Functional Outcome in Percutaneous Achilles Tendon Repair.

Background: Rupture of the Achilles tendon is a considerable cause of morbidity with reduced function following injury. Randomized studies have so far failed to show a difference in outcome between operative and nonoperative management of Achilles tendon rupture, provided that no re-rupture occurs. Percutaneous Achilles repair has been suggested to result in superior patient satisfaction compared with open repair in patients with an acute Achilles tendon rupture. Aim and Objectives: To assess and evaluate the functional outcome after percutaneous repair in patients of the acute and closed Achilles tendon ruptures. Materials and Methods: It was a prospective study conducted on patients diagnosed as having rupture of the Achilles tendon. A total of 25 patients with mean age of 44.4 (range 19-65) years were taken, who underwent percutaneous Achilles tendon repair. Results: The number of patients who reported excellent or good scores (ATRS > 80) at 3, 6 and 12 months were 0%, 16% and 100%, respectively. The mean AOFAS hind foot score at 3-, 6- and 12-month follow-ups was 77.9 ± 4.3, 92.04 ± 2.4 and 96.16.32 ± 1.1, respectively. The number of patients who reported excellent or good scores (AOFAS > 74) at 3, 6 and 12 months were 76%, 100% and 100%, respectively. Most of the patients in our study showed no complications, and only 2 (8%) of patients had the features of sural nerve injury which was resolved in the subsequent follow-ups. Conclusion: Percutaneous repair of the Achilles tendon is an effective procedure which gives excellent functional outcome with very few complications. The percutaneous technique gives an additional advantage of less operative time, no wound complications, less damage to the soft tissues, and improved cosmesis as compared to the open repair.

The link between glycemic control measures and eye microvascular complications in a clinical cohort of type 2 diabetes with microRNA-223-3p signature.

BACKGROUND: Type 2 diabetes (T2D) is a critical healthcare challenge and priority in Qatar which is listed amongst the top 10 countries in the world, with its prevalence presently at 17% double the global average. MicroRNAs (miRNAs) are implicated in the pathogenesis of (T2D) and long-term microvascular complications including diabetic retinopathy (DR). METHODS: In this study, a T2D cohort that accurately matches the characteristics of the general population was employed to find microRNA (miRNA) signatures that are correlated with glycemic and ß cell function measurements. Targeted miRNA profiling was performed in (471) T2D individuals with or without DR and (491) (non-diabetic) healthy controls from the Qatar Biobank. Discovery analysis identified 20 differentially expressed miRNAs in T2D compared to controls, of which miR-223-3p was significantly upregulated (fold change:5.16, p = 3.6e-02) and positively correlated with glucose and hemoglobin A1c (HbA1c) levels (p-value = 9.88e-04 and 1.64e-05, respectively), but did not show any significant associations with insulin or C-peptide. Accordingly, we performed functional validation using a miR-223-3p mimic (overexpression) under control and hyperglycemia-induced conditions in a zebrafish model. RESULTS: Over-expression of miR-223-3p alone was associated with significantly higher glucose (42.7 mg/dL, n = 75 vs 38.7 mg/dL, n = 75, p = 0.02) and degenerated retinal vasculature, and altered retinal morphology involving changes in the ganglion cell layer and inner and outer nuclear layers. Assessment of retinal angiogenesis revealed significant upregulation in the expression of vascular endothelial growth factor and its receptors, including kinase insert domain receptor. Further, the pancreatic markers, pancreatic and duodenal homeobox 1, and the insulin gene expressions were upregulated in the miR-223-3p group. CONCLUSION: Our zebrafish model validates a novel correlation between miR-223-3p and DR development. Targeting miR-223-3p in T2D patients may serve as a promising therapeutic strategy to control DR in at-risk individuals.

Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi-Bickel Syndrome.

Fanconi−Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized by the accumulation of glycogen mainly in the liver. It is inherited in an autosomal recessive manner due to mutations in the SLC2A2 gene. SLC2A2 encodes for the glucose transporter GLUT2 and is expressed in tissues that are involved in glucose homeostasis. The molecular mechanisms of dysglycemia in FBS are still not clearly understood. In this study, we report two cases of FBS with classical phenotypes of FBS associated with dysglycemia. Genomic DNA was extracted and analyzed by whole-genome and Sanger sequencing, and patient PBMCs were used for molecular analysis. One patient had an exonic SLC2A2 mutation (c.1093C>T in exon 9, R365X), while the other patient had a novel intronic SLC2A2 mutation (c.613-7T>G). Surprisingly, the exonic mutation resulted in the overexpression of dysfunctional GLUT2, resulting in the dysregulated expression of other glucose transporters. The intronic mutation did not affect the coding sequence of GLUT2, its expression, or glucose transport activity. However, it was associated with the expression of miRNAs correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p implicated in insulin production and secretion. Our findings suggest that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression and/or activity or, indirectly, by the dysregulated expression of miRNAs implicated in glucose homeostasis.

Understanding the Mechanism of Dysglycemia in a Fanconi-Bickel Syndrome Patient.

Fanconi-Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized mainly by the accumulation of glycogen in the liver and kidney. It is inherited as an autosomal recessive disorder caused by mutations in the SLC2A2 gene, which encodes for GLUT2. Patients with FBS have dysglycemia but the molecular mechanisms of dysglycemia are still not clearly understood. Therefore, we aimed to understand the underlying molecular mechanisms of dysglycemia in a patient with FBS. Genomic DNA was isolated from a peripheral blood sample and analyzed by whole genome and Sanger sequencing. CRISPR-Cas9 was used to introduce a mutation that mimics the patient's mutation in a human kidney cell line expressing GLUT2 (HEK293T). Mutant cells were used for molecular analysis to investigate the effects of the mutation on the expression and function of GLUT2, as well as the expression of other genes implicated in dysglycemia. The patient was found to have a homozygous nonsense mutation (c.901C>T, R301X) in the SLC2A2 gene. CRISPR-Cas9 successfully mimicked the patient's mutation in HEK293T cells. The mutant cells showed overexpression of a dysfunctional GLUT2 protein, resulting in reduced glucose release activity and enhanced intracellular glucose accumulation. In addition, other glucose transporters (SGLT1 and SGLT2 in the kidney) were found to be induced in the mutant cells. These findings suggest the last loops (loops 9-12) of GLUT2 are essential for glucose transport activity and indicate that GLUT2 dysfunction is associated with dysglycemia in FBS.

Development of a Critical Appraisal Tool (AIMRDA) for the Peer-Review of Studies Assessing the Anticancer Activity of Natural Products: A Step towards Reproducibility.

The journal of APJCP (Asian Pacific Journal of Cancer Prevention) focuses to gather relevant and up-to-date novel information's related to cancer sciences. The research methodologies and approaches adopted by the researcher are prone to variation which may be desirable in the context of novel scientific findings however, the reproducibility for these studies needs to be unified and assured. The reproducibility issues are highly concerned when preclinical studies are reported in cancer, for natural products in particular. The natural products and medicinal plants are prone to a wide variation in terms of phytochemistry and phyto-pharmacology, ultimately affecting the end results for cancer studies. Hence the need for specific guidelines to adopt a best-practice in cancer research are utmost essential. The current AIMRDA guidelines aims to develop a consensus-based tool in order to enhance the quality and assure the reproducibility of studies reporting natural products in cancer prevention. A core working committee of the experts developed an initial draft for the guidelines where more focus was kept for the inclusion of specific items not covered in previous published tools. The initial draft was peer-reviewed, experts-views provided, and improved by a scientific committee comprising of field research experts, editorial experts of different journals, and academics working in different organization worldwide. The feedback from continuous online meetings, mail communications, and webinars resulted a final draft in the shape of a checklist tool, covering the best practices related to the field of natural products research in cancer prevention and treatment. It is mandatory for the authors to read and follow the AIMRDA tool, and be aware of the good-practices to be followed in cancer research prior to any submission to APJCP. Though the tool is developed based on experts in the field, it needs to be further updated and validated in practice via implementation in the field.

Anticancer Activity of Camel Milk via Induction of Autophagic Death in Human Colorectal and Breast Cancer Cells

Background/ Objective: Camel milk is traditionally known for its human health benefits and believed to be a remedy for various human ailments including cancer. The study was aimed to evaluate the inhibitory effects of commercially available camel milk on cancer cells and its underlying mechanism(s). Materials and Methods: Two cell lines: colorectal cancer HCT 116 and breast cancer MCF-7 were cultured with different doses of camel milk. The effects of camel milk on cell death were determined by MTT assay, viability by trypan blue exclusion assay and migration by in vitro scratch assay. The mechanism was elucidated by western blotting and confocal microscopy was used to confirm autophagy. Results: Camel milk significantly reduced proliferation, viability as well as migration of both the cells. The accumulation of LC3-II protein along with reduction in expression of p62 and Atg 5-12, the autophagy proteins implied induction of autophagy. The (GFP)-LC3 puncta detected by confocal microscopy confirmed the autophagosome formation in response to camel milk treatment. Conclusion: Camel milk exerted antiproliferative effects on human colorectal HCT 116 and breast MCF-7 cancer cells by inducing autophagy.

Humanoid infers Archimedes' principle: understanding physical relations and object affordances through cumulative learning experiences.

Emerging studies indicate that several species such as corvids, apes and children solve 'The Crow and the Pitcher' task (from Aesop's Fables) in diverse conditions. Hidden beneath this fascinating paradigm is a fundamental question: by cumulatively interacting with different objects, how can an agent abstract the underlying cause-effect relations to predict and creatively exploit potential affordances of novel objects in the context of sought goals? Re-enacting this Aesop's Fable task on a humanoid within an open-ended 'learning-prediction-abstraction' loop, we address this problem and (i) present a brain-guided neural framework that emulates rapid one-shot encoding of ongoing experiences into a long-term memory and (ii) propose four task-agnostic learning rules (elimination, growth, uncertainty and status quo) that correlate predictions from remembered past experiences with the unfolding present situation to gradually abstract the underlying causal relations. Driven by the proposed architecture, the ensuing robot behaviours illustrated causal learning and anticipation similar to natural agents. Results further demonstrate that by cumulatively interacting with few objects, the predictions of the robot in case of novel objects converge close to the physical law, i.e. the Archimedes principle: this being independent of both the objects explored during learning and the order of their cumulative exploration.

Dynamics of competitive learning: the role of updates and memory.

We examine the effects of memory and different updating paradigms in a game-theoretic model of competitive learning, where agents are influenced in their choice of strategy by both the choices made by, and the consequent success rates of, their immediate neighbors. We apply parallel and sequential updates in all possible combinations to the two competing rules and find, typically, that the phase diagram of the model consists of a disordered phase separating two ordered phases at coexistence. A major result is that the corresponding critical exponents belong to the generalized universality class of the voter model. When the two strategies are distinct but not too different, we find the expected linear-response behavior as a function of their difference. Finally, we look at the extreme situation when a superior strategy, accompanied by a short memory of earlier outcomes, is pitted against its inverse; interestingly, we find that a long memory of earlier outcomes can occasionally compensate for the choice of a globally inferior strategy.

Learning with a network of competing synapses.

Competition between synapses arises in some forms of correlation-based plasticity. Here we propose a game theory-inspired model of synaptic interactions whose dynamics is driven by competition between synapses in their weak and strong states, which are characterized by different timescales. The learning of inputs and memory are meaningfully definable in an effective description of networked synaptic populations. We study, numerically and analytically, the dynamic responses of the effective system to various signal types, particularly with reference to an existing empirical motor adaptation model. The dependence of the system-level behavior on the synaptic parameters, and the signal strength, is brought out in a clear manner, thus illuminating issues such as those of optimal performance, and the functional role of multiple timescales.

Humoral immune responses and protective efficacy of sequential B- and T-cell epitopes of V antigen of Yersinia pestis by intranasal immunization in microparticles.

Capsular F1 and secretory V antigen are the putative vaccine candidates for plague, caused by Yersinia pestis. Contemplating this, we studied the immunogenicity and protective efficacy of collinearly synthesized B- and T-cell epitopes (B-T constructs) of V antigen entrapped in poly (DL-lactide-co-glycolide) microparticles immunized intranasally using single dose immunization schedule in outbred, H-2(b) and H-2(d) mice. High antibody levels were observed in terms of IgG, IgA and SIgA peak titers in sera and mucosal washes to different B-T constructs. The constructs ai, bi and fi especially showed high peak antibody titers ranging from 51,200 to 204,000, which were maintained till day 120 post immunization. IgG/IgA Specific activity in sera and washes correlated well with the peak antibody titers. Moreover, all the B-T constructs showed mixed IgG1 and IgG2a/2b response, variable immunoreactivity as well as memory response with V antigen. B-T constructs, viz ai, ak, bi, fi, di and ik showed comparatively high isotype levels. These constructs showed high immunoreactivity, and good recall response with V antigen. Finally, in vivo protective study in BALB/c mice demonstrated the protective efficacy of three B-T constructs (ai, bi and fi) against lethal doses of Yersinia pestis till day 20 post challenge, while construct 'id' showed partial protection.

Intranasal administration of peptide antigens of HIV with mucosal adjuvant CpG ODN coentrapped in microparticles enhances the mucosal and systemic immune responses.

The mucosal immune system acts as a first line of defense against infection caused by luminal pathogens. Because HIV is transmitted primarily via mucosal associated tissues, particularly with sexual transmission, understanding antiviral immunity present at these sites is important. As most of the peptide antigens show poor immunogenicity when immunized alone but after incorporating the same peptide antigens along with adjuvant CpG ODN in microparticles has shown enhanced immunogenicity in the murine model. In the present study we have investigated the immunomodulatory effects of two adjuvants, CpG 1826 and CpG 2006 (Class B, Also known as type K) to the four peptide antigens of HIV such as envelope glycoproteins gp41 Leucine Zipper, gp41 fusion domain and gp120-C2 as well as regulatory protein (Nef) in microparticles, exploring nasal route with single immunization schedule. Peptide (s) alone in the microparticles elicited low peptide specific IgG and IgA peak titres in the sera, whereas the inclusion of CpG ODN with peptides in microparticles significantly enhanced peptide specific IgG and IgA peak titres and such responses were sustained for longer durations. Similarly higher SIgA response was achieved in the mucosal washes with CpG encapsulated in microparticles. Such presence of SIgA in washes was further correlated with the presence of secretory component (SC) in the respective washes. Both adjuvants induced excellent peptide specific IgG and IgA immune responses. Thus the overall study highlighted the importance of CpG ODNs as a mucosal adjuvant for weaker peptide antigens and thus can explore for developing peptide based vaccine against HIV.