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Normal saline (NS) is recommended for the treatment of chloride-depletion alkalosis (CDA). However, its use in patients with drinking water restrictions or fluid volume deficiencies may lead to hypernatremia. We report the case of a 42-year-old Japanese man with ileus due to sigmoidal volvulus, who presented with CDA. After endoscopic decompression, NS was administered to treat the CDA. Despite the administration of NS, CDA persisted and hypernatremia developed. The infusion was then changed to high cation-gap amino acids (HCG-AA), which improved both metabolic alkalosis and hypernatremia. Thus, HCG-AA may be useful for the treatment of hypernatremia in patients with CDA., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs mental ability and interrupts cognitive function. Heavy metal exposure like aluminum chloride is associated with neurotoxicity linked to neuro-inflammation, oxidative stress, accumulation of amyloid plaques, phosphorylation of tau proteins associated with AD like symptoms. The objective of the present investigation was to assess the effect 3-acetyl coumarin (3AC) in a rat model of AD. Preliminary screening was performed with SWISS ADME to check for the bioavailability of 3-AC and likeness score which proved favorable. 3-AC docked against Caspase 3, NF-κβ and tau protein kinase I exhibited good binding energies. Male rats were divided into six groups (n = 5). AlCl 3 (100 mg/kg BW) was administered for 28 days before starting treatment to induce AD. Normal control rats received vehicle. Treatment groups received 10, 20 and 30 mg/kg 3-AC for 28 days. Rivastigmine (2 mg/kg) was the standard. Behavioral tests (EPM, MWM) were performed at 7-day intervals throughout study period. Rats showed improved spatial memory and learning in treatment groups during behavioral tests. Rats were euthanized on day 28. Inflammatory markers (IL-1β, IL-16 and TNFα) exhibited significant improvement (p < 0.001) in treated rats. Oxidative stress enzymes (SOD, CAT, GSH, MDA) were restored. Caspase3 and NF-κβ quantified through qRT-PCR also decreased significantly (p < 0.001) when compared to disease control group. Levels of acetyl cholinesterase, dopamine and noradrenaline were also restored in treated rats significantly (p < 0.001). 3-AC treatment restored neuroprotection probably because of anti-inflammatory, anti-oxidant and anti-cholinesterase potential; hence, this can be considered a promising therapeutic potential alternative., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: For patients with nasopharyngeal carcinoma (NPC), the incidence of malnutrition is quite high, and malnutrition has severe effects on NPC patients. However, there is currently no recognized gold standard or specific nutritional assessment tool available to assess malnutrition in NPC patients. Our objective was to develop and verify a new nomogram model for NPC patients., Methods: Data were collected from NPC patients. To evaluate risk factors for malnutrition, univariate and multivariate logistic regression analyses were used. Based on the risk factors, a new nomogram model was developed. The efficacy of the model was evaluated and validated., Results: Logistic regression analysis showed that age ≥ 65 years, the number of chemotherapy cycles completed ≥ 1, a high total radiation dose received, low body mass index (BMI), low albumin, and low chloride were the risk factors. The assessment effect of the new model was good by evaluation and validation; it can be used as an assessment tool for malnutrition in NPC patients., Conclusions: Age ≥ 65 years, completing ≥ 1 chemotherapy cycles, a high total radiation dose received, low BMI, low albumin, and low chloride levels are risk factors for malnutrition in NPC patients. The assessment effect of the new model, developed based on these risk factors, is good, and it can be used as an assessment tool for malnutrition in NPC patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl - ) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

Introduction: type 2 Diabetes mellitus is a chronic metabolic disease with devastating effects on patients and results in numerous healthcare challenges in terms of its management and the cost burden among the affected. Successful management involves maintaining optimal glycemic control to prevent complications, with adherence to antidiabetic medications playing a crucial role in achieving this objective. Additionally, maintaining a healthy electrolyte balance is key for overall well-being and physiological function. However, the correlation between glycated hemoglobin and electrolyte balance remains under investigated, particularly in patients with suboptimal adherence. The aim of this research was to study the relationship between glycated hemoglobin and electrolytes among diabetic patients with poor adherence to antidiabetic medications., Methods: this study was conducted at Samburu County Referral Hospital in Samburu County, Kenya. We employed a descriptive cross-sectional design focusing on adult diabetic patients aged 18 years and above who had visited the diabetic clinic over a three-month period. To evaluate their adherence levels, we employed a Morisky Medication Adherence Scale-8. Seventy-two diabetic patients who got adherence level scores of < 6 were categorized as having low adherence and their blood samples were collected for measuring glycated hemoglobin levels and electrolytes levels particularly potassium, sodium, calcium, magnesium, phosphorus and chloride. Relationship between electrolytes and glycated hemoglobin among diabetic patients with poor adherence to antidiabetics was determined using Karl Pearson correlation., Results: among the study participants, the lowest hemoglobin A1C (HbA1c) level recorded was 5.1% while the highest was 15.0% and the majority (41.7%) fell within the HbA1c range of 5-7%. A high proportion of individuals (58.3%) with poor adherence to antidiabetics had elevated HbA1c levels, indicating poor glycemic control. The correlations observed between glycated hemoglobin and electrolytes which included magnesium, sodium, chloride, calcium and phosphorus was r= -0.07, -0.32, -0.05 -0.24 and -0.04 respectively., Conclusion: this study concluded that there is a relationship between electrolytes and glycated hemoglobin among diabetic patients with poor adherence to antidiabetics. A statistically significant negative correlation was observed between glycated hemoglobin and calcium level (r=-0.2398 P ≤0.05) and also sodium (r=-0.31369 P≤0.05). A negative correlation (P≥0.05) was observed between phosphorus, magnesium, chloride and potassium with HbA1c levels though not statistically significant., Competing Interests: The authors declare no competing interests., (Copyright: Francis Lengeiya et al.)

Introduction: The study aims to present a case of acute mercuric chloride poisoning treated successfully with continuous renal replacement therapy using the CytoSorb filter., Case Description: A 21-year-old female patient after a suicide attempt by intentional ingestion of mercuric chloride, was admitted to the hospital with features of multiple organ damage for specific treatment. The performed laboratory tests confirmed high levels of mercury in the blood (1051 μg/L) and urine (22,960 μg/L). Due to acute renal failure, continuous renal replacement therapy (CRRT) CVVHD Ci-Ca was initiated; the procedure was then converted to CVVHDF Ci-Ca with ultrafiltration to optimise therapy, and CytoSorb was added to the artificial kidney system on day 3. Specific antidote therapy (DMPS) was administered concurrently. The ongoing treatment resulted in a reduction in subjective complaints, a decrease in blood mercury levels to 580 μg/L, and an improvement in parenchymal organ function., Conclusion: In the event of poisoning with inorganic mercury compounds (mercuric chloride), continuous renal replacement therapy using the CytoSorb filter as an extracorporeal blood purification method may be considered., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Decongestion is a therapeutic target in acute heart failure (AHF). Acetazolamide is a diuretic that decreases proximal tubular sodium reabsorption, and may also reverse hypochloremia Objectives: We assessed the decongestive, natriuretic, and chloride‑regaining effects as well as the renal safety profile of oral acetazolamide (250 mg) used as an add‑on therapy in patients with AHF., Patients and Methods: This prospective, randomized study was conducted at the Institute of Heart Diseases in Wrocław, Poland. It involved patients with AHF who were randomly assigned to receive either 250 mg of oral acetazolamide or standard care, and who underwent clinical and laboratory follow‑up for 3 consecutive days since the beginning of the treatment and at discharge., Results: The study population comprised 61 patients (71% men), of whom 31 (51%) were included in the acetazolamide group. The mean (SD) age of the patients was 68 (13) years. In comparison with the controls, the acetazolamide group demonstrated significantly higher cumulative diuresis after 48 and 72 hours since treatment implementation, negative fluid balance, weight loss after 48 hours of treatment, weight loss throughout the hospitalization, natriuresis, and serum chloride concentration. In terms of the renal safety profile, no increase in the creatinine concentration and urinary renal biomarker levels was noted., Conclusions: Oral acetazolamide seems to be a valuable add‑on therapy that helps achieve comprehensive decongestion in patients with AHF.

We present the case of a 70-year-old woman with cancer affecting a substantial area of her breast, characterized by persistent bleeding from the primary tumor. Pathological findings revealed a hormone-sensitive mucinous carcinoma. CT indicated a primary tumor in close proximity to the greater pectoral muscle, left axillary lymph node metastasis, and oligometastases in her right lung. Although she declined surgery and chemotherapy, she agreed to receive Mohs' paste and endocrine therapy. The paste was applied locally, and local control was achieved after 2 weeks. Five years later, CR was still maintained in her left breast. Mohs' paste played a crucial role in achieving local control of the exudation and bleeding from the exposed, unresected cancer. It proved to be an outstanding component of hormone-sensitive local treatment, working synergistically with systemic drug therapy and hormonal therapy.

Background: Sodium bicarbonate (SB) infusion is commonly used to correct metabolic acidosis, but its clinical efficacy remains controversial. This study aims to investigate whether acid-base balance parameters should be a consideration for administering SB treatment., Methods: Children with metabolic acidosis (pH < 7.35 and bicarbonate < 22 mmol/L) who were treated with or without 50 mg/ml SB injection were grouped and extracted from a retrospective cohort database of the Pediatric Intensive Care Unit. The interaction between acid-base balance parameters and SB treatment on mortality was analyzed through mortality curves and cross-effect models. Logistic regression was conducted to estimate the risk of death following SB treatment in the overall children as well as in subgroups, and potential confounding factors were adjusted for. After employing propensity score matching to account for confounding factors, further analysis was performed to evaluate the effectiveness of SB treatment within each chloride subgroup., Results: A total of 5865 children with metabolic acidosis were enrolled, of which 2462 (42.0%) received SB treatment. In the overall population, it was found that SB treatment did not reduce hospital mortality or 28-day mortality. Interactions between acid-base balance parameters (chloride and anion gap) and SB treatment on mortality were observed. Subgroup analysis clarified that when chloride levels were below 107 mmol/L, children treated with SB had higher in-hospital mortality (29.8% vs 14.9%) and 28-day mortality (26.5% vs 13.4%), with adjusted ORs of 2.065 (95% CI, 1.435-2.97) and 1.947 (95% CI, 1.332-2.846), respectively. In contrast, when chloride levels were greater than or equal to 113 mmol/L, children treated with SB had a shorter stay in the PICU (median: 1.1 days vs 5.1 days, adjusted p = 0.004) and lower in-hospital mortality (4.3% vs 10.3%) and 28-day mortality (4.0% vs 8.4%), with adjusted ORs of 0.515 (95% CI, 0.337-0.788) and 0.614 (95% CI, 0.391-0.965), respectively. After controlling for confounding factors through matching, the impact of SB treatment on the risk of death in each chloride subgroup was consistent with the aforementioned results. However, treatment with SB did not significantly increase the risk of death in newborns or children with moderate to severe metabolic acidosis when chloride levels were below 107 mmol/L (p > 0.05)., Conclusions: The use of sodium bicarbonate for treating metabolic acidosis has been found to increase mortality in children with low chloride levels but decrease mortality in those with high chloride levels in this study. Further prospective multi-center clinical studies and basic research are needed to validate these findings., (© 2023. The Author(s).)

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by hippocampal, and cortical neuron deterioration, oxidative stress, and severe cognitive dysfunction. Aluminum is a neurotoxin inducer for cognitive impairments associated with AD. The treatment approaches for AD are unsatisfactory. Boswellia papyrifera and Syzygium aromaticum are known for their pharmacological assets, including antioxidant activity. Therefore, the current study explored the possible mitigating effects of a combination of Boswellia papyrifera and Syzygium aromaticum against aluminum chloride (AlCl3) induced AD. The AD model was established using AlCl3 (100 mg/kg), and the rats were orally administrated with Boswellia papyrifera or Syzygium aromaticum or a combination of them daily for 8 weeks. The Y-maze test was used to test cognition in the rats, while acetylcholinesterase (AChE) and oxidative stress markers were estimated in homogenates of the cerebral cortex and hippocampus. Also, the histopathological examination of the cortex and hippocampus were investigated. The results revealed that administration of either B. papyrifera or S. aromaticum extracts significantly improved the cognitive functions of AD rats, enhanced AChE levels, increased oxidative enzymes levels, including SOD and GSH, and reduced MDA levels in homogenates of the cerebral cortex and hippocampus and confirmed by improvement in histological examination. However, using a combination therapy gave better results compared to a single treatment. In conclusion, the present study provided primary evidence for using a combination of B. papyrifera and S. aromaticum to treat cognitive dysfunction associated with AlCl3 Induced AD by improving the AChE levels and modulating oxidative stress in the brain.

Introduction: Cystic fibrosis (CF), a potentially fatal genetic disease, is caused by loss-of-function mutations in the gene encoding for the CFTR chloride/bicarbonate channel. Modulator drugs rescuing mutant CFTR traffic and function are now in the clinic, providing unprecedented breakthrough therapies for people with CF (PwCF) carrying specific genotypes. However, several CFTR variants are unresponsive to these therapies., Area Covered: We discussed several therapeutic approaches that are under development to tackle the fundamental cause of CF, including strategies targeting defective CFTR mRNA and/or protein expression and function. Alternatively, defective chloride secretion and dehydration in CF epithelia could be restored by exploiting pharmacological modulation of alternative targets, i.e., ion channels/transporters that concur with CFTR to maintain the airway surface liquid homeostasis (e.g., ENaC, TMEM16A, SLC26A4, SLC26A9, and ATP12A). Finally, we assessed progress and challenges in the development of gene-based therapies to replace or correct the mutant CFTR gene., Expert Opinion: CFTR modulators are benefiting many PwCF responsive to these drugs, yielding substantial improvements in various clinical outcomes. Meanwhile, the CF therapy development pipeline continues to expand with the development of novel CFTR modulators and alternative therapeutic strategies with the ultimate goal of providing effective therapies for all PwCF in the foreseeable future.

CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with CF and at least one F508del allele in Europe. In the US, the ETI label has been expanded to 177 rare CFTR mutations responsive in Fischer rat thyroid cells, including G85E , but not N1303K . However, knowledge on the effect of ETI on G85E or N1303K CFTR function remains limited. In vitro effects of ETI were measured in primary human nasal epithelial cultures (pHNECs) of a G85E homozygous patient and an N1303K homozygous patient. Effects of ETI therapy in vivo in these patients were assessed using clinical outcomes, including multiple breath washout and lung MRI, and the CFTR biomarkers sweat chloride concentration (SCC), nasal potential difference (NPD) and intestinal current measurement (ICM), before and after initiation of ETI. ETI increased CFTR-mediated chloride transport in G85E / G85E and N1303K / N1303K pHNECs. In the G85E / G85E and the N1303K / N1303K patient, we observed an improvement in lung function, SCC, and CFTR function in the respiratory and rectal epithelium after initiation of ETI. The approach of combining preclinical in vitro testing with subsequent in vivo verification can facilitate access to CFTR modulator therapy and enhance precision medicine for patients carrying rare CFTR mutations.

Background: To review clinical characteristics, auxiliary examination results, treatment effects, and outcomes of patients with autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A)., Methods: We collated and retrospectively analyzed clinical data of 15 patients admitted with clinical characteristics of an autoimmune GFAP-A acute encephalitis or meningitis phenotype., Results: All patients were diagnosed with acute-onset meningoencephalitis and meningoencephalomyelitis. Initial presentations included pyrexia and headache at onset; dual symptoms of prominent tremor with urinary and bowel dysfunction; ataxia, psychiatric and behavioral abnormalities, and impaired consciousness; neck resistance; reduced extremity muscle strength; blurred vision; epileptic seizures; and reduced basic blood pressure. Cerebrospinal fluid (CSF) examination showed that the degree of protein elevation was significantly higher than the degree of increase in white blood cells. Moreover, in the absence of obvious low chloride and glucose levels, CSF chloride levels decreased in 13 patients, accompanied by a CSF glucose level decrease in four. Brain abnormalities were found in magnetic resonance imaging of ten patients, with a linear radial perivascular enhancement present in the lateral ventricles of two patients and symmetric abnormalities in the splenium of the corpus callosum in three patients., Conclusions: Autoimmune GFAP-A may be a spectrum disorder, with acute- or subacute-onset meningitis, encephalitis, and myelitis being the main phenotypes. When used for acute stage treatment, combined hormone and immunoglobulin therapy was superior to hormone pulse therapy or immunoglobulin pulse therapy alone. However, hormone pulse therapy alone without immunoglobulin pulse therapy was associated with a greater number of remaining neurological deficits., (© 2023. The Author(s).)

We studied 83 cardiac-surgery patients with nasal S. aureus carriage who received 4 intranasal administrations of XF-73 nasal gel or placebo <24 hours before surgery. One hour before surgery, patients exhibited a S. aureus nasal carriage reduction of 2.5 log 10 with XF-73 compared to 0.4 log 10 CFU/mL for those who received placebo (95% CI, -2.7 to -1.5; P < .0001).

Pyroptosis is a newly identified form of cell death, morphologically characterized by excessive cell swelling. In the present study, paclitaxel (PTX) combined with platinum were used as first‑line chemotherapy, against ovarian cancer cells by inducing multiple types of cell death. However, it remains unclear whether PTX can induce pyroptosis in ovarian cancer cells. It was recently reported that PTX inhibited chloride channels, an inhibition known to cause cell swelling. In the present study, it was first verified that pyroptosis‑like cell death, as well as cleaved‑caspase‑3 and cleaved‑gasdermin E (GSDME) were induced by PTX in A2780 ovarian cancer cells. PTX inhibited the background‑ and hypotonicity‑activated chloride currents, promoted intracellular chloride ion accumulation, those manifestations are similar to those of the classic volume‑regulatory anion channel (VRAC) blocker, 4‑(2‑butyl‑6,7‑dichloro‑2‑cy-clopentyl‑indan‑1‑on5‑yl) oxobutyric acid (DCPIB). Of note, both DCPIB and the downregulation of VRAC constituent protein leucine‑rich repeat‑containing 8a themselves could not induce persisted cell swelling and pyroptosis‑like phenotypes. However, they could enhance the effects of PTX in inducing pyroptosis‑like phenotypes, such as marked cell swelling, cell membrane rupture and excessive activation of caspase‑3 and GSDME N‑terminal fragment, which ultimately caused marked pyroptosis in A2780 cells. These findings revealed a potential mechanism of PTX and offered new insights into the effects of a synergistical combination of PTX and VRACs blockers in ovarian cancer chemotherapy.

Background: Contraction alkalosis is characterized by low serum sodium and chloride and high serum carbon dioxide and bicarbonate levels. Case Report: A 28-year-old Caucasian active-duty male with a history of autosomal dominant polycystic kidney disease and diarrhea-predominant Irritable Bowel Syndrome (D-IBS) presented to his primary care provider (PCP) with elevated blood pressure (136/96 mmHg), was diagnosed with stage-2 hypertension, and started oral HCTZ (25 mg/day). His medications included dicyclomine (10 mg oral three times daily). Subsequently, (Visit 1), his blood pressure was 130/91 mmHg and he was started on telmisartan (20 mg/day). At Visit 2, 4 weeks later, his blood pressure improved (121/73 mmHg); however, blood chemistry revealed elevated serum CO2 (32 mEq/L) and chloride (94 mmol/L). Four days later, the patient presented to the Emergency Department with dyspnea and swallowing difficulty. The patient returned to his PCP 3 days later complaining of cough, congestion, vomiting, and mild dyspnea, blood pressure of 124/84 mmHg. Two months later, sudden onset of projectile vomiting and abdominal pain while running was reported, resolved by rehydration and a single oral dose of prochlorperazine 25 mg. Three months later, (Visit 3), he complained of lightheadedness and cloudy judgment, suggesting contraction alkalosis. HCTZ was discontinued and telmisartan was increased to 20 mg twice daily. A follow-up blood chemistry panel 2 weeks later revealed serum chloride and CO2 levels within normal limits and blood pressure under 130/80 mmHg. Conclusion: This is the first known report of contraction alkalosis driven by drug-drug interaction between dicyclomine and HCTZ.

Current chemotherapy against the Surra organism, Trypanosoma evansi has several limitations in terms of efficacy, toxicity, availability and emerging resistance. These reasons make the search of new chemo-preventive and chemo-therapeutic agent with high potency and low toxicity. Alkaloid phyto-molecules, berberine has shown promising anti-kinetoplastid activity against T. cruzi, T. congolense, T. brucei, Leishmania donovani and L. tropica. However, till date, there is no investigation of therapeutic efficacy of berberine chloride (BC) against T. evansi. The IC 50 value of BC for growth inhibition of T. evansi at 24 h of culture was calculated as 12.15 µM. The specific selectivity index (SSI) of BC was calculated as 19.01 and 10.43 against Vero cell line and Equine PBMC's, respectively. Thirteen drug target genes affecting various metabolic pathways were studied to investigate the mode of trypanocidal action of BC. In transcript analysis, the mRNA expression of arginine kinase 1 remained refractory to exposure with BC, which provides metabolic plasticity in adverse environmental conditions. In contrary, rest all the drug target gene were down-regulated, which indicates that drug severely affect DNA replication, cell proliferation, energy homeostasis, redox homeostasis and calcium homeostasis of T. evansi, leading to the death of parasite in low concentrations. It is the first attempt to investigate in vitro anti-trypanosomal activity of BC against T. evansi. These data imply that phytochemicals as alternative strategies can be explored in the future as an alternative treatment for Surra in animal., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Previous studies showed that the combination of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) corrector and potentiator, lumacaftor-ivacaftor (LUMA-IVA) provides meaningful clinical benefits in patients with cystic fibrosis who are homozygous for the Phe508del CFTR mutation. However, little is known about the effect of LUMA-IVA on Proinflammatory Cytokines (PICs)., Objectives: To investigate the impact of LUMA-IVA CFTR modulation on circulatory and airway cytokines before and after 12 months of LUMA-IVA treatment in a real-world setting., Methods: We assessed both plasma and sputum PICs, as well as standard clinical outcomes including Forced Expiratory Volume in one second (FEV 1 ) %predicted, Body Mass Index (BMI), sweat chloride and pulmonary exacerbations at baseline and prospectively for one year post commencement of LUMA-IVA in 44 patients with cystic fibrosis aged 16 years and older homozygous for the Phe508del CFTR mutation., Results: Significant reduction in plasma cytokines including interleukin (IL)-8 (p<0.05), tumour necrosis factor (TNF)-α (p<0.001), IL-1ß (p<0.001) levels were observed while plasma IL-6 showed no significant change (p=0.599) post-LUMA-IVA therapy. Significant reduction in sputum IL-6 (p<0.05), IL-8 (p<0.01), IL-1ß (p<0.001) and TNF-α (p<0.001) levels were observed after LUMA-IVA therapy. No significant change was noted in anti-inflammatory cytokine IL-10 levels in both plasma and sputum (p=0.305) and (p=0.585) respectively. Clinically significant improvements in FEV 1 %predicted (mean+3.38%, p=0.002), BMI (mean+0.8 kg/m 2 , p<0.001), sweat chloride (mean -19 mmol/L, p<0.001), as well as reduction in intravenous antibiotics usage (mean -0.73, p<0.001) and hospitalisation (mean -0.38, p=0.002) were observed after initiation of LUMA-IVA therapy., Conclusion: This real-world study demonstrates that LUMA-IVA has significant and sustained beneficial effects on both circulatory and airway inflammation. Our findings suggest that LUMA-IVA may improve inflammatory responses, which could potentially contribute to improved standard clinical outcomes., Competing Interests: Competing interests: PA, DM, YM, TV, CF, MD, and JAE report no conflicts of interest. BJP has received honoraria/ speakers’ fees from Gilead Sciences, Novartis Pharmaceutical, and Vertex Pharmaceutical, outside the submitted work. DMM reports an APC grant from University College Cork and the Wilton Respiratory Research Fund funding to support this research. He is the past recipient of an ERS fellowship. He has received fees for consultancy work from Novartis, Bayer, AstraZeneca, Menarini, Nycomed, Gilead, Boehringer Ingelheim, Teva, Rowex and Munidpharm. He has received speaker’s fee from Pfizer, Menarini, GSK, Bayer, MSD and Novartis. He has travelled to international symposia as a guest of AstraZeneca and Novartis., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cystic fibrosis (CF) is one of the most common autosomal recessive genetic diseases in Caucasians, but CF patients in China are rare, and it was listed as the first batch of rare diseases in China in 2018. In recent years, CF has been gradually recognized in China, and the number of CF patients reported in China in the past 10 years is more than 2.5 times the total number in the previous 30 years, and the total number of CF patients is estimated to be more than 20 000. The research progress of CF gene modification has led to the innovation of CF treatment. However, the sweat test as an important test for the diagnosis of CF has not been widely implemented in China. At present, the diagnosis and treatment of CF in China still lacks standardized recommendations. In view of these updates, the Chinese Experts Cystic Fibrosis Consensus Committee has formed "the Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis" based on extensive opinion gathering, literatures review, multiple meetings and discussions. This consensus collects 38 core issues related to CF, including pathogenesis, epidemiology, clinical characteristics, diagnosis, treatment, rehabilitation, and patient management. Finally, 32 recommendations were formulated. The consensus used the modified GRADE methodology to grade the evidence evaluation and recommendations. This is the current state of CF consensus in China, and we hope to improve the diagnosis and treatment of CF in China in the future. Summary of recommendations Question 1: How can CF be identified? CF should be suspected if there is: (1) a family history of CF; (2) delayed meconium expulsion or meconium ileus; (3) pancreatic exocrine insufficiency, mainly characterized by long-standing steatorrhea and malnutrition; (4) recurrent lower respiratory tract infections of infantile onset, especially Pseudomonas aeruginosa (PA), Staphylococcus aureus infections of respiratory aetiology; (5) chronic sinusitis, especially when combined with juvenile presentation of nasal polyps; (6) chest CT abnormalities such as the presence of air trapping, bronchiectasis (upper lobe predominant); (7) pseudo-Bartter syndrome; (8) absence of vas deferens in males; (9) clubbing in young bronchiectasis patients(1C). Question 2: What are the diagnostic criteria for CF? 1.1 Presence of one or more of the characteristic clinical manifestations or family history consistent with CF, and meeting at least one of the following definite diagnostic criteria in 1.2 or 1.3.1.2 Sweat chloride testing:(1) Concentrations of more than 60 mmol/L are diagnostic; (2) concentrations between 30-59 mmol/L are intermediate, and genetic variation must be considered to confirm the diagnosis; (3) concentrations less than 30 mmol/L are considered normal.1.3 Genetic testing:(1) Detection of two disease-causing CFTR (cystic fibrosis transmembrane conductance regulator) mutations on biallelic alleles; (2) The CFTR variants are of undetermined significance, but tests such as sweat chloride concentration, intestinal current measurement, or nasal mucosal potential difference suggest abnormal CFTR function, then CF is diagnostic(1C). Question 3: What is the diagnostic process for CF arranged? Sweat chloride testing and CFTR gene analysis are recommended in all patients suspected of CF(1D). Question 4: What is the value of sweat chloride testing in the diagnosis of CF? Sweat chloride testing is the gold standard for the clinical diagnosis of CF(1C). Question 5: What is the value of CFTR genetic testing in Chinese CF diagnosis? Biallelic pathogenic variants of CFTR are a definitive diagnosis of CF(1D). Question 6: What is the diagnostic value of imaging for CF? Chest CT is a sensitive test for early stages of lung disease in patients with CF and is appropriate in younger patients and to assess disease progression. The imaging findings of abdominal visceral involvement in CF lack specificity(2C). Question 7: How to evaluate the pancreatic function of CF patients? Fecal elastase may be used as the first indicator to assess pancreatic exocrine function in patients with CF (2C). Question 8: How to diagnose hepatic abnormality of CF? CF related liver disease was diagnosed when CF was confirmed and 2 of the following 4 criteria were met: (1) hepatomegaly and/or splenomegaly confirmed by ultrasound; (2) ALT, AST, and GGT on three consecutive occasions above the upper limit of normal on three consecutive occasions for more than 12 months and excluding other causes; (3) had evidence of liver involvement, portal hypertension, or bile duct dilatation by ultrasound; (4) liver biopsy confirmation (focal biliary cirrhosis or multilobular cirrhosis) may be indicated if the diagnosis is suspected(2D). Question 9: How to identify pulmonary exacerbations in patients with CF? Pulmonary exacerbations are indicated when any 4 of the following 12 signs or symptoms are met: increased sputum; new onset haemoptysis or increased haemoptysis; exacerbation of cough; increased dyspnea; malaise, fatigue, or somnolence; body temperature above 38 ℃; anorexia or weight loss; sinus pain or tenderness; increased sinus secretions; new chest signs; FEV 1 ≥10% decline from previous; imaging changes suggestive of pulmonary infection(2D). Question 10: How to diagnose CF related diabetes? Diagnostic criteria for CF related diabetes are the same as those for diabetes in the population(1D). Question 11: How to evaluate the nutritional status of CF patients? Anthropometric parameters reflecting nutritional status should be assessed regularly. And the goal of nutritional assessment is to evaluate and monitor whether pediatric patients are achieving normal standards of growth and development or whether adult patients are maintaining adequate nutritional status(1C). Question 12: Does CF require pathological examination as a diagnostic basis? Pathohistological biopsy is not recommended as a first-line diagnostic method in patients with a suspected diagnosis of CF(1D). Question 13: Do CF patients need long-term macrolides? At least 6 months of azithromycin treatment is recommended for CF patients with chronic PA infection(2A). Question 14: Do CF patients need long-term inhalation of hypertonic saline? Long term treatment with hypertonic saline is recommended for patients with CF(1A). Question 15: Do CF patients need long-term inhalation of Dornase alfa(DNase)? Long term use of DNase is recommended in patients with CF aged 6 years and older(1A). Question 16: Do CF patients need inhalation of mannitol? Inhaled mannitol therapy is recommended for more than 6 months in patients with CF aged 18 years and older when other inhaled treatments are unavailable or intolerable(2A). Question 17: How to deal with PA found in the sputum culture of CF patients? When sputum cultures from patients with CF are positive for PA , it needs to determine the characteristics of the infection first. The purpose for acute infection is to eradicate PA . Chronic colonization does not need to be eradicated, and the main purpose is to reduce the bacterial load and improve symptoms(1A). Question 18: Do CF patients need inhalation of antibiotics? Inhaled antibiotic therapy is recommended for CF patients with PA infection(1A). Question 19: Do CF patients need inhaled or systemic corticosteroids? In patients with CF without asthma or ABPA, routine inhaled or systemic glucocorticoids are not recommended (2A). Question 20: Do CF patients need to inhale bronchodilators? Bronchodilators can be used in the short term to improve symptoms in patients with CF in the presence of airway obstruction, but the long-term benefit is insufficient (2B). Question 21: Do CF patients need expectorant medicine? Patients with CF can take acetylcysteine orally or aerosolized(2A). Question 22: How to deal with acute pulmonary exacerbation in CF patients? Intensive implementation of non-antimicrobial therapy is recommended during pulmonary exacerbations in patients with CF. Antimicrobials with activity against PA were selected for empirical treatment, and the treatment was adjusted according to the results of bacterial culture and drug susceptibility testing. A 21-day long course of anti-infective therapy is not recommended(1B). Question 23: How to treat CF patients with ABPA? Medical therapy is recommended for CF patients with ABPA who meet any of the following criteria: patients with elevated immunoglobulin E levels and concomitant worsening of pulmonary function and/or pulmonary symptoms, or imaging suggesting new infiltrative foci in the chest(1D).Glucocorticoids are recommended for ABPA exacerbations in CF patients without contraindications(2D).Itraconazole should be added if the patient presents with poor response to corticosteroids, recurrence of ABPA, corticosteroid dependence, or corticosteroid toxicity(2D). Question 24: Is lung transplantation recommended for patients with CF? When is it recommended? Patients with CF may be evaluated for lung transplantation when they meet the following criteria after optimal medical therapy: (1) FEV 1 <30% predicted; (2) FEV 1 <40% predicted (<50% predicted in children) with the following: 6-minute walk distance<400 meters; PaCO 2 >50 mmHg(1 mmHg=0.133 kPa); hypoxia at rest or after activity; pulmonary artery pressure measured by cardiotocography>50 mmHg or right heart dysfunction; continued deterioration despite aggressive supplementation of nutritional support; two exacerbations requiring intravenous antibiotic therapy per year; massive hemoptysis (>240 ml) requiring pulmonary artery embolization; presented with pneumothorax; (3) FEV 1 <50% predicted and rapid decline in lung function or rapid worsening of symptoms; (4) Presented with an acute exacerbation requiring positive pressure mechanical ventilation(2C). Question 25: How to deal with pancreatic disease in CF patients? Pancreatic enzyme replacement therapy is recommended in patients with CF pancreatic disease(1A). Question 26: How to deal with hepatobiliary disease in CF patients? Ursodeoxycholic acid is not recommended in asymptomatic patients with CF hepatobiliary disease(2B). Question 27: How to deal with gastrointestinal problems such as acid regurgitation in CF patients? Acid suppression is recommended for CF patients with gastrointestinal symptoms such as acid regurgitation (2B). Question 28: How to deal with CF related diabetes? Insulin therapy is recommended in CF related diabetes(1B). Question 29: How should nutritional support be given to patients with CF? Energy intake in patients with CF is recommended to be 110%-200% of the energy requirement of a healthy person under equivalent physiological conditions. And maintaining adequate protein, appropriate intake of fats, electrolytes, and fat-soluble vitamins are recommanded(1A). Question 30: How should respiratory rehabilitation be performed in patients with CF? Airway clearance therapy and appropriate exercise are recommended for patients with CF(1A). Question 31: What is included in the follow-up of CF patient? Patients with CF should have regular follow-up. Adult patients are recommended to be followed every 3-6 months, and children should be followed more frequently(2A). Question 32: How should CF patients avoid infections? Inpatients and outpatients are recommended to be separated according to microbiota carriage status(1D).Good hand hygiene is recommended for the patients with CF and their contacts(1D).It is recommended that CF patients wear masks in healthcare settings. This may reduce the release of potentially infectious aerosols during coughing (1D).Annual influenza vaccination is recommended for patients with CF>6 months of age and for all family members of patients with CF and all healthcare workers caring for these patients(2D).Palivizumab may be considered for the prevention of respiratory syncytial virus infection in patients with CF under two years of age(2A).

Objective: To evaluate the effectiveness of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) and to characterize its safety profile in cystic fibrosis (CF) patients in a real-world clinical setting., Methods: This was a prospective observational study carried out in a CF referral center in Portugal involving adult CF patients who started treatment with ELX/TEZ/IVA. Clinical characteristics of the patients were collected, and effectiveness and safety data were evaluated., Results: Of the 56 patients followed in the center at the time of the study, 28 were eligible for ELX/TEZ/IVA treatment in accordance with the Portuguese National Authority for Medicines and Health Products at the time of the study. Of these, 24 met the follow-up time requirement to be included in the clinical effectiveness analysis. The mean follow-up time was 167.3 ± 96.4 days. Adverse events were generally mild and self-limited. Significant improvements in lung function, BMI, sweat chloride concentration, and number of pulmonary exacerbations were observed. No significant differences in outcomes between F508del homozygous and heterozygous patients were found. The effectiveness of this new CFTR modulator combination also applied to patients with advanced lung disease., Conclusions: Treatment with ELX/TEZ/IVA showed effective improvement in real-world clinical practice, namely in lung function, BMI, sweat chloride concentration, and number of pulmonary exacerbations, with no safety concerns.

SLC12A5, a neuron-specific potassium-chloride co-transporter, has been reported to promote tumor progression, however, the underlying mechanism remains unclear. Here we report that SLC12A5 functions as an oncogene to promote tumor progression and castration resistance of prostate cancer through the N6-methyladenosine (m 6 A) reader YTHDC1 and the transcription factor HOXB13. We have shown that the level of SLC12A5 was increased in prostate cancer, in comparison to its normal counterparts, and further elevated in castration-resistant prostate cancer (CRPC). The enhanced expression of SLC12A5 mRNA was associated with neuroendocrine prostate cancer (NEPC) progression and poor survival in prostate cancer. Furthermore, we demonstrated that SLC12A5 promoted the castration resistance development of prostate cancer in addition to the cell proliferation and migration. Interestingly, SLC12A5 was detected in the cell nucleus and formed a complex with nuclear m 6 A reader YTHDC1, which in turn upregulated HOXB13 to promote the prostate cancer progression. Therefore, our findings reveal a mechanism that how the potassium-chloride cotransporter SLC12A5 promotes the tumor progression and provide a therapeutic opportunity for prostate cancer to apply the neurological disorder drug SLC12A5 inhibitors., (© 2023. The Author(s).)

Local control of disintegrating advanced breast cancer is often difficult because of the exudate, bleeding, and the foul odor. The current author encountered a case of large breast cancer with ulceration in which drug therapy and local control with Mohs' paste allowed disease control. The patient was a 61-year-old woman. There was a large ulcerated lump in her right breast, and exudate, bleeding, and a foul odor were present. The woman was diagnosed with hormone-sensitive mucinous carcinoma based on a biopsy, and diagnostic imaging revealed axillary lymph node metastasis and multiple metastases in both lungs. Mohs' paste was used locally, and local control was achieved after 1 month. A year and a half after the start of systemic drug therapy, the breast lump disappeared, and lung metastases and lymph node metastasis had almost disappeared. A CR has been maintained 3 years and 5 months later. Mohs' paste was extremely useful in achieving local control of exudation and bleeding from exposed unresected cancer. This was an excellent treatment in the patient's terminal stages and as part of local treatment in combination with systemic drug therapy.

Background and Objectives : Diabetes mellitus (DM) is a complex disease affecting the whole metabolic balance of the body and resulting in multiple organ complications: cardiovascular, neuronal, renal, etc. Our study focuses on investigating the effect of zinc chloride (Zn) on certain blood parameters suggestive for assessing the metabolic disturbances, the liver and kidney function, the oxidative stress and the immune defense capacity in experimental-induced DM with streptozotocin (STZ) and cholesterol in rats. Materials and Methods : The animals were assigned to three groups, as follows: Group 1 (Control): buffer citrate solution 0.1 mL/100 g body; Group 2 (STZ): 20 mg/kg body STZ and fat diet (10 g cholesterol/100 g diet); Group 3 (STZ+Zn): 20 mg/kg body STZ + 5 mg/kg body Zn chloride and the same fat diet. DM was induced by administering STZ in a single take daily, for three consecutive days, Zn and citrate buffer were administered orally for a month. The protocol was approved by the Ethics Committee of the University 'Grigore T Popa' Iasi, in agreement with the International Regulations about the handling of laboratory animals. Results: The use of STZ in rats fed with cholesterol was correlated with important weight gain, hyperglycemia, the intensification of the transaminases activity and the increase in serum alkaline phosphatase, cholesterol, triglyceride, urea, creatinine and in malondialdehyde. Conclusions : The treatment with Zn resulted in weight loss and a decrease in blood sugar in diabetic rats. Supplementation with Zn notably reduced oxidative stress, preserved the pancreatic architecture and restored the liver and kidney function and structure in STZ-induced DM in rats.

Background: On the basis of increased mortality associated with hyperchloremia among critically ill patients, we investigated the effect of occurrence of early hyperchloremia on death or disability at 90 days in patients with intracerebral hemorrhage (ICH)., Methods: We analyzed the data from Antihypertensive Treatment of Cerebral Hemorrhage 2 trial, which recruited patients with spontaneous ICH within 4.5 h of symptom onset. Patients with increased serum chloride levels (110 mmol/L or greater) at either baseline or 24, 48, or 72 h after randomization were identified. We further graded hyperchloremia into one occurrence or two or more occurrences within the first 72 h. Two logistic regression analyses were performed to determine the effects of hyperchloremia on (1) death within 90 days and (2) death or disability at 90 days after adjustment for potential confounders., Results: Among the total of 1,000 patients analyzed, hyperchloremia within 72 h was seen in 114 patients with one occurrence and in 154 patients with two or more occurrences. Patients with one occurrence of hyperchloremia (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-5.5) and those with two or more occurrences (OR 2.6, 95% CI 1.3-5.0) had significantly higher odds of death within 90 days after adjustment for age, race and ethnicity, National Institutes of Health Stroke Scale score strata, hematoma volume, presence or absence of intraventricular hemorrhage, cigarette smoking, previous stroke, and maximum hourly dose of nicardipine. Patients with two or more occurrences of hyperchloremia (OR 3.4, 95% CI 2.1-5.6) had significantly higher odds of death or disability at 90 days compared with patients without hyperchloremia after adjustment for the abovementioned potential confounders., Conclusions: The independent association between hyperchloremia and death or disability at 90 days suggests that avoidance of hyperchloremia may reduce the observed death or disability in patients with ICH., Clinical Trial Registration: ClinicalTrials.gov: NCT01176565., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background and Aim: The objective of this retrospective, observational, noninterventional cohort study was to investigate prognostic factors of overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) and to develop a novel prognostic model., Methods: A total of 4049 patients with aNSCLC diagnosed between January 2011 and February 2020 who received atezolizumab, nivolumab, or pembrolizumab as second-line monotherapy were selected from a real-world deidentified database to build the cohort. Patients could not have received first-line treatment with clinical study drug(s) nor immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte-associated protein 4 therapies., Results: Patients had a median age of 69 years; 45% were female, 75% White, 70% had stage IV at initial diagnosis, and 70% had nonsquamous histology. A Cox proportional hazards model with lasso regularization was used to build a prognostic model for OS using 18 baseline demographic and clinical factors based on the real-world data cohort. The risk-increasing prognostic factors were abnormally low albumin and chloride levels, Eastern Cooperative Oncology Group performance status score ≥ 2, and abnormally high levels of alkaline phosphatase and white blood cells. The risk-decreasing prognostic factors were PD-L1 positivity, longer time from advanced diagnosis to start of first-line therapy, and higher systolic blood pressure. The performance of the model was validated using data from the OAK trial, and the c-index for the OAK trial validation cohort was 0.65 and 0.67 for the real-world data cohort., Conclusions: Based on baseline demographic and clinical factors from a real-world setting, this prognostic model was developed to discriminate the risk of death in patients with aNSCLC treated with checkpoint inhibitors as second-line monotherapy, and it performed well in the real-world data and clinical trial cohorts., (© 2022 F.Hoffmann-La Roche Ltd/Genentech, Inc. Cancer Reports published by Wiley Periodicals LLC.)

The physiologic bile acid ursodeoxycholic acid (UDCA) has potent anticholestatic and weak litholytic properties and has been used for centuries as a remedy for cholestatic liver diseases. Today, UDCA at 13-15 mg/kg/day is the standard first line medication for all people with primary biliary cholangitis (PBC), the most frequent chronic cholestatic liver disease where UDCA clearly improves long-term survival. For many other chronic cholestatic conditions, anticholestatic effects are described, but long-term data are incomplete. While UDCA's litholytic properties can be explained by lowering biliary cholesterol hypersaturation, its beneficial effects in cholestatic diseases build on different mechanisms of action, namely: (i) stimulation of hepatobiliary secretion by post-transcriptional mechanisms including membrane targeting and insertion of key transporters and ion channels, (ii) stabilization of a biliary bicarbonate umbrella by stimulation of biliary chloride/bicarbonate secretion, and (iii) inhibition of hepatocyte and cholangiocyte apoptosis and reduction of endoplasmic reticulum stress induced by toxic endogenous bile acids.

Seizure clusters (also referred to as acute repetitive seizures) consist of several seizures interspersed with brief interictal periods. Seizure clusters can break down γ-aminobutyric acidergic (GABAergic) inhibition of dentate granule cells, leading to hyperactivation. Functional changes to GABA A receptors, which play a vital neuroinhibitory role, can include altered GABA A receptor subunit trafficking and cellular localization, intracellular chloride accumulation, and dysregulation of proteins critical to chloride homeostasis. A reduction in neuroinhibition and potentiation of excitatory neurotransmission in CA1 pyramidal neurons represent pathological mechanisms that underlie seizure clusters. Benzodiazepines are well-established treatments for seizure clusters; however, there remain barriers to appropriate care. At the clinical level, there is variability in seizure cluster definitions, such as the number and/or type of seizures associated with a cluster as well as the interictal duration between seizures. This can lead to delays in diagnosis and timely treatment. There are gaps in understanding between clinicians, their patients, and caregivers regarding acute treatment for seizure clusters, such as the use of rescue medications and emergency services. This lack of consensus to define seizure clusters in addition to a lack of education for appropriate treatment can affect quality of life for patients and place a greater burden on patient families and caregivers. For patients with seizure clusters, the sense of unpredictability can lead to continuous traumatic stress, during which patients and families live with a heightened level of anxiety. Clinicians can affect patient quality of life and clinical outcomes through improved seizure cluster education and treatment, such as the development and implementation of a personalized seizure action plan as well as prescriptions for suitable rescue medications indicated for seizure clusters and instructions for their proper use. In all, the combination of targeted therapy along with patient education and support can improve quality of life., (© 2022 International League Against Epilepsy.)

Background: An imbalance of macrophage M1/M2 polarization significantly influences the pathogenesis of inflammatory bowel disease. Qingchang Wenzhong decoction (QCWZD) has a proven therapeutic effect on patients with inflammatory bowel disease (IBD) and can significantly inhibit the inflammatory response in mice with colitis. However, its effect on macrophages during IBD treatment remains nebulous. Aim of the Study . Explore the mechanism underlying QCWZD effects in a dextran sulfate sodium (DSS)-induced colitis mouse model in vivo and RAW264.7 cell in vitro by observing macrophage polarization dynamics., Methods: The main active components of QCWZD were determined using high-performance liquid chromatography. Surface marker expression on M1-type macrophages was analyzed using flow cytometry and immunofluorescence. The effect on inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor- α (TNF- α ) released by M1 type macrophages was determined using ELSA and RT-PCR. The expression of key proteins in the JAK2/STAT3 signaling pathway was analyzed using western blotting. QCWZD cytotoxicity in macrophages was measured using CCK8 and Annexin V-FITC/PI assays., Results: The main active components of QCWZD were berberine chloride, coptisine chloride, epiberberine chloride, gallic acid, ginsenoside Rg1, ginsenoside Rb1, indigo, indirubin, notoginsenoside R1, palmatine chloride, and 6-curcumin. QCWZD markedly alleviated DSS-induced colitis in mice, as revealed by the rescued weight loss and disease activity index, attenuated the colonic shortening and mucosal injury associated with the inhibition of M1 macrophage polarization and expression of related cytokines, such as IL-6 and TNF- α , in vivo and in vitro . Furthermore, QCWZD decreased the iNOS, JAK2, and STAT3 levels in vivo and in vitro , regulating the JAK2/STAT3 signaling pathway., Conclusion: QCWZD administration improves intestinal inflammation by inhibiting M1 macrophage polarization. The JAK2/STAT3 signaling pathway may mediate the effects of QCWZD on M1 macrophage polarization in colitis treatment. This study presents a novel macrophage-mediated therapeutic strategy for the treatment of IBD., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Qiongqiong Lu et al.)

Objective: This study aimed to systematically evaluate the clinical efficacy of dexamethasone in patients with tuberculous meningitis (TBM) through meta-analysis., Method: PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and the Wanfang Databases were searched, and all relevant Chinese and English literature from 2000 to 2021 were retrieved from each database. We collected randomized controlled trials of conventional antituberculosis drugs combined with dexamethasone treatment (treatment group) and conventional antituberculosis drug treatment or combined with placebo treatment (control group) in TBM patients. Meta-analysis was performed with Stata16.0 software., Results: A total of 1645 articles were retrieved, and 11 articles were finally included in the study. Meta-analysis results showed that the treatment group had a significantly higher response rate and lower incidence of adverse reactions compared with the control group. Additionally, compared with the control group, the postoperative cerebrospinal fluid cell count, protein content, and glucose in the treatment group were significantly lower, while the chloride level increased., Conclusion: Conventional antituberculosis drugs combined with dexamethasone therapy can improve cerebrospinal fluid cell count, protein content, glucose, and chloride levels in patients with TBM. This treatment can improve the treatment effective rate and reduce the incidence of adverse reactions, which is considered an effective treatment for TBM. Our results provide strong evidence for enhancing existing treatment regimens and developing novel combination therapy to improve TBM treatment efficacy., Competing Interests: The authors declare that there are no conflicts of interest between them., (Copyright © 2022 Wei Wang et al.)

Introduction: The present study examined the possible estimation of plasma renin activity (PRA) by serum and urinary concentrations of chloride versus sodium in acute and chronic heart failure (HF)., Methods: Data from 29 patients with acute HF (48% men; 80.3 ± 12 years) and 26 patients with recovery of HF after decongestive therapy (50% men; 81.2 ± 12 years) were analyzed. Blood and urine samples were obtained immediately before decongestive therapy in acute HF patients. Clinical tests included peripheral blood tests, serum and spot urinary electrolytes, and plasma neurohormones. Sodium- or chloride-related indices included serum ([sNa+] or [sCl-]) and urinary ([uNa+] or [uCl-]) concentrations, their differences, and their ratio. Linear regression analysis was used for correlation coefficients., Results: PRA levels higher than the normal range were detected in only 5 (17%) of 29 patients with acute HF, but in as many as 11 (42%) of 26 patients with chronic HF. In the 29 patients with acute HF, all the chloride- and sodium-related indices except for [sNa+] were correlated with PRA: the [sCl-]/[uCl-] ratio was best correlated with PRA (R2 = 0.84, p < 0.0001) followed by the [sNa+]/[uNa+] ratio (R2 = 0.64, p < 0.0001). In the 26 patients with chronic HF, however, both the [sCl-] (R2 = 0.36, p = 0.001) and [sNa+] (R2 = 0.22, p = 0.016) were only weakly correlated with PRA., Conclusion: In acute HF, chloride-related indices derived from serum and urinary concentrations were firmly associated with PRA or better than sodium-related indices. In chronic HF, either chloride- or sodium-related indices were not firmly associated with PRA, presumably due to influence of cardiovascular medication., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Cancer is a collection of diseases caused by specific changes at the genomic level that support cell proliferation indefinitely. Traditionally, ion channels are known to control a variety of cellular processes including electrical signal generation and transmission, secretion, and contraction by controlling ionic gradients. However, recent studies had brought to light important facts on ion channels in cancer biology.In this review we discuss the mechanism linking potassium or chloride ion channel activity to biochemical pathways controlling proliferation in cancer cells and the potential advantages of targeting ion channels as an anticancer therapeutic option., (© 2021. Springer Nature Switzerland AG.)

Background: Studies have shown complications of normal saline infusion because of its high-chloride content. Therefore, in the present study, we aimed to explore whether the use of low- versus high-chloride solutions benefited the unselected and specifically perioperative patients and was associated with different outcomes., Methods: Studies on the use of low- versus high-chloride content intravenous solutions for perioperative patients, published up to July 15, 2019, were systematically reviewed, and primary and secondary outcomes were quantitatively summarized., Results: A total of 14 eligible randomized controlled trials with 943 perioperative patients were included. Five studies reported all-cause mortality, and eight studies provided detailed data on renal replacement therapy (RRT). The pooled result suggested no statistically significant difference in the effect of low- versus high-chloride solutions on all-cause mortality (risk ratio (RR) = 1.39; 95%confidence interval (CI) = 0.23-8.26) and RRT (RR = 1.05; 95%CI = 0.63-1.76). The pooled results on acute kidney injury (AKI) and the use of allogenic blood transfusion ( P > 0.05) were similar., Conclusion: Among specific perioperative patients, the use of low- versus high-chloride content intravenous solutions did not reduce the all-cause mortality, risk of severe AKI, or rate of RRT use. Further large randomized clinical trials are needed to confirm or refute this finding., Competing Interests: The authors declare no competing interests., (Copyright © 2021 Xuan Song et al.)

After being in the therapeutic wilderness for several decades, acute myeloid leukemia has been recently thrust into the limelight with a series of drug approvals. Technical refinements in production, genetic manipulation and chemical modification of monoclonal antibodies led to growing interest in antibodies-based treatment strategies. Much of the focus of these efforts in acute myeloid leukemia has been on CD33 as a target. On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin for treatment of relapsed or refractory CD33 + acute myeloid leukemia. This signals a new chapter in the long and unusual story of gemtuzumab ozogamicin, which was the first antibody-drug conjugate approved for human use by the Food and Drug Administration. In this review we have analyzed the history of this drug which, among several mishaps, is experiencing a second youth and still represents a field to be further explored.

The lower limit of soluble zinc content that can possibly be applied onto a wounded skin as a healing promoter was not known. This study examined skin wound healing process of rats inflicted by partial thickness thermal burn wound as a function of applied soluble zinc contents (0.1 ml of zinc chloride solution 0.01% (w/w) or 5.0% (w/w)). The size, surface morphology and histological profiles of wound beds of untreated rats and those treated with zinc chloride solutions were characterized. A soluble zinc content as low as 10.5 μg/cm 2 of skin negated skin wound healing when compared to the untreated rats. This was alarming as the commercial products currently in the market are formulated with a high level of zinc content. Albeit the zinc salt employed was water-insoluble, a minute fraction of soluble zinc might be available to the treatment sites. This could be partially responsible for the late adverse effects such as pruritis and inflammation reported with calamine/diphenhydramine lotion, medicated shampoo, Olay Complete defense moisturizing lotion and Zineryt ® topical solution. The skin irritation was likely a resultant oxidative stress action of soluble zinc, where a small fraction could be adequate to negate the skin homeostasis.[Figure: see text]Key messagesZinc is essentially a cofactor for skin collagen formation.Soluble zinc content as low as 10.5 μg/cm 2 of skin irritates skin and negates burn wound healing.Skin irritation of commercial products relates to minute soluble zinc content availability.

Mohs paste is useful for controlling exudates from wounds and infections and is used to treat patients with inoperable skin tumors. Unfortunately, Mohs paste is difficult to preserve because its viscosity and stickiness increase dramatically immediately after preparation, resulting in decreased usability. In this study, the combined use of cryopreservation and kneading was shown to improve long-term storage of Mohs paste. At 25°C, Mohs pastes solidified rapidly, and viscosity reached approximately 700 Pa·s 5 h after preparation. In contrast, cryopreservation at -20°C attenuated hardening of Mohs pastes, and kneading also decreased viscosity. The viscosity of Mohs pastes cotreated with cryopreservation and kneading after 7 months of storage was <70 Pa·s. In addition, tissue invasion with these stored pastes was similar to freshly prepared Mohs paste. Results suggest that the combination of cryopreservation and kneading permits Mohs paste to be stored over extended periods, which may increase the utility of the paste for clinical use.

Background: Lupoid cutaneous leishmaniasis (LCL) is known as a rare but serious complication of anthroponotic cutaneous leishmaniasis (ACL) resistant to conventional treatments. Sodium chlorosum, a pro-oxidative preparation of pharmaceutical sodium chlorite (NaClO 2 ), has been successfully used for the treatment of Old World cutaneous leishmaniasis lesions (OWCL) and of some LCL cases in Afghanistan. This clinical trial study aimed to evaluate the effect of a last resort therapy with topical 0.09% sodium chlorosum on LCL in Iran., Methods: Twenty Iranian patients (12 women and 8 men) with LCL refractory to treatment were included in this salvage study. A magistral preparation of sodium chlorosum (10 mM NaClO 2 in amphiphilic basic cream) was applied twice daily to the lesions for 6 weeks and continued up to 12 weeks in patients who showed a clinical response within the first 6 weeks. Responders were followed up for a maximum of 1 year. Lesions were photographed during weekly visits. Disappearance of erythema and indurated lesions were rated as complete clinical response., Results: Patients with a mean age of 28.6 (±24.3) and with an ACL proven lesion history of 3.8 (±1.4) years were treated for an average of 7.9 (±1.8) weeks. At the end of the treatment period (12th week), a complete response was observed in 9 of 20 patients (45%). During the one-year follow-up period, LCL lesions recurred in 4 of these 9 patients (with one patient showing only a tiny lesion) and one case lost to follow up whereas the other four remained completely lesion-free. Mild temporary side-effects such as erythema and itching were seen in 4 of 20 patients (20%)., Conclusions: Topical sodium chlorosum showed promising therapeutic results and can be considered as safe, painless, and relatively effective treatment for LCL, an ethical prerequisite for a two-armed controlled trial., Trial Registration: This study was registered in Iranian registry of clinical trials on 2019-02-02 with registration number IRCT20190114042356N1.

Estrogen receptor-positive (ER+) breast carcinoma therapy faces the challenges of estrogen receptors heterogeneity and endocrine therapy resistance. Selectively attacking glutathione (GSH) biosynthesis which is the metabolic vulnerability of ER+ breast carcinoma could bypass conventional treatment limitations through blocking oxidative stress disorders-driven tumor cell proliferation. Herein, we developed drug-organics-inorganics self-assembled nanosystem (DFTA) with doxorubicin (DOX) as chemotherapeutic agent, ferric chloride (FeCl 3 ) as ferroptosis inducer and tannic acid (TA) as activator of superoxide dismutase (SOD)-like reaction in intracellular cascade for the combined therapy in ER+ breast carcinoma. DFTA displayed a particle size of 106.4 ± 0.7 nm with flat irregular nanonetwork-like shape and predominant photothermal effect produced in the assembly process. The drug release from DFTA could be triggered by photothermal excitation efficiently. ELISA analysis showed that DFTA + laser group significantly reduced intracellular GSH level through reactive oxygen species (ROS)-produced intracellular oxidative stress cascade amplification and photothermal therapy (PT)-mediated ROS production. Furthermore, in vivo antitumor efficiency evaluation showed that the tumor inhibition ratio of DFTA + laser was as high as 93.38 % even though the dosage of iron and DOX reduced by about 9 times and 1.5 times respectively. In summary, our study established a high-efficiency nanosystem based on triple combination therapy of chemotherapy, ferroptosis and PT, which might be a promising nanosystem for effective ER+ breast carcinoma therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The neuro-protective effects of rubidium and lithium as alkali metals have been reported for different central nervous system dysfunctions including mania and depression. The aim of this study was evaluating as well as comparing the effects of rubidium chloride (RbCl) and lithium chloride (LiCl) on different seizures paradigms in mice and determining the involvement of NMDA receptors and nitrergic pathway. To assess the seizures threshold, animals received intravenous pentylenetetrazole (PTZ, 0.5%; 1 mL/min). Male NMRI mice (6-8 weeks) received intraperitoneal (i.p.) injections of different doses of RbCl and LiCl. Doses greater than 10 mg/kg of RbCl showed a significant anticonvulsant activity 60 min after administration; the anticonvulsant effects of LiCl was observed at the doses more than 5 mg/kg and after 30 min in PTZ-induced seizure threshold. But, RbCl (10, 20 mg/kg, i.p) or LiCl (5, 10 mg/kg, i.p) injection did not induce protection against maximal electroshock (MES) or intraperitoneal injection of PTZ lethal dose (80 mg/kg)-induced seizure models. Pre-treatment with L-NAME (non-selective nitric oxide synthase (NOS) inhibitor, 10 mg/kg; i.p.) and 7-nitroindazole (selective neuronal NOS inhibitor, 30 mg/kg; i.p.) enhanced the anticonvulsive effects of both RbCl (5 mg/kg, i.p.) and LiCl (1 mg/kg, i.p.) in PTZ-induced seizure threshold model. Injection of MK-801 (NMDA receptor antagonist, 0.05 mg/kg; i.p.) before RbCl (5 mg/kg, i.p.; P < 0.001) and LiCl (1 mg/kg, i.p.; P < 0.001) administration increased the anti-seizure activity. But, treatment with L-arginine (precursor of nitric oxide, 100 mg/kg; i.p.) decreased the seizure threshold of both RbCl (20 mg/kg, i.p.; P < 0.001) and LiCl (10 mg/kg, i.p.; P < 0.001). Measurement of nitrite levels in hippocampus of animals revealed a remarkable reduction after treatment with RbCl (20 mg/kg, i.p; P < 0.05) and LiCl (10 mg/kg, i.p; P < 0.01). To conclude, rubidium may protect central nervous system against seizures in PTZ-induced seizures threshold model through NMDA/nitrergic pathways with a similarity to lithium effects in mice., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Intravenous 0.9% saline has saved countless lives since it was introduced over a century ago. It remains the most widespread crystalloid in both adult and pediatric practice. However, in recent years, evidence of deleterious effects is accruing. These include increased mortality, acute kidney injury (AKI), metabolic acidosis, and coagulopathy. The predominant cause for these sequelae appears to be the excess chloride concentration of 0.9% saline relative to plasma. This has led to development of balanced isotonic solutions such as PlasmaLyte. This review summarizes current evidence for adverse effects of chloride-rich intravenous fluid and considers whether 0.9% saline should still be used in 2018 or abandoned as a historical treatment in favor of balanced crystalloid solutions.

Maslinic acid is a pentacyclic triterpene with a plethora of biological activities, including anti-inflammatory, antioxidant, antimicrobial, cardioprotective, and antitumor effects. New derivatives with improved properties and broad-spectrum activity can be obtained following structural changes of the compound. The present study was aimed to characterize a benzylamide derivative of maslinic acid-benzyl (2α, 3β) 2,3-diacetoxy-olean - 12-en-28-amide (EM2)-with respect to the anti-angiogenic and anti-inflammatory effects in two in vivo experimental models. Consequently, the compound showed good tolerability and lack of irritation in the chorioallantoic membrane assay with no impairment of the normal angiogenic process during the tested stages of development. In the acute ear inflammation murine model, application of EM2 induced a mild anti-inflammatory effect that was potentiated by the association with zinc chloride (ZnCl 2 ). A decrease in dermal thickness of mice ears was observed when EM2 and ZnCl 2 were applied separately or in combination. Moreover, hyalinization of the dermis appeared only when EM2 was associated with ZnCl 2 , strongly suggesting the role of their combination in wound healing.

We report a case of advanced left breast cancer with continuous bleeding from the primary tumor surface in an 81-year-old woman. Pathological findings showed invasive carcinoma with positive expression of hormone receptors. CT and bone scintigraphy showed primary tumor invasion of the greater pectoral muscle and multiple bone metastases. She received Mohs' chemosurgery, endocrine therapy, and denosumab. The bleeding was maintained by weekly treatment. Most of the bulging surface of the tumor decreased and dried up 2 months later. The tumor disappeared almost completely, and the bone metastases achieved stable status 3 months later. Until currently, the primary tumor and metastasis have been controlled for 1.5 years. Mohs' paste was effective for controlling bleeding and exudates of unresectable cancer bulging from the skin surface and played an important role in cancer treatment with systemic therapy.

Asian and African elephants are frequently afflicted by foot disorders that can be very challenging to manage even with aggressive therapy. Such conditions may have indirect life-threatening effects. Mohs' paste (zinc chloride based escharotic agent) was used to treat a female Indian elephant (Elephas maximus indicus) aged 39 years with foot disorder at Kanazawa Zoological Gardens. Degenerated hyperplastic tissue was observed inside the hoofs of digits 2 and 5. Mohs' paste was applied on the lesions, which coagulated the hyperplastic tissue and restrained its proliferation. Subsequently, the hyperplastic tissue could be trimmed with little pain, and the disorder became manageable. Mohs' paste treatment was effective and is expected to be an alternative treatment for hoof disorder.

We report a case involving a 65-year-old woman with skin invasion and destruction by left large breast cancer(T4cN0M0, Stage ⅢB). She had severe anemia with recurrent bleeding on the cancer surface and needed blood transfusion, and massive malodorous effusion from the skin lesion resulted in hypoalbuminemia and recurrent bacteremia. Metronidazole gel treatment for malodorous effusion and postmenopausal hormonal therapy were administered at first. After using Mohs' paste 4 times with 1- or 2-week intervals, the bleeding and effusion stopped, and the primary cancer tumor almost disappeared. Bacteremia also improved with antibiotics, and amelioration of distress was observed. Following this, systemic chemotherapy was performed. Mohs' paste was a very useful method for symptom management of malignant skin lesions with bleeding and massive effusion.

Locally advanced breast cancer with skin invasion often causes malodor, bleeding, and massive exudates, which degrades patients' quality of life(QOL). A 61-year-old woman presented with locally advanced breast cancer with malodor and massive exudates, which had carcinomatous pleurisy causing dyspnea. We administered endocrine therapy and chemotherapy and used Mohs paste for local therapy. The exposed part of the tumor was fixed using Mohs paste. After continuing to apply Vaseline over the fixed part, the lesion spontaneously detached without surgical removal and completely epithelized, and malodor and exudates disappeared. Cancerous pleurisy also improved, and dyspnea disappeared. Local treatment using Mohs paste and systemic pharmacotherapy dramatically improved her QOL.

Context and Aims: Off-pump coronary artery bypass graft (OPCABG) is a form of CABG surgery. It is performed without the use of cardiopulmonary bypass machine as a surgical treatment for coronary heart disease. Acute kidney injury (AKI) is one of the common postoperative complications of OPCABG. Previous studies suggest important differences related to intravenous fluid (IVF) chloride content and renal function. We hypothesize that perioperative use of chloride restricted IVFs may decrease incidence and severity of postoperative AKI in patients undergoing OPCABG., Methods: Six hundred patients were randomly divided into two groups of 300 each. In Group A (n = 300), chloride liberal IVFs, namely, hydroxyethyl starch (130/0.4) in 0.9% normal saline (Voluven), 0.9% normal saline, and Ringer's lactate were used for perioperative fluid management. In Group B (n = 300), chloride-restricted IVFs, namely, hydroxyethyl starch (130/0.4) in balanced colloid solution (Volulyte) and balanced salt crystalloid solution (PlasmaLyte A), were used for perioperative fluid management. Serum creatinine values were taken preoperatively, postoperatively at 24 h and at 48 h. Postoperative AKI was determined by AKI network (AKIN) criteria., Results: In Group A, 9.2% patients and in Group B 4.6% patients developed Stage-I AKI determined by AKIN criteria which was statistically significant (P < 0.05)., Conclusion: Perioperative use of chloride restricted IVF was found to decrease incidence of postoperative AKI. The use of chloride liberal IVF was associated with hyperchloremic metabolic acidosis., Competing Interests: There are no conflicts of interest

In rats, mice, and humans, it is known that zinc deficiency may be related to anemia, and zinc supplementation influences hemoglobin production. Our previous studies indicate that in fish, zinc supplementation stimulates red blood cell (RBC) formation (erythropoiesis). However, it is not clear whether the mechanism of zinc-induced erythropoiesis stimulation in fish also occurs in rats. We induced anemia in rats using phenylhydrazine (PHZ) and injected either saline or ZnSO₄ solution. We found that an appropriate amount of zinc stimulated erythropoiesis in the PHZ-induced anemic rats. The effects of ZnSO₄ injection were dose-dependent. When the concentration of ZnSO₄ was higher than 2.8 mg zinc/kg body weight, the RBC level of the anemic rats increased from 60 ± 7% to 88 ± 10% that of the normal rats in two days. Rat bone marrow cells with or without ZnCl₂ supplementation were cultured in suspension in vitro. In the cell culture when the zinc concentration was at 0.3 mM, a 1.6-fold proliferation of nascent immature reticulocytes (new RBCs) was observed after one day. In the rat blood, zinc was combined with serum transferrin to induce erythropoiesis. The stimulation of RBC formation by zinc appears to be common among different animals., Competing Interests: All the authors declared no competing interests.