2nd Loop Research Articles

Assessment of pharmacological safety of a new dipeptide mimetic of the 2nd loop of BDNF when co-administered with ethanol

To assess the pharmacological safety of the dipeptide mimetic of the 2nd loop of BDNF (compound GTS-201) when co-administered with ethanol, its effect on the alteration in motor activity induced by ethanol during acute and subchronic administration in mice C57Bl/6 and DBA/2 was studied. It was found that GTS-201 at a dose of 5.0 mg / kg, i.p., without affecting spontaneous motor activity per se, after a preliminary acute administration prevented the development of a sedative reaction caused by ethanol (2.0 g/ kg, i.p.) in C57Bl/6 mice. After subchronic administration, GTS-201 is devoid of psychostimulant effect and impact on the formation of ethanol-induced behavioral sensitization in DBA/2 mice. The data obtained indicate the absence of a psychostimulant component and synergism in the pharmacological profile of GTS-201 when used with ethanol at low dose.

102 Postoperative Haemoglobin Monitoring in Neck of Femur Fracture Patients. Can a Simple Teaching Session Improve Patient Safety on the Orthopaedic Ward?

Abstract Aim Patients who suffer neck of femur fractures (NOF#) are typically frail and at risk of postoperative anaemia which can contribute to a high mortality in this demographic. This QiP reviewed how well postoperative haemoglobin (Hb) was being monitored on a Orthopaedic unit and assessed the effectiveness of a teaching session to improve this. A secondary measure was to compare day 1 and day 3 Hb to establish an evidence base for the timing of postoperative Hb monitoring. Method Two cycles (1st loop: 8/3/21–21/3/21, n = 21. 2nd loop:3/7/21–16/7/21, n=15) were performed either side of a teaching session. Day 1 and day 3 post-op Hb were recorded. Inclusion criteria were patients who fitted NOF# best practice tariffs. Results Pre-intervention saw 90% of patients have day 1 Hb and 52% have day 3 Hb taken, this increased to 93% and 67% post intervention. 81% of patients showed a Hb drop between day 1 and day 3 (mean = 11 g/dL), with 90% of day 1 bloods already below reference range. Conclusions We demonstrated that a teaching session highlighting the importance of Hb monitoring in this patient demographic can improve the monitoring of postoperative haemoglobin and thus improve patient safety. Secondly, a Hb drop is possible from day 1 to day 3 and therefore a day 1 Hb should not be relied on. Future work will aim to investigate the longer-term trend of postoperative Hb to establish when an outpatient Hb should be performed.

Small Bowel Adenocarcinoma Simulating Superior Mesenteric Artery Syndrome (SMAS): A Case Report

The adenocarcinoma of the small intestine is a rare tumor of all gastrointestinal cancers often occurs on a predisposing ground we report the case of a 40-year-old patient chronic smoker has 1 pack year weaned 2 years ago, alcoholic weaned 5 years ago whose symptomatology dates back to 3 months by the appearance of epigastralgia and vomiting post prandial, Complicated by a high occlusive syndrome made of post prandial vomiting with abdominal pain all evolving in a context of alteration of general state made the patient was addressed to the service of digestive cancer surgery and liver transplantation of CHU Ibn Rochd Casablanca.
 The patient had an abdominal CT scan which showed duodenojejunal distension with incarceration of an undistended loop at the level of the aorto-mesenteric clamp.
 The patient was sent to the operating room in emergency, he underwent a segmental Greco-Resection of 15 cm taking away a jejunal mass under laparoscopy with extra corporal anastomosis latero-lateral jejuno-jejunal with at the exploration one notes the presence of a tumoral mass of 3cm mobile at the level of the 2nd loop jejunal stenosing responsible for a jejunal distension upstream measuring 4cm in diameter.
 The anatomopathological study of the specimen showed a moderately differentiated and invasive adenocarcinoma, classified as pT3N1Mx.
 The postoperative follow-up was marked by a deep venous thrombosis involving the ileo-femoral-popliteal axis of the ilio-femoral-popliteal trunk on day 2 postoperatively, for which the patient was put on low molecular weight Heparin at a curative dose with compression stockings and monitoring.
 The patient had resumed transit in the form of gas on postoperative day 3, with a correct assessment, and was declared discharged on postoperative day 6.
 The patient's file was discussed in a multidisciplinary consultation meeting and the decision was to undergo adjuvant chemotherapy and oesogastroduodal fibroscopy (FOGD) and colonoscopy to look for predisposing diseases.

P128 The implications of SARS-CoV-2 on a Cardiothoracic unit

IntroductionThe effort to prevent healthcare systems becoming overrun during the 2020 COVID-19 pandemic has come at the cost of delaying operations and with that bringing difficult risk analysis to help decide which operations should go ahead. With COVID-19 being a novel disease there is limited evidence for guidance on this issue. We have previously presented work highlighting the high risk of mortality associated with a perioperative cardiothoracic patient becoming COVID-19 positive and thus decided to implement a series of changes to departmental perioperative practice. This work presents these interventions and compares the infection and the mortality rate with those before the intervention was put in place.MethodTwo retrospective loops were performed. Pre intervention, 5/3/20 – 20/4/20, and post intervention, 21/4/20- 23/6/20. Inclusion criteria: patients who had received cardiothoracic surgery at University Hospital of Wales within 4 weeks of the positive COVID-19 PCR (1st loop n = 53, 2nd loop n = 40). Exclusion criteria included re-admissions from greater than 4 weeks (n = 2). Interventions included 14 day pre op isolation, a strict multifaceted screening regime, reverse barrier nursing and delaying operations if diagnostic uncertainty.Results9/51 patients from the pre intervention loop and 2/40 from post intervention loop tested +ve for COVID-19. The pre intervention mortality was 5/9 and post intervention mortality was 0/2.ConclusionOur data suggest that simple changes to perioperative practice can decrease the transmission of COVID-19 during this period. Thus, allowing surgical services to run at a reduced risk

Bisquinolinium-fluorescein conjugates as specific fluorescence probes of c-myc Pu22 G-quadruplex and their bioimaging and anticancer activities

Targeting G-quadruplexes in the c-myc gene promoter region is one of the few therapeutic opportunities through inhibiting the c-myc protein overexpression. However, the design of probes recognizing c-myc G-quadruplexes with high selectivity and specificity and the more evaluation of cellular system still remain a big challenge. Here, two novel bisquinolinium-fluorescein conjugates (1a and 1b) with the alkyl linkers, have been designed and evaluated their selectivity and specificity for parallel c-myc Pu22 G-quadruplex. Compared with conjugate 1b with longer alkyl linker, conjugate 1a with shorter alkyl linker, exhibited higher fluorescence response and specificity towards c-myc Pu22 G-quadruplex than other wild-type c-myc G-quadruplexes, human telomere G-quadruplexes, other G-quadruplexes in the promoter regions and double-stranded DNA. According to the binding mode, the interaction of compound 1a with the 2nd loop around the 3′-end G-quartet through regulating the length of the alkyl linker, excited its fluorescence and enhanced its selectivity towards c-myc Pu22 G-quadruplex. Furthermore, conjugate 1a could selectively recognize c-myc Pu22 G-quadruplex DNA in cells through microscopy experiments, and inhibit cell proliferation possibly by reducing c-myc protein expression in cancer cells. This study provides guidance to design the high-performance fluorescence probes towards c-myc G-quadrulex by regulating the alkyl linker in the conjugate of G-quadruplex binder and fluorescence ligand, and develop anticancer drugs targeting c-myc G-quadruplex.

Низкомолекулярный миметик 2-й петли BDNF снижает потребление этанола у самок крыс

Низкомолекулярный миметик 2-й петли BDNF снижает потребление этанола у самок крыс

A Novel Cysteine Knot Protein for Enhancing Sperm Motility That Might Facilitate the Evolution of Internal Fertilization in Amphibians.

Internal fertilization ensures successful reproduction of tetrapod vertebrates on land, although how this mode of reproduction evolved is unknown. Here, we identified a novel gene encoding sperm motility-initiating substance (SMIS), a key protein for the internal fertilization of the urodele Cynops pyrrhogaster by Edman degradation of an isolated protein and subsequent reverse transcription polymerase chain reaction. The SMIS gene encoded a 150 amino-acid sequence including the cysteine knot (CK) motif. No gene with substantial similarity to the SMIS was in the data bank of any model organisms. An active site of the SMIS was in the C-terminal region of the 2nd loop of CK motif. A synthetic peptide including the active site sequence bound to the midpiece and initiated/enhanced the circular motion of C. pyrrhogaster sperm, which allows penetration of the egg jelly specialized for the internal fertilization of this species. The synthetic peptide bound to whole sperm of Rhacophorus arboreus and enhanced the rotary motion, which is adapted to propel the sperm through egg coat matrix specialized for arboreal reproduction, while it bound to the tip of head and tail of Bufo japonicus sperm, and enhanced the vibratory motion, which is suited to sperm penetration through the egg jelly specialized for the reproduction of that species in freshwater. The polyclonal antibody against the active site of the SMIS specifically bound to egg coat matrix of R. arboreus. These findings suggest that diversification of amphibian reproductive modes accompanies the specialization of egg coat and the adaptation of sperm motility to penetrate the specialized egg coat, and SMIS acts as the sperm motility enhancer of anurans and urodeles that might facilitate to adaptively optimize sperm motility for allowing the establishment of internal fertilization.

Audit of Patients Undergoing Thyroid Surgery in an Attempt to Improve the Standard of Care

Objectives: Improve the standard of care for patients undergoing thyroid surgery. Recognized complications include hypocalcemia and recurrent laryngeal nerve (RLN) damage. We aimed to review our practice and improve it by adhering to the criteria set out by the National Institute of Clinical Excellence (NICE). Methods: Retrospective audit looking at patients undergoing thyroid surgery over a 6-month period (09/2012). Pro forma methods were used to establish the adequacy of documentation including the use of nerve monitoring equipment, identification and stimulation of the RLN, and the recording of pre- and postoperative vocal cord checks (n = 18). Retrospective re-audit after recommendations to complete the loop (n = 8) over a 4-month period. Results: The first part of the audit cycle identified haphazard management of calcium levels in the postoperative period, incomplete documentation of vocal cord checks, and RLN identification and testing during surgery. Recommendations and guidance to staff, as well as a revised protocol on calcium management, resulted in improved care overall following re-audit. In part 2 of the audit cycle; only 1 patient became hypocalcemic in the postoperative period and was managed successfully following the protocol. RLN detection, testing, and monitoring were documented in all patients. The 2nd loop showed that all patients were receiving documented RLN identification and stimulation intraoperatively; all patients had documented pre- and postoperative cord checks and use of a nerve monitor (n=10). Conclusions: The audit shows we were able to meet the criteria set out by NICE.

Correlation of fulminant hepatitis B, HBeAg start-codon depletions and escape mutations in the 2nd loop of the HBsAg a-determinant

Correlation of fulminant hepatitis B, HBeAg start-codon depletions and escape mutations in the 2nd loop of the HBsAg a-determinant

Correlation of fulminant hepatitis B and escape mutations in the 2nd loop of the HBsAg a-determinant

Correlation of fulminant hepatitis B and escape mutations in the 2nd loop of the HBsAg a-determinant

Identification of amino acids in human colipase that mediate adsorption to lipid emulsions and mixed micelles

The adsorption of colipase is essential for pancreatic triglyceride lipase activity and efficient dietary fat digestion. Yet, little is known about which specific amino acids in the hydrophobic surface of colipase influence adsorption. In this study, we systematically substituted alanine or tryptophan at residues implicated in adsorption of colipase to an interface. We expressed, purified recombinant colipase mutants and characterized the ability of each alanine mutant to restore activity to lipase in the presence of bile salts. The functions of L16A, Y55A, I79A and F84A colipase were most impaired with activities ranging from 20 to 60% of wild-type colipase. We next characterized the fluorescence properties of the tryptophan mutants in the absence and presence of bile–salt–oleic acid mixed micelles. We performed steady-state emission spectra to determine peak shift and I330/I350 ratio and acrylamide quenching curves to characterize the environment of the residues. The analysis supports a model of adsorption that includes residues Leu 34 and Leu 36 on the 2nd loop, Tyr 55 and Tyr 59 on the 3rd loop and Ile 75 and Ile 79 on the 4th loop. The analysis confirms that Phe 84 is not part of the adsorption surface and likely stabilizes the conformation of colipase. Contrary to the predictions of computer modeling, the results provide strong support for an essential role of Tyr 55 in colipase adsorption to mixed micelles. The results indicate that the adsorption of colipase to mixed micelles is mediated by specific residues residing in a defined surface of colipase.

Pathogenic role of anti-M3 muscarinic acetylcholine receptor immune response in Sjögren's syndrome

M3 muscarinic acetylcholine receptor (M3R) is expressed in exocrine glands (e.g., salivary glands [SGs] and lachrymal glands), and plays a crucial role in exocrine secretion. M3R reactive T cells have been detected in circulating mononuclear cells of 40% of patients with Sjögren's syndrome (SS), and the major T cell epitopes of M3R in those patients with HLA-DR B1×0901 are located in the second loop of M3R. Moreover, autoantibodies (autoAbs) against M3R are also present in sera of around 50% of patients with SS, and several B cell epitopes, such as N-region, 1st, 2nd, and 3rd loop of M3R, have been identified. Functional analysis using human SG cell lines showed that autoAbs against the 2nd loop of M3R suppressed intracellular Ca(2+) influx, suggesting inhibition of saliva secretion. To clarify whether the M3R reactive immune response induces autoimmune sialadenitis (AIS), M3R(-/-) mice were immunized with M3R synthetic peptides and their splenocytes transferred into Rag1(-/-) mice. The recipients developed severe sialadenitis, and cell transfer studies indicated that T cells are key factors in the pathogenesis of AIS. These results indicate that the M3R immune reaction plays a key pathogenic role in AIS, suggesting that M3R molecule acts as an autoantigen in the pathogenesis of SS.

Learning from incidents – A method for assessing the effectiveness of the learning cycle

This paper describes a method for assessing the effectiveness in the steps of the learning cycle: the 1st loop with reporting – analysis – decision – implementation – follow-up, and the 2nd loop on an aggregated basis. For each step, the dimensions considered the most relevant for the learning process (scope, quality, timing and information distribution) and for each dimension the most relevant aspects (e.g. completeness and detail) were defined. A method for a semi-quantitative assessment of the effectiveness of the learning cycle was developed using these dimensions and aspects and scales for rating. The method will give clear indications of areas for improvement when applied. The results of the method can also be used for correlation with other safety parameters, e.g. results from safety audits and safety climate inquiries. The method is intended to be used on a sample of the broad range of incidents normally seen in process industry companies. The method was tested on a two-year incident reporting material from six companies from various types of process industries. It was found that the method and the tools worked very well in practice. The results gave interesting insights into the effectiveness of learning from the incidents.

Experimental optimization of the 2nd loop configuration for feedforward amplifiers in terms of their efficiency and linearity

In this paper, we report the results of the experimental optimization of the 2nd-loop configuration for feedforward amplifiers in terms of their efficiency and linearity. We consider two parameters in the 2nd-loop of a feedforward amplifier: (i) the size ratio between the main and error amplifiers and (ii) the coupling factor of the error signal coupler. Experiments are performed using a multicarrier down-link WCDMA signal under various configurations. The measured data, which are normalized with respect to the overall power capacity of the main and error amplifiers, show that, among the different 2nd-loop configurations, the best compromised efficiency (13.4%) at a given adjacent channel leakage ratio (ACLR) level (−50 dBc) is observed for a size ratio of around 3.0 and a coupling factor of around 7.2 dB. © 2006 Wiley Periodicals, Inc. Microwave Opt Technol Lett 48: 617–621, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.21425

The middle portion in the second cytoplasmic loop of the thyrotropin receptor plays a crucial role in adenylate cyclase activation.

We have examined the role of the 2nd cytoplasmic loop of the TSH receptor (TSHR) in TSH- and TSHR autoantibody-stimulated cAMP and inositol phosphate formation using mutants created by substituting sequences from the alpha 1- or beta 2-adrenergic receptors (AR). Unlike similar substitution mutants involving the 3rd cytoplasmic loop that lose agonist-induced inositol phosphate but not cAMP increase after transfection into Cos-7 cells, mutants involving the 2nd loop showed significant change in generating both signals. Mutant B525, which substitutes residues 525-527 with a comparable beta 2-AR sequence, exhibited a complete loss in TSH- or Graves' immunoglobulin G-increased cAMP signaling and a lesser loss in phosphoinositide signaling. This is a unique mutant in which cAMP response was completely lost in all those involving the 2nd or 3rd cytoplasmic loop. On the other hand, mutant B528, in which residues 528-532 are substituted with a comparable beta 2-AR sequence, exhibited the most profound loss in phosphoinositide signaling. Mutants involving portions surrounding residues 528-532 in the 2nd cytoplasmic loop had milder losses in agonist-increased phosphoinositide signaling and much lesser losses in agonist-increased cAMP generation. The transfection efficiency of all transfectants was the same. All transfectants with mutant or wild type TSHR had a similar amount and identical profile of TSHR mRNA in Northern blots and TSHR forms on Western blots. Thus, the 2nd cytoplasmic loop is important for agonist-induced cAMP as well as for phosphoinositide signal generation, whereas the 3rd loop appears to be important only for the latter. The most important determinant for agonist-increased cAMP signal generation is in the middle of the 2nd loop, around residues 525-527. In contrast, the determinants most critical for agonist-induced phosphoinositide signaling are also located in the middle of the 2nd loop, around residues 528-532, and those with less importance are broadly distributed.