A two-stage approach to primary TKA using articulating antibiotic-loaded spacers improve function and eradicate infection in septic arthritic knees.

PURPOSE: The treatment of an infected arthritic knee might be challenging. The failure rate has been reported to be high for open or arthroscopic debridement. A subsequently high rate of infection has been noted in these patients undergoing primary total knee arthroplasty (TKA). In the present study, a two-stage approach using an articulating spacer was used. The hypothesis was that the procedure would eradicate the infection and improve pain and function in these patients. METHODS: A total of 16 consecutive patients were enrolled in this retrospective study. The mean follow-up time was 6.1 years (range 2.0-9.9 years). Patients with advanced osteoarthritis and infection of the knee were included. All patients had previously undergone one or more failed arthroscopic or open procedures for the eradication of infection. All patients received the same homemade metal-on-plastic articulating antibiotic spacer. Double antibiotic therapy was given for 2 weeks intravenously and orally for 4 weeks. TKA implantation was performed 6 weeks after the first stage. RESULTS: The infection was eradicated without recurrence in all patients. The functional results were significantly improved, and pain was significantly reduced after spacer and TKA implantation. The mean amount of knee flexion was 95 ± 30° preoperatively, and it increased to 109 ± 14° (p = 0.012) after spacer implantation and to 119 ± 10° (p = 0.002) after TKA implantation. The mean KSS objective was 58 ± 12 preoperatively, and it increased to 75 ± 14 (p < 0.0001) after spacer implantation and to 96 ± 3 (p < 0.0001) after TKA implantation. The mean KSS function was 17 ± 11 preoperatively, and it increased to 46 ± 10 (p < 0.0001) after spacer implantation and to 86 ± 6 (p < 0.0001) after TKA implantation. The mean VAS score was 65 ± 11 preoperatively, and it decreased to 2 ± 4 (p < 0.0001) after spacer implantation and to 1 ± 2 (p < 0.0001) after TKA implantation. CONCLUSION: The two-stage procedure for the treatment of infected arthritic knees after failed eradication surgery was effective in all patients. Using an antibiotic articulating metal-on-plastic cement spacer showed improved functional results between the stages and at the final follow-up. No intra- or postoperative complications occurred.

Handheld computer-navigated constrained total knee arthroplasty for complex extra-articular deformities.

INTRODUCTION: The present study aimed to assess the postoperative alignment and clinical outcomes of patients with complex extra-articular deformities (EADs) undergoing computer-assisted surgery (CAS) for constrained total knee arthroplasty (TKA) with modular stem extensions. MATERIALS AND METHODS: From May 2015 to July 2018, ten patients with EADs scheduled for constrained TKA were enrolled retrospectively. The preoperative average deviation from neutral (= 180°) mechanical axis was 15.3° (range of coronal alignment: 150.9° varus-202.9° valgus). Alignment was assessed using an accelerometer-based handheld CAS system. On long-leg films, the positions of the components and possible stems were analysed and templated preoperatively. The average follow-up was 3.3 years (range: 2.0-4.6 years). RESULTS: The postoperative mechanical axis was within ± 3.0° from neutral in nine patients. In all patients, the Knee Society score (KSS) and range of motion improved significantly. A constrained condylar and a rotating hinge prosthesis were used in five patients each. In eight patients, the 100-mm cementless stem that was preferred by the authors was found to be unusable for the femur or the tibia in the planning stage. For the femur, a cementless 100-mm stem was used in three, and a cemented 30-mm stem in five patients; a femoral stem was not usable in two patients. For the tibia, a cementless 100-mm stem was used in six, and a cemented 30-mm stem in two patients; a monoblock rotating hinge tibia was used in two patients. CONCLUSIONS: Complex EADs were excellently managed during constrained TKA implantation using the handheld CAS system. Templating allowed the possible stem lengths to be identified and prevented anatomical conflict with the CAS-configured mechanical alignment. Limb alignment and function improved significantly after surgery. No intra- or postoperative complications occurred. LEVEL OF EVIDENCE: Level IV, retrospective study.

Patient-specific total knee arthroplasty: the importance of planning by the surgeon.

PURPOSE: The purpose of the study was to evaluate the accuracy of the planning of the patient-specific pin guides in total knee arthroplasty (TKA). This planning was performed primarily by a technician of the company and offered to the surgeon. All parameters of the implantation can either be modified or accepted by the surgeon. The hypothesis was that the plan needs preoperative intervention by the surgeon. METHODS: A prospective study in 50 patients was carried out. All patients received the same posterior-stabilised implant with patient-specific instrumentation. All surgical parameters (coronal, sagittal, rotational alignment, femoral and tibial resection levels and implant sizes) were checked by the orthopaedic surgeon and changed if necessary. RESULTS: Preoperatively, the femoral size was changed in 8 patients (16 %), the femoral flexion in 23 patients (46 %), the femoral shift in 34 patients (68 %), the tibial size in 24 patients (48 %) and the tibial rotation in all patients. The epicondylar axis was accepted in 47 patients (94 %) in the technician plan. Mean planning time was 8 ± 4 min. Intraoperatively, the femoral anterior-posterior size was in 50 patients (100 %) the same as in the surgeon and in 42 patients (84 %) the same as in the technician plan (p = 0.003). The tibial component implanted was in 42 patients (84 %) the same as in the surgeon and in 19 patients (38 %) the same as in the technician plan (p < 0.0001). A femoral distal recut was necessary in 31 patients (62 %) and a change of the tibial proximal cut in 17 patients (34 %) during surgery. Intraoperatively, no changes of the femoral and tibial alignment, the femoral anterior-posterior size, the femoral flexion, the femoral shift, the femoral and tibial rotation were necessary. Postoperatively, the coronal mechanical overall axis was within ±3° in 47 patients (94 %) with a maximum deviation of 5.6°. CONCLUSIONS: Significant changes of the technician plan were necessary to get an accurate preoperative plan. Intraoperative changes were significant less compared to the surgeon than to the technician plan. No major changes (alignment, femoral anterior-posterior size and rotation) of the surgeon plan were necessary. Surgeons using patient-specific pin guides in TKA may verify the default plan provided by the technician. A blind reply on the technician plan may be not recommended. LEVEL OF EVIDENCE: Therapeutic study, Level III.

Custom-fit minimally invasive total knee arthroplasty: effect on blood loss and early clinical outcomes.

PURPOSE: Recently, new custom-fit pin guides in total knee arthroplasty (TKA) have been introduced. Use of these guides may reduce operating time. Use of the guides combined with the absence of intramedullary alignment jigs may lead to reduced blood loss and improved early outcomes. Our aim was to evaluate blood loss and early clinical outcomes in patients undergoing minimally invasive TKA using custom-fit magnetic resonance imaging (MRI)-based pin guides. METHODS: A prospective study in 80 patients was carried out. Patients were divided randomly into 2 equal groups. In one group, intramedullary alignment jigs were used. In the second group, custom-fit MRI-based pin guides were used. All patients received the same cemented posterior-stabilized implant through a mini-midvastus approach. The volume in the drain bottles was recorded after 48 h. Hb loss was estimated by subtracting the postoperative from the preoperative Hb level. Transfusion requirements and surgical time were recorded. Outcome measures were Knee Society Scores (KSS), knee flexion, knee swelling and pain. RESULTS: There was lower mean drainage of blood in the custom-fit group (391 ml vs. 603 ml; p < 0.0001). There was no difference in estimated loss of Hb (3.6 g/dl vs. 4.1 g/dl; n.s.) and in transfusion requirements (7.5 % vs. 10 %; n.s.). Surgical time was reduced in the custom-fit group (12 min less; p = 0.001). KSS measured at week 2, 6 and 12 showed no significant difference between groups. Knee flexion measured on days 7, 10 and at week 6, 12 and knee swelling and pain measured on days 1, 3, 10 and at week 6, 12 showed no significant difference between groups. CONCLUSIONS: Using custom-fit pin guides reduces blood drainage, but not the estimated Hb loss in minimally invasive TKA and does not affect transfusion rate. Surgical time is reduced. There is no effect on the early clinical outcomes. LEVEL OF EVIDENCE: Therapeutic study, Level I.

Biomechanical validation of additively manufactured artificial femoral bones.

Replicating the mechanical behavior of human bones, especially cancellous bone tissue, is challenging. Typically, conventional bone models primarily consist of polyurethane foam surrounded by a solid shell. Although nearly isotropic foam components have mechanical properties similar to cancellous bone, they do not represent the anisotropy and inhomogeneity of bone architecture. To consider the architecture of bone, models were developed whose core was additively manufactured based on CT data. This core was subsequently coated with glass fiber composite. Specimens consisting of a gyroid-structure were fabricated using fused filament fabrication (FFF) techniques from different materials and various filler levels. Subsequent compression tests showed good accordance between the mechanical behavior of the printed specimens and human bone. The unidirectional fiberglass composite showed higher strength and stiffness than human cortical bone in 3-point bending tests, with comparable material behaviors being observed. During biomechanical investigation of the entire assembly, femoral prosthetic stems were inserted into both artificial and human bones under controlled conditions, while recording occurring forces and strains. All of the artificial prototypes, made of different materials, showed analogous behavior to human bone. In conclusion, it was shown that low-cost FFF technique can be used to generate valid bone models and selectively modify their properties by changing the infill.

Increasing the efficiency of polymer solar cells by silicon nanowires.

Silicon nanowires have been introduced into P3HT:[60]PCBM solar cells, resulting in hybrid organic/inorganic solar cells. A cell efficiency of 4.2% has been achieved, which is a relative improvement of 10% compared to a reference cell produced without nanowires. This increase in cell performance is possibly due to an enhancement of the electron transport properties imposed by the silicon nanowires. In this paper, we present a novel approach for introducing the nanowires by mixing them into the polymer blend and subsequently coating the polymer/nanowire blend onto a substrate. This new onset may represent a viable pathway to producing nanowire-enhanced polymer solar cells in a reel to reel process.

The painful knee after TKA: a diagnostic algorithm for failure analysis.

Pain after total knee arthroplasty (TKA) represents a common observation in about 20% of the patients after surgery. Some of these painful knees require early revision surgery within 5 years. Obvious causes of failure might be identified with clinical examinations and standard radiographs only, whereas the unexplained painful TKA still remains a challenge for the surgeon. It is generally accepted that a clear understanding of the failure mechanism in each case is required prior considering revision surgery. A practical 10-step diagnostic algorithm is described for failure analysis in more detail. The evaluation of a painful TKA includes an extended history, analysis of the type of pain, psychological exploration, thorough clinical examination including spine, hip and ankle, laboratory tests, joint aspiration and test infiltration, radiographic analysis and special imaging techniques. It is also important to enquire about the length and type of conservative therapy. Using this diagnostic algorithm, a sufficient failure analysis is possible in almost all patients with painful TKA.

Infections caused by extended-spectrum ß-lactamase-producing Enterobacterales after rectal colonization with ESBL-producing Escherichia coli or Klebsiella pneumoniae.

OBJECTIVES: Infections as a result of extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) are considered infections with a high public health burden. In this study, we aimed to identify incidences of and risk factors for healthcare-associated infections (HAIs) after rectal colonization with ESBL-producing Escherichia coli (ESBL-EC) or Klebsiella pneumoniae (ESBL-KP). METHODS: This prospective cohort study was performed in 2014 and 2015. Patients colonized with ESBL-EC or ESBL-KP were monitored for subsequent HAI with ESBL-E and other pathogens. In the case of an ESBL-E infection, rectal and clinical isolates were compared using pulsed-field gel electrophoresis (PFGE), and whole-genome sequencing (WGS) for ESBL-KP isolates. Proportional hazard models were applied to identify risk factors for HAIs, and to analyse competing risks. RESULTS: Among all patients admitted to the hospital during the study period, 13.6% were rectally screened for third-generation cephalosporin-resistant Enterobacterales (3GCREB). A total of 2386 rectal carriers of ESBL-EC and 585 of ESBL-KP were included in the study. Incidence density (ID) for HAI with ESBL-E was 2.74 per 1000 patient days at risk (95% confidence interval (CI) 2.16-3.43) among carriers of ESBL-EC, while it was 4.44 per 1000 patient days at risk (95% CI 3.17-6.04) among carriers of ESBL-KP. In contrast, ID for HAI with other pathogens was 4.36 per 1000 patient days at risk (95% CI 3.62-5.21) among carriers of ESBL-EC, and 5.00 per 1000 patient days at risk (95% CI 3.64-6.69) among carriers of ESBL-KP. Cox proportional hazard regression analyses identified colonization with ESBL-KP (HR = 1.58, 95% CI 1.068-2.325) compared with ESBL-EC as independent risk factor for HAI with ESBL-E. The results were consistent over all competing risk analyses. CONCLUSIONS: Clinicians should be aware of the increased risk of ESBL-E infections among patients colonized with ESBL-KP compared with ESBL-EC that might be caused by underlying diseases, higher pathogenicity of ESBL-KP and other factors.

[Treatment of infected total knee arthroplasty. 2-5-year results following two-stage reimplantation]. / Infizierte Knietotalendoprothese. 2- bis 5-Jahres-Ergebnisse nach zweizeitigem Prothesenwechsel.

BACKGROUND: The 2-5-year results for the treatment of deep infection of total knee arthroplasty (TKA) after two-stage reimplantation are presented. An articulating temporary antibiotic spacer prosthesis (TASP) and a standardized antibiotic regimen were used. PATIENTS AND METHODS: In a prospective study, 33 consecutive patients were treated with TASP. This articulating spacer was made on the table by cleaning and autoclaving removed parts of the TKA. Intravenous double antibiotic therapy in combination with rifampin was given for 10 days, followed by oral therapy for 4 weeks. RESULTS: At a mean follow-up period of 47 months (31-67), three patients had reinfection (success rate 91%). The average Hospital for Special Surgery knee score increased from 67 points (44-84) to 85 points (53-97) after reimplantation. Based on these results, 24 knees (73%) were rated excellent, five (15%) were rated good, three (9%) were rated fair, and one patient (3%) had a poor result. Complications included one case of temporary peroneal palsy, one dislocation of the spacer due to an insufficient extensor mechanism, and one fracture of the tibia due to substantial primary metaphyseal bone loss. CONCLUSION: Using TASP, the disadvantages of joint fixation between the two stages could be reduced. There was no difference in the reinfection rate compared with procedures using fixed spacer blocks. TASP facilitates reimplantation and yields good functional results.

Modelling the fracture-healing process as a moving-interface problem using an interface-capturing approach.

We present a novel numerical model of the fracture-healing process using interface-capturing techniques, a well-known approach from fields like fluid dynamics, to describe tissue growth. One advantage of this method is its direct connection to experimentally observable parameters, including tissue-growth velocities. In our model, osteogenesis, chondrogenesis and revascularisation are triggered by mechanical stimuli via mechano-transduction based on previously established hypothesis of Claes and Heigele. After experimentally verifying the convergence of the numerical method, we compare the predictions of our model with those of the already established Ulm bone-healing model, which serves as a benchmark, and corroborate our results with existing animal experiments. We demonstrate that the new model can predict the history of the interfragmentary movement and forecast a tissue evolution that appears similar to the experimental results. Furthermore, we compare the relative tissue concentration in the healing domain with outcomes of animal experiments. Finally, we discuss the possible application of the model to new fields, where numerical simulations could also prove beneficial.

Publisher Correction: Spiral Form of the Human Cochlea Results from Spatial Constraints.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Giardia in a selected population of dogs and cats in Germany - diagnostics, coinfections and assemblages.

Infections with the zoonotic endoparasite Giardia duodenalis are widely spread among dogs and cats worldwide. Since the question whether the infection might be transmitted from domestic animals to their owners is still an important topic, a reliable detection of patent Giardia infections and the determination of the associated Giardia assemblages is of major concern. The objectives of the present study were to determine the prevalence of Giardia infections in dogs and cats living in Germany using different diagnostic tests and to identify the Giardia assemblages of infected animals. Furthermore, a possible correlation of coinfections with other endoparasites was analysed. All samples were investigated by enzyme-linked immunosorbent assay (ELISA), merthiolate-iodine-formalin concentration technique (MIFC) and zinc chloride flotation. ELISA-positive samples were additionally screened with a direct immunofluorescence assay (IFA). Faecal DNA was extracted from all Giardia cyst-positive samples and used for multilocus sequence typing with nested PCRs targeting the following gene loci: SSU rRNA (SSU), glutamate dehydrogenase (gdh) and triosephosphate isomerase (tpi). Samples from dogs and cats tested positive for Giardia coproantigen (ELISA) in 30.6% and 17.9%, respectively. The MIFC technique revealed Giardia cysts in 33.9% of canine and in 34.6% of feline ELISA-positive samples, while using IFA, cysts were present in 90.4% of canine and in 76.9% of feline ELISA-positive samples. Coinfections with other endoparasites besides Giardia were found in both dogs and cats, yet a statistically significant correlation could solely be drawn for the canine samples. The success rate of the different PCR protocols varied between 23.1% (tpi) and 91.3% (SSU) for dogs and between 25.0% (gdh) and 90.0% (SSU) for cats. Dog-specific Giardia assemblages C and D were detected in 42 and 55 canine isolates, respectively. The cat-specific Giardia assemblage F was detected in 14 feline isolates. Two canine and two feline samples harboured the zoonotic assemblage A. According to the results of the study, Giardia is a common endoparasite in dogs and cats from Germany. The exclusive application of MIFC is insufficient for a reliable identification of patent Giardia infections since the IFA revealed a higher sensitivity for the detection of Giardia cysts in feline and canine faecal samples. Even though the majority of investigated animals harboured the species-specific Giardia assemblages C, D and F, a zoonotic potential arising from assemblage A could not be excluded.

Personalized risk prediction of postoperative cognitive impairment - rationale for the EU-funded BioCog project.

Postoperative cognitive impairment is among the most common medical complications associated with surgical interventions - particularly in elderly patients. In our aging society, it is an urgent medical need to determine preoperative individual risk prediction to allow more accurate cost-benefit decisions prior to elective surgeries. So far, risk prediction is mainly based on clinical parameters. However, these parameters only give a rough estimate of the individual risk. At present, there are no molecular or neuroimaging biomarkers available to improve risk prediction and little is known about the etiology and pathophysiology of this clinical condition. In this short review, we summarize the current state of knowledge and briefly present the recently started BioCog project (Biomarker Development for Postoperative Cognitive Impairment in the Elderly), which is funded by the European Union. It is the goal of this research and development (R&D) project, which involves academic and industry partners throughout Europe, to deliver a multivariate algorithm based on clinical assessments as well as molecular and neuroimaging biomarkers to overcome the currently unsatisfying situation.

[From tibiofemoral instability to dislocation in total knee arthroplasty]. / Von der tibiofemoralen Instabilität zur Luxation in der Knieendoprothetik.

Tibiofemoral instability is increasingly recognized as a mode of failure in total knee arthroplasty (TKA). Severe instability may lead to dislocation. Wrong surgical technique and wrong choice of constraint of the prostheses are the main causes for instability. Malalignment, malrotation and intraoperatively uncorrected instability especially in flexion may lead to an unstable total knee arthroplasty. Cruciate-retaining designs and mobile platforms can be considered only in the presence of well-balanced ligaments. Cruciate-substituting designs give more stability and many people find them more forgiving. However, correction of varus-valgus instability and severe flexion laxity cannot be provided. Varus-valgus contrained designs cannot compensate for the absence of medial and lateral collateral ligaments. Such cases are most reliably treated with a linked implant (rotating hinge). The exact analysis of the cause of an unstable or dislocated total knee arthroplasty represents the most essential basis of a successful treatment. Exchange of the prostheses represents the most successful procedure. Correction of implantation failures should be performed. A more constrained design should be used if insufficient ligaments are found. Post-traumatic instability or dislocation represents an exception.

The proper time for hearing screening in newborns.

The proper time for hearing screening in newborns via recordings of transiently evoked otoacoustic emission, TEOAE, has been estimated. 269 healthy neonates were investigated during five consecutive days after birth. On the first day, the results of screening were positive in 51 newborns only, 19.0%. In the following days, the number of the positive results systematically grew. In all inspected newborns, 100.0%, the TEOAE procedure was positive on the fifth day only. The fifth and following postnatal days are considered thus to be an appropriate time for hearing assessments in neonates.

Spiral Form of the Human Cochlea Results from Spatial Constraints.

The human inner ear has an intricate spiral shape often compared to shells of mollusks, particularly to the nautilus shell. It has inspired many functional hearing theories. The reasons for this complex geometry remain unresolved. We digitized 138 human cochleae at microscopic resolution and observed an astonishing interindividual variability in the shape. A 3D analytical cochlear model was developed that fits the analyzed data with high precision. The cochlear geometry neither matched a proposed function, namely sound focusing similar to a whispering gallery, nor did it have the form of a nautilus. Instead, the innate cochlear blueprint and its actual ontogenetic variants were determined by spatial constraints and resulted from an efficient packing of the cochlear duct within the petrous bone. The analytical model predicts well the individual 3D cochlear geometry from few clinical measures and represents a clinical tool for an individualized approach to neurosensory restoration with cochlear implants.

Melt growth and properties of bulk BaSnO3 single crystals.

We present the first-time growth of bulk BaSnO3 single crystals from the melt by direct solidification, their basic electrical and optical properties as well as their structural quality. Our measurement of the melting point (MP) of BaSnO3 amounts to 1855 °C ± 25 K. At this temperature an intensive decomposition and non-stoichiometric evaporation takes place as the partial pressure of SnO(g) is about 90 times higher than that of BaO(g). X ray powder diffraction identified only the BaSnO3 perovskite phase, while narrow rocking curves having a full width at half maximum of 26 arcsec and etch pit densities below 106 cm-2 confirm a high degree of structural perfection of the single crystals. In this respect they surpass the structural properties of those single crystals that were reported in the literature. The electrical conductivity of nominally undoped crystals depends on the growth conditions and ranges from insulating to medium n-type conductivity. After post-growth annealing in an oxidizing atmosphere undoped crystals are generally insulating. Doping the crystals with lanthanum during growth results in a high n-type conductivity. For a La doping concentration of 0.123 wt.% we measured an electron concentration of 3.3 × 1019 cm-3 and an electron mobility of 219 cm2 V-1 s-1. Based on optical absorption measurements we determined an energy of 3.17 ± 0.04 eV at 5 K and of 2.99 ± 0.04 eV at 297 K for the indirect band gap of BaSnO3.

Unchanged sarcoplasmic reticulum Ca2+-ATPase activity, reduced Ca2+ sensitivity, and negative force-frequency relationship in transgenic rats overexpressing the mouse renin gene.

Transgenic rats overexpressing the mouse Ren-2 gene [TG(mREN2)27 rats, TGR] were used to characterize alterations in force generation and relaxation following cardiac hypertrophy. Age-matched Sprague-Dawley rats were used as the control group. The beta-adrenoceptor dependent increase in force of contraction was reduced in the transgenic animals but not the Ca2+-dependent increase in force generation. Additionally, force of contraction decreased after increasing stimulation frequencies (up to 7 Hz), but the frequency-dependent decrease in force of contraction was significantly more pronounced in the transgenic group. The Ca2+ sensitivity in chemically skinned fiber preparations of TGR was reduced than that in Sprague-Dawley rats while maximum effectiveness was the same. Unexpectedly, the sarcoplasmic reticulum Ca2+-ATPase activity measured in crude membrane preparations from TGR did not differ from that in Sprague-Dawley rats; however, the activity of the Na+/K+-ATPase was less while the Na+/Ca2+-exchanger activity was significantly greater. In the same preparations the protein expression of SERCA2 was reduced in TGR while expression of phospholamban and calsequestrin remained the same. Thus in the model of cardiac hypertrophy harboring the mouse Ren-2 gene the hypothesized correlation between SERCA2 function and force-frequency relationship was not observed. Possible reasons for the more negative force-frequency relationship in TGR included changes at the level of the myofilaments and altered intracellular Na+ homeostasis which may result from the reciprocal changes in the Na+/K+-ATPase and the Na+/Ca2+-exchanger activity.

2-(diethylamino)thieno1,3oxazin-4-ones as stable inhibitors of human leukocyte elastase.

A series of 2-(diethylamino)thieno1,3oxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase (HLE). The Gewald thiophene synthesis was utilized to obtain several ethyl 2-aminothiophene-3-carboxylates. These precursors were subjected to a five-step route to obtain thieno2,3-d1,3oxazin-4-ones bearing various substituents at positions 5 and 6. Both thieno2,3-d and thieno3,2-d fused oxazin-4-ones possess extraordinary chemical stability, which was expressed as rate constants of the alkaline hydrolysis. The kinetic parameters of the HLE inhibition were determined. The most potent compound, 2-(diethylamino)-4H-1benzothieno2,3-d1,3oxazin-4-one, exhibited a K(i) value of 5.8 nM. 2-(Diethylamino)thieno1, 3oxazin-4-ones act as acyl-enzyme inhibitors of HLE, similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. The isosteric benzene-thiophene replacement accounts for an enhanced stability of the acyl-enzyme intermediates.

Immunologic findings in workers formerly exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin and its congeners.

One hundred ninety-two workers in a German pesticide factory who were exposed to polychlorinated dibenzodioxins and -furans (PCDD/PCDF) were investigated for former and present diseases and laboratory changes of the immune system. Moreover, in a subgroup of 29 highly exposed and 28 control persons, proliferation studies were performed. In addition to assays such as blood count, immunoglobulins, serum electrophoresis, monoclonal bands, surface markers, autoantibodies, and lymphocyte proliferation, two new methods, the rise of tetanus antibody concentration after vaccination and the in vitro resistance of lymphocytes to chromate, were used to diagnose the morphologic and functional state of the immune system. There was no stringent correlation of actual PCDD/PCDF concentrations with the occurrence of infections or with one of the immune parameters. In addition, outcomes of the tetanus vaccination and the chromate resistance test were not correlated with PCDD/PCDF. However, the chromate resistance of lymphocytes stimulated by phytohemagglutinin of highly exposed persons was significantly lower than that for the control group. These findings indicate that the function of lymphocytes can be stressed and possibly impaired by high exposure to PCDD/PCDF.