COVID-19 as a mediator of interferon deficiency and hyperinflammation: Rationale for the use of JAK1/2 inhibitors in combination with interferon.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits an interferon (IFN) deficiency state, which aggravates the type I interferon deficiency and slow IFN responses, which associate with e.g. aging and obesity. Additionally, SARS-CoV-2 may also elicit a cytokine storm, which accounts for disease progression and ultimately the urgent need of ventilator support. Based upon several reports, it has been argued that early treatment with IFN-alpha2 or IFN-beta, preferentially in the early disease stage, may prohibit disease progression. Similarly, preliminary studies have shown that JAK1/2 inhibitor treatment with ruxolitinib or baricitinib may decrease mortality by dampening the deadly cytokine storm, which - in addition to the virus itself - also contributes to multi-organ thrombosis and multi-organ failure. Herein, we describe the rationale for treatment with IFNs (alpha2 or beta) and ruxolitinib emphasizing the urgent need to explore these agents in the treatment of SARS-CoV-2 - both as monotherapies and in combination. In this context, we take advantage of several safety and efficacy studies in patients with the chronic myeloproliferative blood cancers (essential thrombocythemia, polycythemia vera and myelofibrosis) (MPNs), in whom IFN-alpha2 and ruxolitinib have been used successfully for the last 10 (ruxolitinib) to 30 years (IFN) as monotherapies and most recently in combination as well. In the context of these agents being highly immunomodulating (IFN boosting immune cells and JAK1/2 inhibitors being highly immunosuppressive and anti-inflammatory), we also discuss if statins and hydroxyurea, both agents possessing anti-inflammatory, antithrombotic and antiviral potentials, might be inexpensive agents to be repurposed in the treatment of SARS-CoV-2.

Indocyanine green plasma disappearance rate as dynamic liver function test in critically ill patients.

BACKGROUND: Indocyanine green (ICG) is a water-soluble fluorescent dye that is bound to plasma protein when administered intravenously. Removal of ICG from the blood depends on hepatic blood flow, function of the parenchymal cells and biliary excretion. ICG elimination is described as a useful dynamic liver function test. METHODS: In this review, we looked at the most recent literature to clarify why ICG is useful in critically ill patients, the validity of the ICG plasma disappearance rate (ICG-PDR) measured transcutaneously and whether ICG-PDR has any prognostic value. CONCLUSION: In conclusion, measuring ICG-PDR is a valuable method for dynamic assessment of liver function, and is found to be a valuable prognostic tool in predicting survival for septic patients, patients presenting with acute liver failure and critically ill patients.

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.

Blood pressure and plasma catecholamines in acute and prolonged hypoxia: effects of local hypothermia.

This study measured the pressor and plasma catecholamine response to local hypothermia during adaptation to hypobaric hypoxia. Eight healthy men were studied at rest and after 10 and 45 min of local cooling of one hand and forearm as well as after 30 min of rewarming at sea level and again 24 h and 5 days after rapid, passive transport to high altitude (4,559 m). Acute mountain sickness scores ranged from 5 to 16 (maximal attainable score: 20) on the first day but were reduced to 0-8 by the fifth day. Systolic blood pressure, heart rate, and plasma epinephrine increased on day 1 at altitude compared with sea level but declined again on day 5, whereas diastolic and mean blood pressures continued to rise in parallel with plasma norepinephrine. With local cooling, an increased vasoactive response was seen on the fifth day at altitude. Very high pressures were obtained, and the pressure elevation was prolonged. Heart rate increased twice as much on day 5 compared with the other two occasions. Thoracic fluid index increased with cooling on day 5, suggesting an increase in pulmonary vascular resistance. In conclusion, prolonged hypoxia seems to elicit an augmented pressor response to local cooling in the systemic and most likely also the pulmonary circulation.

Plasma volume in acute hypoxia: comparison of a carbon monoxide rebreathing method and dye dilution with Evans' blue.

Exposure to acute hypoxia is associated with changes in body fluid homeostasis and plasma volume (PV). This study compared a dye dilution technique using Evans' blue (PV[Evans']) with a carbon monoxide (CO) rebreathing method (PV[CO]) for measurements of PV in ten normal subjects at sea level and again 24 h after rapid passive ascent to high altitude (4,350 m). Hypobaric hypoxia decreased arterial oxygen saturation to 79 (74-83)% (mean with 95% confidence intervals). The PV(Evans') remained unchanged from 3.49 (3.30-3.68) l at sea level to 3.46 (3.24-3.68) l at high altitude. In contrast PV(CO) decreased from 3.39 (3.17-3.61) l at sea level to 3.04 (2.75-3.33) l at high altitude (P < 0.05). Compared with sea level, this resulted in an increase of the mean bias between the two methods [from 0.11 (-0.05-0.27) l at sea level to 0.43 (0.26-0.60) l at high altitude] so that the ratio between PV(Evans') and PV(CO) increased from 1.04 (0.99-1.09) at sea level to 1.15 (1.06-1.24) at high altitude (P < 0.05). In conclusion, the two methods were not interchangeable as measures of hypoxia-induced changes in PV. The mechanism responsible for the bias remains unknown, but it is suggested that the results may reflect a redistribution of albumin caused by the combined effects in hypoxia of both an increased capillary permeability to albumin and a decrease in PV. As a result, the small perivascular compartment of albumin beyond the endothelium may increase without changes in the overall albumin distribution volume.

Somatostatin attenuates the hyperthermia induced increase in neutrophil concentration.

This study was designed to test the hypothesis that the immune changes seen during in vivo whole body hyperthermia are mediated by elevations in the plasma concentrations of either catecholamines, growth hormone or beta-endorphins. Eight healthy volunteers were immersed in a hot water bath (WI; water temperature 39.5 degrees C) for 2 h during which their rectal temperature rose to 39.5 degrees C. In a single blind, randomized, cross-over study the stress hormone effects were blocked one at a time by administration of propranolol, somatostatin or naloxone; the results were compared to those obtained during saline infusion (control). Blood samples were collected before, at the end of 2 h of WI (body temperature 39.5 degrees C), and 2 h later. Hormone blockade did not abolish the hyperthermia-induced recruitment of natural killer (NK) cells to the blood, and no influence was observed on the percentages or concentrations of any other subpopulations of blood mononuclear cells, except that the number of cluster designation (CD)3+ cells slightly increased after hyperthermia only in the propranolol experiment. Furthermore, the NK cell activity, both unstimulated and interferon-alpha or interleukin-2 stimulated, did not differ from the control situation. It is of interest, however, that somatostatin partly abolished the hyperthermia induced increase in the neutrophil number. Based on these data and previous results showing that growth hormone infusion increases the concentration of neutrophils in the blood, it is suggested that growth hormone is at least partly responsible for hyperthermia induced neutrocytosis.

Influence of minor increases in plasma catecholamines on natural killer cell activity.

This study was designed to test the hypothesis that the modulations of the human immune system in relation to in vivo whole body hyperthermia may be ascribed to elevations in the plasma epinephrine and norepinephrine concentrations. In a single-blind, controlled, cross-over study, 8 healthy volunteers were selectively infused norepinephrine and epinephrine, respectively, for 1 h, in order to obtain twofold increases in the plasma concentrations of these hormones, thereby mimicking the increases seen during in vivo whole body hyperthermia. Epinephrine infusion increased baseline, interleukin-2 and interferon-alpha stimulated natural killer cell activity, and the percentage and concentration of cluster designation (CD)16+ cells, whereas the neutrophil and lymphocyte count or the CD3+, CD4+, CD8+, CD19+ and CD14+ cell subtypes were not influenced. Norepinephrine infusion did not cause any changes in these variables. It is concluded that epinephrine, but not norepinephrine, may be responsible for the hyperthermia-induced effects on natural killer cells.

Effects of elevated plasma noradrenaline concentration on the immune system in humans.

This study was designed to test the hypothesis that elevated plasma noradrenaline concentrations contribute to the exercise-induced modulation of the activity and percentage of the natural killer (NK) cells, and the leucocyte concentration. In a single blind, controlled, cross-over study, eight healthy men had noradrenaline infused for 1 h and achieved plasma noradrenaline concentrations comparable (20-fold increment) to those previously observed in cycle ergometer exercise (75% of maximal oxygen uptake for 1 h). The noradrenaline infusion increased the unstimulated, the interleukin-2 and interferon-alpha stimulated NK cell activity, and the percentage of CD16+ cells. The natural lytic activity per CD16+ cell however, did not change. The concentration of neutrophils, lymphocytes and CD16+ cells increased during the infusion. The neutrophil concentration remained elevated 2 h after infusion, at which time the lymphocyte count was back to normal. These results are comparable with the effects in the exercise model, and it is suggested that the augmented plasma noradrenaline concentrations, seen during extreme exercise, may participate in the exercise-induced immune changes.

Immune changes during whole body hot water immersion: the role of growth hormone.

NASA: Studies examined the role of growth hormone, catecholamines, and beta-endorphins in changes in natural killer cell activity, subtypes of blood mononuclear cells, and leukocyte concentration in response to hot water immersion in humans. The response of leukocytes and neutrophils to 2 hours of hot water immersion and simultaneous administration of propranolol, somatostatin, naloxone, or isotonic saline are reported.^ieng

Hypoxemia increases serum interleukin-6 in humans.

Serum concentrations of interleukin (IL) 1 beta, IL-1 receptor antagonist (IL-1ra), IL-6, tumor necrosis factor (TNF) alpha, and C-reactive protein (CRP) were determined in ten healthy men at sea level and during four days of altitude hypoxia (4350m above sea level). The mean (SD) arterial blood oxygen saturations were 78.6 (7.3)%, 82.4 (4.9)%, and 83.4 (5.3)% in the first, second, and third days at altitude, respectively. A symptom score of acute mountain sickness (AMS) revealed that the subjects had mostly light symptoms of AMS. Mean serum IL-6 increased from 1.36 (1.04) pg x ml(-1) at sea level to 3.10 (1.65), 4.71 (2.81), and 3,54 (2.17) pg x ml(-1) during the first three days at altitude, and to 9.96 (8.90) pg x ml(-1) on the fourth day at altitude (ANOVA p = 0.002). No changes occurred in serum concentrations of IL-1 beta, IL-1ra, TNF alpha, or CRP. The serum IL-6 were related to SaO2, (r = -0.45, p = 0.003), but not to heart rates or AMS scores. In conclusion, human serum concentrations of IL-6 increased during altitude hypoxia whereas the other proinflammatory cytokines remained unchanged. The major role of IL-6 during altitude hypoxia seem not to be mediation of inflammation, instead, the role of IL-6 could be to stimulate the erythropoiesis at altitude.

Preoperative evaluation of intubation conditions in patients scheduled for elective surgery.

Prediction of a difficult airway is a continuing problem. Several tests have been developed in order to overcome this problem. It has been proposed that using more than one test could increase the degree of predictability. One hundred patients scheduled for general surgery were successfully evaluated using three methods: 1. The size of the tongue in relation to the oral cavity (Mallampati gradation). 2. The thyromental and the mandibular length. 3. The atlanto-occipital angle. Seven patients had a difficult laryngoscopy and were difficult to intubate. It was possible to predict differenties in all seven patients, but it was found that only the Mallampati gradation and the atlanto-occipital angle contributed significantly to predictability. The cost of predicting further difficulties in all patients with a difficult laryngoscopy was a false positive prediction in a further 13 patients who had no problems with laryngoscopy or intubation. By increasing the specificity of the tests the number of false positive classifications could be reduced to 10 patients, but this would have led to the missing of one patient with a difficult laryngoscopy.

Diurnal variations of serum erythropoietin at sea level and altitude.

This study tested the hypothesis that the diurnal variations of serum-erythropoietin concentration (serum-EPO) observed in normoxia also exist in hypoxia. The study also attempted to investigate the regulation of EPO production during sustained hypoxia. Nine subjects were investigated at sea level and during 4 days at an altitude of 4350 m. Median sea level serum-EPO concentration was 6 (range 6-13) U.l-1. Serum-EPO concentration increased after 18 and 42 h at altitude, [58 (range 39-240) and 54 (range 36-340) U.l-1, respectively], and then decreased after 64 and 88 h at altitude [34 (range 18-290) and 31 (range 17-104) U.l-1, respectively]. These changes of serum-EPO concentration were correlated to the changes in arterial blood oxygen saturation (r = -0.60, P = 0.0009), pH (r = 0.67, P = 0.003), and in-vivo venous blood oxygen half saturation tension (r = -0.68, P = 0.004) but not to the changes in 2, 3 diphosphoglycerate. After 64 h at altitude, six of the nine subjects had down-regulated their serum-EPO concentrations so that median values were three times above those at sea level. These six subjects had significant diurnal variations of serum-EPO concentration at sea level; the nadir occurred between 0800-1600 hours [6 (range 4-13) U.l-1], and peak concentrations occurred at 0400 hours [9 (range 8-14) U.l-1, P = 0.02]. After 64 h at altitude, the subjects had significant diurnal variations of serum-EPO concentration; the nadir occurred at 1600 hours [20 (range 16-26) U.l-1], and peak concentrations occurred at 0400 hours [31 (range 20-38) U.l-1, P = 0.02]. This study demonstrated diurnal variations of serum-EPO concentration in normoxia and hypoxia, with comparable time courses of median values. The results also suggested that EPO production at altitude is influenced by changes in pH and haemoglobin oxygen affinity.

Percutaneous osteosynthesis with two screws in treating femoral neck fractures.

In a consecutive, retrospective study, 182 patients were followed 1 year after surgical treatment of a fractured femoral neck. The patients were admitted on alternate days to the neighboring departments of orthopedic surgery O and phi, respectively. In Department O, the patients were submitted to sliding screw-plate (SSP) osteosynthesis, while patients in Department phi were treated with two percutaneously introduced screws. Our results showed that double-screw osteosynthesis can be performed significantly quicker and with less blood loss than application of SSP. Healing of the fractures in the two groups did not differ significantly, nor did the cumulative rate of failure or the frequency of secondary surgical procedures. We find that, judged from these parameters, percutaneously introduced double-screw osteosynthesis is at least as effective as SSP osteosynthesis.

[The national patient registry. Evaluation of data quality]. / Landspatientregisteret. Evaluering af datakvaliteten.

The Danish National Patient Register, which includes information on all patients admitted to hospitals, has been evaluated as concerns the quality of the data included. The material examined consisted of a representative sample of 1094 patients from departments all over the country (gynaecology and obstetrics, medicine, surgery and paediatrics). Recoding of data, clinical as well as administrative, based on copies of the case records from the hospitals was carried out by two clinically working physicians (registrars). For the administrative data e.g. length of stay, satisfactory concordance was found. The validity of clinical information depended on clinical speciality and degree of diagnostic specificity. Based on the international classification the agreement on the three digit diagnostic level was better than on the five digit diagnostic level. For surgery the agreement was better than for medicine. The agreement between the diagnostic information (primary diagnosis) and the recoder in choosing primary diagnosis varied from 66-83 percent on the five digit level and between 73-89 percent on the three digit diagnostic level. If cases where the diagnosis in the registry could be regarded as an acceptable alternative were included, the agreement between the registry and recoding was 75-90%. In a subsample of the material double coding by the two coders was carried out and it was remarkable that, taken as a whole, the degree of agreement between the two coders was of the same size as between recoder and the registry. It is anticipated, however, that introduction of ICD-10 with more clear-cut rules for choice of primary diagnosis in morbidity coding will contribute to better validity and consequently improved hospital statistics.

Mast cells and elastosis in ultraviolet-irradiated hairless mice.

Earlier studies of ultraviolet (UV) irradiated hairless mice have suggested a relation between elastosis and mast cells. To examine whether such a relation exists, we examined groups of hairless mice irradiated with equal doses of UV. The narrow UV bands had peaks at 292, 300, 307, 317 and 336 nm. The groups were irradiated 5 times per week during 1 year. It was shown that the shorter the wavelengths, the more pronounced was the degree of elastosis. Sections from dorsal skin were prepared for light microscopy and stained with orcein, making it possible to detect the elastosis at the same time as the mast cells. We used a projection microscope and a computer analyzing system connected to a video scanner for the calculations. The mast cell count was higher in the irradiated groups than in the control group. The number of mast cells was higher in the groups irradiated with the shortest wavelengths (292 and 300 nm). In groups irradiated with wavelengths shorter than 307 nm a subepidermal clearance zone containing significantly fewer mast cells than the rest of the upper dermal layer was found. We suggest that the mast cells might have a digesting function, as this layer was cleared of elastotic fibers and few mast cells were seen here.

Clinical variability of possible malignant hyperthermia as revealed by two cases.

Two cases of possible clinical malignant hyperthermia are described. The variability of the clinical symptoms and signs is discussed and the necessity of performing the diagnostic in vitro muscle contracture test is emphasized.

Injuries in high-skilled and low-skilled soccer: a prospective study.

Fifty-five male soccer players organized in three teams, one high and two lower ranking, were followed prospectively during 1 year to register the rate, type and severity of injuries in highly skilled and low-skilled players. The injury rate of the low-skilled players was significantly higher than that of the better players. The reason for this is that low-skilled players play in more competitions. and this is where injuries tend to occur. When we stratified on game/practice, the low-skilled players' excess risk disappeared and no difference was found in the severity of injuries. Different ways of collecting data in epidemiological studies of soccer are discussed and it is concluded that the most precise and accurate collection of data can only be obtained by direct supervision and examination of soccer players in the field.