Aspiration cytology of ameloblastic fibroma: a diagnostic challenge

Ameloblastic fibroma of the jaw is a rare, benign mixed odontogenic tumor, having little tendency for local invasion and a low recurrence rate. Cytologic distinction from ameloblastoma, ameloblastic fibrosarcoma, and intraosseous adenoid cystic carcinoma is necessary, in view of the different biologic behavior. A painful, slow-growing swelling of the jaw in a 5-yr-old child clinicoradiologically considered as a benign cystic lesion was aspirated. Sheets of small monomorphic epithelial cells with peripheral palisading by columnar cells were seen on cytology smears. The striking feature was central hyaline globules in some tubules. A cytologic possibility of adenomatoid odontogenic tumor was suggested. Histopathology, however, confirmed it to be an ameloblastic fibroma.     

Radiation-related cytological changes in oral malignant cells

Carcinoma of the oral cavity constitutes approximately 40% of overall malignant tumours in India, with an incidence of about 56,000 cases per year. Radiation responses in oral cancer cells by cytology have not been extensively studied. 102 patients with squamous cell carcinoma of the oral cavity treated by fractionated radiotherapy were studied. Serial scrape smears were taken from each tumour before and after irradiation. The abnormal nuclear counts per 1000 malignant cells were 1.6 and 14.1(p<0.001) for micronucleation, 0.9 and 5.5 (p<0.001) for nuclear budding, 7.6 and 28.1(p<0.001) for binucleation and 2.4 and 11.7(p<0.001) for multinucleation respectively. The study showed a significant rise in radiation induced cytological responses. In addition, radiation changes observed included abnormal and incomplete divisions of a nucleus, fibroblast like appearance cells, and enlargement of nuclear size as well as cytoplasmic granulation. These changes may have an important role to play in understanding the mechanism of cell killing after radiotherapy.     

Multi-Center Analysis of Liver Transplantation for Combined Hepatocellular Carcinoma-Cholangiocarcinoma Liver Tumors

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Pre‐ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress‐dependent autophagy via PERK and IRE1 signalings

Melatonin has demonstrated a potential protective effect in central nervous system. Thus, it is interesting to determine whether pre‐ischemia melatonin administration could protect against cerebral ischemia/reperfusion (IR)‐related injury and the underlying molecular mechanisms. In this study, we revealed that IR injury significantly activated endoplasmic reticulum (ER) stress and autophagy in a middle cerebral artery occlusion mouse model. Pre‐ischemia melatonin treatment was able to attenuate IR‐induced ER stress and autophagy. In addition, with tandem RFP‐GFP‐LC3 adeno‐associated virus, we demonstrated pre‐ischemic melatonin significantly alleviated IR‐induced autophagic flux. Furthermore, we showed that IR induced neuronal apoptosis through ER stress related signalings. Moreover, IR‐induced autophagy was significantly blocked by ER stress inhibitor (4‐PBA), as well as ER‐related signaling inhibitors (PERK inhibitor, GSK; IRE1 inhibitor, 3,5‐dibromosalicylaldehyde). Finally, we revealed that melatonin significantly alleviated cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency, which were remarkably abolished by tunicamycin (ER stress activator) and rapamycin (autophagy activator), respectively. In summary, our study provides strong evidence that pre‐ischemia melatonin administration significantly protects against cerebral IR injury through inhibiting ER stress‐dependent autophagy. Our findings shed light on the novel preventive and therapeutic strategy of daily administration of melatonin, especially among the population with high risk of cerebral ischemic stroke.     

Study of treatment outcomes of multidrug-resistant tuberculosis under programmatic conditions and factors influencing the outcomes in Hyderabad District

BackgroundTreatment outcomes for Multidrug-Resistant Tuberculosis (MDR TB) is generally poor. The study aims to know about the treatment outcomes of MDR-TB under programmatic conditions in Hyderabad District and to analyze the factors influencing the treatment outcomes.MethodsThis is a retrospective study in which 377 patients of Hyderabad district, Telangana state who were diagnosed with MDR TB and registered at Drug Resistance TB Treatment site of Government General & Chest Hospital, Hyderabad from 4th quarter 2008 to 4th quarter 2013 were included in the study. Impact of Demographic factors (age, sex; Nutritional status (BMI); Co-morbid condition (Diabetes, HIV, Hypothyroidism); Programmatic factors (time delay in the initiation of treatment); Initial Resistance pattern on the outcomes were studied and analyzed.ResultsThe treatment outcomes of Multidrug-Resistant Tuberculosis under Programmatic Conditions were: 57% cured, 21.8% died, 19.6% defaulted, 1.1% failed and 0.5% switched to XDR. Age, Sex, BMI had a statistically significant impact on treatment outcomes. Hypothyroidism and Delay in the initiation of treatment >1 a month had an impact on the outcomes though not statistically significant. NO impact on treatment outcomes was found when Rifampicin resistance & INH sensitive patients were compared with those resistant to both INH and Rifampicin.ConclusionTo reduce MDR-TB transmission in the community, improvement of treatment outcomes, via ensuring adherence, paying special attention to elderly patients is required. The Programmatic Management of Drug Resistance Tuberculosis (PMDT) should seriously think of providing Nutritional support to patients with low BMI to improve outcomes. In the programmatic conditions if we could address the problems like delay in initiation of treatment and proper management of comorbidities like HIV, Diabetes, Hypothyroidism would definitely improve the treatment outcomes.     

Randomized Controlled Trial in Advance Stage Breast Cancer Patients for the Effectiveness on Stress Marker and Pain through Sudarshan Kriya and Pranayam

Objective:

The objective of this study is to examine the effect of a cognitive, behavioral stress management module of Sudarshan Kriya (SK) and P on levels of serum cortisol and pain among the women suffering from advanced stage breast cancer.

Materials and Methods:

Participants (n = 147) were screened and randomized to receive standard care (n = 69) versus standard along with SK and Pranayam (P) intervention (n = 78) imparted in one 18 hrs workshop spread during 3 days. Participants were expected to practice it at home 20 min daily as adjuvant to standard pharmacological treatment for pain.

Results:

There was a significant difference in blood cortisol levels after 3 months of practice of SK and P. Mean blood levels in the intervention arm were 341.2 ng/ml against 549.2 ng/ml in the control arm (P ≤ 0.002). Pain perception in comparison to control arm reduced by 3 points in SK and P arm on 0-10 verbal scale of pain.

Conclusion:

SK and P is an effective intervention in reducing stress and pain among advance stage patients of breast cancer.     

The Parkinson’s disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

Inositol-1,4,5-triphosphate (IP₃) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP₃, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson’s disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models. In primary neurons, knockdown or pharmacological inhibition of ITPKB increased levels of phosphorylated, insoluble α-synuclein pathology following treatment with α-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced α-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown increases intracellular calcium levels in neurons, leading to an accumulation of calcium in mitochondria that increases respiration and inhibits the initiation of autophagy, suggesting that ITPKB regulates α-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondrial calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondrial calcium uniporter complex, which was also sufficient to reduce α-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of α-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by a variety of motor symptoms (including unbalanced gait, resting tremor, and bradykinesia) that are accompanied by psychosis and dementia at later stages of disease. The onset of motor symptoms is largely caused by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the corresponding depletion of dopamine innervation in the striatum. Although the cause of neuron loss is unknown, the hallmark pathological feature of PD is the presence of intraneuronal inclusions composed of misfolded and fibrillar α-synuclein (α-syn) in the neurites and soma, termed Lewy neurites and Lewy bodies, respectively (1). Protein-coding single-nucleotide polymorphisms (SNPs), duplications, and triplications in the gene encoding α-syn (SNCA) all cause early-onset, familial forms of PD and result in accelerated aggregation of α-syn protein into insoluble, fibrillar aggregates (1, 2). Recent evidence suggests that these aggregates can spread from cell to cell, leading to the propagation of pathology to neuroanatomically connected brain regions (3, 4). Therefore, therapeutic approaches that reduce the aggregation or spreading of pathological α-syn species represent potential disease-modifying therapies for PD.In addition to SNCA, mutations in several other genes have been identified that cause rare, familial forms of PD. These genes are primarily involved in the autophagic clearance of intracellular aggregates or damaged organelles, especially mitochondria (5–8). Genome-wide association studies (GWAS) have also identified common SNPs in several genes related to endolysosomal function, such as GBA and LRRK2, that are associated with increased risk of PD (8–11). GBA and LRRK2 mutations have been shown to affect lysosomal and mitochondrial phenotypes (12–14), which contribute to the accumulation of PD-like neuropathology in mouse models, primary neurons, and human iPSC-derived cells (15–18). These findings highlight the role of the lysosomal and mitochondria quality control pathways in PD and demonstrate that perturbations in these pathways are sufficient to increase α-syn aggregation. Despite this, the etiology of sporadic PD is not fully understood, and the specific genes and pathways that are tractable for therapeutic modulation remain elusive. Therefore, the discovery of new genes associated with sporadic PD may be critical for both understanding disease pathogenesis and identifying novel therapeutic approaches.Recently, Chang et al. conducted a GWAS analysis that identified 17 novel gene loci significantly associated with sporadic PD in a European population including more than 26,000 patients across three independent cohorts (19). The lead GWAS SNP in the novel 1q42 locus was rs4653767. This is an intronic SNP in the gene encoding inositol-1,4,5-triphosphate kinase B (ITPKB) and produces a thymine-to-cytosine nucleotide substitution that is protective against developing PD (odds ratio [OR] = 0.92, P = 2.4 × 10⁻¹⁰). A follow up meta-analysis study of 37,688 PD patients, which included the discovery cohort, and 18,618 proxy cases strengthened the GWAS finding at this locus (OR = 0.92, P = 1.4 × 10⁻¹⁵). Furthermore, this locus was still significant when the analysis was performed on only the new independent cases and proxy cases (OR = 0.92, P = 2.8 × 10⁻⁵) (20). The rs4653767-C allele is present in similar frequencies across populations (27% in non-Finnish European and 29% in East Asian populations) and was found to have the same direction of effect (OR = 0.87, P = 0.016) in a targeted replication study of the European PD loci in an East Asian cohort (21). ITPKB is also highly expressed in several brain regions related to PD, including the SNpc, striatum, and cerebral cortex (22).ITPKB is one of three ubiquitously expressed kinases known to phosphorylate inositol-1,4,5-triphosphate (IP₃), an intracellular messenger produced from phosphatidylinositol-4,5-bisphosphate by phospholipase C (23, 24). IP₃ binds to IP₃ receptors (IP₃Rs) in the endoplasmic reticulum (ER) to stimulate the release of calcium ions from the ER into the cytosol to mediate various downstream signaling pathways. IP₃ kinases (ITPKA, ITPKB, and ITPKC) add a fourth phosphate group to IP₃ producing inositol-1,3,4,5-tetrakisphosphate (IP₄), which has no activity on IP₃Rs. Thus, IP₃ kinases negatively regulate IP₃-mediated calcium release from the ER. While the role of this pathway in peripheral cell types under normal physiological conditions is well understood (25, 26), whether ITPKB is involved in the pathogenesis of PD is unknown. Here, we investigate whether the modulation of ITPKB expression or kinase activity impacts the accumulation of α-syn pathology in cellular models of PD.