Wearable microfluidic-based e-skin sweat sensors

Electronic skins (e-skins) are soft (deformable and stretchable) state-of-the-art wearable devices that emulate the attributes of human skin and act as a Human–Machine Interface (HMI). Recent advances in e-skin for real-time detection of medical signals such as pulse, temperature, electromyogram (EMG), electroencephalogram (EEG), electrooculogram (EOG), electrocardiogram (ECG), and other bioelectric signals laid down an intelligent foundation for early prediction and diagnosis of diseases with a motive of reducing the risk of the ailment reaching to the end stage. In particular, sweat testing has been employed in diverse applications ranging from medical diagnosis of diabetes, cystic fibrosis, tuberculosis, blood pressure, and autonomic neuropathy to evaluating fluid and electrolyte balance in athletes. Typically, sweat testing techniques are done by trained experts and require off-body measurements, which prevent individuals from de-coding health issues quickly and independently. With the onset of soft electronics, wearable sweat sensors overcome this disadvantage via in situ sweat measurements with real-time feedback, timely diagnosis, creating the potential for preventive care and treatment. Over the past few decades, wearable microfluidic-based e-skin sweat sensors have paved a new way, promising sensing interfaces that are highly compatible with arranging medical and electronic applications. The present review highlights the recent research carried out in the microfluidic-based wearable sweat sensors with a critical focus on real-time sensing of lactate, chloride, and glucose concentration; sweat rate, simultaneously with pH, and total sweat loss for preventive care, timely diagnosis, and point-of-care health and fitness monitoring.

Electronic skins are soft wearable devices that emulate attributes of human skin and act as a human–machine interface for early prediction and real-time monitoring of disease.     

MMP-10 is overexpressed, proteolytically active, and a potential target for therapeutic intervention in human lung carcinomas

Matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix is a major factor for tumor development and expansion. This study analysed MMP-10 protein expression and activity in human lung tumors of various grade, stage, and type to address the relationship between MMP-10 and tumor characteristics and to evaluate MMP-10 as a therapeutic target in non small cell lung carcinoma (NSCLC). Unlike the majority of MMPs, MMP-10 was located in the tumor mass as opposed to tumor stroma. MMP-10 protein was observed at low levels in normal human lung tissues and at significantly higher levels in all types of NSCLC. No correlation was observed between MMP-10 protein expression and tumor type, stage, or lymph node invasion. To discriminate between active and inactive forms of MMP-10 in samples of human NSCLC, we have developed an ex vivo fluorescent assay. Measurable MMP-10 activity was detected in 42 of 50 specimens of lung cancer and only 2 of 10 specimens of histologically normal lung tissue. No relationship was observed between MMP-10 activity levels and clinicopathologic characteristics. Our results suggest that MMP-10 is expressed and active at high levels in human NSCLC compared to normal lung tissues, and, as such, is a potential target for the development of novel therapeutics for lung cancer treatment.     

Immunomodulatory studies of a bioactive fraction from the fruit of Prunus cerasus in BALB/c mice

In order to evaluate the role of ethyl acetate fraction (PNRS-EtOAC) obtained from the Prunus cerasus fruit in the modulation of immune responses, detailed studies were carried out using a panel of in vivo assays. Oral administration of PNRS-EtOAC (25-100 mg/kg) stimulated the IgM and IgG titre expressed in the form of hemagglutination antibody (HA) titre. Further, it elicited a dose related increase in the delayed type hypersensitivity reaction (DTH) after 24 and 48 h in BALB/c mice. Besides augmenting the humoral and cell mediated immune response, the concentration of cytokines (IFN-γ, IL-4, and TNF-α) in serum with respect to T cell interactions, i.e. the proliferation of lymphocytes were significantly increased at 50 mg/kg compared with the control. The results in these studies demonstrated the immunostimulatory effect of PNRS-EtOAC in a dose-dependent manner with respect to the macrophage activation possibly expressing the phagocytosis and nitrite production by the enhancement of TNF-α production as a mode of action.     

Acute peg in hole docking in the management of infected non-union of long bones

The Ilizarov method has been studied extensively in the management of non-union of long bones. In most cases this involves filling of defects present primarily or after débridement by bone transport. Acute docking over gaps longer than 2 cm has not been adequately studied, however. The purpose of this paper is to report the efficacy of acute peg in hole docking as a bone graft-sparing modality in the management of infected non-union of long bones.     

DBU mediated one-pot synthesis of triazolo triazines via Dimroth type rearrangement

Herein we report an efficient one-pot synthesis of [1,2,4]triazolo[1,5 a][1,3,5]triazines from commercially available substituted aryl/heteroaryl aldehydes and substituted 2-hydrazinyl-1,3,5-triazines via N-bromosuccinimide (NBS) mediated oxidative C–N bond formation. Isomerisation of [1,2,4]triazolo[4,3-a][1,3,5]triazines to [1,2,4]triazolo[1,5-a][1,3,5]triazines is driven by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) affording both isomers with good to excellent yields (70–96%).

We demonstrate a simple yet efficient one-pot synthesis of two triazolotriazine isomers via DBU mediated Dimroth type rearrangement with excellent yields.

Purines are nitrogen-containing heterocycles and are structural motifs in the nucleobases adenine and guanine of DNA as well as RNA. Purine nucleotides (ATP, GTP, cAMP, cGMP, NAD, FAD) also act as co-factors, substrates, or mediators in the functioning of numerous proteins.¹ Therefore, bioisosteres of purines are widely explored and exploited by pharmaceutical chemists in developing new drug entities. Heterocycles containig the 1,3,5-triazine ring act as bioisosteres of purine, which exist as two isomers, namely [1,2,4]triazolo[4,3-a][1,3,5]triazine and [1,2,4]triazolo[1,5-a][1,3,5]triazine (Fig. 1), which have been extensively studied as adenosine receptor antagonists,^2,3 as well as for other pharmacological activities^1,4,5 (Fig. 2). Literature reports suggest that [1,2,4]triazolo[1,5-a][1,3,5]triazine has been exploited extensively in drug discovery as compared to its corresponding isomer. Further, from the literature it is evident that symmetrical disubstituted triazines,^6–9 especially morpholine^10–12 substituted, have displayed broad pharmacological activities.Open in a separate windowFig. 1Structure of isomers of triazolo–triazine.Open in a separate windowFig. 2Biologically active molecules of [1,2,4]triazolo[4,3-a][1,3,5]triazine (1) and [1,2,4]triazolo[1,5-a][1,3,5]triazine (2, 3, 4).Various synthetic methods have been reported for the C–N bond formation by employing different starting materials^13–15via oxidative cyclisation,¹⁶ high temperature condition^17–19 and/or metal-catalysed reactions.²⁰ However, the current reported protocols were environmentally unfriendly as they suffered from drawbacks such as, multistep, and tedious procedures, use of carcinogenic solvents, high-temperature, expensive and toxic metal-catalysts, and other hazardous reagents.Furthermore, there is very less reported research on these heterocycles, and that can be because of the unavailability of the efficient and cheaper methods. Thus, there is a need to develop new versatile synthetic method for the synthesis of disubstituted triazolotriazine heterocycles of pharmacological interest.In 1970, for the first time Kobe²¹et al. (scheme a) reported the synthesis of [1,2,4]triazolo[4,3-a][1,3,5]triazine utilizing lead tetraacetate in benzene under reflux conditions (Fig. 3). However, no further Isomerization was carried out and resulted low to moderate yield. Deshpande²²et al. reported (scheme b) the reaction of 2-hydrazinyl-1,3,5-triazine with various substituted benzoic acids. The product formed was treated with P₂O₅, refluxed in xylene for 10h to yield [1,2,4]triazolo[4,3-a][1,3,5]triazine. Further, Isomerization of the resulting product was carried out in 2% methanolic-NaOH solution resulting in poor yields. Recently, Stefano²³et al. (scheme c) reported, a multistep protocol by reacting the intermediate with bis(methyl-sulfanyl)methylenecyanamide at 180 °C under N₂ for 3h resulting in low yield due to the formation of several side products. In addition no isomerization studies were carried out, and only the [1,2,4]triazolo[1,5-a][1,3,5]triazine analogs were reported.Open in a separate windowFig. 3Different approaches for the synthesis of triazolo triazines.Herein, we report an economical one-pot synthesis of [1,2,4]triazolo[1,5-a][1,3,5]triazine analogs via Dimroth type rearrangement of [1,2,4]triazolo[4,3-a][1,3,5]triazine derivatives. This one pot novel methodology was carried out by reacting readily available, inexpensive starting materials such as substituted aryl/heteroaryl benzaldehydes and substituted 2-hydrazinyl-1,3,5-triazine in methanol (a mild solvent)²⁴ at room temperature giving excellent yields of the desired product. For cyclization reaction, an eco-friendly reagent NBS²⁵ was used and the resulting product was treated with DBU to yield its corresponding desired isomer. To the best of our knowledge this is the first report for the greener synthesis of symmetric disubstituted triazolotriazine heterocycles via Dimroth type rearrangement. We believe that this simple, yet novel methodology could be further exploited by the researchers in pharmaceutical industries and academics settings in drug discovery.Formation of the Schiff base was initiated reacting 4,4′-(6-hydrazinyl-1,3,5-triazine-2,4-diyl)dimorpholine 1a and unsubstituted benzaldehyde as shown in

Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics

OBJECTIVE: Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D(4) receptors, serotonin 5-HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics. METHOD: Positron emission tomography with the radioligands [(11)C]SCH23390 and [(11)C]raclopride was used to investigate D(1) and D(2) receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone. RESULTS: Mean striatal D(1) occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D(2) occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D(1)/D(2) occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31). CONCLUSIONS: Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.