Use of multiple pharmacodynamic measures to deconstruct the Nix-TB regimen in a short-course murine model of tuberculosis.

A major challenge for tuberculosis (TB) drug development is to prioritize promising combination regimens from a large and growing number of possibilities. This includes demonstrating individual drug contributions to the activity of higher-order combinations. A BALB/c mouse TB infection model was used to evaluate the contributions of each drug and pairwise combination in the clinically relevant Nix-TB regimen [bedaquiline-pretomanid-linezolid (BPaL)] during the first 3 weeks of treatment at human equivalent doses. The rRNA synthesis (RS) ratio, an exploratory pharmacodynamic (PD) marker of ongoing Mycobacterium tuberculosis rRNA synthesis, together with solid culture CFU counts and liquid culture time to positivity (TTP) were used as PD markers of treatment response in lung tissue; and their time-course profiles were mathematically modeled using rate equations with pharmacologically interpretable parameters. Antimicrobial interactions were quantified using Bliss independence and Isserlis formulas. Subadditive (or antagonistic) and additive effects on bacillary load, assessed by CFU and TTP, were found for bedaquiline-pretomanid and linezolid-containing pairs, respectively. In contrast, subadditive and additive effects on rRNA synthesis were found for pretomanid-linezolid and bedaquiline-containing pairs, respectively. Additionally, accurate predictions of the response to BPaL for all three PD markers were made using only the single-drug and pairwise effects together with an assumption of negligible three-way drug interactions. The results represent an experimental and PD modeling approach aimed at reducing combinatorial complexity and improving the cost-effectiveness of in vivo systems for preclinical TB regimen development.

Use of Multiple Pharmacodynamic Measures to Deconstruct the Nix-TB Regimen in a Short-Course Murine Model of Tuberculosis.

A major challenge for tuberculosis (TB) drug development is to prioritize promising combination regimens from a large and growing number of possibilities. This includes demonstrating individual drug contributions to the activity of higher-order combinations. A BALB/c mouse TB infection model was used to evaluate the contributions of each drug and pairwise combination in the clinically relevant Nix-TB regimen (bedaquiline-pretomanid-linezolid [BPaL]) during the first three weeks of treatment at human equivalent doses. RS ratio, an exploratory pharmacodynamic (PD) marker of ongoing Mycobacterium tuberculosis rRNA synthesis, to-gether with solid culture CFU and liquid culture time to positivity (TTP) were used as PD markers of treatment response in lung tissue; and their time course profiles were mathematically modeled using rate equations with pharmacologically interpretable parameters. Antimicrobial interactions were quantified using Bliss independence and Isserlis formulas. Subadditive (or antagonistic) and additive effects on bacillary load, assessed by CFU and TTP, were found for bedaquiline-pretomanid and linezolid-containing pairs, respectively. In contrast, subadditive and additive effects on rRNA synthesis were found for pretomanid-linezolid and bedaquiline-containing pairs, respectively. Additionally, accurate predictions of the response to BPaL for all three PD markers were made using only the single-drug and pairwise effects together with an assumption of negligible three-way drug interactions. The results represent an experimental and PD modeling approach aimed at reducing combinatorial complexity and improving the cost-effectiveness of in vivo systems for preclinical TB regimen development.

Osteogenesis and angiogenesis of a bulk metallic glass for biomedical implants.

Implantation is an essential issue in orthopedic surgery. Bulk metallic glasses (BMGs), as a kind of novel materials, attract lots of attentions in biological field owing to their comprehensive excellent properties. Here, we show that a Zr61Ti2Cu25Al12 (at. %) BMG (Zr-based BMG) displays the best cytocompatibility, pronounced positive effects on cellular migration, and tube formation from in-vitro tests as compared to those of commercial-pure titanium and poly-ether-ether-ketone. The in-vivo micro-CT and histological evaluation demonstrate the Zr-based BMG can significantly promote a bone formation. Immunofluorescence tests and digital reconstructed radiographs manifest a stimulated effect on early blood vessel formation from the Zr-based BMG. Accordingly, the intimate connection and coupling effect between angiogenesis and osteogenesis must be effective during bone regeneration after implanting Zr-based BMG. Dynamic gait analysis in rats after implanting Zr-based BMG demonstrates a tendency to decrease the pain level during recovery, simultaneously, without abnormal ionic accumulation and inflammatory reactions. Considering suitable mechanical properties, we provide a realistic candidate of the Zr61Ti2Cu25Al12 BMG for biomedical applications.

In-situ tensile testing of ZrCu-based metallic glass composites.

ZrCu-based bulk metallic glass composites (BMGCs) are well known for their plastic deformability, superior to traditional metallic glasses (MGs), which is attributed to a unique dual-phases structure, namely, the glassy matrix and unstable B2 phase. In the present study, in-situ tensile testing is used to trace the deformation process of a ZrCu-based BMGC. Three deformation stages of the BMGC, i.e., the elastic-elastic stage, the elastic-plastic stage, and the plastic-plastic stage are identified. In the elastic-elastic and elastic-plastic stages, the yield strength and elastic limit are major influenced by the volume fraction of the B2 crystals. In the plastic-plastic stage, the B2 phase stimulates the formation of multiple shear bands and deflects the direction of shear bands by disturbing the stress field in front of the crack tip. The deformation-induced martensitic transformation of the metastable B2 phase contributes to the plasticity and work hardening of the composite. This study highlights the formation and propagation of multiple shear bands and reveals the interactions of shear bands with structural heterogeneities in situ. Especially, the blocking of shear bands by crystals and the martensitic transformation of the B2 phase are critical for the mechanistic deformation process and illustrate the function of the B2 phase in the present BMGCs.

[Arthroscopic double-row reconstruction of high-grade subscapularis tendon tears]. / Arthroskopische Doppelreihenrekonstruktion hochgradiger Rupturen der Subskapularissehne.

OBJECTIVE: Reconstruction of tendon integrity to maintain glenohumeral joint centration and hence to restore shoulder functional range of motion and to reduce pain. INDICATIONS: Isolated or combined full-thickness subscapularis tendon tears (≥upper two-thirds of the tendon) without both substantial soft tissue degeneration and cranialization of the humeral head. CONTRAINDICATIONS: Chronic tears of the subscapularis tendon with higher grade muscle atrophy, fatty infiltration, and static decentration of the humeral head. SURGICAL TECHNIQUE: After arthroscopic three-sided subscapularis tendon release, two double-loaded suture anchors are placed medially to the humeral footprint. Next to the suture passage, the suture limbs are tied and secured laterally with up to two knotless anchors creating a transosseous-equivalent repair. POSTOPERATIVE MANAGEMENT: The affected arm is placed in a shoulder brace with 20° of abduction and slight internal rotation for 6 weeks postoperatively. Rehabilitation protocol including progressive physical therapy from a maximum protection phase to a minimum protection phase is required. Overhead activities are permitted after 6 months. RESULTS: While previous studies have demonstrated superior biomechanical properties and clinical results after double-row compared to single-row and transosseous fixation techniques, further mid- to long-term clinical investigations are needed to confirm these findings.

[Arthroscopic rotator cuff surgery : New and established methods]. / Arthroskopische Rotatorenmanschettenchirurgie : Neues und Bewährtes.

This present article summarizes established and current developments and aspects of rotator cuff surgery. Achieved milestones as well as current approaches are presented and assessed with respect to their clinical and radiographic impact. Despite biomechanical and technical improvements in modern rotator cuff repair techniques, re-defect and re-tearing rates could not be fully eliminated. Meanwhile, the importance of biological processes around successful tendon-bone reintegration has been increasingly recognized. Hence, this article presents the current scientific standing regarding biological growth factors, platelet-rich plasma and rotator cuff augmentation techniques (with allogenic/autologous grafts). In summary, there are clear biomechanical advantages as well as many promising approaches to biological augmentation; however, the latter have not yet been transferred into regular clinical application.

Inductive flash-annealing of bulk metallic glasses.

We developed a temperature-controlled inductive flash-annealing device, which heats bulk metallic glasses (BMGs) at defined rates of up to 200 K/s to a given temperature. Subsequent instantaneous quenching in water allows preserving the microstructures obtained at various stages of crystallization. One Zr-based and two CuZr-based BMGs were flash-annealed at the onset of crystallization with different heating rates in order to prepare advanced BMG-matrix composites. The highly reproducible composite microstructures contain uniformly dispersed crystals and a narrow crystal size distribution. In order to assess the limitations of the present process, which mainly originate from non-uniform inductive heating, the skin depth was calculated. It is determined to be about 2.3 mm, which enables flash-annealing of rather bulky samples. The cooling rate was estimated from the interlamellar spacing of eutectic Al-Cu alloys to be on the order of 103 K/s. This ensures that decomposition of the microstructure during quenching is prevented. The present flash-annealing procedure is applicable to a wide variety of glass-forming liquids and has a large potential for tailoring the microstructure and, consequently, the mechanical properties of BMG-matrix composites.

Influence of the Ag concentration on the medium-range order in a CuZrAlAg bulk metallic glass.

Fluctuation electron microscopy of bulk metallic glasses of CuZrAl(Ag) demonstrates that medium-range order is sensitive to minor compositional changes. By analyzing nanodiffraction patterns medium-range order is detected with crystal-like motifs based on the B2 CuZr structure and its distorted structures resembling the martensitic ones. This result demonstrates some structural homology between the metallic glass and its high temperature crystalline phase. The amount of medium-range order seems slightly affected with increasing Ag concentration (0, 2, 5 at.%) but the structural motifs of the medium-range ordered clusters become more diverse at the highest Ag concentration. The decrease of dominant clusters is consistent with the destabilization of the B2 structure measured by calorimetry and accounts for the increased glass-forming ability.

Combined arthroscopic tenodesis of the long head of biceps and rotator cuff repair in antero-superior cuff tears.

PURPOSE AND HYPOTHESIS: This study evaluates the functional and cosmetic results following fixation of the long head of the biceps (LHB) tendon at the antero-medial footprint anchor of a rotator cuff reconstruction, using the "lasso-loop" technique. METHODS: 39 patients with a mean age of 62 years with a rotator cuff tear and associated lesion of the LHB tendon were included in this study. Besides rotator cuff repair in an arthroscopic anchor technique, all patients received additional LHB tenodeses using the lasso-loop technique. Clinical follow-up consisted of the Constant score (CS), LHB score, DASH score, and WORC index. Relevant sub-items, such as elbow flexion strength and cosmesis, were compared to the contralateral arm. RESULTS: At an average follow-up of 22 months (11-39 months), the CS resulted in an average of 81 points. The biceps-specific LHB score showed a mean value of 89 points. The analysis of the DASH score showed an average of 16.9 points and the analysis of the WORC index showed an average result of 79.7 %. Distalization of the biceps muscle was objectively in three cases (7.7 %) (as observed by the examiner) and subjectively in one of those cases (as noted by the patient). There was a loss in elbow flexion strength compared to the contralateral side; however, this loss was not statistically significant and not associated with clinical apparent re-tear or insufficiency of the tenodesis. DISCUSSION: The arthroscopic lasso-loop tenodesis of the LHB tendon is a time and cost-efficient technique. No additional anchor is needed when included in the rotator cuff repair. Functional and cosmetical results as well as results from the biceps-specific LHB score were good to excellent. The loss in elbow flexion strength is most likely associated with concomitant rotator cuff lesion. CONCLUSION: The lasso-loop fixation technique of the LHB tendon using the antero-medial footprint anchor in rotator cuff tears is a reliable and cost-efficient procedure. LEVEL OF EVIDENCE: III.

[Rotator cuff avulsion fractures. Current concepts in the surgical treatment]. / Knöcherne Ausrisse der Rotatorenmanschette. Aktuelle Behandlungskonzepte zur operativen Versorgung.

Rotator cuff avulsion fractures represent rare lesions in younger individuals and are caused by different trauma mechanisms. The present article outlines current concepts regarding diagnosis, indications, and surgical approaches to the treatment of greater and lesser tuberosity fractures, as discussed in the international literature. Modified arthroscopic double-row rotator cuff repair techniques allow for the anatomical reduction and retention of fragments and the treatment of concomitant intra-articular lesions at the same time. Moreover, the article provides practical hints on different surgical repair techniques, their respective limitations and results from the literature.

Two-phase quasi-equilibrium in ß-type Ti-based bulk metallic glass composites.

The microstructural evolution of cast Ti/Zr-based bulk metallic glass composites (BMGCs) containing ß-Ti still remains ambiguous. This is why to date the strategies and alloys suitable for producing such BMGCs with precisely controllable volume fractions and crystallite sizes are still rather limited. In this work, a Ti-based BMGC containing ß-Ti was developed in the Ti-Zr-Cu-Co-Be system. The glassy matrix of this BMGC possesses an exceptional glass-forming ability and as a consequence, the volume fractions as well as the composition of the ß-Ti dendrites remain constant over a wide range of cooling rates. This finding can be explained in terms of a two-phase quasi-equilibrium between the supercooled liquid and ß-Ti, which the system attains on cooling. The two-phase quasi-equilibrium allows predicting the crystalline and glassy volume fractions by means of the lever rule and we succeeded in reproducing these values by slight variations in the alloy composition at a fixed cooling rate. The two-phase quasi-equilibrium could be of critical importance for understanding and designing the microstructures of BMGCs containing the ß-phase. Its implications on the nucleation and growth of the crystalline phase are elaborated.

A tensile deformation model for in-situ dendrite/metallic glass matrix composites.

In-situ dendrite/metallic glass matrix composites (MGMCs) with a composition of Ti46Zr20V12Cu5Be17 exhibit ultimate tensile strength of 1510 MPa and fracture strain of about 7.6%. A tensile deformation model is established, based on the five-stage classification: (1) elastic-elastic, (2) elastic-plastic, (3) plastic-plastic (yield platform), (4) plastic-plastic (work hardening), and (5) plastic-plastic (softening) stages, analogous to the tensile behavior of common carbon steels. The constitutive relations strongly elucidate the tensile deformation mechanism. In parallel, the simulation results by a finite-element method (FEM) are in good agreement with the experimental findings and theoretical calculations. The present study gives a mathematical model to clarify the work-hardening behavior of dendrites and softening of the amorphous matrix. Furthermore, the model can be employed to simulate the tensile behavior of in-situ dendrite/MGMCs.

Effect of microstructure on the mechanical properties of as-cast Ti-Nb-Al-Cu-Ni alloys for biomedical application.

The correlation between the microstructure and mechanical behavior during tensile loading of Ti68.8Nb13.6Al6.5Cu6Ni5.1 and Ti71.8Nb14.1Al6.7Cu4Ni3.4 alloys was investigated. The present alloys were prepared by the non-equilibrium processing applying relatively high cooling rates. The microstructure consists of a dendritic bcc ß-Ti solid solution and fine intermetallic precipitates in the interdendritic region. The volume fraction of the intermetallic phases decreases significantly with slightly decreasing the Cu and Ni content. Consequently, the fracture mechanism in tension changes from cleavage to shear. This in turn strongly enhances the ductility of the alloy and as a result Ti71.8Nb14.1Al6.7Cu4Ni3.4 demonstrates a significant tensile ductility of about 14% combined with the high yield strength of above 820 MPa already in the as-cast state. The results demonstrate that the control of precipitates can significantly enhance the ductility and yet maintaining the high strength and the low Young's modulus of these alloys. The achieved high bio performance (ratio of strength to Young's modulus) is comparable (or even superior) with that of the recently developed Ti-based biomedical alloys.

Origin of intermittent plastic flow and instability of shear band sliding in bulk metallic glasses.

Intermittent or serrated plastic flow is widely observed in the deformation of bulk metallic glasses (BMGs) or other disordered solids at low temperatures. However, the underlying physical process responsible for the phenomena is still poorly understood. Here, we give an interpretation of the serrated flow behavior in BMGs by relating the atomic-scale deformation with the macroscopic shear band behavior. Our theoretical analysis shows that serrated flow in fact arises from an intrinsic dynamic instability of the shear band sliding, which is determined by a critical stiffness parameter in stick-slip dynamics. Based on this, the transition from serrated to nonserrated flow with the strain rate or the temperature is well predicted and the effects of various extrinsic and intrinsic factors on shear band stability can be quantitatively analyzed in BMGs. Our results, which are verified by a series of compression tests on various BMGs, provide key ingredients to fundamentally understand serrated flow and may bridge the gap between the atomic-scale physics and the larger-scale shear band dynamics governing the deformation of BMGs.

[Value of one-stage surgical treatment of diffuse peritonitis (relaparotomy on demand): a single-center analysis]. / Stellenwert der einzeitigen chirurgischen Therapie bei diffuser Peritonitis (Relaparotomie "on demand"): eine unizentrische Analyse.

BACKGROUND: Despite modern surgical and intensive-care concepts, diffuse peritonitis remains a major source of high morbidity and mortality. The aim of this study was to critically evaluate the value of relaparotomy on demand (ROD) for patients with diffuse peritonitis. PATIENTS AND RESULTS: In a retrospective analysis, the clinical course of 231 patients with diffuse peritonitis was analysed. The mean Mannheim Peritonitis Index (MPI) was 25.3. Overall lethality in this cohort was 14.3 %. In 214 patients, source control was successful during the index operation, and these patients were treated according to an on-demand strategy. For 178 of these patients, there was no demand for a relaparotomy, whereas 36 of these patients required further surgical interventions. Lethality for these subgroups was 9 % (no relaparotomy) and 27 % (relaparotomy), respectively. CONCLUSIONS: This retrospective analysis confirms that an on-demand strategy is reasonable and feasible after successful source control and lavage. However, it still remains of clinical importance to identify parameters that may assist in selecting those patients who require a relaparotomy.

Arthroscopic refixation of a combined fracture of the greater and lesser tuberosity of the proximal humerus.

UNLABELLED: Combined fractures of the greater and the lesser tuberosity are very rare injuries. This is a case report on arthroscopic treatment using suture anchors and one distal fixation screw. Clinical and radiographic follow-up showed recovery of active motion and consolidation of the fragments in anatomic positions. LEVEL OF EVIDENCE: V.

[Arthroscopically assisted stabilization of acute injury to the acromioclavicular joint with the double TightRope™ technique: one-year results]. / Arthroskopisch assistierte Stabilisierung akuter Schultereckgelenkverletzungen in Doppel-TightRope™-Technik : Einjahresergebnisse.

BACKGROUND: The aim of this study was to evaluate the clinical and radiological results of 37 consecutive patients (Ø age 37.9; 4♀, 33♂) following arthroscopically assisted and image intensifier-controlled AC joint reconstruction using the double TightRope™ technique for acute AC joint separations grade V according to Rockwood. MATERIAL AND METHODS: After 12 months 30 patients with a mean age of 38.8 years (range 18.6-65.8 years) could be included. The postoperative assessment included the Subjective Shoulder Value (SSV), Constant Score (CS), and Taft Score (TF) as well as radiological evaluation using bilateral stress views and bilateral Alexander views for determining vertical and horizontal AC joint instability. RESULTS: The clinical scores reached 91.4±9.8% for SSV, 87.8±5.2 for CS, and 10.1±2.1 points for TF. The initial coracoclavicular distance (CCD) was 22.1±5.6 mm and could be reduced to 8.6±2.8 mm postoperatively (p<0.05). The CCD increased at final follow-up to 12.8±2.4 mm. The difference of the CCD compared to the contralateral side was initially 13.7±4.8 mm; postoperatively it was 0.3±3.0 mm with an increase at final follow-up to 3.6±3.5 mm. A posterior instability on the Alexander view occurred in 53.3% of patients. A correlation between inferior clinical results and horizontal instability could be detected. Only one patient was slightly tender to palpation at the AC joint. CONCLUSION: Following arthroscopic AC joint stabilization using the double TightRope™ technique, despite partial recurrent instability, favorable clinical results can be expected.

The Aryl Hydrocarbon Receptor Influences Transplant Outcomes in Response to Environmental Signals.

The aryl hydrocarbon receptor (AHR) is a cytosolic transcription factor with numerous endogenous and xenobiotic ligands, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recent data suggests that TCDD may induce regulatory T cells, while a second AHR ligand, FICZ, promotes Th17 differentiation. The aim was to examine whether injection of recipient mice with either TCDD or FICZ altered skin allograft rejection in a fully mismatched model. TCDD or FICZ was given to recipient C57BL/6 mice intraperitoneally (IP). Twenty-four hr later, donor skin was grafted from BALB/c mice. An additional dose of FICZ was given on day 3. Treatment with TCDD delayed graft rejection for more than 4 weeks while FICZ treatment accelerated rejection by 1 - 2 days. In vivo exposure with TCDD led to a rise in the frequency of FoxP3(+) CD4(+) T cells in the spleen, while FICZ increased IL-17 secretion by splenocytes from treated animals. Activation of the AHR receptor by different AHR ligands in vivo resulted in opposing effects on skin graft survival. AHR serves as a sensor to environmental signals, with effects on the acquired immune system that may alter outcomes after organ transplantation. This model will be useful to further delineate direct effects of the environment on the immune system and outcomes of organ transplantation.

Influence of age on the cell biological characteristics and the stimulation potential of male human tenocyte-like cells.

The incidence of rotator cuff tears and recurrent defects positively correlate with patient age. However, this observation has never been analysed at the cellular level. The present study aims to better understand this correlation by investigating cellular characteristics of rotator cuff tenocytes of different age groups. Additionally, previous studies reported on stimulating effects of Bone Morphogenetic Protein (BMP) -2 and BMP-7 on tenocytes. Thus, the second aim was to investigate, whether the stimulation potential of tenocytes demonstrates age-related differences. Tenocyte-like cells from supraspinatus tendons of young and aged patients were analysed for the following cell biological characteristics: cell density, cell growth, marker expression, collagen-I protein synthesis, stem cell phenotype, potential for multipotent differentiation and self-renewal. To analyse the stimulation potential, cells were treated with BMP-2 and BMP-7 in 2D-/3D-cultures. Measured parameters included cell activity, marker expression and collagen-I protein synthesis. An effect of age was seen for cell growth and stem cell potential but not on extracellular matrix level. Cells from both groups responded to BMP-7 by increasing cell activity, collagen-I expression and protein synthesis. BMP-2 led to smaller increases in these parameters when compared to BMP-7. In general, 3D-cultivation improved the stimulation compared to 2D-culture. The cell biological characteristics of tenocyte-like cells, considered important for successful restoration of the tendon-bone unit, were inferior in elderly donors. This may help explain higher rates of recurrent defects seen in elderly patients. Regarding the stimulation potential, on a cellular level young and aged patients may benefit from biological augmentation with BMPs.

Characterization of tendon cell cultures of the human rotator cuff.

Rotator cuff tears are common soft tissue injuries of the musculoskeletal system that heal by formation of repair tissue and may lead to high retear rates and joint dysfunction. In particular, tissue from chronic, large tendon tears is of such degenerative nature that it may be prone to retear after surgical repair. Besides several biomechanical approaches, biologically based strategies such as application of growth factors may be promising for increasing cell activity and production of extracellular tendon matrix at the tendon-to-bone unit. As a precondition for subsequent experimental growth factor application, the aim of the present study was to establish and characterize a human rotator cuff tendon cell culture. Long head biceps (LHB)- and supraspinatus muscle (SSP)- tendon samples from donor patients undergoing shoulder surgery were cultivated and examined at the RNA level for expression of collagen type-I, -II and -III, biglycan, decorin, tenascin-C, aggrecan, osteocalcin, tenomodulin and scleraxis (by Real-time PCR). Finally, results were compared to chondrocytes and osteoblasts as control cells. An expression pattern was found which may reflect a human rotator cuff tenocyte-like cell culture. Both SSP and LHB tenocyte-like cells differed from chondrocyte cell cultures in terms of reduced expression of collagen type-II (p