PI3Kα has been identified as an oncogene in human tumors. By use of rational drug design, a targeted covalent inhibitor 3 (CNX-1351) was created that potently and specifically inhibits PI3Kα. We ...demonstrate, using mass spectrometry and X-ray crystallography, that the selective inhibitor covalently modifies PI3Kα on cysteine 862 (C862), an amino acid unique to the α isoform, and that PI3Kβ, -γ, and -δ are not covalently modified. 3 is able to potently (EC50 < 100 nM) and specifically inhibit signaling in PI3Kα-dependent cancer cell lines, and this leads to a potent antiproliferative effect (GI50 < 100 nM). A covalent probe, 8 (CNX-1220), which selectively bonds to PI3Kα, was used to investigate the duration of occupancy of 3 with PI3Kα in vivo. This is the first report of a PI3Kα-selective inhibitor, and these data demonstrate the biological impact of selectively targeting PI3Kα.
Introduction: Coronavirus disease 2019 (COVID-19) mainly involves the lungs; it also affects the endocrine system including the hypothalamic-pituitary adrenal axis (HPA).
Aims: To assess and compare ...the changes in the HPA axis in survivors of SARS CoV-2 infection 3 months after recovery.
Methods: A cross-sectional, descriptive study was undertaken at JIPMER, including 69 patients 318 years of age, after 3 months after the diagnosis of COVID-19. At baseline, a fasting sample was collected for basal cortisol, thyroid function, and biochemical investigations between 8.00-9.00 AM. A low dose Synacthen test (1 mg) was performed in all patient's blood samples for serum cortisol collected after 30 and 60 minutes of intravenous administration.
Results: The mean age (SD) was 49.74 ± 12.05 years, 24 (34.78%) were female and 45 (65.2%) were male patients. 20 (28.98%) patients had mild, 10 (14.4%) had moderate and 39 (56.52%) patients had severe COVID-19 infection. 62 (89.85%) patients had post covid symptoms. Out of the sixty-nine patients with COVID-19, nine patients (9/69, 13.04%) had peak serum cortisol <18 mg/dL suggestive of secondary adrenal insufficiency. Peak serum cortisol did not differ according to disease severity Mild, (13.03 ± 4.08 mg/dL) vs moderate, (11.52 ± 2.40 mg/dL) vs severe, (13.70 ± 1.43 mg/dL), P = 0.67. In addition, there was no difference in peak serum cortisol in patients with or without adrenal insufficiency (12.99 ± 2.54 mg/dL) vs (22.44±5.52 mg/dL), P = 0.09 respectively.
Conclusion: HPA axis is affected in 13.04% of patients 3 months after presentation with COVID-19. These findings have important implications for the clinical care and long-term follow-up of patients after COVID-19.
Background: This research set out to collate and contrast three popular luting agents-heated composite resin, resin-modified glass ionomer cement (RMGIC), and resin cement, and light-cure resin ...cement by measuring their shear bond strengths. Shear bond strength was measured between lithium disilicate discs (IPS E-max) and specimens luted with heated composite resin (Tetric N-Ceram, Ivoclar Vivadent), self-adhesive resin cement (3M ESPE Rely X U200), light-activated resin cement (Rely X Veneer cement), and resin-modified glass ionomer cement (Fuji Plus, GC America). A comparison was made between the shear bond strength of standard luting cement and heated composite resin on lithium disilicate discs.MATERIALS AND METHODSForty-eight lithium disilicate disc samples are collected and put on acrylic blocks for this investigation. To improve luting cement adhesion, the discs are etched with 5% hydrofluoric acid (HF) gel. For easier handling and lower viscosity during luting, the composite resin is heated to between 55 and 68°C on a digital wax melter. Shear bond strength tests were executed with the universal testing device after the following luting cement was applied in the center of the test specimen (lithium disilicate discs). Statistics software was used for the calculations and analysis.RESULTSIn accordance with the findings of the tests, shear bond strengths ranged from 2.2851 ± 0.5901 for nanohybrid composite resin to 7.3740 ± 0.6969 for self-adhesive resin cement and 4.4647 ± 0.9774 for light-activated resin cement. A statistically significant (p≤0.001) difference between the groups was found. Mean shear bond strength was significantly highest in the self-adhesive resin cement group, followed by the light-activated resin cement group, resin-modified GIC, and least with the nanohybrid composite resin group.CONCLUSIONComposite resins; in fixation of indirect restorations can have their viscosity reduced by preheating in a device, but they must be employed as soon as possible after removal. Standardizing the methods of heating composite resins for cementation is necessary to achieve desirable outcomes and direct the physician in their application. Although preheating composite resins for luting operations can be utilized to decrease the material's viscosity and enhance the restoration setting; it may not increase bond strength.
Introduction: Primary hyperparathyroidism (PHPT) is a rare disease in paediatric age group with an estimated incidence of 2-5 cases in 100,000 live births. PHPT is characterized by excessive ...secretion of parathyroid hormone (PTH), responsible for hypercalcemia and hypophosphatemia. Most cases of PHPT are not hereditary and the familial PHPT accounts for 10-20% of cases.
Case Description: A 14 year old male child brought with complaints of pain abdomen in left loin radiating to left groin and was associated with nausea and vomiting. On evaluation there was hypercalcemia (13.48 mg/dl (normal range-8.8 - 10.6 mg/dl), hypophosphatemia (3.61 mg/dl) (normal range -4.0 - 7.0 mg/dl) and elevated intact PTH (231.5 pg/ml (18.4 - 80.1 pg/mL) suggestive of PTH dependent hypercalcemia. Further 4D computerised tomography neck and sestamibi scan localised to right superior parathyroid adenoma and ultrasound scan didn't show parathyroid lesion. Subsequently he underwent right superior parathyroid adenectomy and serum calcium levels normalized after surgery. Clinical exome sequencing revealed heterozygous mutation c.2594T>C,P.phe86ser in the SLC12A1gene. Follow up after 2months revealed normocalcemia (9.6 mg/dl) (8.8 - 10.6 mg/dl).
Discussion: Solute Carrier Family 12-member 1 (SLC12A1) gene encodes the sodium-potassium-chloride co-transporter (NKCC2) at the apical membrane of the thick ascending loop of Henle (TAL). Bartter's syndrome (BS) type I is a rare, renal tubular disorder associated with mutation of the SLC12A1 gene. The many allelic variants reported present with a spectrum of phenotypes, biochemical abnormalities and clinical severities. The case described suggest an association between primary hyperparathyroidism and loss of function mutation of SLC12A1, which may result in an aberrant threshold of the calcium sensing receptor at the level of the kidney
Conclusion: We hereby report a novel mutation (c.2594T>C,P.phe86ser) associated with primary hyperparathyroidism in SLC12A1 gene. This case report adds to the existing literature for emerging role of SLC12A1 gene in calcium homeostasis.
Background:
AAA syndrome is a rare cause of primary adrenal insufficiency associated with alacrimia, achalasia and neurological dysfunction. The existing literature consists mostly of case series. ...Here we describe the series of cases who presented to our hospital.
Aims and Objectives:
To describe the clinical charecteristics of patients with AAA syndrome.
Results:
A total 8 cases were analysed. Median age of presentation was 4.5 years. Alacrima, achalasia, adrenal insuffciency were present in 8,7, and 5 patients respectively. 4 patients presented with achalasia and 4 with adrenal insufficiency. None of the patients had salt wasting. 3 out of 8 patients had neurological signs and 6 out of 8 patients had autonomic dysfunction. Associated primary hypothyroidism, developmental delay, skin conditions were seen in 3/8, 3/8, and 2/8 of total patients respectively. Genetic evaluation was done in 7 patients and two showed homozygous mutations, one of which was novel. Genetic evaluation pending in one patient.
Conclusion:
We present here the retrospective data showing the the clinical charecteristics of patients with AAA syndrome.
With the development of wireless communication technologies, IEEE 802.11 standard (Wi-Fi) has undergone a rapid growth, thanks to low cost and high-speed connectivity. Hence effective mechanisms need ...to be developed to exploit the diversity across a multiple access points and to provide a uniform load distribution in order to improve the QoS of users and to improve the overall composite capacity. In this paper, we propose a handoff scheme considering the current active application in use rather than a single fixed threshold value and dynamically changing the threshold value depending upon the currently active applications. In addition to it, we also propose a pro-active Load Balancing scheme which completely avoids unnecessary overloading of access points by considering the load at the target access point before associating with it.
The rules underlying the structure of antigen receptor repertoires are not yet fully defined, despite their enormous importance for the understanding of adaptive immunity. With current technology, ...the large antigen receptor repertoires of mice and humans cannot be comprehensively studied. To circumvent the problems associated with incomplete sampling, we have studied the immunogenetic features of one of the smallest known vertebrates, the cyprinid fish
sp. "Singkep" ("minifish"). Despite its small size, minifish has the key genetic facilities characterizing the principal vertebrate lymphocyte lineages. As described for mammals, the frequency distributions of immunoglobulin and T cell receptor clonotypes exhibit the features of fractal systems, demonstrating that self-similarity is a fundamental property of antigen receptor repertoires of vertebrates, irrespective of body size. Hence, minifish achieve immunocompetence via a few thousand lymphocytes organized in robust scale-free networks, thereby ensuring immune reactivity even when cells are lost or clone sizes fluctuate during immune responses.
Dental implants have been a broadly recognised treatment modality to replace missing teeth and in order to restore the oral functions. The utilisation of root form endosseous implants have increased ...considerably and this option has become much more sophisticated with the introduction of latest designs and concepts. Long term post placement studies have revealed that prosthetic complications, including screw loosening, screw fracture, framework and implant fracture. Abutment screw loosening is the second most cause of failure of implant supported crowns, after loss of osseointegration. This condition is mostly witnessed in single implant supported restoration. Management of screw loosening is a challenging procedure and this clinical report describes the management of an implant abutment screw loosening of lower back teeth region with minimal damage to the existing restoration making it possible to be reused.
In an abutment - Implant fracture, it is generally a challenge for the clinician to remove the fractured fragments. A fractured abutment screw of a single crown or fixed dental prostheses supported ...by an endosseous implant is a complication. In some cases, the screw cannot be removed, and alternative solutions should be considered. This clinical report describes a fractured abutment screw prostheses and cold welded screw , which was impossible to retrieve.
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