Triphala inhibits alpha-synuclein fibrillization and their interaction study by NMR provides insights into the self-association of the protein

The process of assembly and accumulation of the intrinsically disordered protein (IDP), alpha-synuclein (αSyn) into amyloid fibrils is a pathogenic process leading to several neurodegenerative disorders such as Parkinson''s disease, multiple system atrophy and others. Although several molecules are known to inhibit αSyn fibrillization, the mechanism of inhibition is just beginning to emerge. Here, we report the inhibition of fibrillization of αSyn by Triphala, a herbal preparation in the traditional Indian medical system of Ayurveda. Triphala was found to be a rich source of polyphenols which are known to act as amyloid inhibitors. ThT fluorescence and TEM studies showed that Triphala inhibited the fibrillization of αSyn. However, it was observed that Triphala does not disaggregate preformed αSyn fibrils. Further, native-PAGE showed that Triphala reduces the propensity of αSyn to oligomerize during the lag phase of fibrillization. Our NMR results showed that certain stretches of residues in the N-terminal and NAC regions of αSyn play an anchor role in the self-association process of the protein, thereby providing mechanistic insights into the early events during αSyn fibrillization.

Triphala inhibits αSyn self-association by interacting with anchoring regions which are responsible for αSyn oligomerization.     

Decision support system for age-related macular degeneration using discrete wavelet transform

Age-related macular degeneration (AMD) affects the central vision and subsequently may lead to visual loss in people over 60 years of age. There is no permanent cure for AMD, but early detection and successive treatment may improve the visual acuity. AMD is mainly classified into dry and wet type; however, dry AMD is more common in aging population. AMD is characterized by drusen, yellow pigmentation, and neovascularization. These lesions are examined through visual inspection of retinal fundus images by ophthalmologists. It is laborious, time-consuming, and resource-intensive. Hence, in this study, we have proposed an automated AMD detection system using discrete wavelet transform (DWT) and feature ranking strategies. The first four-order statistical moments (mean, variance, skewness, and kurtosis), energy, entropy, and Gini index-based features are extracted from DWT coefficients. We have used five (t test, Kullback–Lieber Divergence (KLD), Chernoff Bound and Bhattacharyya Distance, receiver operating characteristics curve-based, and Wilcoxon) feature ranking strategies to identify optimal feature set. A set of supervised classifiers namely support vector machine (SVM), decision tree, \(k\) -nearest neighbor ( \(k\) -NN), Naive Bayes, and probabilistic neural network were used to evaluate the highest performance measure using minimum number of features in classifying normal and dry AMD classes. The proposed framework obtained an average accuracy of 93.70 %, sensitivity of 91.11 %, and specificity of 96.30 % using KLD ranking and SVM classifier. We have also formulated an AMD Risk Index using selected features to classify the normal and dry AMD classes using one number. The proposed system can be used to assist the clinicians and also for mass AMD screening programs.     

Hla type as a predictor of mixed connective tissue disease differentiation ten-year clinical and immunogenetic followup of 46 patients

Objective. To determine any clinical or genetic markers of differentiation and outcome in a previously described cohort of 46 patients with mixed connective tissue disease (MCTD). Methods. Patients were clinically evaluated, chart notes reviewed, and HLA subtyping and immunology profiles performed where possible. Eleven had died and 7 were lost to followup. Results. MCTD had differentiated into systemic lupus erythematosus in 12 patients and into systemic sclerosis in 13. The latter was associated with HLA-DR5 (P = 0.038), and nondifferentiation was associated with HLA-DR2 or DR4 (P = 0.007). Three HLA-DR4 positive patients had MCTD that evolved into rheumatoid arthritis. Erosive and/or deforming arthritis was associated with HLA-DR1 or DR4 (P = 0.015). HLA-DR3 was associated with interstitial lung fibrosis (P = 0.044) and keratoconjunctivitis sicca (0.001 < P < 0.01). Severe Raynaud's phenomenon predicted higher mortality (0.01 < P < 0.05). Conclusion. We suggest that MCTD is, for most patients, an intermediate stage in a genetically determined progression to a recognized connective tissue disease. Those whose disease remains undifferentiated might be considered a distinct subset.     

Expression and shedding of intercellular adhesion molecule 1 and lymphocyte function–associated antigen 3 by normal and scleroderma fibroblasts.

Objective. To examine intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 3 (LFA-3) in cultures of normal and systemic sclerosis (SSc) dermal fibroblasts. Methods. The surface and soluble forms of ICAM-1 and LFA-3 were measured by flow cytometry and capture enzyme-linked immunosorbent assay, respectively. Results. Surface ICAM-1 was significantly higher on SSc fibroblasts compared with normal controls. β-estradiol did not directly enhance ICAM-1 or LFA-3 expression in either normal or SSc cells, but significantly augmented the cytokine-induced increase in ICAM-1. Soluble ICAM-1 (sICAM-1) and sLFA-3 were detected in fibroblast cultures. While no difference was found in the level of sLFA-3, the shedding of sICAM-1 was significantly increased (P < 0.001) in cells from SSc patients. Conclusion. SSc fibroblasts express intrinsically elevated levels of surface ICAM-1 and release higher levels of sICAM-1 in vitro. Increased expression of ICAM-1 by interferon-γ and tumor necrosis factor α alone, and the further induction in combination with β-estradiol may underlie an aspect of fibroblast dysfunction in SSc and the female predisposition to the disease.     

Acute lower respiratory tract infection due to Chlamydia species in children under five years of age

BACKGROUND: The contribution of Chlamydia spp in respiratory tract infections in paediatric population from India has not been studied in detail. METHODS: Sixty children under five years of age who were admitted with acute lower respiratory tract infection during a one year period were investigated for Chlamydial aetiology of respiratory infection. Diagnosis was based on antigen detection by direct immunofluorescence (DIF) in throat swab along with anti-Chlamydial immunoglobulin G (IgG) antibody demonstration by solid phase enzyme immunoassay (EIA). RESULTS: Chlamydia spp antigen was detected in seven (11.6%) cases, C. pneumoniae in six (10%) and C. trachoniatis in one (1.6%). Chlamydia spp IgG antibody in serum was demonstrated in 24 (40%) cases, of which C. pneumoniae IgG was denconstrated in 18 (30%) cases. Taking the criteria of antigen detection (n=7) and high IgG antibody titre of > or = 1:512 (n=5) for a positive case, 12 (20%) children were found to be suffering from recent Chlamydial infection. CONCLUSION: Chlamydia spp plays a significant role in respiratory tract infections in Indian paediatric population. Diagnostic procedure like antigen detection in throat swab is rapid, less cumbersome and feasible and should be more widely used along with antibody demonstration to determine the aetiological agent early in the course of illness.     

Antiinflammatory and antinociceptive activities of gossypin and procumbentin – cyclooxygenase‐2 (COX‐2) inhibition studies

In the present study the antiinflammatory and antinociceptive activities of a few selected flavonoids were investigated. Procumbentin, gossypin, chrysin and methylhespiridin were studied for antiinflammatory and antinociceptive activities using in vitro enzymatic assays and in animal models utilizing acetic acid‐induced writhing in mice and hind paw edema in rats. In vitro studies were performed using TMPD (NNN′N′‐tetramethyl‐p‐phenylene diamine) and oxygraphic methods for COX‐1 (cyclooxygenase‐1), COX‐2, 5‐LOX (5‐lipoxygenase) and 15‐LOX. Gossypin and procumbentin showed COX‐2 inhibitory activity and exhibited IC₅₀ (COX‐2/COX‐1) ratios of 0.14 and 0.11, respectively. None of the flavonoids tested in this study showed LOX inhibitory activity. Four groups were studied for each test compound following intraperitoneal (i.p.) administration of doses of 10, 30 and 100 mg/kg. Antiinflammatory activity was measured by the carrageenin‐induced rat hind paw edema model and antinociceptive activity by acetic acid‐induced writhing. Procumbentin and gossypin showed antinociceptive activity at the 100 mg/kg dose. Gossypin showed antiinflammatory activity at doses of 10, 30, 100 mg/kg. Procumbentin and gossypin exhibited COX‐2 inhibitory activity when tested by in vitro methods. Procumbentin and gossypin showed antinociceptive, and gossypin showed antiinflammatory, activities. Copyright © 2008 John Wiley & Sons, Ltd.     

Long term results of a phase II trial of Induction Chemotherapy with Uracil-Ftegafur (UFT), Vinorelbine and Cisplatin (UFTVP) followed by Radiotherapy concomitant with UFT and Carboplatin (RT/UFTJ) in Non-Resectable Locally Advanced (Stage IV-B) Squamous Cell Head and Neck Carcinoma

Purpose. To evaluate the response of advanced squamous cell head and neck carcinoma to a combination of induction chemotherapy and radiotherapy. Methods. We present long-term results of a phase II trial of Induction Chemotherapy with UFT 200 mg/m² p.o. days 1 to 21, Vinorelbine 25 mg/m² i.v. days 1 and 8 and Cisplatin 100 mg/m² i.v. day 1 (UFTVP) each 21 days for 4 courses, followed by Radiotherapy concomitant with UFT 100 mg/m² p.o. daily and Carboplatin AUC = 0.5 i.v. weekly (RT/UFTJ) in patients (pts) with Non-Resectable Locally Advanced (Stage IV-B) Squamous Cell Head and Neck Carcinoma (IV-B-SCHNC). Primary endpoint was Complete Response to induction UFTVP and secondary endpoints were Disease Free Status Rate after locoregional treatment and long-term Overall Survival. Between 1994 and 1997, 32 pts were included. Results. Complete Response to Induction UFTVP was 59% (95% CI: 48%-70%). Main toxicity of UFTVP was G 3,4 neutropenia (94% of pts; 25% developed febrile neutropenia and 1 of this pts dead). After Induction Chemotherapy with UFTVP, 30 pts received radiotherapy and 25 of them received cocomitant Carboplatin and UFT (RT/UFTJ): main toxicity was mucositis (G3-4: 72%) and one patient died during RT/UFTJ because pneumonia. Twenty-five pts (78%) were alive and disease free at the end of the whole treatment. Actuarial 5 year Overall survival is 32%. Conclusion. Although toxicity is important, this approach has interesting activity and deserves further investigation. In the January issue of Clin Transl Oncol the following article was published with a wrong reference: Fernando Rivera, María E Vega-Villegas, Marta F. López-Brea, Almudena García-Casta?o, Ana de Juan, Francisco Javier Ramos, Antonio Collado, Piedad Galdós, Antonio Rubio, Adolfo del Valle, Julio Rama, Marta Mayorga and Jaime Sanz-Ortiz Long term results of a phase II trial of Induction Chemotherapy with Uracil-Ftegafur (UFT), Vinorelbine and Cisplatin (UFTVP) followed by Radiotherapy concomitant with UFT and Carboplatin (RT/UFTJ) in Non-Resectable Locally Advanced (Stage IV-B) Squamous Cell Head and Neck Carcinoma and Peripheral Blood Stem Cell Support (PBSCS) with Febrile Neutropenia Clin Transl Oncol. 2007 Jan;9:40-47 DOI 10.1007/s12094-007-0008-5 The correct reference should be as follows: Fernando Rivera, María E Vega-Villegas, Marta F. López-Brea, Almudena García-Casta?o, Ana de Juan, Francisco Javier Ramos, Antonio Collado, Piedad Galdós, Antonio Rubio, Adolfo del Valle, Julio Rama, Marta Mayorga and Jaime Sanz-Ortiz Long term results of a phase II trial of Induction Chemotherapy with Uracil-Ftegafur (UFT), Vinorelbine and Cisplatin (UFTVP) followed by Radiotherapy concomitant with UFT and Carboplatin (RT/UFTJ) in Non-Resectable Locally Advanced (Stage IV-B) Squamous Cell Head and Neck Carcinoma Clin Transl Oncol. 2007 Jan;9:40-47The original article can be found online at