During liver injury, intrahepatic macrophage compartment is augmented by circulating monocytes that infiltrate the liver driven by C-C motif chemokine ligand/C-C motif chemokine receptor (CCL/CCR) axis including CCL1‒CCR8 axis, thereby contributing to liver inflammation. Numerous small molecular receptor antagonists, including R243, have been developed for targeting CCR8; however, these agents face challenges in clinical translation, potentially attributed to their poor pharmacokinetic profiles, lack of target specificity, and potential adverse effects. In this study, we designed four CCR8 antagonizing peptides (AP8i-AP8iv) and performed molecular characterization in silico and therapeutic investigation in vitro and in vivo. Based on in silico docking, molecular dynamic simulation using homology build model and in-vitro (competitive) binding studies, AP8ii (YEWRFYHG) evidenced highly favorable and selective interactions at the CCR8-active site. AP8ii inhibited CCL1-driven chemotaxis and LPS/IFNγ-induced pro-inflammatory activation of monocytes-macrophages in vitro. In a CCl₄-induced acute liver injury mouse model, AP8ii treatment decreased intrahepatic infiltration of circulating monocytes. Moreover, AP8ii reduced liver inflammation, as indicated by decreased F4/80, IL6 and iNOS expression, diminished ALT levels, and attenuated fibrosis, as indicated by reduced collagen-I expression. In conclusion, we report a novel CCR8-antagonizing peptide that inhibited CCL1-driven intrahepatic monocytes infiltration and differentiation into pro-inflammatory phenotype, consequently ameliorating liver inflammation and fibrogenesis in an acute liver injury mouse model.

Purpose: The study aims to report late toxicities in locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) treated with intensity-modulated radiation therapy (IMRT). Materials and Methods: A retrospective study was conducted on 103 patients of LAHNSCC treated with IMRT. We analyzed the cumulative incidence of late xerostomia, dysphagia, and aspiration at an interval of 6-month, 1-year, 2-year, and 3-year from the start of IMRT. Results: At a median follow up of 4.2 years (interquartile range, 3.5 to 6 years), the cumulative incidence of grade ≥2 late xerostomia was 5.5%, dysphagia was 6.9%, and aspiration was 11.1%. Logistic regression showed that Dmean of ≥26 Gy to parotids had higher risk of xerostomia (hazard ratio [HR] = 5.19; 95% confidence interval [CI], 1.90–14.22; p = 0.001). Late dysphagia was associated with Dmean of ≥45 Gy to pharyngeal constrictors (PC) (HR = 7; 95% CI, 1.84–26.61; p =0.004), ≥55 Gy to larynx (HR = 3.25; 95% CI, 1.15–9.11; p = 0.025), and adjuvant RT (HR = 5.26; 95% CI, 1.85–14.87; p = 0.002). Aspiration was associated with Dmean of ≥45 Gy to larynx (HR = 6.5; 95% CI, 1.93–21.88; p = 0.003), Dmean of ≥55 Gy to PC (HR = 3.54; 95% CI, 1.25–9.98; p = 0.017), and patients having late dysphagia (HR = 4.37; 95% CI, 1.55–12.31; p = 0.005). Conclusions IMRT is a feasible radiation delivery technique in LAHNSCC with a decreased late toxicity profile.

The POLG gene encodes mitochondrial DNA polymerase, and mutations in this gene cause a spectrum of disorders related to mitochondrial DNA depletion or deletion. Dystonia has only rarely been reported as an early and prominent manifestation of POLG mutations. We report a case of a 30-year-old male presenting with lower limb dystonia with peripheral neuropathy and demonstrate that the dystonia was levodopa responsive (with video findings). Whole-genome sequencing revealed biallelic variants in the POLG gene: a known pathogenic variant [NM_001126131.2:c.2209G>C (p.Gly737Arg)] and a novel likely pathogenic variant [NM_001126131.2:c.3305A>C (p.Gln1102Pro)]. A genetic diagnosis was made before the appearance of more readily recognizable features of mitochondrial disease, allowing us to avoid invasive tissue biopsies or potentially deleterious treatments, such as sodium valproate. A POLG-related disorder should be suspected in cases of dystonia with peripheral neuropathy, and this diagnosis may have implications for further investigations and management.

The POLG gene encodes mitochondrial DNA polymerase, and mutations in this gene cause a spectrum of disorders related to mitochondrial DNA depletion or deletion. Dystonia has only rarely been reported as an early and prominent manifestation of POLG mutations. We report a case of a 30-year-old male presenting with lower limb dystonia with peripheral neuropathy and demonstrate that the dystonia was levodopa responsive (with video findings). Whole-genome sequencing revealed biallelic variants in the POLG gene: a known pathogenic variant [NM_001126131.2:c.2209G>C (p.Gly737Arg)] and a novel likely pathogenic variant [NM_001126131.2:c.3305A>C (p.Gln1102Pro)]. A genetic diagnosis was made before the appearance of more readily recognizable features of mitochondrial disease, allowing us to avoid invasive tissue biopsies or potentially deleterious treatments, such as sodium valproate. A POLG-related disorder should be suspected in cases of dystonia with peripheral neuropathy, and this diagnosis may have implications for further investigations and management.

Introduction: Bicondylar tibial plateau fractures account for 10-30% of tibial plateau fractures. Despite recent advancements in the management of unstable bicondylar tibial plateau fractures, the outcomes are often poor. The present study aimed to evaluate the functional outcomes and complications of internal fixation of bicondylar tibial plateau fractures with the dual plating using two incisions. Materials and methods: The present study included 30 patients (26 males; 4 females, mean age 35.6 years; range, 19 to 65 years) with bicondylar tibial plateau fractures who were treated with dual plating between January 2017 to August 2019. Out of 30 patients, 5 patients had Schatzker type (V) and 25 patients had Schatzker type (VI) bicondylar tibial plateau fracture. All patients were treated with dual plating using two incisions. In all patient’s similar standard physical rehabilitation therapy was followed. All complications including intra and post-operative were assessed and recorded. The patients were followed-up for over 24 months. Functional outcomes were assessed with Rasmussen’s functional grading system, Oxford knee score, and range of motion of knee joint. Radiological outcomes were evaluated using Rasmussen’s radiological scoring system. Result: All fractures united with a mean time of 18 weeks. The average knee range of motion was 1.5° - 130° (range: 0° - 10° for extension lag, range: 100° -135° for flexion). Mean Rasmussen's functional grading score at the final follow-up was 26.75. All patients showed excellent or good radiographic results according to Rasmussen’s radiological scoring with a mean score of 8.5 (range 6-10). The postoperative radiographs showed mean MPTA was 84.3° and the mean PPTA was 6.2°. In the present study, complications were encountered in five patients. However, there were no cases of secondary loss of reduction, failure of the implant, malunion, or non-union. Conclusion: The surgical treatment of bicondylar tibial plateau fractures with dual locking represents a significant treatment option and provides rigid fixation in these fractures with good functional and radiological outcomes.

Purpose: The study aims to report late toxicities in locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) treated with intensity-modulated radiation therapy (IMRT). Materials and Methods: A retrospective study was conducted on 103 patients of LAHNSCC treated with IMRT. We analyzed the cumulative incidence of late xerostomia, dysphagia, and aspiration at an interval of 6-month, 1-year, 2-year, and 3-year from the start of IMRT. Results: At a median follow up of 4.2 years (interquartile range, 3.5 to 6 years), the cumulative incidence of grade ≥2 late xerostomia was 5.5%, dysphagia was 6.9%, and aspiration was 11.1%. Logistic regression showed that Dmean of ≥26 Gy to parotids had higher risk of xerostomia (hazard ratio [HR] = 5.19; 95% confidence interval [CI], 1.90–14.22; p = 0.001). Late dysphagia was associated with Dmean of ≥45 Gy to pharyngeal constrictors (PC) (HR = 7; 95% CI, 1.84–26.61; p =0.004), ≥55 Gy to larynx (HR = 3.25; 95% CI, 1.15–9.11; p = 0.025), and adjuvant RT (HR = 5.26; 95% CI, 1.85–14.87; p = 0.002). Aspiration was associated with Dmean of ≥45 Gy to larynx (HR = 6.5; 95% CI, 1.93–21.88; p = 0.003), Dmean of ≥55 Gy to PC (HR = 3.54; 95% CI, 1.25–9.98; p = 0.017), and patients having late dysphagia (HR = 4.37; 95% CI, 1.55–12.31; p = 0.005). Conclusions IMRT is a feasible radiation delivery technique in LAHNSCC with a decreased late toxicity profile.

PURPOSE: To investigate the incidence of bladder cancer (BC) in Sri Lanka and to compare risk factors and outcomes with those of other South Asian nations and South Asian migrants to the United Kingdom (UK) and the United States (US). MATERIALS AND METHODS: The incidence of BC in Sri Lanka was examined by using two separate cancer registry databases over a 5-year period. Smoking rates were compiled by using a population-based survey from 2001 to 2009 and the relative risk was calculated by using published data. RESULTS: A total of 637 new cases of BC were diagnosed over the 5-year period. Sri Lankan BC incidence increased from 1985 but remained low (1.36 and 0.3 per 100,000 in males and females) and was similar to the incidence in other South Asian countries. The incidence was lower, however, than in migrant populations in the US and the UK. In densely populated districts of Sri Lanka, these rates almost doubled. Urothelial carcinoma accounted for 72%. The prevalence of male smokers in Sri Lanka was 39%, whereas Pakistan had higher smoking rates with a 6-fold increase in BC. CONCLUSIONS: Sri Lankan BC incidence was low, similar to other South Asian countries (apart from Pakistan), but the actual incidence is likely higher than the cancer registry rates. Smoking is likely to be the main risk factor for BC. Possible under-reporting in rural areas could account for the low rates of BC in Sri Lanka. Any genetic or environmental protective effects of BC in South Asians seem to be lost on migration to the UK or the US and with higher levels of smoking, as seen in Pakistan.
Asian Continental Ancestry Group ; Great Britain ; Humans ; Incidence ; Male ; Pakistan ; Prevalence ; Risk Factors ; Smoke ; Smoking ; Sri Lanka ; Transients and Migrants ; United States ; Urinary Bladder ; Urinary Bladder Neoplasms

OBJECTIVETo study the morphology, biochemistry and bioactivity of the epidermal glands of the glandular morphotype of Christella parasitica (C. parasitica) (L.) H. Lev.

METHODSMorphological studies on epidermal glands were carried out by using light microscope and scanning electron microscope. To prepare the extract, the shade-dried fronds of glandular morphotype were soaked in acetone. For antibacterial studies paper disc method was followed by using various pathogenic bacteria.

RESULTSDetailed micromorphological, phytochemical and bioactivity studies on a medicinal fern C. parasitica (L.) H. Lev. showed its intraspecific variation in antibacterial activity. The presence or absence of the epidermal glands was the key factor for antibacterial activity in the morphovariants of this species. The epidermal glands were orange-coloured, stalked and elongated ones of about 84.2 µm × 45 µm, and distributed on the undersurface of costa, costules and veins in croziers, young and mature leaves. Frequency of glands varied from 15/cm on costa in mature leaves to 140/cm on costules in croziers. The acetone extract of the glands showed antibacterial activities and also toxic effect against mosquito larvae and tadpoles of frog. Preliminary phytochemical analysis and HPLC studies of the gland extract showed the presence of various kinds of terpenoids, alkaloids, tannins, saponins and flavonoids in it.

CONCLUSIONSThe present study shows that epidermal glands of the glandular morphotype of C. parasitica (L.) H. Lev. have several bioactive compounds and such rare morphovariant should be conserved in nature. The next step is to isolate the pure compounds and to screen the bioactivity of individual compounds of the epidermal glands.

Acetone ; Animals ; Anti-Bacterial Agents ; chemistry ; pharmacology ; Anura ; Bacteria ; drug effects ; Culicidae ; Ferns ; chemistry ; Larva ; drug effects ; Microbial Sensitivity Tests ; Phytochemicals ; chemistry ; pharmacology ; Plant Extracts ; chemistry ; pharmacology ; Plant Leaves ; chemistry