Vascular Nanomedicine: Site specific delivery of elastin stabilizing therapeutics to damaged arteries

Elastin, a structural protein in the extra-cellular matrix, plays a critical role in the normal functioning of blood vessels. Apart from performing its primary function of providing resilience to arteries, it also plays major role in regulating cell-cell and cell-matrix interactions, response to injury, and morphogenesis. Medial arterial calcification (MAC) and abdominal aortic aneurysm (AAA) are two diseases where the structural and functional integrity of elastin is severely compromised. Although the clinical presentation of MAC and AAA differ, they have one common underlying causative mechanism--pathological degradation of elastin. Hence prevention of elastin degradation in the early stages of MAC and AAA can mitigate, partially if not wholly, the fatal consequences of both the diseases. The work presented here is motivated by the overwhelming statistics of people afflicted by elastin associated cardiovascular diseases and the unavailability of cure for the same. Overall goal of our research is to understand role of elastin degradation in cardiovascular diseases and to develop a targeted vascular drug delivery system that is minimally invasive, biodegradable, and non-toxic, that prevents elastin from degradation. Our hope is that such treatment will also help regenerate elastin, thereby providing a multi-fold treatment option for elasto-degenerative vascular diseases. For this purpose, we have first confirmed the combined role of degraded elastin and hyperglycemia in the pathogenesis of MAC. We have shown that in the absence of degraded elastin and TGF-β1 (abundantly present in diabetic arteries) vascular smooth muscle cells maintain their homeostatic state, regardless of environmental glucose concentrations. However simultaneous exposure to glucose, elastin peptides and TGF-β1 causes the pathological transgenesis of vascular cells to osteoblast-like cells. We show that plant derived polyphenols bind to vascular elastin with great affinity resulting in improved resistance to elastolytic digestion. We further show that the same polyphenols interact with monomeric tropoelastin released by the vascular cells and dramatically increasing their self-assembly in-vitro. In addition, we demonstrate the elastogenic ability of these polyphenols in aiding the crosslinking of tropoelastin released by aneurysmal cells converting it into mature elastin. Finally, we developed a nanoparticle system functionalized with elastin antibody on the surface that, upon systemic delivery, can recognize and bind to sites of damaged elastin in the aorta. We are able to show that this nanoparticle system works in representative animal models for MAC and AAA. These nanoparticles demonstrated spatial and functional specificity for degraded elastin. In conclusion, our work is focused on understanding the role of elastin degradation in vascular calcification and aortic aneurysms. We tested approaches to halt elastin degradation and to regenerate elastin in arteries so that homeostasis can be achieved

Exploring the Relationships Between Mindfulness, Self-compassion, and Ethnic Identity Development

Ethnic identity development is a process that occurs for all individuals, and weakness in ethnic identity is associated with numerous psychosocial difficulties. Security in ethnic identity can be difficult for those exposed to varying attitudes and behaviors in a multicultural society. As such, the current study examined the influence of mindfulness and self-compassion on ethnic identity development. a sample of 479 undergraduate students completed online self-report questionnaires measuring demographic information, mindfulness, self-compassion, ethnic identity status, and self-esteem. Results suggested that mindfulness and self-compassion are significant negative predictors of ethnic identity, and that self-compassion was a better predictor of ethnic identity status than was mindfulness. Self-compassion did not moderate the relationship between mindfulness and ethnic identity status, as was hypothesized. the sample included primarily Caucasian (n = 278) individuals born in the United States, which likely limited generalizability of findings. Implications of the current findings and suggestions for future research are discussed

Evaluation of abnormal uterine bleeding by transvaginal sonography, sonohysterography and correlation with endometrial histopathology

Background: Abnormal uterine bleeding (AUB) in reproductive-age women is common, leading to one-third of outpatient visits by this population and this proportion crosses the two-third threshold in peri or post-menopausal group. Annually 5-10% of women of reproductive age seek medical care for AUB, which negatively impacts quality of life. The aim of the present study was to study the role of transvaginal sonography (TVS) and sonohysterography (SHG) in abnormal uterine bleeding.Methods: The present study was carried out at Department of Obstetrics and Gynaecology, Era’s Lucknow Medical College, Lucknow in collaboration with Department of Radiology and Pathology, Era’s Lucknow Medical College, Lucknow. It was a prospective study carried out over a period of 1 year. Detailed history regarding their present complaints, menstrual history along with thorough examination was noted on the proforma designed for the study. Those with active and heavy bleeding underwent TVS and D&C for diagnostic and therapeutic purposes in the same sitting. However others without active bleeding underwent TVS, SIS in mid cycle and D&C in premenstrual period.Results: The present study was carried out at Department of Obstetrics and Gynaecology, Era’s Lucknow Medical College, Lucknow in collaboration with Department of Radiology and Pathology, Era’s Lucknow Medical College, Lucknow. It was a prospective study carried out over a period of 1 year. Detailed history regarding their present complaints, menstrual history along with thorough examination was noted on the proforma designed for the study. Those with active and heavy bleeding underwent TVS and D&C for diagnostic and therapeutic purposes in the same sitting. However others without active bleeding underwent TVS, SIS in mid cycle and D&C in premenstrual period.Conclusions: The findings in present study show a relative supremacy of SIS over TVS in diagnosis of uterine abnormalities in cases of abnormal uterine bleeding

Anti-neutrophil cytoplasmic antibodies negative eosinophilic granulomatous polyangiitis glomerulonephritis in children - A diagnostic dilemma

Anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) refers to small-to-medium vessel vasculitis with multisystemic involvement and is characterized by the presence of ANCA to specifically either proteinase-3 (PR3) or myeloperoxidase (MPO). Eosinophilic granulomatous polyangiitis earlier called as Churg-Strauss vasculitis is a clinicopathological variant of AAV or AAV with granulomatous necrotizing small vessel vasculitis primarily affecting individuals with severe asthma or allergies and rarely reported in the pediatric population. We report a 9-year-old child with pauci-immune crescentic eosinophilic granulomatousglomerulonephritis with heavy eosinophilic infiltration of skin and subcutaneous tissue and negative ANCA. Although he had a recurrent history of cough, there was no history of use of oral or inhalational bronchodilator therapy indicating asthma and no history suggestive history of allergy. He showed significant and rapid clinical as well as biochemical improvement on aggressive immunosuppressive therapy along with plasma exchanges and is under regular follow-up. Diagnosing Eosinophilic granulomatous Polyangiitis glomerulonephritis in children is difficult due to a varied clinical presentation at onset which may evolve over a period of time and due to lack of specific diagnostic tests. High index of suspicion is the key to early diagnosis and successful management

Cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID).

Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is an effective strategy for the early recognition of infants with a CF diagnosis. Some infants with a positive NBS result for CF have an inconclusive diagnosis and evidence suggests the number of these infants is increasing, as more extensive gene analysis is integrated into screening protocols. There is an internationally agreed, but complex, designation for infants with an unclear diagnosis after a positive screening result: cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). Infants with a CRMS/CFSPID designation have no clinical evidence of disease and do not meet the criteria for a CF diagnosis, but the NBS result indicates some risk of developing CF or a CFTR-related disorder. In this review, we describe the accurate designation of these and reflect on emerging management pathways, with particular attention given to clear and consistent communication.Educational aimsTo clarify the definition of the global harmonised designation: cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive, inconclusive diagnosis (CFSPID).To understand what impact a CRMS/CFSPID result has for the patient and their family

Occurrence characteristics of electromagnetic ion cyclotron waves at sub-auroral Antarctic station Maitri during solar cycle 24

We present a statistical study of electromagnetic ion cyclotron (EMIC) waves observed at Antarctic station (geographic 70.7° S, 11.8° E, L=5) on quiet and disturbed days during 2011–2017. The data span a fairly good period of both ascending and descending phases of the solar cycle 24, which has witnessed extremely low activity. We noted EMIC wave occurrence by examining wave power in different frequency ranges in the spectrogram. EMIC wave occurrence during ascending and descending phases of solar cycle 24, its local time, seasonal dependence and durations have been examined. There are total 2367 days for which data are available. Overall, EMIC waves are observed for 3166.5 h (≈5.57% of total duration) which has contributions from 1263 days. We find a significantly higher EMIC wave occurrence during the descending phase (≈ 6.83%) as compared to the ascending phase (≈ 4.08%) of the solar cycle, which implies nearly a twofold increase in EMIC wave occurrence. This feature is attributed to the higher solar wind dynamic pressure during descending phase of solar activity. There is no evident difference in the percentage occurrence of EMIC waves on magnetically disturbed and quiet days. On ground, EMIC waves show marginally higher occurrence during winter as compared to summer. This seasonal tendency is attributed to lower electron densities and conductivities in the ionosphere, which can affect the propagation of EMIC waves through ionospheric ducts. In local time, the probability distribution function of EMIC wave occurrence shows enhancement during 11.7–20.7 LT (i.e., afternoon–dusk sector). Daily durations of EMIC waves are in the range of 5–1015 min and it is noted that the longer duration (240–1015 min) events are prevalent on quiet days and are mostly seen during the descending phase of solar cycle

Prevalence of goitre, iodine uptake and salt iodization level in Mahasamund district of Chhattisgarh: a baseline study in Central India

Background: Iodine deficiency disorder (IDD) is the single most important preventable cause of brain damage. Iodine deficiency disorders (IDDs) refer to all of the consequences of iodine deficiency in a population, which can be prevented by taking adequate amount of Iodine.  The objectives was to ascertain the prevalence goitre among 6-12 year children by clinical examination in Mahasamund district; 2) to document the iodine uptake status reflected by random urinary excretion levels in a sub-sample of 6-12 year children covered for clinical examination, and 3) to evaluate the coverage of iodized salt at community level (i.e. at household and retail shop) on-the-spot test by using rapid salt testing kit.Methods: A cross sectional community based survey was done in Mahasamund district during April 2015 to September 2015. The study population was children in the age group of 6-12 years. 30 cluster sampling methodology was applied using PPS sampling technique, based on latest survey guidelines of NIDDCP of Govt. of India. The parameters studied were prevalence of goitre, urinary iodine excretion, and iodine content in salt at community level (i.e. household and shop).Results: A total of 2700 children aged from 6-12 years were assessed clinically for goitre. The total goitre prevalence was 4.29% (95% CI: 3.3-5.27). The median urinary iodine excretion (MUIE) was 106.67μg/L (range 11-216.7μg /L) among surveyed children.  37.4% of the urinary iodine excretion values were <100 μg/L. The households consuming inadequately iodized salt (i.e. iodine content ≤15 ppm) was 20% in the surveyed district.Conclusions: Although prevalence of goitre and median urinary iodine excretion among surveyed population was found satisfactory against the norms set by NIDDCP in surveyed district but universal salt iodization (USI) is yet to achieve in surveyed district.

Privacy Risks of Securing Machine Learning Models against Adversarial Examples

The arms race between attacks and defenses for machine learning models has come to a forefront in recent years, in both the security community and the privacy community. However, one big limitation of previous research is that the security domain and the privacy domain have typically been considered separately. It is thus unclear whether the defense methods in one domain will have any unexpected impact on the other domain. In this paper, we take a step towards resolving this limitation by combining the two domains. In particular, we measure the success of membership inference attacks against six state-of-the-art defense methods that mitigate the risk of adversarial examples (i.e., evasion attacks). Membership inference attacks determine whether or not an individual data record has been part of a model's training set. The accuracy of such attacks reflects the information leakage of training algorithms about individual members of the training set. Adversarial defense methods against adversarial examples influence the model's decision boundaries such that model predictions remain unchanged for a small area around each input. However, this objective is optimized on training data. Thus, individual data records in the training set have a significant influence on robust models. This makes the models more vulnerable to inference attacks. To perform the membership inference attacks, we leverage the existing inference methods that exploit model predictions. We also propose two new inference methods that exploit structural properties of robust models on adversarially perturbed data. Our experimental evaluation demonstrates that compared with the natural training (undefended) approach, adversarial defense methods can indeed increase the target model's risk against membership inference attacks.Comment: ACM CCS 2019, code is available at https://github.com/inspire-group/privacy-vs-robustnes

Vocal cord palsy as a sequela of paediatric cardiac surgery – a review

Background: Vocal cord palsy is one of the recognised complications of complex cardiac surgery in the paediatric population. While there is an abundance of literature highlighting the presence of this complication, there is a scarcity of research focusing on the pathophysiology, presentation, diagnosis, and treatment options available for children affected by vocal cord palsy. Materials and methods: Electronic searches were conducted using the search terms: “Vocal Cord Palsy,” “VCP,” “Vocal Cord Injury,” “Paediatric Heart Surgery,” “Congenital Heart Surgery,” “Pediatric Heart Surgery,” “Vocal Fold Movement Impairment,” “VFMI,” “Vocal Fold Palsy,” “PDA Ligation.” The inclusion criteria were any articles discussing the outcomes of vocal cord palsy following paediatric cardiac surgery. Results: The two main populations affected by vocal cord palsy are children undergoing aortic arch surgery or those undergoing PDA ligation. There is paucity of prospective follow-up studies; it is therefore difficult to reliably assess the current approaches and the long-term implications of management options. Conclusion: Vocal cord palsy can be a devastating complication following cardiac surgery, which if left untreated, could potentially result in debilitation of quality of life and in severe circumstances could even lead to death. Currently, there is not enough high-quality evidence in the literature to aid recognition, diagnosis, and management leaving clinicians to extrapolate evidence from adult studies to make clinical judgements. Future research with a focus on the paediatric perspective is necessary in providing evidence for good standards of care

Clinical and microbiological features of infection in alcoholic hepatitis: an international cohort study

BACKGROUND: Previous studies have described the clinical impact of infection in alcoholic hepatitis (AH) but none have comprehensively explored the aetiopathogenesis of infection in this setting. We examined the causes, consequences and treatment of infection in a cohort of patients with AH. METHODS: We undertook a retrospective cohort study of patients with AH admitted between 2009 and 2014 to seven centres in Europe and the USA. Clinical and microbiological data were extracted from medical records. Survival was analysed with Kaplan-Meier analysis and Cox proportional hazards analysis to control the data for competing factors. Propensity score matching was used to examine the efficacy of prophylactic antibiotics administered in the absence of infection. RESULTS: We identified 404 patients with AH. Of these, 199 (49%) showed clinical or culture evidence of infection. Gut commensal bacteria, particularly Escherichia coli and Enterobacter species, were most commonly isolated in culture. Fungal infection was rarely seen. Cultured organisms and antibiotic resistance differed markedly between centres. Infection was an independent risk factor for death (hazard ratio for death at 90 days 2.33, 95% confidence interval 1.63-3.35, p < 0.001). Initiation of antibiotic therapy on admission in the absence of infection did not reduce mortality or alter the incidence of subsequent infections. Corticosteroid use increased the incidence of infection but this did not impact on survival. CONCLUSIONS: In this large real-world cohort of patients with AH, infection was common and was associated with reduced short-term survival. Gram-negative, gut commensal bacteria were the predominant infective organisms, consistent with increased translocation of gut bacteria in AH; however, the characteristics of infection differ between centres. Infection should be actively sought and treated, but we saw no benefits of prophylactic antibiotics