IVC flow ratios (p > 0.1) for the OptiFlo model. The power loss characteristic curve for different left and right pulmonary artery ratios was flatter for the OptiFlo than the one-diameter offset reference model. Pulmonary artery flow was much more streamlined in the OptiFlo compared with the one-diameter offset model. CONCLUSIONS: The OptiFlo TCPC design exhibits lower power losses with better adaptive distribution of hepatic blood to both lungs and lower blood flow disturbances compared with the planar one-diameter offset TCPC model. Its significantly superior hemodynamic performance at higher cardiac outputs (exercise) rationalizes further design and feasibility studies toward a workable clinical model.

Impaired power output and cardiac index with hypoplastic left heart syndrome: a magnetic resonance imaging study.

BACKGROUND: Unfavorable cardiac mechanics in children with hypoplastic left heart syndrome (HLHS) when compared with other single-ventricle defects may affect long-term morbidity and outcome. Using noninvasive phase contrast magnetic resonance imaging (PC MRI), we examined cardiac mechanics in children with HLHS and compared the results to other single-ventricle defects. METHODS: Eighteen children with HLHS and 18 children with other single-ventricle defects were studied after the Fontan operation. Phase contrast MRI scans were obtained perpendicular to the ascending aorta, and flow was quantified using an in-house segmentation and reconstruction scheme. The total power output was determined using the modified Bernoulli equation along with cardiac output and systemic vascular resistance index. RESULTS: Compared with non-HLHS congenital heart defects, children with HLHS had significantly lower power output (1.40 +/- 0.39 versus 1.78 +/- 0.38 W/m2, p < 0.004) and cardiac index (3.15 +/- 0.97 versus 4.09 +/- 1.23 L x Min(-1) x m(-2), p < 0.009) with a concomitant higher systemic vascular resistance index (28.94 +/- 11.5 versus 22.7 +/- 8.53 WU, p < 0.03) despite generating similar systolic blood pressures (112.9 +/- 22.4 versus 115.2 +/- 23 mm Hg, p > 0.05). CONCLUSIONS: Minimally invasive measurements with PC MRI in children with HLHS showed significantly lower power output and cardiac index when compared with other single-ventricle physiologies. Abnormal aortic flow patterns may contribute to power loss and may have long-term survival and morbidity implications associated with the Fontan procedure. Elevated systemic vascular resistance index despite similar blood pressure opens avenues for therapeutic intervention for afterload reduction.