Hyperosmolarity disrupts tight junction via TNF-α/MMP pathway in primary human corneal epithelial cells

AIM:To investigate the mechanism of the tight junction(TJ) disruption and the association between tumor necrosis factor(TNF)-α and matrix metalloproteinase(MMPs) under hyperosmotic condition in primary human corneal epithelial cells(HCECs).METHODS:The cultured HCECs were exposed to media which adding sodium chloride(Na Cl) for hyperosmolar stress or adding rh-TNF-α(10 ng/m L). NF-κB inhibitor(5 μmol/L) or GM-6001(potent and broad spectrum MMP inhibitor, 20 μmol/L)was added 1 h before that treatment. The integrity of TJ proteins was determined by immunofluorescent(IF) staining. The m RNA levels of TNF-α and MMPs were evaluated by quantitative reverse transcription polymerase chain reaction(RT-q PCR) and the protein expression by enzyme-linked immunosorbent assay(ELISA).RESULTS:TJ proteins ZO-1 and Occludin were disrupted in primary HCECs exposed to hyperosmotic medium. The m RNA expression and protein production of TNF-α increased significantly in hyperosmotic media at 500 m Os M. TNF-α mediated the expression and production of MMP-1, MMP-13, MMP-9, and MMP-3 stimulated by hyperosmotic stress. The production of MMPs in hyperosmolar media were increased through the increase of TNF-α. GM-6001 prevent the destruction of ZO-1 and Occludin in hyperosmolar stress and rh-TNF-α treated medium. TNF-α induced activation of MMPs was involved in the TJ disruption by hyperosmolarity.CONCLUSION:TJ proteins ZO-1 and Occludin are disrupted by hyperosmolar stress and TNF-α, but protected by MMP inhibitor(GM-6001). It suggests that TNF-α/MMP pathway mediates the TJ disruption in primary HCECs exposed to hyperosmotic stress.

Severe hypernatremia in hyperglycemic conditions;managing it effectively:A case report

BACKGROUND Diabetic ketoacidosis(DKA)and hyperglycemic hyperosmolar state(HHS)are common acute complications of diabetes mellitus with a high risk of mortality.When combined with hypernatremia,the complications can be even worse.Hypernatremia is a rarely associated with DKA and HHS as both are usually accompanied by normal sodium or hyponatremia.As a result,a structured and systematic treatment approach is critical.We discuss the therapeutic approach and implications of this uncommon presentation.CASE SUMMARY A 62-year-old man with no known past medical history presented to emergency department with altered mental status.Initial work up in emergency room showed severe hyperglycemia with a glucose level of 1093 mg/dL and severe hypernatremia with a serum sodium level of 169 mEq/L.He was admitted to the intensive care unit(ICU)and was started on insulin drip as per DKA protocol.Within 12 h of ICU admission,blood sugar was 300 mg/dL.But his mental status didn’t show much improvement.He was dehydrated and had a corrected serum sodium level of>190 mEq/L.As a result,dextrose 5%in water and ringer's lactate were started.He was also given free water via an nasogastric(NG)tube and IV Desmopressin to improve his free water deficit,which improved his serum sodium to 140 mEq/L.CONCLUSION The combination of DKA,HHS and hypernatremia is rare and extremely challenging to manage,but the most challenging part of this condition is selecting the correct type of fluids to treat these conditions.Our case illustrates that desmopressin and free water administration via the NG route can be helpful in this situation.

Prolotherapy in Musculoskeletal Disorders, Guideline for Orthopedic Application

Purpose: Prolotherapy is a therapeutic method that involves injecting an irritant substance into injured areas of tendons, ligaments, and articular spaces. It has a wide application in orthopedic fields, including arthritis, tendinopathies, and back pain. Protocol of injection varies extensively based on the pathological condition. This review aims to discuss orthopedic applications of prolotherapy and its related outcomes, intending to introduce more specific injection protocols in each field. Methods: In a narrative review of literature, various musculoskeletal indications and contraindications of prolotherapy, as well as the method and location of injection, solution type, procedure intervals and frequencies, outcomes and side effects are investigated to reveal all aspects of the current knowledge about this new approach. Results: Chronic back pain, osteoarthritis, and tendinopathies are considered the most common indications for prolotherapy. Protocol of injection varies from one condition to another. The actual concentration of administered dextrose ranges from 12.5% to 25%. Results of the different studies indicate that prolotherapy could have a pleasing effect on improving patient’s pain and functional outcomes. No severe complication has been mentioned in previous investigations. Conclusion: Prolotherapy is a new therapeutic option that can be suggested as an effective method in recalcitrant musculoskeletal conditions.

Diabetic ketoacidosis: Treatment in the intensive care unit or general medical/surgical ward?

Diabetic ketoacidosis(DKA) is defined as an acute metabolic disorder, which is characterized by an increased presence of circulating ketones, and the development of ketoacidosis in the presence of hyperglycemia. This syndrome occurs as a result of insulin deficiency. Patients can be dramatically ill, however, with aggressive treatment, most patients recover rapidly. Despite being a low-risk condition, the development of acidosis, is one of the admission criteria to the intensive care unit(ICU) for these patients, in order to provide close monitoring, and recognize complications that could result from the use of aggressive therapy, such as continuous infusions if insulin. In some institutions, DKA is treated in the emergency department and general medical/surgical wards to avoid ICU overcrowding.

Overlap of diabetic ketoacidosis and hyperosmolar hyperglycemic state

Diabetic ketoacidosis(DKA)and hyperosmolar hyperglycemia state(HHS)are two life-threatening metabolic complications of diabetes that significantly increase mortality and morbidity.Despite major advances,reaching a uniform consensus regarding the diagnostic criteria and treatment of both conditions has been challenging.A significant overlap between these two extremes of the hyperglycemic crisis spectrum poses an additional hurdle.It has well been noted that a complete biochemical and clinical patient evaluation with timely diagnosis and treatment is vital for symptom resolution.Worldwide,there is a lack of large-scale studies that help define how hyperglycemic crises should be managed.This article will provide a comprehensive review of the pathophysiology,diagnosis,and management of DKA-HHS overlap.

The Role of Renal Regulatory Mechanisms in the Evolution and Treatment of Pediatric Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is a life threatening complication of diabetes mellitus in pediatric patients with new onset insulin dependent diabetes. Despite advances in therapy mortality from DKA, especially in children less than two years, remains high. This review highlights the role of obligatory renal defense mechanisms in the evolution of DKA and its implication for therapy: to accomplish this goal the review starts with a cursory description of the pathogenesis and pathophysiology of metabolic derangements in DKA as a basis for understanding the renal compensatory mechanisms geared towards restoration of acid-base balance;then, the next section of the review describes how alterations in fluid and electrolyte balance at the onset of DKA and the extent of renal regulatory defense mechanisms geared towards its restoration can predispose to cerebral edema at the beginning of therapy. We conclude by suggesting that restoration of fluid and electrolyte balance should be based on the severity of metabolic acidosis as determined by the extent of renal impairment at the onset and during the course of DKA rather than strictly by protocols.

Case Report: A Severe Hypernatremia with Multiple Organ Failure, about a Clinical Observation

A hypernatremia severity is often associated with a poor prognosis, especially if it is associated with multiple organ failure. In a country with very limited resources, the prognosis may be favorable in the absence of renal replacement. We report the case of a 63 years old woman, hypertensive and diabetic, admitted to the ICU for unconsciousness. Clinically, neurological examination notes a Glasgow of 8/15 (Y2, V2, M4) and a left hemiplegia. Temperature was 39°C. Diuresis was 100 ml during the first 24 hours. Blood pressure was 90/60 mmHg, tachycardia at 133/min. Cardiac auscultation is normal. Vascular axes were weakly perceptible. Oxygen saturation was 95%. The skin examination notes a dry skin and mucous membranes, a flattening of the superficial veins, sunken eyes and a persistent skin fold. There is no hepatomegaly or splenomegaly, or jaundice. Biological point of view note natremia: 176 mmol/L;osmolarity: 390 mosmol/kg;creatinin: 300 μmol/L;glycemia > 6 g/L;transaminases 217 UI. Diagnostics: malignant hypernatremia with a high plasma osmolarity associated with an acute anuric renal failure, hydro electrolytic disorders, an abnormal liver function, a fever of central origin and a stroke. The treatment consisted of a correction of the electrolyte disorders by infusion of isotonic and hypotonic fluids with insulin. In a country with very limited resources, the severe hypernatremia prognosis associated with anuric acute renal failure may be favorable in the absence of renal replacement.

The Impact of the FreeStyle LibreTM Flash Glucose Monitoring System on Glycemic Control in Patients with Diabetes;Observational Multicenter 15-Months Study

Objectives: The study was to determine the impact of using the FreeStyle LibreTM flash glucose monitoring system on glycemic control and the rate of events due to diabetes in people with diabetes from different types and age groups. Methods: a retrospective cohort chart review study was carried out at three centers in the Taif region in the Kingdom of Saudi Arabia: The study was approved by an accredited centralized institutional review board. Paper or electronic medical records were included for individuals of any age with diabetes (type 1, type 2, gestational diabetes) managed with diet, insulin therapy, or/and oral antihyperglycemic medication and/or non-insulin injection therapy. The primary outcome measure was the laboratory HbA1c level as well as reduction. Secondary outcome measures were frequency of severe hypoglycemia, admission to hospital or ER visit related to diabetes complications, and severe hyperglycemia (DKA or HHS). Results: Data was analyzed from 1695 patients. The average HbA1c before using the flash glucose monitoring system was 9.60% ± 1.44% and 3 months HbA1c after using the FreeStyle LibreTM flash glucose monitoring system was 8.70% + 1.45% for a difference of -0.90% ([95% CI -0.92: -0.88];p 65 years, (p-values Conclusion: The benefits of using the FreeStyle LibreTM flash glucose monitoring system are self-evident in reducing HbA1c and events due to hyperglycemia or hypoglycemia.

COVID-19 Vaccine Related Hyperosmolar Hyperglycemic State and Normalized Glycemia within 2 Months

To protect from COVID-19 pandemic, several vaccines were developed infection with expected immunity against a SARS-CoV-2 infection. Short time side effects are reported. New onset diabetes was reported after SARS-CoV-2 infection. Here we report a case of new onset diabetes presenting with hyperosmolar hyperglycemic state, whose symptoms followed right after the second dose of Pfizer-BioNTech COVID-19 Vaccine. He is a 56-year old, obese Afro-American Veteran with no family history of diabetes and with HbA1C of 5.6 forty-five days prior to the hospitalization. He noted polyurea and excessive thirst following the second dose Pfizer-BioNTech COVID-19 vaccine. Hospitalized with hyperosmolar state and HbA1C of more than 14, he was treated initially with insulin drip and changed to basal, bolus regimen. In addition, he had new onset of oral thrush, requiring antifungal therapy. He needed higher doses of insulin during hospitalization and at discharge. He rapidly recovered and could be tapered off insulin in 4 months and recovered to normal glycemic state. We conclude that this is the second state to present with hyperosmolar state, and first case with rapid recovery of glycemic state.