Clinical Utility of Pro-inflammatory Oligomeric Glycoprotein Tenascin-C in the Diagnosis of Seropositive and Seronegative Rheumatoid Arthritis.

Owing to limited usefulness of Rheumatoid Factor and anti-CCP in rheumatoid arthritis, there is a need to identify a more sensitive and specific biomarker to detect rheumatoid arthritis (RA), particularly seronegative RA cases. Tenascin-C is an extracellular matrix glycoprotein, which has been implicated in the pathophysiology of RA. The objective of our study was to evaluate the diagnostic utility of serum Tenascin-C in seropositive and seronegative rheumatoid arthritis patients. We conducted a cross-sectional case control study. Sixty patients who fulfilled the ACR 2010 criteria for rheumatoid arthritis were included in the study. Thirty patients were found to be positive for RF and/or anti-CCP and 30 were negative for both RF and anti-CCP. Thirty age and gender-matched healthy subjects were taken as controls. Serum Tenascin-C was measured by quantitative sandwich enzyme immunoassay technique. The mean serum concentration of Tenascin-C in controls, seronegative and seropositive cases was 0.66 ng/ml, 20.54 ng/ml and 23.42 ng/ml, respectively. Tenascin-C levels were significantly higher in RA cases compared to controls (p < 0.0001). There was no significant difference in Tenascin-C between seropositive and seronegative cases (p = 0.603). ROC curve analysis showed a sensitivity of 96.6% and specificity of 100% with AUC of 0.98 at 2.21 ng/ml as cut-off value for diagnosing RA. Tenascin-C is elevated in both seronegative and seropositive RA, which indicates that it can be used as a sensitive marker for RA. The addition of Tenascin-C to the existing RF and anti-CCP may help in identifying a large number of patients with RA, particularly seronegative rheumatoid arthritis cases.

Advances in congestive heart failure biomarkers.

Congestive heart failure (CHF) is the leading cause of morbidity and mortality in the elderly worldwide. Although many biomarkers associated with in heart failure, these are generally prognostic and identify patients with moderate and severe disease. Unfortunately, the role of biomarkers in decision making for early and advanced heart failure remains largely unexplored. Previous studies suggest the natriuretic peptides have the potential to improve the diagnosis of heart failure, but they still have significant limitations related to cut-off values. Although some promising cardiac biomarkers have emerged, comprehensive data from large cohort studies is lacking. The utility of multiple biomarkers that reflect various pathophysiologic pathways are increasingly being explored in heart failure risk stratification and to diagnose disease conditions promptly and accurately. MicroRNAs serve as mediators and/or regulators of renin-angiotensin-induced cardiac remodeling by directly targeting enzymes, receptors and signaling molecules. The role of miRNA in HF diagnosis is a promising area of research and further exploration may offer both diagnostic and prognostic applications and phenotype-specific targets. In this review, we provide insight into the classification of different biochemical and molecular markers associated with CHF, examine clinical usefulness in CHF and highlight the most clinically relevant.

RECOMMENDATIONS FOR USE AND SCORING OF ORAL HEALTH IMPACT PROFILE VERSIONS.

BACKGROUND: OHIP's original seven-domain structure does not fit empirical data, but a psychometrically sound and clinically more plausible structure with the four OHRQoL dimensions Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact has emerged. Consequently, use and scoring of available OHIP versions need to be revisited. AIM: We assessed how well the overall construct OHRQoL and its four dimensions were measured with several OHIP versions (20, 19, 14, and 5 items) to derive recommendations which instruments should be used and how to score them. METHODS: Data came from the "Dimensions of OHRQoL Project" and used the project's learning sample (5,173 prosthodontic patients and general population subjects with 49-item OHIP data). We computed correlations among OHIP versions' summary scores. Correlations between OHRQoL dimensions, on one hand, and OHIP versions' domain scores or OHIP-5's items, on the other hand, were also computed. OHIP use and scoring recommendations were derived for psychometrically solid but also practical OHRQoL assessment. RESULTS: Summary scores of 5-, 14-, 19- and 49-item versions correlated highly (r = 0.91-0.98), suggesting similar OHRQoL construct measurement across versions. The OHRQoL dimensions Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact were best measured by the OHIP domain scores for Physical Disability, Physical Pain, Psychological Discomfort, and Handicap, respectively. CONCLUSION: Recommendations were derived which OHIP should be preferably used and how OHIP versions should be scored to capture the overall construct and the dimensions of OHRQoL. Psychometrically solid and practical OHRQoL assessment in all settings across all oral health conditions can be achieved with the 5-item OHIP.

Serum Human Epididymis Protein-4 (HE4) - A novel Approach to Differentiate Malignant Frombenign Breast Tumors.

BACKGROUND: The lack of sensitivity and specificity of existing diagnostic markers like Carbohydrate Antigen 15-3(CA15-3) and Carcinoembryonic antigen (CEA) in breast cancer stimulates the search for new biomarkers to improve diagnostic sensitivity especially in differentiating benign and malignant breast tumors. Expression of Human epididymal protein 4 (HE4) has been demonstrated in ductal carcinoma of the breast tissue. So we tried to evaluate serum HE4 levels as diagnostic marker in breast cancer patients and to comparatively assess serum HE4, CEA and CA15-3 in breast tumor patients both benign and malignant. METHODS: Total 90 female subjects were included in the study. We selected 30 breast cancer cases (Malignant group) and 30 benign breast lump cases (Benign group) based on histopathology report. And other 30 were age matched apparently healthy controls (Control group). HE4, CEA and CA15-3 were analysed in serum samples of all subjects by Electrochemiluminiscence immunoassay method. RESULTS: A significant difference in the median (IQR) of HE4 (pmol/l) was identified among malignant, benign and control groups {62.4(52.6-73.7) vs 49.3(39.8-57.4) vs 52.3(50.6-63.3) P=0.0009} respectively. The cutoff value for prediction of breast cancer was determined at >54.5 pmol/l for HE4, with a sensitivity of 73.3%, specificity of 65.3%, whereas cutoff value of CA 15-3 was >21.24 (U/ml) with a sensitivity of 56.7%, specificity of 74.5%. For CEA at cutoff value >0.99 (ng/ml) the sensitivity and specificity were 96.7 % and 62.7% respectively. AUC for HE4, CA15-3 and CEA were 0.725, 0.644 and 0.857 respectively. CONCLUSION: Our study demonstrated that serum levels of HE4 were significantly higher in malignant group compared to benign and control groups. There is no significant difference between HE4 levels between benign and control groups. These results indicate that HE4 appears as a useful and highly specific biomarker for breast cancer, which can differentiate between malignant and benign tumors.

Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease.

COVID 19 is known to cause immune dysregulation and vitamin D is a known immunomodulator. This study aims to objectively investigate the impact of Pulse D therapy in reducing the inflammatory markers of COVID-19. Consented COVID-19 patients with hypovitaminosis D were evaluated for inflammatory markers (N/L ratio, CRP, LDH, IL6, Ferritin) along with vitamin D on 0th day and 9th/11th day as per their respective BMI category. Subjects were randomised into VD and NVD groups. VD group received Pulse D therapy (targeted daily supplementation of 60,000 IUs of vitamin D for 8 or 10 days depending upon their BMI) in addition to the standard treatment. NVD group received standard treatment alone. Differences in the variables between the two groups were analysed for statistical significance. Eighty seven out of one hundred and thirty subjects have completed the study (VD:44, NVD:43). Vitamin D level has increased from 16 ± 6 ng/ml to 89 ± 32 ng/ml after Pulse D therapy in VD group and highly significant (p < 0.01) reduction of all the measured inflammatory markers was noted. Reduction of markers in NVD group was insignificant (p > 0.05). The difference in the reduction of markers between the groups (NVD vs VD) was highly significant (p < 0.01). Therapeutic improvement in vitamin D to 80-100 ng/ml has significantly reduced the inflammatory markers associated with COVID-19 without any side effects. Hence, adjunctive Pulse D therapy can be added safely to the existing treatment protocols of COVID-19 for improved outcomes.

Evaluation of Galectin-3 as a Novel Diagnostic Biomarker in Patients with Heart Failure with Preserved Ejection Fraction.

Background Heart failure is a complex cardiovascular disease with a variety of etiologies and heterogeneity. The N-terminal pro-B-type natriuretic peptide (NT-proBNP) value has limited usefulness in diagnosing heart failure with preserved ejection fraction (HFpEF). Aim The aim of the present study is to evaluate serum Galectin-3 as a diagnostic biomarker in patients with HFpEF and to compare Galectin-3 with NT-proBNP levels. Materials and Methods A cross-sectional case-control study including 63 cases of heart failure with ejection fraction ≥50% confirmed by echocardiography. NT-proBNP levels in serum were measured by electrochemiluminescence immunoassay and Galectin-3 levels in serum were measured by using an enzyme-linked-immunosorbent serologic assay kit. Results The median levels of serum Galectin-3 and NT-proBNP in patients were significantly higher than those of controls (26.59 vs. 5.27 and 927 vs. 49.3, p < 0.0001). A positive correlation was observed between serum levels of Galection-3 and NT-ProBNP ( r : 0.21, p = 0.048). At cut-off values of 10.1 ng/mL and 160 pg/mL, serum Galectin-3 has 77.78% sensitivity, 95% specificity with an area under the curve (AUC) of 0.93, and serum NT-proBNP has 71.43% sensitivity, 100% specificity with an AUC of 0.87, respectively, for diagnosing HFpEF. The comparison of receiver operating characteristics curves showed that Galectin-3 has better AUC compared with NT-proBNP in diagnosing HFpEF. Serum Galectin-3 showed a positive correlation with NT-proBNP and lipid parameters. Conclusion Galectin-3 with higher sensitivity and AUC can be used as a valuable biomarker for the diagnosis of HFpEF. Simultaneous testing of both Galectin-3 and NT-proBNP can further improve the detection of patients with HFpEF.

Adaptive Neuro-Fuzzy Inference System-Based Exploration of the Interrelationships of 25-Hydroxyvitamin D, Calcium, Phosphorus with Parathyroid Hormone Production.

The rationale of the current study was to assess the prevalence of 25-hydroxyvitamin D (25-OHD) deficiency and hyperparathyroidism in South Indian population and to explore interrelationships of 25-OHD, Ca, P towards parathyroid hormone (PTH) production using adaptive neuro-fuzzy inference system (ANFIS). A total of 407 subjects (228 men 179 women) with the mean age 56.8 ± 14.1 were tested for these parameters. In view of the skewed distribution of biochemical variables, data segregation was performed in tertiles and this data was trained to generate fuzzy interference system based on subclusters. The optimized model had 358 nodes and followed 44 fuzzy rules for prediction. This ANFIS model demonstrates that the deficiency of 25-OHD and Calcium triggers PTH production. PTH elevation is significant when Phosphorus is in the highest tertile. The associations observed by this model were consistent with the Kendall-Tau correlation matrix, which revealed inverse associations of Ca with P; and Ca with PTH and positive associations of P with PTH, and Ca with 25-OHD. Furthermore, the association statistics of the machine learning algorithm were also consistent, which suggested that depletion of Ca below 8.245 mg/dl was shown to elevate PTH levels greater than 167 pg/ml when P > 4.66. Subnormal depletion in 25-OHD (9.3-16.2 ng/ml) is associated with subnormal elevation in PTH (47-73.6 pg/ml). To conclude, ANFIS and machine learning algorithm are in agreement with each other in stating that 25-OHD deficiency triggers lower calcium levels, lower calcium and higher phosphorus trigger PTH production.

Embolization using hydrogel-coated coils for pulmonary arteriovenous malformations.

PURPOSE: To prospectively evaluate the efficacy and safety of embolization using hydrogel-coated coils for the treatment of pulmonary arteriovenous malformations (PAVMs). MATERIALS AND METHODS: The outcomes of 21 PAVMs in 19 patients (3 men and 16 women; mean age, 58.8±15.2 [SD] years; age range 14-78 years) treated by venous sac embolization (VSE) with additional feeding artery embolization were prospectively evaluated. For VSE, using one or more 0.018-inch hydrogel-coated coils was mandatory. Recanalization and/or reperfusion were evaluated by pulmonary arteriography 1 year after embolization. RESULTS: The mean feeding artery and venous sac sizes were 4.0mm and 8.5mm, respectively. Embolization was successfully completed in 20/21 PAVMs, yielding a technical success rate of 95%. The feeding artery was also embolized in 17/20 successful PAVMs (85%). A technical failure occurred in one PAVM, where embolization was abandoned because of migration of one bare coil to the left ventricle. The mean numbers of hydrogel-coated coils and bare platinum detachable coils used for VSE were 3.3±2.1 (SD) (range, 1-8) and 4.4±3.9 (SD) (range, 1-17), respectively. The mean percentages of hydrogel-coated coils in number, length, and estimated volume were 42.9%, 33.3%, and 72.7% respectively. One patient with one PAVM was lost to follow-up after 3 months. Neither recanalization nor reperfusion was noted in the remaining 19 PAVMs (success rate, 19/19 [100%]). One grade 4 (coil migration) adverse event occurred, and it was treated without any sequelae. CONCLUSION: VSE using hydrogel-coated coils with additional feeding artery embolization is a safe and effective treatment for PAVM.

Leadership in an academic discipline.

Leading an academic discipline poses moral and ethical challenges, requiring a special set of capabilities. Leadership in a clinical academic discipline involves leading the transformation of education, research, leadership and patient care. Daily struggles within strategic, political and cultural milieu are the norm and effective leaders are able to navigate through these struggles and see opportunities for growth.

Hepcidin and Ferritin: Important Mediators in Inflammation Associated Anemia in Systemic Lupus Erythematosus Patients.

Systemic Lupus Erythematosus is an autoimmune disease with female preponderance. Anemia is found in 50% of Systemic Lupus Erythematosus patients. This is a cross sectional case control study with 30 female Systemic Lupus Erythematosus patients having inflammation associated anemia (Hemoglobin < 10.0 gm/dl) and 30 age matched controls with the aim to measure serum hepcidin and ferritin levels, correlate and study their role as homeostatic regulators of iron metabolism and utility as markers. Serum transferrin, ferritin, iron, total iron binding capacity, hsCRP, liver enzymes and renal parameters were analyzed by using automated analyser. Hepcidin levels were estimated by Sandwich-ELISA method. There was significant decrease in Iron (p < 0.0001), Iron Binding capacity (p < 0.0001), Transferrin (p < 0.0001) in patients, and a significant increase in inflammatory markers: hs-CRP (p < 0.0001), ESR (p < 0.0001) compared to controls. Significant increase in both Hepcidin (p < 0.0001) and Ferritin (p < 0.0001) was observed in patients with significant positive correlation (r = 0.711) with each other. Additionally, ferritin and hepcidin significantly positively correlated with hs-CRP and ESR (r = 0.526, 0.735); (r = 0.427, 0.742) respectively. Negative correlation with hemoglobin, iron, total iron binding capacity and transferrin with hepcidin (r = - 0.80, - 0.307, - 0.553, - 0.584) and ferritin (r = -0.722, - 0.22, - 0.654, - 0.728) was observed respectively. On ROC analysis both hepcidin and ferritin has sensitivity of 96.7%, specificity of 100% at cut-off values of 110 and 49 respectively. AUC of hepcidin was 0.993 and ferritin was 0.978. We have established a positive linear correlation between Hepcidin and Ferritin levels in disease activity and the changes correlated with the inflammatory state and anemia in patients, making them important mediators and potential markers of inflammation associated anemia.

Possible antithrombotic effects of Angelica keiskei (Ashitaba).

Angelica keiskei Koidzumi (Ashitaba) is a large perennial herb that is native to the Pacific coast of Japan, and it has recently become popular as herbal medicine, dietary supplement and health food in Asian countries. The structures of various constituents isolated from Ashitaba such as chalcones, flavanones and coumarins have been precisely characterized, and many of them have bioactivities. A recent study clarified that Angelica keiskei exerts actions that lead to the prevention of thrombosis. Here, we introduce the possibility that ingesting Ashitaba could help to prevent thrombotic diseases.

8-Nitro-cGMP is a promoter of osteoclast differentiation induced by RANKL.

Osteoclasts are multinucleated giant cells differentiated from monocyte-macrophage-lineage cells under stimulation of receptor activator of nuclear factor κ-B (RANK) ligand (RANKL) produced by osteoblasts and osteocytes. Although it has been reported that nitric oxide (NO) and reactive oxygen species (ROS) are involved in this process, the mechanism by which these labile molecules promote osteoclast differentiation are not fully understood. In this study, we investigated the formation and function of 8-nitro-cGMP, a downstream molecule of NO and ROS, in the process of osteoclast differentiation in vitro. 8-Nitro-cGMP was detected in mouse bone marrow macrophages and osteoclasts differentiated from macrophages in the presence of RANKL. Inhibition of NO synthase suppressed the formation of 8-nitro-cGMP as well as RANKL-induced osteoclast differentiation from macrophages. On the other hand, RANKL-induced osteoclast differentiation was promoted by addition of 8-nitro-cGMP to the cultures. In addition, 8-nitro-cGMP enhanced the mRNA expression of RANK, the receptor for RANKL. However, 8-bromo-cGMP, a membrane-permeable derivative of cGMP, did not have an effect on either RANKL-induced osteoclast differentiation or expression of the RANK gene. These results suggest that 8-nitro-cGMP is a novel positive regulator of osteoclast differentiation, which might help to explain the roles of NO and ROS in osteoclast differentiation.

Note: Sample holder with open area for increased deposition rate in plasma immersion ion implantation and deposition.

A sample holder with a large open area offers several benefits when used in the process of plasma immersion ion implantation and deposition in which the plasma is generated by a high voltage applied to the sample holder: The ignition voltage of the plasma is lower, and the deposition rate can be several times higher than in the case of a normal plate-like holder. There is a more pronounced edge effect regarding the film thickness. Other film properties are also affected; for diamond-like carbon films, the film structure exhibits more disorder. The hardness of the samples is similar, with the surfaces of the samples being very smooth.

Shortened dental arch and prosthetic effect on oral health-related quality of life: a systematic review and meta-analysis.

This systematic review aimed to compare oral health-related quality of life (OHRQoL) between two tooth replacement strategies - the shortened dental arch (SDA) concept and conventional treatment with removable partial dental prosthesis (RPDP) or implant-supported fixed partial dental prosthesis (IFPDP) - for distal extension of edentulous space in the posterior area. We retrieved eligible randomised controlled trials (RCTs) and non-RCTs published between 1980 and November 2016 retrieved from MEDLINE and the Cochrane Central Register of Controlled Trials. The primary outcome was OHRQoL evaluated using validated questionnaires. Two reviewers independently screened and selected the articles, evaluated the risk of bias and determined the standardised weighted mean difference (SWMD) in OHRQoL scores between the two strategies using a random effects model. Two RCTs and one non-RCT involving 516 participants were included in this review. All studies employed the oral health impact profile (OHIP) for evaluation of OHRQoL. There was no statistically significant difference in OHIP summary scores between SDA and RPDP at 6 (SWMD = 0·24) or 12 (SWMD = 0·40) months post-treatment. Only one non-RCT had reported higher OHRQoL with IFPDP than with SDA; however, because of the small sample size, there was no significant difference in OHIP summary scores between the two strategies at 6 (SWMD = -0·59) or 12 (SWMD = -0·67) months post-treatment. In terms of OHRQoL in partially dentate patients, the SDA concept appears to be as feasible as RPDP restoration. Further clinical trials are required to clarify the effect of IFPDP restoration on OHRQoL.

A randomized controlled phase II clinical trial comparing ONO-4053, a novel DP1 antagonist, with a leukotriene receptor antagonist pranlukast in patients with seasonal allergic rhinitis.

BACKGROUND: Prostaglandin D2 (PGD2 ) is primarily produced by mast cells and is contributing to the nasal symptoms including nasal obstruction and rhinorrhea. OBJECTIVE: This study aimed to evaluate the efficacy and safety of a novel PGD2 receptor 1 (DP1) antagonist, ONO-4053, in patients with seasonal allergic rhinitis (SAR). METHODS: This study was a multicenter, randomized, double-blind, parallel-group study of patients with SAR. Following a one-week period of placebo run-in, patients who met the study criteria were randomized to either the ONO-4053, leukotriene receptor antagonist pranlukast, or placebo group for a two-week treatment period. A total of 200 patients were planned to be randomly assigned to receive ONO-4053, pranlukast, or placebo in a 2:2:1 ratio. Nasal and eye symptoms were evaluated. RESULTS: Both ONO-4053 and pranlukast had higher efficacy than placebo on all nasal and eye symptoms. ONO-4053 outperformed pranlukast in a total of three nasal symptom scores (T3NSS) as well as in individual scores for sneezing, rhinorrhea, and nasal itching. For T3NSS, the Bayesian posterior probabilities that pranlukast was better than placebo and ONO-4053 was better than pranlukast were 70.0% and 81.6%, respectively, suggesting that ONO-4053 has a higher efficacy compared with pranlukast. There was no safety-related issue in this study. CONCLUSIONS: We demonstrated that the efficacy of ONO-4053 was greater than that of pranlukast with a similar safety profile. This study indicates the potential of ONO-4053 for use as a treatment for SAR (JapicCTI-142706).

Patterns of impaired oral health-related quality of life dimensions.

How dental patients are affected by oral conditions can be described with the concept of oral health-related quality of life (OHRQoL). This concept intends to make the patient experience measurable. OHRQoL is multidimensional, and Oral Function, Oro-facial Pain, Oro-facial Appearance and Psychosocial Impact were suggested as its four dimensions and consequently four scores are needed for comprehensive OHRQoL assessment. When only the presence of dimensional impact is measured, a pattern of affected OHRQoL dimensions would describe in a simple way how oral conditions influence the individual. By determining which patterns of impact on OHRQoL dimensions exist in prosthodontic patients and general population subjects, we aimed to identify in which combinations oral conditions' functional, painful, aesthetical and psychosocial impact occurs. Data came from the Dimensions of OHRQoL Project with Oral Health Impact Profile (OHIP)-49 data from 6349 general population subjects and 2999 prosthodontic patients in the Learning Sample (N = 5173) and the Validation Sample (N = 5022). We hypothesised that all 16 patterns of OHRQoL dimensions should occur in these individuals who suffered mainly from tooth loss, its causes and consequences. A dimension was considered impaired when at least one item in the dimension was affected frequently. The 16 possible patterns of impaired OHRQoL dimensions were found in patients and general population subjects in both Learning and Validation Samples. In a four-dimensional OHRQoL model consisting Oral Function, Oro-facial Pain, Oro-facial Appearance and Psychosocial Impact, oral conditions' impact can occur in any combination of the OHRQoL dimensions.

Effect of prosthetic restoration on masticatory function in patients with shortened dental arches: a multicentre study.

The aim of this multicentre study was to investigate the effect of prosthetic restoration for missing posterior teeth on mastication in patients with shortened dental arches (SDAs). Partially dentate patients who had an intact teeth in anterior region and missed distal molar(s) (2-12 missing occlusal units) classified as Kennedy Class I or Class II were recruited from seven university-based dental hospitals in Japan. Of the 125 subjects who underwent baseline (pre-treatment) and follow-up/post-treatment evaluation, 53 chose no replacement of missing teeth and 72 chose treatment with removable partial dentures (n = 53) or implant-supported fixed partial dentures (n = 19). Objective masticatory performance (MP) was evaluated using a gummy jelly test. Perception of chewing ability (CA) was rated using a food intake questionnaire. In the no-treatment group, mean MP and CA scores at baseline were similar to those at follow-up evaluation (P > 0·05). In the treatment group, mean MP after treatment was significantly greater than the pre-treatment mean MP (P < 0·05). However, the mean perceived CA in the treatment groups was similar at pre- and post-treatment (P > 0·05). In a subgroup analysis of subjects in the treatment group, subjects with lower pre-treatment CA showed a significant CA increase after treatment (P = 0·004), but those with higher pre-treatment CA showed a significant decrease in CA (P = 0·001). These results suggest that prosthetic restoration for SDAs may benefit objective masticatory performance in patients needing replacement of missing posterior teeth, but the benefit in subjective chewing ability seems to be limited in subjects with perceived impairment in chewing ability before treatment.