Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress.

To survive, mammalian cells must adapt to environmental challenges. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe hyperosmotic stress, cells enter a transient hibernation-like state in anticipation of recovery. We demonstrate this adaptive pausing response (APR) is a coordinated cellular response that limits ATP supply and consumption through mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery. We further show that recovery from severe stress involves ISR (integrated stress response) signaling that permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress via a hibernation-like mechanism that preserves vital elements of cellular function under harsh environmental conditions.

Effect of Hypertonic Saline Solution on the Ventilatory Mechanics of Lungs Donated After Brain Death.

INTRODUCTION: Brain death (BD) compromises the viability of the lung for donation. Hypertonic saline solution (HSS) induces rapid intravascular volume expansion and immunomodulatory action. We investigated its role in ventilatory mechanics (VMs) and in the inflammatory activity of the lungs of rats subjected to BD. METHODS: Wistar rats were divided into four groups: control, n = 10: intact rats subjected to extraction of the heart-lung block; BD, n = 8 (BD): rats treated with isotonic saline solution (4 mL/kg) immediately after BD; hypertonic saline 0 h, n = 9 (Hip.0'): rats treated with HSS (4 mL/kg) immediately after BD; and hypertonic saline 1 h, n = 9 (Hip.60'), rats treated with HSS (4 mL/kg) 60 min after BD. The hemodynamic characteristics, gas exchange, VMs, inflammatory mediators, and histopathological evaluation of the lung were evaluated over 240 min of BD. RESULTS: In VMs, we observed increased airway resistance, tissue resistance, tissue elastance, and respiratory system compliance in the BD group (P < 0.037), while the treated groups showed no impairment over time (P > 0.05). In the histological analysis, the BD group showed a greater area of perivascular edema and a higher neutrophil count than the control group and the Hip.60' group (P < 0.05). CONCLUSIONS: Treatment with HSS was effective in preventing changes in the elastic and resistive pulmonary components, keeping them at baseline levels. Late treatment reduced perivascular and neutrophilic edema in lung tissue.

Comparative-effectiveness study evaluating outcomes for transforaminal epidural steroid injections performed with 3% hypertonic saline or normal saline in lumbosacral radicular pain.

BACKGROUND: Transforaminal epidural steroid injections (TFESI) are commonly employed to treat lumbosacral radiculopathy. Despite anti-inflammatory properties, the addition of 3% hypertonic saline has not been studied. OBJECTIVE: Compare the effectiveness of adding 0.9% NaCl (N-group) vs. 3% NaCl (H-group) in TFESI performed for lumbosacral radiculopathy. METHODS: This retrospective study compared TFESI performed with lidocaine, triamcinolone and 0.9% NaCl vs. lidocaine, triamcinolone and 3% NaCl. The primary outcome was the proportion of patients who experienced a ≥ 30% reduction in pain on a verbal rating scale (VRS; 0-100) at 3 months. Secondary outcome measures included the proportion of patients who improved by at least 30% for pain at 1 and 6 months, and who experienced ≥15% from baseline on the Oswestry disability index (ODI) at follow-up. RESULTS: The H-group experienced more successful pain outcomes than the N-group at 3 months (59.09% vs. 41.51%; P = .002) but not at 1 month (67.53% vs. 64.78%; P = .61) or 6 months (27.13% vs 21.55%: P = .31). For functional outcome, there was a higher proportion of responders in the H-group than the N-group at 3 months (70.31% vs. 53.46%; P = .002). Female, age ≤ 60 years, and duration of pain ≤ 6 months were associated with superior outcomes at the 3-month endpoint. Although those with a herniated disc experienced better outcomes in general with TFESI, the only difference favoring the H-group was for spondylolisthesis patients. CONCLUSIONS: 3% hypertonic saline is a viable alternative to normal saline as an adjunct for TFESI, with randomized studies needed to compare its effectiveness to steroids as a possible alternative. REGISTRATION: Thai Clinical Trials Registry ID TCTR 20231110006.

Thoracic Society of Australia and New Zealand position statement: The safe clinical use of sputum induction for bio-sampling of the lower airways in children and adults.

Sputum induction is widely used in clinical settings for collection of biological samples from the lower airways. However, in recent years sputum induction has been associated with serious adverse events and even death. This position statement was commissioned by the Thoracic Society of Australia and New Zealand to address major adverse events of two deaths associated with sputum induction that have occurred in Australia in 2021, and outlines best practice for the safe use of sputum induction. The statement resulted from systematic literature searches by a multi-disciplinary group including respiratory physicians, nurses and physiotherapists (paediatric and adults focused). Consumers had input to an advanced draft of the position statement. The position statement covers indications for sputum induction, informed consent, scope of practice of personnel administering the procedure, infection control considerations, details about the sputum induction procedure, safety considerations and risk assessment in clinical settings.

Is post-hypertonic lysis of human red blood cells caused by excessive cell volume regulation?

Human red blood cells (RBC) exposed to hypertonic media are subject to post-hypertonic lysis - an injury that only develops during resuspension to an isotonic medium. The nature of post-hypertonic lysis was previously hypothesized to be osmotic when cation leaks were observed, and salt loading was suggested as a cause of the cell swelling upon resuspension in an isotonic medium. However, it was problematic to account for the salt loading since the plasma membrane of human RBCs was considered impermeable to cations. In this study, the hypertonicity-related behavior of human RBCs is revisited within the framework of modern cell physiology, considering current knowledge on membrane ion transport mechanisms - an account still missing. It is recognized here that the hypertonic behavior of human RBCs is consistent with the acute regulatory volume increase (RVI) response - a healthy physiological reaction initiated by cells to regulate their volume by salt accumulation. It is shown by reviewing the published studies that human RBCs can increase cation conductance considerably by activating cell volume-regulated ion transport pathways inactive under normal isotonic conditions and thus facilitate salt loading. A simplified physiological model accounting for transmembrane ion fluxes and membrane voltage predicts the isotonic cell swelling associated with increased cation conductance, eventually reaching hemolytic volume. The proposed involvement of cell volume regulation mechanisms shows the potential to explain the complex nature of the osmotic response of human RBCs and other cells. Cryobiological implications, including mechanisms of cryoprotection, are discussed.

Mucus Transpiration as the Basis for Chronic Cough and Cough Hypersensitivity.

Chronic cough is characterized by a state of cough hypersensitivity. We analyze the process of transpiration, by which water appears to evaporate from laryngeal and tracheal mucus as from the surface of a leaf, as a potential cause of cough hypersensitivity. In this process, osmotic pressure differences form across mucus, pulling water toward the air, and preventing mucus dehydration. Recent research suggests that these osmotic differences grow on encounter with dry and dirty air, amplifying pressure on upper airway epithelia and initiating a cascade of biophysical events that potentially elevate levels of ATP, promote inflammation and acidity, threaten water condensation, and diminish mucus water permeability. Among consequences of this inflammatory cascade is tendency to cough. Studies of isotonic, hypotonic, and hypertonic aerosols targeted to the upper airways give insights to the nature of mucus transpiration and its relationship to a water layer that forms by condensation in the upper airways on exhalation. They also suggest that, while hypertonic NaCl and mannitol may provoke cough and bronchoconstriction, hypertonic salts with permeating anions and non-permeating cations may relieve these same upper respiratory dysfunctions. Understanding of mucus transpiration and its role in cough hypersensitivity can lead to new treatment modalities for chronic cough and other airway dysfunctions promoted by the breathing of dry and dirty air.

Effect of continuous hypertonic saline infusion on clinical outcomes in patients with traumatic brain injury.

Osmotic therapy has been recognized as an important treatment option for patients with traumatic brain injury (TBI). Nevertheless, the effect of hypertonic saline (HTS) remains unknown, as findings are primarily based on a large database. This study aimed to elucidate the effect of HTS on the clinical outcomes of patients with TBI admitted to the intensive care unit (ICU). We retrospectively identified patients with moderate-to-severe TBI from two public databases: Medical Information Mart for Intensive Care (MIMIC)-IV and eICU Collaborative Research Database (eICU-CRD). A marginal structural Cox model (MSCM) was used, with time-dependent variates designed to reflect exposure over time during ICU stay. Trajectory modeling based on the intracranial pressure evolution pattern allowed for the identification of subgroups. Overall, 130 (6.65%) of 1955 eligible patients underwent HTS. MSCM indicated that the HTS significantly associated with higher infection complications (e.g., urinary tract infection (HR 1.88, 95% CI 1.26-2.81, p = 0.002)) and increased ICU LOS (HR 2.02, 95% CI 1.71-2.40, p < 0.001). A protective effect of HTS on GCS was found in subgroups with medium and low intracranial pressure. Our study revealed no significant difference in mortality between patients who underwent HTS and those who did not. Increased occurrence rates of infection and electrolyte imbalance are inevitable outcomes of continuous HTS infusion. Although the study suggests slight beneficial effects, including better neurological outcomes, these results warrant further validation.

Effectiveness of hypertonic saline infusion in management of traumatic brain injury: an updated systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This study aimed to find out the efficacy of using Hypertonic saline solution (HSS) over mannitol in the management of TBI by comparing their performance in improving different outcomes. METHODS: Electronic databases were searched for randomized controlled trials (RCTs) assessing the impact of HSS vs. mannitol on ICP in patients who suffered TBI. Outcomes of interest were mortality, neurologic functional outcomes, risk ratio (RR) of successful ICP treatment, reduction in ICP after 30-60 and 90-120 min, improvement in cerebral perfusion pressure (CPP) at 30-60 and 90-120 min, and also treatment failure. Evaluations were reported as RR or mean difference (MD) with 95% confidence intervals (CIs) using weighted random-effects models. RESULTS: The analysis included 624 patients from 15 RCTs. HSS infusion had a significant impact on the improvement of CPP at 30-60 min [MD = 5.54, 95% CI (3.04, 8.03),p < 0.001] compared to mannitol. However, results yielded no significant difference between HSS and mannitol in terms of mortality, neurologic functional outcomes, successful ICP treatment, reduction in ICP after 30-60 min and 90-120 min, improvement in CPP at 90-120 min, and treatment failure. CONCLUSION: HSS and mannitol are both effective treatments for elevated ICP due to TBI. However, further research is required to derive a better comparison.

Hyperosmolar therapies for neurological deterioration in mild and moderate traumatic brain injury: towards new research.

The scoping review by Nicolò Marchesini and colleagues about the use of hyperosmolar therapies (HTs) in patients with traumatic brain injury (TBI) points out a significant gap in scientific literature regarding this topic. Although there are few high-quality recommendations, it is important to provide care under certain physiologic parameters. Through this letter we comment on the importance of guidelines to administer and monitor the use of HTs in the Neuro-ICU.

Hypertonic Saline Versus Other Intracranial-Pressure-Lowering Agents for Patients with Acute Traumatic Brain Injury: A Systematic Review and Meta-analysis.

Acute traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. Intracranial pressure (ICP)-lowering is a critical management priority in patients with moderate to severe acute TBI. We aimed to evaluate the clinical efficacy and safety of hypertonic saline (HTS) versus other ICP-lowering agents in patients with TBI. We conducted a systematic search from 2000 onward for randomized controlled trials (RCTs) comparing HTS vs. other ICP-lowering agents in patients with TBI of all ages. The primary outcome was the Glasgow Outcome Scale (GOS) score at 6 months (PROSPERO CRD42022324370). Ten RCTs (760 patients) were included. Six RCTs were included in the quantitative analysis. There was no evidence of an effect of HTS on the GOS score (favorable vs. unfavorable) compared with other agents (risk ratio [RR] 0.82, 95% confidence interval [CI] 0.48-1.40; n = 406; 2 RCTs). There was no evidence of an effect of HTS on all-cause mortality (RR 0.96, 95% CI 0.60-1.55; n = 486; 5 RCTs) or total length of stay (RR 2.36, 95% CI - 0.53 to 5.25; n = 89; 3 RCTs). HTS was associated with adverse hypernatremia compared with other agents (RR 2.13, 95% CI 1.09-4.17; n = 386; 2 RCTs). The point estimate favored a reduction in uncontrolled ICP with HTS, but this was not statistically significant (RR 0.52, 95% CI 0.26-1.04; n = 423; 3 RCTs). Most included RCTs were at unclear or high risk of bias because of lack of blinding, incomplete outcome data, and selective reporting. We found no evidence of an effect of HTS on clinically important outcomes and that HTS is associated with adverse hypernatremia. The included evidence was of low to very low certainty, but ongoing RCTs may help to the reduce this uncertainty. In addition, heterogeneity in GOS score reporting reflects the need for a standardized TBI core outcome set.

Safety and Effect on Intracranial Pressure of 3% Hypertonic Saline Bolus Via Peripheral Intravenous Catheter for Neurological Emergencies.

BACKGROUND: Elevated intracranial pressure (ICP) is a neurological emergency in patients with acute brain injuries. Such a state requires immediate and effective interventions to prevent potential neurological deterioration. Current clinical guidelines recommend hypertonic saline (HTS) and mannitol as first-line therapeutic agents. Notably, HTS is conventionally administered through central venous catheters (CVCs), which may introduce delays in treatment due to the complexities associated with CVC placement. These delays can critically affect patient outcomes, necessitating the exploration of more rapid therapeutic avenues. This study aimed to investigate the safety and effect on ICP of administering rapid boluses of 3% HTS via peripheral intravenous (PIV) catheters. METHODS: A retrospective cohort study was performed on patients admitted to Sisters of Saint Mary Health Saint Louis University Hospital from March 2019 to September 2022 who received at least one 3% HTS bolus via PIV at a rate of 999 mL/hour for neurological emergencies. Outcomes assessed included complications related to 3% HTS bolus and its effect on ICP. RESULTS: Of 216 3% HTS boluses administered in 124 patients, complications occurred in 8 administrations (3.7%). Pain at the injection site (4 administrations; 1.9%) and thrombophlebitis (3 administrations; 1.4%) were most common. The median ICP reduced by 6 mm Hg after 3% HTS bolus administration (p < 0.001). CONCLUSIONS: Rapid bolus administration of 3% HTS via PIV catheters presents itself as a relatively safe approach to treat neurological emergencies. Its implementation could provide an invaluable alternative to the traditional CVC-based administration, potentially minimizing CVC-associated complications and expediting life-saving interventions for patients with neurological emergencies, especially in the field and emergency department settings.

Intraoperative Hypertonic Saline Irrigation Preventing Seroma Formation in the Treatment of Axillary Bromhidrosis.

PURPOSE: Subcutaneous seroma formation (SF) is commonly seen after axillary bromhidrosis surgeries and its treatment can be challenging and long. Current prevention methods are not consistent, and the treatment includes repeated aspirations and drains, both are associated with higher risk for infections. The purpose of this article is to present a novel and simple technique of intraoperative hypertonic saline irrigation (IHSI) to axillary bromhidrosis subcutaneous dead space, which prevents postoperative SF and enables early drain removal due to reduced secretions. METHODS: From 2015 to 2022, we performed the intraoperative irrigation of the cavity through normal saline in 100 patients with primary axillary bromhidrosis. Through an incision approximately 3 cm long at the central axillary crease, the entire subcutaneous tissues containing apocrine glands were initially dissected with straight scissors within the axillary area, and then, the undermined apocrine glands were removed with curved scissors. The skin was defatted to become a full-thickness skin flap. Any suspected hemorrhagic spots were immediately coagulated electrosurgically. Negative pressure drains were placed, and intraoperative irrigation of the cavity through the drains with 20 ml of NaCl 0.9% or NaCl 10% left at site for 10 min applies different saline solutions in the same patients. RESULTS: The volume of drainage on the 1st postoperative day was 6.54±0.36 mL for the group B, which was significantly less than 15.23±0.42 mL for the group A (p < 0.05). The time of drain removal for the group B was 24 h, which was shorter than 48 h for the group A. In group B, 4 percent of axillae showed significant SF postoperatively, which was lower than the 20 percent of axillae associated with the group A (p < 0.05). The rate of incision infection for the group B was 2 percent, which was significantly lower than the 6 percent of axillae in the group A (p < 0.05). Two percent of axillae showed skin edge necrosis postoperatively in the group B, which was lower than the 10 percent of axillae associated with the group A (p < 0.05). CONCLUSIONS: IHSI enhances adhesion formation and reduces secretion rate in subcutaneous dissection space after axillary bromhidrosis surgeries, therefore enables early drain removal and prevents SF, incision infection and skin edge necrosis. As a result, reducing the pain of patients, decreasing inconveniency and cost saving of multiple outpatient visits or additional surgery. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Effectiveness of 5-Fluorouracil and Hypertonic Glucose in the Prevention of Post-mastectomy Seroma in an Experimental Animal Model.

INTRODUCTION: Seroma is a frequent complication that can affect the final result of reconstructive and cosmetic surgeries. METHODOLOGY: This study evaluated the effectiveness of 5-Fluorouracil and 75% hypertonic glucose in preventing seroma in a mastectomy rat model, as well as cellular and vascular events in adjacent tissues. A left mastectomy with lymphadenectomy was performed in 60 Wistar-Albino female rats. Animals randomly allocated to the control group (Group I; n = 20) were sutured right after mastectomy. The intervention groups received 1.0 mL of 75% hypertonic glucose (Group II; n = 20) or 1.0 mL of 5-Fluorouracil (Group III; n = 20) at the surgical site before suturing. The assessment of the presence of seroma was performed in all animals at 24, 48, and 72 h and on the 7th and 12th postoperative day. After the 12th day, a tissue sample was taken from the surgical site and sent for histological analysis. The occurrence of seroma was assessed using GEE. A significance level of 5% was adopted. RESULTS: Differences in seroma formation over time were observed for both Control Group I (p=0.041) and Intervention Group II (p<0.001). In Intervention Group III, there was no difference in the percentage and volume of seroma across the assessment points (p=0.627). When both the Control and Intervention Group II were compared to Intervention Group III, we found a reduction in seroma formation in the last group. The reduction in the inflammatory process was more regular to Intervention Group III. CONCLUSION: In this animal model, 5-Fluorouracil was more effective in preventing seroma formation than 75% Hypertonic Glucose. No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Experimentally Induced Pain Results in Reduced Activity of the Rotator Cuff Muscles in Healthy Subjects.

Shoulder pain is a complex, prevalent problem that is multifactorial in nature. While there are many potential causes, one common suspect is the rotator cuff musculature. The purpose of the present study was to induce pain in the supraspinatus muscle of healthy subjects and observe the resulting changes in muscle activity. Eight muscles on 23 subjects were assessed using electromyography: anterior, middle, and posterior deltoid; pectoralis major; upper trapezius; latissimus dorsi; serratus anterior; supraspinatus; and infraspinatus. It was hypothesized that the rotator cuff muscles would display reduced activity during pain, and that reductions in activity would remain after the pain had dissipated. Both of the rotator cuff muscles measured did indeed display reduced activity in a majority of the dynamic, isometric, and maximal contractions. Many of those reductions remained after the pain had subsided.

Efficacy of Intravenous 20% Mannitol vs 3% Hypertonic Saline in Reducing Intracranial Pressure in Nontraumatic Brain Injury: A Systematic Review and Meta-analysis.

Background: Nontraumatic brain injury encompasses various pathological processes and medical conditions that result in brain dysfunction and neurological impairment without direct physical trauma. The study aimed to assess the efficacy of intravenous administration of 20% mannitol and 3% hypertonic saline to reduce intracranial pressure in nontraumatic brain injury. Materials and methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed for study selection and data extraction. The search was conducted in the PubMed, Embase, and Scopus databases, including articles published in English from January 2003 to December 2023. Our study included randomized controlled trials, comparative studies, prospective analyses, and retrospective cohort studies. We extracted data on baseline characteristics of patients, intervention details, major outcomes, and complications. Quality assessment was performed using the Jadad scale and the Robvis assessment tool for risk of bias. Results: A total of 14 studies involving 1,536 patients were included in the analysis. Seven studies reported hypertonic saline as more effective in reducing intracranial pressure, while three studies found similar effectiveness for both interventions. Adverse events were reported in only three studies. The studies that reported complication rates ranged from 21 to 79%. A meta-analysis was conducted on five studies, showing varying rates of adverse events associated with mannitol and hypertonic saline. Conclusion: Both hypertonic saline solution and mannitol have been explored as treatment options for decreasing intracranial pressure in nontraumatic brain injuries. While some studies indicate the superiority of hypertonic saline, others report similar effectiveness between the two interventions. How to cite this article: Choudhury A, Ravikant, Bairwa M, Jithesh G, Kumar S, Kumar N. Efficacy of Intravenous 20% Mannitol vs 3% Hypertonic Saline in Reducing Intracranial Pressure in Nontraumatic Brain Injury: A Systematic Review and Meta-analysis. Indian J Crit Care Med 2024;28(7):686-695.

Efficacy of hypertonic saline in treatment of corneal edema: A randomized crossover trial.

Background: To determine the efficacy of sodium chloride (NaCl) 5% drops in comparison to 6% ointment and study tear Osmolarity as an objective measure correlating with clinical findings in the treatment of corneal edema. Methods: This is a prospective, randomized, interventional, open-label, crossover study of 40 eyes of 40 patients with corneal edema due to Bullous keratopathy and Fuchs endothelial dystrophy. Subjects were divided into 2 groups by simple randomization: group A received NaCl 5% drops and group B received NaCl 6% ointment. Both treatments were administered four times daily for seven days. Subsequently, after a 1-week wash-out period, switch over of treatment was done. Central corneal thickness (CCT) and tear osmolarity were primarily efficacy variables. Results: Baseline parameters were comparable. The median reduction in CCT from baseline (706.7 ± 58.41 µm), at 6 hours with NaCl 5% drops was 23 µm (-27, 74) and that with NaCl6% ointment was 37.5 µm (-7, 85). The reduction in CCT was more with 6% ointment (p = 0.013). The difference in reduction in CCT between two treatments at one week was not statistically significant, although there was a substantial reduction in thickness with each treatment individually. The change in tear osmolarity from the baseline at 2 Hours with both NaCl5% drops and 6% ointment was significant, and it remained so till 6 h. Side-effects such as stickiness, stinginess, blurring, and foreign body sensation were more with 6% eye ointment. Conclusion: Topical NaCl 6% eye ointment in QID dosage is more effective than NaCl 5% drops in the medical management of corneal edema. In patients symptomatically intolerant to ointment, NaCl 5% eye drops may be prescribed as an effective option.

[A case of neonatal Netherton syndrome]. / 新生儿Netherton综合征1例.

A male infant, aged 6 days, was admitted to the hospital due to respiratory distress and systemic desquamative rash after birth. The infant presented with erythema and desquamative rash, respiratory failure, recurrent infections, chronic diarrhea, hypernatremic dehydration, and growth retardation. Comprehensive treatment, including anti-infection therapy, intravenous immunoglobulin administration, and skin care, resulted in improvement of the rash, but recurrent infections persisted. Second-generation sequencing revealed a homozygous mutation in the SPINK5 gene, consistent with the pathogenic variation of Netherton syndrome. The family opted for palliative care, and the infant died at the age of 2 months after discharge. This report documents a case of Netherton syndrome caused by the SPINK5 gene mutation in the neonatal period, and highlights multidisciplinary diagnosis and therapy for this condition.

AMPK-related protein kinase ARK5 regulates subcellular localization of RNA-binding protein hnRNP A1 during hypertonic stress.

The heterogeneous nuclear ribonucleoprotein hnRNP A1 is a nucleocytoplasmic-shuttling RNA-binding protein that plays an important role in nucleic acid metabolism and gene expression regulation. The function of hnRNP A1 is determined in part by its specific location within the cell. Although some work has been done to elucidate the signaling pathways that regulate the cellular localization of hnRNP A1, the precise mechanism(s), including physiological and pathophysiological conditions that alter hnRNP A1 localization, are not known. We previously conducted an unbiased RNAi-based kinome-wide screen to identify kinases that regulate hnRNP A1 localization during hypertonic stress. One of the hits from this screen is AMPK-related protein kinase 5 (ARK5). Here, we validate ARK5 as the kinase responsible for controlling hnRNP A1 subcellular localization in response to hypertonic stress. We find using immunoprecipitation and in vitro kinase assay methods that ARK5 directly interacts with and phosphorylates hnRNP A1 on serine residues within the F-peptide region. We further show that the M9 motif of hnRNP A1 is essential for the ARK5-hnRNP A1 interaction and subsequent phosphorylation. In addition, the silencing of ARK5 increases the expression of antiapoptotic protein Bcl-xL and consequently delays caspase activation during hypertonic stress. Our results indicate that ARK5 phosphorylates hnRNP A1 and regulates its subcellular localization during hypertonic stress.

New insights on diagnosis and treatment of AVP deficiency.

Arginine vasopressin deficiency (AVP-D) is one of the main entities of the polyuria-polydipsia syndrome. Its correct diagnosis and differentiation from the other two causes - AVP resistance and primary polydipsia - is crucial as this determines the further management of these patients.Over the last years, several new diagnostic tests using copeptin, the stable surrogate marker of AVP, have been introduced. Among them, hypertonic saline stimulated copeptin was confirmed to reliably and safely improve the diagnostic accuracy to diagnose AVP-D. Due to its simplicity, arginine stimulated copeptin was put forward as alternative test procedure. Glucagon-stimulated copeptin also showed promising results, while the oral growth hormone secretagogue Macimorelin failed to provide a sufficient stimulus. Interestingly, an approach using machine learning techniques also showed promising results concerning diagnostic accuracy.Once AVP-D is diagnosed, further workup is needed to evaluate its etiology. This will partly define the further treatment and management. In general, treatment of AVP-D focuses on desmopressin substitution, with oral formulations currently showing the best tolerance and safety profile. However, in addition to desmopressin substitution, recent data also showed that psychopathological factors play an important role in managing AVP-D patients.

Catheter-associated deep vein thrombosis in children with severe traumatic brain injury: A single-center experience.

BACKGROUND: This study was performed to describe the single-center experience of deep vein thrombosis (DVT) in children with severe traumatic brain injury (sTBI) who were mechanically ventilated with a central line, and to identify potentially modifiable risk factors. It was hypothesized that children with DVT would have a longer duration of central venous line (CVL) and a higher use of hypertonic saline (HTS) compared to those without DVT. PROCEDURE/METHODS: This was a retrospective study of children (0-18 years) with sTBI, who were intubated, had a CVL, and a minimum intensive care unit (ICU) stay of 3 days. Children were analyzed by the presence or absence of DVT. HTS use was evaluated using milliliter per kilogram (ml/kg) of 3% equivalents. Univariable and multivariable logistic regression models were used to determine which factors were associated with DVT. RESULTS: Seventy-seven children met inclusion criteria, 23 (29.9%) had a DVT detected in an extremity. On univariable analysis, children with DVT identified in an extremity had prolonged CVL use (14 vs. 8.5 days, p = .021) and longer duration of mechanical ventilation (15 vs. 10 days, p = .013). HTS 3% equivalent ml/kg was not different between groups. On multivariable analysis, mechanical ventilation duration was associated with DVT detection in an extremity, whereas neither CVL duration nor HTS use had an association. CONCLUSIONS: There was a high incidence of extremity DVT detected in children with sTBI who received invasive mechanical ventilation and had a CVL. HTS administration was not associated with DVT detection in an extremity.