TMBIM6 regulates redox-associated posttranslational modifications of IRE1α and ER stress response failure in aging mice and humans.

Age-associated persistent ER stress is the result of declining chaperone systems of the ER that reduces cellular functions, induces apoptosis, and leads to age-related diseases. This study investigated the previously unknown regulatory mechanism of TMBIM6 during age-associated hepatic abnormalities. Wild-type (WT) and the TMBIM6 knockout (TMBIM6-/-) mice liver, human liver samples from different age groups were used to demonstrate the effect of physiological aging on liver. For TMBIM6 rescue experiments, TMBIM6-/- old mice and stable human hepatic cell lines expressing TMBIM 6 were used to study the functional role of TMBIM6 on aging-associated steatosis and its associated mechanisms. In aging humans and mice, we observed declined expression of TMBIM6 and aberrant UPR expression, which were associated with high hepatic lipid accumulation. During aging, TMBIM6-deficient mice had increased senescence than their WT counterparts. We identified redox-mediated posttranslational modifications of IRE1α such as S-nitrosylation and sulfonation were higher in TMBIM6-deficient aging mice and humans, which impaired the ER stress response signaling. Sulfonation of IRE1α enhanced regulated IRE1α-dependent decay (RIDD) activity inducing TMBIM6 decay, whereas S-nitrosylation of IRE1α inhibited XBP1 splicing enhancing the cell death. Moreover, the degradation of miR-338-3p by strong IRE1α cleavage activity enhanced the expression of PTP1B, resulting in diminishing phosphorylation of PERK. The re-expression of TMBIM6 reduced IRE1α modifications, preserved ER homeostasis, reduced senescence and senescence-associated lipid accumulation in human hepatic cells and TMBIM6-depleted mice. S-nitrosylation or sulfonation of IRE1α and its controller, the TMBIM6, might be the potential therapeutic targets for maintaining ER homeostasis in aging and aging-associated liver diseases.

Agreement Between Non-Invasive (Oscillatory) and Invasive Intra-Arterial Blood Pressure in the Pediatric Cardiac Critical Care Unit.

OBJECTIVE: We assessed the agreement between non-invasive (oscillatory) blood pressure (NIBP) measurements and invasive intra-arterial blood pressure (IBP) in the pediatric cardiac critical care unit. METHODS: Children with intra-arterial lines as per standard management protocol were enrolled. NIBP was measured every 4 hourly and the corresponding IBP reading was recorded. RESULTS: A total of 839 brachial NIBP, 834 IBP femoral (IF), and 137 IBP radial (IR) readings were noted on 45 participants. The mean difference (95% CI) for agreement between NIBP and IF was -2.3 (-27.1, 22.5) mmHg for systolic, 0.9 (-21.3, 23.1) mmHg for diastolic and 0.3 (-23.3, 23.9) mmHg for mean BP. Similar results were found between NIBP and IR and between IF and IR. The interrater agreement [Kappa (95% CI)] was fair between NIBP and IF [0.54 (0.48, 0.61)], and IF and IR [0.62 (0.48, 0.76)] but lower between NIBP and IR [0.37(0.20, 0.55)] when values were classified as hypotensive, normotensive, and hypertensive. CONCLUSIONS: NIBP cannot replace but can supplement IBP in the pediatric cardiac critical care setting.

Chalcone suppresses tumor growth through NOX4-IRE1α sulfonation-RIDD-miR-23b axis.

Chalcone is a polyphenolic compound found abundantly in natural plant components. They have been acclaimed as potential antitumor compounds in multiple tumor cells. However, not much attention has been paid to elucidate its antitumor mechanism of action. Here, chalcone was demonstrated to trigger endoplasmic reticulum (ER) stress-induced apoptosis through sulfonation of IRE1α by ER-localized NADPH oxidase 4 (NOX4). IRE1α-sulfonation at a cysteine residue was shown to induce "regulated IRE1α-dependent decay" (RIDD) of mRNA rather than specific splicing of XBP1. The IRE1α sulfonation-induced RIDD degraded miR-23b, enhancing the expression of NOX4. The expression of NOX4 was also upregulated in breast, and prostate cancer tissue. In chalcone-administered mice in vivo, tumor growth was regressed by the consistent mechanisms "NOX4-IRE1α sulfonation-RIDD". Similarly, NOX4 activation and IRE1α sulfonation were also highly increased under severe ER stress conditions. Together, these findings suggest chalcone as a lead anticancer compound where it acts through NOX4-IRE1α-RIDD-miR-23b axis providing a promising vision of chalcone derivatives' anticancer mechanism.

Molecular structure and quantum descriptors of cefradine by using vibrational spectroscopy (IR and Raman), NBO, AIM, chemical reactivity and molecular docking.

This study aims to investigate the structural and vibrational features of cefradine (the first-generation cephalosporin antibiotic) based on spectroscopic experiments and theoretical quantum chemical approach. The fundamental structural aspects of cefradine have been examined based on optimized geometry, spectroscopic behavior, intermolecular interaction, chemical reactivity, intramolecular hydrogen bonding, and molecular docking analysis. The most stable minimum energy conformer of the title molecule was identified by performing a one-dimensional potential energy surface scan along the rotational bonds at B3LYP/6-311++G (d,p) level of theory. The vibrational features of the molecule and information about the coupled modes were predicted. The chemical reactivity and stability of all the possible conformers of cefradine were estimated based on the HOMO-LUMO energy gap and NBO approach. The overall picture of accumulation of charges on individual atoms of the molecule was predicted by molecular electrostatic potential (MEP) surface map which in turn identifies the nucleophilic and electrophilic region or sites. The quantitative analysis of electrophilicity and nucleophilicity indices was done by Hirshfeld charge analysis and it was found that N8 atom is the most prominent site for nucleophilic attack while C14 atom is feasible for electrophilic attack. QTAIM study has also been performed to investigate the nature and strength of hydrogen bonding interactions. Besides, molecular docking studies were performed to examine the active binding residues of the target.

Granular Cell Tumor of Female Urethra - the Second Such Reported Case.

Granular cell tumors are very uncommon tumor specially in female urethra. In the literature, there has been only one case reported so far. Here we describe our experience with this very rare entity in a case of a 26-year-old female patient with granular cell tumor of urethra with its clinical and histopathological findings.

Endoplasmic Reticulum (ER) Stress Response Failure in Diseases.

Recent work provides evidence for the new terminology, 'endoplasmic reticulum (ER) stress response or sensing failure', in relation to metabolic disease. We seek to identify and amass possible conditions of ER stress response failure in various metabolic and age-related pathogenesis, including obesity and diabetes.

Local complications of intravenous access - an often underestimated entity.

CONTEXT: Obtaining intravenous (IV) access is one of the very frequent invasive procedures performed in hospital care settings. This has several complications some of which are serious in nature. However, the incidence and seriousness of these complications as well as the burden of this complication on patient management are often underestimated. Identification of susceptible patients and the risk factors are important to ensure better outcomes. AIMS: The aim of this study was to document the various local complications of intravenous access and to identify the risk factors associated with it. SETTINGS AND DESIGN: Prospective observational study with three hundred and one surgical patients. Study duration of 1 year. METHODS AND MATERIAL: Indication of IV access, site, size of IV cannula used, category of personnel involved as well as local complications at access site were documented. Dressing at cannula site were changed every 72 h or earlier. Cannula and site of access were changed in case of any complication. STATISTICAL ANALYSIS USED: Results analysed using SPSS software (IBM Inc). Frequency calculated as average and percentage. Chi-square test used for statistical significance. Relative risk calculated. RESULTS: Females, overweight, diabetics and smokers were found at more risk. Requirement of major surgery, IV access by paramedical personnel, IV access over joints and when kept beyond 3 days were found to have more complications. 5.7% of patients had serious complications requiring surgical intervention. CONCLUSIONS: Our study shows that local complications at IV access site are very common with occurrence in more than fifty percent patients. Several risk factors are identified. Not all demographic and clinical risk factors are readily modifiable. However many of the complications can easily be minimized by following basic precautions.

Hyperhidrosis Prevalence: A Disease Underreported by Patients and Underdiagnosed by Physicians.

BACKGROUND: Hyperhidrosis (HH) is a disorder characterized by excessive sweating beyond required for normal thermoregulation, as a result of the excessive functioning of the sudomotor sweat control system. HH is broadly classified into 2 categories: primary HH and secondary. Our aim was to study the prevalence of HH in patients attending dermatological outpatients. METHODS: Randomly selected 832 attendees of dermatology outpatient department were requested to fill out a questionnaire for their presenting concerns to attend, the demography information (age, gender, and occupation), and presence of excessive visible sweating symptoms after the informed, written, and understood consent. This questionnaire was then evaluated by the researchers. And those who had a history of excessive sweating were evaluated in detail about HH by another questionnaire. RESULTS: The overall prevalence of HH was 17.9% (149/832), whereas only self-reported prevalence was 10.2% (85/832) in the dermatology outpatients. Of 149 patients, 110 (73.8%) were of primary HH followed by 39 (26.2%) of secondary HH. CONCLUSION: This study showed a higher prevalence of HH in the attendees of dermatology outpatients of a tertiary care center but estimates that this disease affects a much larger proportion of individuals in the Nepalese population.

Invertebrate and vertebrate models in aging research.

Therapeutic interventions that can delay age associated diseases and ensure a longer health-span is a major goal of aging research. Consequent to understanding that aging is a modifiable trait, a large number of studies are currently being undertaken to elucidate the mechanism(s) of the aging process. Research on human aging and longevity is difficult, due to longer time frame, ethical concerns and environmental variables. Most of the present day understanding about the aging process comes through studies conducted on model organisms. These provide suitable platforms for understanding underlying mechanism(s) which control aging and have led to major discoveries that emphasize the evolutionarily conserved molecular pathways as key players that respond to extra and intracellular signals. This is a review of various invertebrate and vertebrate models including yeast, Drosophila, C. elegans, rodents, naked mole rat, and birds, currently used in aging research with emphasis on how well they can mimic aging in higher animals and humans.

Cardiovascular Changes Due to Dental Anxiety During Local Anesthesia Injection for Extraction.

AIM OF THE STUDY: The present study evaluated the cardiovascular changes related to anxiety of the patient undergoing local anesthesia injection for extraction in Indian population. METHODOLOGY: In total, 100 Indian male patients were enrolled in the prospective study. Anxiety was measured at 15 min before local anesthetic delivery using Corah's Dental Anxiety Scale (DAS). Cardiovascular response data including blood pressure, heart rate, oxygen saturation and electrocardiographic changes were measured at five time points from 5 min before to 15 min after the administration of anesthetic. RESULTS: The mean anxiety scale score before administration of anesthetic was 8.24 (± 3.55) with a range from 4 to 20. Younger age was associated with a higher anxiety scale score. Severe preoperative anxiety (DAS > 12) was associated with significantly increased heart rate and blood pressure during administration of anesthetic. Significant ECG change was present at the time and 5 min after local anesthesia administration. Pain on injection was also associated with increased heart rate and blood pressure during anesthetic administration. CONCLUSION: The present study shows that significant cardiovascular changes do occur due to dental anxiety at the time of local anesthesia administration for tooth extraction in Indian population.

Erythrocyte Senescence in a Model of Rat Displaying Hutchinson-Gilford Progeria Syndrome.

BACKGROUND: Increased oxidative stress is a major cause of aging and age-related diseases. Erythrocytes serve as good model for aging studies. Dihydrotachysterol is known to induce premature aging feature in rats mimicking Hutchinson-Gilford progeria syndrome. AIM: In the present study, attempts have been made to explore the differential response of young and senescent erythrocytes separated by density gradient centrifugation from accelerated senescence model of rats mimicking Hutchinson-Gilford progeria syndrome and naturally aged rats. METHODS: The erythrocytes of naturally aged and progeroid rats were separated into distinct, young and old cells on the basis of their differential densities. The parameters of oxidative stress and membrane transport systems were studied. DISCUSSION AND CONCLUSION: Our study provides evidence that organismal aging negatively affects oxidative stress markers and membrane transport systems in both young and old erythrocytes. This study further substantiates that the changes in progeria model of rats resemble natural aging in terms of erythrocyte senescence.

Redox imbalance in a model of rat mimicking Hutchinson-Gilford progeria syndrome.

Although several etiological factors contribute to the complexity of the aging process, the ultimate component of macromolecular damage and consequent cell death involves the altered redox balance inclined towards increased ROS production and/or decreased antioxidant protection. Given that, the chronic dihydrotachysterol (DHT) intoxication in rats induce Hutchinson Gilford progeria like syndrome, the present study provides the evidence for altered redox balance as evidenced by alteration in parameters of oxidative stress in blood plasma and erythrocytes including MDA, GSH, FRAP AOPP PMRS, AGEs, AChE and osmotic fragility which substantiate the suitability of the model for aging studies.

Comparison of 2 mm single locking miniplates versus 2 mm two non-locking miniplates in symphysis and parasymphysis fracture of mandible.

INTRODUCTION: The purpose of this study is to compare the efficacy of single 2 mm locking miniplates versus two 2 mm non-locking (conventional) miniplates in symphysis and parasymphysis fracture of mandible. METHOD: This present study included 40 patients of maxillofacial trauma having mandibular symphysis/parasymphysis fractures in which open reduction and internal fixation is indicated. Patients were selected according to the inclusion criteria and divided into two groups, i.e. Group 1: consisted of 20 patients, requiring open reduction and internal fixation with 2 mm two non-locking titanium plate and Group 2: consisted of 20 patients, requiring open reduction and internal fixation with 2.0 mm single ultra-locking titanium plate. Fracture was then stabilized and postoperative clinical examination was carried out on 3rd day, 1st, 2nd, 4th, and 8th week. RESULT: Results of this study suggested that the use of single 2.0 mm locking miniplate could be a viable option instead of using two miniplates in anterior mandibular fracture as advocated by Champy, as it provides equally good outcome along with placement of lesser implant material. DISCUSSION: Single locking miniplates give the advantage of equally good stability and early restoration of function with almost similar results as seen in osteosynthesis with two miniplates. It was also found that less precision was required in plate adaptation when using single locking miniplate. This study suggests that there is not much difference in surgical outcome with the use of either single locking miniplate or two conventional miniplates in anterior mandibular region.

Forgotten triangles of neck.

The purpose of this manuscript is to add some more information in the present scientific literature on these nearly forgotten triangles of surgical importance. The neck is an area that lends itself to anatomical geometry, such as triangles. Many triangles of the neck have been described, and some are well-known, yet, some have been nearly forgotten, i.e., Lesser's triangle, Farabeuf triangle, Pirogoff's triangle, and Beclard's triangle. From the anatomic and surgical point of view, the neck is an amazingly interesting place. It is like a connection where crucial functional units meet and pass. Added surgical landmarks are always helpful to the surgeon while dealing with the neck. Described triangles of neck in this article are always reliable and constant landmarks for head and neck surgeons.

Evaluation of trapezoidal-shaped 3-D plates for internal fixation of mandibular subcondylar fractures in adults.

AIMS: The purpose of this study is to evaluate the clinical results and to assess the efficacy, stability, and rigidity of trapezoidal 3-D plates for osteosynthesis in adult mandibular subcondylar fracture patients. METHODS: This study included 15 cases of trauma having mandibular subcondylar fractures, in which open reduction and internal fixation are indicated. After selecting patient according to the inclusion criteria, all patients underwent open reduction and rigid fixation. Fracture was then stabilized using 4 hole, 2.0 mm trapezoidal-shaped 3-D titanium plates using retromandibular incision. Postoperative clinical examination was carried out on 3rd day; 1st, 2nd, and 4th weeks; and 3rd and 6th months. RESULTS: The results of this study suggest that the fixation of mandibular subcondylar fracture with trapezoidal-shaped 3-D plates provides three-dimensional stability and carries low morbidity. CONCLUSION: Patients with gross displacement of condylar fragment, major reduction in posterior facial height, and deranged occlusion can be successfully managed by open reduction of condylar fracture and its fixation using 3-D plates.

Use of Three-dimensional Plates in Mid-face Fracture: A Prospective Study.

AIM: The aim of our study was to evaluate the advantages and disadvantages of three-dimensional (3D) plating system in the treatment of mid-face fractures. PATIENTS AND METHODS: Thirty mid-face fractures in 18 patients at various anatomic locations were treated by open reduction and internal fixation using 3D plates. All patients were followed at regular intervals of 4th, 8th and 12th weeks respectively. Patients were assessed postoperatively for postoperative complication and occlusal stability. The incidence of neurosensory deficit, infection, masticatory difficulty, nonunion and malunion was also assessed. RESULTS: A significant reduction in fracture (72.2%) and occlusal stability (72.2%) was seen. The overall complication rate was (16.6%) which included two patients who developed postoperative paresthesia of lip, three patients had infection and two cases of masticatory difficulty which later subsided by higher antibiotics and 4 weeks of MMF. No evidence of nonunion and malunion was noted. CONCLUSION: Single 3D titanium plates with 1.7 mm diameter holes and 1.7 mm screws were reliable and an effective treatment modality for mid-face fracture. CLINICAL SIGNIFICANCE: Because of unique biogeometrical design owing to lesser amount of hardware material (fixation device) resulting into increased stability, the fixation in mid-face fractures is better in comparison to conventional 1.5 mm miniplate fixation.

Evaluation of effects of a preoperative 2-hour fast with glutamine and carbohydrate rich drink on insulin resistance in maxillofacial surgery.

INTRODUCTION: The aim of this prospective, randomized, single-blinded study was to compare the effects of preoperative fast for clear fluids on insulin resistance and hemodynamic stability on patient undergoing maxillofacial surgery. METHOD: In this study 20 patients undergoing maxillofacial surgery were randomized into four groups i.e. - group I patients with standard 08 h fasting before anesthesia, group-II patients were given 400 ml and 200 ml of water 08 h and 2 h respectively before anesthesia, group III patients were given 400 ml water with 50 gms of glucose and 40 gm of glutamine 08 h before anesthesia and 200 ml water with 25 gms of glucose and 10 gm of glutamine 2 h before anesthesia, group IV patients were given 400 ml water with 50 gms of glucose 08 h before anesthesia and 200 ml water with 25 gms of glucose 2 h before anesthesia. Blood samples were collected pre-operatively and post-operatively. RESULTS: Overall results suggest that Post-operative insulin resistance was greater in control patients (2.0 [0.3]) compared with the other 3 groups (placebo = 1.8 [0.9]); glutamine = (1.8 [0.6]); carbohydrate = (1.9 [0.6]). DISCUSSION: This study shows that shortening of pre-operative fasting time for clear fluids until 2- h prior to anesthesia may induce a favorable environment for the post-operative course. In conclusion, Glutamine with carbohydrate drink can be used safely in surgical patients.

M235T polymorphism in the AGT gene and A/G(I8-83) substitution in the REN gene correlate with end-stage renal disease.

BACKGROUND/AIMS: This study aimed at investigating if M235T polymorphism in the AGT gene and A/G(I8-83) polymorphism in the REN gene correlate with end-stage renal disease (ESRD). METHODS: We analyzed 173 ESRD patients and 329 individuals with normal kidney function for differences in the genotype distribution of AGT-M235T and REN-A/G(I8-83) polymorphisms between the two groups. The data for cases and controls were compared using the χ(2) test. RESULTS: We found significantly higher levels of serum creatinine and CRP in cases in comparison to controls (p < 0.0001). Data comparison showed a significant association of AGT M235T substitution with ESRD in the dominant model (p = 0.008) and in the comparison of the heterozygous substitution with the homozygous common genotype (p = 0.005). Similarly, REN A/G(I8-83) polymorphism showed a significant difference in the distribution of genotypes between cases and controls (p < 0.038) such that a heterozygous substitution was significantly more common in the ESRD cases in comparison to the homozygous common genotype (p = 0.023). CONCLUSION: We conclude that heterozygous substitutions at the AGT M235T and REN A/G(I8-83) loci correlate significantly with ESRD in a north Indian population.

Depleted TGF-ß1 levels in end stage renal disease patients from North India.

End stage renal disease is a clinical state that extends from chronic renal failure and is marked by an irreversible loss of renal function. TGF-ß1 mediated renal fibrosis is a common pathology implicated in this form of kidney disease. In this study circulating protein and mRNA levels of TGF-ß1 cytokine were investigated among ESRD patients and respective controls from North India. Physician diagnosed 192 ESRD patients, on hemodialysis, and 130 normal controls participated in the present study. TGF-ß1 circulating levels were measured by ELISA and its expression was quantified using competitive-PCR. Mean TGF-ß1 protein levels were 2.7-fold lower in ESRD patients as compared to normal controls (p<0.001). Additionally, TGF-ß1 mRNA transcripts of this cytokine were also significantly lower in the diseased population compared to controls (p<0.001). These results imply that TGF-ß1 has not played its anticipated pro-fibrotic role and anti-inflammatory function in the studied population.

Primary and secondary closure technique following removal of impacted mandibular third molars: A comparative study.

AIM: The purpose of this study was to evaluate and compare the post operative healing, using primary versus second closure techniques after impacted mandibular third molar removal. MATERIALS AND METHODS: The study consisted of twelve patients, Seven males and five females under 30 years of age were divided into two groups as Group A and Group B in the randomized fashion. In the Group A, closure was done by primary intention and in the Group B, by secondary closure. A comparison between both groups was done with a follow-up period of 6 h to 6 days with regards to postoperative pain and swelling. RESULTS: The statistical analysis (analysis of variance for repeated measures, P < 0.05) showed that pain was greater in Group A, although it decreased over time similarly in the two groups. Pain and swelling was less severe with secondary healing than with primary healing. CONCLUSION: The outcome of this study suggested that secondary closure technique is better than primary closure technique for removal of impacted mandibular third molar with regards to postoperative pain and swelling.