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Background Anaplastic thyroid cancer (ATC) is aggressive with a poor prognosis, partly because of the immunosuppressive microenvironment created by tumor-associated macrophages (TAMs). Purpose To understand the relationship between TAM infiltration, tumor vascularization, and corresponding drug delivery by using ferumoxytol-enhanced MRI and macrin in an ATC mouse model. Materials and Methods ATC tumors were generated in 6-8-week-old female B6129SF1/J mice through intrathyroid injection to model orthotopic tumors, or intravenously to model hematogenous metastasis, and prospectively enrolled randomly into treatment cohorts (

Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40-treatment in mice as a model of Th1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-𝛾 and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-𝛾 were not toxic themselves, but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways following anti-PD-1 and anti-CTLA4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in Th1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.

Das „complex regional pain syndrome“ (CRPS) stellt nach wie vor eine nicht abschliesend atiologisch geklarte Komplikation nach distalen Radiusfrakturen dar. Die Inzidenz des Auftretens eines CRPS nach distalen Radiusfrakturen variiert zwischen 1 und 37 %. Pathophysiologisch wird nach aktuellen Erkenntnissen ein komplexes Zusammenspiel von inflammatorischen, somatosensorischen, motorischen und vegetativ-autonomen Veranderungen angenommen, die zu einer persistierenden maladaptiven Antwort und Sensibilisierung des zentralen und peripheren Nervensystems mit den entsprechenden Symptomen fuhren. Entscheidend fur die Diagnosestellung sind eine detaillierte Anamneseerhebung sowie die klinisch-handchirurgische, neurologische und schmerzmedizinische Untersuchung mit Bestatigung der „Budapest-Kriterien“. Unter den apparativen Moglichkeiten haben die Dreiphasenskelettszintigraphie wie auch die Temperaturmessung einen gewissen Stellenwert. Eine moglichst fruh begonnene multimodale Therapie ist am erfolgversprechendsten. Dabei stehen in aller Regel schmerzmedizinische und funktionelle Aspekte im Rahmen einer multimodalen Rehabilitation im Vordergrund.

Social dis-integration is still a latent problem faced by the Indonesians up to the present time. As a big archipelago country with more than 230 million inhabitants scattered in thousands of islands, the intensity of social conflict always present and there is a tendency to increase. This article describes about social conflict based on sociological theoritical perspective. Basic factors which can arise social conflict are pluralities in religion and ethnic, disharmonious relationship between the majority and the minority, disparity between the poor and the rich, disparity between centre and periphery, as well as disparity between periphery and periphery. But actually all of these factors are based on unequality in the distribution of life resources and social position.

Tumor associated macrophages (TAMs) are widely implicated in cancer progression, and TAM levels can influence drug responses, particularly to immunotherapy and nanomedicines. However, it has been difficult to quantify total TAM numbers and their dynamic spatiotemporal distribution in a non-invasive and translationally relevant manner. Here, we address this need by developing a pharmacokinetically optimized, (64)Cu-labeled polyglucose nanoparticle (Macrin) for quantitative positron emission tomography (PET) imaging of macrophages in tumors. By combining PET with high resolution in vivo confocal microscopy and ex vivo imaging of optically cleared tissue, we found that Macrin was taken up by macrophages with >90% selectivity. Uptake correlated with the content of macrophages in both healthy tissue and tumors (R(2) > 0.9), and showed striking heterogeneity in the TAM content of an orthotopic and immunocompetent mouse model of lung carcinoma. In a proof-of-principle application, we imaged Macrin to monitor the macrophage response to neo-adjuvant therapy, using a panel of chemotherapeutic and γ-irradiation regimens. Multiple treatments elicited 180–650% increase in TAMs. Imaging identified especially TAM-rich tumors thought to exhibit enhanced permeability and retention of nanotherapeutics. Indeed, these TAM-rich tumors accumulated >700% higher amounts of a model poly(D,L-lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG) therapeutic nanoparticle compared to TAM-deficient tumors, suggesting that imaging may guide patient selection into nanomedicine trials. In an orthotopic breast cancer model, chemoradiation enhanced TAM and Macrin accumulation in tumors, which corresponded to the improved delivery and efficacy of two model nanotherapies, PEGylated liposomal doxorubicin and a TAM-targeted nanoformulation of the toll-like receptor 7/8 agonist resiquimod (R848). Thus, Macrin imaging offers a selective and translational means to quantify TAMs and inform therapeutic decisions.

Tumour-associated macrophages are abundant in many cancers, and often display an immune-suppressive M2-like phenotype that fosters tumour growth and promotes resistance to therapy. Yet, macrophages are highly plastic and can also acquire an anti-tumorigenic M1-like phenotype. Here, we show that R848, an agonist of the toll-like receptors TLR7 and TLR8 identified in a morphometric-based screen, is a potent driver of the M1 phenotype in vitro and that R848-loaded β-cyclodextrin nanoparticles (CDNP-R848) lead to efficient drug delivery to tumour-associated macrophages in vivo. As a monotherapy, the administration of CDNP-R848 in multiple tumour models in mice altered the functional orientation of the tumour immune microenvironment towards an M1 phenotype, leading to controlled tumour growth and protecting the animals against tumour rechallenge. When used in combination with the immune checkpoint inhibitor anti-PD-1, we observed improved immunotherapy response rates, including in a tumour model resistant to anti-PD-1 therapy alone. Our findings demonstrate the ability of rationally engineered drug-nanoparticle combinations to efficiently modulate tumour-associated macrophages for cancer immunotherapy.

Efficient delivery of therapeutic nanoparticles (TNPs) to tumors is critical in improving efficacy, yet strategies that universally maximize tumoral targeting by TNP modification have been difficult to achieve in the clinic. Instead of focusing on TNP optimization, here we show that the tumor microenvironment itself can be therapeutically primed to facilitate accumulation of multiple clinically relevant TNPs. Building on the recent finding that tumor associated macrophages (TAM) can serve as nanoparticle drug depots, we demonstrate that local tumor irradiation substantially increases TAM relative to tumor cells, and thus TNP delivery. High-resolution intravital imaging reveals that following radiation, TAM primarily accumulate adjacent to microvasculature, elicit dynamic bursts of extravasation, and subsequently enhance drug uptake in neighboring tumor cells. TAM depletion eliminates otherwise beneficial radiation effects on TNP accumulation and efficacy, and controls with un-encapsulated drug show radiation effects are more pronounced with TNPs. Priming with combined radiation and cyclophosphamide enhances vascular bursting and tumoral TNP concentration, in some cases leading to a 6-fold increase of TNP accumulation in the tumor, reaching 6% of the injected dose per gram tissue (ID/g). Radiation therapy alters tumors for enhanced TNP delivery in a TAM-dependent fashion, and these observations have implications for the design of next-generation tumor targeted nanomaterials and clinical trials for adjuvant strategies.

Objectives: Creating functional small-diameter tissue-engineered blood vessels has not been successful to date. Moreover, the processes underlying the in vivo remodeling of these grafts and the fate of cells seeded onto scaffolds remain unclear. Here we addressed these unmet scientific needs by using intravital molecular imaging to monitor the development of tissue-engineered vascular grafts (TEVG) implanted in mouse carotid artery. Methods and Results: Green fluorescent protein–labeled human bone marrow–derived mesenchymal stem cells and cord blood–derived endothelial progenitor cells were seeded on polyglycolic acid–poly-L-lactic acid scaffolds to construct small-caliber TEVG that were subsequently implanted in the carotid artery position of nude mice (n = 9). Mice were injected with near-infrared agents and imaged using intravital fluorescence microscope at 0, 7, and 35 days to validate in vivo the TEVG remodeling capability (Prosense680; VisEn, Woburn, MA) and patency (Angiosense750; VisEn). Imaging coregistered strong proteolytic activity and blood flow through anastomoses at both 7 and 35 days postimplantation. In addition, image analyses showed green fluorescent protein signal produced from mesenchymal stem cell up to 35 days postimplantation. Comprehensive correlative histopathological analyses corroborated intravital imaging findings. Conclusions: Multispectral imaging offers simultaneous characterization of in vivo remodeling enzyme activity, functionality, and cell fate of viable small-caliber TEVG.

Eosinophils are multifunctional leukocytes that degrade and remodel tissue extracellular matrix through production of proteolytic enzymes, release of proinflammatory factors to initiate and propagate inflammatory responses, and direct activation of mucus secretion and smooth muscle cell constriction. Thus, eosinophils are central effector cells during allergic airway inflammation and an important clinical therapeutic target. Here we describe the use of an injectable MMP-targeted optical sensor that specifically and quantitatively resolves eosinophil activity in the lungs of mice with experimental allergic airway inflammation. Through the use of real-time molecular imaging methods, we report the visualization of eosinophil responses in vivo and at different scales. Eosinophil responses were seen at single-cell resolution in conducting airways using near-infrared fluorescence fiberoptic bronchoscopy, in lung parenchyma using intravital microscopy, and in the whole body using fluorescence-mediated molecular tomography. Using these real-time imaging methods, we confirmed the immunosuppressive effects of the glucocorticoid drug dexamethasone in the mouse model of allergic airway inflammation and identified a viridin-derived prodrug that potently inhibited the accumulation and enzyme activity of eosinophils in the lungs. The combination of sensitive enzyme-targeted sensors with noninvasive molecular imaging approaches permitted evaluation of airway inflammation severity and was used as a model to rapidly screen for new drug effects. Both fluorescence-mediated tomography and fiberoptic bronchoscopy techniques have the potential to be translated into the clinic.

Background— Arterial calcification is associated with cardiovascular events; however, mechanisms of calcification in atherosclerosis remain obscure. Methods and Results— We tested the hypothesis that inflammation promotes osteogenesis in atherosclerotic plaques using in vivo molecular imaging in apolipoprotein E −/− mice (20 to 30 weeks old, n=35). A bisphosphonate-derivatized near-infrared fluorescent imaging agent (excitation 750 nm) visualized osteogenic activity that was otherwise undetectable by x-ray computed tomography. Flow cytometry validated the target specifically in osteoblast-like cells. A spectrally distinct near-infrared fluorescent nanoparticle (excitation 680 nm) was coinjected to simultaneously image macrophages. Fluorescence reflectance mapping demonstrated an association between osteogenic activity and macrophages in aortas of apolipoprotein E −/− mice ( R 2 =0.93). Intravital dual-channel fluorescence microscopy was used to further monitor osteogenic changes in inflamed carotid arteries at 20 and 30 weeks of age and revealed that macrophage burden and osteogenesis concomitantly increased during plaque progression ( P P P P Conclusions— This serial in vivo study demonstrates the real-time association of macrophage burden with osteogenic activity in early-stage atherosclerosis and offers a cellular-resolution tool to identify preclinical microcalcifications.

Therapeutic nanoparticles (TNPs) have shown heterogeneous responses in human clinical trials, raising questions of whether imaging should be used to identify patients with a higher likelihood of NP accumulation and thus therapeutic response. Despite extensive debate about the enhanced permeability and retention (EPR) effect in tumors, it is increasingly clear that EPR is extremely variable; yet, little experimental data exist to predict the clinical utility of EPR and its influence on TNP efficacy. We hypothesized that a 30-nm magnetic NP (MNP) in clinical use could predict colocalization of TNPs by magnetic resonance imaging (MRI). To this end, we performed single-cell resolution imaging of fluorescently labeled MNPs and TNPs and studied their intratumoral distribution in mice. MNPs circulated in the tumor microvasculature and demonstrated sustained uptake into cells of the tumor microenvironment within minutes. MNPs could predictably demonstrate areas of colocalization for a model TNP, poly(d,l-lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG), within the tumor microenvironment with >85% accuracy and circulating within the microvasculature with >95% accuracy, despite their markedly different sizes and compositions. Computational analysis of NP transport enabled predictive modeling of TNP distribution based on imaging data and identified key parameters governing intratumoral NP accumulation and macrophage uptake. Finally, MRI accurately predicted initial treatment response and drug accumulation in a preclinical efficacy study using a paclitaxel-encapsulated NP in tumor-bearing mice. These approaches yield valuable insight into the in vivo kinetics of NP distribution and suggest that clinically relevant imaging modalities and agents can be used to select patients with high EPR for treatment with TNPs.

A study has been made of the effect of post-weld normalisation heat treatment parameters on the impact resistance of flash welded AISI type 1330 steel joints. Bars machined from the as welded joints were normalised by annealing at various temperatures for different time intervals, followed by cooling in air. Charpy specimens were machined with their notched section coinciding with the weld plane, and then impact tested at 0°C. The Charpy energy values were modelled in terms of the heat treatment parameters (temperature and time) using appropriate mathematical expressions. Exponential and polynomial formulations were adopted, and the average deviation of the modelled energy values from the experimental data was shown to be less than 10%. The optimum normalisation parameters, which ensure highest impact resistance, were predicted by the proposed models, and are presented and discussed in terms of pertinent microstructural aspects of the heat treated joints.

Patients with acetabular (AF) and pelvic ring fractures (BrF) make heavy demands on hospital resources and face difficulties in rehabilitation. From the patients' point of view, milestones in recovery are quality of life and return to productivity. We studied 42 patients with acetabular and 64 patients with pelvic ring fractures over a period of 10 years. The average follow-up took place 4 years after discharge. The injury severity score (ISS) did not correlate to long-term disability and quality of life (QoL) based on the Rosser index, data on return to productivity, or to radiological and clinical outcome. This study emphasizes the need for new injury scoring systems that better predict the recovery and ability to return to work of trauma patients after surviving pelvic fractures. Proper follow-up evaluations should analyze the patients' quality of life and working activity beside traditional items such as radiological and clinical findings.

Wir berichten uber einen jungen Mann, der als Mofafahrer von einem Pkw mitgeschleift wurde und dabei eine atlanto-occipitale Dislokation erlitt. Er uberlebte die Verletzung tetraplegisch. Der Unfallmechanismus, die anatomischen Besonderheiten und die grose Variationsbreite der klinischen Symptomatik werden dargestellt. Das von uns gewahlte operative Vorgehen wird den in der Literatur beschriebenen Verfahren gegenubergestellt.

Aims Westernized countries face a growing burden of cardiovascular calcification and osteoporosis. Despite its vast clinical significance, the precise nature of this reciprocal relationship remains obscure. We hypothesize that cardiovascular calcification progresses with inflammation and inversely correlates with bone tissue mineral density (TMD). Methods and results Arterial, valvular, and bone metabolism were visualized using near-infrared fluorescence (NIRF) molecular imaging agents, targeting macrophages and osteogenesis. We detected significant arterial and aortic valve calcification in apoE−/− mice with or without chronic renal disease (CRD, 30 weeks old; n = 28), correlating with the severity of atherosclerosis. We demonstrated decreases in osteogenic activity in the femurs of apoE−/− mice when compared with WT mice, which was further reduced with CRD. Three-dimensional micro-computed tomography imaging of the cortical and cancellous regions of femurs quantified structural remodelling and reductions in TMD in apoE−/− and CRD apoE−/− mice. We established significant correlations between arterial and valvular calcification and loss of TMD ( R 2 = 0.67 and 0.71, respectively). Finally, we performed macrophage-targeted molecular imaging to explore a link between inflammation and osteoporosis in vivo . Although macrophage burden, visualized as uptake of NIRF-conjugated iron nanoparticles, was directly related to the degree of arterial and valvular inflammation and calcification, the same method inversely correlated inflammation with TMD ( R 2 = 0.73; 0.83; 0.75, respectively). Conclusion This study provides direct in vivo evidence that in arteries and aortic valves, macrophage burden and calcification associate with each other, whereas inflammation inversely correlates with bone mineralization. Thus, understanding inflammatory signalling mechanisms may offer insight into selective abrogation of divergent calcific phenomena.

Background— Clinical studies have demonstrated that 50% of individuals with chronic renal disease (CRD) die of cardiovascular causes, including advanced calcific arterial and valvular disease; however, the mechanisms of accelerated calcification in CRD remain obscure, and no therapies can prevent disease progression. We recently demonstrated in vivo that inflammation triggers cardiovascular calcification. In vitro evidence also indicates that elastin degradation products may promote osteogenesis. Here, we used genetically modified mice and molecular imaging to test the hypothesis in vivo that cathepsin S (catS), a potent elastolytic proteinase, accelerates calcification in atherosclerotic mice with CRD induced by 5/6 nephrectomy. Methods and Results— Apolipoprotein-deficient (apoE −/− )/catS +/+ (n=24) and apoE −/− /catS −/− (n=24) mice were assigned to CRD and control groups. CRD mice had significantly higher serum phosphate, creatinine, and cystatin C levels than those without CRD. To visualize catS activity and osteogenesis in vivo, we coadministered catS-activatable and calcification-targeted molecular imaging agents 10 weeks after nephrectomy. Imaging coregistered increased catS and osteogenic activities in the CRD apoE −/− /catS +/+ cohort, whereas CRD apoE −/− /catS −/− mice exhibited less calcification. Quantitative histology demonstrated greater catS-associated elastin fragmentation and calcification in CRD apoE −/− /catS +/+ than CRD apoE −/− /catS −/− aortas and aortic valves. Notably, catS deletion did not cause compensatory increases in RNA levels of other elastolytic cathepsins or matrix metalloproteinases. Elastin peptide and recombinant catS significantly increased calcification in smooth muscle cells in vitro, a process further amplified in phosphate-enriched culture medium. Conclusions— The present study provides direct in vivo evidence that catS-induced elastolysis accelerates arterial and aortic valve calcification in CRD, providing new insight into the pathophysiology of cardiovascular calcification.

Summary Background Erosive oral lichen planus (EOLP) is a T-cell mediated inflammatory disease leading to severe pain and impairment. As current therapies are of limited efficacy, application of calcineurin inhibitors is considered to be a potential option. Objectives To investigate the efficacy of pimecrolimus cream 1% (Elidel®) compared with vehicle cream in the treatment of EOLP. Methods Twenty patients were enrolled in a prospective, double-blind, randomized, vehicle-controlled trial and assigned to either pimecrolimus or vehicle group. Study medication was applied for 30 days followed by 30 days of observation without therapy. In case of unresponsiveness, treatment was continued for 30 days with open-label pimecrolimus. EOLP was monitored on days 0, 30 and 60. Safety was assessed by patient documentation, measurement of pimecrolimus levels and blood counts. Results Within 30 days erosions cleared completely in seven of 10 patients treated with pimecrolimus and in two of 10 patients treated with vehicle. The clinical EOLP ‘composite score’ including mucosal erosions and pain sensation was significantly reduced in the pimecrolimus-treated group compared with vehicle (P = 0·025). In the three of 10 patients not responding to pimecrolimus, EOLP cleared after an additional 30 days of treatment with pimecrolimus. Following termination of the therapy, sustained remission of EOLP was detected in 83% of patients demonstrating long-lasting effects of pimecrolimus treatment. No severe adverse events were observed. In five patients pimecrolimus blood levels were detected, all of which stayed below 4 ng mL−1. Conclusions Pimecrolimus cream 1% effectively treats EOLP with long-lasting therapeutic effects and is therefore a promising therapeutic option for EOLP.

A new force detector for atomic force microscope measurements is presented. A tip carrying an organic monolayer is covered by a thin metal layer that forms a tunneling gap which can be modulated by the surface forces. This arrangement eliminates the adjustment problems of the usual atomic force microscopy devices. Several experimental methods of tip preparation are discussed. — Scanning tunneling microscope images of adsorbed monolayers of n-octadecyl — trichlorosilane, tetraethyleneglycol laurylether, and n-hexadecane are presented.

This paper presents the development strategy of a high performance S/390 CMOS microprocessor subsystem packaged on a 127 mm MCM. The MCM houses the complete processor core components like BU, FPU, L1-cache, L2-cache, bus-switch and DMA-controller. This multichip module set another milestone regarding miniaturization complexity and testability. The MCM-internal-net count was above 10.000 while the signals leaving the MCM passed 1700. Chipsize is up to 14.5 mm/spl times/14.5 mm.

Vom 01.01.1997 bis zum 31.12.1998 wurden 102 Patienten mit Humeruskopffrakturen operativ behandelt. Das Durchschnittsalter lag bei 64,8 Jahren. Die A0-Klassifikation zeigte 17,9% A-, 49,3% B- und 32,8% C-Frakturen. Die A- und B-Frakturen wurden in 84% mit der T-Abstutzplatte versorgt, wahrend bei den C-Frakturen die minimalinvasiven Verfahren, gefolgt von Endoprothesen, zum Einsatz kamen. Komplikationen: Infektionen bei 8 Patienten, Humeruskopfnekrose 11 Patienten und in 34% die Varusabkippung des Humeruskopfes. Unter Anwendung des Nachuntersuchungsscores nach Neer hatten Patienten mit A-Frakturen in 54% und Patienten mit B-Frakturen in 66% ein gutes und sehr gutes funktionelles Ergebnis. Bei Patienten mit C-Frakturen hingegen lag in uber 90% ein schlechtes und sehr schlechtes Nachuntersuchungsergebnis vor.

We evaluated the drug deaths in western Austria during the period from 1981 to 1991. The increase of fatal cases is partly due to a change in statistical methods and the definition of ‘drug victims’. In this paper a survey is given concerning the drug deaths investigated forensically and toxicologically in our area of responsibility.

The original network hypothesis of Niels Jerne (1974) has a built-in therapeutic application as a vaccine which was first recognized by Eichmann and Rajewsky (1975). Subsequently, a formal approach to the preventive or therapeutic utility of anti-idiotypic antibodies was developed which is best known as the so-called “internal image antigen” concept (Jerne 1982 and Bona 1984). A great deal of experimental support for this concept has been obtained in animal models (as summarized in Kohler 1989). Recently, the concept has been moved to clinical settings in therapeutic trials of certain cancers (Herlyn 1987; Kageshita 1988; Mittelman 1992) and HIV-1 infection (Kang 1992).

The effects of an inflammatory insult on albumin of the rat liver were investigated at the cellular level and were correlated with serum albumin concentration. After SC injection of turpentine, the livers were perfused and fixed in vivo; serial liver sections were stained using a streptavidin-ABC-immunoperoxidase technique with an antibody to rat albumin. Albumin and total protein were measured at intervals after turpentine injection in whole livers and in serum. Fibrinogen was determined in plasma only. Twenty-four hours after turpentine injection serum albumin had dropped by 25% and was at 50% of its initial value at Day 3. Serum fibrinogen increased 2.4-fold within 24 hr and decreased thereafter. Liver homogenates showed no significant changes in albumin concentration. Immunohistochemically, all hepatocytes stained positive for albumin in normal animals. During inflammation, the immunostainable albumin content vanished entirely in a majority of all hepatocytes while remaining unchanged in other cells, thus producing a strikingly patchy staining pattern. No signs of resumption of albumin accumulation in depleted hepatocytes were seen after 8 days, despite a clear trend towards normalization of serum albumin concentration. These results suggest that individual hepatocytes differ widely in their response to agents that suppress albumin synthesis in an acute-phase reaction.

It has been estimated that up to 30% of detectable polyps in patients regress spontaneously. One major challenge in the evaluation of effective therapy of cancer is the readout for tumor regression and favorable biological response to therapy. Inducible near infra-red (NIR) fluorescent probes were utilized to visualize intestinal polyps of mice hemizygous for a novel truncation of the Adenomatous Polyposis coli (APC) gene. Laser Scanning Confocal Microscopy in live mice allowed visualization of cathepsin activity in richly vascularized benign dysplastic lesions. Using biotinylated suicide inhibitors we quantified increased activities of the Cathepsin B & Z in the polyps. More than (3/4) of the probe signal was localized in CD11b(+)Gr1(+) myeloid derived suppressor cells (MDSC) and CD11b(+)F4/80(+) macrophages infiltrating the lesions. Polyposis was attenuated through genetic ablation of cathepsin B, and suppressed by neutralization of TNFalpha in mice. In both cases, diminished probe signal was accounted for by loss of MDSC. Thus, in vivo NIR imaging of focal cathepsin activity reveals inflammatory reactions etiologically linked with cancer progression and is a suitable approach for monitoring response to therapy.

The effect of pitch errors on the transmission error of a gear pair has been much studied. In particular, it has been thought that, if pitch error alone is present, the frequency spectrum of the corresponding transmission error will have no components either at the tooth contact frequency or any of its harmonics. This result is here examined, and it is concluded that it is invalid. It is shown that, in general, tooth contact harmonics of significant amplitudes will exist.

It is shown that the model proposed for a condensation of quasi-2-dimensional space charge layers, subjected to quantising electric and magnetic fields, into Wigner magneto-quantum crystals, allowing the additional development of lossless, liquid-like edge currents, permits an unconstrained interpretation of all experimental results obtained so far. In particular, the recent data of G. Ebert et al. (1985) including measurements between Hall probes connected with the interior of the plane of the space charge layer, even for non-homogeneous electron concentrations perpendicular to the device current, reveal the exclusivity of an explanation by this model. An interpretation by partial electron localisation within the semiconductor host crystal cannot be managed.

In 18 patients suffering from chronic renal failure (being haemodialysed three times weekly for 22.2 +/- 27.9 months), sensory conduction velocity and relative refractory period of the sural nerve were estimated immediately before and after dialysis. Before haemodialysis all but one patient had conduction velocities within the normal range (x +/- 2 SD), but 50% had prolonged refractory periods. After dialysis the refractory period decreased to become normal in all but one patient. Visual evoked potential latencies showed no systematic alterations. A membrane abnormality due to uraemic poisoning is assumed to cause the reversible prolongation of the refractory period.

Data are presented on the activity of several successful and unsuccessful materials for systemic control of cattle grubs, Hypoderma lineatum (De Vill.) and H. bovis (L.). Rounel, applied as drench or bolus at approximately 110 mg./kg., proved highly effective (99% or better) except where infestation levels averaged less than one grub per head. Dimethoate, oral as well as intramuscular at 15 mg./kg., was highly effective (94%) but was accompanied by depression (as much as 56%) of cholinesterase activity coupled with at least initial weight gain deceleration. Dowco 109 ( O -(4- tert -butyl-2-chlorophenyl) O -methyl methylphosphoramidothioate) when sprayed at a concentration of 0.75% proved highly effective (100%) and was accompanied by no detectable cholinesterase depression, but when sprayed at 0.5% over the entire body or on the backs of cattle alone, this material failed or gave marginal control (27%-76%). Bayer 21/199 ( O -(3-chloro-4-methylumbelliferone) O,O -diethyl phosphorothioate, as wettable powder or as emulsion, was sprayed at 0.5% and at 0.25% under conditions of complete or partial coverage of cattle. The results with this material (at 0.5%) show considerable irregularity, ranging from excellent (91% to 97%) to poor (under 65%) but not directly correlated with formulation or degree of coverage. The tests at 0.25% concentration failed (43% control or less). Nicarbazin (complex of 4,4'- dinitrocarbanilide and 2-hydroxy-4,6-dimethyl pyrimidine), provided as a multiple oral dosage of 25 mg./kg., was unsuccessful (26%), but when administered as single oral dosages at 125 mg./kg. was successful though poor (65%), and at 250 mg./kg. was moderately successful (86%). Six other materials, each of which had shown promise in in vitro tests, were unsuccessful (27% control or less); these materials are: (I) 9-amino-6-chloro- 2-methoxyaeridine; (II) 4,4' dimethylbenzhydryl amine HCl; (III) di-n-butyl tin dilaurate; (IV) I-phenyl-3-(5-nitro-2-thia zolyl) urea; (V) 2-(p-nitrobenzamido)-5-nitrothiazole; and Monacrin®, 9-aminoacridine HCl. The data presented on gains in weight do not provide evidence of a relationship between grub control and weight-gaining ability of calves maintained under dry-lot conditions. In general, the degree of grub control obtained appeared better in experiments involving heavily infested cattle than in lightly infested animals.

Es wird ein kindskopfgroser Schleimbeutel der Sitzgegend beschrieben. Seiner Lage nach kann er aus keinem der normalerweise in der Beckenregion vorkommenden Schleimbeutel entstanden sein. Ursachlich last er sich auf ein Trauma (Zerrung) zuruckfuhren. Er scheint sich als Gleitkissen zwischen einem grosen Blutergus und den daruber hinziehenden Muskeln neu gebildet zu haben. Eigenartige, am Os ischii entstandene Knochendellen, lassen sich weniger durch das Hygrom selbst, als durch das Trauma, das auch zur Entstehung des Hygroms fuhrte, erklaren.

Carbimazole in daily doses of either 15 or 45 mg acutely depressed the thyroidal 131I-uptake (measured at 2, 8 and 24 hours after administration of the tracer) in 34 healthy human volunteers. Fourteen of these subjects were kept on carbimazole for four weeks. A gradual recovery of the radioiodine uptake was observed in every individual. By the end of the fourth week the 24 h uptake had risen by 100% over the value observed with acute suppression in the 15 mg carbimazole group (i. e. from 5.7 to 11.4%) and by 500% in the 45 mg carbimazole group (i.e. from 2.7 to 15.8%). The corresponding figures for the 8 h uptake were 100 to 250% and for the 2 h uptake 40 to 60%. In three individuals the uptake in the fourth week of carbimazole treatment was distinctly higher than the pretreatment control values. Thus the acute suppression of a complete blocking dose of carbimazole on thyroidal radioiodine uptake is partially or even totally overcome within a few weeks of chronic treatment. It is therefore possible, in human subjects, to produce experimentally a high thyroidal radioiodine uptake by antithyroid drug treatment alone, in the absence of concomitant severe iodine deficiency. This finding may have a bearing on the interpretation of radioiodine studies carried out on endemic goitre. Comparable findings were obtained in 23 hyperthyroid patients treated with carbimazole for a mean of 28 weeks. In order to elucidate the mechanisms responsible for the later rise of an acutely carbimazole suppressed uptake, the serum PB127I and TSH concentration was measured at weekly intervals. Whereas the PBI fell both in this and in another series of volunteers by the end of the fourth week of carbimazole treatment, no significant change in serum TSH concentration was measurable by radioimmunoassay. Nevertheless, the hypothesis is put forward that a biologically significant increase in serum TSH concentration had occurred, which was not detectable by the radioimmunoassay techniques available at the present time. There are indeed reasons to suspect that biologically important variations in TSH secretion may occur which fail to bring the serum TSH concentration beyond the normal range defined by radioimmunoassay.

Technical ronnel incorporated in a 3: 1 salt-bonemeal mixture was made available on a free-choice basis to cattle grub-infested calves for periods of 28 to 66 days. Outstanding control (100%) was achieved at concentrations of 48 and 40 grams ronnel per pound of mixture for 66 days. Inadequate control was obtained at lower levels (16 grams per pound) and over shorter periods (28 days). Six-fold variations in average total mineral consumption (0.31 to 1.88 oz. per day) were observed. Accompanying physiological events such as reduced erythrocyte cholinesterase activity (as low as 21% of pretreatment activity) and transient weight gain depression at higher levels of ingestion suggest that further research with this or other appropriate systemic chemicals- be pursued before general recommendations for use be made.

Durch einen Hufschlag auf den Bauch wurde das Duodenum im retroperitonealen Teil zirkular abgequetscht, obwohl die Gewalteinwirkung so gering war, das innerhalb der Bauchhohle keine Organschadigungen eingetreten waren. -Es empfiehlt sich daher, auch bei Fehlen nennenswerter Quetschungen der Bauchorgane den Retroperitonealraum genau zu besichtigen und auf einen etwaigen Ergus hinter dem Peritoneum zu achten. -Durch Naht des Duodenums wurde der Fall ohne Dranage geheilt. Wegen Narbenstenose muste spater eine G.E. angelegt werden.

The advent of the microprocessor has opened up new avenues for the system designer to provide more powerful, more reliable and more user oriented computer systems to the user community for the same or lower costs. The problem confronting the designer is: How to achieve these goals? This paper describes one such method called Distributed Function Multiple Processor (DFMP).The system described uses several micro processors each with its own memory to form a cluster. These processors are differentiated by the functions they perform such as file managing, intelligent terminal, etc. and communicate via a Restricted Cross Bar Switch (RCBS). Further, several clusters or nodes can be linked to form a local network. Interprocessor and internode communications are controlled by a special processor called the Interprocessor Controller (PC) located in each node. The IPC's use an adaptive technique to determine traffic flows.

Three cases of congenital leukaemia associated with hydrops and intrauterine death are described. The leukaemic infiltrates, which involved both the infants and the placentas, were of monocytic, lymphoblastic, and myeloblastic types, respectively. The general lack of recognition of the condition is probably due to inadequate histological examination of the stillborn infant and the placenta.

Eight patients with terminal renal failure (GFR less than 5 ml/min) received guanfacine intravenously or orally at the beginning of a haemodialysis session lasting 5 hours. After intravenous administration the elimination rate constant of the unchanged drug was calculated to be 0.59 h-1, corresponding to an elimination half-life of about 12 h, which is similar to the values of patients with normal renal function. Following oral ingestion, only 2.4% of the guanfacine dose administered were extracted unchanged in the dialysate during the haemodialysis period. The clearance by dialysis was 53 ml/min for guanfacine, which represents about 15% of the total clearance of guanfacine reported in the literature. The low dialysis clearance of guanfacine is consistent with the high rate of biotransformation of the drug and its binding to red blood cells and plasma proteins. Thus guanfacine may be dosed independently of haemodialysis treatment periods.