The Role of Angiopoietins in Cardiovascular Outcomes of Kidney Transplant Recipients- An Ancillary Study From the FAVORIT.

INTRODUCTION: Kidney transplant recipients (KTRs) have increased risk of cardiovascular disease (CVD) mortality. We investigated vascular biomarkers, angiopoietin-1 and angiopoietin-2 (angpt-1, -2), in CVD development in KTRs. METHODS: This ancillary study from the FAVORIT, evaluates the associations of baseline plasma angpt-1,-2 levels in CVD development (primary outcome) and graft failure (GF) and death (secondary outcomes) in 2000 deceased donor KTRs. We used Cox regression to analyze the association of biomarker quartiles with outcomes. We adjusted for demographic, CVD and transplant-related variables; medications; urine albumin-to-creatinine ratio and randomization status. We calculated areas under the curves (AUC) to predict CVD or death, and GF or death by incorporating biomarkers alongside clinical variables. RESULTS: Participants' median age was 52 IQR [45, 59] years: with 37% women and 73% identifying as white. Median time from transplantation was 3.99 IQR [1.58, 7.93] years and to CVD development was 2.54 IQR [1.11-3.80] years. Quartiles of angpt-1 were not associated with outcomes. Whereas higher levels of angpt-2 (quartile 4) were associated with about 2 times the risk of CVD, GF and death [aHR 1.85 (1.25 - 2.73), P<.01; 2.24 (1.36 - 3.70), P<.01; 2.30 (1.48 - 3.58), P<.01, respectively] as compared to quartile 1. Adding angiopoietins to pre-existing clinical variables improved prediction of CVD or death (AUC improved from 0.70 to 0.72, P=0.005) and GF or death (AUC improved from 0.68 to 0.70, P =0.005). Angpt-2 may partially explain the increased risk of future CVD in KTRs. Further research is needed to assess the utility of using angiopoietins in the clinical care of KTRs. CONCLUSION: Angpt-2 may be a useful prognostic tool for future CVD in KTRs. Combining angiopoietins with clinical markers may tailor follow-up to mitigate CVD risk.

Increased Intestinal Permeability and Decreased Resiliency of the Intestinal Barrier in Alcoholic Liver Disease.

INTRODUCTION: Only 20%-30% of individuals with alcohol use disorder (AUD) develop alcoholic liver disease (ALD). While the development of gut-derived endotoxemia is understood to be a required cofactor, increased intestinal permeability in ALD is not completely understood. METHODS: We recruited 178 subjects-58 healthy controls (HCs), 32 with ALD, 53 with AUD but no liver disease (ALC), and 35 with metabolic dysfunction-associated steatotic liver disease (MASLD). Intestinal permeability was assessed by a sugar cocktail as a percentage of oral dose. The permeability test was repeated after an aspirin challenge in a subset. RESULTS: Five-hour urinary lactulose/mannitol ratio (primarily representing small intestinal permeability) was not statistically different in HC, ALC, ALD, and MASLD groups ( P = 0.40). Twenty-four-hour urinary sucralose (representing whole gut permeability) was increased in ALD ( F = 5.3, P < 0.01) and distinguished ALD from ALC; 24-hour sucralose/lactulose ratio (primarily representing colon permeability) separated the ALD group ( F = 10.2, P < 0.01) from the MASLD group. After aspirin challenge, intestinal permeability increased in all groups and ALD had the largest increase. DISCUSSION: In a group of patients, we confirmed that (i) the ALD group has increased intestinal permeability compared with the HC, ALC, or MASLD group. In addition, because small bowel permeability (lactulose/mannitol ratio) is normal, the disruption of intestinal barrier seems to be primarily in the large intestine; (ii) decreased resiliency of intestinal barrier to injurious agents (such as NSAID) might be the mechanism for gut leak in subset of AUD who develop ALD.

Correlates of Spontaneous Blood Pressure Reduction Following Severe Inpatient Hypertension Development.

BACKGROUND: Severe hypertension (sHTN) is prevalent in 10% of hospitalized patients and treatment guidelines are lacking. As such, patients who develop sHTN might unnecessarily receive antihypertensive medications which could lead to worse outcomes. Our goal was to investigate correlates of spontaneous blood pressure (BP) reduction to help guide future treatment decisions and avoid harm associated with aggressive BP treatment. METHODS: This is a retrospective cohort study of hospitalized adults between 2016 and 2020 who developed sHTN, SBP >180 or DBP >110 mm Hg, after admission. Spontaneous BP reduction was defined as a SBP <160 and a DBP <100 mm Hg achieved within 3 h of sHTN in the absence of antihypertensive therapy. Multivariable logistic regression was used to identify correlates of spontaneous BP reduction. RESULTS: Of the 12,825 patients who developed sHTN, 44.2% had spontaneous BP reduction. After adjustment, we found that patients most likely to experience a BP drop received steroids before onset of sHTN (Odds ratio [OR]: 1.3 [1.09, 1.56]), had higher potassium levels on admission (OR: 1.2 [1.09, 1.24]) and were more likely to have a history of chronic pulmonary disease (OR: 1.1 [1.01, 1.18]) or cardiac arrythmia (OR: 1.1 [1.01, 1.18]). While numerically different, these differences were not clinically relevant. CONCLUSIONS: Our findings indicate that almost half the patients who develop sHTN have spontaneous BP reduction. Conventional clinical and demographic characteristics were not strong predictors of spontaneous BP reduction following sHTN development. More research is needed to confirm our findings and help guide treatment of sHTN.

Promising Strategies of Colloidal Drug Delivery-Based Approaches in Psoriasis Management.

Psoriasis is a chronic inflammatory autoimmune disorder that moderately affects social and interpersonal relationships. Conventional treatments for psoriasis have certain problems, such as poor drug penetration through the skin, hyper-pigmentation, and a burning sensation on normal and diseased skin. Colloidal drug delivery systems overcome the pitfalls of conventional approaches for psoriasis therapeutics and have improved patient safety parameters, compliance, and superior effectiveness. They also entail reduced toxicity. This comprehensive review's topics include the pathogenesis of psoriasis, causes and types of psoriasis, conventional treatment alternatives for psoriasis, the need for colloidal drug delivery systems, and recent studies in colloidal drug delivery systems for the treatment of psoriasis. This review briefly describes colloidal drug delivery approaches, such as emulsion systems-i.e., multiple emulsion, microemulsion, and nano-emulsion; vesicular systems-i.e., liposomes, ethosomes, noisomes, and transferosomes; and particulate systems-i.e., solid lipid nanoparticles, solid lipid microparticles, nano-structured lipid carriers, dendrimers, nanocrystals, polymeric nanoparticles, and gold nanoparticles. The review was compiled through an extensive search of the literature through the PubMed, Google Scholar, and ScienceDirect databases. A survey of literature revealed seven formulations based upon emulsion systems, six vesicular drug delivery systems, and fourteen particulate systems reported for antipsoriatic drugs. Based on the literature studies of colloidal approaches for psoriasis management carried out in recent years, it has been concluded that colloidal pharmaceutical formulations could be investigated broadly and have a broad scope for effective management of many skin disorders in the coming decades.

Common Gastrointestinal Medications Implicated in Drug-Induced Liver Injury.

Content available: Author Interview and Audio Recording.

Identifying Patterns of Failure and Risk Factors for Recurrence in Patients of Paratesticular Sarcomas: Protocol of a Systematic Review and Meta-Analysis.

INTRODUCTION: Para testicular sarcomas are rare mesenchymal tumors that affect patients of all ages. Unlike other sites of sarcoma, they tend to be of lower grade and have a higher propensity for lymphatic spread. Management is hampered by the small number of patients who differ in terms of tumor grade and histology. Current treatment approaches are based on case reports, small case series and literature reviews, resulting in a number of unresolved issues. The consensus on the type of surgery and adjuvant treatment is yet to be determined. The local relapse rates in the scrotum and groin after orchidectomy comes out to be 25%-37%, indicating the need for either aggressive surgery or adjuvant treatment. There is a paucity of data identifying the patterns of failure and risk factors for recurrence, which will help clinicians tailor appropriate treatment. METHODS: We aim to perform a systematic review and meta-analysis of the available data in the last 50 years in a methodologically rigorous and transparent manner to identify patterns of failure and high-risk factors for recurrence. The protocol is prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA-P) 2015 guidelines. The protocol is registered in the International Prospective Register of Systematic Reviews (CRD42021237134). HIGHLIGHTS: Para testicular sarcomas are rare mesenchymal tumors that affects patients of all ages. Current treatment approaches are based on case reports, small case series and literature reviews, resulting in a number of unresolved issues. A systemic review was performed in 2013 based on survival rates, prognostic factors, and relapse sites on paratesticular sarcomas. However, it lacks a comprehensive review that can guide radiation oncologists to select in which patient's postoperative radiotherapy is warranted and define the target volume based on histopathological type, stage, and grade of the tumor. After 2013, new case series with improved methodology and sample size are published, which adds new information to the literature. In one case series, 22 patients with spermatic cord sarcoma were discussed, while in another study, long-term outcome analysis of 51 patients was discussed, and another study discussed eight patients.

Alteration in biochemical parameters during plateletpheresis in healthy donors: A compendious analysis.

OBJECTIVES: During plateletpheresis, citrate induces hypocalcemia and hypomagnesemia, which are usually transient and self-limiting, but they can lead to significant donor discomfort. The aim of study was to determine the effect of citrate infusion on a multitude of biochemical parameters during plateletpheresis in healthy donors and to correlate changes with adverse donor reactions. METHODS: The study was conducted on 60 healthy plateletpheresis donors. Blood samples were drawn on three occasions, a baseline pre-donation sample, 30min at start of procedure and 30min post procedure. Heparinized samples were taken to measure ionized calcium and plain samples to measure serum calcium, serum magnesium, parathyroid hormone, total protein and serum albumin. RESULTS: There was statistically significant decline in mean total calcium (9.27±0.66mg/dl to 8.72±0.87mg/dl) and ionized calcium (3.8±0.51mg/dl to 2.9±0.67mg/dl) from baseline until 30min after the start of procedure respectively. A significant fall in serum magnesium, total protein and serum albumin was observed. The mean parathyroid hormone showed significant increase from baseline levels till at the completion of procedure (19.94±12.1pg/ml to 92.08±36.78pg/ml). If the yield was set constant, there was negative correlation between ACD used and pre-donation platelet count. Majority of adverse donor reactions were hypocalcemic reactions, which were more with Amicus double yield plateletpheresis and were managed with calcium supplementation. CONCLUSION: Plateletpheresis induces marked reduction in serum calcium and magnesium levels. Moreover, increase in parathyroid hormone levels was significant. In addition, decline in total protein and serum albumin may be a concern in donors also participating in plasmapheresis.

Dissecting Cellulitis of the Scalp: A Rare Dermatological Manifestation of Crohn's Disease.

Dissecting cellulitis is an inflammatory disease of the skin. We report a case of recurrent dissecting cellulitis in a patient with Crohn's disease. A 31-year-old man with a history of purulent scalp lesions presented with night sweats, weight loss, abdominal pain, and hematochezia. Colonoscopy revealed a diffuse friable mucosa with extensive pseudopolyps. Scalp biopsy demonstrated epidermoid inclusion cysts with granulation tissue and chronic inflammatory cell infiltration, indicative of dissecting cellulitis. The incidence of dissecting cellulitis with Crohn's disease is underreported. This dermatologic condition has a tendency to recur, and considering an underlying disease is key for its appropriate treatment.

Prospective Evaluation of Psychosocial Impact after One Year of Orthodontic Treatment Using PIDAQ Adapted for Indian Population.

INTRODUCTION: The impact of dental appearance, malocclusion and treatment for the same on psychological and functional well-being has drawn increasing attention over the past decade. Various psychometric instruments alongside normative indices have been used to predict orthodontic concerns. Evaluating the patients' experience during the orthodontic treatment can help us understand the true benefits and advantages of orthodontic therapy. AIM: The aim of the present study was to evaluate the change in the psychosocial impact of malocclusion using the Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) adapted for the Indian population after one year of fixed orthodontic treatment. MATERIALS AND METHODS: This interventional study was conducted on 93 patients requiring fixed orthodontic treatment. Brazilian, Chinese, Spanish, Nepali and Moroccan versions of the PIDAQ have been published but the questionnaire is not available in Hindi. In the present study, the original PIDAQ was translated into Hindi language to adapt it for the Indian population and was validated by back translation and pretest. All the subjects answered the Hindi version of the questionnaire at pretreatment (T1) and at one year of orthodontic treatment (T2). Additionally, the Index of Orthodontic Treatment Need (IOTN) was applied to measure the severity and self-perception of malocclusion. The data were analysed using paired t-test, Wilcoxon signed rank test and Kruskal-Wallis test. RESULTS: Significant reduction was found in the total PIDAQ score and each factor's score (p<0.001) after one year of orthodontic treatment. There was a positive association of the psychosocial impact of malocclusion with the IOTN-AC (IOTN-Aesthetic Component). Adolescent females were found to be most concerned with their dentofacial appearance. CONCLUSION: Results showed significant improvement in the psychosocial impact of malocclusion with a reduction in the self-perceived needs of patients with orthodontic treatment. The psychometric instrument used may be recommended as an Oral Health Related Quality of Life (OHRQoL) assessment tool for the population in India for further research.

Tumor-associated B-cells induce tumor heterogeneity and therapy resistance.

In melanoma, therapies with inhibitors to oncogenic BRAFV600E are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3. Consistently, resistance of melanomas to BRAF and/or MEK inhibitors is associated with increased CD20 and IGF-1 transcript levels in tumors and IGF-1 expression in tumor-associated B cells. Furthermore, first clinical data from a pilot trial in therapy-resistant metastatic melanoma patients show anti-tumor activity through B-cell depletion by anti-CD20 antibody. Our findings establish a mechanism of acquired therapy resistance through tumor-associated B cells with important clinical implications.Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.

Gadolinium based contrast agents in current practice: Risks of accumulation and toxicity in patients with normal renal function.

Despite being decked as the most prized compounds in the nugget box of contrast agents for clinical radiologists, and carrying an indisputable tag of safety of the US Food and Drug Administration for close to three decades, all may not be seemingly well with the family of gadolinium compounds. If the first signs of violations of primum non nocere in relation to gadolinium-based contrast agents (GBCAs) appeared in the millennium year with the first published report of skin fibrosis in patients with compromised renal function, the causal relationship between the development of nephrogenic systemic fibrosis (NSF) and GBCAs, first proposed by two European groups in 2006, further precluded their use in renocompromised patients. The toxicity, pharmacokinetics, and pharmacodynamics of GBCAs, however, has come under hawk-eyed scrutiny with recent reports that gadolinium tends to deposit cumulatively in the brain of patients with normal hepatobiliary function and intact blood-brain barrier. While the jury on the long-term hazard significance of this critical scientific finding is still out, the use of GBCAs must be guided by due clinical diligence, avoidance of repeated doses, and preferring GBCAs with the best safety profiles.

Tumor-associated B cells in cutaneous primary melanoma and improved clinical outcome.

B cells often infiltrate the microenvironment of human tumors. B cells can both positively and negatively regulate antitumor immune responses. In several human cancers, higher numbers of CD20(+) TAB are associated with a favorable prognosis, whereas in human primary melanomas, this association is contentious. In this study, we determined the association of TAB numbers in cutaneous primary melanoma tissue samples and patients' overall survival. The CD20 immunohistochemistry on archival nonmetastasized and metastasized cutaneous primary melanoma tissues from 2 independent patient cohorts was performed. One cohort was used in class comparison for metastasis, the most important prognostic factor for overall survival, and the other cohort for a subsequent survival analysis. Survival association was further validated with RNA data from a third independent cohort. Whole tissue sections were read automatically via quantitative digital imaging and analysis. Survival data were analyzed by Cox proportional hazard modeling. We discovered that cutaneous primary melanomas without metastasis contain significantly more TAB than primary melanomas that had metastasized. At time of first diagnosis, a higher number of TAB is associated with a significantly better overall survival in patients with cutaneous primary melanomas of >1 mm Breslow depth. Also, higher CD20/CD19 tumor mRNA levels are correlated with a significantly better overall survival. Thus, our data support TAB numbers as a prognostic biomarker in cutaneous primary melanoma patients with a tumor of >1 mm Breslow depth. For a survey in larger studies, whole tissue section analysis seems to be key to accurate assessment of TAB numbers.

RanBP3 Regulates Melanoma Cell Proliferation via Selective Control of Nuclear Export.

Chromosome region maintenance 1-mediated nucleocytoplasmic transport has been shown as a potential anticancer target in various malignancies. However, the role of the most characterized chromosome region maintenance 1 cofactor ran binding protein 3 (RanBP3) in cancer cell biology has never been investigated. Utilizing a loss-of-function experimental setting in a vast collection of genetically varied melanoma cell lines, we observed the requirement of RanBP3 in melanoma cell proliferation and survival. Mechanistically, we suggest the reinstatement of transforming growth factor-ß (TGF-ß)-Smad2/3-p21(Cip1) tumor-suppressor axis as part of the RanBP3 silencing-associated antiproliferative program. Employing extensive nuclear export sequence analyses and immunofluorescence-based protein localization studies, we further present evidence suggesting the requirement of RanBP3 function for the nuclear exit of the weak nuclear export sequence-harboring extracellular signal-regulated kinase protein, although it is dispensable for general CRM1-mediated nuclear export of strong nuclear export sequence-harboring cargoes. Rendering mechanistic support to RanBP3 silencing-mediated apoptosis, consequent to extracellular signal-regulated kinase nuclear entrapment, we observed increased levels of cytoplasmically restricted nonphosphorylated/active proapoptotic Bcl-2-antagonist of cell death (BAD) protein. Last, we present evidence suggesting the frequently activated mitogen-activated protein kinase signaling in melanoma as a potential founding basis for a deregulated post-translational control of RanBP3 activity. Collectively, the presented data suggest RanBP3 as a potential target for therapeutic intervention in human melanoma.

Comprehensive comparative and semiquantitative proteome of a very low number of native and matched epstein-barr-virus-transformed B lymphocytes infiltrating human melanoma.

Melanoma, the deadliest form of skin cancer, is highly immunogenic and frequently infiltrated with immune cells including B cells. The role of tumor-infiltrating B cells (TIBCs) in melanoma is as yet unresolved, possibly due to technical challenges in obtaining TIBCs in sufficient quantity for extensive studies and due to the limited life span of B cells in vitro. A comprehensive workflow has thus been developed for successful isolation and proteomic analysis of a low number of TIBCs from fresh, human melanoma tissue. In addition, we generated in vitro-proliferating TIBC cultures using simultaneous stimulation with Epstein-Barr virus (EBV) and the TLR9 ligand CpG-oligodesoxynucleotide (CpG ODN). The FASP method and iTRAQ labeling were utilized to obtain a comparative, semiquantitative proteome to assess EBV-induced changes in TIBCs. By using as few as 100 000 B cells (∼5 µg protein)/sample for our proteomic study, a total number of 6507 proteins were identified. EBV-induced changes in TIBCs are similar to those already reported for peripheral B cells and largely involve changes in cell cycle proliferation, apoptosis, and interferon response, while most of the proteins were not significantly altered. This study provides an essential, further step toward detailed characterization of TIBCs including functional in vitro analysis.

Cowden syndrome- Clinico-radiological illustration of a rare case.

Cowden syndrome (CS) or multiple hamartoma syndrome is an infrequent genodermatoses, which is inherited as an autosomal dominant trait resulting from the mutation in the Phosphatase and Tensin homolog gene on the arm 10q and is principally characterized by multiple hamartomas with an increased risk of development of malignancies. Facial and oral signs are remarkable in the form of multiple papules and trichilemmomas on the face. We report one such rare case of CS in a 19-year-old patient who was diagnosed on the basis of her oral mucosal lesions and was further investigated and diagnosed with other hamartomas. The present case report signifies the responsibility of the oral physician in the early diagnosis of this progressive pathological syndrome as it leaves its footmark in the oral cavity in the form of oral mucosal lesions.

An unusual cause for trismus caused by mandibular coronoid osteoma: a case report.

Osteoma is a dense bony proliferation of otherwise normal membranous bone. This tumor is essentially restricted to the craniofacial skeleton and is rarely diagnosed in other bones. The mandible and the paranasal sinuses are the most common sites, while the involvement of the coronoid process has been reported in only 6 cases so far. This report demonstrated a case of osteoma occurring at the mandibular coronoid process in a 26-year-old female patient. The patient was managed with surgical resection of the osteoma followed by physiotherapy.

Cysticercosis involving muscle of mastication: a review and report of two cases.

Cysticercosis is a parasitic infection caused by the larval stages of the parasitic cestode, Taenia solium. It is a common disease in developing countries where it is also endemic. The central nervous system (CNS) is the most important primary site of infection and the disease can present with solitary or multiple space occupying lesions. Cases of cysticercosis presenting as isolated muscle mass (pseudotumours) without involvement of the CNS have also been recently described in the literature. We present two cases who presented to us with pain, swelling, and tenderness involving the temporalis muscle along with trismus. Ultrasonography and MRI findings were suggestive of cysticercosis involving the temporalis muscle which resolved after the albendazole therapy.