Morbidity Profile and Healthcare Service Utilization Pattern Among Geriatric Population in the Rural Himalayan Region of Uttarakhand, India: A Cross-Sectional Study.

OBJECTIVES: The increasing elderly population, along with their health problems, is a matter of concern, especially in the difficult terrains of the hilly Himalayan region of northern India. Hence, the present study was conducted to assess the healthcare-seeking behavior of the elderly and adherence to medication. METHODS: The present community-based cross-sectional study was conducted on 250 elderly participants by a consecutive sampling method. Data were collected during the months of July 2021 to October 2021 after obtaining institutional ethical clearance. Bivariate logistic regression was done to assess factors associated with healthcare services utilization patterns and adherence to medications in chronic diseases. Significant factors were then analyzed with a multivariate logistic regression model. Variables with p-value <0.05 on multivariate analysis were considered statistically significant. RESULTS: The mean age of the study participants was 67.2 (±8.09) years, and 52% were males. Chronic illness was diagnosed in 45.6% participants. Only 121 (48.4%) participants were aware of health insurance schemes among whom 95 (38%) were registered. Appropriate healthcare-seeking behavior for acute illness episodes was seen in 68.9% of participants. A government healthcare facility was the most preferred facility. Low adherence to chronic disease medication was seen in 41.2%. Participants registered under any health insurance scheme had higher adherence to medications (OR=0.36; 95% CI, 0.15-0.86; p-value=0.02). CONCLUSIONS: The majority of the participants preferred government healthcare facilities. Registration under any health insurance scheme was found to significantly influence adherence to medications. Further qualitative studies can be of paramount importance in understanding the perspectives of the geriatric population in the study area.

Innovative App (ExoDont) and Other Conventional Methods to Improve Patient Compliance After Minor Oral Surgical Procedures: Pilot, Nonrandomized, and Prospective Comparative Study.

BACKGROUND: Postoperative care is influenced by various factors such as compliance, comprehension, retention of instructions, and other unaccounted elements. It is imperative that patients adhere to the instructions and prescribed regimen for smooth and placid healing. ExoDont, an Android-based mobile health app, was designed to ensure a smooth postoperative period for patients after a dental extraction. Besides providing postoperative instructions at defined intervals, the app also sends drug reminders as an added advantage over other available, conventional methods. OBJECTIVE: The aim of this study was to compare the compliance rate of individuals with respect to the prescribed regimen and postoperative instructions. Additionally, we aimed to assess any changes in the postoperative complication rate of patients assigned to 3 categories: the verbal, verbal plus written, and ExoDont app-based delivery groups. METHODS: We conducted a pilot, nonrandomized, and prospective comparative study in which patients after tooth extraction were assigned to 3 groups-verbal (Group A), verbal plus written (Group B), and ExoDont app-based delivery (Group C)-based on the eligibility criteria, and a 1-week follow-up was planned to obtain the responses regarding compliance and postoperative complications from the participants. RESULTS: In total, 90 patients were recruited and equally divided into 3 groups. Compliance to prescribed drug was found to be the highest in Group C, where of the 30 participants, 25 (83%) and 28 (93%) followed the entire course of antibiotics and analgesics, respectively. For postoperative instructions, higher compliance was observed in Group C in relation to compliance to diet restrictions (P=.001), not rinsing for 24 hours (P<.001), and warm saline rinses after 24 hours (P=.001). However, the difference was not significant for smoking restrictions (P=.07) and avoiding alcohol (P=.16). Moreover, the difference in postoperative complication rate was not statistically significant among the 3 groups (P=.31). CONCLUSIONS: As evident from the results, it is anticipated that the ExoDont app will be helpful in circumventing the unaccounted possibilities of missing the prescribed dosage and postoperative instructions and ensuring the smooth recovery of patients after dental extraction. However, future studies are required to establish this app-based method of delivery of postoperative instructions as a viable option in routine clinical practice.

Characterization of 4-hydroxyphenylpyruvate dioxygenases, inhibition by herbicides and engineering for herbicide tolerance in crops.

4-Hydroxyphenylpyruvate dioxgenase (HPPD) enzymes from rat and from several plants contained only about a single inhibitor-binding active site per dimer which matched the content of iron in the purified Arabidopsis thaliana and Avena sativa enzymes. The dimeric HPPDs were about 10 fold more catalytically active than the tetrameric P. fluorescens enzyme with kcat/KmHPP values ranging from 0.8 to 2.5 s-1 µM-1. Most were also highly sensitive to herbicides with, for example, Ki values for mesotrione ranging from 25 to 100 pM. Curiously HPPDs from cool climate grasses were much less herbicide-sensitive. When likewise expressed in Nicotinia tabacum, Avena sativa HPPD, Ki value of 11 nM for mesotrione, conferred far greater tolerance to mesotrione (CallistoTM) than did any of the more sensitive HPPDs. Targeted mutagenesis of the Avena HPPD led to the discovery of 4 mutations imparting improved inherent tolerance, defined as the ratio of Ki to KmHPP, by about 16 fold without any loss of catalytic activity. The Nicotinia line with the highest expression of this quadruple mutant exhibited substantial resistance even up to a 3 kg/ha post-emergence application of mesotrione. The maximum observed expression level of heterologous plant HPPDs in tobacco was ca. 0.35% of the total soluble protein whereas the endogenous tobacco HPPD constituted only ca. 0.00075%. At such high expression even HPPDs with impaired catalytic activity could be effective. A quintuple mutant Avena sativa HPPD conferred substantial tolerance across a broad range of HPPD herbicide chemistries despite being only ca. 5 % as catalytically active as the wild type enzyme. Testing various wild type and mutant HPPDs in tobacco revealed that tolerance to field rates of herbicide generally requires about two order of magnitude increases in both inherent herbicide tolerance and expression relative to endogenous levels. This double hurdle may explain why target-site based resistance to HPPD-inhibiting herbicides has been slow to evolve in weeds.

Preparation and preliminary evaluation of novel beta-cyclodextrin/IUDR prodrug formulations.

PURPOSE: Iododeoxyuridine (IUdR) has a very short in vivo half-life and consequently achieves low target-tissue concentrations with concomitant lower efficacy than would be predicted from in vitro studies. This work reports the preparation of IUdR:beta-cyclodextrin (beta-CyD) inclusion complexes designed to reduce in vivo inactivation of IUdR. METHODS: IUdR was derivatized with either 1-adamantanecarbonyl chloride or 4-(1-adamantyl-carbamoyl)butanoic acid, to prepare 5'-O-(1-adamantoyl)-5-iodo-2'-deoxyuridine 1 and 5'-O-(4-(1-adamantylcarbamoyl)butoyl)-5-iodo-2'-deoxy-uridine 4, respectively. beta-CyD complexes 5 and 6 were formed by vigorous stirring of 1:1 solutions of beta-CyD and 1 or 4, respectively, in D2O under argon. Complexation was inferred from DSC, powder x-ray diffractometry and NMR spectrometry. The dissociation of 5 in water and under cholesterol challenge, and the effect of complexation on the stability of 1 was determined by incubation in plasma. RESULTS: IUdR coupling with adamantanecarbonyl chloride proceeded smoothly to afford 1 (69 %) and the di-substituted derivative, 3',5'-di-O-(1-adamantoyl)-5-iodo-2'-deoxyuridine 2 (8 %); 4 was obtained in 42 % yield. The formation of 1:1 complexes 5 and 6 was inferred from NMR chemical shift data. In serum, 1 was 90 % hydrolyzed to IUdR in 30 min, compared to 10 % hydrolysis of 1 to IUdR when from complex 5. CONCLUSIONS: Inclusion complexes were formed between beta-CyD and adamantamine-IUdR conjugates at 1:1 molar ratios. The complex 5 was resistant to dissociation by cholesterol challenge, and 5 was more slowly converted to IUdR than non-complexed 1. In vivo studies are required to further exploit the beta-CyD inclusion complex approach for improved delivery of nucleoside derivatives.

Crystal structure of the retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture.

The retinoblastoma susceptibility protein, Rb, has a key role in regulating cell-cycle progression via interactions involving the central "pocket" and C-terminal regions. While the N-terminal domain of Rb is dispensable for this function, it is nonetheless strongly conserved and harbors missense mutations found in hereditary retinoblastoma, indicating that disruption of its function is oncogenic. The crystal structure of the Rb N-terminal domain (RbN), reveals a globular entity formed by two rigidly connected cyclin-like folds. The similarity of RbN to the A and B boxes of the Rb pocket domain suggests that Rb evolved through domain duplication. Structural and functional analysis provides insight into oncogenicity of mutations in RbN and identifies a unique phosphorylation-regulated site of protein interaction. Additionally, this analysis suggests a coherent conformation for the Rb holoprotein in which RbN and pocket domains directly interact, and which can be modulated through ligand binding and possibly Rb phosphorylation.

Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1.

Client protein activation by Hsp90 involves a plethora of cochaperones whose roles are poorly defined. A ubiquitous family of stress-regulated proteins have been identified (Aha1, activator of Hsp90 ATPase) that bind directly to Hsp90 and are required for the in vivo Hsp90-dependent activation of clients such as v-Src, implicating them as cochaperones of the Hsp90 system. In vitro, Aha1 and its shorter homolog, Hch1, stimulate the inherent ATPase activity of yeast and human Hsp90. The identification of these Hsp90 cochaperone activators adds to the complex roles of cochaperones in regulating the ATPase-coupled conformational changes of the Hsp90 chaperone cycle.

Regulation of Hsp90 ATPase activity by the co-chaperone Cdc37p/p50cdc37.

In vivo activation of client proteins by Hsp90 depends on its ATPase-coupled conformational cycle and on interaction with a variety of co-chaperone proteins. For some client proteins the co-chaperone Sti1/Hop/p60 acts as a "scaffold," recruiting Hsp70 and the bound client to Hsp90 early in the cycle and suppressing ATP turnover by Hsp90 during the loading phase. Recruitment of protein kinase clients to the Hsp90 complex appears to involve a specialized co-chaperone, Cdc37p/p50(cdc37), whose binding to Hsp90 is mutually exclusive of Sti1/Hop/p60. We now show that Cdc37p/p50(cdc37), like Sti1/Hop/p60, also suppresses ATP turnover by Hsp90 supporting the idea that client protein loading to Hsp90 requires a "relaxed" ADP-bound conformation. Like Sti1/Hop/p60, Cdc37p/p50(cdc37) binds to Hsp90 as a dimer, and the suppressed ATPase activity of Hsp90 is restored when Cdc37p/p50(cdc37) is displaced by the immunophilin co-chaperone Cpr6/Cyp40. However, unlike Sti1/Hop/p60, which can displace geldanamycin upon binding to Hsp90, Cdc37p/p50(cdc37) forms a stable complex with geldanamycin-bound Hsp90 and may be sequestered in geldanamycin-inhibited Hsp90 complexes in vivo.