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The authors regret that the second affiliation for Author Paola Queirolo was not included in the published paper. The full author details are given below and have been updated in the online article. Paola Queirolo p, v p Division of Medical Oncology for Melanoma, Sarcoma, and Rare Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy v Ospedale Policlinico San Martino IRCCS, Genoa, Italy The authors would like to apologise for any inconvenience caused. © 2021 Elsevier Ltd

Our primary goal was to determine if leukocytes are a source of nerve growth factor (NGF) in mouse spleen. Noradrenergic nerves were localized to arteries and white pulp in normal spleens but only to arteries in ultra-immunodeficient R2G2 mice that lack leukocytes. NGF mRNA was detected in vascular cells and leukocytes of normal spleen, and several of the latter were T cells based on double labeling for NGF mRNA and CD3. Our findings indicate NGF is produced by vascular cells and to a lesser extent by leukocytes in spleen and provide support for pleiotropic actions in spleen and salivary glands.

Background: BRAF/MEK inhibitor combinations are established treatments for BRAF V600–mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up. Methods: In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600–mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups. Results: At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4–39.2) for COMBO450, 23.5 months (95% CI, 19.6–33.6) for ENCO300 and 16.9 months (95% CI, 14.0–24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48–0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0–20.2), ENCO300 was 9.6 months (95% CI, 7.4–14.8) and VEM was 7.3 months (95% CI, 5.6–7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39–0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM. Conclusions: Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600–mutated melanoma. © 2019 The Authors

Background: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib. Patients and methods: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. Results: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event. Conclusion: Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. Trial registration: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38). © 2019 The Author(s)

Background: Combined BRAF-MEK inhibitor therapy is the standard of care for BRAF V600 -mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAF V600 -mutant melanoma. Methods: COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAF V600E or BRAF V600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) via interactive response technology to receive either oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib. Efficacy analyses were by intention-to-treat. Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment. The results of part 2 will be published separately. This study is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38. Findings: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8–16·9), median progression-free survival was 14·9 months (95% CI 11·0–18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6–8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41–0·71; two-sided p

Background: Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAFV600-mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival. Methods: COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAFV600E or BRAFV600K mutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38. Findings: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9–37·5). Median overall survival was 33·6 months (95% CI 24·4–39·2) with encorafenib plus binimetinib and 16·9 months (14·0–24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47–0·79]; two-sided p

Zusammenfassung Die intrakutane Zungeninjektion von Maul- und Klauenseuche-Virus ist schmerzlos moglich, wenn eine Leitungsanaesthesie des Nervus lingualis und hypoglossus durch 10 ccm Tutocain stattfindet. Durch Injektion des Anaestheticums von der Mundhohle her ist die Wirkung in 96,4% (Zimmermann), von der Kehlganggegend her in 90% (Garbe) der Falle schnell zu erzielen. Summary The use of conduction anesthesia of the tongue nerves in artificial foot-and-mouth virus infection in cattle It is possible to inject foot-and-mouth virus intracutaneously into the tongue without causing pain, if a preparatory conduction anesthesia of the nervus lingualis and hypoglossus is made, using 10 cc Tutocain. Injected through the mouth the anethetic takes quick effect in 96,4% of the cases (Zimmermann), injected from the outside of the throat the anethetic was effective in 90% (Garbe). Resume Emploi de l'anesthesie sur le trajet des nerfs de la langue pour l'inoculation artificielle du virus de la fievre aphteuse a des bovins L'inoculation dans la muqueuse de la langue du virus de la fievre aphteuse est possible sans douleur, grâe a une anesthesie locale sur le trajet du nerf lingual et du nerf hypoglosse avec 10 cm3 de tutocaine. L'anesthesie peut etre obtenue rapidement dans 96,4% des cas en faisant l'injection a partir de la cavite buccale (Zimmermann), et dans 90% des cas a partir de la region de l'auge (Garbe). Resumen La aplicacion de la anestesia de conduccion de los nervios linguales en la infeccion artificial de los bovidos con el virus de la glosopeda La infeccion lingual intracutanea del virus de la fiebre aftosa se puede realizar sin provocar dolor cuando se efectua una anestesia previa de conduccion de los nervios lingual e hipogloso con 10 c. c. de tutocaina. La accion se alcanza rapidamente mediante la inyeccion del anestesico desde la cavidad bucal en el 96,4% (Zimmermann), desde el conducto laringeo en el 90% (Garbe) de los casos.

Zusammenfassung Eine monovalente Lebendvakzine (Typ A4) gegen die Maul- und Klauenseuche ist auf ihre Unschadlichkeit und Wirksamkeit beim Rind gepruft worden. Die Lebendvakzine wurde aus Virus der 418.—422. und 542. sowie 558. Passage in Kalbernierenkulturen hergestellt. Die Lebendvakzine war vom klinischen Gesiditspunkt aus nach intramuskularer Impfung fur deutsche und danische Rinder unschadlich. Das Impfvirus hatte die Fahigkeit, sich in Haut und Schleimhauten zu vermehren, weit-gehend verloren. Es wurde von den vakzinierten Tieren mit dem Speichel, dem Harn und der Milch mehrere Tage lang ausgeschieden. Das ausgeschiedene Virus war aber nicht mehr in der Lage, per Kontakt ungeimpfte Rinder und Schweine krankzumachen. Die Kontagiositat des Impfvirus scheint durch weitere Passagen in Kalbernierenkulturen abzunehmen. Eine Reaktivierung des Impfvirus durch mehrere direkte Rind-Rind-Passagen trat nicht ein. Die Lebendvakzine besas eine ausgezeichnete Wirksamkeit. Die erzielte Immunitat war so stark, das sie die Impflinge nicht nur gegen eine Infektion mit dem homologen Naturvirus, sondern auch gegen eine Infektion mit den heterologen Varianten A1, A2, A3, A5 und A7 schutzte. Das Virus der 558. Kulturpassage zeigte gegenuber dem der 419. Kultur-passage keine Verminderung der immunisierenden Eigenschaften. Summary The safety and effectiveness of a monovalent live Foot-and-Mouth disease vaccine Type A in the Ox A monovalent live vaccine (Type A4) against Foot-and-Mouth disease was prepared from virus after 418–422, 542 and 558 passages in calf kidney cultures. Vaccine produced no clinical symptoms when inoculated intramuscularly into German and Danish cattle. The virus had almost entirely lost its ability to multiply in the skin and mucous membranes. Although the virus was excreted for several days by vaccinated animals in the saliva, urine and milk, it was no longer able to produce disease in uninoculated incontact cattle and pigs. The contagiousness of the virus seemed to decrease with further passages in calf kidney culture. Repeated passage from bovine to bovine did not produce any reactivation of the virus. The vaccine showed a remarkably high degree of effectiveness in that the immunity it provoked was sufficient to protect not only against the homologous strain but also against the heterologous variants A1, A2, A3, A5 and A7. The virus of the 558th passage was no less effective in immunising than that of the 419th. Resume Inocuite et efficacite d'un vaccin monovalent contre la fievre aphteuse (Vaccin vivant type A chez le boeuf) Un vaccin vivant monovalent (type A4) contre la fievre aphteuse a ete eprouve du point de vue de l'inocuite et de l'efficacite chez le boeuf. Le vaccin vivant fut obtenu apres 412 a 422, 542 et 558 passages dans des cultures de tissu renal de veau. Le vaccin vivant se montra cliniquement inoffensif apres injection intramusculaire. Le virus avait presque totalement perdu la propriete de se multiplier dans la peau et les muqueuses. Il fut elimine par les animaux vaccines pendant plusieurs jours dans la salive, l'urine et le lait. Le virus elimine n'etait plus en mesure de provoquer la maladie par contact chez des bovins ou des porcs non vaccines. La contagiosite du virus vaccinal semble diminuer si l'on augmente le nombre des passages dans les cultures de tissu renal de veau. Plusieurs passages directs de boeuf a boeuf ne provoquerent aucune reactivation du virus. Le vaccin vivant fit preuve d'une efficacite remarquable. L'immunite acquise etait si forte qu'elle protegeait les animaux vaccines non seulement contre le virus naturel homologue, mais aussi contre les variantes heterologues A1, A2, A3, A5 et A7. Le virus obtenu apres 558 passages en culture ne montra aucune diminution des proprietes immunisantes par rapport au 419e passages. Resumen Innocuidad y actividad de una vacuna monovalente viva contra la glosopeda, tipo A, en el ganado vacuno Se ha estudiado una vacuna monovalente (tipo A4) viva contra la fiebre aftosa en cuanto a su innocuidad y actividad en los bovinos. La vacuna viva se prepare utilizando mutantes de virus de los pases 418–422 y de los 542 y 558 en cultivos renales de ternera. Desde el punto de vista clinico, la vacuna viva es apatogena para bovidos tras inoculacion intramuscular. El virus de inoculacion habia perdido en gran parte la facultad de multiplicarse en piel y mucosas. Era excretado por los animales vacunados con la saliva, la orina y leche a lo largo de varios dias. Pero el virus eliminado ya no era capaz de hacer enfermar, por contacto, a vacas y cerdos no vacunados. La contagiosidad del virus de inoculacion parece decrecer por medio de nuevos pases en cultivos renales de ternera. No se produjo el reactivamiento del virus de inoculacion mediante varios pases directos vaca — vaca. La vacuna viva poseia una actividad excelente. La inmunidad conseguida era tan marcada que no solo protegia a los animales vacunados frente a una infeccion con el virus natural homologo, sino tambien frente a una infeccion con las variantes heterologas A1, A2, A3, A5 y A7. El virus del pase cultural numero 558 no presentaba disminucion alguna de sus propiedades inmunizantes frente al del pase cultural numero 419.

The POLAR Investigation of the Sun (POLARIS) mission uses a combination of a gravity assist and solar sail propulsion to place a spacecraft in a 0.48 AU circular orbit around the Sun with an inclination of 75 degrees with respect to solar equator. This challenging orbit is made possible by the challenging development of solar sail propulsion. This first extended view of the high-latitude regions of the Sun will enable crucial observations not possible from the ecliptic viewpoint or from Solar Orbiter. While Solar Orbiter would give the first glimpse of the high latitude magnetic field and flows to probe the solar dynamo, it does not have sufficient viewing of the polar regions to achieve POLARIS' primary objective : determining the relation between the magnetism and dynamics of the Sun's polar regions and the solar cycle., 23 pages, 14 figures, 4 tables, Accepted by Experimental Astronomy

A dual 6.8-10.7-GHz receive/transmit module with synthesized local oscillators (LOs) has been developed. The use of 72 MMICs (monolithic microwave integrated circuits) allows this complex module to be implemented in a small, lightweight package suitable for use in airborne systems. This module is combined with receive and transmit block converter modules to build a 2-18-GHz electronic warfare (EW) system. Use of a synthesized first LO along with a LO cancellation scheme provides excellent frequency stability and low phase noise. >

the end of the case. We dissect the peritoneum over the sacral promontory to expose the anterior longitudinal ligament. The rectovaginal space is developed and the bladder is dissected off the vagina. The Y-shaped polypropylene mesh is prepared by rolling and suturing the sacral extension to keep it out of the way during vaginal suturing and placing a hole in the posterior arm of the mesh to fit over the transcervical cannula. It is inserted through the transcervical cannula and secured to the anterior and posterior vaginal wall with permanent sutures, using extracorporeal knot tying. Needles are introduced and removed through the transcervical cannula. We then suture the sacral extension to the anterior longitudinal ligament. A barbed delayed absorbable suture is then used to close the peritoneum, and the 0-Vicryl suture that was placed transvaginally as a cerclage is tied down when the transcervical cannula is removed. Conclusion: We describe our streamlined laparoscopic approach using 5 mm skin incisions and transcervical morcellation for advanced uterine prolapse. DISCLOSURE OF RELEVANT FINANCIAL RELATIONSHIPS

Detailed comparisons have been completed between the MF radars (MFR) in the Canadian prairies and three other systems: two ground-based Fabry-Perot interferometers (FPI) and the UARS high resolution Doppler imager (HRDI) system. The radars were at Sylvan Lake (52°N, 114°W), Robsart (49°N, 109°W) and the main continuing facility is at Saskatoon (52°N, 107°W). Statistical comparisons of hourly mean winds (1988-1992) for the Saskatoon MFR and FPI (557.7 nm green line) using scatter plots, wind speed-ratios, and direction-difference histograms show excellent agreement for Saskatoon. No serious biases in speeds or directions occur at the height of best agreement, 98 km. If anything, the MFR speeds appear bigger. The same applies to the Sylvan Lake MFR and Calgary FPI, where the best height is 88 km. In both cases these are close to the preferred heights for the emission layers. Differences between measurements seen on individual days are likely related to the influence of gravity waves (GW) upon the optical and radar systems, each of which have inherent spatial averaging (350, 50 km respectively), as well as the spatial difference between the nominal measurement locations. For HRDI, similar statistical comparisons are made, using single-overpass satellite winds and hourly means (to improve data quality) from MFR. Heights of best agreement, based upon direction-difference histograms, are shown; there is a tendency, beginning near 87 km, for these MFR heights to be 2 or 3 km greater than the HRDI heights. Speeds at these heights are typically larger for the satellite (MFR/HRDI = 0.7–0.8). Reasons for the differences are investigated. It is shown that the estimated errors and short-term (90 min) differences are larger for HRDI than for the MFR, indicating more noise or GW contamination. This leads to modest but significant differences in median speed-ratio (MFR/HRDI < 1). Also, comparison of the two systems is made under conditions when they agree best and when they show large disagreement. For the latter cases both systems show higher relative errors, and the HRDI vectors are frequently small. It is suggested that spatial or temporal GW wind fluctuations are the likely cause of the larger HRDI-MFR disagreement when wind speeds are small. No satisfactory explanation exists for the overall discrepancy in speeds between the MFR and HRDI.

Introduction In many work environments with sensitive and complex technologies, human error due to the unfortunate events is very important. So it is necessary to recognise and find root causes of human errors to prevent and limit the consequences of them. This study aimed to identify operator9s human error in one of the sensitive units of oil refinery. Methods This study was taken to identify, assess and control human errors in Tar unit of Isfahan oil refinery. Data collected using by task observation and interviewing with safety authorities, unit and shift supervisors and operators to hierarchical task analysis (HTA) and human error identification by SHERPA technique. Results With analyses SHERPA work sheets, 198 human errors were identified respectively 134(67.64%) action errors, 23(11.61%) checking errors, 11(5.6%) communication errors, 24 (12.12%) retrieval error and 6(3.03) selection errors. ‘Performance monitoring’ and ‘communication’ Critical tasks was the main tasks of control room operators. 64% of human error in the control room operators of the occurrence probability of ‘low’ and 36% probability of occurrence of ‘moderate’ were estimated. Also, 59% of the identified errors of control room operators have no required recovery but only 29% of their outcomes were sensitive. Conclusions The results showed SHERPA technique can be used serve as an effective technique to detect human errors in oil refineries and petrochemical.

Nach Gelenkverletzungen mit ihren moglichen Folgeschaden gilt es, die Funktionseinheit von Muskeln, Ligamenten und Gelenkstrukturen umfassend wieder herzustellen. In der kybernetischen Kette nimmt die Muskulatur sowohl als Sensor mit ihren vielen Rezeptoren wie auch als Haupteffektor die wichtigste Stelle ein [7]. Schon bei der operativen Rekonstruktion empfiehlt es sich, durch minimalste Zugange nur mit der eben erforderlichen Zusatztraumatisierung auszukommen, um nicht zusatzlich sog. Mechanorezeptoren und dadurch intakte Regelkreise zu zerstoren.

1) Untersucht wurde der Einflus von Saure und Lauge auf die Entwicklung der fruhen Wundreaktionen an der intakten und der mechanisch verletzten Meerschweinchenhaut. Die zellularen und fermenthistochemischen Reaktionen zeigten hierbei ein unterschiedliches Verhalten: Die Gewebsleukozytose nach mechanischer Hautverletzung wird durch chemische Einflusse weniger behindert als die reaktive Aktivitatssteigerung der Enzyme im Wundrand, welche sich durch Saure starker und durch Lauge weniger beeintrachtigt zeigte. Aktivitatsveranderungen strukturgebundener Enzyme waren nach alleiniger Saure- und Laugenwirkung in der Haut nicht nachzuweisen, sondern praktisch nur nach mechanischen Verletzungen. Die zellulare Reaktion entwickelt sich am Rande der Laugen-Nekrose starker verdichtet, bei der Saure-Nekrose breiter und mehr diffus. Charakteristische Kernveranderungen fanden sich bei der Laugenwirkung starker ausgepragt. 2) An der mechanisch unverletzten Haut fanden sich nach Saureeinwirkung signifikante Histaminuberschusse, wahrend die Serotoninfreisetzung deutlich abgeschwacht war. In der Schnitt-Saure-Gruppe ergab sich eine Verminderung des Histamingehaltes und eine signifikante Zunahme des Serotonins. Das Verhalten der sog. freien Gewebshormone nach Einwirkung chemischer Mittel auf die Meerschweinchenhaut ist zum Teil gegenlaufig. 3) Bei postmortaler Schnittverletzung und anschliesender Veratzung fand sich ein deutlicher Histaminanstieg im Wundgebiet. Bekanntlich gilt der Uberschus an freiem Histamin gegenuber der unverletzten Vergleichshaut als Vitalreaktion. Da es auch postmortal durch chemische Einflusse zu einer Entspeicherung der Mastzellen und damit zur Freisetzung von Histamin kommen kann, ist bei Hautveratzungen eine vorsichtigere Interpretation angebracht.

Even when the extraction method of Fazekas for the determination of the so-called free histamine and serotonin is used, different dorsal skin areas of laboratory animals show certain differences in the amine content, which reach higher values for histamine than for 5-HT. 1) Related to the animal collective, no differences in the mean values of the 5-HT and histamine content between the right and left side of damaged dorsal skin of guinea pigs resulted, although in single cases remarkable differences (up to 1.26 microgram/g) were found. Descending from nuchal to caudal a decrease of the amine content--less in case of 5-HT, more in case of histamine--is noticed. The observed topical differences possibly depend on the continous moulting of the animals. 2) From these analytical data a method for statistical prediction is derived, which allows to state, when and with which probability a single difference value exceeds the normal variance. Applied to the comparative measurements wounded skin/control skin it is thus made possible to test the validity of the findings obtained in practical cases. 3) Postmortal changes of the amine content of the wounded as well as the normal skin are not detectable for the 5-HT, while in the case of histamine solely the values of the damaged skin first show a decrease (24 h p.m.), followed by an increase (48 h p.m., bacterial neogenesis?).

Es wird uber tierexperimentelle Untersuchungen berichtet, die sich unter Einbeziehung histologischer, enzymhistochemischer und biochemischer Methoden mit den fruhen Reparationsvorgangen nach Leberschnittverletzungen beschaftigen. Die reaktiven Veranderungen auf zellularer und histochemischer Ebene zeigen gegenuber den an Hautverletzungen bekannten Verlaufen z. T. erhebliche Unterschiede: 1. Die Gewebsleukozytose war fur die Bestimmung des Wundalters weniger geeignet, da die fruhzeitig nachweisbare leukozytare Reaktion sich im weiteren Verlauf nur unwesentlich anderte. Bei den kurzen Uberlebenszeiten zeigten die Leberepithelien in der Umgebung der Schnittverletzung Hypoxidosezeichen und Glykogenverlust. Andere histomorphologische Veranderungen traten erst nach 24 h auf, so die Proliferation von organspezifischen und mesenchymalen Zellen. 2. Die mit histochemischen Methoden nachweisbaren Aktivitatsveranderungen der Enzyme im Verletzungsbereich lieferten insbesondere fur die fruhe Wundphase wichtige diagnostische Parameter. 3. In den ersten 12 h fand sich eine deutliche Zunahme des Histamingehaltes im Wundgebiet, der Serotoninspiegel zeigte ein gegenlaufiges Verhalten. 4. Wir empfehlen daher, zur Schatzung des Wundalters bei Leberverletzungen enzymhistochemische Methoden mit einzubeziehen.

Untersucht wurde der Einflus von Blutverlust und Alkoholintoxikation auf die Wundreaktionen in der 1.–12. Stunde nach Schnittverletzung in der Ruckenhaut des Meerschweinchens. Als wichtigstes Ergebnis fand sich ein unterschiedliches Verhalten der zellularen und der ferment-histochemischen Reaktion: Wahrend Beginn und zeitliche Progredienz der Wundleukozytose nicht beeinflust wurden, fand sich die parallel verlaufende Aktivierung verschiedener strukturgebundener Enzyme signifikant verzogert und abgeschwacht. Angesichts der hamatogenen Abkunft der Infiltratzellen spricht der erstere Befund fur die Vermutung, das die lokalreflektorische Hyperaemie des Wundgebiets in der Hierarchie der biologischen Regelkreise gegenuber der kollapsgesteuerten dermalen Vasokonstriktion, jedenfalls beim Meerschweinchen, eine gesicherte Praeferenz geniest. Bei der Entblutungsreihe wurde eine Verzogerung der Freisetzung von Histamin und Serotonin festgestellt. Die Prasenzminderung der lokalen Mediatoren der Grundsubstanzentmischung wird als Ursache einer verschlechterten Ausgangslage fur Enzymaktivierungen im mesenchymalen Bereich angesehen.

Der Einflus von Schlafmitteln (Barbital und Carbromal) auf die rechtsmedizinisch gangigen Methoden der Wundaltersbestimmung wurde im Tierexperiment uberpruft. 1) Die zellularen Reaktionen im Wundgebiet (Ruckenschnittverletzung am Meerschweinchen) werden durch mittelschwere Schlafmittelintoxikationen gehemmt. Die histomorphologischen Wundreaktionen sind unter Carbromal etwa doppelt so stark wie unter Barbital beeintrachtigt. 2) Fermenthistochemisch fand sich durchgangig eine masige Verzogerung der Aktivitatssteigerungen bei Barbitalvergiftung, eine starkere Reaktionsminderung unter Carbromaleinflus. 3) Nach Barbitalvergiftungen traten signifikante Erhohungen des Histamin-bzw. Serotoningehaltes im Wundgebiet nicht mehr auf. Unter Carbromaleinflus fand sich ebenfalls kein erhohter Histamingehalt, aber ein gegenuber der Kontrollgruppe vermehrter Serotoningehalt im Wundrand. Die zellularen Reaktionen sind danach unter vitalitatsmindernden Einflussen wohl als zuverlassigster Indikator der Wundaltersbestimmung anzusehen; auch sie durften jedoch durch klinisch behandlungsbedurftige Schlafmittelintoxikationen erheblich beeintrachtigt werden. Mogliche pathophysiologische Zusammenhange der Alteration morphologischer und biochemischer Wundreaktionen mit dem Schockgeschehen im allgemeinen werden diskutiert.

1. The effect of endotoxin (1μg/kg i.v.) on the phagocytic activity of the reticulo-endothelial system (carbon-clearance test) has been studied in mice. There were two peaks of stimulation, 3 and 24 h after application. A high weight of the spleen was only seen at the second peak. 2. Following cyclophosphamide (300 mg/kg i.V.), an initial increase in phagocytic activity (12 h) gave way to a subsequent long-lasting suppression, accompanied by a marked weight loss of the spleen. 3. In mice treated with cyclophosphamide the phagocytic activity could be stimulated by endotoxin, but not to a degree achieved by endotoxin in untreated animals. Reduction of spleen weight by cyclophosphamide could not be reversed by endotoxin. 4. Polyvinylpyridin-N-oxide (100 mg/kg i.v.)-an antisilicotic agent-stimulated phagocytic activity. This effect was transitory and disappeared within 8 days. We therefore assume that the long-lasting antisilicotic action cannot be mediated by elevated phagocytosis. 5. Injection of polyvinylpyridin-N-oxide did not protect animals from the cytotoxic action of cyclophosphamide.

Die Art der Kinine, die in menschlichem Plasma durch Pankreaskallikrein entsteht, wurde mit einem biologischen Verfahren und chromatographisch untersucht. Um eine Inaktivierung der gebildeten Kinine und des zugesetzten Pankreaskallikrein zu verhindern, wurde das Plasma mit Saure vorbehandelt und mit Phenanthrolin versetzt.

Die Entstehung von Plasmakininen in menschlichem Plasma wurde unter verschiedenen Bedingungen studiert. Nach erschopfender Kininentwicklung mit Pankreaskallikrein kann durch Glaskontakt noch weiteres Kinin freigelegt werden und umgekehrt. Demnach sind zwei verschiedene Kininogene (I und II) vorhanden, die jeweils nur von Pankreaskallikrein bzw. dem durch Glaskontakt aktivierten Ferment (Kininogenase II) utilisiert werden. Kininogenase II ist nicht identisch mit Serumkallikrein. Serumkallikrein (Kininogenase I) ist aber in menschlichem Plasma ebenfalls enthalten. Es wird wahrend der Glasbehandlung von Plasma inaktiviert. In aktiver Form liegt es in saurebehandeltem Plasma vor. Es wirkt auf das auch von Pankreaskallikrein benutzte Substrat Kininogen I ein, moglicherweise auch auserdem auf Kininogen II, das sonst von Kininogenase II umgesetzt wird. Es wird gefolgert, das im menschlichen Plasma zwei verschiedene kininbildende Systeme existieren, die — in unterschiedlicher Verteilung — auch in tierischen Plasmen vorkommen. Hundeplasma enthalt Kininogen I und Kininogenase I, ihm fehlt das System II. Umgekehrt enthalt Rattenplasma das System II, aber offenbar kein Kininogen I.

Im Tierversuch (Meerschweinchen) und an menschlichem Sektions-material wurden der Histamingehalt und die Aktivitat der Histidindecarboxylase in Hautverletzungen verschiedenen Alters zwischen 2 min und 48 Std untersucht. Im Tierversuch fanden sich periodische Zunahmen des freien Gewebshistamins und der extrahierbaren HDC mit Maxima um die 1.–2. und die 24.–48. Std sowohl im Wundrand als auch in entfernten Hautarealen mit korrespondierender Tendenz der Ausgangswerte.

1. Sensitized guinea pigs were protected with antihistamine and slowly injected (within 3 min) with antigen. 50% of the animals survived. After rapid injection of the same antigen dose (≙ 20 mg/kg ovalbumin) all animals died. 2. The lung histamine content was decreased to about half of the normal value in animals which died during the treatment as well as in surviving guinea pigs. 1 week later the lung histamine content was again within the normal range. 3. During this period an additional anaphylactic shock resulted only in a small reduction of the overall lethality (about 20%). Although no antihistamine had been given the animals died significantly later. Plasma histamine levels were depressed, sometimes to about 1/10 of the values found normally in anaphylactic shock. The lung histamine content did increase from 2 to 5 μg per g tissue. All parameters measured were normal 1 week after the antigen infusion. 4. During the same period of time the lethality of an anaphylatoxin shock was not reduced. Plasma histamine levels were diminished whereas the histamine content of the lungs did increase. As compared to an anaphylatoxin shock in unpretreated animals not exposed to antigen plasma histamine levels were in the normal range after 1 day. At this moment lung histamine content was still reduced by the antigen pretreatment. 5. We assume that the guinea pig lung contains two different histamine pools, one having a short half-life (less 1 day) and being depleted in anaphylatoxin shock, the other recovering more slowly (within 1 week), and being released in addition in anaphylaxis. The first one corresponds well with the properties of the non-mastcell-store described by Brodie et al. (1966), the latter seems to be identical with the typical mastcell-pool.

1. The phagocytic activity of the reticulo-endothelial system in mice (carbon-clearance test) is depressed after intravenous injection of Cu-chlorophyllin. Both extent and duration of this reduction are dose-dependent and followed by a stimulation. The weights of liver and spleen are unchanged. 2. Cu-chlorophyllin depresses the endotoxin (1 μg/kg i.v.) stimulated RES too. The first peak 3 h after endotoxin application is more affected by Cu-chlorophyllin than the second one, which is accompanied by an increased weight of the spleen. 3. The carbon-suspension itself, which is used during the carbon-clearance test, stimulates the phagocytic activity from 8 h until 8 days. It increases the weight of the liver and spleen. 4. From these results it is concluded that the reduction in phagocytic activity is due to a specific direct action of Cu-chlorophyllin on the phagocyting cells.

Alcohol--orally given in concentrations from 1 to 4 g/kg body-weight--leads to a reduction of mast cells in the guinea pig lung. At the same time a minor decrease of histamine concentration was observed. The incompatibility reaction with alcohol after disulfiram intake (DAR) shows an additional degranulation oft mast cells of the lungs and decrease of histamine-content. So far, there seems little difference between the influence of disulfiram alone and the DAR. Besides thrombocytes and basophile leucocytes, the mast cells of the lung are responsible for the release of histamine and serotonine during higher alcohol concentrations and alcohol-disulfiram-reactions. We think that the intolerance phenomena of humans after alcohol--f.e. in form of flush-reaction--is at least partly related to the concomitant influence oft mast cell-substances.

Even when the extraction method of Fazekas for the determination of the so-called free histamine and serotonin is used, different dorsal skin areas of laboratory animals show certain differences in the amine content, which reach higher values for histamine than for 5-HT. 1) Related to the animal collective, no differences in the mean values of the 5-HT and histamine content between the right and left side of damaged dorsal skin of guinea pigs resulted, although in single cases remarkable differences (up to 1.26 microgram/g) were found. Descending from nuchal to caudal a decrease of the amine content--less in case of 5-HT, more in case of histamine--is noticed. The observed topical differences possibly depend on the continous moulting of the animals. 2) From these analytical data a method for statistical prediction is derived, which allows to state, when and with which probability a single difference value exceeds the normal variance. Applied to the comparative measurements wounded skin/control skin it is thus made possible to test the validity of the findings obtained in practical cases. 3) Postmortal changes of the amine content of the wounded as well as the normal skin are not detectable for the 5-HT, while in the case of histamine solely the values of the damaged skin first show a decrease (24 h p.m.), followed by an increase (48 h p.m., bacterial neogenesis?).

The influence of loss of blood and alcohol intoxication on wound reactions in the first 12 hours after incisions into the skin of the back of guinea pigs was examined. As the most important result we found differences in the cellular and zymohistochemical reactions: while begin and progression of the dermal leucocytosis were not influenced, the parallel running activation of different structure bound enzymes was significantly delayed and decreased. Considering the first result and the haematogenous origin of the leucocytes there is reason to believe that in the hierarchy of the biological control circuit-at least in guinea pigs-the local reflex hyperaemia of the wound area certainly is primary to the dermal vasoconstriction during collapse. The animals with haemorrhagic shock showed a retardation in the liberation of histamine and serotonin. This decrease of the local mediators of the stromae dissociation is considered the reason of the impaired initial enzyme activities in the mesenchymal tissue.

Trotz Beachtung der athiologischen Moglichkeiten [9], die zu chronisch rezidivierenden Schmerzen der Lenden-Beckenregion fuhren konnen und der daraus hergeleiteten Diagnostik einschlieslich kleinem Labor und bildgebender Verfahren verbleibt die grose Anzahl von Patienten, bei denen sich lediglich muskulare Dysbalancen meist antagonistischer Muskelgruppen und Storungen des motorischen Stereotyps finden.

1) The influence of acids and bases on the development of the early wound reactions in the intact and the mechanically injured skin of guinea pigs was investigated. The cellular and the enzymohistochemical reactions showed to be different: the tissue leucocytosis after mechanical trauma is less restrained by chemical effects than the reactive increase of enzymic activity in the border of wounds, which proved to be affected by acids more than by bases. Changes in activity of structure bound enzymes could not be demonstrated in the skin after mere action of acids and bases, but only after mechanical trauma. The cellular reaction is in the border of the base necrosis more compact, in case of the acid necrosis broader and more diffuse. Characteristic changes in the nucleus were preferentially found after basic reaction. 2) In the mechanically unhurt skin a significant excess of histamine was found after the action of acids, while the liberation of serotonin was distinctly decreased. After incision and addition of acid the histamine level was decreased and the serotonin concentration significantly increased. After exposition of guinea pig skin to chemicals, the concentrations of the so-called tissue hormones showed a contrary course. 3) After postmortal incision and following cauterization a distinct increase of histamine was found in the wound area. Generally the excess of free histamine in comparison to the unhurt skin is considered to be a vital reaction. But because degranulation of mast cells and liberation of histamine can also be caused by chemical influence in the postmortal period, a critical interpretation in cases of skin exposition to acids or bases is necessary.

Estimation of the age of skeletal remains is usually based on subjective evaluation of the morphological grade of decomposition. This assumes, that the investigator is provided with pertinent experience. Experimentally elaborated physical and chemical methods proposed for objectification of the statements did not yet assest until today due to lacking temporal correlation. Our investigations were stimulated by observations on fossil bones indicating that the collagenbound amino acids diminish very slowly dependent on geological age. Samples of 53 skeletons of five to 2500 years were pulverized and subjected to acid hydrolysis. The amino acids released from bone collagen were separated by means of thin-layer chromatography and detected by isatin and ninhydrin reagents. The dye complexes of alanine, hydroxyproline, proline, tyrosine, and valine were measured densitometrically and quantified through calibration curves. We established, that the concentrations of the amino acids exhibited a time dependent reduction as equivalent of a loss collagen. The temporal correlation is very narrow (r less than -- 0,8) and sufficient for datings within plus/minus ten years of the more recent bones. Environmental conditions during post-mortem decay seem to have little influence on this process.

Orale Verabreichung von Alkohol in einer Dosierung von 1 bis 4 g/kg fuhrt beim Meerschweinchen zu einer dosisabhangigen Reduktion der Mastzellzahl in der Lunge; gleichzeitig kommt es zu einer Abnahme des Lungenhistamingehaltes. Die nach Disulfiram-Vorbereitung durch Alkohol ausgeloste Unvertraglichkeitsreaktion (DAR) fuhrt zu einer zusatzlichen Entspeicherung von Lungenmastzellen und Verminderung des Histaminspiegels in der Lunge. Die Unterschiede zwischen den Auswirkungen von Disulfiram allein und der DAR sind nicht so eindeutig. Als Quelle der Histamin- und Serotonin-Liberation unter dem Einflus hoherer Alkoholdosen und im Verlauf der DAR kommt danach neben Thrombozyten und Blut-Basophilen besonders auch der Mastzellspeicher des Lungengewebes infrage. Wir halten es fur nicht unwahrscheinlich, das auch beim Menschen Intoleranzerscheinungen nach Alkoholgenus, die ja auch auserhalb der DAR vielfach mit flushartigen Symptomen verbunden sind, wenigstens teilweise auf die Mitwirkung mastocytogener Mediatoren zuruckgehen.

The influence of hypnotics (barbital and carbromal) on the development of the early wound reactions in mechanically injured skin of guinea pigs was investigated: 1) The cellular reactions in incised wounds were retarded after moderate intoxication by hypnotics (300 mg/kg barbital; 3 g/kg carbromal). The histomorphological changes in wounds were inhibited by carbromal twice as much as by barbital. The hitherto published investigations had not shown any retardation of the early cellular inflammation by weakening influences such as loss of blood or alcohol without symptoms of shock (Berg et al., 1977) or local disturbances by acids and bases (Kampmann et al., 1978). 2). A moderate delay of the activity of structure bound enzymes was found in barbital intoxication, a stronger restriction under the influence of carbromal. 3) After barbital intoxication significant elevation of histamine or serotonin in wounds was not seen. Under the influence of carbromal there was also no increase of histamine but an increase of serotonin. Thus, although the cellular reactions seem to be the most reliable indicator among the methods for the determinations of wound age under devitalizing influences, their value is reduced in cases of intoxications by hypnotics needing treatment. Possible pathophysiological connections of the alterations of morphological and biochemical wound reaction with shock are discussed.

Prevention of and compensation for muscular weaknesses in postural disorders and physical disability are priority tasks of physiotherapy. A range of typical exercises are therefore being used to strengthen weakened groups of muscles, some of them traditionally already included in school sports. Most therapy concepts primarily focus on muscle strengthening, without taking into consideration that it is crucial to redress muscular imbalances by stretching contracted muscle groups as well. Based on this experience, the effectiveness of several specifically modified exercises was tested, derived from the usual range of physiotherapy activities in strengthening very commonly weakened muscle groups, i.e. the abdominal, gluteal, sacrospinalis and shoulder-blade affixing musculature. To increase exercise effectiveness, training machines were used in addition. Stretching exercises were carried out initially, in terms of passive stretching with isometric pre-tension. The following muscle groups were stretched: rectus femoris m., iliopsoas m., pectoralis m., and lumbar sacrospinalis m. Altogether, 64 patients between age 16 and 27 were examined following training therapy, 58 patients presented pure postural disorders, 6 had slight cerebral movement disorders. Two almost equal study groups were formed, one (31 patients) receiving only gymnastic exercises, the other (33 patients) using training machines. The muscular situation was tested after 6 months by means of Janda's semiquantitative muscle-testing. For further objective assessment of therapy outcome, Neugebauer's 'back-index' was determined. Muscular harmony and spinal balance were found to have significantly improved in the second group who had used the training machines. A slight reduction of muscle spasticity in addition was found in the patients with cerebral movement disorders.

The early phase of wound repair after liver incisions was investigated by histological, enzyme-histochemical, and biochemical methods in guinea pigs. There are considerable differences in cellular and histochemical reactions in comparison to incisions of the skin: 1. The rapid leukocytic reaction showed little change during the observation interval (48 h). In short survival times epithelial cells show signs of hypoxidosis and loss of glycogen at the edge of an incision. Proliferation of organ-specific and mesenchymal cells was observed after more than 24 h. 2. Alterations of the investigated enzymes in the traumatic area are important diagnostic parameters in the early stages of wound healing. 3. In the early 12 h after injury distinct increase of histamine was observed, while serotonin was noticed to decrease. 4. Therefore, the determination of wound age in the early wound reactions after injuries of the liver should include enzymehistochemical methods.

1. Kininogen and protein concentrations were determined in plasma of guinea pigs before and during anaphylactic shock. 2. There was no correlation between kininogen and plasma protein in untreated animals (r=0.17; n=42). 3. The alterations in kininogen and total protein were strongly correlated in acute and in protracted shock. 4. Even 1.5 and 5 min after challenge, a consumption of kininogen could not be demonstrated.