Early and intensive Motor Training for people with spinal cord injuries (the SCI-MT Trial): description of the intervention.

STUDY DESIGN: Descriptive. OBJECTIVES: The primary objective is to describe the intervention that will be provided in a large multi-centre randomised controlled trial titled: Early and Intensive Motor Training for people with Spinal Cord Injuries (the SCI-MT Trial). The secondary objective is to describe the strategies that will be used to operationalise and standardise the Motor Training provided to participants while keeping the intervention person-centred. METHODS: The paper focuses on the rationale and principles of Motor Training for people with spinal cord injuries (SCI). The description of the intervention is based on the Template for Intervention Description and Replication (TIDieR) checklist. Specifically, it addresses the following 6 criteria of the TIDieR checklist: why the effectiveness of Motor Training is being examined; what, how, where and when the Motor Training will be administered; and how much Motor Training will be provided. RESULTS: A detailed intervention manual has been developed to help standardise the delivery of the intervention. CONCLUSIONS: This paper describes the details of a complex intervention administered as part of a large randomised controlled trial. It will facilitate the subsequent interpretation of the trial results and enable the intervention to be reproduced in clinical practice and future trials.

Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

Frequently repeated measurements -our experience of collecting data with SMS.

BACKGROUND: As technology is advancing, so are the possibilities for new data collection methods in research, potentially improving data quality and validity of the results. In Sweden, a system using frequent repeated data collection using text messages, SMS Track, has been used in clinical research for more than a decade. In this paper, compliance with repeated text message questions was examined across five different studies, i.e. if compliance was 1: associated with study-specific factors (age or gender of the subjects, the condition, its' severity or course, i.e. improvement, relapse or steady state) and/or. 2: associated with the methodology itself (the question being asked, the frequency and number of questions, duration of data collection, initial compliance or the management of the system). METHODS: Descriptive comparisons were done across five studies. Three studies were collecting weekly responses over at least 52 weeks ("Weekly studies") and were used to investigate the effect of age, sex and pain severity on compliance, the effect of early compliance for late compliance, and finally the early occurrence of two successive weeks with non-compliance. RESULT: Compliance was excellent across all five studies, and only influenced somewhat by age, sex and pain-level. The factor "study" remained significant in the final model thus the observed differences may be a result of the conditions studied but does not seem to be attributable to severity or development of these conditions. Number and frequency of questions did not influence compliance, nor did study duration. CONCLUSIONS: Compliance was excellent in the included studies and was not affected by population factors. However, differences in compliance were observed that cannot be easily explained and warrant further investigation. In particular, the nature of the variables or the management of the study are potential areas for further investigations.

Assessment of unsupported sitting in patients with spinal cord injury.

STUDY DESIGN: Cross-sectional study using a consecutive sample. OBJECTIVES: To modify the Motor Assessment Scale (MAS) item 3 'balanced sitting' and the Sitting Balance Score (SBS) to ensure suitability for patients with spinal cord injury (SCI), and to assess the inter-rater reliability and validity of these instruments. SETTING: Spinal Care Unit, clinical setting. METHODS: Unsupported sitting was tested by three physiotherapists using MAS and SBS in 48 in-patients with SCI. The validity of the scales was tested using neurological level and extent of injury according to the International Standards for Neurological Classification of Spinal Cord Injury, time since injury and the patients' function, as measured by Functional Independence Measure (FIM) item 9-13 and Five Additional Mobility and Locomotor Items (5AML). RESULTS: The inter-rater reliability was for MAS (k(w)=0.83-0.91) and for SBS (k(w)=0.69-0.96). The correlation between the balance scales were in relation to; neurological injury level (r(s)=0.19-0.51), extent of injury (r(s)=0.57-0.68) and the functional tests as measured by FIM items 9-13 (r(s)=0.13-0.68, highest for going up and down stairs) and 5AML (r(s)=0.10-0.49). The spread of data on the scales was poor. CONCLUSION: The inter-rater reliability of MAS and SBS was very good. The validity was little to moderate, probably because the chosen functional tests measured complex functional tasks and not only unsupported sitting. Both tests appear to be feasible in clinical settings, but will need major revisions. These results can therefore be used as a base for constructing new, better tests of unsupported sitting.

Norepinephrine in low to moderate doses may not increase luminal concentrations of L-lactate in the gut in patients with septic shock.

AIM: To investigate the effect of different doses of norepinephrine (noradrenaline) on luminal concentrations of L-lactate in the rectum and stomach in patients with fluid-resuscitated septic shock. METHODS: This was a paired cross-over study in which the dose of norepinephrine was titrated to mean arterial blood pressures (MAPs) of 65 and 85 mmHg in random sequence. It was performed in a mixed intensive care unit at a university hospital. Eight patients with fluid-resuscitated septic shock requiring norepinephrine (>0.1 microg/kg/min) were included. Patients were treated with norepinephrine to a MAP of either 65 or 85 mmHg for 2 h. After a 'washout' period of 2 h, the dose of norepinephrine was titrated to the other endpoint of MAP for another 2 h. The concentrations of L-lactate in the rectal and gastric lumen were estimated by 1-h equilibrium dialysis during the second hour of the treatment periods. RESULTS: MAP and central venous oxygen saturation were increased by increasing the dose of norepinephrine [median (range) (microg/kg/min): 0.07 (0.00-0.60) and 0.18 (0.11-1.00) at MAPs of 65 and 85 mmHg, respectively], whereas the metabolic markers were unaffected [luminal concentrations (mmol/l) of L-lactate in the rectum of 1.9 (0.8-6.4) and 1.8 (0.9-5.7) (P =0.94) and in the stomach of 1.1 (0.1-10.0) and 1.3 (0.3-9.7) (P =0.88) at MAPs of 65 and 85 mmHg, respectively]. CONCLUSION: In this small study, luminal concentrations of L-lactate in the rectum and stomach were unaffected by norepinephrine at low to moderate doses. These data suggest that norepinephrine may not increase luminal concentrations of l-lactate in the gut in patients with fluid-resuscitated septic shock.

Effects of endotoxaemia on markers of permeability, metabolism and inflammation in the large bowel of healthy subjects.

BACKGROUND: Increased permeability and increased luminal concentrations of L-lactate have previously been shown in the large bowel in septic patients. To advance these observations, a human model of colorectal barrier failure in sepsis is desirable. Therefore, we assessed the effects of endotoxaemia on markers of permeability, metabolism and inflammation in the large bowel in healthy subjects. METHODS: Twelve healthy male subjects received intravenous endotoxin (2 ng/kg body weight) or saline in a paired cross-over design. Colorectal permeability was assessed after 3, 6, 9 and 12 h by the systemic recovery of luminally instilled (99m)Tc-diethylenetriaminepentaacetate. Luminal concentrations of L-lactate were assessed by equilibrium dialysis. Mucosal biopsies from the large bowel were sampled after 6 and 12 h, and the apoptotic ratio of the epithelium was assessed by terminal deoxynucleotidyl transferase-mediated desoxyuridinetriphosphate nick end-labelling (TUNEL) assay and the expression of inducible nitric oxide synthase (iNOS) mRNA by reverse transcriptase-polymerase chain reaction. RESULTS: Systemic effects of endotoxaemia were observed, including fever, tachycardia and strongly increased plasma values of tumour necrosis factor-alpha. By contrast, the colorectal permeability, luminal lactate concentrations, mucosal infiltration of inflammatory cells, epithelial apoptotic ratio and expression of iNOS were all unaffected by endotoxin. CONCLUSIONS: No effect of a single intravenous dose of endotoxin was observed on markers of large bowel permeability, metabolism and inflammation in healthy subjects. This suggests that this part of the gut is relatively resistant to the systemic inflammation induced by experimental endotoxaemia in humans.

Increased concentrations of L-lactate in the rectal lumen in patients undergoing cardiopulmonary bypass.

BACKGROUND: Gut ischaemia may contribute to morbidity in patients after cardiopulmonary bypass (CPB), but little is known about the metabolic state of the large bowel in such patients. Therefore we estimated the concentrations of L-lactate and Pco(2) in rectal mucosa in patients undergoing cardiac surgery with or without the use of CPB. METHODS: Patients undergoing coronary artery bypass grafting (CABG) (n=12) or off-pump CABG (n=10) were subjected to equilibrium dialysis of the rectal lumen during the procedure and in the first 4 h afterwards. Dialysate concentrations of L-lactate and Pco(2) were measured using an auto-analyser and compared with values obtained in healthy subjects (n=10). RESULTS: During CPB, a 2- to 3-fold increase in luminal concentrations of L-lactate was observed (CABG vs off-pump CABG, P=0.05; CABG vs healthy subjects, P<0.01). The dialysate concentrations of L-lactate were higher than the mean systemic values (luminal-arterial gradient mean (sd) 0.9 (1.0) mmol litre(-1), P<0.05), and the two values were positively correlated (P<0.05). Luminal L-lactate concentrations remained elevated 4 h after the operation. In contrast, dialysate Pco(2) was equally high in patient and control groups and substantially higher than values observed in arterial blood. CONCLUSIONS: Uncomplicated CPB is associated with moderate but sustained increases in luminal concentrations of L-lactate in the rectum, indicating metabolic dysfunction of the mucosa in the large bowel.

Activation of nuclear factor kappaB in colonic mucosa from patients with collagenous and ulcerative colitis.

BACKGROUND AND AIMS: Expression of inducible nitric oxide synthase (iNOS) is greatly upregulated in the colonic mucosa of patients with collagenous and ulcerative colitis. As the transcription factor nuclear factor kappaB (NFkappaB) is a major inducer of iNOS gene expression, we compared activation and transcriptional activity of NFkappaB in colonic mucosal biopsies from these patients. PATIENTS: Eight patients with collagenous colitis, six with relapsing ulcerative colitis, and eight with uninflamed bowel were studied. METHODS: NFkappaB DNA binding activity was assessed by electrophoretic mobility shift assay and inhibitor of NFkappaB (IkappaB) kinase (IKK) activity by immunocomplex kinase assay. In vivo recruitment of NFkappaB to the iNOS promoter was determined by chromatin immunoprecipitation analysis and transcriptional activity by NFkappaB gene expression profiling arrays. Cells showing NFkappaB activation were identified by immunohistochemistry. RESULTS: In collagenous and ulcerative colitis, as opposed to uninflamed bowel, IKKbeta activity and strong NFkappaB DNA binding gave rise to activation of identical NFkappaB subunits and recruitment of transcriptionally active p65 to the iNOS promoter. In collagenous colitis, activated NFkappaB was observed only in epithelial cells while up to 10% of lamina propria macrophages showed activation in ulcerative colitis. CONCLUSIONS: In collagenous and ulcerative colitis, colonic mucosal NFkappaB is activated and recruited to the iNOS promoter in vivo via an IKKbeta mediated pathway. As collagenous colitis is not associated with tissue injury, these data challenge the prevailing view that activation of NFkappaB per se mediates tissue injury. Our results suggest that downstream inflammatory reactions leading to tissue damage originate in lamina propria immune cells, as increased NFkappaB activity in collagenous colitis was localised solely in epithelial cells, but present also in macrophages in ulcerative colitis.

Terlipressin increased the concentration of L-lactate in the rectal lumen in a patient with septic shock.

Terlipressin--a long-acting analogue of vasopressin--has been described to restore blood pressure in patients with catecholamine-resistant septic shock without obvious complications. We administered low-dose terlipressin (a single i.v.-bolus of 0.5 mg) to a patient with severe, hyperdynamic septic shock requiring high dosage of noradrenalin. After terlipressin the dose of noradrenalin could be reduced by 2/3 to obtain the same blood pressure. Two hours after terlipressin, the cardiac index had decreased from 6.2 to 3.3 l min(-1) m(-2) and the concentration of L-lactate in the rectal lumen, as assessed by equilibrium dialysis, increased from 3.6 to 7.2 mmol l(-1). In contrast, the systemic concentration of L-lactate was unaffected around 2.8 mmol l(-1). After 8 h the effect of terlipressin started to decline, and after an additional 12 h the systemic haemodynamics, dose of noradrenalin and concentrations of rectal and systemic L-lactate were the same as prior to the administration of terlipressin. As a strong vasopressor, terlipressin may have further impaired the metabolic dysfunction in the rectal mucosa either directly via vasoconstriction of mucosal vessels or through decreased cardiac output in this patient with noradrenalin-treated septic shock.

Leptin binding activity (LBA) in plasma of nondiabetic and diabetic adolescents and obese children: relation to auxologic and hormonal data.

Leptin circulates in serum bound to high molecular weight proteins. Hypothesizing that leptin binding proteins may regulate the functional efficiency of leptin, we characterized auxologic and hormonal factors that influence leptin binding in three disparate groups: normal adolescents, obese children, and teenagers with type I diabetes mellitus (IDDM). Specific leptin binding activity (sLBA) was assessed by column chromatography after incubation of serum with 125I-leptin in the presence and absence of excess unlabeled leptin. Mean sLBA was 17.0 +/- 7% (SD) in the healthy adolescents (n=41), 6.6 +/-4.3% in the obese children (n=26), and 14.9 +/-7.3% in the diabetic teenagers (n=17). At any value of sLBA, obese children had higher serum leptin levels than non-obese adolescents or diabetic teenagers, consistent with "leptin resistance" in the obese group. sLBA was higher in males than in females only in those with diabetes (18.6 +/- 7.3 vs 10.9 +/- 5.1%, p<0.05). sLBA correlated inversely with serum insulin-like growth factor-I values in the normal group (r= -0.45, p<0.01) and with insulin in the obese children (r= -0.53, p<0.01). There was no correlation between sLBA or serum leptin values and HbA1c, in the diabetic group. The serum leptin concentration was the principal determinant explaining the total variability of sLBA in all three cohorts. However, body mass index (BMI = weight/ height2) accounted for more of the total variability of percent specific binding in the healthy adolescents than in the other groups. We conclude that sLBA reflects circulating leptin levels, body composition, and hormonal milieu. Thus, in addition to leptin, qualitative and quantitative characteristics of leptin binding may play a physiological role in the regulation of appetite and in the "leptin resistance" of obesity.

Women doctors campaign against female circumcision.

PIP: Several countries have enacted laws condemning or forbidding the practice of female genital mutilation that has accompanied immigrants or refugees from countries where the practice is prevalent. In the past 20 years, Denmark has received almost 9000 Somali refugees, and 1000 of these are girls at risk of female genital mutilation. Since 1992, the Danish Medical Women's Association has been conducting workshops on female genital mutilation for health professionals and refugee organizations. These sessions stress how important it is for obstetricians and midwives to discuss female genital mutilation with their patients and their patients' husbands through the use of professional interpreters. The workshop leaders also describe the practice and emphasize the fact that no religion requires it. One of the workshop leaders also holds regular discussions for Somali women in their own language. She involves men who have been taught that mutilation is necessary without being told the consequences. Some Danish midwives restitch formerly mutilated patients, but it has been found that very few women request reinfibulation after childbirth if they understand the consequences. There is no indication to date that female genital mutilation has been performed in Denmark, but some refugee girls have been taken elsewhere for the mutilation. The Danish Medical Women's Association has suggested that the Ministry of Justice establish a program of education for refugee parents contemplating the procedure.^ieng

Studies of 3 beta-hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin-stimulated delta 5-steroid levels.

Classic 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) deficiency congenital adrenal hyperplasia (CAH) results from a mutation in the type II 3 beta HSD gene encoding adrenal and gonadal 3 beta HSD. We investigated the type II and type I 3 beta HSD gene sequences in 15 infants and children with premature pubarche (PP; mean/range of age at PP, 4/0.08-9 yr) and elevated ACTH-stimulated delta 5 precursor steroid levels. Compared to Tanner I control subjects of similar age, ACTH-stimulated hormonal levels were at 2.3-10.7 SD for 17-hydroxypregnenolone (delta 5-17P) in all PP subjects, at 2.2-17 SD for dehydroepi-androsterone (DHEA) and 2.4-5.6 SD for the delta 5-17P/cortisol (F) ratio in all PP subjects except 1 infant, and at 2.3-10 SD for the DHEA/ androstenedione (delta 5-A) ratio in 8 PP subjects. Compared to Tanner II normal children, the hormonal levels were at 3-8 SD for delta 5-17P in all 13 PP children, at 2.3-4.7 SD for the delta 5-17P/F ratio in 6 PP children, and at 2.3-6.5 SD for DHEA and 3.5-9 SD for the DHEA/delta 4-A ratio in 7 PP children. Type II 3 beta HSD gene sequences, including regions of a putative promoter, all exons (I, II, III, and IV), and exon-intron boundaries, were normal in all subjects. Sequences of the type I 3 beta HSD gene encoding extraadrenal and extragonadal 3 beta HSD were normal in the 6 patients tested. The ACTH-stimulated delta 5-17P levels and delta 5-17P/F ratios in the PP children without type II 3 beta HSD gene mutation were exceedingly lower than the respective reported hormonal data for children with 3 beta HSD deficiency CAH with proven type II 3 beta HSD gene mutation. The ACTH-stimulated DHEA levels and DHEA/delta 4-A ratios were not exceedingly different between the children with and without type II 3 beta HSD gene mutation. These findings suggest that the degree of ACTH-stimulated delta 5 precursor steroid abnormality, such as delta 5-17P levels up to 10 SD above the normal mean level found in our PP patients, is not caused by a mild variant of 3 beta HSD deficiency CAH resulting from type II or type I 3 beta HSD gene mutation. The hormonal criterion for ACTH-stimulated delta 5-17P levels in patients with mild variant 3 beta HSD deficiency, therefore, is predicted to be higher than 10 SD above the normal mean value.

High-density lipoproteins (HDL) stimulate placental lactogen secretion in pregnant ewes: further evidence for a role of HDL in placental lactogen secretion during pregnancy.

Previous studies from our laboratory showed that high-density lipoproteins (HDL) stimulate the release of human placental lactogen (PL) from cultured trophoblast cells from normal pregnant women. To determine whether HDL stimulates PL secretion in vivo, ovine HDL was infused over 2-5 min into 11 pregnant ewes (22 separate experiments) at 86-130 days of gestation via an indwelling catheter into the maternal jugular vein. The HDL, freshly prepared from the plasma of pregnant ewes by differential flotation ultracentrifugation, was greater than 99% purified as judged by SDS-PAGE. Plasma samples were obtained from the ewes before and at 0.5-h intervals for 6 h following the infusions and were assayed for PL by a specific homologous radioimmunoassay. The maternal infusion of HDL at doses of 302-784 mg (5.3-13.8 mg/kg body weight) stimulated significant increases in maternal plasma PL concentrations in six out of eight experiments (six ewes), and the infusion of 108-264 mg (1.9-4.6 mg/kg) stimulated plasma PL concentrations in two out of six experiments. In contrast, HDL at doses less than 100 mg were without effect in eight experiments. The response to the HDL infusions was characterized by a sustained increase in plasma PL concentrations beginning 1.5-2.5 h after the infusions, reaching a maximum 274.2 +/- 21.9% of the baseline value (P less than 0.001). In contrast, the maternal infusion of lipoprotein-free plasma proteins or saline had no effect on maternal plasma PL concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of insulin, proinsulin and pancreatic extract on myelination and remyelination in organotypic nerve tissue in culture.

The effect of insulin, proinsulin and crude pancreatic extract was studied in organotypic nerve tissue cultures, principally in relation to the development of myelin. Cultures were exposed to media supplemented with these substances beginning on the first day of explantation. By 4 days in vitro, there was a good neuritic outgrowth from all the fragments. That from the insulin and pancreatic extract-fed were more profuse and extended further than from the control group. By 8-12 days in vitro it was also possible to observe more myelinated axons in these treated groups. The pattern of changes in the myelin associated enzyme activity, 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) paralleled the differential increase in myelination. Insulin-fed cultures showed a more rapid increase in CNPase activity, which, after 21 days in vitro reached a plateau about 30-50% over that of the controls. Cultures treated with pancreatic extract showed a similar pattern of increased activity, while in proinsulin-treated explants the activity was only significantly higher after 21 days in vitro. To study the effect of these substances on remyelination, well myelinated cultures were completely demyelinated by exposure to anti-white matter antiserum and were subsequently exposed to the same normal control or supplemented media. The amount of myelin and concomitantly the CNPase activity increased rapidly and in the same proportion between the various groups as was observed previously during primary myelination. Insulin as well as crude pancreatic extract and, to some extent, proinsulin demonstrated a marked effect on the time of onset and principally on the total amount of myelin developed by treated cultures as compared to those maintained in normal nutrient medium.