Protocolized reduction of non-resuscitation fluids versus usual care in septic shock patients (REDUSE): a randomized multicentre feasibility trial.

BACKGROUND/PURPOSE: Non-resuscitation fluids constitute the majority of fluid administered for septic shock patients in the intensive care unit (ICU). This multicentre, randomized, feasibility trial was conducted to test the hypothesis that a restrictive protocol targeting non-resuscitation fluids reduces the overall volume administered compared with usual care. METHODS: Adults with septic shock in six Swedish ICUs were randomized within 12 h of ICU admission to receive either protocolized reduction of non-resuscitation fluids or usual care. The primary outcome was the total volume of fluid administered within three days of inclusion. RESULTS: Median (IQR) total volume of fluid in the first three days, was 6008 ml (interquartile range [IQR] 3960-8123) in the restrictive fluid group (n = 44), and 9765 ml (IQR 6804-12,401) in the control group (n = 48); corresponding to a Hodges-Lehmann median difference of 3560 ml [95% confidence interval 1614-5302]; p < 0.001). Outcome data on all-cause mortality, days alive and free of mechanical ventilation and acute kidney injury or ischemic events in the ICU within 90 days of inclusion were recorded in 98/98 (100%), 95/98 (98%) and 95/98 (98%) of participants respectively. Cognition and health-related quality of life at six months were recorded in 39/52 (75%) and 41/52 (79%) of surviving participants, respectively. Ninety out of 134 patients (67%) of eligible patients were randomized, and 15/98 (15%) of the participants experienced at least one protocol violation. CONCLUSION: Protocolized reduction of non-resuscitation fluids in patients with septic shock resulted in a large decrease in fluid administration compared with usual care. A trial using this design to test if reducing non-resuscitation fluids improves outcomes is feasible. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05249088, 18 February 2022. https://clinicaltrials.gov/ct2/show/NCT05249088.

Cognition in myotonic dystrophy type 1: a 5-year follow-up study.

BACKGROUND AND PURPOSE: Studies on cognitive decline in myotonic dystrophy type 1 (DM1) are characterized by conflicting results. The purpose of the present study was to analyse possible decline in classical/adult onset DM1 at a 5-year follow-up and to explore the correlation with disease-related and demographic factors. METHODS: Patients with DM1 (n = 37) were examined with a comprehensive neuropsychological test battery yielding measures on memory, attention, verbal, visuospatial and executive functions. Assessment of muscle impairment and CTG repeat expansion size was performed. RESULTS: A majority of the participants (65%) performed worse at follow-up. Compared to normative data, patients scored significantly worse on tests measuring memory, attention, visuospatial construction and verbal ability. Neither CTG repeat size nor muscle impairment related to cognitive decline. However, age at onset and disease duration were correlated with the number of tests in which performance was below 1 SD at both baseline and follow-up examination. CONCLUSIONS: Measurements show that classical/adult onset DM1 is characterized by cognitive decline. Both earlier onset and longer duration of the disease are indicative of more cognitive deficits.

Gravitational waves from color-magnetic "mountains" in neutron stars.

Neutron stars may harbor the true ground state of matter in the form of strange quark matter. If present, this type of matter is expected to be a color superconductor, a consequence of quark pairing with respect to the color and flavor degrees of freedom. The stellar magnetic field threading the quark core becomes a color-magnetic admixture and, in the event that superconductivity is of type II, leads to the formation of color-magnetic vortices. In this Letter, we show that the volume-averaged color-magnetic vortex tension force should naturally lead to a significant degree of nonaxisymmetry in systems such as radio pulsars. We show that gravitational radiation from such color-magnetic "mountains" in young pulsars, such as the Crab and Vela, could be observable by the future Einstein Telescope, thus, becoming a probe of paired quark matter in neutron stars. The detectability threshold can be pushed up toward the sensitivity level of Advanced LIGO if we invoke an interior magnetic field about a factor ten stronger than the surface polar field.

'Prevent undernutrition and prescribe oral nutritional supplements correctly': an educational intervention for district nurses.

AIM: The aim of this study was to evaluate district nurses' (DN) perceived nutritional care and actual level of knowledge about nutritional care before and after a continuing educational intervention. BACKGROUND: Nutritional treatment is an important part of nursing care, and health professionals responsible for nutritional care for older adults must therefore have sufficient understanding of nutritional problems to provide appropriate support. Previous research has shown that nutritional problems frequently go unrecognized and that health care personnel often lacks knowledge about nutritional care and relevant methods of assessing nutritional status. However, little is known about DNs' knowledge about nutritional care. METHODS: An evaluative study with a study-specific questionnaire administered before and after a 2.5-day continuing educational course for DNs in primary health care in Stockholm County, Sweden. The course was given over a period of two to three months. The questionnaire measured DNs' perceived nutritional care and actual level of knowledge about nutritional care. FINDINGS: A total of 456 DNs completed the questionnaire both before and after the intervention. Participants' mean age was 50 years. They had worked a mean of 26 years in health care and 10 years as DNs. Before the intervention, many DNs reported that they did not work with nutritional care in an optimal way. After the intervention, significant improvements were found in perceived nutritional care and actual level of knowledge about the topic. However, not all DNs achieved the learning objectives of the course, so work remains to be done to ensure that DNs have sufficient knowledge of nutritional care to provide appropriate support and correctly prescribe oral nutritional supplements. CONCLUSIONS: The study provides new information on DNs' perceived nutritional care and actual level of knowledge. The result of the intervention helps lay the foundation for good nutritional care for older patients in primary care.

Cerebrospinal fluid tau and amyloid beta42 protein in patients with myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is associated with brain morphology changes including neurofibrillary degeneration. METHODS: We have examined cerebrospinal fluid (CSF) markers indicative of neuronal degeneration and amyloidogenesis; total tau (T-tau), phosphorylated tau (P-tau) and beta amyloid 1-42 (Abeta42), in 32 patients with DM1. RESULTS AND CONCLUSIONS: Associations between CSF markers and CTG repeat expansion size, brain MRI findings, and neuropsychological test results were analysed. As compared with matched controls Abeta42 was significantly decreased (P = 0.001), whilst levels of T-tau were increased (P < 0.001). No difference was found between measures considering P-tau levels. At present the clinical implications of these findings is unclear, because of an overlap between CSF values of DM1 patients and healthy controls, but also regarding modest associations between CSF markers and other measures. However notably, the Tau pathology, as seen in DM1, differs from Alzheimers disease, considering the lack of increased levels of P-tau.

Characterization of the human lipoprotein lipase (LPL) promoter: evidence of two cis-regulatory regions, LP-alpha and LP-beta, of importance for the differentiation-linked induction of the LPL gene during adipogenesis.

When preadipocytes differentiate into adipocytes, several differentiation-linked genes are activated. Lipoprotein lipase (LPL) is one of the first genes induced during this process. To investigate early events in adipocyte development, we have focused on the transcriptional activation of the LPL gene. For this purpose, we have cloned and fused different parts of intragenic and flanking sequences with a chloramphenicol acetyltransferase reporter gene. Transient transfection experiments and DNase I hypersensitivity assays indicate that several positive as well as negative elements contribute to transcriptional regulation of the LPL gene. When reporter gene constructs were stably introduced into preadipocytes, we were able to monitor and compare the activation patterns of different promoter deletion mutants at selected time points representing the process of adipocyte development. We could delimit two cis-regulatory elements important for gradual activation of the LPL gene during adipocyte development in vitro. These elements, LP-alpha (-702 to -666) and LP-beta (-468 to -430), contain a striking similarity to a consensus sequence known to bind the transcription factors HNF-3 and fork head. Results of gel mobility shift assays and DNase I and exonuclease III in vitro protection assays indicate that factors with DNA-binding properties similar to those of the HNF-3/fork head family of transcription factors are present in adipocytes and interact with LP-alpha and LP-beta. We also demonstrate that LP-alpha and LP-beta were both capable of conferring a differentiation-linked expression pattern to a heterolog promoter, thus mimicking the expression of the endogenous LPL gene during adipocyte differentiation. These findings indicate that interactions with LP-alpha and LP-beta could be a part of a differentiation switch governing induction of the LPL gene during adipocyte differentiation.

Insulin can enhance GLUT4 gene expression in 3T3-F442A cells and this effect is mimicked by vanadate but counteracted by cAMP and high glucose--potential implications for insulin resistance.

UNLABELLED: It is well-established that high levels of cAMP or glucose can produce insulin resistance. The aim of this study was to characterize the interaction between these agents and insulin with respect to adipose tissue/muscle glucose transporter isoform (glucose transporter 4, GLUT4) gene regulation in cultured 3T3-F442A adipocytes and to further elucidate the GLUT4-related mechanisms in insulin resistance. Insulin (10(4) microU/ml) treatment for 16 h clearly increased GLUT4 mRNA level in cells cultured in medium containing 5.6 mM glucose but not in cells cultured in medium with high glucose (25 mM). 8-Bromo-cAMP (1 or 4 mM) or N(6)-monobutyryl cAMP, a hydrolyzable and a non-hydrolyzable cAMP analog, respectively, markedly decreased the GLUT4 mRNA level irrespective of glucose concentrations. In addition, these cAMP analogs also inhibited the upregulating effect of insulin on GLUT4 mRNA level. Interestingly, the tyrosine phosphatase inhibitor vanadate (1-50 microM) clearly increased GLUT4 mRNA level in a time- and concentration-dependent manner. Furthermore, cAMP-induced inhibition of the insulin effect was also prevented by vanadate. In parallel to the effects on GLUT4 gene expression, both insulin, vanadate and cAMP produced similar changes in cellular GLUT4 protein content and cAMP impaired the effect of insulin to stimulate (14)C-deoxyglucose uptake. In contrast, insulin, vanadate or cAMP did not alter insulin receptor (IR) mRNA or the cellular content of IR protein. IN CONCLUSION: (1) Both insulin and vanadate elicit a stimulating effect on GLUT4 gene expression in 3T3-F442A cells, but a prerequisite is that the surrounding glucose concentration is low. (2) Cyclic AMP impairs the insulin effect on GLUT4 gene expression, but this is prevented by vanadate, probably by enhancing the tyrosine phosphorylation of signalling peptides and/or transcription factors. (3) IR gene and protein expression is not altered by insulin, vanadate or cAMP in this cell type. (4) The changes in GLUT4 gene expression produced by cAMP or vanadate are accompanied by similar alterations in GLUT4 protein expression and glucose uptake, suggesting a role of GLUT4 gene expression for the long-term regulation of cellular insulin action on glucose transport.

S gene (Corneodesmosin) diversity and its relationship to psoriasis; high content of cSNP in the HLA-linked S gene.

Psoriasis is a heterogeneous disease in which several reports suggest the presence of a susceptibility gene in or in the proximity of the human leukocyte antigen complex in chromosome 6p. There is an association between HLA-Cw6 and young onset of the disease. The S gene (corneodesmosin), located 160 kb telomeric of HLA-C, is a strong candidate for psoriasis due to its reportedly exclusive expression in differentiating keratinocytes. We have studied this gene in a large Swedish psoriasis population and we report a strikingly high degree of polymorphism in the coding parts of the gene, 1 every 100 base pairs. We used a stratified approach to compare the polymorphic variants in patients and controls. A single nucleotide polymorphism in the coding region leading to an amino acid exchange (Ser-->Phe) that differed significantly between patients and controls was identified (position 619). Owing to a high allele frequency in a larger control group, however, and an insignificant influence of the variant on the age at onset distribution curve based on a large psoriasis population, we could not confirm that this coding single nucleotide polymorphism was involved in disease etiology. We also examined the single nucleotide polymorphism in position 1243, recently proposed to have an influence on the pathogenesis of the disease. This polymorphism showed less association to the disease as compared with the single nucleotide polymorphism at positions 619 and 722. Such a high degree of variation present also in an HLA gene which is not involved in immune response indicates the difficulty involved in assessing the role of a specific allele in the pathogenesis of a complex disease in this region. A strong association effect due to linkage disequilibrium in an extended region in the HLA complex is also a complicating factor.

Cytogenetic analysis of 477 psoriatics revealed an increased frequency of aberrations involving chromosome region 11q.

Psoriasis is an inflammatory skin disorder affecting approximately 3% of the population. Genetic studies published so far have shown a complex genetic inheritance with heterogeneity and a putative major susceptibility locus in the HLA region on chromosome 6. We have collected a large amount of material consisting mostly of small nuclear families in order to perform a genome-wide scan for psoriasis-associated genes. In order to focus the scan properly on possible candidate regions, we performed a cytogenetic analysis of 477 unrelated psoriatics. We divided our findings into sporadic, affecting a minor fraction of the cells, and constitutional, i.e. they were present in all cells examined. We found three cases of balanced translocation, all of which involved chromosome 11q. Two of these had a breakpoint in q12-13, whilst one involved the telomeric part of chromosome 11q. In order to characterise further the breakpoint on 11q12-13, we used bacterial artificial chromosomes (BACs) analysed by fluorescent in situ hybridisation (FISH). We were able to show that the persons had a close, but not identical breakpoints; they were separated by at least 5 cM. The major atopy locus is located in this region, as well as a locus for insulin-dependent diabetes mellitus, both being conditions with a pathogenetic mechanism involving antigen presentation.

Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden.

We have performed a pair-wise linkage study in the search for psoriasis susceptibility regions. A preliminary scan was performed on 20 families. In this set we obtained indications of linkage on chromosome 3q21. This region was further investigated using material from a total of 104 families (set 1B) resulting in a non-parametric linkage (NPL) of 1.77. The material was stratified in families whose parental origin is in southwest Sweden (set 1C). A maximum NPL value of 2.77 was obtained in this group. A transmission disequilibrium test (TDT) was performed on the stratified material (set 1C) and a significant P value of 0.005 was obtained, at marker D3S1269. The locus was confirmed with TDT in replicate material consisting of 148 families in which a single member was affected (P value 0.0007) at marker D3S1551. Thus, we have observed a significant P value using TDT in the vicinity of markers D3S1269/D3S1551, suggesting a novel psoriasis susceptibility region.

Genome-wide linkage analysis of Scandinavian affected sib-pairs supports presence of susceptibility loci for celiac disease on chromosomes 5 and 11.

Celiac disease (CD) is a common chronic inflammatory disorder of the small intestine with a multifactorial aetiology. HLA is a well-known risk factor, but other genetic factors also influence disease susceptibility. To identify the genes involved in this disorder, we performed a genome-wide scan on 106 well-defined Swedish and Norwegian families with at least two affected siblings. We investigated familial segregation of 398 microsatellite markers, and utilised non-parametric linkage analysis. The strongest linkage with disease was found to the HLA locus (6p) (P<0.000006). There were eight regions besides HLA with a point wise P value below 0.05. Among these eight regions were 11q and 5q, both of which have been suggested in several linkage studies of independent celiac disease families. We also performed a stratification analysis of families according to their HLA genotypes. This resulted in significant differences on chromosome 2q. These results indicate that 11q, 5q and possibly also 2q are true susceptibility regions in CD.

MR imaging of syringohydromyelia and Chiari malformations in myelomeningocele patients with scoliosis.

The brain and spinal cord were examined with MR imaging in 30 myelomeningocele patients 3-32 years old to study the prevalence of syringohydromyelia and Chiari malformations and to correlate these conditions with developmental scoliosis and spontaneously arrested hydrocephalus. Twelve patients had neurologic deficits above the level of the myelomeningocele and 10 had spontaneously arrested hydrocephalus. MR visualized syringohydromyelia in four patients with widened or focally bulging spinal cords and in eight patients with atrophic spinal cords. All patients had Chiari malformations, 28 of type II and two of type I. Syringohydromyelia was not correlated with type of scoliosis, result of ventriculoperitoneal shunting procedures, radiologic level of the myelomeningocele, or extent of the Chiari malformation. The two patients with the most rapid progression of thoracic scoliosis had the most extensive syringohydromyelia and radiologically low lumbar levels. Neurologic deterioration due to syringohydromyelia and Chiari malformations is probably more common in myelomeningocele than has been recognized previously and may cause developmental scoliosis, loss of ambulation, impaired extremity function, and progressive cranial nerve paralysis.

Stronger association with HLA-Cw6 than with corneodesmosin (S-gene) polymorphisms in Swedish psoriasis patients.

Psoriasis vulgaris is strongly associated with certain human leukocyte antigens, especially in early onset. The purpose of this study was to study the HLA-Cw6 allele and its contribution to disease susceptibility in a set of 104 families with at least two affected siblings. A sequencing method was utilized to examine the two exons that build up the antigen binding site of the C locus receptor. DNA from patients homozygous for Cw6 based on haplotype information were sequenced. The results confirmed the identity of the Cw6 allele in affected individuals with the consensus sequence for Cw*0602. We screened the set of families for psoriasis patients homozygous for Cw6 and found 11 individuals with a mean age at onset of 16.1 years. The corresponding figure for the Cw6 heterozygotes was 18.45 years and for the Cw6-negatives 22.36 years. This is indicative of a gene dose effect. We performed a transmission disequilibrium test (TDT) on the Cw6 allele per se, used as a biallelic marker. The analysis resulted in a P-value of 5.3 x 10(-17) (t167/nt45). This greatly exceeds our previous results of a TDT in the region, including microsatellite markers and single nucleotide polymorphisms (SNPs) in the coding part of the S gene (corneodesmosin), which is a suggested candidate gene in the region. The maximum nonparametric linkage (NPL) value was also reached using HLA-C as a marker. We conclude that Cw6 is the allele which shows the highest degree of association with psoriasis in our set of families and we propose that it directly influences the age at onset of the disease rather than increasing the genetic load in accordance with a polygenic theory.

Fish-induced variation in abdominal spine length of Leucorrhinia dubia (Odonata) larvae?

The lengths of dorsal and lateral spines on abdominal segments 4, 6 and 9 were measured on last-instar larvae of Leucorrhinia dubia (Odonata) from seven natural lentic systems containing fish and nine systems lacking fish. Larvae from systems with fish had significantly longer spines than larvae from systems without fish. In contrast, lake/pond area and pH had no effect on the length of spines. The length of the spines was not correlated with larval size, but there was a high correlation between the length of the three spines measured. Also, abundances of L. dubia larvae differed between systems, being significantly lower in systems with fish. Laboratory experiments showed that perch (Perca fluviatilis) handled long-spined larvae for significantly longer times than short-spined larvae. The results suggest that fish predators may induce morphological defences in insects.

Evaluation of syringomyelia and Chiari malformations using ultra-low magnetic resonance imaging.

The accuracy of ultra-low field magnetic resonance imaging (MRI) compared to medium-field MRI in detecting syringomyelia and associated Chiari malformations is examined. In all cases the size of the syrinxes and the type and extent of the Chiari malformations was clearly shown at low-field MRI. The present spatial solution and high sensitivity allows for low-field imagers to localize even minor morphological changes of the spinal cord, brainstem, and cerebellum.

Accuracy of radiological staging procedures in non-seminomatous testis cancer compared with findings from surgical exploration and histopathological studies of extirpated tissue.

Preliminary and reviewed statements describing results from abdominal CT and US were compared with surgical findings and with the report from the histopathological investigation of extirpated retroperitoneal tissue. No false positive diagnoses of retroperitoneal metastases were made by CT investigation, while US made one false positive but revealed metastases in one patient overlooked by CT. The overall accuracies (correct answers/all patients) were 81% with CT and 80% with US (31 and 21 patients in Group I respectively). Surgical exploration alone was no more sensitive than either of the two other methods. CT and US are highly reliable when positive but the risks of obtaining false negative results are considerable.

Influence of "nuclear" estrogen receptor content on prognosis of early stage carcinoma of the uterine body. A short-time follow-up.

Sixty-five patients with Stage I and II endometrial carcinoma were investigated. After a short-time follow-up (17-24 months) significant differences in frequency of relapses were observed between patients with tumors containing low amounts of estrogen receptor (ER less than 60 fmol/mg DNA) in the nuclear pellet, and those with tumors containing greater than 60 fmol ER/mg DNA (p = 0.01). Other prognostic factors showed no differences in frequency of relapses. In this small patient material with a short-time follow-up we therefore suggest that ER in the nuclear pellet may be an important prognostic factor.

An angiographic technique for three-dimensional determination of arterial supply patterns in cadaver soft tissue.

A method for arterial tree mapping that can be used in cadaver soft tissue is presented. In situ angiograms and photographs are supplemented with profile angiograms of relatively narrow bands of tissue from the removed specimen. The described method was better suited for mapping the course and supply patterns of a soft-tissue arterial network than either in situ angiograms or dissection. While practical problems were encountered with most of the solutions used for providing radiopacity or structural support to the vessels, pure barium sulfate was found to be suitable because it filled the vascular tree to the capillary level without leakage during excision of the specimen.