Thiopental and decompressive craniectomy as last-tier ICP-treatments in aneurysmal subarachnoid hemorrhage: is functional recovery within reach?

The study aimed to investigate the indication and functional outcome after barbiturates and decompressive craniectomy (DC) as last-tier treatments for elevated intracranial pressure (ICP) in aneurysmal subarachnoid hemorrhage (aSAH). This observational study included 891 aSAH patients treated at a single center between 2008 and 2018. Data on demography, admission status, radiology, ICP, clinical course, and outcome 1-year post-ictus were collected. Patients treated with thiopental (barbiturate) and DC were the main target group.Thirty-nine patients (4%) were treated with thiopental alone and 52 (6%) with DC. These patients were younger and had a worse neurological status than those who did not require these treatments. Before thiopental, the median midline shift was 0 mm, whereas basal cisterns were compressed/obliterated in 66%. The median percentage of monitoring time with ICP > 20 mmHg immediately before treatment was 38%, which did not improve after 6 h of infusion. Before DC, the median midline shift was 10 mm, and the median percentage of monitoring time with ICP > 20 mmHg before DC was 56%, which both significantly improved postoperatively. At follow-up, 52% of the patients not given thiopental or operated with DC reached favorable outcome, whereas this occurred in 10% of the thiopental and DC patients.In summary, 10% of the aSAH cohort required thiopental, DC, or both. Thiopental and DC are important integrated last-tier treatment options, but careful patient selection is needed due to the risk of saving many patients into a state of suffering.

Transcriptional analysis of islets of Langerhans from organ donors of different ages.

Insulin secretion is impaired with increasing age. In this study, we aimed to determine whether aging induces specific transcriptional changes in human islets. Laser capture microdissection was used to extract pancreatic islet tissue from 37 deceased organ donors aged 1-81 years. The transcriptomes of the extracted islets were analysed using Ion AmpliSeq sequencing. 346 genes that co-vary significantly with age were found. There was an increased transcription of genes linked to senescence, and several aspects of the cell cycle machinery were downregulated with increasing age. We detected numerous genes not linked to aging in previous studies likely because earlier studies analysed islet cells isolated by enzymatic digestion which might affect the islet transcriptome. Among the novel genes demonstrated to correlate with age, we found an upregulation of SPP1 encoding osteopontin. In beta cells, osteopontin has been seen to be protective against both cytotoxicity and hyperglycaemia. In summary, we present a transcriptional profile of aging in human islets and identify genes that could affect disease course in diabetes.

Characterization of host defense molecules in the human pancreas.

The gut microbiota can play a role in pancreatitis and, likely, in the development of type 1 diabetes (T1D). Anti-microbial peptides and secretory proteins are important mediators of the innate immune response against bacteria but their expression in the human pancreas is not fully known. In this study, immunohistochemistry was used to analyze the expression of seven anti-microbial peptides (Defensin α1, α4, ß1-4 and Cathelicidin) and two secretory proteins with known antimicrobial properties (REG3A and GP2) in pancreatic and duodenal biopsies from 10 non-diabetic organ donors and one organ donor that died at onset of T1D. Immunohistochemical data was compared with previously published whole-transcriptome data sets. Seven (Defensin α1, ß2, ß3, α4, GP2, Cathelicidin, and REG3A) host defense molecules showed positive staining patterns in most non-diabetic organ donors, whereas two (Defensin ß1 and ß4) were negative in all non-diabetic donors. Two molecules (Defensin α1 and GP2) were restricted to the exocrine pancreas whereas two (Defensin ß3, α4) were only expressed in islet tissue. Cathelicidin, ß2, and REG3A were expressed in both islets and exocrine tissue. The donor that died at onset of T1D had generally less positivity for the host defense molecules, but, notably, this pancreas was the only one where defensin ß1 was found. Neither donor age, immune-cell infiltration, nor duodenal expression correlated to the pancreatic expression of host defense molecules. In conclusion, these findings could have important implications for the inflammatory processes in diabetes and pancreatitis as we find several host defense molecules expressed by the pancreatic tissue.

Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism.

It is currently unknown how the islet transcriptional pattern changes as glucose metabolism deteriorates and progresses to fulminant type 2 diabetes (T2D). In this study, we hypothesized that islets from donors with elevated HbA1c levels, but not yet diagnosed with T2D, would show signs of cell stress on a transcriptional level. Laser capture microdissection and qPCR arrays including 330 genes related to mitochondria, oxidative stress, or the unfolded protein response were used to extract and analyze islets from organ donors with HbA1c <5.5% (37 mmol/mol), elevated HbA1c (6.0-6.5% (42-48 mmol/mol)), high HbA1c (>6.5% (48 mmol/mol)) or established T2D. Principal component analysis and hierarchical clustering based on the expression of all 330 genes displayed no obvious separation of the four different donor groups, indicating that the inter-donor variations were larger than the differences between groups. However, 44 genes were differentially expressed (P < 0.05, false discovery rate <30%) between islets from donors with HbA1c <5.5% (37 mmol/mol) compared with islets from T2D subjects. Twelve genes were differentially expressed compared to control islets in both donors with established T2D and donors with elevated HbA1c (6.0-6.5% (42-48 mmol/mol)). Overexpressed genes were related mainly to the unfolded protein response, whereas underexpressed genes were related to mitochondria. Our data on transcriptional changes in human islets retrieved by LCM from high-quality biopsies, as pre-diabetes progresses to established T2D, increase our understanding on how islet stress contributes to the disease development.