Tau-aggregation inhibition: promising role of nanoencapsulated dietary molecules in the management of Alzheimer's disease.

Alzheimer's disease (AD) is a cumulative form of dementia associated with memory loss, cognition impairment, and finally leading to death. AD is characterized by abnormal deposits of extracellular beta-amyloid and intracellular Tau-protein tangles throughout the brain. During pathological conditions of AD, Tau protein undergoes various modifications and aggregates over time. A number of clinical trials on patients with AD symptoms have indicated the effectiveness of Tau-based therapies over anti-Aß treatments. Thus, there is a huge paradigm shift toward Tau aggregation inhibitors. Several bioactives of plants and microbes have been suggested to cross the neuronal cell membrane and play a crucial role in managing neurodegenerative disorders. Bioactives mainly act as active modulators of AD pathology besides having antioxidant and anti-inflammatory potential. Studies also demonstrated the potential role of dietary molecules in inhibiting the formation of Tau aggregates and removing toxic Tau. Further, these molecules in nonencapsulated form exert enhanced Tau aggregation inhibition activity both in in vitro and in vivo studies suggesting a remarkable role of nanoencapsulation in AD management. The present article aims to review and discuss the structure-function relationship of Tau protein, the post-translational modifications that aid Tau aggregation and potential bioactives that inhibit Tau aggregation.

More and more of less and less: Is genomics-based breeding of dry direct-seeded rice (DDSR) varieties the need of hour?

Rice is a staple food for half of the world's population. Changing climatic conditions, water and labour scarcity are the major challenges that shall limit future rice production. Dry direct-seeded rice (DDSR) is emerging as an efficient, resources conserving, mechanized, climate smart and economically viable strategy to be adopted as an alternative to puddled transplanted rice (TPR) with the potential to address the problem of labour-water shortages and ensure sustainable rice cultivation. Despite these benefits, several constraints obstruct the adoption of DDSR. In principle, the plant type for DDSR should be different from one for TPR, which could be achieved by developing rice varieties that combine the traits of upland and lowland varieties. In this context, recent advances in precise phenotyping and NGS-based trait mapping led to identification of promising donors and QTLs/genes for DDSR favourable traits to be employed in genomic breeding. This review discusses the important traits influencing DDSR, research studies to clarify the need for breeding DDSR-specific varieties to achieve enhanced grain yield, climate resilience and nutrition demand. We anticipate that in the coming years, genomic breeding for developing DDSR-specific varieties would be a regular practice and might be further strengthened by combining superior haplotypes regulating important DDSR traits by haplotype-based breeding.

Hydroxyl radical induced oxidation of theophylline in water: a kinetic and mechanistic study.

Oxidative destruction and mineralization of emerging organic pollutants by hydroxyl radicals (˙OH) is a well established area of research. The possibility of generating hazardous by-products in the case of ˙OH reaction demands extensive investigations on the degradation mechanism. A combination of pulse radiolysis and steady state photolysis (H2O2/UV photolysis) followed by high resolution mass spectrometric (HRMS) analysis have been employed to explicate the kinetic and mechanistic features of the destruction of theophylline, a model pharmaceutical compound and an identified pollutant, by ˙OH in the present study. The oxidative destruction of this molecule, for intermediate product studies, was initially achieved by H2O2/UV photolysis. The transient absorption spectrum corresponding to the reaction of ˙OH with theophylline at pH 6, primarily caused by the generation of (T8-OH)˙, was characterised by an absorption band at 330 nm (k2 = (8.22 ± 0.03) × 10(9) dm(3) mol(-1) s(-1)). A significantly different spectrum (λmax: 340 nm) was observed at highly alkaline pH (10.2) due to the deprotonation of this radical (pKa∼ 10.0). Specific one electron oxidants such as sulphate radical anions (SO4˙(-)) and azide radicals (N3˙) produce the deprotonated form (T(-H)˙) of the radical cation (T˙(+)) of theophylline (pKa 3.1) with k2 values of (7.51 ± 0.04) × 10(9) dm(3) mol(-1) s(-1) and (7.61 ± 0.02) × 10(9) dm(3) mol(-1) s(-1) respectively. Conversely, oxide radicals (O˙(-)) react with theophylline via a hydrogen abstraction protocol with a rather slow k2 value of (1.95 ± 0.02) × 10(9) dm(3) mol(-1) s(-1). The transient spectral studies were complemented by the end product profile acquired by HRMS analysis. Various transformation products of theophylline induced by ˙OH were identified by this technique which include derivatives of uric acids (i, iv & v) and xanthines (ii, iii & vi). Further breakdown of the early formed product due to ˙OH attack leads to ring opened compounds (ix-xiv). The kinetic and mechanistic data furnished in the present study serve as a basic frame work for the construction of ˙OH induced water treatment systems as well as to understand the biological implications of compounds of this kind.

Assessment of acute and subacute toxicity, pharmacokinetics, and biodistribution of eugenol nanoparticles after oral exposure in Wistar rats.

The present study aimed to assess the safety, toxicity, biodistribution, and pharmacokinetics of eugenol nanoparticles (EONs) following oral administration in Wistar rat models. In the acute toxicity study, the rats were given a fixed dose of 50, 300, and 2000 mg/kg body weight per group orally and screened for 2 weeks after administration. In the subacute study, three different doses (500, 1000, and 2000 mg/kg BW) of EON were administered for 28 days. The results indicated no significant differences in food and water consumption, bodyweight change, hematological and biochemical parameters, relative organ weights, gross findings, or histopathology compared to the control. Additionally, no significant changes were observed in the expression profiles of inflammatory cytokines such as IL-1, IL-6, and TNFα in the plasma, confirming the absence of systemic inflammation. Biodistribution analysis revealed rapid absorption of eugenol and improved bioavailability due to gradual and sustained release, leading to a maximum eugenol concentration of 15.05 µg/mL (Cmax) at approximately 8 h (Tmax) in the blood plasma. Thus, the study provides valuable insights into the utilization of EON for enhancing the stability, solubility, and sustained release of eugenol and highlights its promising safety profile in vivo.

Improvement of dissolution behavior of poorly water soluble drugs by biodegradable polymeric submicron carriers containing sparingly methylated ß-cyclodextrin.

The objective of this study was to develop submicron carriers of two drugs that are practically insoluble in water, i.e. meloxicam and aceclofenac, to improve their dissolution behavior. The phase solubility of the drugs was studied using different concentrations of sparingly methylated ß-cyclodextrin, Kleptose(®) Crysmeß (Crysmeb), in the presence and absence of 0.2 % w/v water-soluble chitosan. Drug-loaded submicron particles (SMPs) were prepared using chitosan chlorhydrate and Crysmeb by the ionotropic gelation method. The SMPs were characterized in terms of powder X-ray diffraction, Fourier transforms infrared spectroscopy, size determination, process yield, drug loading, encapsulation efficiency, surface morphology and in vitro release. The drug loading in the SMPs was enhanced in the presence of Crysmeb. The in vitro drug release was found to be enhanced with SMPs prepared using higher concentrations of Crysmeb. These results indicate that SMPs formed from chitosan chlorhydrate and Crysmeb are promising submicron carriers for enhancing the dissolution of meloxicam and aceclofenac.

Amyloid-ß-Derived Peptidomimetics Inhibits Tau Aggregation.

The aggregation of tau protein is one of the hallmarks for Alzheimer's disease, resulting in neurodegeneration. The peptidomimetics strategy to prevent tau aggregation is more specific over other small molecules. In the present study, we analyzed the effect of amyloid-ß-derived peptidomimetics for inhibiting heparin-induced tau aggregation in vitro. These peptides and their derivatives were known to prevent aggregation of amyloid-ß. KLVFF is a hydrophobic sequence of the pentapeptide that prevented tau aggregation as observed by thioflavin S fluorescence, transmission electron microscopy, and circular dichroism spectroscopy. P4 and P5 also prevented assembly of tau into aggregates and formed short fibrils. The ß-sheet breaker LPFFD was however ineffective in preventing tau aggregation. The peptides further demonstrated reversal of tau-induced cytotoxicity in a dose-dependent manner. Our results suggested that these peptides can also be used to inhibit tau aggregation and also, toxicity induced by tau could be considered as potential molecules that have an effect on tau as well as amyloid-ß.

Influence of sodium caseinate, maltodextrin, pectin and their Maillard conjugate on the stability, in vitro release, anti-oxidant property and cell viability of eugenol-olive oil nanoemulsions.

The influence of protein (sodium caseinate-SC), polysaccharide (maltodextrin-MD; pectin-PC) and their Maillard conjugates (sodium caseinate maltodextrin conjugate-SCMDC; sodium caseinate pectin conjugate-SCPCC) were studied on the physico-chemical and biological properties of eugenol nanoemulsions/powder. The chemical composition was optimized using Taguchi design. The particles size of eugenol nanoemulsions with SC, MD, PC, SCMDC and SCPCC were 104.6, 323.5, 1872, 181.7, and 454.4 nm, respectively while their zeta potentials were -31.2, -28.5, -21.4, -40.1 and -25.1 mV, respectively. Turbidity studies revealed higher stability of nanoemulsion prepared with Maillard conjugate (SCMDC) compared to protein or polysaccharides alone. The dispersion of SCMDC eugenol nanoparticles in buffer was prepared to study its stability at different pH (3.0, 5.0, and 7.0) and temperature (4°, 37°, 60 °C) range. In-vitro enzymatic release study showed 31 and 74% release of eugenol after 6 h at pH 2.4 and 7.4, respectively. In vitro antioxidant capacity of SCMDC encapsulated eugenol was higher than native eugenol, as demonstrated by free radical scavenging assays. In comparison to native eugenol, E:SCMDC eugenol showed reduced toxicity. These findings suggested that nanoencapsulated eugenol (E:SCMDC) have a huge potential in nutraceutical and therapeutic applications.

Unusual methods of suicide: complexities in investigation.

Differentiation between suicide and homicide often becomes difficult owing to the unusual methods of suicide used by the victim and the complexities thus posed. Investigating the cases of unusual suicides provides a considerable challenge to the authorities concerned. The issue of homicide should often be ruled out in such cases, which require careful evaluation. This is best done by correlating the morbid anatomical findings at autopsy with the death scene analysis coupled with psychological autopsy. Many forensic practitioners have reported unusual methods of suicide at their respective workplaces. Various types of unusual methods of suicide and the complexities involved in their investigation are presented and discussed.

Congenital insensitivity to pain in a 1-year-old boy.

Congenital insensitivity to pain (CIP) is a rare autosomal recessive genetic condition which causes reduced pain sensation, thermal sensation, and habit of self-mutilation. It is a life-threatening condition where due to reduced pain sensation, patient might not understand the severity of the injury which can eventually lead to death. Such people live a compromised life and can also affect them psychologically. Here, we are reporting a case of an infant with clinical features suggestive of CIP with a mutation in exon 5 of PRDM12 gene. The child has minimal response to pain along with self-mutilation and mental retardation.

Severe caudal regression syndrome with overlapping features of VACTERL complex: antenatal detection and follow up.

Caudal regression is a rare syndrome with a spectrum of structural defects involving multiple organ systems. Spinal anomalies, a charecteristic feature of the entity, can vary from isolated partial agenesis of the coccyx to lumbosacral agenesis with involvement of the thoracic spine in the most severe cases. The aetiology of this syndrome is not well-known. Maternal diabetes, genetic predisposition and vascular hypoperfusion have been suggested as possible causative factors. Severe forms of the disease are commonly associated with cardiac, renal and respiratory problems with overlapping feature of VACTERL complex (vertebral, anorectal, cardiac, tracheoesophageal, renal and limb anomalies). In this case report, we describe imaging appearances of severe caudal regression syndrome, VACTERL complex associated with multisystem anomalies, detected on a screening antenatal scan during second trimester. Some unusual features of the syndrome including sternal anomaly and absent bony hemithorax are highlighted.

Ambras syndrome: A rare case report.

Congenital generalized hypertrichosis associated with gingival hyperplasia are rare cases published in literature. The frequency incidence of generalized congenital hypertrichosis is about one to billions of people. Hypertrichosis and gingival hyperplasia are termed as Ambras syndrome (AS), which can be noticed at birth or soon after. Here, is a rare case report of 4-year-old male child who presented with generalized hypertrichosis with gingival fibromatosis and dysmorphic facial features.

Late relapse of testicular germ cell tumors.

The successful multidisciplinary approach for the management of germ cell tumors of the testis has resulted in survival rates of greater than 90% overall. While the majority of relapses in patients with germ cell tumors occur within the first 2 years of treatment, the incidence of late relapse beyond 2 years has been increasing over recent years. The pattern of late relapse suggests that an inadequately controlled retroperitoneum is a major predisposing factor, with up to 80% of late relapses occurring in the retroperitoneum. These tumors tend to be chemorefractory and overall prognosis for patients with late relapse of germ cell tumors is relatively poor, with survival rates of approximately 30% to 40%. In this review, we present the recent data regarding the clinical presentation, patterns of relapse, histologic findings, appropriate treatment options, and outcomes for men with late relapse of germ cell tumors.

Oxidative degradation of fensulfothion by hydroxyl radical in aqueous medium.

Oxidative degradation of fensulfothion, a model organophosphorus compound, has been investigated by pulse radiolysis and H2O2/UV photolysis. A nearly complete transformation of fensulfothion was observed within 4min of irradiation. Very little Total Organic Carbon (TOC) reduction was obtained at this time scale. When the product studies at this stage were conducted using LC-MS/MS analyses, nearly 20 transformation products were obtained. The entire products were identified as from the reaction of OH with fensulfothion or with some of its initially transformed products. Nearly 80% reduction in TOC was observed when photolysis was conducted using higher concentrations of H2O2 at longer time scale. A reaction rate constant (bimolecular) of 1.10×10(10)dm(3)mol(-1)s(-1) was obtained for the reaction of OH with fensulfothion using pulse radiolysis technique. The transient absorption spectrum obtained from the reaction of OH has a maximum at 280nm and a weak, broad maximum around 500nm along with a small shoulder around 340nm. The intermediate spectrum is assigned to the radical cation of fensulfothion (3) and the hydroxyl radical adducts (1 and 2). This assignment is supported by the intermediate spectrum (λmax at 280nm) from the reaction of sulfate radical anion (SO4(-)) (k2=3.20×10(9)dm(3)mol(-1)s(-1)) which is a one electron oxidant. It is thus demonstrated that the combination of both pulse radiolysis and the product estimation using LC-MS/MS is ideal in probing the complete mechanism which is very important in the mineralization reactions using Advanced Oxidation Processes.

Outcome of very low birth weight infants with abnormal antenatal Doppler flow patterns: a prospective cohort study.

BACKGROUND: Fetal growth restriction and abnormal Doppler flow studies are commonly associated. Neonatal outcomes are not well known particularly in developing countries, where the burden of the disease is the highest. OBJECTIVE: To determine outcomes of preterm infants with history of absent/reversed end-diastolic umbilical artery Doppler flow (AREDF) vs. infants with forward end-diastolic flow (FEDF). DESIGN: Cohort study. SETTING: Tertiary care perinatal center in India. PARTICIPANTS: 103 AREDF very low birth weight (<1500 gm) (VLBW) infants and 117 FEDF VLBW infants were prospectively enrolled. RESULTS: At 40 weeks adjusted post-menstrual age, AREDF vs. FEDF group had a higher risk for death in the NICU (12% vs. 1%), respiratory distress syndrome (33% vs. 19%), and cystic periventricular leukomalacia (12% vs. 1%). At 12-18 months corrected age, AREDF vs. FEDF group had a trend towards increased risk for cerebral palsy (7% vs. 1%, P=0.06). After logistic regression analysis, adjusting for confounders, AREDF was independently associated only with mortality in the NICU. CONCLUSIONS: AREDF is an independent predictor of adverse outcomes in preterm infants in a developing country setting.

Analgesic efficacy of diazepam and placebo in patients with temporomandibular disorders: a double blind randomized clinical trial.

AIM: The aim of the study was to evaluate and compare the analgesic efficacy of placebo and diazepam in patients with temporomandibular disorder. MATERIALS AND METHODS: Thirty-five patients were recruited with a diagnosis of temporomandibular disorder based on standard clinical diagnostic criteria for temporomandibular disorder. The patients were put in to one of the two groups: placebo or diazepam at random. The average pain intensity was recorded with visual analog scale (VAS) at pretreatment, at weekly interval till the completion of a three-week trial and at post-treatment visit on the eighth week from baseline. The secondary outcome measures were changes in masticatory muscle tenderness, viz. massater muscle, lateral pterygoid muscle, medial pterygoid muscle and temporalis muscle and changes in mouth opening. STATISTICAL ANALYSIS: Intra-group comparison for analgesic efficacy and mouth opening was carried out by Wilcoxon's signed ranked test. Inter-group comparison for analgesic efficacy was also carried out using Mann-Whitney's test. RESULTS: A statistically significant (P<0.01) decrease in temporomandibular disorder pain in the placebo group (65%) and statistically highly significant (P<0.001) decrease in the diazepam group (72%) were observed on VAS after three weeks of treatment. The inter-group comparison demonstrated no statistically significant difference between the groups. CONCLUSION: This study suggests that the placebo can give near similar results as diazepam can. So the role of placebo should also be considered as one of the important management strategies. In the short term, reduction in the masticatory muscle tenderness and significant improvement in the mouth opening in both the groups were observed.

Reaction of hydroxyl radicals with azacytosines: a pulse radiolysis and theoretical study.

Pulse radiolysis and density functional theory (DFT) calculations at B3LYP/6-31+G(d,p) level have been carried out to probe the reaction of the water-derived hydroxyl radicals (*OH) with 5-azacytosine (5Ac) and 5-azacytidine (5Acyd) at near neutral and basic pH. A low percentage of nitrogen-centered oxidizing radicals, and a high percentage of non-oxidizing carbon-centered radicals were identified based on the reaction of transient intermediates with 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate), ABTS2-. Theoretical calculations suggests that the N3 atom in 5Ac is the most reactive center as it is the main contributor of HOMO, whereas C5 atom is the prime donor for the HOMO of cytosine (Cyt) where the major addition site is C5. The order of stability of the adduct species were found to be C6-OH_5Ac*>C4-OH_5Ac*>N3-OH_5Ac*>N5-OH_5Ac* both in the gaseous and solution phase (using the PCM model) respectively due to the additions of *OH at C6, C4, N3, and N5 atoms. These additions occur in direct manner, without the intervention of any precursor complex formation. The possibility of a 1,2-hydrogen shift from the C6 to N5 in the nitrogen-centered C6-OH_5Ac* radical is considered in order to account for the experimental observation of the high yield of non-oxidizing radicals, and found that such a conversion requires activation energy of about 32 kcal/mol, and hence this possibility is ruled out. The hydrogen abstraction reactions were assumed to occur from precursor complexes (hydrogen bonded complexes represented as S1, S2, S3, and S4) resulted from the electrostatic interactions of the lone pairs on the N3, N5, and O8 atoms with the incoming *OH radical. It was found that the conversion of these precursor complexes to their respective transition states has ample barrier heights, and it persists even when the effect of solvent is considered. It was also found that the formation of precursor complexes itself is highly endergonic in solution phase. Hence, the abstraction reactions will not occur in the present case. Finally, the time dependent density functional theory (TDDFT) calculations predicted an absorption maximum of 292 nm for the N3-OH_5Ac* adduct, which is close to the experimentally observed spectral maxima at 290 nm. Hence, it is assumed that the addition to the most reactive center N3, which results the N3-OH_5Ac* radical, occurs via a kinetically driven process.

Modifying provider behavior: a low-tech approach to pharmaceutical ordering.

OBJECTIVE: To determine if a clinically structured, paper-based prescription form can modify pharmaceutical prescribing behavior without restricting physician freedom to select the most appropriate medication for an individual patient. DESIGN: Uncontrolled, nonrandomized, time series design. SETTING: The urgent care clinic of a university-affiliated, county-supported hospital that provides care for underserved, vulnerable populations. PATIENTS: Patients (N = 2189) who had a prescription written at the intervention site during the study. INTERVENTION: Four-phase interventions lasting 2 weeks each, with a washout period between each phase, consisting of: (1). collection of baseline data utilizing the traditional prescription blank, (2). introduction of the pre-formatted prescription form, (3). use of the pre-formatted prescription form with medication cost added, and (4). pre-formatted prescription form with target drug (ranitidine) removed. MEASUREMENTS AND MAIN RESULTS: Physicians were less likely to prescribe ranitidine compared to cimetidine after the introduction of the cost information (P <.01) and again after the removal of ranitidine from the pre-formatted prescription form (P <.001). CONCLUSIONS: A structured, paper-based prescription order form can shift prescribing practices without inhibiting physicians' ordering freedom.