Rickettsial Cerebellitis: A Rare Neurological Manifestation.

Scrub typhus is a vector-borne disease caused by gram-negative bacilli, Orientia tsutsugamushi. The vector of scrub typhus is the mite. The clinical manifestations often present with either a simple fever or life-threatening multi-organ dysfunction. Neurological manifestations also vary, and the incidence of neurological manifestations is unknown. Cerebellitis is one of the rare neurological manifestations associated with scrub typhus. In this case report, we present the case of a 35-year-old man who tested positive for scrub typhus (IgM enzyme-linked immunosorbent assay (ELISA) blood test) with a history of fever and cerebellar signs and symptoms. He was managed with antibacterial agents and made a good recovery.

Targeting NF-κB pathway for the anti-inflammatory potential of Bhadradarvadi kashayam on stimulated RAW 264.7 macrophages.

Macrophage-arbitrated inflammation is associated with the regulation of rheumatoid arthritis (RA). Low risk and better efficiency are steered herbal drugs more credible than conventional medicines in RA management. Bhadradarvadi (BDK) concoction has been traditionally used for rheumatism in Ayurveda. However, the mechanisms at the molecular level are still elusive. This study was designed to inspect the process of immunomodulation and anti-inflammatory properties of BDK in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages for the first time. BDK concoction was prepared and evaluated with the stimulated murine macrophage-like RAW 264.7 cell lines. TNF-α, IL6, and PGE2 were quantified by ELISA. The normalization of the fold change in the expression of the target gene mRNA was done by comparing the values of the ß-actin housekeeping gene using the 2-ΔΔCt comparative cycle threshold. The expression of TNF-α, IL6, iNOS, and COX-2 in the RAW 264.7 macrophage cells was analyzed using flow cytometry. Our results showed that BDK (150-350 µl/ml) treatment significantly decreased the inflammatory cytokines (TNF-α, and IL-6) and inflammatory mediators (PGE2) in LPS-stimulated RAW 264.7 macrophage cells. The pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) expression, inflammatory enzymes (iNOS and COX-2), and NF-κBp65 were significantly downregulated at transcriptome level in LPS-stimulated RAW 264.7 macrophage cells. The flow cytometry analysis revealed that BDK treatment diminished the TNF-α, IL-6, iNOS, and COX-2 expression at the proteome level, as well as obstruction of NF-κB-p65 nuclear translocation was observed by immunofluorescence analysis in LPS-stimulated RAW 264.7 macrophage cells. Collectively, BDK can intensely augment the anti-inflammatory activities via inhibiting the NF-κB signaling pathway trigger for treating autoimmune disorders including RA.

Assessing Oncologists' Attitudes Concerning Comprehensive Genomic Profiling in Stage IV Lung Adenocarcinoma in Brazil.

Introduction: Advances in comprehensive genomic profiling (CGP) of lung adenocarcinomas (LUADs) led to personalized treatment for patients. This study evaluated medical oncologists' attitudes toward CGP in a scenario where sponsored funding for CGP was available. Methods: We designed an online survey assessing CGP use and treating physicians' confidence, composed of three self-confidence domains, which are as follows: confidence in interpreting CGP results, confidence in treating oncogenic-driven LUAD, and confidence in managing tyrosine kinase inhibitor adverse events. The survey was distributed to medical oncologists who treat lung cancer in Brazil. Comparisons between groups were performed using the chi-square or Fisher's exact test. Univariable and multivariable (adjusted OR) analyses were performed. Results: Among 104 respondents who treat patients with lung cancer, 55% were from the Southeast region, 28% had high lung cancer clinical load, and 33% had in-house molecular testing. More than half (51%) of the participants request CGP systematically to stage IV LUAD. As for provider confidence, 67% stated being confident in all three domains: 76% confident in interpreting CGP, 84% confident in treating oncogenic-driven LUAD, and 81% in managing tyrosine kinase inhibitor adverse events. Providers' confidence was associated with systematically requesting CGP to stage IV LUAD (p = 0.013). After controlling for the variables of interest, systematic requesting CGP for stage IV LUAD revealed a significant association with the provider's confidence (adjusted OR = 0.35, p = 0.028, 95% CI: 0.14-0.84). The major challenge for properly requesting CGP was the long turnaround time and the fear of treatment delays. Conclusions: Even though CGP for stage IV LUAD in Brazil is fully sponsored, only half of the oncologists in our survey systematically request it.. Requesting CGP was associated with providers' confidence. Improving access and promoting providers' awareness of CGP utility is necessary to increase CGP use and better inform treatment decisions.

Echocardiographic Correlates of Mortality Among Cardiac Intensive Care Unit Patients With Cardiogenic Shock.

BACKGROUND: Prior studies have shown worse outcomes in patients with cardiogenic shock (CS) who have reduced left ventricular ejection fraction (LVEF), but the association between other transthoracic echocardiogram (TTE) findings and mortality in CS patients remains uncertain. We hypothesized that Doppler TTE measurements would outperform LVEF for risk stratification. METHODS: Retrospective analysis of cardiac intensive care unit patients with an admission diagnosis of CS and a TTE within 1 day of admission. Hospital survivors and inpatient deaths were compared, and multivariable logistic regression was used to analyze the associations between TTE variables and hospital mortality. RESULTS: We included 1,085 patients, with a median age of 69.5 (59.6, 77.5) years; 37% were females and 62% had an acute coronary syndrome. Most patients (66%) had moderate or severe left ventricular (LV) systolic dysfunction, and 48% had moderate or severe right ventricular (RV) systolic dysfunction. Hospital mortality occurred in 31%, and inpatient deaths had a lower median LVEF (29% vs. 35%, P < 0.001). Patients with mild or no LV or RV dysfunction were at lower risk of adjusted hospital mortality (P < 0.01). The LV outflow tract (LVOT) velocity-time integral (VTI) was the single best predictor of hospital mortality. After multivariable adjustment, both the LVEF and LVOT VTI remained strongly associated with hospital mortality (P < 0.001). CONCLUSIONS: Early comprehensive Doppler TTE can provide important prognostic insights in CS patients, highlighting its potential utility in clinical practice. The LVOT VTI, reflecting forward flow, is an important measurement to obtain on bedside TTE.

Dual-Venc acquisition for 4D flow MRI in aortic stenosis with spiral readouts.

BACKGROUND: Single Venc 4D flow MRI with Cartesian readout is hampered by poor velocity resolution and noise when imaging during diastole. Dual Venc acquisitions typically require the acquisition of two distinct datasets, which leads to longer scan times. PURPOSE/HYPOTHESIS: To design and develop a 4D Spiral Dual Venc sequence. The sequence allows for separate systolic and diastolic Venc s as part of a single acquisition with a prescribed switch time. The implemented sequence was hypothesized to be comparable to Cartesian 4D flow, but with increased velocity resolution in the diastolic phase and with better scan efficiency and reduced noise. STUDY TYPE: Prospective. POPULATION: The studied populations were two phantoms-a straight pipe with a stenotic narrowing and a phantom of the aortic arch which included a calcific polymeric valve-under both steady and pulsatile flows, six healthy volunteers, and eight patients with severe aortic stenosis (AS). FIELD STRENGTH/SEQUENCE: 1.5T, Dual Venc 4D flow with spiral readouts. ASSESSMENT: Data from the proposed sequence were compared with data from 4D Cartesian Dual Venc and Single Venc acquisitions. Noise was assessed from the acquired velocity data with the pump turned off and by varying Venc . Steady acquisitions were compared to the proximal slice of the lowest Single Venc acquisition. STATISTICAL TESTS: Steady flows were compared using relative-root-mean-squared-error (RRMSE). For in vivo flows and pulsatile in vitro flows, net flow for corresponding timepoints were compared with the Pearson correlation test (P < 0.01). RESULTS: For steady flows, RRMSEs for Single Venc s ranged from 17.6% to 19.4%, and 9.6% to 16.5% for Dual Venc s. The net flow correlation coefficient for the aortic arch phantom was 0.975, and 0.995 for the stenotic phantom. Normal volunteer and patient comparisons yielded a correlation of 0.970 and 0.952, respectively. in vitro and in vivo pulsatile flow waveforms closely matched. DATA CONCLUSION: The Dual Venc offers improved noise properties and velocity resolution, while the spiral trajectory offers a scan efficient acquisition with short echo time yielding reduced flow artifacts. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2020;52:117-128.

Morphological and elemental mapping of gallstones using synchrotron microtomography and synchrotron X-ray fluorescence spectroscopy.

BACKGROUND AND AIM: Regional differences in gallstone (GS) composition are well documented in the Indian subcontinent. The reasons for the same are unknown. Etiopathogenesis of GS remains elusive despite advances in instrumentation. This was an in-depth analysis of the chemical, structural, and elemental composition of GS with special reference to synchroton studies. METHODS: We used high-end sensitive analytical complementary microscopic and spectroscopic methods techniques, such as X-ray diffraction, scanning electron microscopy, Fourier transform infrared, synchrotron X-ray fluorescence spectroscopy (SR-XRF), and 2D and 3D synchrotron microtomography (SR-µCT), to study the ultra structure and trace element composition of three major types of GS (cholesterol, mixed, and pigment). SR-XRF quantified the trace elements in GS. RESULTS: The cholesterol GS (monohydrate and anhydrate) were crystalline, with high calcium content. The pigment GS were amorphous, featureless, black, and fragile, with high calcium bilirubinate and carbonate salts. They had the highest concentration of iron (average 31.50 ppm) and copper (average 92.73 ppm), with bacterial inclusion. The mixed stones had features of both cholesterol and pigment GS with intermediate levels of copper (average 20.8 ppm) and iron (average 17.78 ppm). CONCLUSION: SR-µCT has, for the first time, provided cross-sectional computed imaging delineating the framework of GS and mineral distribution. It provided excellent mapping of cholesterol GS. SR-XRF confirmed that pigment GS had high concentrations of copper and iron with bacterial inclusions, the latter possibly serving as a nidus to the formation of these stones.

Patient Engagement.

As the health system shifts toward population health approach, there is increasing attention to decreasing costs and improving quality. Measuring and improving patient engagement will become a requisite core competency for health systems and care providers. Approximately 70% of deaths and 40% of costs are attributable to a few chronic diseases, which are largely modifiable by practices such as smoking cessation, healthy eating, and exercise, each of which requires patients to play an active role in owning their health. Caregivers and the health system can support patient engagement, making it more likely that patients will take ownership for their health.

Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles.

The effect of surfactant and dopant on the properties of zinc oxide nanoparticles were studied by preparing polyethylene glycol (PEG) capped ZnO and tungsten doped PEG capped ZnO nanoparticles via the electrochemical method. These nanoparticles were characterized using X-Ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), Ultraviolet Diffuse Reflection Spectroscopy (UV-DRS), Scanning Electron Microscopy (SEM) and Electron Dispersive Analysis of X Rays (EDAX). The photocatalytic degradation of malachite green dye using these nanoparticles was studied under visible light. The effects of various reaction parameters like dye concentration, catalyst concentration, pH and time were studied to optimize the photodegradation reaction. Reusability of these nanoparticles was studied and no significant change was observed in the degradation efficiency of PEG capped ZnO till the fourth cycle, while there was a gradual decrease in the degradation efficiency of tungsten doped PEG capped ZnO. Langmuir- Hinshelwood kinetic model well describes the photodegradation capacity and the degradation of malachite green follows pseudo-first order kinetics.Photocatalytic studies reveal that PEG capping increases the degradation properties of ZnO while tungsten doping decreases the extent of PEG capping and has a detrimental effect on the degradation properties of ZnO. The prepared nanoparticles exhibit significant antibacterial properties against gram-positive Bacillus cereus and gram-negative Escherichia coli bacterial strains by agar well diffusion method.

Symposium review: Novel strategies to genetically improve mastitis resistance in dairy cattle.

Mastitis is a disease of major economic importance to the dairy cattle sector because of the high incidence of clinical mastitis and prevalence of subclinical mastitis and, consequently, the costs associated with treatment, production losses, and reduced animal welfare. Disease-recording systems compiling data from a large number of farms are still not widely implemented around the world; thus, selection for mastitis resistance is often based on genetically correlated indicator traits such as somatic cell count (SCC), udder depth, and fore udder attachment. However, in the past years, several countries have initiated collection systems of clinical mastitis, based on producers recording data in most cases. The large data sets generated have enabled researchers to assess incidence of this disease and to investigate the genetic background of clinical mastitis itself, as well as its relationships with other traits of interest to the dairy industry. The genetic correlations between clinical mastitis and its previous proxies were estimated more accurately and confirmed the strong relationship of clinical mastitis with SCC and udder depth. New traits deriving from SCC were also studied, with the most relevant findings being associated with mean somatic cell score (SCS) in early lactation, standard deviation of SCS, and excessive test-day SCC pattern. Genetic correlations between clinical mastitis and other economically important traits indicated that selection for mastitis resistance would also improve resistance against other diseases and enhance both fertility and longevity. However, milk yield remains negatively correlated with clinical mastitis, emphasizing the importance of including health traits in the breeding objectives to achieve genetic progress for all important traits. These studies enabled the establishment of new genetic and genomic evaluation models, which are more efficient for selection to mastitis resistance. Further studies that are potential keys for future improvement of mastitis resistance are deep investigation of the bacteriology of mastitis, identification of novel indicator traits and tools for selection, and development of a larger female reference population to improve reliability of genomic evaluations. These cutting-edge studies will result in a better understanding of the genetic background of mastitis resistance and enable a more accurate phenotyping and genetic selection to improve mastitis resistance, and consequently, animal welfare and industry profitability.

Design of Boron Nitride/Gelatin Electrospun Nanofibers for Bone Tissue Engineering.

Gelatin is a biodegradable biopolymer obtained by collagen denaturation, which shows poor mechanical properties. Hence, improving its mechanical properties is very essential toward the fabrication of efficient nontoxic material for biomedical applications. For this aim, various methods are employed using external fillers such as ceramics or bioglass. In this report, we introduce boron nitride (BN)-reinforced gelatin as a new class of two-dimensional biocompatible nanomaterials. The effect of the nanofiller on the mechanical behavior is analyzed. BN is efficiently exfoliated using the biopolymer gelatin as shown through Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD). The exfoliated BN reinforces gelatin electrospun fibers, which results in an increase in the Young's modulus. The Electrospun Mats (ESM) are stable after the glutaraldehyde cross-linking, and the fibrous morphology is preserved. The cross-linked gelatin/BN ESM is highly bioactive in forming bonelike hydroxyapatite as shown by scanning electron microscopy. Due to their enhanced mineralization ability, the cross-linked ESM have been tested on human bone cells (HOS osteosarcoma cell line). The cell attachment, proliferation, and biocompatibility results show that the ESM are nontoxic and biodegradable. The analysis of osteoblast gene expression and the measurement of alkaline phosphatase activity confirm that these materials are suitable for bone tissue engineering.

Genetic analysis of groups of mid-infrared predicted fatty acids in milk.

The objective of this study was to investigate genetic variability of mid-infrared predicted fatty acid groups in Canadian Holstein cattle. Genetic parameters were estimated for 5 groups of fatty acids: short-chain (4 to 10 carbons), medium-chain (11 to 16 carbons), long-chain (17 to 22 carbons), saturated, and unsaturated fatty acids. The data set included 49,127 test-day records from 10,029 first-lactation Holstein cows in 810 herds. The random regression animal test-day model included days in milk, herd-test date, and age-season of calving (polynomial regression) as fixed effects, herd-year of calving, animal additive genetic effect, and permanent environment effects as random polynomial regressions, and random residual effect. Legendre polynomials of the third degree were selected for the fixed regression for age-season of calving effect and Legendre polynomials of the fourth degree were selected for the random regression for animal additive genetic, permanent environment, and herd-year effect. The average daily heritability over the lactation for the medium-chain fatty acid group (0.32) was higher than for the short-chain (0.24) and long-chain (0.23) fatty acid groups. The average daily heritability for the saturated fatty acid group (0.33) was greater than for the unsaturated fatty acid group (0.21). Estimated average daily genetic correlations were positive among all fatty acid groups and ranged from moderate to high (0.63-0.96). The genetic correlations illustrated similarities and differences in their origin and the makeup of the groupings based on chain length and saturation. These results provide evidence for the existence of genetic variation in mid-infrared predicted fatty acid groups, and the possibility of improving milk fatty acid profile through genetic selection in Canadian dairy cattle.

A Comprehensive Study of Tumor Necrosis Factor-Alpha Genetic Polymorphisms, its Expression in Skin and Relation to Histopathological Features in Psoriasis.

BACKGROUND: Tumor necrosis factor-alpha (TNFα) is an important inflammatory mediator in psoriasis and several genetic polymorphisms of this cytokine have been reported. Majority of studies have focused on the increased G- A polymorphism at the -308 position in psoriasis. There has been no comprehensive study evaluating the genetic polymorphisms, TNFα expression in the skin and histopathology. We are undertaking this study to outline TNFα genetic polymorphisms, its skin expression and histopathological correlation to help determine its role at the genetic and protein level. MATERIALS AND METHODS: 112 patients of psoriasis and 243 healthy controls were included in this prospective study. 5 ml of peripheral blood was collected to study the TNFα genetic polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. Histopathological analysis of biopsies from the 112 patients were done using visual analogue scale and correlated with the findings. 61 of these cases were analyzed for TNFα expression by immunohistochemistry. The results of study were statistically analyzed using SPSS 13.0 statistical package program. RESULTS: A strong association of TNFα -308 G/A polymorphism in psoriasis cases was detected. The A allele of the TNFα -308 G/A polymorphism occurs rarely in the Indian population, however there is an over representation of this allele in psoriatic patients. There was no association seen between TNFα genotype and histopathological severity of psoriasis. CONCLUSION: The study emphasized the central role of TNFα in the pathogenesis of psoriasis. TNFα genotyping may be helpful in identifying subjects in whom anti-TNFα therapeutic strategies may be tried.

Calcium alginate-carboxymethyl cellulose beads for colon-targeted drug delivery.

The present study delineates preparation, characterization and application of calcium alginate (CA)-carboxymethyl cellulose (CMC) beads for colon-specific oral drug delivery. Here, we exploited pH responsive swelling, mucoadhesivity and colonic microflora-catered biodegradability of the formulations for colon-specific drug delivery. The CA-CMC beads were prepared by ionic gelation method and its physicochemical characterization was done by SEM, XRD, EDAX, DSC and texture analyzer. The swelling and mucoadhesivity of the beads was found higher at the simulated colonic environment. Variation was more prominent in compositions with lower CMC concentrations. CA-CMC formulations degraded slowly in simulated colonic fluid, however the degradation rate increased drastically in the presence of colonic microflora. In vitro release study of anticancer drug 5-fluorouracil (5-FU) showed a release (>90%) in the presence of colonic enzymes. A critical analysis of drug release profile along with FRAP (fluorescence recovery after photobleaching) study revealed that the presence of CMC in the formulation retarded the release rate of 5-FU. 5-FU-loaded formulations were tested against colon adenocarcinoma cells (HT-29). Cytotoxicity data, nuclear condensation-fragmentation and apoptosis analysis (by flow cytometry) together confirmed the therapeutic potential of the CA-CMC formulations. In conclusion, CA-CMC beads can be used for colon-specific drug delivery.

Advances in chalcones with anticancer activities.

Chalcones are naturally occurring compounds exhibiting broad spectrum biological activities including anticancer activity through multiple mechanisms. Literature on anticancer chalcones highlights the employment of three pronged strategies, namely; structural manipulation of both aryl rings, replacement of aryl rings with heteroaryl scaffolds, molecular hybridization through conjugation with other pharmacologically interesting scaffolds for enhancement of anticancer properties. Methoxy substitutions on both the aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings appear to influence anticancer and other activities. Similarly, heterocyclic rings either as ring A or B in chalcones, also influence the anticancer activity shown by this class of compounds. Hybrid chalcones formulated by chemically linking chalcones to other prominent anticancer scaffolds such as pyrrol[2,1-c][1,4]benzodiazepines, benzothiazoles, imidazolones have demonstrated synergistic or additive pharmacological activities. The successful application of these three pronged strategies for discovering novel anticancer agents based on chalcone scaffold has resulted in many novel and chemically diverse chalcones with potential therapeutic application for many types of cancer. This review summarizes the concerted efforts expended on the design and development of anticancer chalcones recorded in recent literature and also provides an overview of the patents published in this area between 2007 and 2014 (WO2013022951, WO201201745 & US2012029489).

Pilot Study of the Effect of Lanthanum Carbonate (Fosrenol®) In Patients with Calciphylaxis: A Wisconsin Network for Health Research (WiNHR) Study.

BACKGROUND: Currently there is a lack of effective treatment options for patients with calciphylaxis. There is anecdotal evidence that non-calcium based phosphorus binders may offer some benefit. The aim of this pilot study is to determine if lanthanum carbonate is effective in inducing remission of calciphylaxis lesions and demonstrate an improved DLQI (Dermatology Life Quality Index). METHODS: This is a multi-site exploratory pilot study conducted through the Wisconsin Network for Health Research (WiNHR), a collaboration of health services researchers across the state of Wisconsin. Dialysis patients were recruited from in-center dialysis units, clinics and hospital admissions over a period of 24-months. RESULTS: Due to the low inclusion rate, the trial was terminated after which 4 patients were prospectively analyzed. Dose of lanthanum carbonate was escalated to 3750 mg divided into 3 meals and titrated according to level of serum phosphorus. Gastrointestinal symptoms were the most common adverse effect. All 4 patients achieved complete remission by definition of skin re-epithelialization. Secondary outcome measurements showed a significant improvement in serum albumin (B coeff 0.17, 95% CI 0.002-0.031; p=0.023) and a significant improvement in overall DLQI score (B coeff -0.46, 95% CI -0.85- -0.08; p=0.019). CONCLUSIONS: Lanthanum carbonate appears to be efficacious as an adjunctive therapy to improve calciphylaxis lesions and symptom burden. More prospective clinical trials are warranted to determine the feasibility of this novel treatment strategy.

Development of ribonucleotide reductase inhibitors: a review on structure activity relationships.

Ribonucleotide reductase (RNR, E.C. 1.17.4.1), which is composed of two dissimilar proteins (subunits), often referred as R1 (containing polythiols) and R2 (containing non-heme iron and a free tyrosyl radical), which contribute to the role played by the enzyme. RNRs are one of the important targets in anticancer and antiviral drug development and many RNR inhibitors have been discovered at the end of the 20(th) century; many of them are already in clinical use. Triapine (3-AP) is one of the important RNR inhibitors belonging to the class of thiosemicarbazone derivatives, used in the treatment of various cancers. The structure activity relationship (SAR) studies on the investigated RNR inhibitors showed that the nitrogen atom in the pyridine (or other heterocycles) forms coordination complexes with the metal ions along with the imine, oxo and thio atoms of the thiosemicarbazone or semicarbazone pharmacophores. The computational analyses results in the adenine and purine derivatives suggest that the nitrogen atoms in the adenine rings make several hydrogen bonds with the water molecules present in the active site, as well as Gly249 and Glu288 residues. The OH group in third position of the sugar moiety interacts with the Ser217 (C=O) and the water molecules through hydrogen bonds. The aromatic rings in the molecules interact with the tyrosine residues. The thiosemicarbazone or semicarbazone derivatives explain that the flexibility and polar properties in the thiosemicarbazone or semicarbazone pharmacophoric regions allow the molecules to coordinate with the metal ion (especially iron) present in the RNR enzymes. This review concluded that RNR inhibitors composed of different fragments such as aryl, heteroaryl, sugar moiety, polar groups, flexible bonds, etc which are required for the binding of the molecules to the RNR enzymes. Further, the fragmental analysis of the RNR inhibitors on different toxicological and metabolic targets can provide significant novel molecules with acceptable pharmacokinetic properties.

Aryl- and heteroaryl-thiosemicarbazone derivatives and their metal complexes: a pharmacological template.

In this review, we discuss the current patents concerning aryl/heteroaryl thiosemicarbazone derivatives as regards to their activities and properties, including coordination (chelation) properties. The mode of action of the aryl/heteroaryl thiosemicarbazone derivatives involves metal coordination with proteins or biological fluids that have metal ions in their structure. Additionally, these molecules can also form multiple hydrogen bonds through their (thio) amide and N3 nitrogen that ensure a strong interaction with the receptor. In some cases, strong π-π interactions can be observed too. Special attention is given to pyridyl, bis-pyridyl, benzoylpyridyl and isatin thiosemicarbazone derivatives that exhibit significant anticancer, antiviral and other activities in free and in metal complexed forms. This key biological role is often related with their capability to inhibit the enzyme ribonucleotide reductase, similar to what is observed with potent anticancer drugs such as Triapine and methisazone. Recent studies have revealed that thiosemicarbazone can also inhibit topoisomerase II α enzyme. Thiosemicarbazone derivatives form coordination complex with various metals such as Zn, Cu, Fe, Co, Ni, Pt, Pd, etc., and these complexes provide better activities than the free thiosemicarbazones. Recent patents show that the controlled or sustained release dosage form of the thiosemicarbazone derivatives along with ionizing radiations is used for the treatment of proliferative diseases (US20110152281, US20110245304, US20120172217).

Human ether-a-go-go-related gene channel blockers and its structural analysis for drug design.

The human ether-a-go-go-related gene (hERG) is a K+ channel protein mainly expressed in the heart and the nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death. In this present review, we have focused the physicochemical properties responsible for the hERG blocking activity of structurally different compounds. The reported research works showed that the hydrophobicity on the van der Waals (vdW) surface of the molecules (aroused from the aromatic ring) necessary for the hERG blocking activity along with topological and electronic properties. The quinolizidine alkaloids (natural products) such as oxymatrine, sophoridine, sophocarpine and matrine carry the common molecular structure of O=C=N-C-C-C-N that possessed positive ionotropic effect and hERG blocking activity. Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial. The isoquinoline alkaloid, neferine (Nef) induces a concentration-dependent decrease in current amplitude (IC50 of 7.419 MM). Most of these natural product compounds contain non-flexible aromatic structures but have significant activity due to the presence of optimum hydrophobicity. Recent research works revealed that Eag and hERG channels are expressed by a variety of cancer cell lines and tissues. The Eag channel showed an oncogenic potential while hERG channels are associated with more aggressive tumors and have a role in mediating invasion. This review concluded that the consideration of physicochemical properties necessary for the hERG blocking activity will guide to develop novel drugs with less cardiotoxicity.