Precision Medicine Approach for Cardiometabolic Risk Factors in Therapeutic Apheresis.

Lipoprotein apheresis (LA) is currently the most powerful intervention possible to reach a maximal reduction of lipids in patients with familial hypercholesterolemia and lipoprotein(a) hyperlipidemia. Although LA is an invasive method, it has few side effects and the best results in preventing further major cardiovascular events. It has been suggested that the highly significant reduction of cardiovascular complications in patients with severe lipid disorders achieved by LA is mediated not only by the potent reduction of lipid levels but also by the removal of other proinflammatory and proatherogenic factors. Here we performed a comprehensive proteomic analysis of patients on LA treatment using intra-individually a set of differently sized apheresis filters with the INUSpheresis system. This study revealed that proteomic analysis correlates well with routine clinical chemistry in these patients. The method is eminently suited to discover new biomarkers and risk factors for cardiovascular disease in these patients. Different filters achieve reduction and removal of proatherogenic proteins in different quantities. This includes not only apolipoproteins, C-reactive protein, fibrinogen, and plasminogen but also proteins like complement factor B (CFAB), protein AMBP, afamin, and the low affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) among others that have been described as atherosclerosis and metabolic vascular diseases promoting factors. We therefore conclude that future trials should be designed to develop an individualized therapy approach for patients on LA based on their metabolic and vascular risk profile. Furthermore, the power of such cascade filter treatment protocols may improve the prevention of cardiometabolic disease and its complications.

Is There a Role for Environmental and Metabolic Factors Predisposing to Severe COVID-19?

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic affects people around the world. However, there have been striking differences in the number of infected individuals and deaths in different countries. Particularly, within Central Europe in countries that are similar in ethnicity, age, and medical standards and have performed similar steps of containment, such differences in mortality rates remain inexplicable. We suggest to consider and explore environmental factors to explain these intriguing variations. Countries like Northern Italy, France, Spain, and UK have suffered from 5 times more deaths from the corona virus infection than neighboring countries like Germany, Switzerland, Austria, and Denmark related to the size of their respective populations. There is a striking correlation between the level of environmental pollutants including pesticides, dioxins, and air pollution such as NO2 known to affect immune function and healthy metabolism with the rate of mortality in COVID-19 pandemic in these European countries. There is also a correlation with the use of chlorination of drinking water in these regions. In addition to the improvement of environmental protective programs, there are possibilities to lower the blood levels of these pollutants by therapeutic apheresis. Furthermore, therapeutic apheresis might be an effective method to improve metabolic inflammation, altered vascular perfusion, and neurodegeneration observed as long-term complications of COVID-19 disease.

[Rheopheresis for recurrent sudden hearing loss : therapeutic options for patients refractory to infusion therapy]. / Rheopherese bei rezidivierendem Hörsturz : Therapieoption für Patienten nach erfolgloser Infusionstherapie.

BACKGROUND AND OBJECTIVE: For patients suffering from recurrent sudden hearing loss (SHL) that is refractory to infusion therapy, new therapeutic options must be established. PATIENTS AND METHODS: Patients suffering from recurrent and progressive SHL refractory to infusion therapy according to German guidelines were analysed retrospectively. After unsuccessful infusion therapy following the last onset of SHL, patients were treated with Rheopheresis twice. Hearing gain and recovery of speech discrimination were analysed. RESULTS: Twenty-five patients with a mean of 2.1+/-0.4 events of SHL within 30.0+/-21.6 months were examined. The patients' mean hearing loss before the first onset of SHL was 34 dB and was reduced by infusion therapy to 20 dB. With the second onset of SHL, hearing loss remained almost unchanged after infusion therapy. Patients showed a mean improvement of 20 dB after two consecutive Rheopheresis treatments. Forty percent showed complete remission of SHL, and a further 28% showed partial remission. CONCLUSION: Rheopheresis can efficiently improve the hearing of patients with recurrent SHL refractory to infusion therapy.

Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn.

OBJECTIVE: Because of case reports describing hypoxemia on withdrawal of inhaled nitric oxide (I-NO), we prospectively examined this safety issue in newborns with persistent pulmonary hypertension who were classified as treatment successes or failures during a course of I-NO therapy. METHODS: Randomized, placebo-controlled, double-masked, dose-response clinical trial at 25 tertiary centers from April 1994 to June 1996. Change in oxygenation and outcome (death and/or extracorporeal membrane oxygenation) during or immediately after withdrawing I-NO were the principal endpoints. Patients (n = 155) were term infants, <3 days old at study entry with echocardiographic evidence of persistent pulmonary hypertension of the newborn. Exclusion criteria included previous surfactant treatment, high-frequency ventilation, or lung hypoplasia. Withdrawal from treatment gas (0, 5, 20, or 80 ppm) started once treatment success or failure criteria were met. Withdrawal of treatment gas occurred at 20% decrements at <4 hours between steps. RESULTS: The patient profile was similar for placebo and I-NO groups. Treatment started at an oxygenation index (OI) of 25 +/- 10 (mean +/- SD) at 26 +/- 18 hours after birth. For infants classified as treatment successes (mean duration of therapy = 88 hours, OI <10), decreases in the arterial partial pressure of oxygen (PaO(2)) were observed only at the final step of withdrawal. On cessation from 1, 4, and 16 ppm, patients receiving I-NO demonstrated a dose-related reduction in PaO(2) (-11 +/- 23, -28 +/- 24, and -50 +/- 48 mm Hg, respectively). For infants classified as treatment failures (mean duration of therapy = 10 hours), no change in OI occurred for the placebo group (-13 +/- 36%, OI of 31 +/- 11 after the withdrawal process); however a 42 +/- 101% increase in OI to 46 +/- 21 occurred for the pooled nitric oxide doses. One death was possibly related to withdrawal of I-NO. CONCLUSION: For infants classified as treatment successes, a dose response between the I-NO dose and decrease in PaO(2) after discontinuing I-NO was found. A reduction in I-NO to 1 ppm before discontinuation of the drug seems to minimize the decrease in PaO(2) seen. For infants failing treatment, discontinuation of I-NO could pose a life-threatening reduction in oxygenation should extracorporeal membrane oxygenation not be readily available or I-NO cannot be continued on transport.

Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. The I-NO/PPHN Study Group.

OBJECTIVES: To assess the dose-related effects of inhaled nitric oxide (I-NO) as a specific adjunct to early conventional therapy for term infants with persistent pulmonary hypertension (PPHN), with regard to neonatal outcome, oxygenation, and safety. METHODS: Randomized, placebo-controlled, double-masked, dose-response, clinical trial at 25 tertiary centers from April 1994 to June 1996. The primary endpoint was the PPHN Major Sequelae Index ([MSI], including the incidence of death, extracorporeal membrane oxygenation (ECMO), neurologic injury, or bronchopulmonary dysplasia [BPD]). Patients required a fraction of inspired oxygen [FIO2] of 1.0, a mean airway pressure >/=10 cm H2O on a conventional ventilator, and echocardiographic evidence of PPHN. Exogenous surfactant, concomitant high-frequency ventilation, and lung hypoplasia were exclusion factors. Control (0 ppm) or nitric oxide (NO) (5, 20, or 80 ppm) treatments were administered until success or failure criteria were met. Due to slowing recruitment, the trial was stopped at N = 155 (320 planned). RESULTS: The baseline oxygenation index (OI) was 24 +/- 9 at 25 +/- 17 hours old (mean +/- SD). Efficacy results were similar among NO doses. By 30 minutes (no ventilator changes) the PaO2 for only the NO groups increased significantly from 64 +/- 39 to 109 +/- 78 Torr (pooled) and systemic arterial pressure remained unchanged. The baseline adjusted time-weighted OI was also significantly reduced in the NO groups (-5 +/- 8) for the first 24 hours of treatment. The MSI rate was 59% for the control and 50% for the NO doses (P = .36). The ECMO rate was 34% for control and 22% for the NO doses (P = .12). Elevated methemoglobin (>7%) and nitrogen dioxide (NO2) (>3 ppm) were observed only in the 80 ppm NO group, otherwise no adverse events could be attributed to I-NO, including BPD. CONCLUSION: For term infants with PPHN, early I-NO as the sole adjunct to conventional management produced an acute and sustained improvement in oxygenation for 24 hours without short-term side effects (5 and 20 ppm doses), and the suggestion that ECMO use may be reduced.

HA-1A in septic patients with ARDS: results from the pivotal trial.

OBJECTIVE: To evaluate the effects of HA-1A, a human monoclonal antiendotoxin antibody, in septic patients with ARDS. DESIGN: Substudy of a multicenter, double-blinded, placebo-controlled trial of HA-1A in septic patients. PATIENTS: 63 septic patients with ARDS at the time of study entry. INTERVENTION: A single intravenous injection of HA-1A (100 mg) or placebo. RESULTS: A quantitative radiographic score, the PaO2/FIO2 ratio and an index of the severity of ARDS did not show a significant difference between the treatment and placebo groups at 3, 5 and 7 days after treatment. The duration of endotracheal intubation did not differ between the two groups. 15 of 30 HA-1A treated patients (50%) and 23 of 33 placebo-treated patients (69.7%) died within 28 days. The daily mortality was always lower in the HA-1A group, but this difference was not statistically significant at 28 days. The 28-day survival curves for the two treatment groups adjusted by covariate analysis were not significantly different (p = 0.07). Using logistic regression, a significant independent effect of HA-1A treatment was detected upon the early survival rate at 7 days (p = 0.03) but not at 14 and 28 days. CONCLUSION: A single injection of HA-1A in septic patients with ARDS did not reverse acute respiratory failure or improve long-term survival.

HA-1A. A human monoclonal antibody for the treatment of gram-negative sepsis.

HA-1A is a human monoclonal IgM antibody that binds to endotoxin. The results of the clinical trials of HA-1A demonstrate that HA-1A reduces mortality among patients with sepsis and gram-negative bacteremia. Secondary endpoints, including resolution of organ failure, discharge from intensive care unit, and discharge from the hospital, support the beneficial effects of the antibody. The antibody is well tolerated with rare side effects, including hypotension and urticarial rash. No anti-HA-1A antibodies have been detected.

Membrane differential filtration is safe and effective for the long-term treatment of Refsum syndrome--an update of treatment modalities and pathophysiological cognition.

Refsum's disease is a complex and difficult to diagnose storage disease caused by complex autosomal recessive peroxisomal disorder in which mutations of phytanolyl/pristanoyl-CoA-hydroxilase are the main cause. Poorly metabolised phytanic acid (PA), pristanic acid (PrA) and picolenic acid (PiA) accumulates in fatty tissues, myelin sheaths, heart, kidneys and retina, leading to retinitis pigmentosa, peripheral dissociative polyneuropathy, cerebellar ataxia ("sailors" walk), renal, cardiac and liver impairment. 65% of plasma PA and PrA is localized within VLDL, LDL and HDL lipoprotein particles. Dietary restriction of PA is mostly not sufficient to prevent acute attacks and stabilize the progressive course. LDL and VLDL bound PA/PrA can be effectively eliminated from plasma with extracorporal LDL-apheresis using membrane differential filtration. Mostly additive malnutrition will become worse the clinical picture. Latest experience with black cumin oil (nigella sativa) in a dose of 3 g/day shows a support and a regression of some malnutrition effects in PA restricted dietary and a supportive effect to MDF.

Lipoprotein (a) immunapheresis in the treatment of familial lipoprotein (a) hyperlipoproteinemia in a patient with coronary heart disease.

This paper reports 2 years' experience with lipoprotein (a) (Lp[a]) immunapheresis which was successfully handled on a now 40-year-old patient with familial Lp(a) hyperlipoproteinemia inducing severe coronary heart disease with 2 myocardial infarctions and diffuse coronary sclerosis. Continued treatment by Lp(a) immunabsorption with specific sheep antibodies reduced stenosis in coronary vessels more than 50% and stopped the progression of coronary heart disease. A special apheresis technique and the results of continued absorption effects are described.

[Psychiatry and EDP. First experience with specialty-specific additional documentation-psychiatry with computer epicrisis]. / Psychiatrie und EDV. Erste Erfahrungen mit einer fachspezifischen Anschlussdokumentation-Psychiatrie mit Rechnerepikrise

A supplementary documentation on psychiatry, of which the purpose is to systematically collect certain predetermined patient data, was prepared as part of the electronic data processing project "Basic processes of patient-related information processing" which has been mapped out by workers at the Dresden Medical Academy. A psychiatric "computer-based epicrisis" has been formulated and introduced into daily psychiatric practice. A brief description of documents serving as vouchers is followed by a discussion of the advantages and disadvantages of such a method as well as the basic possibilities of development.

White blood cell consumption in the microcirculation after a major burn.

The mesenteric microvasculature was observed before and after a distant full-thickness cutaneous burn in rats. Diameters, flow velocities, and white blood cell sticking and emigration were measured. Between 30 and 360 minutes postburn 13 to 16 WBC's were found to stick to the venular walls which had an area of 1.57 x 10(4) microns(2). Therefore, the number of WBC's emigrating from the vascular compartment during the 6-hour observation period could be as many as 0.51 X 10(9)/kg. Based on known values for total stores of WBC's, the data suggest that granulocyte sticking and emigration could account for a consumption of granulocytes that on an acute basis could deplete the body stores, which could explain the apparent decrease in total body granulocytes seen clinically following major thermal trauma.

Illness associated with contamination of drinking water supplies with phenol.

In January 1984 the River Dee in north Wales was contaminated with phenol, with subsequent contamination of the tap water received by about two million consumers. A retrospective postal survey of 594 households was undertaken to determine whether consumption of this contaminated water was associated with illness. Subjects in areas that received contaminated water reported significantly more gastrointestinal illness than those in a nearby unexposed area (32.6% v 8.7%, p less than 0.00001) as well as reporting a higher incidence of any symptoms (43.6% v 18.4%, p less than 0.00001). Symptoms were consistent with phenol poisoning and bore a strong temporal relation to the pollution of the supply, but they developed at concentrations of phenols previously considered to be safe by the water authorities concerned. Chlorophenols produced during the treatment of water may have aggravated the problem.

Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group.

OBJECTIVE: To compare the effectiveness of 100 mg of HA-1A and placebo in reducing the 14-day all-cause mortality rate in patients with septic shock and gram-negative bacteremia in the Centocor: HA-1A Efficacy in Septic Shock (CHESS) trial, and to assess the safety of 100 mg of HA-1A given to patients with septic shock who did not have gram-negative bacteremia. DESIGN: Large, simple, group-sequential, randomized, double-blind, multicenter, placebo-controlled trial. SETTING: 603 investigators at 513 community and university-affiliated hospitals in the United States. PATIENTS: Within 6 hours before enrollment, the patients had been in shock with a systolic blood pressure of less than 90 mm Hg after adequate fluid challenge or had received vasopressors to maintain blood pressure. These episodes of shock began within 24 hours of enrollment. A presumptive clinical diagnosis of gram-negative infection as the cause of the shock episode and a commitment from the patients' physicians to provide full supportive care were required. MEASUREMENTS: Blood cultures were obtained within 48 hours of enrollment, and death at day 14 after treatment was recorded. Adverse events occurring within 14 days after enrollment were also tabulated. RESULTS: 2199 patients were enrolled; 621 (28.2%) met all enrollment criteria, received HA-1A or placebo, and had confirmed gram-negative bacteremia. Mortality rates in this group were as follows: placebo, 32% (95 and HA-1A, 33% (109 of 328) (P = 0.864, Fisher exact test, two-tailed; 95% CI for the difference, -6.2% to 8.6%). Mortality rates in the patients without gram-negative bacteremia were as follows: placebo, 37% (292 of 793) and HA-1A, 41% (318 of 785) (P = 0.073, Fisher exact test, one-tailed; CI, -0.8% to 8.8%). CONCLUSIONS: In this trial, HA-1A was not effective in reducing the 14-day mortality rate in patients with gram-negative bacteremia and septic shock. These data do not support using septic shock as an indication for HA-1A treatment. If HA-1A is effective in reducing the mortality rate in patients dying from endotoxemia, these patients must be identified using other treatment criteria.

Phase I trial of the recombinant soluble complement receptor 1 in acute lung injury and acute respiratory distress syndrome.

OBJECTIVE: To determine the safety, pharmacokinetics, biological effects, and immunogenicity of recombinant soluble complement receptor 1 (TP10) in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). DESIGN: Open label, ascending dosage, phase I trial. SETTING: Two academic teaching hospitals. PATIENTS: A total of 24 patients diagnosed with ALI/ARDS. INTERVENTION: A single, 30-min intravenous infusion of 0.1, 0.3, 1, 3, or 10 mg/kg TP10. MEASUREMENTS AND MAIN RESULTS: Serum levels of TP10 increased in proportion to the dose. Mean variable estimates (+/-SD) were half-life of disposition 69.7 +/- 39.7 hrs, plasma clearance 2.39 +/- 1.32 mL/hr/kg, and volume of distribution 190.6 +/- 135.0 mL/kg. Inhibition of complement activity, measured by CH50, was significant for the interaction of dose and time (p = .024). The C3a levels demonstrated a trend for dose which did not reach statistical significance (p = .090) and soluble C5b-9 levels were significant only for dose (p = .023). As expected by the proposed physiologic mechanism, C4a levels were not affected by TP10, dose, or time. The overall mortality rate was 33%. Neither the type nor the frequency rate of specific adverse events were substantially different between dose groups. Seven adverse events in four patients were thought to be possibly related to TP10. CONCLUSIONS: TP10 has a half-life of approximately 70 hrs and at doses > or =1 mg/kg, significantly inhibits complement activity at the levels of C3 and C5 in patients with ALI/ARDS. Complement inhibition was more prolonged over time with TP10 doses of 3 and 10 mg/kg. TP10 appears to be safe at the doses tested. Further studies will be required to completely assess the impact of TP10 on pathophysiology and clinical outcome in patients with ALI/ARDS.

Treatment of bacterial meningitis with once daily ceftriaxone therapy.

Ceftriaxone, a cephalosporin with an extended half-life and excellent antibacterial activity was used to treat bacterial meningitis, given as a single daily intravenous dose of 100 mg/kg on day one, followed by 80 mg/kg daily. A total of 22 patients were treated, of whom 14 had Haemophilus influenzae type b, five had Streptococcus pneumoniae and three Neisseria meningitidis isolated from their CSF. The CSF of all patients became sterile within 24-48 h. The CSF ceftriaxone concentrations 24 h after dosing were 10 to 100-fold higher than the MIC of the pathogenic bacteria early in therapy, and five to 50-fold higher at the end of therapy. Side effects encountered included mild diarrhoea (32%), thrombocytosis (77%) and neutropenia (9%), but none caused therapy to be stopped. Ceftriaxone is a safe and effective antibiotic for the treatment of bacterial meningitis when administered once daily.

Effect of prophylactic digitalization on the development of myocardial hypertrophy.

The effect of prophylactic digitalization on the development of left ventricular hypertrophy was studied in adult rats. Digitoxin, 0.1 mg/100 g body wt or solvent was given daily for 1 wk prior to either aortic constriction or sham operation and was continued until the animals were killed, either 1 or 4 wk after surgery. A hemodynamic study was done in those animals killed 1 wk after surgery; hearts of all animals were examined for evidence of myocardial hypertrophy. Constriction of the ascending aorta had no significant effect on cardiac output but did reduce peak flow velocity and flow acceleration. An increase in left ventricular mass, RNA, and hydroxyproline was found in the animals with aortic constriction. Digitoxin treatment did not alter peak flow velocity or flow acceleration, but did significantly increase isovolumic (dP/dt)P-1. Digitoxin had no effect on body weight, heart weight, RNA, or hydroxyproline in either the sham-operated animals or in the animals with aortic constriction. Therefore, despite plasma digitoxin levels sufficient to affect myocardial contractility, left ventricular hypertrophy still developed after aortic constriction.

The antiviral effect of zidovudine and ribavirin in clinical trials and the use of p24 antigen levels as a virologic marker.

The inhibition of viremia and p24 core antigenemia in patients infected with human immunodeficiency virus (HIV) was evaluated in separate multicenter, double-blind, placebo-controlled trials of zidovudine and ribavirin. Of 29 patients (14 with AIDS and 15 with AIDS-related complex [ARC]) enrolled in the zidovudine study, 16 received 250 mg of zidovudine every 4 h and 13 received placebo. No difference in HIV isolation from peripheral blood was observed at 20 w in treated versus placebo groups (79% vs. 82%). In patients tolerating zidovudine, mean p24 antigen levels dropped to 8.2% +/- 8.1% of their baseline values, whereas in placebo recipients mean p24 antigen levels declined to 61.3% +/- 40.8% of their baseline values (P less than .005). In the ribavirin study, patients with ARC treated with either 800 mg or 600 mg ribavirin daily or with placebo showed no consistent reduction in p24 antigenemia or decrease in HIV isolation. These data indicate that decline in p24 antigenemia can be a useful virologic marker in evaluation of new antiretroviral drugs.