Recent developments of P-glycoprotein inhibitors and its structure-activity relationship (SAR) studies.

P-glycoprotein (P-gp) over-expression is a key factor in multi-drug resistance (MDR), which is a major factor in the failure of cancer treatment. P-gp inhibitors have been demonstrated to have powerful pharmacological properties and may be used as a therapeutic approach to overcome the MDR in cancer cells. Combining clinical investigations with biochemical and computational research may potentially lead to a clearer understanding of the pharmacological properties and the mechanisms of action of these P-gp inhibitors. The task of turning these discoveries into effective therapeutic candidates for a variety of malignancies, including resistant and metastatic kinds, falls on medicinal chemists. A variety of P-gp inhibitors with great potency, high selectivity, and minimal toxicity have been identified in recent years. The latest advances in drug design, characterization, structure-activity relationship (SAR) research, and modes of action of newly synthesized, powerful small molecules P-gp inhibitors over the previous ten years are highlighted in this review. P-gp transporter over-expression has been linked to MDR, therefore the development of P-gp inhibitors will expand our understanding of the processes and functions of P-gp-mediated drug efflux, which will be helpful for drug discovery and clinical cancer therapies.

Decreased Systemic Levels of Endocan-1 and CXCL16 in Psoriasis Are Restored following Narrowband UVB Treatment.

BACKGROUND: In psoriasis, a common immune-mediated disease affecting 2-3% of the population worldwide, there is an increased prevalence of extracutaneous diseases including obesity, the metabolic syndrome, and cardiovascular disease. This is believed to be linked to systemic inflammation. In previous studies, we have explored various markers in plasma and serum to characterize the ongoing systemic inflammation in psoriasis patients compared to controls. We have identified several markers that were altered in psoriasis patients, but which all were unresponsive to narrowband UVB (NB-UVB) treatment. OBJECTIVE: The objective of the study was to evaluate the effect of NB-UVB treatment on markers of cardiovascular risk and systemic inflammation in psoriasis. METHODS: The levels of 17 potential biomarkers with an association with cardiovascular risk were quantitated in plasma from 37 age- and gender-matched psoriasis patients and controls at baseline and in 21 psoriasis patients after 12 weeks of NB-UVB treatment to identify a systemic treatment response. RESULTS: We identified the mediators endocan-1, CXCL16, and sVEGFR1, which were systemically decreased in psoriasis at baseline, as well as FABP3, FABP4, and sIL-1R1, which showed normal baseline levels. After 10-12 weeks of NB-UVB treatment, endocan-1 and CXCL16 were restored to normal levels, while sVEGFR1, FABP3, FABP4, and sIL-1R1 showed a significant reduction. CONCLUSION: The current study expands the number of potential biomarkers in psoriasis by including a greater number and variety of mediators, approaching the systemic inflammation from additional vantage points, including soluble immune receptors and adipocyte contribution, to provide a more complete picture of the systemic inflammatory state in psoriasis.

Efficacy of oral methylcobalamin in treatment of vitamin B12 deficiency anemia in children.

To demonstrate the efficacy of oral methylcobalamin in treating vitamin B12 (vitB12) deficiency anemia, our prospective observational study enrolled 28 children with both macrocytic anemia and low holotranscobalamin (HoloTC) levels. Their hematological and biochemical parameters pre- and posttreatment at 1 month were compared. Hemoglobin showed mean increase of 2.89 g/dl (P < 0.001), rising above 10 g/dl in 24 patients (85.7%). Reticulocytes peaked at 1 week. Mean fall in mean corpuscular volume of 24.83 fl (P < 0.001) and mean improvement in platelets of 122,100/µl (P = 0.001) were noted, and mean rise in HoloTC and vitB12 were 111.36 pmol/l (P < 0.001) and 918.34 pg/ml (P < 0.001), respectively. Thus, initial responses to oral methylcobalamin in children with vitB12 deficiency anemia were adequate.

Synthesis of imidazoles via cascade reaction of nitroallylic acetates with amidines and studies on their trypanocidal activity.

A one-pot, two step synthesis of highly substituted imidazoles has been carried out in good to excellent yields for the first time via a cascade intermolecular aza-SN2'-intramolecular aza-Michael addition involving a variety of Morita-Baylis-Hillman acetates of nitroalkenes and amidines in the presence of DABCO at room temperature. The synthetic and biological utility of the products has been demonstrated. In particular, some of the imidazoles exhibited potent activity against T. cruzi, the etiological agent of Chagas disease.

Adverse pregnancy outcome in patients with low pregnancy-associated plasma protein-A: The Indian Experience.

AIM: The aim of our study was to examine the association of low pregnancy-associated plasma protein-A (PAPP-A) with adverse pregnancy outcome. MATERIAL AND METHODS: A total of 1640 consecutive pregnant women between 9(+5) and 13(+6) weeks of pregnancy were recruited. One hundred and thirty women with PAPP-A levels < 0.4 multiple of median were followed till delivery and the outcome information was obtained for fetal loss, birthweight, growth restriction, preterm birth, reduced liquor and development of pre-eclampsia. RESULTS: During the study period, 130 (7.92%) women had low PAPP-A and were considered as cases and 200 women with normal PAPP-A were controls. Intrauterine growth restriction was observed in 28 (21.54%) cases as compared to 10 (5%) controls. Pre-eclampsia presented in 24 (18.46%) cases and in 18 (9%) controls. Twenty (15.38%) cases had preterm delivery compared to 12 (6%) controls. Fifty-six (43.08%) cases delivered low-birthweight babies compared to 22 (11%) controls. Thus, the incidence of intrauterine growth restriction, preterm birth and low birthweight was significantly more in the cases as compared to the control group. CONCLUSIONS: PAPP-A is a valuable analyte for predicting risk of adverse pregnancy outcome and women with low serum PAPP-A levels would benefit from closer surveillance.

Human gene variants linked to enhanced NLRP3 activity limit intramacrophage growth of Mycobacterium tuberculosis.

Activation of the NLRP3 inflammasome and subsequent generation of interleukin 1ß is initiated in macrophages upon recognition of several stimuli. In the present work, we show that gain-of-function gene variants of inflammasome components known to predispose individuals to inflammatory disorders have a host-protective role during infection with Mycobacterium tuberculosis. By isolation of macrophages from patients and healthy blood donors with genetic variants in NLRP3 and CARD8 and subsequent infection of the cells with virulent M. tuberculosis, we show that these gene variants, combined, are associated with increased control of bacterial growth in human macrophages.

T-cell lymphoblastic lymphoma of Tenon's capsule: an unusual presentation.

Lymphoid neoplasms of the orbit account for approximately 6-8 % of all orbital tumors and 15 % of all ocular adnexal tumors. We report an unusual case of T-cell lymphoblastic lymphoma occurring in a 30-year-old man, presenting as red, painless, firm swelling in the Tenon's capsule of the eye.

NOS2-derived low levels of NO drive psoriasis pathogenesis.

Psoriasis is an IL-23/Th17-mediated skin disorder with a strong genetic predisposition. The impact of its susceptibility gene nitric oxide synthase 2 (NOS2) remains unknown. Here, we demonstrate strong NOS2 mRNA expression in psoriatic epidermis, an effect that is IL-17 dependent. However, its complete translation to protein is prevented by the IL-17-induced miR-31 implying marginally upregulated NO levels in psoriatic skin. We demonstrate that lower levels of NO, as opposed to higher levels, increase keratinocyte proliferation and mediate IL-17 downstream effects. We hypothesized that the psoriatic phenotype may be alleviated by either eliminating or increasing cellular NO levels. In fact, using the imiquimod psoriasis mouse model, we found a profound impact on the psoriatic inflammation in both IMQ-treated NOS2 KO mice and wild-type mice treated with IMQ and the NO-releasing berdazimer gel. In conclusion, we demonstrate that IL-17 induces NOS2 and fine-tunes its translation towards a window of proinflammatory and hyperproliferative effects and identify NO donor therapy as a new treatment modality for psoriasis.

Synthesis of withasomnines and their non-natural analogues from aldehydes and 4-nitro-1-butanol in three steps.

Total synthesis of all three pyrazole-based withasomnine alkaloids and selected examples of their non-natural analogs has been achieved from readily available aldehydes and 4-nitro-1-butanol in three steps. Since 4-nitro-1-butanol in turn is prepared in two steps via Michael addition of nitromethane to acrylate followed by borane reduction of the ester group and the key 1,3-dipolar cycloaddition step is carried out with commercially available TMSCHN2, this approach is a very convenient and economical one.

A simple cost-effective microfluidic platform for rapid synthesis of diverse metal nanoparticles: A novel approach towards fighting SARS-CoV-2.

The latest addition to the family of Coronaviruses, SARS-CoV-2, unleashed its wrath across the globe. The outbreak has been so rapid and widespread that even the most developed countries are still struggling with ways to contain the spread of the virus. The virus began spreading from Wuhan in China in December 2019 and has currently affected more than200 countries worldwide. Nanotechnology has huge potential for killing viruses as severe as HIV, herpes, human papilloma virus, and viruses of the respiratory tract, both inside as well as outside the host. Metal-nanoparticles can be employed for biosensing methodology of viruses/bacteria, along with the development of novel drugs and vaccines for COVID-19 and future pandemics. It is thus required for the nanoparticles to be synthesized quickly along with precise control over their size distribution. In this study, we propose a simple microfluidic-reactor-platform for in-situ metal-nanoparticle synthesis to be used against the pandemic for the development of preventive, diagnostic, and antiviral drug therapies. The device has been fabricated using a customized standard photolithography process using a simple and cost-effective setup. The confirmation on standard silver and gold metal nanoparticle formation in the microfluidic reactor platform was analysed using optical fiber spectrophotometer. This novel microfluidic platform provides the advantage of in-situ synthesis, flow parameter control and reduced agglomeration of nanoparticles over the bulk synthesis due to segregation of nucleation and growth stages inside a microchannel. The results are highly reproducible and hence scaling up of the nanoparticle production is possible without involving complex instrumentation.

Genetic variation and alterations of genes involved in NFκB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer.

Colorectal tumors are continuously exposed to an inflammatory environment, which together with mitogenic signals sustain several cancer hallmarks. Nuclear factor-kappa B (NFκB) is a major regulator of inflammation and variation in NFκB-associated genes could potentially be used as biomarkers to identify patients with increased risk of colorectal cancer (CRC) development, and/or a rapidly progressing disease. In this study, 348 CRC cases and 806 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NFκB pathway-associated genes. Log-rank-tests and Cox proportional hazard regression analysis examined the association between the polymorphisms and CRC-specific survival, whereas chi-square tests and logistic regression analysis were used to test for associations between the polymorphisms and CRC susceptibility. Gene expression and loss of heterozygosity analyses of TNFAIP3 were carried out in a subset of tumors to assess its role as a tumor suppressor in CRC. Heterozygous and polymorphic TNFAIP3 (rs6920220), heterozygous NLRP3 (Q705K) and polymorphic NFκB -94 ATTG ins/del genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2, 95% CI: 2.5-10.9, P < 0.001). TNFAIP3 mRNA levels were significantly decreased in tumors compared with adjacent non-neoplastic mucosa (P < 0.0001) and loss of heterozygosity of 6q23.3 (TNFAIP3) was detected in 17% of cases, whereas only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations. We propose that TNFAIP3 (rs6920220), NLRP3 (Q705K) and NFκB -94 ATTG ins/del polymorphisms are associated with poor survival in patients with advanced CRC and may be used as prognostic markers. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC.

Cost-effective microabsorbance detection based nanoparticle immobilized microfluidic system for potential investigation of diverse chemical contaminants present in drinking water.

The measurement of the concentration of different heavy-metal ions present in the water environments is becoming increasingly essential as water-pollution concerns worsen. The optical sensor has become a good platform for detecting heavy-metal-ion concentration due to its compact size; chemical inertness; and anti-electromagnetic interference. Here, we propose to fabricate a simple and cost-effective microfluidic device for the detection of aqueous-heavy-metal ions such as lead(II), chromium(III) and mercury(II) using an optical-micro-absorbance-spectroscopy/LSPR based principle. Firstly, a disposable-PDMS-micro-device with a rectangular "Z-shaped microfluidic channel" integrated with micro-lens-structure and optical-fibre-coupler-structure was fabricated via cost-effective soft-lithography-technique using a microfabricated SU8 master. Further, the synthesized-Silver-Nanoparticles were also immobilized inside the microchannel structure in some of the micro-devices for nanoparticle-based-sensing studies. The real-time presence of heavy metal ions in the minuscule sample volume was analyzed by passing different-sample concentrations intermittently through the abovementioned microfluidic structure and measuring the bulk-micro-absorbance across its enhanced optical path length coupler-structure. The results specify that the fabricated micro-device can be easily utilized for label-free detection of a minimum of 0.5 ppb for all the aforesaid sample-heavy metal ions. The absorbance-change observed per unit concentration-change of Lead ion, mercury ion and chromium ion (from 0.001 to ∼50 µg/ml) is found on average-1.8 × 10-2 ΔA/µg/ml, 1.1 × 10-2 ΔA/µg/ml, 4.2 × 10-3 ΔA/µg/ml, respectively. For silver nanoparticle-based studies, the absorbance-change observed per unit concentration change of aforesaid heavy-metal-ions (i.e. the sensitivity) was found on average ∼2 times higher in comparison to simple micro-absorbance-based studies. Additionally, the micro-device has a capability for simplistic incessant(real-time)investigation, a preset-analyte-quantity-interface, and management over the injected analyte-evaporation.

3D-Printed Impedance Micropump for Continuous Perfusion of the Sample and Nutrient Medium Integrated with a Liver-On-Chip Prototype.

In recent decades, organ-on-chip devices have gained substantial interest as an alternative for studying the pathophysiological processes relevant to drug screening. Micropumps are being utilized to simulate the in vivo physiological fluid flow more realistically in these organ-on-chip devices. Micropumps play a crucial role in pumping, perfusion, and circulation of fluids in various microdevices such as on-chip PCR, DNA microarrays, miniature bioreactor cell separation, and lab-on-chip biosensing platforms. With the rapid growth in technology, efficient pumping for proper circulation of media and nutrients has become imperative. In this study, we have described the design and development of an open-source impedance micropump for continuous perfusion of nutrient medium in a liver-on-chip prototype. This micropump is controlled via an integrated microcontroller board, with an observed flow rate ranging from 0.2 to 2 mL/min. Google Sketchup 2020 and DLP 3D printing were used to fabricate small precise parts of the impedance micropump. The flow rate was measured to characterize the actuating performance of the micropump. The poly-dimethyl siloxane-based liver-on-chip prototype has been fabricated using a soft photolithography procedure. Further, a study of continuous perfusion of culture medium through the liver-on-chip containing the Hepg2 cell line was successfully performed by integrating it with the impedance micropump. Hoechst staining and Alamar Blue observed cell viability to confirm the healthy cell growth inside the liver-on-chip microfluidic chip. The compactness of the overall setup allows it to fit in a Petri plate, eliminating chances of contamination while cell handling.

A Novel Framework for Abnormal Risk Classification over Fetal Nuchal Translucency Using Adaptive Stochastic Gradient Descent Algorithm.

In most maternity hospitals, an ultrasound scan in the mid-trimester is now a standard element of antenatal care. More fetal abnormalities are being detected in scans as technology advances and ability improves. Fetal anomalies are developmental abnormalities in a fetus that arise during pregnancy, birth defects and congenital abnormalities are related terms. Fetal abnormalities have been commonly observed in industrialized countries over the previous few decades. Three out of every 1000 pregnant mothers suffer a fetal anomaly. This research work proposes an Adaptive Stochastic Gradient Descent Algorithm to evaluate the risk of fetal abnormality. Findings of this work suggest that proposed innovative method can successfully classify the anomalies linked with nuchal translucency thickening. Parameters such an accuracy, recall, precision, and F1-score are analyzed. The accuracy achieved through the suggested technique is 98.642.%.

Assessment of Smartphone Apps for Common Neurologic Conditions (Headache, Insomnia, and Pain): Cross-sectional Study.

BACKGROUND: There are thousands of apps for individuals struggling with headache, insomnia, and pain, but it is difficult to establish which of these apps are best suited for patients' specific needs. If clinicians were to have access to a platform that would allow them to make an informed decision on the efficacy and feasibility of smartphone apps for patient care, they would feel confident in prescribing specific apps. OBJECTIVE: We sought to evaluate the quality of apps for some of the top common, disabling neurologic conditions (headache, insomnia, and pain) based on principles derived from the American Psychiatric Association's (APA) app evaluation model. METHODS: We used the Mobile Health Index and Navigation database and expanded upon the database's current supported conditions by adding 177 new app entries. Each app was rated for consistency with the APA's app evaluation model, which includes 105 objective questions based on the following 5 major classes of consideration: (1) accessibility, (2) privacy and security, (3) clinical foundation, (4) engagement style, and (5) interoperability. These characteristics were evaluated to gain a broader understanding of the significant features of each app category in comparison against a control group. RESULTS: Approximately 90% (187/201) of all apps evaluated were free to download, but only 50% (63/201) of headache- and pain-related apps were truly free. Most (87/106, 81%) sleep apps were not truly free to use. The apps had similar limitations with limited privacy, accessibility, and crisis management resources. For example, only 17% (35/201) of the apps were available in Spanish. The apps offered mostly self-help tools with little tailoring; symptom tracking was the most common feature in headache- (32/48, 67%) and pain-related apps (21/47, 45%), whereas mindfulness was the most common feature in sleep-related apps (73/106, 69%). CONCLUSIONS: Although there are many apps for headache, pain, and insomnia, all 3 types of apps have room for improvement around accessibility and privacy. Pain and headache apps share many common features, whereas insomnia apps offer mostly mindfulness-based resources. Given the many available apps to pick from, clinicians and patients should seek apps that offer the highest-quality features, such as complete privacy, remedial features, and the ability to download the app at no cost. These results suggest that there are many opportunities for the improvement of apps centered on headache, insomnia, and pain.

The use of virtual complementary and integrative therapies by neurology outpatients: An exploratory analysis of two cross-sectional studies assessing the use of technology as treatment in an academic neurology department in New York City.

Background: Prior to the COVID-19 pandemic, about half of patients from populations that sought care in neurology tried complementary and integrative therapies (CITs). With the increased utilization of telehealth services, we sought to determine whether patients also increased their use of virtual CITs. Methods: We examined datasets from two separate cross-sectional surveys that included cohorts of patients with neurological disorders. One was a dataset from a study that examined patient and provider experiences with teleneurology visits; the other was a study that assessed patients with a history of COVID-19 infection who presented for neurologic evaluation. We assessed and reported the use of virtual (and non-virtual) CITs using descriptive statistics, and determined whether there were clinical characteristics that predicted the use of CITs using logistic regression analyses. Findings: Patients who postponed medical treatment for non-COVID-19-related problems during the pandemic were more likely to seek CITs. Virtual exercise, virtual psychotherapy, and relaxation/meditation smartphone applications were the most frequent types of virtual CITs chosen by patients. In both studies, age was a key demographic factor associated with mobile/virtual CIT usage. Interpretations: Our investigation demonstrates that virtual CIT-related technologies were utilized in the treatment of neurologic conditions during the pandemic, particularly by those patients who deferred non-COVID-related care.

Highly selective synthesis of pyrazole and spiropyrazoline phosphonates via base-assisted reaction of the Bestmann-Ohira reagent with enones.

Novel carbonylated pyrazole phosphonates have been synthesized as single regioisomers by treating conjugated enones, dienones, tropone, and quinone with the Bestmann-Ohira reagent under KOH/EtOH conditions at room temperature. Through an "interrupted" version of the above reaction, carbonylated spiropyrazoline phosphonates have been synthesized from arylidenecycloalkanones under similar conditions (K(2)CO(3)/EtOH) with absolute regio- and diastereoselectivity. The key structures were confirmed by detailed spectroscopic analysis and X-ray crystallography.

Two adult siblings with atypical cryopyrin-associated periodic syndrome due to a novel M299V mutation in NLRP3.

OBJECTIVE: The NALP3 inflammasome is a multiprotein complex that triggers caspase 1-mediated interleukin-1beta (IL-1beta) release. Mutations in the gene encoding NALP3 (NLRP3) underlie the cryopyrin-associated periodic syndrome (CAPS). The aim of this study was to report a novel NLRP3 mutation in 2 siblings of Swedish descent in whom symptoms first presented in adulthood. METHODS: Mutation analysis of NLRP3 was performed on DNA from patients with CAPS and 100 control subjects. For assessment of caspase 1 and IL-1beta, blood was collected from patients and age- and sex-matched healthy control subjects. Genetic constructs containing mutant or wild-type NLRP3 were transduced into THP-1 cells, followed by assessment of IL-1beta levels in cell supernatant. RESULTS: Both siblings carried a novel M299V mutation in NLRP3, which was not present in the control population. The samples obtained from the patients displayed increased caspase 1 activity and elevated IL-1beta levels at basal conditions as compared with healthy control subjects. THP-1 cells expressing mutated M299V revealed almost 10-fold higher IL-1beta production compared with the wild-type construct. CONCLUSION: M299V is an activating mutation in NLRP3 resulting in elevated spontaneous caspase 1 activity and IL-1beta levels. The classic CAPS phenotype was lacking in these adult siblings. Whereas one sibling displayed a milder phenotype that has so far responded satisfactorily to oral nonsteroidal antiinflammatory drugs in combination with low-dose corticosteroids, the inflammatory symptoms in the sibling with the more severe case responded well to IL-1beta blockade. Understanding the pathogenic mechanism underlying such disorders can be helpful for the physician. Our study reinforces the importance of genetic testing and laboratory investigations in combination with careful phenotypic evaluation for the diagnosis of such patients.

Bilateral Proptosis in a Child-A Rare Manifestation of Ventriculoperitoneal Shunt Obstruction.

Ventriculoperitoneal shunt (VPS) obstruction may have a myriad of presentations. We reported a case of an 11-year-old girl presenting with acute, bilateral proptosis secondary to VPS obstruction. While neuroimaging was interpreted as unremarkable, fundoscopy revealed bilateral papilledema and lumbar puncture showed elevated intracranial pressure. Neurosurgical exploration demonstrated VPS valve obstruction and a new VPS was inserted. Postoperatively, she developed a recurrent extradural hematoma, which was initially evacuated and later managed conservatively. To our knowledge, this is the first report of bilateral proptosis secondary to VPS obstruction. This case highlights the value of key clinical findings and limitations of neuroimaging.

Enhanced Inflammasome Activity in Patients with Psoriasis Promotes Systemic Inflammation.

Psoriasis is linked to systemic inflammation and cardiovascular comorbidities, but studies of the underlying cellular mechanisms are lacking. The NLRP3 inflammasome is genetically associated with psoriasis, and its activation is increasingly linked with cardiovascular disease. In this study, we show that patients with psoriasis exhibited higher plasma levels of inflammasome-generated IL-1ß and IL-18, without any correlation to skin lesion severity. Increased constitutive expression of the inflammasome sensors NLRP3, NLRP1, and AIM2 was found in peripheral blood cells of the patients and also of those with mild disease, and this was accompanied by an increased caspase-1 reactivity in the myeloid blood subsets. TNF-α was found to activate selectively the NLRP3 inflammasome without the requirement for a priming signal. TNF-α was found to signal through the TNFR‒caspase-8‒caspase-1 alternative inflammasome pathway, which proceeds independently of pyroptosis. Patients who received anti-TNF therapy had normalized plasma IL-1ß and IL-18 levels as well as normalized caspase-1 reactivity. This was in contrast to the patients treated with methotrexate who exhibited persistent, increased caspase-1 reactivity. Thus, we show that the TNF-α-mediated activation of NLRP3 inflammasomes in patients with psoriasis may contribute to systemic inflammation. Anti-TNF therapy normalized inflammasome function, suggesting a mechanism for the cardiovascular risk‒reducing effect.