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The field of G protein-coupled receptor (GPCR) research has greatly benefited from the spatiotemporal resolution provided by light controllable, i.e., photoswitchable ligands. Most of the developed tools have targeted the Rhodopsin-like family (Class A), the largest family of GPCRs. However, to date, all such Class A photoswitchable ligands were designed to act at the orthosteric binding site of these receptors. Herein, we report the development of the first photoswitchable allosteric modulators of Class A GPCRs, designed to target the M 1 muscarinic acetylcholine receptor. The presented benzyl quinolone carboxylic acid (BQCA) derivatives, Photo-BQCisA and Photo-BQCtrAns, exhibit complementary photopharmacological behavior and allow reversible control of the receptor using light as an external stimulus. This makes them valuable tools to further investigate M 1 receptor signaling and a proof of concept for photoswitchable allosteric modulators at Class A receptors., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The direct analysis of molecules contained within human breath has had significant implications for clinical and diagnostic applications in recent decades. However, attempts to compare one study to another or to reproduce previous work are hampered by: variability between sampling methodologies, human phenotypic variability, complex interactions between compounds within breath, and confounding signals from comorbidities. Towards this end, we have endeavored to create an averaged healthy human 'profile' against which follow-on studies might be compared. Through the use of direct secondary electrospray ionization combined with a high-resolution mass spectrometry and in-house bioinformatics pipeline, we seek to curate an average healthy human profile for breath and use this model to distinguish differences inter- and intra-day for human volunteers. Breath samples were significantly different in PERMANOVA analysis and ANOSIM analysis based on Time of Day, Participant ID, Date of Sample, Sex of Participant, and Age of Participant ( p < 0.001). Optimal binning analysis identify strong associations between specific features and variables. These include 227 breath features identified as unique identifiers for 28 of the 31 participants. Four signals were identified to be strongly associated with female participants and one with male participants. A total of 37 signals were identified to be strongly associated with the time-of-day samples were taken. Threshold indicator taxa analysis indicated a shift in significant breath features across the age gradient of participants with peak disruption of breath metabolites occurring at around age 32. Forty-eight features were identified after filtering from which a healthy human breath profile for all participants was created., (Creative Commons Attribution license.)

It is well known that the orthotropic tissue structure decisively influences the mechanical and electrical properties of the heart. Numerous approaches to compute the orthotropic tissue structure in computational heart models have been developed in the past decades. In this study, we investigate to what extent different Laplace-Dirichlet-Rule-Based-Methods (LDRBMs) influence the local orthotropic tissue structure and thus the electromechanical behaviour of the subsequent cardiac simulation. In detail, we are utilising three Laplace-Dirichlet-Rule-Based-Methods and compare: (i) the local myofibre orientation; (ii) important global characteristics (ejection fraction, peak pressure, apex shortening, myocardial volume reduction, fractional wall thickening); (iii) local characteristics (active fibre stress, fibre strain). We observe that the orthotropic tissue structures for the three LDRBMs show significant differences in the local myofibre orientation. The global characteristics myocardial volume reduction and peak pressure are rather insensitive to a change in local myofibre orientation, while the ejection fraction is moderately influenced by the different LDRBMs. Moreover, the apical shortening and fractional wall thickening exhibit a sensitive behaviour to a change in the local myofibre orientation. The highest sensitivity can be observed for the local characteristics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Interobserver agreement (IOA) is important for research and practice, and supports the consistency of behavioral data (Kahng et al., 2011). Although general parameters for how much IOA is needed have been suggested (Bailey & Burch, 2018), it is unknown if the total number of sessions with IOA might impact the IOA coefficient. In this study, IOA was reanalyzed using functional analysis data at various cutoffs. Obtained IOA from these analyses was then compared to the original IOA. Overall, results suggested that, at least when using highly trained observers in a structured clinical setting, there were no significant differences in IOA across cutoffs. However, IOA was sensitive to overall rate of responding in the functional analysis. These data are encouraging, particularly for practitioners, because they provide preliminary support that the amount of sessions with IOA may not be as important as the consistency of the data., (© 2021 Society for the Experimental Analysis of Behavior.)

Objectives: Immediate ischemic stroke treatment improves outcomes and early alteplase administration is recommended for patients within window. We implemented stroke guidelines through a neuro-resuscitation initiative (NRI) and hypothesized that the intervention would decrease times to assessment and treatment., Methods: We analyzed quality assurance data for EMS and triage patients arriving to our academic emergency department with suspected ischemic stroke to compare outcomes 12 months before to 6 months after initiative implementation at an academic certified primary stroke center in the U.S. Southwest. We examined four time-based outcomes: neurology at bedside, CT head without contrast, CT head angiogram, and alteplase administration. We summarized times with median and IQR values and compared pre and post times to event (in minutes) with Wilcoxon rank sum tests and Kaplan-Meier survival curves., Results: We identified 203 EMS (83 pre, 120 post) and 66 (11 pre, 55 post) triage Stroke Alert patients. We observed decreased times for all outcomes in both the EMS and triage samples; however, only those in the EMS sample were significant. In the EMS sample, neurology at bedside median times decreased from 20 min to 2 min (p < 0.001); median minutes to CT head without contrast decreased from 16 min to 9 min (p < 0.001); median minutes to CT head angiogram decreased from 71 min to 21 min (p = 0.007); and, median minutes to alteplase decreased from 72 min to 49.5 min (p = 0.04)., Conclusions: An academic ED led stroke care initiative streamlined evaluation and care with significantly shortened times to all four events., Competing Interests: Declaration of competing interest None of the authors report any conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC 50 values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives 1b and 1c as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of 1c might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment.

Introduction: Grand Canyon National Park has seen an increase in visitors traversing the canyon from rim to rim (R2R) in a single day. R2R hikers travel over 33.8 km (21 mi) over 3300 m (11,000 ft) of elevation change and endure large temperature changes. Grand Canyon emergency medical service providers provide emergency medical services to over 1100 visitors annually. Direct guidance by Preventive Search and Rescue rangers has improved safety. The objective of this study was to examine visitors attempting an R2R traverse and to enhance PSAR rangers' anticipatory guidance., Methods: We conducted an observational study of R2R hikers in the spring and fall of 2015. Hikers consented to study inclusion and were interviewed at the starting trailhead, canyon bottom, and exit trailhead. We performed a survey and collected biometric data., Results: We enrolled 617 visitors with a median age of 43 y (interquartile range [IQR] 33-53); 65% were male and 46% had hiked the R2R a median number of 3 times previously (IQR 2-7). Hydration strategies included water bottle only (20%), hydration bladder only (31%), and both water bottle and hydration bladder (48%). R2R crossers had an average start time of 0530 (SD 1.3 h) and median crossing time of 11.9 h (IQR 10.7-13.3). Crossing time and self-reported fatigue were negatively correlated with prior R2R experience (P=0.02)., Conclusions: Crossing R2R in a day is hazardous and associated with risk of injury and illness. The results of this study can be used by Preventive Search and Rescue to reduce these risks by educating hikers., (Copyright © 2018 Wilderness Medical Society. All rights reserved.)

Background: The recent conflicts in Iraq and Afghanistan have exposed thousands of service members to intense stress, and as a result, many have developed posttraumatic stress disorder (PTSD). The role of military deployment experiences and PTSD in coronary heart disease (CHD) is not well defined, especially in young US service members with recent combat exposure., Methods and Results: We conducted a prospective cohort study to investigate the relationships between wartime experiences, PTSD, and CHD. Current and former US military personnel from all service branches participating in the Millennium Cohort Study during 2001 to 2008 (n=60 025) were evaluated for newly self-reported CHD. Electronic medical record review for International Classification of Diseases, Ninth Revision, Clinical Modification codes for CHD was conducted among a subpopulation of active duty members (n=23 794). Logistic regression models examined the associations between combat experiences and PTSD with CHD with adjustment for established CHD risk factors. A total of 627 participants (1.0%) newly reported CHD over an average of 5.6 years of follow-up. Deployers with combat experiences had an increased odds of newly reporting CHD (odds ratio, 1.63; 95% confidence interval, 1.11-2.40) and having a diagnosis code for new-onset CHD (odds ratio, 1.93; 95% confidence interval, 1.31-2.84) compared with noncombat deployers. Screening positive for PTSD symptoms was associated with self-reported CHD before but not after adjustment for depression and anxiety and was not associated with a new diagnosis code for CHD., Conclusions: Combat deployments are associated with new-onset CHD among young US service members and veterans. Experiences of intense stress may increase the risk for CHD over a relatively short period among young adults.

There is converging evidence that physical activity influences affective states. It has been found that aerobic exercise programs can significantly diminish negative affect. Moreover, among healthy individuals, moderate levels of physical activity seem to increase energetic arousal and positive affect. However, the predictive utility of affective states for bodily movement has rarely been investigated. In this study, we examined whether momentarily assessed affect is associated with bodily movement in everyday life. Using a previously published data set (Schwerdtfeger, Eberhardt, & Chmitorz, 2008), we reanalyzed 12-hr ecological momentary assessment (EMA) data from 124 healthy volunteers. Electronic momentary positive-activated affect (EMA-PAA) and negative affect (EMA-NA) were assessed via handheld computers, and bodily movement was recorded via accelerosensors. Generalized linear mixed models were calculated. Results indicated that EMAPAA increases were accompanied by bodily movement increases of varying intensity. EMA-NA was also positively associated with increases in certain kinds of bodily movement. In light of previous research, this finding suggests that affect and bodily movement may have circular effects on each other.

Epidermal growth factor receptor (EGFR)-specific monoclonal antibodies predominantly inhibit colorectal cancer (CRC) growth by interfering with receptor signaling. Recent analyses have shown that patients with CRC with mutated KRAS and BRAF oncogenes do not profit from treatment with such antibodies. Here we have used the binding domains of cetuximab and pantitumumab for constructing T cell-engaging BiTE antibodies. Both EGFR-specific BiTE antibodies mediated potent redirected lysis of KRAS- and BRAF-mutated CRC lines by human T cells at subpicomolar concentrations. The cetuximab-based BiTE antibody also prevented at very low doses growth of tumors from KRAS- and BRAF-mutated human CRC xenografts, whereas cetuximab was not effective. In nonhuman primates, no significant adverse events were observed during treatment for 3 wk at BiTE serum concentrations inducing, within 1 d, complete lysis of EGFR-overexpressing cancer cells. EGFR-specific BiTE antibodies may have potential to treat CRC that does not respond to conventional antibodies.

Carcinoembryonic antigen (CEA, CD66e) is a well-characterized tumor-associated antigen that is frequently overexpressed in tumors. Phospholipases release CEA from tumor cells resulting in high circulating serum levels of soluble CEA (sCEA) that has been validated as marker for progression of colorectal, breast, and lung cancers. sCEA also acts as a competitive inhibitor for anticancer strategies targeting membrane-bound CEA. As a novel therapeutic approach for treatment of tumors expressing CEA on their cell surface, we constructed a series of bispecific single-chain antibodies (bscAb) combining various single-chain variable fragments recognizing human CEA with a deimmunized single-chain variable fragments recognizing human CD3. CEA/CD3-bscAbs redirected human T cells to lyse CEA-expressing tumor cells in vitro and in vivo. Efficient tumor cell lysis was achieved in vitro at bscAb concentrations from 1 pg/mL (19 fM) to 8.9 pg/mL with preactivated CD8 T cells, and 200 to 500 pg/mL with unstimulated peripheral blood mononuclear cell. The cytotoxic activity of a subset of CEA/CD3-bscAbs was not competitively inhibited by sCEA at concentrations that exceeded levels found in the serum of most cancer patients. Treatment with CEA/CD3-bscAbs prevented the growth of human colorectal cancer lines in a severe combined immunodeficiency mouse model modified to show human T cell killing of tumors. A murine surrogate CEA/CD3-bscAb capable of recruiting murine T cells for redirected tumor lysis in immunocompetent mice prevented the growth of lung tumors expressing human CEA. Together, our results reveal a unique opportunity for targeting cytotoxic T cells toward CEA-expressing tumors without being competitively inhibited by sCEA and establish CEA/CD3-bscAb as a promising and potent therapeutic approach.

Objective: Among other benefits, school-based health centres (SBHCs) are thought to provide opportunities to identify and help adolescents with risk-taking behaviours. The present study examined the use of SBHCs at three high schools in Cape Breton, Nova Scotia, to determine the extent to which SBHCs reach students at risk, and whether there are sex differences with respect to this reach., Methods: Self-administered surveys of students in grades 10 to 12 at the three high schools were carried out in May 2006., Results: The response rate was 70% of registered students. Boys were more often at risk than girls due to substance use, while girls were more often at risk due to sexual activity and suicidal thoughts. More girls visited SBHC nurses than boys (49% versus 10%; P<0.001). After adjusting for age, boys who saw a SBHC nurse were significantly more likely to engage in all risk-taking behaviours than boys who did not see a nurse; girls who saw a nurse engaged in most risk-taking behaviours significantly more often than girls who did not. However, no more than 22% of students with each specific risk behaviour used SBHCs to address those risks, with the exception of girls consulting for sexual health reasons, who made up 59% of all girls in the schools who reported being sexually active., Conclusions: Boys infrequently use SBHCs, and many at-risk students of both sexes do not use SBHCs. If the full potential for these SBHCs to help students with risk behaviours is to be realized, the need to increase reach to students is clear.

Macrophages play a crucial role in the defense against pathogens. Distinct macrophage populations can be defined by the expression of restricted cell surface proteins. Resident tissue macrophages, encompassing Kupffer cells of the liver and red pulp macrophages of the spleen, characteristically express the F4/80 molecule, a cell surface glycoprotein related to the seven transmembrane-spanning family of hormone receptors. In this study, gene targeting was used to simultaneously inactivate the F4/80 molecule in the germ line of the mouse and to produce a mouse line that expresses the Cre recombinase under the direct control of the F4/80 promoter (F4/80-Cre knock-in). F4/80-deficient mice are healthy and fertile. Macrophage populations in tissues can develop in the absence of F4/80 expression. Functional analysis revealed that the generation of T-cell-independent B-cell responses and macrophage antimicrobial defense after infection with Listeria monocytogenes are not impaired in the absence of F4/80. Interestingly, tissues of F4/80-deficient mice could not be labeled with anti-BM8, another macrophage subset-specific marker with hitherto undefined molecular antigenic structure. Recombinant expression of a F4/80 cDNA in heterologous cells confirmed this observation, indicating that the targets recognized by the F4/80 and BM8 monoclonal antibodies are identical.

Birds flying at high altitudes have occasionally been observed above mountain areas and the open sea. For the first time the regular occurrence of migrating birds flying within a low-level jet at heights of 5000 to almost 9000 m asl. have now been verified by radar above the Negev desert in southern Israel. Tracks of rather large birds with wing-beat frequencies of 5-6 Hz were measured to have horizontal flight speeds up to 50 m/s. Visual observations, seasonal occurrence, and wing-beat frequencies allowed to associate them with small species of the order Ciconiiformes (mainly Ardeidae) and possibly with members of the Laro-Limicolae group. These wading birds seem prone to continuing nocturnal migration into daytime under favorable conditions and to make use of high wind speeds at sometimes extreme altitudes.

The biological functions mediated by the death domain of the 55-kDa tumor necrosis factor receptor (TNFRp55) in vivo are still elusive. TNFRp55 mutants lacking a functional death domain were expressed in TNFRp55-/- and in TNFRp55+/- mice as transgenes under control of the H-2Kb promoter. Analysis of these animals revealed that signals originating from the TNFRp55 death domain are indispensable for the protection against Listeria monocytogenes, the expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in the spleen and the development of splenic germinal centers. Furthermore, the transgenic coexpression of the TNFRp55 mutants in TNFRp55+/- mice exerts a dominant negative effect on the signaling of the endogenous receptor chains in vivo.

Unlabelled: The impact of a new test on the market, the beta-hydroxybutyric acid (BOH) assay, on clinical decision-making in the emergency department (ED) has not been well studied. In this retrospective analysis, we studied the potential benefit of this new test in the ED decision-making process in diabetic patients. BOH levels were measured on all patients who had glucose and acetone levels ordered by the emergency physician during a 3-month period in the ED of a university tertiary referral center. Two groups were analyzed: group 1 was acetone-positive and BOH-positive (n = 13); group 2 was acetone-negative BOH-positive (n = 31). There was no difference between the two groups in terms of gender (p = 0.55) or age (p = 0. 47). The length of stay (p = 0.97) and number of complications (p = 0.89) were also similar between the two groups., Conclusion: This study suggests that in those diabetic patients with a negative acetone test and a positive BOH test, the addition of the positive result on the BOH test may provide additional prognostic information for predicting hospital length of stay and number of in-hospital complications.

Performance characteristics of the Abbott nonpretreatment AxSYM Digoxin II assay were evaluated for quantification of digoxin at four independent sites. Correlation of digoxin measurements with the Abbott pretreatment AxSYM, Baxter Stratus II, Abbott TDx/ TDxFLx II, Abbott IMx, Emit 2000, and Beckman Synchron CX digoxin assays showed acceptable agreement, as indicated by: slope values > 0.84, r > 0.90, y-intercepts for all comparisons at or below the assay detection limit, and Sy/x ranging between 7.5% and 15.4% of the average digoxin value. Susceptibility to interference from digoxin-like immunoreactive factors (DLIFs) was examined in 233 samples from renal patients, liver disease patients, cord blood, and third-trimester pregnancies; the AxSYM Digoxin II assay demonstrated the least DLIFs interference. DLIF susceptibility for four of the methods was significantly greater (P < 0.05) than in the AxSYM Digoxin II assay; susceptibilities of the Stratus II and Emit 2000 methods were similar to the AxSYM Digoxin II assay.

The reconstruction of lost muscle functions in cases of brachial plexus lesion is possible even in those cases where primary nerve reconstruction was not performed or unsuccessful. If there are only few motor nerves available, we prefer free latissimus dorsi transplantation or pedicled latissimus dorsi transposition for replacement of biceps and finger flexors. The combination of elbow flexion and finger flexion becomes possible when the transposed motor is passed around a suitable pulley in the elbow region like the flexor carpi ulnaris or carpi radialis.

Experimental efforts are being undertaken to improve nerve transplantation as a method for peripheral nerve repair. Major disadvantages of nerve transplantation are the creation of neurologic deficits at the donor site and the limited availability of nerve grafts. Mackinnon and Dellon propose the interposition of synthetic, biodegradable tubes as a nerve conduit for clinical use. This method is described according to its theoretical background and the surgical technique. The interposition of synthetic tubes seems possible for short defects in finger nerves, but will render unfavourable results in long defects of peripheral mixed nerves.

Secondary reconstruction of lost muscle function in brachial plexus injuries is performed by dynamic muscle and tendon transposition, by free microvascular muscle transplantation and by static surgical procedures. In cases of weak function of the finger flexors, static opponensplasty is required. In these cases our procedure is the internal fixation of the base of the metacarpal I to the base of the metacarpal II without stabilisation of cancellous bone. From 1987 to 1992 we operated 15 patients by this procedure. Results are showing sufficient stabilisation and good function.

From 1981 to 1990 110 scaphoid non-unions were operated on in our clinic. The period from 1986 to 1990 was followed up. During this time, 45 cases were surgically treated: 27 by Matti-Russe plasty, 11 by Herbert screw, and 7 by vascularized radial bone graft. The following criteria were compared: 1. Radiological signs of healing; 2. Period of immobilization; 3. Clinical results. The shortest period of immobilization and best wrist function was observed in patients treated by Herbert screw.

Our concept for the reconstruction of brachial plexus injuries includes an intercostal nerve transfer to the vascularized ulnar nerve graft. A free neurovascular latissimus dorsi is then transferred in a second stage operation. For optimization of the regeneration result, the operative planning of the second step includes nerve biopsies and enzymhistochemical evaluation for the distribution of motor axons. The staining method according to Scabolcz et al. is described and clinical cases are presented.

Preservation of peripheral nerves may, in the near future, play an important role in reconstructive surgery, especially if recent advances in immunosuppressive therapy are taken into account. Therefore, it has to be investigated whether peripheral nerves can be stored for some time after harvesting without diminishing their regenerative potential. Previous experiments of our group could demonstrate only little benefit of organ storage solution (HTK) or normal saline (NaCl 0.9%) to peripheral nerves when kept at cold ischaemia of 4 degrees C for 32 and 72 hours. In this presentation, we are reporting the results of peripheral nerve storage in Dulbecco's Modified Eagle Medium which has been used for Schwann cell culture. In 30 adult Sprague-Dawley rats, a 2.5 cm segment of the right sciatic nerve was harvested and kept at 4 degrees C for 14, 32, 72, and 120 hours. It was then reimplanted into the donor animal; regeneration quality was assessed clinically, histologically and morphometrically after 6 weeks. Best regeneration results were obtained in the 32 and 72 hour groups; regeneration here was comparable to the normal controls. These results are explained with the positive effect of nerve predegeneration.

The question whether delayed surgical treatment has any effect on recovery and invalidity in severe infections of the hand was evaluated in 91 cases. Immediate surgical treatment led to complete recovery in 90% of the cases, whereas surgical intervention one week later led to a significantly higher complication and amputation rate.

New methods in culturing epithelial autografts and the consequent use of free tissue transfer after early necrectomy of burns lead to an increase in survival rate and quality of life. The reconstruction of functional structures brings better results and early rehabilitation. The different stages are described, and the results of combined methods shown in several case reports.

Progress in micro- or macroreplantation has resulted in higher survival rates of formerly amputated parts. Progress has been made as a result of intensive laboratory training and considerable experience due to the popular application of microsurgical techniques. More amputated digits or limbs may survive because the time of ischemia can be exceeded in using cold storage or perfusion. Homo- or heterodigital vessel transposition, expanded indications for vein graft interposition, as well as heterotopic transplantation allow for extremity preservation even in crush injuries, and in disastrous multiple amputations combined with contusion or avulsion. Nowadays, microvascular digital replantation with vessel anastomosis distal to the distal interphalangeal joint in adults is technically feasible. Finger amputations in children are a prime indication for replantation. Maintenance of extremity length is possible in applying external fixation. Emergency free flaps or compound tissue transfer under the "Urgence differée" condition may provide reliable soft tissue coverage. Secondary reconstruction with regard to bone defects, tendon repair, and eventual nerve grafting have to be aspired, finally leading to an improvement of functional results in daily and leisure activities as well as in early professional readaptation.

Since the introduction of Cyclosporine A (CsA) in 1972, several studies have focused on its effects on experimental autologous peripheral nerve transplants. Although several studies have reported neurotoxicity of CsA in the central nervous system, no such data exist regarding the peripheral nervous system. The present study focuses on the effects of CsA in the therapeutic and toxic doses on axon regeneration, particularly the rate and quality of axon regeneration. Autologous nerve transplantation was performed in Lewis rats and axon regeneration evaluated clinically (motor function, body weight), electroneurographically and histologically. In transplanted nerves, even high doses of CsA (30 mg/kg bodyweight) did not lead to delayed or impaired axon regeneration. Long-term application in normal peripheral nerves did however cause axon degeneration with edema and vacuolisation of myelin sheaths, retraction of myelin sheaths from the node of Ranvier, and marked enhancement of the Schmidt-Lantermann incisures. As neurological side effects such as tremor and paresthesia have been reported under application of CsA in man, the above data might be of clinical relevance.

After 138 nerve sutures in the upper extremity the static and moving two-point discrimination tests were performed in the normal and the injured hand. Moving two-point discrimination recovered to a better level in 61%, the same level in 38%, and a worse level in 1% than static two-point discrimination after nerve repair.

The following experimental studies show different stages of regeneration and rejection in autologous and allogenic nerve grafts in 162 rats with and without immunosuppression with Cyclosporin A. Allografts were used in congenic rats differing only in major histocompatibility complex (MHC). Nerve regeneration was studied in autologous grafts with and without treatment with Cy A and with toxic doses of Cy A. No difference in nerve regeneration was seen in these groups. Allografts were transplanted between congenic rats type LEW 1 A and 1 U and vice versa with and without treatment with Cy A. Various degrees of rejection from slight to moderate were seen. Without Cy A-treatment, nerve grafts were totally destroyed after four weeks. With Cy A, nerve grafting resulted in complete regeneration.