The role of susceptibility-weighted imaging & contrast-enhanced MRI in the diagnosis of primary CNS vasculitis: a large case series.

Primary CNS Vasculitis (PCNSV) is a rare, diverse, and polymorphic CNS blood vessel inflammatory condition. Due to its rarity, clinical variability, heterogeneous imaging results, and lack of definitive laboratory markers, PCNSV diagnosis is challenging. This retrospective cohort analysis identified patients with histological diagnosis of PCNSV. Demographic data, clinical presentation, neuroimaging studies, and histopathologic findings were recorded. We enrolled 56 patients with a positive biopsy of CNS vasculitis. Most patients had cerebral hemisphere or brainstem symptoms. Most brain MRI lesions were bilateral, diffuse discrete to confluent white matter lesions. Frontal lobe lesions predominated, followed by inferior cerebellar lesions. Susceptibility-weighted imaging (SWI) hemorrhages in 96.4% (54/56) of patients, either solitary microhemorrhages or a combination of micro and macrohemorrhages. Contrast-enhanced T1-WIs revealed parenchymal enhancement in 96.3% (52/54 patients). The most prevalent pattern of enhancement observed was dot-linear (87%), followed by nodular (61.1%), perivascular (25.9%), and patchy (16.7%). Venulitis was found in 19 of 20 individuals in cerebral DSA. Hemorrhages in SWI and dot-linear enhancement pattern should be incorporated as MINOR diagnostic criteria to diagnose PCNSV accurately within an appropriate clinical context. Microhemorrhages in SWI and venulitis in DSA, should be regarded as a potential marker for PCNSV.

Shrinking lung syndrome mimicking diaphragmatic palsy in systemic lupus erythematosus.

A 25-year-old woman presented with 1 year of progressive orthopnoea, initially explained as bilateral diaphragmatic paresis caused by seronegative myasthenia gravis. She required assisted ventilation and received pyridostigmine and corticosteroids. She had minimal (particularly proximal) symmetrical tetraparesis with apparent bilateral diaphragmatic weakness, but had normal sensation. Further investigation suggested an overlap myositis with shrinking lung syndrome from systemic lupus erythematosus. She improved following immunosuppression with pulse corticosteroids and rituximab, and at 3 months no longer needed bilevel positive airway pressure support.

Fine mapping of a new common bean anthracnose resistance gene (Co-18) to the proximal end of Pv10 in Indian landrace KRC-5.

KEY MESSAGE: Mapping and fine mapping of bean anthracnose resistance genes is a continuous process. We report fine mapping of anthracnose resistance gene Co-18 which is the first anthracnose gene mapped to Pv10. The discovery of resistance gene is a major gain in the bean anthracnose pathosystem research. Among the Indian common bean landraces, KRC-5 exhibit high levels of resistance to the bean anthracnose pathogen Colletotrichum lindemuthianum. To precisely map the anthracnose resistance gene, we used a Recombinant Inbred Line (F2:9 RIL) population (KRC-5 × Jawala). The inheritance test revealed that KRC-5 carries a dominant resistance gene temporarily designated as Co-18. We discovered two RAPD markers linked to Co-18 among 287 RAPD markers. These RAPD markers were eventually developed into SCARs (Sc-OPR15 and Sc-OPF6) and flank Co-18 on chromosome Pv10 at a distance of 5.3 and 4.2 cM, respectively. At 4.0-4.1 Mb on Pv10, we detected a SNP (single-nucleotide polymorphism) signal. We synthesized 58 SSRs and 83 InDels from a pool of 135 SSRs and 1134 InDels, respectively. Five SSRs, four InDels, and two SCARs were used to generate the high-density linkage map, which led to the identification of two SSRs (SSR24 and SSR36) that are tightly linked to Co-18. These two SSRs flank the Co-18 to 178 kb genomic region with 13 candidate genes including five NLR (nucleotide-binding and leucine-rich repeat) genes. The closely linked markers SSR24 and SSR36 will be used in cloning and pyramiding of the Co-18 gene with other R genes to develop durable resistant bean varieties.

Unusual presentation of aneurysmal bone cyst (ABC) in children: pediatric intracranial osteosarcoma with secondary ABC.

A 13-year-old female patient presented with painless vision loss and proptosis for 18 months. Imaging findings were highly suggestive of a supraorbital aneurysmal bone cyst (ABC) for which she underwent complete surgical excision. Postoperatively, she developed left hemiparesis. Computed tomography angiography (CTA) revealed right complete internal carotid arterial (ICA) thrombosis. This was managed conservatively, and she improved in hemiparesis over the next 3 weeks. Histopathology report revealed osteosarcoma with secondary ABC, for which she was referred for radiotherapy. At 1.5 months follow-up, the patient's left lower limb power improved to 4 + /5. She was walking without support, and her left upper limb power was 4/5.

Celiac artery thrombosis presenting as acute abdomen.

Mesenteric vascular thrombosis, typically of the superior mesenteric artery, is a frequent occurrence in patients with hypercoagulable conditions. Isolated involvement of the celiac artery is rare. Patients with celiac artery thrombosis can present with an acute abdomen or occasionally with acid peptic symptoms. A delay in diagnosis is associated with high rates of morbidity and mortality. We present a rare case of splenic infarction with celiac trunk thrombosis in a 54-year-old patient with underlying antiphospholipid (APLA) syndrome who presented with epigastric pain that was mistaken for symptoms of acid reflux.

3D-QSAR-based design, synthesis and biological evaluation of 2,4-disubstituted quinoline derivatives as antimalarial agents.

2,4-Disubstituted quinoline derivatives were designed based on a 3D-QSAR study, synthesized and evaluated for antimalarial activity. A large dataset of 178 quinoline derivatives was used to perform a 3D-QSAR study using CoMFA and CoMSIA models. PLS analysis provided statistically validated results for CoMFA (r2ncv = 0.969, q2 = 0.677, r2cv = 0.682) and CoMSIA (r2ncv = 0.962, q2 = 0.741, r2cv = 0.683) models. Two series of a total of 40 2,4-disubstituted quinoline derivatives were designed with amide (quinoline-4-carboxamide) and secondary amine (4-aminoquinoline) linkers at the -C4 position of the quinoline ring. For the purpose of selecting better compounds for synthesis with good pEC50 values, activity prediction was carried out using CoMFA and CoMSIA models. Finally, a total of 10 2,4-disubstituted quinoline derivatives were synthesized, and screened for their antimalarial activity based on the reduction of parasitaemia. Compound #5 with amide linker and compound #19 with secondary amine linkers at the -C4 position of the quinoline ring showed maximum reductions of 64% and 57%, respectively, in the level of parasitaemia. In vivo screening assay confirmed and validated the findings of the 3D-QSAR study for the design of quinoline derivatives.

Intracranial myeloid sarcoma as the first presentation of acute myeloid leukemia and literature review.

INTRODUCTION: Intracranial myeloid sarcoma is a rare extramedullary presentation of acute myeloid leukemia (AML). It can involve the meninges and ependyma presenting as extra-axial mass lesion. Rarely, it can also invade the brain parenchyma. It is commonly seen in children. It is usually misdiagnosed due to its close resemblance to other intracranial tumors (meningioma, metastasis, Ewing's sarcomas, and lymphoma). These are underdiagnosed if they precede the diagnosis of leukemia. CASE REPORT: A 7-year-old boy with isolated intracranial myeloid sarcoma who presented with raised intracranial pressure (ICP) which was successfully managed by surgical excision. CONCLUSION: Isolated intracranial myeloid sarcoma is a rare presentation of AML. Leukemia can be diagnosed early during the postoperative period and can be started on therapy timely. These patients requires regular follow-ups (clinical, laboratory and radiological) to detect relapses early.

Optimising plasma clozapine levels to improve treatment response: an individual patient data meta-analysis and receiver operating characteristic curve analysis.

BACKGROUND: Although clozapine is the most efficacious medication for treatment-refractory schizophrenia, not all patients will have an adequate response. Optimising clozapine dose using therapeutic drug monitoring could therefore maximise response. AIMS: Using individual patient data, we undertook a receiver operating characteristic (ROC) curve analysis to determine an optimal therapeutic range for clozapine levels to guide clinical practice. METHOD: We conducted a systematic review of PubMed, PsycINFO and Embase for studies that provided individual participant level data on clozapine levels and response. These data were analysed using ROC curves to determine the prediction performance of plasma clozapine levels for treatment response. RESULTS: We included data on 294 individual participants from nine studies. ROC analysis yielded an area under the curve of 0.612. The clozapine level at the point of optimal diagnostic benefit was 372 ng/mL; at this level, the response sensitivity was 57.3%, and specificity 65.7%. The interquartile range for treatment response was 223-558 ng/mL. There was no improvement in ROC performance with mixed models including patient gender, age or length of trial. Clozapine dose and clozapine concentration to dose ratio did not provide significantly meaningful prediction of response to clozapine. CONCLUSIONS: Clozapine dose should be optimised based on clozapine therapeutic levels. We found that a range between 250 and 550 ng/mL could be recommended, while noting that a level of >350 ng/mL is the most optimal for response. Although some patients may not respond without clozapine levels >550 ng/mL, the benefits should be weighed against the increased risk of adverse drug reactions.

Correlation of age at seizure onset with GABAA receptor subunit and chloride Co-transporter configuration in Focal cortical dysplasia (FCD).

Focal cortical dysplasia (FCD) represents a group of malformations of cortical development, which are speculated to be related to early developmental defects in the cerebral cortex. According to dysmature cerebral development hypothesis of FCD altered GABAA receptor function is known to contribute to abnormal neuronal network. Here, we studied the possible association between age at seizure onset in FCD with the subunit configuration of GABAA receptors in resected brain specimens obtained from patients with FCD. We observed a significantly higher ratio of α4/α1 subunit-containing GABAA receptors in patients with early onset (EO) FCD as compared to those with late onset (LO) FCD as is seen during the course of development where α4-containing GABAA receptors expression is high as compared to α1-containing GABAA receptors expression. Likewise, the influx to efflux chloride co-transporter expression of NKCC1/KCC2 was also increased in patients with EO FCD as seen during brain development. In addition, we observed that the ratio of GABA/Glutamate neurotransmitters was lower in patients with EO FCD as compared to that in patients with LO FCD. Our findings suggest altered configuration of GABAA receptors in FCD which could be contributing to aberrant depolarizing GABAergic activity. In particular, we observed a correlation of age at seizure onset in FCD with subunit configuration of GABAA receptors, levels of NKCC1/KCC2 and the ratio of GABA/Glutamate neurotransmitters such that the patients with EO FCD exhibited a more critically modulated GABAergic network.

An institutional review of treatment outcomes in extraosseous Ewing's sarcoma- the largest Asian experience.

PURPOSE: To analyze the treatment strategies, outcomes and factors impacting these outcomes in extraosseous ewings sarcoma (EOES). MATERIAL AND METHODS: A search of the hospital database yielded a total of 109 EOES patients registered in last 10 years out of which 25 patients were excluded from analysis due to incomplete medical records. Demographic and clinical characteristics were reported using descriptive statistics. Overall survival (OS) was taken from the time of diagnosis to death. Patients who were alive or lost to follow up were censored from the survival analysis. A total of 12 clinical and treatment related variables were taken into univariate analysis and those showing significance or a trend towards significance were taken up for multivariate analysis. Further a cluster analysis was done in a quest to find a subgroup which would have a better survival outcome as compared to other clusters. SPSS version 23 was used for statistical analysis. RESULTS: Chest wall (n=26), lower extremity (n=22) and paraspinal area (n=14) were the common sites involved. Localised swelling (n=43) was the most common presenting symptom and the median time to presentation was 2 months. Overall survival of the entire cohort at 5 years was 52 percent. Stage at presentation had a significant impact (P value<0.001) on estimated median OS (localised 70 months versus 36 months in metastatic stage). Cluster analysis showed that, patients with localised stage at presentation, good response to chemotherapy, negative resection margin and no adjuvant RT had a median survival of 69 months. CONCLUSION: Judicious use of trimodality treatment in EOES yields optimal results and it also adds significantly onto the scarce literature on this subtype of sarcoma.

Comparison of High Spermatic Vessel Ligation and Low Spermatic Vessel Ligation in an Undescended Model of Rat Testis.

Aims: The aim of this study was to compare the immediate and long-term outcomes after high spermatic vessel ligation (HSVL) and low spermatic vessel ligation (LSVL) in a high undescended testis (UDT) model in rats. Materials and Methods: A prospective randomized controlled study was conducted on 24 male Wistar rats. The rats were randomly divided into three groups. Group A underwent a sham laparotomy and acted as the control. Group B underwent HSVL of both testicular vessels. Group C underwent LSVL of both testicular vessels. Each group was again subdivided into two subgroups. One sub-group underwent blood collection and testicular biopsy of both testes 24 h after the procedure to demonstrate immediate changes. Other subgroups underwent blood sample collection and testicular biopsy of both testes on day 50 following the procedure for hormonal changes and long-term changes. Results: All the testes in HSVL showed atrophy (100%) in the long term, whereas LSVL showed atrophy in 12.5% of testes, even though both groups showed adequate neovascularization. Testes in HSVL showed poor bleeding on incision at both 24 h and day 50. On histology, 75% of testes in HSVL showed complete necrosis, and 50% in LSVL showed partial necrosis at 24 h. On day 50, all the testes in HSVL (100%) showed complete necrosis with dystrophic calcification, whereas all the testes in LSVL showed normal histology with good maturation of seminiferous tubules. There was no significant difference in testosterone levels between both groups. Conclusions: Both immediate and long-term changes following LSVL showed an increase in blood flow to the testis after ligation through collaterals and reverses early ischemic changes to the testis. Given the higher testicular atrophic rate after HSVL, LSVL or at least low ligation can be preferred for the management of high intra-abdominal UDT.

Role of chest radiography in the diagnosis of pulmonary tuberculosis during nCovid19 pandemic.

Pulmonary tuberculosis and nCovid 19 share many common risk factors. nCovid19 may increase the risk to develop pulmonary tuberculosis. Pulmonary tuberculosis may precede, co-exist or follow nCovid19. Careful evaluation of chest radiography is useful to differentiate tuberculosis from nCovid19 bronchopneumonia. Symptoms of tuberculosis may be mistaken for long covid. A normal chest x ray in the absence of sputum production may help to rule out tuberculosis in such cases. All patients with nCovid19 bronchopneumonia should undergo a careful chest x ray evaluation for any lesions suggestive of tuberculosis. All patients with chest radiological abnormality should undergo sputum examination to rule tuberculosis as atypical radiological manifestations may be more common in patients with nCovid19. Symptoms, signs, clinical features and chest radiographic features of Pulmonary tuberculosis and nCovid19 bronchopneumonia may overlap in some cases. Correlation of chest radiographic findings with epidemiologic history, clinical presentation, and RT-PCR test results or in later stages antibody titres will help in confirming or excluding the diagnosis in suspected cases of nCovid19. In pulmonary tuberculosis definitive diagnosis should be established by bacteriological confirmation. Molecular diagnostic tools should be used to confirm or exclude tuberculosis in suspect cases as the results are rapid, accurate and reliable.

Challenges in diagnosis and treatment of tuberculosis in elderly.

Tuberculosis (TB) is a major infectious disease worldwide. Early diagnosis and prompt treatment reduces the transmission, morbidity and mortality in tuberculosis. Elderly (age >65 years) have many risk factors to develop tuberculosis. Recent survey in India showed incidence of TB higher in elderly. They may not have classical symptoms, clinical and radiological signs of TB which can lead to delayed diagnosis or misdiagnosis. In addition, elderly have many comorbid and coexisting diseases which make diagnosis and treatment of TB challenging. Comorbidities, poor general health status and other medications may lead to increased drug adverse reactions and poor adherence to treatment in elderly. Hence special emphasis should be given to elderly for early diagnosis and treatment. Elderly with multiple comorbidities require individualized approach for better outcome.

Computational Design of Phosphatidylinositol 3-Kinase Inhibitors.

One of the most sought-after therapeutic targets for treating human cancers is the phosphoinositide 3-kinase; PI3k is an integral part of the PI3K/protein kinase B signaling arcade. This pathway is frequently activated in malignancies. Drug resistance and dose-limiting adverse effects are currently associated challenges with the existing anticancer chemotherapy. Therefore, in this research, a series of pyrimidine derivatives were designed and evaluated against human PI3K by using molecular docking analysis. The docking results were further verified by molecular dynamic simulation, which analyzed the strength of the macromolecular complex with respect to time. Compounds IV and XIV were found to be the most potent inhibitors of the human PI3K receptor with a high degree of stability within the active site of the target receptor for a timeframe of 50 ns. Thus, both of these compounds could be important drug candidates for the development of PI3K inhibitors as a prospective anticancer agent.

Improving the ACS Triage-Using High Sensitivity TroponinI and Copeptin for Early 'Rule-Out' of AMI.

Rule-out of acute myocardial infarction (AMI) in patients presenting with acute chest pain at the emergency department (ED) is a major challenge across the globe. Patients presenting very early with chest pain may provide a diagnostic challenge even when using a cardiac necrosis specific biomarker, high sensitivity troponin (hs-Tn) as they are elevated at 3-6 h after the symptom onset. Copeptin is a marker of acute hemodynamic stress which is released within few minutes of the occurrence of MI and is elevated immediately at the presentation of patients with AMI. This indicates a complementary pathophysiology and kinetics of these two biomarkers. Hence, we evaluated whether or not a protocol with combined testing of copeptin and hs-TnI at admission in patients presenting with chest pain within 6 h in low to intermediate risk and suspected ACS leads to an earlier diagnosis of AMI and thereby, aids to prevent a higher proportion of major adverse cardiac events than the current standard protocol followed in ED. A total of 148 patients as per the inclusion criterion were recruited for the study. The dual biomarker copeptin and hs-TnI allows a rule-out of AMI at presentation with a sensitivity of 100% and NPV of 99.8%. Hence, the use of dual biomarker in conjunction with clinical assessment may obviate the need for a prolonged stay in the ED and retesting hs-TnI after 2 h (for delta check) in more than two-thirds of the patients. The inclusion of these tests could have an impact on the economic burden of the ED without jeopardizing the outcome for the patient.