Guanidino quinazolines and pyrimidines promote readthrough of premature termination codons in cells with native nonsense mutations.

Using small molecules to induce readthrough of premature termination codons is a promising therapeutic approach to treating genetic diseases and cancers caused by nonsense mutations, as evidenced by the widespread use of ataluren to treat nonsense mutation Duchene muscular dystrophy. Herein we describe a series of novel guanidino quinazoline and pyrimidine scaffolds that induce readthrough in both HDQ-P1 mammary carcinoma cells and mdx myotubes. Linkage of basic, tertiary amines with aliphatic, hydrophobic substituents to the terminal guanidine nitrogen of these scaffolds led to significant potency increases. Further potency gains were achieved by flanking the pyrimidine ring with hydrophobic substituents, inducing readthrough at concentrations as low as 120 nM and demonstrating the potential of these compounds to be used either in combination with ataluren or as stand-alone therapeutics.

Covid-19 Opens up domestic market for Indian shrimp.

COVID-19 pandemic presents both a challenge and an opportunity to the Indian shrimp sector. With revitalizing the institutional arrangements and redirecting the focus, the Indian shrimp industry can flourish just by adapting to the needs of the local demand, even when the export prospects are uncertain. This paper takes a historical perspective of Indian shrimp farming and exports and suggests a domestic alternative/supplementary market for Indian farmed shrimp, resulting from COVID-19.

Study of Pulmonary Function Tests in Diabetic Nephropathy.

Type 2 diabetes mellitus which is an universal public health problem is associated with the development of micro- and macrovascular complications. Complications of diabetes on eyes, kidneys and nerves are well documented but studies on lung involvement in diabetes and its correlation with nephropathy are sparse. This study was taken to assess pulmonary functions in patients with diabetic nephropathy and to find out correlation of pulmonary function with duration of diabetes and assess the prevalence pulmonary hypertension in patients with nephropathy. MATERIAL: This was a cross-sectional study which included 50 diabetic subjects, 50 diabetics with overt nephropathy, and 50 healthy subjects without diabetes as the control group. Diabetic subjects were matched to the control group in terms of age, sex, and BMI. Pulmonary function tests were performed and the results were compared between groups. Pulmonary artery pressures were assessed by 2D ECHO and results were interpreted using SPSS 21.0 version for windows. OBSERVATION: Mean FEV 1% was 98.12 (+/-10.06), 75.88 (+/-14.10) and 57.64 (+/-13.49), Mean FVC% was 86.78 (+/- 8.77), 69.82(+/-13.88) and 53.02(+/-13.41), The mean PEF% was 88.62 (+/-14.47), 59.40 (+/-18.59) and 48.96 (+/-20.94) among healthy subjects with no diabetes, diabetes mellitus group and diabetic nephropathy group respectively and the difference observed was statistically significant (p value <0.001). Restrictive pattern of lung function impairment was observed in diabetic patients which was more pronounced in Diabetic nephropathy group. Mean FEV1% was 71.03 (+/-13.19), 66.74 (+/-18.34) and 60.29 (+/-15.25),Mean FVC% was 65.66 (+/-11.06), 60.79 (+/-18.00) and 56.38 (+/-16.55) was observed among the participants having diabetes less than 10yrs, 10 to 20 years and > 20 years respectively. The difference in mean FEV1%, FVC % with duration of DM was not statistically significant. PAH was present in 3 patients (6%) in diabetes mellitus group and in 20 (40%) in diabetes nephropathy group and the difference observed was statistically significant p < 0.0001. FEV1, FVC and PEF % were significantly reduced in PAH group when compared to the No PAH group with p values <0.0001. CONCLUSION: This study showed that Pulmonary function tests are impaired in diabetics, showing a restrictive pattern and impairment was pronounced in diabetics with nephropathy. Derangement of pulmonary functions was independent of duration of diabetes. Pulmonary hypertension was more common in diabetic nephropathy group.

Tropical Beaches Attenuate Groundwater Nitrogen Pollution Flowing to the Ocean.

Tropical urbanized coastal regions are hotspots for the discharge of nutrient-enriched groundwater, which can affect sensitive coastal ecosystems. Here, we investigated how a beach modifies groundwater nutrient loads in southern India (Varkala Beach), using flux measurements and stable isotopes. Fresh groundwater was highly enriched in NO3 from sewage or manure. Submarine groundwater discharge and nearshore groundwater discharge were equally important contributors to coastal NO3 fluxes with 303 mmol NO3 m-1 day-1 in submarine and 334 mmol NO3 m-1 day-1 in nearshore groundwater discharge. However, N/P ratios in nearshore groundwater discharge were up to 3 orders of magnitude greater than that in submarine groundwater, which can promote harmful algae blooms. As groundwater flowed through the beach, N/P ratios decreased toward Redfield ratios due to the removal of 30-50% of NO3 due to denitrification and production of PO4 due to mineralization of organic matter. Overall, tropical beaches can be important natural biogeochemical reactors that attenuate nitrogen pollution and modify N/P ratios in submarine groundwater discharge.

Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study.

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established.Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population.Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death.Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of <80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39-3.71).Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Impact of cytological pitfalls in the Bethesda System of Reporting Thyroid Cytopathology, on surgical decision-making of patients with thyroid nodules: Can these pitfalls be avoided?

INTRODUCTION: The purpose was to assess diagnostic accuracy of the Bethesda System of Reporting Thyroid Cytopathology, reasons for disagreement and cytological pitfalls with impact on surgical decisions in patients with thyroid nodules. METHODS: Cases of thyroid cytology with histological follow up were included followed by cytological-histological correlation and were reviewed to look for reasons for discrepancies. The impact of disagreements and partial agreements on surgical decision was evaluated. Overall and complete diagnostic accuracy were calculated along with sensitivity, specificity, and positive and negative predictive values for malignant and neoplastic lesions. RESULTS: Of 446 cases included in the study, there was complete agreement in 358 cases, partial agreement in 22 cases and disagreement in 66 patients. Overall diagnostic accuracy was 98.5% with sensitivity, specificity, positive predictive value and negative predictive value of 80%, 99.6%, 100%, 72.7% and 94.3% respectively for malignant lesions. Overall diagnostic accuracy was highest for the malignant category. Follicular patterned lesions, Hürthle cell-rich smears and overlapping cytological features between benign and malignant follicular neoplasm were the main reason of discrepancy. The discrepancy in cytological diagnosis altered the decision of type of surgery performed in 13.6% of the patients. CONCLUSION: Fine needle aspiration cytology remains a powerful screening tool to aid decision-making in the majority of the patients. Histological-cytological discrepancy can adversely impact the management of patients. Factors causing an adverse impact on surgical management were rare and potential avoidable reasons for them were identified. Cytological pitfalls may be avoided through screening for minor components, clinico-radiological correlation and experience.

Impact of Coronavirus Outbreaks on Science and Society: Insights from Temporal Bibliometry of SARS and COVID-19.

A global event such as the COVID-19 crisis presents new, often unexpected responses that are fascinating to investigate from both scientific and social standpoints. Despite several documented similarities, the coronavirus pandemic is clearly distinct from the 1918 flu pandemic in terms of our exponentially increased, almost instantaneous ability to access/share information, offering an unprecedented opportunity to visualise rippling effects of global events across space and time. Personal devices provide "big data" on people's movement, the environment and economic trends, while access to the unprecedented flurry in scientific publications and media posts provides a measure of the response of the educated world to the crisis. Most bibliometric (co-authorship, co-citation, or bibliographic coupling) analyses ignore the time dimension, but COVID-19 has made it possible to perform a detailed temporal investigation into the pandemic. Here, we report a comprehensive network analysis based on more than 20,000 published documents on viral epidemics, authored by over 75,000 individuals from 140 nations in the past one year of the crisis. Unlike the 1918 flu pandemic, access to published data over the past two decades enabled a comparison of publishing trends between the ongoing COVID-19 pandemic and those of the 2003 SARS epidemic to study changes in thematic foci and societal pressures dictating research over the course of a crisis.

Preparing IR for COVID-19: The Singapore Experience.

This paper describes country-wide special measures undertaken for interventional radiology staff during the current coronavirus disease 2019 (COVID-19) pandemic. Although each interventional radiology service around the world faces unique challenges, the principles outlined in this article will be useful when designing or strengthening individual practices and integrating them within wider hospital and national measures. Moving beyond the current outbreak, these measures will be useful for any future infectious diseases which are likely to arise.

The detection of lung cancer using massive artificial neural network based on soft tissue technique.

BACKGROUND: A proposed computer aided detection (CAD) scheme faces major issues during subtle nodule recognition. However, radiologists have not noticed subtle nodules in beginning stage of lung cancer while a proposed CAD scheme recognizes non subtle nodules using x-ray images. METHOD: Such an issue has been resolved by creating MANN (Massive Artificial Neural Network) based soft tissue technique from the lung segmented x-ray image. A soft tissue image recognizes nodule candidate for feature extortion and classification. X-ray images are downloaded using Japanese society of radiological technology (JSRT) image set. This image set includes 233 images (140 nodule x-ray images and 93 normal x-ray images). A mean size for a nodule is 17.8 mm and it is validated with computed tomography (CT) image. Thirty percent (42/140) abnormal represents subtle nodules and it is split into five stages (tremendously subtle, very subtle, subtle, observable, relatively observable) by radiologists. RESULT: A proposed CAD scheme without soft tissue technique attained 66.42% (93/140) sensitivity and 66.76% accuracy having 2.5 false positives per image. Utilizing soft tissue technique, many nodules superimposed by ribs as well as clavicles have identified (sensitivity is 72.85% (102/140) and accuracy is 72.96% at one false positive rate). CONCLUSION: In particular, a proposed CAD system determine sensitivity and accuracy in support of subtle nodules (sensitivity is 14/42 = 33.33% and accuracy is 33.66%) is statistically higher than CAD (sensitivity is 13/42 = 30.95% and accuracy is 30.97%) scheme without soft tissue technique. A proposed CAD scheme attained tremendously minimum false positive rate and it is a promising technique in support of cancerous recognition due to improved sensitivity and specificity.

The nucleoside analog clitocine is a potent and efficacious readthrough agent.

Nonsense mutations resulting in a premature stop codon in an open reading frame occur in critical tumor suppressor genes in a large number of the most common forms of cancers and are known to cause or contribute to the progression of disease. Low molecular weight compounds that induce readthrough of nonsense mutations offer a new means of treating patients with genetic disorders or cancers resulting from nonsense mutations. We have identified the nucleoside analog clitocine as a potent and efficacious suppressor of nonsense mutations. We determined that incorporation of clitocine into RNA during transcription is a prerequisite for its readthrough activity; the presence of clitocine in the third position of a premature stop codon directly induces readthrough. We demonstrate that clitocine can induce the production of p53 protein in cells harboring p53 nonsense-mutated alleles. In these cells, clitocine restored production of full-length and functional p53 as evidenced by induced transcriptional activation of downstream p53 target genes, progression of cells into apoptosis, and impeded growth of nonsense-containing human ovarian cancer tumors in xenograft tumor models. Thus, clitocine induces readthrough of nonsense mutations by a previously undescribed mechanism and represents a novel therapeutic modality to treat cancers and genetic diseases caused by nonsense mutations.

The promise of image-guided brachytherapy of better clinical outcomes in treatment of cervical cancer: Does it deliver? An Indian scenario.

PURPOSE: The purpose of this series is to study the effectiveness of MRI based image-guided brachytherapy (IGBT) in Indian patients with cervical cancer who mostly present in later stages with bulky diseases. PATIENTS AND METHODS: 151 cervical cancer patients treated at our institution in last four years, with definitive chemoradiation followed by MRI-based brachytherapy were reviewed. With median follow up of 26 months, Kaplan Meier estimates at two years were calculated for local control (LC), pelvic control (PC), disease-free survival (DFS) and overall survival (OS). Also, severe late sequelae were reported. RESULTS: The patients predominantly presented with locally advanced cervical cancer in FIGO stages IIB (53.6%) and IIIB (23.2%). Tumour dimensions at diagnosis were ≥5 cm in 56.3% and pelvic nodal involvement was found in 38.4% of the patients. 94% of the patients received curative chemoradiation. Mean HRCTV volume at the time of brachytherapy was 42.2 ±â€¯19 cm3 and mean cumulative dose to HRCTV was 78.9 ±â€¯5.6 Gy. Overall LC, PC, DFS and OS at 2 years were 88.7%, 88.1%, 82.2% and 94% respectively. The predictors for local failure were FIGO stage (p = 0.002) and tumour size at diagnosis (p = 0.009). Late grade 3-4 bladder and bowel toxicities were observed in 3.8% of the patients. CONCLUSION: Our review demonstrates that IGBT is an effective strategy to improve locoregional control with limited long-term sequelae in patients with locally advanced extensive cervical cancer in the setting of a developing country.

Usefulness of ultrasonography in diagnosis, percutaneous management and follow up of post-traumatic scalp pseudoaneurysms.

Pseudoaneurysms of the scalp are rare. Most common etiology is trauma. The patients usually present clinically with persistent painful swelling in the scalp few days after the trauma. The lesion may or may not be pulsatile clinically. Ultrasonography (US) is the best modality to assess these pseudoaneurysms. It not only helps in the diagnosis, but also to trace the offending arterial branch and helps in treatment. We present two cases of post-traumatic scalp pseudoaneurysms which were diagnosed with US and were managed by US-guided thrombin injection. Follow up US showed complete resolution. We highlight the importance of US scan in diagnosis, management, and follow up of scalp pseudoaneurysms.

Accuracy and reliability of Babinski sign versus finger and foot tapping in the diagnosis of corticospinal tract lesions.

INTRODUCTION: The Babinski sign is one of the most important clinical signs for detecting corticospinal tract (CST) lesions. However, due to variations in testing and interpretation, it has been associated with low interobserver agreement rates. In this study, the diagnostic value of finger and foot tapping in detecting CST lesions was compared to that of the Babinski sign. MATERIALS AND METHODS: Three groups of participants were recruited: Group 1 - individuals having CST lesions diagnosed on the basis of clinical examination as well as neuroimaging; group 2 - individuals having a non-CST neurological illness; group 3 - normal individuals who were relatives of the patients recruited. The sensitivity and specificity of finger tapping, foot tapping, and Babinski sign were calculated. RESULTS: 375 patients, 125 in each group, were included. The overall sensitivity for Babinski sign was 49.6% and specificity was 85.8%. The overall sensitivity for finger and foot tapping was 79.5% and specificity was 88.4%. The interobserver agreement between the medical students and the neurologist was greater for finger and foot tapping (Kappa = 0.83) when compared to Babinski sign (Kappa = 0.45). CONCLUSION: Finger and foot tapping is a valid and reliable test in the clinical diagnosis of corticospinal lesions. The reliability and validity of Babinski sign is variable and thus its ability to diagnose the manifestations of corticospinal lesions is less when compared to the finger and foot tapping test.

Attenuation of lead neurotoxicity by supplementation of polyunsaturated fatty acid in Wistar rats.

BACKGROUND: Among various types of polyunsaturated fatty acid (PUFA), omega-3 fatty acids play a crucial role in development and function of the brain. This study was undertaken to investigate the possible neuroprotective efficacy of omega-3 fatty acid on lead-induced neurotoxicity in rats. MATERIAL AND METHODS: The experiment was carried out on 32 male Wistar rats divided into four groups. The first group (control) was treated with distilled water and second group with lead acetate at the doses of 3 mg/kg b.wt. (body weight)/oral, whereas third and fourth groups were simultaneously treated with lead acetate (3 mg/kg b.wt.) plus omega-3 fatty acid (300 mg/kg b.wt./oral) and lead acetate (3 mg/kg b.wt.) plus vitamin E (100 mg/kg b.wt./oral), respectively, for a period of 90 days. Their biochemical and histopathological investigations have been carried out. RESULTS: The level of lead was markedly elevated in brain (4.71-fold) and blood (5.65-fold), also increased levels of ROS, GSH, LPO with concomitant reduction in the activities of delta-ALAD, CAT, SOD, and GPx. In addition, lead-induced brain damage was indicated by histopathological changes. Omega-3 fatty acid resulted in marked improvement in most of the biochemical parameters as well as histopathological changes in rats. The results obtained were compared with vitamin E as the standard antioxidant agents. DISCUSSION: Omega-3 fatty acid significantly (P < 0.05) decreased the effect of lead-induced brain damage as well as biochemical changes similar to that of standard drug, vitamin E. So, our result suggested that omega-3 fatty acid may play a protective role in lead-induced neurotoxicity and associated human health risk.

Chest radiography in acute aortic syndrome: pearls and pitfalls.

Acute aortic syndrome is a group of life-threatening diseases of the thoracic aorta that usually present to the emergency department. It includes aortic dissection, aortic intramural hematoma, and penetrating aortic ulcer. Rare aortic pathologies of aorto-esophageal fistula and mycotic aneurysm may also be included in this list. All these conditions require urgent treatment with complex clinical care and management. Most patients who present with chest pain are evaluated with a chest radiograph in the emergency department. It is important that maximum diagnostic information is extracted from the chest radiograph as certain signs on the chest radiograph are extremely useful in pointing towards the diagnosis of acute aortic syndrome.

Pharmacological studies on the anti-inflammatory and immunomodulatory role of pentoxifylline and its interaction with nitric oxide (NO) in experimental arthritis in rats.

AIM: Present study was designed to evaluate protective effects of pentoxifylline and its potentiation with low dose of nitric oxide (NO) modulators in adjuvant-induced experimental arthritis in rats. METHOD: Wistar rats (200-300 g, n = 8 per group) of both sexes were used in the study. On day "0" experimental arthritis was induced by injecting 0.2 ml of Complete Freund's adjuvant (CFA) in sub-planter region of right hind paw of animals. Pentoxifylline treatment alone and in combination with NO modulators was given (i.p.) from day 14 to 28. Various arthritic parameters were recorded and blood and joint synovial fluid was collected for biochemical analysis. RESULTS: CFA inoculation significantly increases (1) arthritic index (2) ankle diameter (3) paw volume (4) histopathology score (5) serum TNF-α, IL-6, IL-1ß and synovial TNF-α levels (p < 0.001) (6) serum Th1 and Th2 cytokine levels g) MDA levels in rat paw tissue homogenates (7) serum NF-κB levels. Significant decrease in serum IL-10 levels and SOD activity was observed in rats after CFA inoculation. Decrease in body weight and suppressed general quality of life of CFA inoculated rats was also observed. These CFA-induced arthritic changes were significantly reversed by pentoxifylline alone and in combination with low dose of NO modulators (p < 0.05). CONCLUSION: These results are suggestive of protective effects of pentoxifylline and its potentiation in combination with low dose of NO modulators. These results may provide new pharmacological therapy for management of rheumatoid arthritis (RA).

The prevalence of malocclusion and its association with dental caries among 12-18-year-old disabled adolescents.

BACKGROUND: To assess the prevalence of malocclusion among 12-18-year-old disabled adolescents in Chennai, Tamil Nadu, India, by using the Dental Aesthetic Index (DAI) and to determine the association of malocclusion with dental caries. METHODS: This cross-sectional study included 243 children with various mental disabilities with or without physical infirmities. The Dental Aesthetic Index (DAI) and the dentition status were recorded using the World Health Organization Oral Health Surveys - Basic Methods (1997) Pro-forma. The Decayed (D), Missing (M) and Filled (F) components of the DMF index were calculated using the Dentition Status and Treatment Need (DSTN). A Chi-square test, ANOVA, and t-test were used to derive inferential statistics. RESULTS: The mean DAI score ± standard deviation was 39.0 ± 12.3. A total of 123 (50.6%) participants (74 males and 49 females) had DAI scores of 36 and above, which indicated a handicapping malocclusion requiring mandatory orthodontic treatment. Sixty-nine (28.4%) adolescents (36 males and 33 females) had DAI scores between 31 and 35, which indicated severe malocclusion, for which orthodontic intervention was desirable. Incisal segment crowding (84.8%) was the most common aspect of the malocclusion. The mean DMFT score was 4.36 ± 3.81, and 82.8% of the participants had a DMFT score > 0. There was no statistically significant correlation between the mean DAI and DMFT scores (r = 0.090, p = 0.15). Only 16 (6.6%) of the adolescents had minor or no anomaly not needing orthodontic treatment. CONCLUSIONS: The prevalence of malocclusion and dental caries was found to be high. However, there was no positive correlation between the severity of malocclusion and dental caries among the surveyed disabled adolescents.