[Avoidance-endurance fast screening (AE-FS) : Content and predictive validity of a 9­item screening instrument for patients with unspecific subacute low back pain]. / Avoidance-Endurance Fast-Screen (AE-FS) : Inhalts- und Vorhersagevalidität eines 9­Item-Screeninginstruments für Patienten mit unspezifischen subakuten Rückenschmerzen.

BACKGROUND: Among screening measures to assess psychosocial risk factors (yellow flags) for chronic low back pain (LBP) economic tools which address dysfunctional endurance pain responses besides emotional distress and fear-avoidance pain processing are rare. Targeting contrasting types of pain processing might improve stratified patient counselling. OBJECTIVE: The aim of the study was to develop a short screening method, based on the avoidance-endurance model of pain and to investigate the prognostic validity for pain intensity, disability and physical function. MATERIAL AND METHODS: A prospective observational study was carried out on 144 patients with subacute LBP (<3 months) from 7 general practitioners and 5 orthopedic practices. The 9­item avoidance-endurance fast screening (AE-FS) was derived from a previous 37-item screening using correlational and receiver operating curve (ROC) analyses and the agreement of subgrouping was calculated using Cohen's kappa. Primary outcomes were assessed after 6 months by mail in 124 patients (86%). Endpoints were pain intensity and disability. RESULTS: The classification of subgroups as high and low risk by both measures had considerable agreement with a value of 0.71 (Cohen's Kappa). The sensitivity to predict pain intensity >2 was high (82%) as was the positive predictive value (80%) but the negative predictive value was moderate (61%). The ROC (AUC) characteristics (95% confidence interval CI) were 0.70 (0.60-0.80) for pain intensity and for limitations in the pain disability index (PDI) 0.70 (0.55-0.87). DISCUSSION: The 9­item AE-FS displayed sufficient prognostic validity for all three outcomes in a sample of primary care patients with subacute LBP. The differentiation of the high-risk patients into fear-avoidance and endurance-related pain processing enables the physician to provide an individualized counselling with the aim of a healthy balance between stress and relaxation.

Effective Connectivity of Cortical Sensorimotor Networks During Finger Movement Tasks: A Simultaneous fNIRS, fMRI, EEG Study.

Recently, interest has been growing to understand the underlying dynamic directional relationship between simultaneously activated regions of the brain during motor task performance. Such directionality analysis (or effective connectivity analysis), based on non-invasive electrophysiological (electroencephalography-EEG) and hemodynamic (functional near infrared spectroscopy-fNIRS; and functional magnetic resonance imaging-fMRI) neuroimaging modalities can provide an estimate of the motor task-related information flow from one brain region to another. Since EEG, fNIRS and fMRI modalities achieve different spatial and temporal resolutions of motor-task related activation in the brain, the aim of this study was to determine the effective connectivity of cortico-cortical sensorimotor networks during finger movement tasks measured by each neuroimaging modality. Nine healthy subjects performed right hand finger movement tasks of different complexity (simple finger tapping-FT, simple finger sequence-SFS, and complex finger sequence-CFS). We focused our observations on three cortical regions of interest (ROIs), namely the contralateral sensorimotor cortex (SMC), the contralateral premotor cortex (PMC) and the contralateral dorsolateral prefrontal cortex (DLPFC). We estimated the effective connectivity between these ROIs using conditional Granger causality (GC) analysis determined from the time series signals measured by fMRI (blood oxygenation level-dependent-BOLD), fNIRS (oxygenated-O2Hb and deoxygenated-HHb hemoglobin), and EEG (scalp and source level analysis) neuroimaging modalities. The effective connectivity analysis showed significant bi-directional information flow between the SMC, PMC, and DLPFC as determined by the EEG (scalp and source), fMRI (BOLD) and fNIRS (O2Hb and HHb) modalities for all three motor tasks. However the source level EEG GC values were significantly greater than the other modalities. In addition, only the source level EEG showed a significantly greater forward than backward information flow between the ROIs. This simultaneous fMRI, fNIRS and EEG study has shown through independent GC analysis of the respective time series that a bi-directional effective connectivity occurs within a cortico-cortical sensorimotor network (SMC, PMC and DLPFC) during finger movement tasks.

The olfactory bulb volume in patients with idiopathic Parkinson's disease.

BACKGROUND AND PURPOSE: This study addresses the question of whether the neuropathological findings on the olfactory bulb (OB) in idiopathic Parkinson's disease (IPD) correspond to a detectable change in volume of the OB. Additionally, the relationship between OB volume and residual olfactory function, clinical disease characteristics and age are investigated. METHODS: Fifty-two IPD patients were investigated and compared to 31 healthy age-matched controls. All participants were scanned using a 3 T magnetic resonance imaging MRI scanner including a T2 DRIVE sequence in coronal slices through the OB. The OB volumes were measured via manual segmentation of the OB. Olfactory testing was carried out using the Sniffin' Sticks test battery. RESULTS: The OB volume in the IPD group was 42.1 mm³ (SD ± 11.6) for the right and 41.5 mm³ (SD ± 11.7) for the left OB and showed no difference from the controls. Additionally, there were no significant correlations between OB volume and disease characteristics such as disease duration or Unified Parkinson's Disease Rating Scale motor score. Likewise, patients' residual smell function did not correlate with their OB volume. In contrast, controls indicated a correlation between smell function and OB volume. CONCLUSION: The study shows that high resolution MRI does not show a detectable volume loss of the OB in PD patients. It is concluded that OB measurement using in vivo high resolution MRI at 3 T is not helpful to identify IPD.

[Comment on Gender-Specific Aspects in Obesity and Metabolic Surgery--Analysis of Data from the German Bariatric Surgery Registry]. / Kommentar zu genderspezifischen Aspekten in der Adipositas- und metabolischen Chirurgie--Daten der Qualitätssicherungsstudie für operative Therapie der Adipositas.

BACKGROUND: The current situation in obesity and metabolic surgery since January 2005 has been investigated with the help of the quality assurance study on surgical therapy for obesity = German Bariatric Surgery Registry (GBSR). The data were acquired and analysed in cooperation with the Institute for Quality Assurance in Surgical Medicine at the Otto-von-Guericke University. METHODS: Data acquisition was done with the help of an online database. On a voluntary basis, all obesity and metabolic surgical interventions since 2005 have been recorded. In addition to the surgical data, the findings of the yearly follow-up investigations were recorded. RESULTS: Since 2005 there have been 1,263 gastric balloon procedures, 11,840 sleeve gastrectomies, 13,722 Roux-en-Y gastric bypasses and 3999 gastric banding operations. The average age of the male patients in all interventions was significantly higher. The average BMI of female patients who received a gastric banding or a gastric balloon procedure was significantly lower than that of the male patients. Men exhibited a higher incidence of comorbidities than women. CONCLUSION: The number of obesity and metabolic surgical interventions in Germany is continuously increasing. The results of the study on surgical therapy for obesity (GBSR) reveal significant differences in the gender-specific incidence of preoperative comorbidities. postoperative complications and mortality. Further studies on gender-specific aspects are necessary in order to optimise patient selection and reduce the incidence of postoperative complications.

Bariatric surgery in adolescents and young adults--safety and effectiveness in a cohort of 345 patients.

OBJECTIVE: To examine the safety and effectiveness of adolescent bariatric surgery and to improve treatment recommendations for this age group. DESIGN: Prospective longitudinal registry. Since January 2005, patients undergoing bariatric surgery in Germany are enlisted in an online registry called 'study for quality assurance in obesity surgeries'. SUBJECTS: Adolescents and young adults up to the age of 21 years, operated from January 2005 to December 2010. MEASUREMENTS: Weight, BMI, comorbidities, complication rates. RESULTS: N=345 primary procedures were recorded by 58 hospitals. N=51 patients were under the age of 18 years. Follow-up information was available for 48% (n=167) of patients, with an average observation period of 544±412 days (median: 388 days). The most common surgical techniques were gastric banding (n=118, 34.2%), gastric bypass (n=116, 33.6%) and sleeve gastrectomy (n=78, 22.6%). Short-term complications (intra-operative; general postoperative; specific postoperative) were slightly lower for gastric banding (0.8%; 2.5%; 0.8%) than for gastric bypass (2.6%; 5.2%; 1.7%) or sleeve gastrectomy (0%; 9.0%; 7.7%). In accordance with published findings, weight and BMI reduction were lower for gastric banding (-28 kg; -9.5 kg m(-2)) compared to gastric bypass (-50 kg; -16.4 kg m(-2)) P< 0.001 or sleeve gastrectomy (-46 kg; -15.4 kg m(-2)) P< 0.001. Outcomes did not differ between the <18 and ≥18-year-old patients. CONCLUSION: Like in adults, bariatric surgery has low short-term complication rates and results in sustained weight loss in adolescents. However, the missing long-term observations prohibit a final conclusion about lasting effectiveness and safety. Clinical trials with structured follow-up programs and mechanisms to ascertain patient adherences are needed.

Human face processing is tuned to sexual age preferences.

Human faces can motivate nurturing behaviour or sexual behaviour when adults see a child or an adult face, respectively. This suggests that face processing is tuned to detecting age cues of sexual maturity to stimulate the appropriate reproductive behaviour: either caretaking or mating. In paedophilia, sexual attraction is directed to sexually immature children. Therefore, we hypothesized that brain networks that normally are tuned to mature faces of the preferred gender show an abnormal tuning to sexual immature faces in paedophilia. Here, we use functional magnetic resonance imaging (fMRI) to test directly for the existence of a network which is tuned to face cues of sexual maturity. During fMRI, participants sexually attracted to either adults or children were exposed to various face images. In individuals attracted to adults, adult faces activated several brain regions significantly more than child faces. These brain regions comprised areas known to be implicated in face processing, and sexual processing, including occipital areas, the ventrolateral prefrontal cortex and, subcortically, the putamen and nucleus caudatus. The same regions were activated in paedophiles, but with a reversed preferential response pattern.

[Severe small bowel involvement and chronic intestinal pseudo-obstruction in systemic sclerosis (scleroderma): Pathophysiological, diagnostic and therapeutic basis, including parenteral nutrition]. / Atteinte sévère de l'intestin grêle et pseudo-obstruction intestinale chronique au cours de la sclérodermie systémique : bases physiopathologiques, diagnostiques et thérapeutiques, dont la nutrition parentérale.

Gastrointestinal involvement in systemic sclerosis can be severe, reaching the critical point of chronic intestinal pseudo-obstruction, secondary to major disorders of small bowel motility. It is associated with some clinical and biological characteristics, in particular the positivity of anti-fibrillarin/U3RNP antibodies. Chronic intestinal pseudo-obstruction (CIPO) is complicated by a small intestinal bacterial overgrowth that requires cyclic antibiotic therapy. CIPO leads to a reduction of the food intake, due to painful symptoms, nausea and vomiting caused by meals, and ultimately to severe malnutrition. Meal splitting is often transiently effective and patients require exogenous nutritional support, mostly parenteral. Systemic sclerosis is not an obstacle to initiation and long-term continuation of parenteral nutrition and central venous catheter implantation is not associated with an increased risk of cutaneous or infectious complications. However, continuation of long-term parenteral nutrition requires monitoring in an expert nutrition center in order to adapt nutritional volumes and intakes and to limit potentially fatal cardiac and hepatobiliary complications. In addition to nutrition, prokinetic treatments, whose side effects must be known, can be associated. Invasive procedures, whose risk-benefit ratio must be carefully assessed, can also be used to treat symptoms exclusively.

[Acute appendicitis - clinical health-service research on the current surgical therapy]. / Akute Appendizitis - Klinische Versorgungsforschung zur aktuellen chirurgischen Therapie.

INTRODUCTION: With about 135,000 operations every year appendectomy is one of the most frequent surgical operations in Germany. Acute appendicitis has shown changes in diagnosis and therapy with time. The status of the laparoscopic appendectomy has had to be redefined recently. The aim of this study was to make an analysis of the current surgical therapy for appendicitis and the individual procedures. PATIENTS AND METHODS: Three prospective multi-centre quality assurance studies (1988 / 89, 1996 / 97; 2008 / 09) of the "An-Institut" acquired 17,732 treatments from all supply levels of Germany. RESULTS: The average age of patients increased within of the three studies from 25.7 to 34.6 years. Within the studies in 1996 / 97 and in 2008 / 09 the share of laparoscopic appendectomy advanced from 33.1 to 85.8 percent. In the study from 2008 / 09 the laparoscopic appendectomy showed a significant advantage over the conventional technique in terms of wound-healing disturbances (p < 0.001) and a clinical duration of stay (p < 0.001). At no stage of the appendix inflammation did the laparoscopic appendectomy lead to a significant increase of intraabdominal abscesses. Compared with the conventional technique the operating time was shorter (46.6 min vs. 53.5 min). Currently the use of a stapler is the mostly frequently applied method of appendiceal stump closure (83.6 percent). CONCLUSION: The laparoscopic appendectomy is the most common method of current operative therapy. In comparison to former publications, there is no proof of any disadvantages of laparoscopic appendectomy.

[Surgical treatment of carcinomas of the oesophagogastric junction - results achieved in multicentre studies]. / Multizentrische Ergebnisse der chirurgischen Therapie der Karzinome des ösophagogastralen Übergangs.

BACKGROUND: Adenocarcinomas of the oesophagogastric junction are increasingly being considered as a separated tumour entity. The prognosis is rather poorer compared with that for distal gastric cancer. Data from a multicentre study as part of research on clinical care aim to reflect the current situation in surgical treatment after inauguration of neoadjuvant modalities. PATIENTS AND METHOD: As part of the ongoing prospective multicentre observational study QCGC 2 (German Gastric Cancer Study 2), 544 adenocarcinomas of the oesophagogastric junction (AEG 1-3) were registered from 01/01/2007 to 12/31/2009. RESULTS: Patients underwent surgical intervention in 108 (76.6 %) of the 141 surgical departments which provided data to the study. In 391 patients (82.5 %), R0 resection was achieved. Almost 60 % of the carcinomas of the oesophagogastric junction were approached in departments with no more than 10 of these tumour lesions through the whole study period (3 years). Endoscopic ultrasonography was performed in 283 cases (53 %); the rate of neoadjuvant treatment was 34.4 % (n = 187). Intraoperative fresh frozen section was only included in intraoperative decision-making in 242 patients (60.8 %). In the revealed heterogeneous spectrum of surgical interventions, a limited number of transthoracic approaches (20 %) and a mediastinal lymphadenectomy rate of only 47 % were found. Hospital lethality was 6.6 %. In the adenocarcinomas of the oesophagogastric junction, a significantly lower median survival (25 months) compared with distal gastric cancer (38 months) was observed depending on the tumour stage. In addition, 5-year survival rate of AEG patients (33.1 %) was distinctly lower than for patients with distal gastric cancer (41.4 %). There was no significantly better survival by neoadjuvant treatment in the group of investigated patients. CONCLUSION: The results in the treatment of carcinomas of the oesophagogastric junction in the multicentre setting including surgical departments of each profile and region even after introduction of multimodal therapeutic concepts are not satisfying. In particular, modern diagnostic and surgical strategies need to be widely used or their percentage has to be increased. In this context, centralisation of the surgical care of this specific tumour entity appears reasonable.

[New data on quality assurance in bariatric surgery in Germany]. / Aktuelle Daten der Qualitätssicherungsstudie für operative Therapie der Adipositas in Deutschland.

BACKGROUND: Since January 1st 2005, the situation of bariatric surgery has been examined in Germany. All data are registered prospectively in cooperation with the Institute of Quality Assurance in Surgery at the Otto-von-Guericke University of Magdeburg. METHODS: The voluntary data registration occurs in an internet online data bank. All primary bariatric procedures as well as re- and redo-procedures are documented. Follow-up data were collected once a year. Participation in the quality assurance study is obligatory for certificated centres. RESULTS: Since 2005 13,879 bariatric procedures have been performed at 83 hospitals. The number of primary procedures has increased from 596 in 2005 to 11,835 in 2010. Revisional surgery has been performed in 1,438 patients since 2005. Sleeve gastrectomy (SG) is the major procedure with 1,564 operations in 2010. The mean BMI was 48.8 kg/m². The incidence of comorbidities was 84.8%. CONCLUSION: Bariatric surgery has become more accepted in Germany. Beside the Roux-en-Y gastric bypass, sleeve gastrectomy is the most frequently performed operation. BMI and incidence of comorbidities are still high in comparison with literature values. Due to the lack of evidence, more randomised studies are necessary to standardise operative techniques and evaluate patient selection criteria. Quality assurance studies support a detailed analysis of these parameters.

Inferring the diurnal variability of OH radical concentrations over the Amazon from BVOC measurements.

The atmospheric oxidation of biogenic volatile organic compounds (BVOC) by OH radicals over tropical rainforests impacts local particle production and the lifetime of globally distributed chemically and radiatively active gases. For the pristine Amazon rainforest during the dry season, we empirically determined the diurnal OH radical variability at the forest-atmosphere interface region between 80 and 325 m from 07:00 to 15:00 LT using BVOC measurements. A dynamic time warping approach was applied showing that median averaged mixing times between 80 to 325 m decrease from 105 to 15 min over this time period. The inferred OH concentrations show evidence for an early morning OH peak (07:00-08:00 LT) and an OH maximum (14:00 LT) reaching 2.2 (0.2, 3.8) × 106 molecules cm-3 controlled by the coupling between BVOC emission fluxes, nocturnal NOx accumulation, convective turbulence, air chemistry and photolysis rates. The results were evaluated with a turbulence resolving transport (DALES), a regional scale (WRF-Chem) and a global (EMAC) atmospheric chemistry model.

Mismatch repair deficiency, chemotherapy and survival for resectable gastric cancer: an observational study from the German staR cohort and a meta-analysis.

PURPOSE: In a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. Further data are required to corroborate these findings. METHODS: Between April 2013 and December 2018, 458 patients with curatively resected GC, including cancers of the esophagogastric junction Siewert type II and III, were identified in the German centers of the staR consortium. Tumor sections were assessed for expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. The association between MMR status and survival was assessed. Similar studies published up to January 2021 were then identified in a MEDLINE search for a meta-analysis. RESULTS: MMR-status and survival data were available for 223 patients (median age 66 years, 62.8% male), 23 patients were MMRd (10.3%). After matching for baseline clinical characteristics, median OS was not reached in any subgroup. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd and MMRp had a HR of 0.67 (95% CI 0.13-3.37, P = 0.63) and 1.44 (95% CI 0.66-3.13, P = 0.36), respectively. The meta-analysis included pooled data from 385 patients. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd had an improved OS with a HR of 0.36 (95% CI 0.14-0.91, P = 0.03), whereas those with MMRp had a HR of 1.18 (95% CI 0.89-1.58, P = 0.26). CONCLUSION: Our data support a positive prognostic effect for MMRd in GC patients treated with surgery only and a differentially negative prognostic effect in patients treated with perioperative chemotherapy. MMR status determined by preoperative biopsies may be used as a predictive biomarker to select patients for perioperative chemotherapy in curatively resectable GC.

Motor cortical representation of the pelvic floor muscles.

PURPOSE: Pelvic floor muscle training involves rhythmical voluntary contractions of the external urethral sphincter and ancillary pelvic floor muscles. The representation of these muscles in the motor cortex has not been located precisely and unambiguously. We used functional magnetic resonance imaging to determine brain activity during slow and fast pelvic floor contractions. MATERIALS AND METHODS: Cerebral responses were recorded in 17 healthy male volunteers, 21 to 47 years old, with normal bladder control. Functional magnetic resonance imaging was performed during metronome paced slow (0.25 Hertz) and fast (0.7 Hertz) contractions of the pelvic floor that mimicked the interruption of voiding. To study the somatotopy of the cortical representations, flexion-extension movements of the right toes were performed as a control task. RESULTS: Functional magnetic resonance imaging during pelvic floor contractions detected activity of the supplementary motor area in the medial wall and of the midcingulate cortex, insula, posterior parietal cortex, putamen, thalamus, cerebellar vermis and upper ventral pons. There were no significant differences in activation between slow and fast contractions. Toe movements involved significantly stronger activity of the paracentral lobule (ie the medial primary motor cortex) than did the pelvic floor contractions. Otherwise the areas active during pelvic floor and leg muscle contractions overlapped considerably. CONCLUSIONS: The motor cortical representation of pelvic floor muscles is located mostly in the supplementary motor area. It extends further ventrally and anteriorly than the representation of distal leg muscles.

[Antibiotic resistance: development in surgical intensive care]. / Resistenzentwicklung in der operativen Intensivtherapie.

BACKGROUND: During the last years we have always found an increase of antibiotic resistance. This increase is combined with high antibiotic consumption. The reasons for the problems are mis-takes in the prescription of antibiotics and the -in-crease of risk-patients because of demographic aging and the development and progress of surgery and medicine. MATERIAL AND METHOD: We describe the general development of bacterial resistance and factors that influence it. Data from two intensive care units are evaluated. We describe the main anti-biotic-resistant isolates for surgery and the mechanisms to avoid the development of bacterial resistance. RESULTS: The emergency increase of bacterial resistance shows severe clinical and economical problems. For surgery especially the multidrug-resistant Gram-negative organisms represent an important hygienic and therapeutic problem. CONCLUSION: In order to positively influence the development of bacterial resistance, strict guidelines, especially for intensive stations, must be consequently applied and controlled. In spite of knowledge of these problems for a number of years many reserves are still available for the care of critical patients.

[Meshes in abdominal wall surgery - an overview]. / Prothetische Materialien in der Bauchwandchirurgie - ein Überblick.

Abdominal wall surgery and hernia repair is nowadays not conceivable without the use of mesh prosthetics. There are countless products from various health-care companies available. This article gives an overview of meshes currently in use, describes their characteristics and indicates the relevant differences between the various groups of implants.

Pathogenetic mechanisms in experimental immune fever.

When rabbits sensitized to human serum albumin (HSA) are challenged intravenously with specific antigen, fever develops and two transferable pyrogens can be demonstrated in the circulation. The first appears prior to the development of fever and has properties consistent with soluble antigen-antibody complexes. These have been shown to be pyrogenic when prepared in vitro and to produce a state of febrile tolerance when repeatedly administered. The second pyrogen, demonstrable during fever in donor rabbits, appears to be similar to endogenous pyrogen described in other experimental fevers. It is postulated that the formation of antigen-antibody complexes constitutes an important initial phase of the febrile reaction in this type of immune fever.

Demonstration and characterization of two distinct human leukocytic pyrogens.

Human monocytes and neutrophils were separated from buffy coats of blood obtained from normal donors. Following incubation with heat-killed staphylococci, monocyte preparations contained 20 times more pyrogenic activity in the supernatant media than did supernates from an equal number of neutrophils. During purification of these pyrogens it was discovered that these cell preparations each produced a distinct and different pyrogen. The pyrogen obtained from neutrophils had a mol wt of 15,000 following Sephadex G-75 gel filtration, an isoelectric point of 6.9, and could be precipitated and recovered from 50% ethanol at -10 degrees C. In contrast, the pyrogen derived from monocyte preparations had a mol wt of 38,000, an isoelectric point of 5.1, and was destroyed in cold ethanol. Both molecules were unaffected by viral neuraminidase but biologically destroyed at 80 degrees C for 20 min and with trypsin at pH 8.0. The febrile peak produced by partially purified neutrophil pyrogen occurred at 40 min while that from monocytes was at 60 min. In addition, monocyte pyrogen produced more sustained fevers for the same peak elevation as neutrophil pyrogen. These studies demonstrate for the first time two chemically and biologically distinctive pyrogens derived from circulating human white blood cells and have important implications for our understanding of the pathogenesis of fever in man.

Studies on the origin of human leukocytic pyrogen.

Release of the protein molecule, leukocytic pyrogen, is one of the many reactions exhibited by leukocytes after phagocytosis. After the ingestion of heat-killed S. albus, a 3-4 hr latent period exists, during which human peripheral leukocytes release no pyrogen, yet cellular metabolism is altered in such a way that pyrogen output may subsequently occur in the absence of further phagocytosis. Transcription of messenger RNA and translation of new protein are initial events in the. activation process, since addition of the inhibitors, actinomycin D, and cycloheximide or puromycin, during this period markedly depressed or abolished subsequent pyrogen release. These effects were noted to be dependent upon the time of addition of the inhibitors. None of the inhibitor drugs interfered with cell viability as measured by phagocytosis and hexose monophosphate shunt activity, nor did they alter the pyrogenicity of preformed leukocytic pyrogen. Vincristine did not inhibit pyrogen formation, consistent with its reported failure to alter RNA synthesis in mature human granulocytes. The glycolytic inhibitor, sodium fluoride, blocked pyrogen release both when added prior to particle ingestion or 1 hr after the initiation of phagocytosis. Whereas inhibition of phagocytosis would explain the sodium fluoride effect prior to 1 hr, this was not observed in leukocyte preparations incubated for 1 hr with S. albus before adding sodium fluoride. When sodium fluoride was added to preparations 2 hr after the start of incubation, the LP production was unimpaired. Potassium cyanide had no effect on cell activation or pyrogen release. These findings suggest that the primary energy supply for the activation process is derived from high energy phosphate bonds provided by anaerobic glycolysis. Since the major amount of cell activation appears to occur in the 1st hr after phagocytosis, this energy might be involved in the induction of a genome leading to the transcription of m-RNA and its translation into new protein or is required for polysome integrity during protein synthesis. It is suggested that this new protein may be leukocytic pyrogen itself, or an enzyme responsible for cleaving it from an inactive precursor.

Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1.

Recombinant human tumor necrosis factor (rTNF alpha) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 microgram/kg) rTNF alpha and rIL-1 produce the same amount of fever and induce comparable levels of PGE2 in rabbit hypothalamic cells in vitro; like IL-1, TNF fever is blocked by drugs that inhibit cyclooxygenase. At higher doses (10 micrograms/kg) rTNF alpha produces biphasic fevers. The first fever reaches peak elevation 45-55 min after bolus injection and likely represents a direct action on the thermoregulatory center. During the second fever peak (3 h later), a circulating endogenous pyrogen can be shown present using passive transfer of plasma into fresh rabbits. This likely represents the in vivo induction of IL-1. In vitro, rTNF alpha induces the release of IL-1 activity from human mononuclear cells with maximal production observed at 50-100 ng/ml of rTNF alpha. In addition, rTNF alpha and rIFN-gamma have a synergistic effect on IL-1 production. The biological activity of rTNF alpha could be distinguished from IL-1 in three ways: the monophasic pyrogenic activity of rIL-1 was destroyed at 70 degrees C, whereas rTNF alpha remained active; anti-IL-1 neutralized IL-1 but did recognize rTNF alpha or natural cachectin nor neutralize its cytotoxic effect; and unlike IL-1, rTNF alpha was not active in the mitogen-stimulated T cell proliferation assay. The possibility that endotoxin was responsible for rTNF alpha fever and/or the induction of IL-1 was ruled-out in several studies: rTNF alpha produced fever in the endotoxin-resistant C3H/HeJ mice; the IL-1-inducing property of rTNF alpha was destroyed either by heat (70 degrees C) or trypsinization, and was unaffected by polymyxin B; pyrogenic tolerance to daily injections of rTNF alpha did not occur; levels of endotoxin, as determined in the Limulus amebocyte lysate, were below the minimum rabbit pyrogen dose; and these levels of endotoxin were confirmed by gas chromatography/mass spectrometry analysis for the presence of beta-hydroxymyristic acid. Although rTNF alpha is not active in T cell proliferation assays, it may mimic IL-1 in a T cell assay, since high concentrations of rTNF alpha induced IL-1 from epithelial or macrophagic cells in the thymocyte preparations. These studies show that TNF (cachectin) is another endogenous pyrogen which, like IL-1 and IFN-alpha, directly stimulate hypothalamic PGE2 synthesis. In addition, rTNF alpha is an endogenous inducer of IL-1.(ABSTRACT TRUNCATED AT 400 WORDS)