Study of a cross-linked hydrogel of Karaya gum and Starch as a controlled drug delivery system

Abstract

A cross-linked hydrogel was synthesized using a hybrid backbone of karaya gum starch and grafted with polyacrylic acid. It showed a maximum swelling ratio (SR) of 30.5?g/g at pH 10 and was explored as an oral drug delivery carrier using paracetamol and aspirin as model drugs. In vitro release experiments revealed that maximum drug release at pH 7.4 in comparison to pH 1.2 (simulated intestinal vs gastric fluid) and neutral medium. The release profiles of these drugs showed no initial burst. It also showed good hemocompatibilty and non-cytotoxicity for its employment as a site specific drug delivery agent.     

Familial clustering of non-nuclear autoantibodies and C3 and C4 complement components in systemic lupus erythematosus

OBJECTIVE: To determine whether key features of systemic lupus erythematosus (SLE), namely, production of non-nuclear antibodies (anti-C1q and anticardiolipin antibodies [aCL]) and depletion of complement components C3 and C4, aggregate in families. In addition, we examined relationships between anti-C1q and C3 and C4 levels. METHODS: The study cohort comprised 1,037 predominantly white (82%) nuclear families in which at least 1 member had SLE. Associations of antibody measurements between probands and their unaffected siblings were examined using parametric and nonparametric analyses, along with associations between unaffected siblings and their parents. The heritability of anti-C1q, C3, and C4 was estimated, and interdependencies between these factors were examined in a regression model accounting for the family structure of the data set. RESULTS: We demonstrated associations between siblings for anti-C1q (odds ratio [OR] 3.74, 95% confidence interval [95% CI] 2.65, 5.28) and IgG and IgM aCL (OR 4.08, 95% CI 1.83, 5.13 and OR 2.06, 95% CI 1.46, 2.91, respectively) and, for anti-C1q, association between unaffected parents and their unaffected offspring (OR 4.34, 95% CI 2.16, 8.72). We also demonstrated significant heritability of anti-C1q, C3, and C4 (approximately 45%). Anti-C1q was negatively associated with C3 and C4 in SLE probands but not in their healthy relatives. CONCLUSION: Non-nuclear antibodies and C3 and C4 cluster within the families of SLE probands, suggesting that specific autoantibody formation is partly genetically determined, even if the total genetic effect in unaffected relatives is insufficient to cause disease. Anti-C1q antibodies accelerate C3 and C4 depletion in patients with SLE but have no effect in the absence of disease.     

Correlation of polyp number and family history of colon cancer with germline MYH mutations.

BACKGROUND & AIMS: Affected individuals with biallelic MYH mutations are believed to display multiple adenomatous polyps without evidence of vertical transmission. Our goal was to determine the detection rate of germline MYH mutations in a high-risk gastrointestinal cancer clinic population by using polyp number as a selection criterion. METHODS: Patients were screened for the 2 most common MYH mutations: Y165C and G382D. The complete MYH coding region was sequenced in cases with a heterozygous mutation. RESULTS: Among 45 patients with more than 15 adenomatous polyps not diagnosed with familial adenomatous polyposis, 7 (15.6%) had biallelic MYH mutations. When 122 participants from a high-risk gastrointestinal cancer clinic who did not fulfill these criteria were tested, 2 additional patients with biallelic mutations were identified. Both had young-onset colorectal cancer (age, <50 y) with fewer than 15 polyps. Surprisingly, most of the 9 patients with biallelic MYH mutations reported family histories consistent with the hereditary nonpolyposis colorectal cancer syndrome (HNPCC), with 7 cases meeting at least 1 of the Bethesda criteria, 5 cases fulfilling 3 Bethesda criteria, and 2 cases fulfilling the Amsterdam II criteria. CONCLUSIONS: Most individuals with MYH mutations exhibit multiple adenomatous polyps. However, 22% of cases were missed when this was the sole criterion for germline testing. A significant number reported a strong family history of cancer that was consistent with HNPCC. MYH testing thus can be considered for patients who meet clinical criteria for HNPCC in the absence of DNA mismatch repair gene mutations.     

Determinants of colorectal cancer screening in women undergoing mammography

OBJECTIVES: Women who participate in screening for breast cancer are more likely to participate in screening for colorectal cancer. We studied such a motivated group of women to identify predictors of, and barriers to, participation in colorectal cancer screening by endoscopy. METHODS: We distributed surveys to 551 women > or = 50 yr of age while they were awaiting mammography at four sites in and around Boston, MA from June to September, 2000. The 40-question survey assessed knowledge, attitudes, and beliefs about, and behaviors toward, breast and colorectal cancer screening. Regression models were used to determine factors associated with having had sigmoidoscopy or colonoscopy. RESULTS: Seventy-nine percent of the women completed all or part of the survey. Half (221/438) reported ever having had sigmoidoscopy or colonoscopy. Of these, 93% did so at the recommendation of their primary care provider. Factors associated with participation in endoscopic screening included compliance with annual fecal occult blood testing, a family history of colorectal cancer, and indifference toward the gender of the doctor performing the endoscopy. CONCLUSIONS: Women undergoing mammography overwhelmingly cite the recommendation of their primary care provider as the reason for participating in colorectal cancer screening by endoscopy. Women who preferred a female endoscopist were less likely to have been screened. Whenever possible, primary care providers should offer women the choice of a female endoscopist for colorectal cancer screening.     

Scavenging of soluble and immobilized CCL21 by ACKR4 regulates peripheral dendritic cell emigration

Leukocyte homing driven by the chemokine CCL21 is pivotal for adaptive immunity because it controls dendritic cell (DC) and T cell migration through CCR7. ACKR4 scavenges CCL21 and has been shown to play an essential role in DC trafficking at the steady state and during immune responses to tumors and cutaneous inflammation. However, the mechanism by which ACKR4 regulates peripheral DC migration is unknown, and the extent to which it regulates CCL21 in steady-state skin and lymph nodes (LNs) is contested. Specifically, our previous findings that CCL21 levels are increased in LNs of ACKR4-deficient mice [I. Comerford et al., Blood 116, 4130–4140 (2010)] were refuted [M. H. Ulvmar et al., Nat. Immunol. 15, 623–630 (2014)], and no differences in CCL21 levels in steady-state skin of ACKR4-deficient mice were reported despite compromised CCR7-dependent DC egress in these animals [S. A. Bryce et al., J. Immunol. 196, 3341–3353 (2016)]. Here, we resolve these issues and reveal that two forms of CCL21, full-length immobilized and cleaved soluble CCL21, exist in steady-state barrier tissues, and both are regulated by ACKR4. Without ACKR4, extracellular CCL21 gradients in barrier sites are saturated and nonfunctional, DCs cannot home directly to lymphatic vessels, and excess soluble CCL21 from peripheral tissues pollutes downstream LNs. The results identify the mechanism by which ACKR4 controls DC migration in barrier tissues and reveal a complex mode of CCL21 regulation in vivo, which enhances understanding of functional chemokine gradient formation.

CCL21 is a chemokine that mediates recruitment of multiple leukocyte subsets through CCR7-mediated signaling during the steady state and inflammation. CCL21 plays crucial roles in priming adaptive immunity via governing egress of dendritic cells (DCs) from barrier tissues and T cell entry and positioning in secondary lymphoid organs (1–5). A well-characterized site of CCL21 gradient formation is the skin, where CCL21 is secreted by lymphatic endothelial cells (LECs) and immobilized on extracellular heparan sulfate moieties via interactions with the charged, elongated C-terminal tail of CCL21 (6–8). Here, immobilized CCL21 gradients are essential for interstitial DC trafficking toward lymphatic vessels (LVs) (8), after which CCL21 further contributes to LV attachment (9), infiltration (10), downstream luminal migration (11), and migration from the lymph node (LN) subcapsular sinus (SCS) to the paracortex (12). In-vitro studies have shown that the C-terminal tail of CCL21 can also be proteolytically cleaved by mature DCs to generate solubilized CCL21 (13), with signaling properties distinct from another soluble CCR7 ligand, CCL19 (14, 15). While CCL19 is dispensable for steady-state DC migration (16), important questions regarding the in vivo processing and function of cleaved CCL21 remain.Both forms of CCL21 are also ligands for the atypical chemokine receptor ACKR4 (17), which regulates chemokine bioavailability rather than directly mediating cell migration. ACKR4 expression has been identified in multiple barrier tissues (18–20) and lymphoid tissues (12, 21) where expression is largely restricted to stromal cell populations, with the exception of germinal-center B cells (22). Despite clear evidence of ACKR4 scavenging of CCL21 in vitro, the extent to which it regulates CCL21 in vivo is disputed. We have shown increased CCL21 in the LNs of Ackr4^−/− mice, which was associated with exacerbated Th17 responses in autoimmunity (23) and an ACKR4-dependent increase in CCL21 in tumors that promotes antitumor immunity (24). However, no differences in dermal CCL21 abundance were previously reported in steady-state Ackr4^−/− mice despite steady-state CCR7-dependent DC migratory defects being independent of CCL19 (19), and the contribution of ACKR4 in regulating LN CCL21 abundance has been disputed despite a clear role for ACKR4 in maintaining interfollicular CCL21 gradients in LN (12). These discrepancies have remained unresolved but point to previously unrecognized complexity in ACKR4-dependent regulation of CCL21 in both barrier and lymphoid tissues.     

Role of a Dentist in Comprehensive Management of a Comatose Patient with Post Traumatic Head Injury and Neuropathological Chewing

Injury of the head and neck region can result in substantial morbidity. Comprehensive management of such patients requires team work of several specialties, including dentists. A young female patient with extensive loss of cranium and associated pathological chewing was referred to the dental department. The lost cranium was replaced by a custom-made, hand-fabricated cranioplast. Trauma due to pathological mastication was reduced by usage of a custom-made mouthguard. Favorable results were seen in the appearance of the patient and after insertion of the mouthguard as evidenced in good healing response. The intricate role of a dental specialist in the team to manage a patient with post traumatic head injury has been highlighted. The take away message is to make the surgical fraternity aware of the scope of dentistry in the comprehensive management of patients requiring special care.