Miracle-dz/UniFAR-FTUs huggingface dataset:
SLEEP - DISORDERS, APNOEAS, CARDIORESPIRATORY EFFECTS & OTHER EMERGING PROBLEMS

Importance of Sleep Studies We all sleep some more than others. Most don’t realize that sleep occupies over 1/3rd of human existence time and this period of life is regulated by fine tuned autonomic sympathetic and parasympathetic drives, homeostatic sleepwakefulness drives and circadian inherent rhythm. Minor aberrations of sleep rhythms as depicted below are themselves quite disturbing for humans such asa) InsomniaAffects 3040% in West and industrialized nations. b) NarcolepsyA neurologically based disorder also called as sleep paralysis. c) CSRD (Circadian Rhythm Sleep Disorders) Consists of jetlag, shift wake sleep disorder, advanced sleep phase syndromes. However, more devastating effects of sleep disturbances termed apnoea, both OSA and also central apnoea are proving to be intricately related to today’s more dreaded lifestyle diseases like Hypertension, IHD, NIDDM[4,5,6,7] Metabolic syndromes and not to forget the US data of over 70 million Americans suffering from these and over 30% of Road and other accidents being related to these[8, 9]. Following data is illuminating about problem of sleep disturbances. White et al diagnosed OSA in 2% women and 4% men in middle age. Wisconsin’s cohort study had 9 to 24% men and 4 to 9% women while studies in Israel and Australia estimated as high as 20 to 25% in the employed. Amongst these people systemic hypertension is seen in 50 to 70% OSHAS; a factor which was independent of obesity, age, alcohol and smoking (Nieto, 2000)[6]. Insulin resistance was seen in a very high percentage of these (15%). In a study by Punjabi & others by Irwin et al (2002 to 2004), oxidative stress was very high[10].
Pathophysiological mechanisms of sudden infant death syndrome

Abstract There is a consensus that sudden infant death syndrome, the leading cause of mortality in the first year of life, is multifactorial. Most of the cases are probably due to respiratory or cardiac disorders. It has been proposed that some cases of sudden infant death might result from ventricular fibrillation triggered by a sudden increase in sympathetic activity affecting the heart with reduced electrical stability. This impairment can be due to an insufficient or delayed development of cardiac vagal innervation, with the resultant lack of its protective effect that has been demonstrated to be present since the third week of life. Clinical studies suggest that some of the sudden infant death victims may have a reduced heart rate variability that could be interpreted as a decreased parasympathetic activity to the heart. On the other hand, a reduced cardiac electrical stability may be provoked by a developmental imbalance in sympathetic innervation such to create a dominance of left-sided nerves. We have demonstrated that an imbalance of this type experimentally induced in puppies increases the susceptibility to ventricular fibrillation and prolongs QT interval. In order to demonstrate a significant relationship between prolonged QT interval and sudden infant death, we performed a large prospective study on 18,832 neonates. QT interval corrected for heart rate (QTc) measured from an electrocardiogram on the fourth day of life, was within the normal limits in nine victims from known causes, while it was exceeding the mean by two standard deviations (>433 msec) in six of 12 sudden infant death victims. If these data are confirmed by a larger multicenter study started in Italy, it will be possible to identify some of the sudden infant death victims by the observation of a prolonged QT interval on the electrocardiogram. In this case a preventive strategy based on a time-limited administration of beta adrenergic blocking agents to the infants at risk, might reduce the incidence of sudden infant death.
General Anaesthetic Considerations for Haemostasis in Orbital Surgery

ABSTRACT Orbital surgery is often conducted in areas with limited exposure where vital structures are tightly crowded together. A bloodless field is paramount in orbital surgery for the proper identification of normal and pathologic tissue and even minimal bleeding can obscure the surgical field, making surgery more difficult and increasing the risk of complications. Surgery for highly vascular orbital lesions is an additional situation where maintaining an adequate surgical field is often challenging but paramount. The role of the anaesthetist in controlling surgical blood loss has been increasingly recognized in the last few decades. Various techniques including hypotensive anaesthesia have been described, but the control of intraoperative bleeding does not rely on a single particular technique, but a series of well-designed interventions that result in optimal conditions. An understanding of the anaesthetic considerations pertinent to haemostasis is invaluable for oculoplastic surgeons. Additionally, with the growing use of endonasal approaches to medial wall decompression and accessing the medial orbit, it has become increasingly important that orbital surgeons understand the anaesthetic requirements of their colleagues in other disciplines.
Ultrasound-guided rectus sheath catheters: A feasible and effective, opioid-sparing, post-operative pain management technique: A case series

Epidural analgesia, though the gold standard of post-operative pain management for laparotomies, is associated with limitations and is contraindicated in many patients. Opioid-based pain management, which is an alternative to epidural, has been implicated in post-operative nausea, vomiting, and ileus. We report successful management of post operative pain with ultrasound guided rectus sheath (RS) catheters. RS block is a promising alternative in scenarios were epidural is contraindicated, has failed or in case of unexpected change in the surgical plan.
How Na+ activates thrombin – a review of the functional and structural data

Abstract Thrombin is the ultimate coagulation factor; it is the final protease generated in the blood coagulation cascade and is the effector of clot formation. Regulation of thrombin activity is thus of great relevance to determining the correct haemostatic balance, with dysregulation leading to bleeding or thrombosis. One of the most enigmatic and controversial regulators of thrombin activity is the monovalent cation Na+. When bound to Na+, thrombin adopts a ‘fast’ conformation which cleaves all procoagulant substrates more rapidly, and when free of Na+, thrombin reverts to a ‘slow’ state which preferentially activates the protein C anticoagulant pathway. Thus, Na+-binding allosterically modulates the activity of thrombin and helps determine the haemostatic balance. Over the last 30 years, there has been much research investigating the structural basis of thrombin allostery. Biochemical and mutagenesis studies established which regions and residues are involved in the slow→fast conformational change, and recently several crystal structures of the putative slow form have been solved. In this article, the biochemical and crystallographic data are reviewed to see if we are any closer to understanding the conformational basis of the Na+ activation of thrombin.
In vivo analysis reveals substrate-gating mutants of a rhomboid intramembrane protease display increased activity in living cells

Abstract Intramembrane proteases hydrolyze peptide bonds within cell membranes. Recent crystal structures revealed that rhomboid intramembrane proteases contain a hydrated active site that opens to the outside of the cell, but is protected laterally from membrane lipids by protein segments. Using Escherichia coli rhomboid (GlpG) structures as a guide, we previously took a mutational approach to identify the GlpG gating mechanism that allows substrates to enter the active site laterally from the membrane. Mutations that weaken contacts keeping the gate closed increase enzyme activity and implicate transmembrane segment 5 as the substrate gate. Since these analyses were performed in vitro with pure proteins in detergent micelles, we have now examined GlpG in its natural environment, within the membrane of live E. coli cells. In striking congruity with in vitro analysis, gate-opening mutants in transmembrane segment 5 display up to a 10-fold increase in protease activity in living cells. Conversely, mutations in other parts of the protease, including the membrane-inserted L1 loop previously thought to be the gate, decrease enzyme activity. These observations provide evidence for the existence of both closed and open forms of GlpG in cells, and show that inter-conversion between them via substrate gating is rate limiting physiologically.
Ropivacaine: A review of its pharmacology and clinical use

Ropivacaine is a long-acting amide local anaesthetic agent and first produced as a pure enantiomer. It produces effects similar to other local anaesthetics via reversible inhibition of sodium ion influx in nerve fibres. Ropivacaine is less lipophilic than bupivacaine and is less likely to penetrate large myelinated motor fibres, resulting in a relatively reduced motor blockade. Thus, ropivacaine has a greater degree of motor sensory differentiation, which could be useful when motor blockade is undesirable. The reduced lipophilicity is also associated with decreased potential for central nervous system toxicity and cardiotoxicity. The drug displays linear and dose proportional pharmacokinetics (up to 80 mg administered intravenously). It is metabolised extensively in the liver and excreted in urine. The present article details the clinical applications of ropivacaine and its current place as a local anaesthetic in the group.
Procalcitonin as an adjunctive biomarker in sepsis

Sepsis can sometimes be difficult to substantiate, and its distinction from non-infectious conditions in critically ill patients is often a challenge. Serum procalcitonin (PCT) assay is one of the biomarkers of sepsis. The present study was aimed to assess the usefulness of PCT assay in critically ill patients with suspected sepsis. The study included 40 patients from the intensive care unit with suspected sepsis. Sepsis was confirmed clinically and/or by positive blood culture. Serum PCT was assayed semi-quantitatively by rapid immunochromatographic technique (within 2 hours of sample receipt). Among 40 critically ill patients, 21 had clinically confirmed sepsis. There were 12 patients with serum PCT ≥10 ng/ml (8, blood culture positive; 1, rickettsia; 2, post-antibiotic blood culture sterile; and 1, non-sepsis); 7 patients with PCT 2-10 ng/ml (4, blood culture positive; 1, falciparum malaria; 2, post-antibiotic blood culture sterile); 3 patients with PCT of 0.5 to 2 ng/ml (sepsis in 1 patient); and 18 patients with PCT < 0.5 ng/ml (sepsis in 2 patients). Patients with PCT ≥ 2 ng/ml had statistically significant correlation with the presence of sepsis (P<0.0001). The PCT assay revealed moderate sensitivity (86%) and high specificity (95%) at a cut-off ≥ 2 ng/ml. The PCT assay was found to be a useful biomarker of sepsis in this study. The assay could be performed and reported rapidly and provided valuable information before availability of culture results. This might assist in avoiding unwarranted antibiotic usage.
Rubber Tube versus Silicone Tube at the Osteotomy Site in External Dacryocystorhinostomy

Background: In external dacryocystorhinostomy a large bony window is created in the lateral nasal wall and a mucosal anastomosis is created between the lacrimal sac and the nasal cavity. The success of the operation depends on the surgical anastomosis remains patent and converting to a wide enough epithelial-lined passage. Objective: To compare the efficacy of using rubber versus silicone tubes at the osteotomy of Dacryocystorhinostomy Design: Prospective, randomized, hospital-based study. Subjects and Methods: 46 patients diagnosed with primary acquired nasolacrimal duct obstruction were assigned randomly to rubber, silicone or control group. The surgical procedures in the three groups were the same except that in patients of rubber and silicone groups, rubber or silicone tubes were placed at osteotomy opening and removed after 3 months. Transnasal endoscopic findings were recorded at the completion of surgery and at 3 months, 6 months and 9 monthes after surgery for the 3 groups. A computer aided digitizer was used to calculate the surface area of the osteotomy site. Results: After removal of their tubes, 3 patients in the rubber group had recurrent epiphora (78.0% success), one patient in silicone group (92.86% success) and 4 patients in control group (77.8% success). The average final surface area of the osteotomy opening of patients with rubber group at the end of follow-up was (9.85 mm2) in the silicone group was (17.47 mm2), whereas in the control group was (8.56 mm2). Conclusion: Silicone tube is better than rubber one in maintaining effective larger osteotomy after Dacryocystorhinostomy. This can improve the long-term success of the operation.
The Role of Mucosal Flaps in External Dacryocystorhinostomy

Purpose: To determine whether a mucosal anastomosis fashioned at the time of external dacryocystorhinostomy (DCR) influences postoperative outcome. Methods: The clinical records of all patients who underwent external DCR at Sydney Eye Hospital between May 2000 and August 2007 were reviewed. Data were collected in regards to surgical technique, clinical outcomes and postoperative management. Chi-square statistical analysis was done to determine the significance of the different flap techniques on surgical success. Results: A total of 260 medical records were reviewed. The main outcome measure was postoperative resolution of symptoms. The mean final follow-up time was 11 months. There was no statistically significant difference in outcome between patients who had both anterior and posterior flaps sutured, compared to those who had anterior flap sutures only (73% vs 79%, p = 0.51). Patients who had no sutured flaps had an overall success rate of 89% compared to those that had at least the anterior flaps sutured together (76%); this difference was not significant (p = 0.45). Conclusion: There was no statistical difference in symptom outcome between patients in whom both mucosal flaps were sutured, those who had only the anterior flap sutured, or those who did not have either flap sutured at the time of surgery.
Characterization of an mGluR2/3 Negative Allosteric Modulator in Rodent Models of Depression

Abstract: There is growing evidence suggesting that antagonists of group II metabotropic glutamate receptors (mGluR2/3) exhibit antidepressant-like properties in several preclinical models of depression. However, all those studies have been performed using competitive group II non-selective orthosteric antagonists. In this study we extensively characterized a group II selective negative allosteric modulator (4-[3-(2,6-Dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one, namely RO4491533, Woltering et al., 2010) in several in vitro biochemical assays and in vivo models of depression. In vitro, RO4491533 completely blocked the glutamate-induced Ca2 + mobilization and the glutamate-induced accumulation in [35S]GTPγS binding in cells expressing recombinant human or rat mGluR2 and in native tissues. Results from Schild plot experiments and reversibility test at the target on both cellular and membrane-based assays confirmed the negative allosteric modulator properties of the compound. RO4491533 was equipotent on mGluR2 and mGluR3 receptors but not active on any other mGluRs. RO4491533 has acceptable PK properties in mice and rats, is bioavailable following oral gavage (F = 30%) and brain-penetrant (CSF conc/total plasma conc ratio = 0.8%). RO4491533 appeared to engage the central mGluR2 and mGluR3 receptors since the compound reversed the hypolocomotor effect of an mGluR2/3 orthosteric agonist LY379268 in a target-specific manner, as did the group II orthosteric mGluR2/3 antagonist LY341495. RO4491533 and LY341495 dose-dependently reduced immobility time of C57Bl6/J mice in the forced swim test. Also, RO4491533 and LY341495 were active in the tail suspension test in a line of Helpless (H) mice, a putative genetic model of depression. These data suggest that mGluR2/3 receptors are viable targets for development of novel pharmacotherapies for depression.
Unmasking of tracheomalacia following short-term mechanical ventilation in a patient of adult respiratory distress syndrome

Patients with chronic obstructive pulmonary disease (COPD) are susceptible to airway malacia, which may be unmasked following mechanical ventilation or tracheostomy decannulation. Dynamic imaging of central airways, a non-invasive test as effective as bronchoscopy to diagnose airway malacia, has increased the recognition of this disorder. We describe a 70-year-old woman admitted with adult respiratory distress syndrome. She had cardiorespiratory arrest on admission, from which she was successfully resuscitated. She had obesity, hypertension, diabetes mellitus, recurrent ventricular tachycardia, sarcoidosis with interstitial lung disease and COPD. She received short-term (18 days) mechanical ventilation with tracheostomy and developed respiratory distress following tracheostomy decannulation.
Inflammatory markers and COPD phenotypes as predictors of COPD exacerbations

Background: COPD exacerbations accelerate disease progression. Aims: To examine if COPD phenotypes and systemic inflammatory markers predict the risk for COPD exacerbations, defined as requiring treatment with either systemic steroids or antibiotics. Methods: 433 COPD patients, GOLD stage II-IV, aged 40-76 yrs were included in the Bergen COPD Cohort Study in 2006/07, and followed for 3 years. Examined baseline predictors were sex, age, body composition, smoking habits, exacerbations the last year prior to baseline, GOLD stage, Charlson comorbidity score (CCS), presence of hypoxemia (PaO2 Univariate and multivariable Poisson models with random effects were fitted to estimate the yearly incidence rate ratios (IRR). Results: Univariately, all variables except sex and CCS were significantly associated with the outcome. Higher levels of the inflammatory markers each predicted an increased yearly IRR (95% CI) per unit increase of the markers with IRR 1.03 (1.01-1.05), 1.07 (1.03-1.13), 1.06 (1.001-1.13), and 1.08 (1.01-1.16), respectively. Multivariately, significant predictors of COPD exacerbations were: age [IRR per 1 yr increase:1.02 (1.003-1.04)], female sex [1.35 (1.06-1.73)], >1 exacerbations last year before baseline [1,58 (1.17-2.13)], GOLD III [1.28 (1.01-1.64)], GOLD IV [2.73 (1.85-4.05)], chronic cough [1.61 (1.28-2.03)], use of inhaled steroids [1.67 (1.29-2.17)]. Conclusion: Clinical COPD characteristics were independent predictors of exacerbations.
Practice nurses’ role and knowledge about diabetes management within rural and remote Australian general practices

AbstractBackground: The increasing prevalence of diabetes and obesity represents a significant disease burden in Australia. Practice nurses (PNs) play an important role in diabetes education and management.Aim: To explore PNs’ roles, knowledge and beliefs about diabetes education and management in rural and remote general practice in Australia.Method: Exploratory study undertaken in three phases: 1) Pilot study to test the performance of the questionnaire; 2) One-shot cross-sectional survey using self-complete questionnaires; 3) Individual interviews.Results: Ten PNs completed the pilot test; the draft questionnaire was deemed appropriate to the study purpose. Then, 65 questionnaires were distributed to PNs and 21 responded. Fourteen respondents had worked in the role <5 years, and most PNs attended diabetes education programmes in their workplace. A minority (40%) used diabetes management guidelines regularly. Most knew obesity to be the most common risk factor for diabetes but only 50% knew that glycosy.
An examination of the proteolytic activity for bovine pregnancy-associated glycoproteins 2 and 12

Abstract The pregnancy-associated glycoproteins (PAGs) represent a complex group of putative aspartic peptidases expressed exclusively in the placentas of species in the Artiodactyla order. The ruminant PAGs segregate into two classes: the ‘ancient’ and ‘modern’ PAGs. Some of the modern PAGs possess alterations in the catalytic center that are predicted to preclude their ability to act as peptidases. The ancient ruminant PAGs in contrast are thought to be peptidases, although no proteolytic activity has been described for these members. The aim of the present study was to investigate (1) if the ancient bovine PAGs (PAG-2 and PAG-12) have proteolytic activity, and (2) if there are any differences in activity between these two closely related members. Recombinant bovine PAG-2 and PAG-12 were expressed in a baculovirus expression system and the purified proteins were analyzed for proteolytic activity against a synthetic fluorescent cathepsin D/E substrate. Both proteins exhibited proteolytic activity with acidic pH optima. The kcat/Km for bovine PAG-2 was 2.7×105 m-1 s-1 and for boPAG-12 it was 6.8×104 m-1 s-1. The enzymes were inhibited by pepstatin A with a Ki of 0.56 and 7.5 nm for boPAG-2 and boPAG-12, respectively. This is the first report describing proteolytic activity in PAGs from ruminant ungulates.
Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status.

INTRODUCTION We performed retrospective analysis of 106 patients with lung cancer for which formalin-fixed paraffin-embedded tissues was available. Their epidermal growth factor receptor (EGFR) mutation status and treatment outcomes are described. MATERIALS AND METHODS All patients with confirmed non-small cell lung cancer (NSCLC) during Jan 2008 to Dec 2010 were included. EGFR sequencing was performed with ABI PRISM 310 genetic analyzer. RESULTS Forty-two (39.6%) patients had mutation in one of the four exons characterized. Patients whose EGFR mutational status was not available at presentation before the start of treatment were started on chemotherapy, n = 46 (43.39%). If EGFR mutational analysis was available and mutations were present, the patients were started on either upfront tyrosine kinase inhibitor (TKI), n = 15 (14.15%) or if on chemotherapy arm were allowed to finish six cycles and then start with maintenance TKIs, n = 26 (24.52%). The median progression free survival for patients with and without mutations was 11 months (95% CI,7-14) and 9 months (95% CI,7-10) respectively. A median PFS of 14 months (95%CI, 12-16) was seen in the mutation-positive group that received both chemotherapy followed by switch maintenance with TKIs versus 8 months (95%CI, 7-8 months) in the group that received only TKI. CONCLUSION The prevalence of EGFR mutations in this population of NSCLC patients was 39.6% with exon 19 mutation being the most common. The observed benefit of addition of chemotherapy over TKI in EGFR mutation-positive group raises the question, can we offer the therapy of chemotherapy-TKI combination to EGFR mutation-positive lung cancer patients as shown in the present study.