Delayed Administration of the K+ Channel Activator Cromakalim Attenuates Cerebral Vasospasm after Experimental Subarachnoid Hemorrhage

Summary ? Background. Delayed cerebral vasospasm remains an unpredictable and inadequately treated complication of aneurysmal subarachnoid hemorrhage (SAH). Recent evidence indicates that the potassium channel activator cromakalim is capable of limiting cerebral vasospasm in rabbits when administered immediately after experimental SAH (i.e. before spastic constriction has been initiated). However, the ultimate clinical value of cromakalim for treating vasospasm will depend in part on its effectiveness when administered after SAH-induced constriction has already been initiated. The present study examined the effects of cromakalim on vasospasm when treatment was initiated after SAH-induced constriction was underway.  Methods. New Zealand white rabbits were subjected to experimental SAH by injecting autologous blood into the cisterna magna. Cromakalim (0.03, 0.1 or 0.3 mg/kg) or vehicle was injected intravenously at 8 hour intervals beginning 24 hours post-SAH. Animals were killed by perfusion fixation 48 hours after SAH. Basilar arteries were removed and sectioned, and cross-sectional area was measured.  Findings. The average cross sectional areas of basilar arteries were reduced by 64% and 68% in the SAH-only and SAH+vehicle groups, respectively. Treatment with cromakalim dose-dependently attenuated SAH-induced constriction. The groups treated with 0.03, 0.1, and 0.3 mg/kg cromakalim exhibited average decreases in cross-sectional area of 57%, 42%, and 19%, respectively.  Interpretation. These findings indicate that cromakalim dose-dependently attenuates cerebral vasospasm when administered 24 hours after experimental SAH in the rabbit. The results suggest K_ATP channel activators, such as cromakalim, could be of benefit for reversing cerebral vasospasm after aneurysmal SAH.     

Molecular cytogenetic analysis of medulloblastomas and supratentorial primitive neuroectodermal tumors by using conventional banding, comparative genomic hybridization, and spectral karyotyping

OBJECT: Medulloblastomas and related primitive neuroectodermal tumors (PNETs) of the central nervous system are malignant, invasive embryonal tumors with predominantly neuronal differentiation that comprise 20% of pediatric brain tumors. Cytogenetic analysis has shown that alterations in chromosome 17, particularly the loss of 17p and the formation of isochromosome 17q, as well as the gain of chromosome 7 are the most common changes among this group of tumors. Comparative genomic hybridization (CGH) studies have largely confirmed these cytogenetic findings and have also identified novel regions of gain, loss, and amplification. The advent of more sophisticated multicolored fluorescence in situ hybridization (FISH) procedures such as spectral karyotyping (SKY) now permits complete recognition of all aberrations including extremely complex rearrangements. The authors report a retrospective analysis of 19 medulloblastoma and five PNET cases studied using combinations of classic banding analysis, FISH, CGH, and SKY to examine comprehensively the chromosomal aberrations present in this tumor group and to attempt to identify common structural rearrangement(s). METHODS: The CGH data demonstrate gains of chromosomes 17q and 7 in 60% of the tumors studied, which confirms data reported in the current literature. However, the authors have also combined the results of all three molecular cytogenetic assays (Giemsa banding, CGH, and SKY) to reveal the frequency of chromosomal rearrangement (gained, lost, or involved in structural rearrangement). CONCLUSIONS: The combined results indicate that chromosomes 7 and 17 are the most frequently rearranged chromosomes (10.1% and 8.9%, respectively, in all rearrangements detected). Furthermore, chromosomes 3 (7.8%), 14 (7%), 10 (6.7%), and 22 (6.5%) were also found to be frequently rearranged, followed by chromosomes 6 (6.5%), 13 (6.2%), and 18 (6.2%). Eight (33%) of 24 tumors exhibited high-level gains or gene amplification. Amplification of MYCN was identified in four tumors, whereas amplification of MYCC was identified in one tumor. One tumor exhibited a high-level gain of chromosome 9p. Additionally, desmoplastic medulloblastomas and large-cell medulloblastomas exhibited higher karyotype heterogeneity, amplification, and aneusomy than classic medulloblastomas.     

Adding collagen to adipose tissue transplant increases engraftment by promoting cell proliferation,neovascularisation and macrophage activity in a rat model

To clarify the effect of collagen addition to transplanted adipose tissue on angiogenesis, cell proliferation and tissue remodelling process and reveal whether collagen addition contributes to improving transplanted adipose tissue engraftment in rats. Adipose tissue was harvested from the inguinal and injected into the back of the rat, in addition to collagen. Engraftment tissue was harvested, semi‐quantitatively evaluated and underwent haematoxylin and eosin or Perilipin staining. Moreover, we evaluated viable adipocyte counts and neovascularisation. Macrophages were evaluated using flow cytometry, and the adiponectin or vascular endothelial growth factor (VEGF) mRNA was detected using real‐time polymerase chain reaction. By collagen addition to transplanted adipose tissue, higher engraftment rate semi‐quantitatively and a greater number of new blood vessels histologically were identified. Perilipin staining revealed a higher adipocyte number. The total cell, M1 macrophage and M2 macrophage count were higher. There was increased adiponectin mRNA significantly at week 4 compared to that at week 1 after transplantation. Note that the expression levels of VEGF mRNA increased. In rats, adding collagen enhanced cell proliferation, induced M2 macrophages, which are involved in wound healing, and promoted adipocytes and neovascularisation. Therefore, collagen addition to transplanted adipose tissue could increase the engraftment rate of adipose tissue.     

Triple Therapy-Based on Tegoprazan,a New Potassium-Competitive Acid Blocker,for First-Line Treatment of Helicobacter pylori Infection: A Randomized,Double-Blind,Phase III,Clinical Trial

Background/AimsWe examined the efficacy and safety of tegoprazan as a part of first-line triple therapy for Helicobacter pylori eradication.MethodsA randomized, double-blind, controlled, multicenter study was performed to evaluate whether tegoprazan (50 mg)-based triple therapy (TPZ) was noninferior to lansoprazole (30 mg)-based triple therapy (LPZ) (with amoxicillin 1 g and clarithromycin 500 mg; all administered twice daily for 7 days) for treating H. pylori. The primary endpoint was the H. pylori eradication rate. Subgroup analyses were performed according to the cytochrome P450 (CYP) 2C19 genotype, the minimum inhibitory concentration (MIC) of amoxicillin and clarithromycin, and underlying gastric diseases.ResultsIn total, 350 H. pylori-positive patients were randomly allocated to the TPZ or LPZ group. The H. pylori eradication rates in the TPZ and LPZ groups were 62.86% (110/175) and 60.57% (106/175) in an intention-to-treat analysis and 69.33% (104/150) and 67.33% (101/150) in a per-protocol analysis (non-inferiority test, p=0.009 and p=0.013), respectively. Subgroup analyses according to MICs or CYP2C19 did not show remarkable differences in eradication rate. Both first-line triple therapies were well-tolerated with no notable differences.ConclusionsTPZ is as effective as proton pump inhibitor-based triple therapy and is as safe as first-line H. pylori eradication therapy but does not overcome the clarithromycin resistance of H. pylori in Korea (ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT03317223","term_id":"NCT03317223"}}NCT03317223).     

Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

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Viral infections in pregnancy

Viral infections are a common complication of pregnancy and in some cases, can have profound effects for the unborn fetus. The human herpesvirus family is composed of large, enveloped DNA viruses that have close structural similarity. The family includes the herpes simplex viruses types 1 and 2, varicella zoster virus, Epstein Barr virus, cytomegalovirus (CMV), and human herpes viruses types 6, 7 and 8. These viruses all share the ability to establish latency and reactivate at a later time. Structural fetal abnormalities can result from intrauterine infection and transmission of the infection during the pregnancy or at the time of delivery can result in important neonatal disease. Human parvovirus B19 is a DNA virus with strong tropism for erythroid precursors and infection during pregnancy can result in fetal hydrops and stillbirth. The causative agents of hepatitis are hepatotropic viruses termed hepatitis A, B, C, D (deltavirus) and E. All except hepatitis B virus are RNA viruses. Vertical transmission of maternal infection with hepatitis B and C can result in significant long term sequelae.     

The microbiome of lung cancer tissue and its association with pathological and clinical parameters

Lung cancer is the primary cause of cancer-related deaths worldwide. Recently, although the microbiome has emerged as the key modulator of the carcinogenesis, it has not been evaluated in lung cancer. Here, we evaluated the microbial composition of lung cancer tissues according to the histologic type and genetic mutation, compared it with that of the adjacent normal lung tissues, and investigated the association between the lung microbiome and clinical parameters. We collected lung tissue samples from 162 patients with non-small cell lung cancer (NSCLC, 162 cancer and 54 adjacent normal tissues), surgically resected between January 2018 and December 2019, and analyzed their microbiome using 16S rRNA gene amplicon sequencing, the QIIME2 pipeline, and statistical analyses. NSCLC tissues had significantly lower alpha diversity than the normal tissues, and their microbial composition differed according to the histologic type and cancer genetic mutation. The genera Romboutsia, Novosphingobium, Acinetobacter, and Prevotella were significantly overrepresented in NSCLC tissues. Alpha diversity steadily declined from a normal to a more advanced stage, and microbial compositional differences were noted along with recurrence. Stenotrophomonas was the most predominant genus in the NSCLC tissues of patients with recurrence. The pathways related to the tricarboxylic acid cycle and L-glutamate and L-glutamine biosynthesis were predominant in adenocarcinoma, whereas those related to purine and pyrimidine nucleotide degradation and formaldehyde assimilation were predominant in squamous cell carcinoma. Our findings suggest that the altered lung cancer microbial composition might be associated with cancer initiation and/or progression.     

A retrospective study of physiotherapy management for patients with pneumonia requiring invasive ventilation in a single-center Australian ICU

Background:Pneumonia is a frequent diagnosis for patients admitted to Australian intensive care units (ICUs) for invasive ventilation. Physiotherapists in ICU provide interventions to enhance respiratory function and physical recovery.Objective:This retrospective cohort study aimed to describe physiotherapy management of adults with pneumonia who require invasive mechanical ventilation in a single Level 3 ICU in a quaternary teaching hospital.Methods:All adults admitted with a medical diagnosis of pneumonia requiring invasive mechanical ventilation over a two-year period were included. Demographic and clinical data, including APACHE II score, ventilator-free days (VFDs) to day 28, ICU length of stay (LOS), and type and frequency of physiotherapy episodes of care delivered in ICU, were collected from electronic medical records. Correlations between VFDs to day 28 and the frequency of physiotherapy interventions delivered per subject were examined using Spearman’s rho analysis.Results:From 208 records screened, 66 subjects with an ICU admission diagnosis of pneumonia, who required invasive mechanical ventilation, were included. Median (IQR) ICU LOS was 10 (5–17) days, and mortality rate was 15.2% (n=10). The cohort had a median of 20.5 (IQR 2–25) VFDs to day 28. Community-acquired pneumonia (66.7%, n=44) was the most frequent type of pneumonia diagnosis. There were 1110 episodes of physiotherapy care, with patients receiving a median of 13.5 (IQR 6.8–21.3) episodes during their ICU stay, with a median rate of 1.2 (IQR 1.0–1.6) episodes per day. Over 96.7% of patients with pneumonia received physiotherapy treatment during their ICU stay. Overall, physiotherapy treatments consisting only of respiratory techniques were most commonly provided (55.1%, n=612). Airway suctioning (92.4%, n=61), patient positioning (72.7%, n=48) or positioning advice to nurses (77.3%, n=51), and hyperinflation techniques (63.6%, n=42) were among the respiratory techniques most delivered.Conclusion:This study described the current intensive care physiotherapy management in a single center for adults with pneumonia who required invasive mechanical ventilation, demonstrating that respiratory physiotherapy interventions are often provided for this ICU patient cohort. Further research is warranted to determine the efficacy of respiratory physiotherapy interventions to justify their use for ICU patients with pneumonia receiving invasive mechanical ventilation.