A study on clinico immuno pathological correlation of skin and pulmonary involvement in systemic sclerosis

INTRODUCTION: Systemic sclerosis is a chronic autoimmune connective tissue disease of unknown etiology involving multiple systems. It is characterized by significant dysfunction of the microvasculature, immune system and connective tissue. The currently used classification of Systemic Sclerosis is by the extent of skin involvement1. The extent of skin disease correlates with the disease course. Though many internal organs are involved, lung involvement is the major cause of morbidity and mortality in SSc. While some studies regard skin involvement as a surrogate marker for pulmonary involvement, there are studies that have shown improvement of sclerosis occurring spontaneously or as a result of treatment and therefore it does not reflect the pulmonary fibrosis. In addition several cutaneous features have been found to be associated with clinical and serological manifestations in systemic sclerosis. In a recent study2 elevated serum level of MMP-12 correlated with the severity of skin fibrosis and activity of interstitial lung disease in systemic sclerosis, suggesting the common pathogenesis between them. So the skin can be useful marker for early diagnosis and to assess pulmonary involvement. AIMS AND OBJECTIVES: 1. To study the skin and pulmonary manifestations in Systemic Sclerosis. 2. To study the correlation of the clinical, pathological, immunological features of skin and pulmonary involvement in Systemic Sclerosis. MATERIALS AND METHODS: SUBJECTS: Patients attending the Rheumatology Care Centre (RCC) outpatient and inpatient of Rajiv Gandhi Government General Hospital, Chennai were recruited from the period of June 2011 to February 2013. 55 eligible cases who fulfilled the inclusion criteria were enrolled. All subjects gave a written informed consent to enroll in this study. The Ethical committee approval was obtained. INCLUSION CRITERIA: American College of Rheumatology preliminary classification criteria. Major criteria or two minor criteria for diagnosis. Major criteria: Scleroderma proximal to the metacarpophalangeal joints. Minor Criteria: 1. Sclerodactyly. 2. Digital pitting scars or loss of finger pad substance. 3. Bibasilar pulmonary fibrosis. EXCLUSION CRITERIA Overlap syndrome, mixed connective tissue disease, other scleroderma spectrum disorders. RESULTS: Total number of cases were 55. The mean age was 35.5 years. The range was from 20-56 years. Majority were females 49 (89.1%) while males were 6 (10.9%). The mean disease duration was 3.1 years with range 4 months to 10 years. CONCLUSION: In this study on Systemic sclerosis there was a female gender Predominance (8:1). • The limited cutaneous SSc were more than diffuse cutaneous type in this study. • There was positive correlation between disease duration and PHT. • 43.6% of the study group were in the 7-15 MRSS Range. • Presence of salt and pepper had significant association with MRSS in this study. • Dyspnea was the most common respiratory symptom and it correlated positively with MRSS. • The MRSS was significantly associated with presence of ILD in the study group. • ILD was more common in diffuse cutaneous type and the mean MRSS was significantly associated with ILD in diffuse cutaneous type. • There was no association between MRSS and PHT in this study. • There was significant association between MRSS and the Medsger disease severity of lung. • Digital pitted scars and Raynaud‟s Phenomenon positively correlated with ILD in this study group. • ANA positivity was seen in 80% of the cases

Serum Uric Acid in Acute Ischemic Stroke

PURPOSE: To estimate the level of serum uric acid in patients with acute ischemic stroke, to find out its association with diabetes and hypertension, to correlate with age and gender and to study its significance in the out come of the stroke patients. METHODS: A cross section study was designed after institutional ethical clearance to screen acute ischemic stroke patients admitted to the hospital within 48 hours of stroke who satisfied a rigid inclusion and exclusion criteria. Another 40 members with similar variables without stroke were taken as control. The serum uric acid level was measured by uricase method. The outcome in the stroke patients was analysed at the end of 2 weeks while in hospital. The data were entered in microsoft excel spread sheet and analysed statistically. RESULTS: There were 102 stroke patients. Among them there were 66 males and 36 females. Their age varied from 30 to 70 years and the mean age was 56.72 years. The uric acid level among the stroke cases varied from 4.12 to 7.2 mg/dL and the mean serum uric acid level was 5.66 mg/dL. It was elevated significantly than the control group (P< 0.001). Stroke patients with diabetics and hypertension had elevated serum uric acid level than the counter parts in the control and the difference was significant statistically (P<0.001). Those stroke cases with elevated uric acid had poor outcome and statistically was significant (P < 0.001). CONCLUSION: Serum uric acid level was increased in stroke patients and was independent of age and gender. Uric acid level among stroke cases was independent of their diabetic and hypertensive status. All the stroke cases who had poor outcome were found to have elevated uric acid level which may be a response to oxidative stress and hence it can be considered as biochemical marker in stroke patients

Secure Digital Information Forward Using Highly Developed AES Techniques in Cloud Computing

Nowadays, in communications, the main criteria are ensuring the digital information and communication in the network. The normal two users' communication exchanges confidential data and files via the web. Secure data communication is the most crucial problem for message transmission networks. To resolve this problem, cryptography uses mathematical encryption and decryption data on adaptation by converting data from a key into an unreadable format. Cryptography provides a method for performing the transmission of confidential or secure communication. The proposed AES (Advanced Encryption Standard)-based Padding Key Encryption (PKE) algorithm encrypts the Data; it generates the secret key in an unreadable format. The receiver decrypts the data using the private key in a readable format. In the proposed PKE algorithm, the sender sends data into plain Text to cypher-text using a secret key to the authorized person; the unauthorized person cannot access the data through the Internet; only an authorized person can view the data through the private key. A method for identifying user groups was developed. Support vector machines (SVM) were used in user behaviour analysis to estimate probability densities so that each user could be predicted to launch applications and sessions independently. The results of the proposed simulation offer a high level of security for transmitting sensitive data or files to recipients compared to other previous methods and user behaviour analysis

mTORC2 signaling drives the development and progression of pancreatic cancer

mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer

CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response.

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.Stand Up 2 Cancer, Lustgarten Foundation, NIH

Associations of the built environment with type 2 diabetes in Asia: a systematic review

Objectives Our study aimed to systematically review the literature and synthesise findings on potential associations of built environment characteristics with type 2 diabetes (T2D) in Asia. Design Systematic review of the literature. Data sources Online databases Medline, Embase and Global Health were used to identify peer-reviewed journal articles published from inception to 23 January 2023. Eligibility criteria Eligible studies included cohort, cross-sectional and case–control studies that explored associations of built environment characteristics with T2D among adults 18 years and older in Asia. Data extraction and synthesis Covidence online was used to remove duplicates and perform title, abstract and full-text screening. Data extraction was carried out by two independent reviewers using the OVID database and data were imported into MS Excel. Out of 5208 identified studies, 28 studies were included in this systematic review. Due to heterogeneity in study design, built environment and outcome definitions, a semiqualitative analysis was conducted, which synthesised results using weighted z-scores. Results Five broad categories of built environment characteristics were associated with T2D in Asia. These included urban green space, walkability, food environment, availability and accessibility of services such as recreational and healthcare facilities and air pollution. We found very strong evidence of a positive association of particulate matter (PM2.5, PM10), nitrogen dioxide and sulfur dioxide (p<0.001) with T2D risk. Conclusion Several built environment attributes were significantly related to T2D in Asia. When compared with Western countries, very few studies have been conducted in Asia. Further research is, therefore, warranted to establish the importance of the built environment on T2D. Such evidence is essential for public health and planning policies to (re)design neighbourhoods and help improve public health across Asian countries

Challenges and opportunities of telehealth digital equity to manage HIV and comorbidities for older persons living with HIV in New York State

Background Older persons living with HIV (PLWH) need routine healthcare to manage HIV and other comorbidities. This mixed methods study investigated digital equity, constituted as access, use and quality, of HIV and specialty telehealth services for PLWH > 50 years during the initial wave of the COVID-19 pandemic when services transitioned to remote care. Methods A survey of closed and open-ended questions was administered to 80 English (N = 63) and Spanish (N = 17) speaking PLWH receiving HIV care at an Academic Medical Center (N = 50) or a Federally Qualified Health Center (N = 30) in New York State. Quantitative analyses examined characteristics predicting telehealth use and visit quality. Qualitative analyses utilized thematic coding to reveal common experiences. Results were integrated to deepen the interpretation. Results Telehealth access and use were shaped by multiple related and unstable factors including devices and connectivity, technology literacy, and comfort including privacy concerns. Participants demonstrated their substantial effort to achieve the visit. The majority of patients with a telehealth visit perceived it as worse than an in-person visit by describing it as less interpersonal, and resulting in poorer outcomes, particularly participants with less formal education. Technology was not only a barrier to access, but also influenced perceptions of quality. Conclusions In the COVID-19 pandemic initial wave, barriers to using telehealth were unequally distributed to those with more significant access and use challenges. Beyond these barriers, examining the components of equity indicate further challenges replicating in-person care using telehealth formats for older PLWH. Work remains to establish telehealth as both equitable and desirable for this population

CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.

Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors

Antiviral activity of the host defense peptide piscidin 1: investigating a membrane-mediated mode of action

Outbreaks of viral diseases are on the rise, fueling the search for antiviral therapeutics that act on a broad range of viruses while remaining safe to human host cells. In this research, we leverage the finding that the plasma membranes of host cells and the lipid bilayers surrounding enveloped viruses differ in lipid composition. We feature Piscidin 1 (P1), a cationic host defense peptide (HDP) that has antimicrobial effects and membrane activity associated with its N-terminal region where a cluster of aromatic residues and copper-binding motif reside. While few HDPs have demonstrated antiviral activity, P1 acts in the micromolar range against several enveloped viruses that vary in envelope lipid composition. Notably, it inhibits HIV-1, a virus that has an envelope enriched in cholesterol, a lipid associated with higher membrane order and stability. Here, we first document through plaque assays that P1 boasts strong activity against SARS-CoV-2, which has an envelope low in cholesterol. Second, we extend previous studies done with homogeneous bilayers and devise cholesterol-containing zwitterionic membranes that contain the liquid disordered (Ld; low in cholesterol) and ordered (Lo, rich in cholesterol) phases. Using dye leakage assays and cryo-electron microscopy on vesicles, we show that P1 has dramatic permeabilizing capability on the Lo/Ld, an effect matched by a strong ability to aggregate, fuse, and thin the membranes. Differential scanning calorimetry and NMR experiments demonstrate that P1 mixes the lipid content of vesicles and alters the stability of the Lo. Structural studies by NMR indicate that P1 interacts with the Lo/Ld by folding into an α-helix that lies parallel to the membrane surface. Altogether, these results show that P1 is more disruptive to phase-separated than homogenous cholesterol-containing bilayers, suggesting an ability to target domain boundaries. Overall, this multi-faceted research highlights how a peptide that interacts strongly with membranes through an aromatic-rich N-terminal motif disrupt viral envelope mimics. This represents an important step towards the development of novel peptides with broad-spectrum antiviral activity

p53 Activation following Rift Valley Fever Virus Infection Contributes to Cell Death and Viral Production

Rift Valley fever virus (RVFV) is an emerging viral zoonosis that is responsible for devastating outbreaks among livestock and is capable of causing potentially fatal disease in humans. Studies have shown that upon infection, certain viruses have the capability of utilizing particular cellular signaling pathways to propagate viral infection. Activation of p53 is important for the DNA damage signaling cascade, initiation of apoptosis, cell cycle arrest and transcriptional regulation of multiple genes. The current study focuses on the role of p53 signaling in RVFV infection and viral replication. These results show an up-regulation of p53 phosphorylation at several serine sites after RVFV MP-12 infection that is highly dependent on the viral protein NSs. qRT-PCR data showed a transcriptional up-regulation of several p53 targeted genes involved in cell cycle and apoptosis regulation following RVFV infection. Cell viability assays demonstrate that loss of p53 results in less RVFV induced cell death. Furthermore, decreased viral titers in p53 null cells indicate that RVFV utilizes p53 to enhance viral production. Collectively, these experiments indicate that the p53 signaling pathway is utilized during RVFV infection to induce cell death and increase viral production