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Collagen fibers within the annulus fibrosus (AF) lamellae are unidirectionally aligned with alternating orientations between adjacent layers. AF constitutive models often combine two adjacent lamellae into a single equivalent layer containing two fiber networks with a crisscross pattern. Additionally, AF models overlook the inter-lamellar matrix (ILM) as well as elastic fiber networks in between lamellae. We developed a nonhomogenous micromechanical model as well as two coarser homogenous hyperelastic and microplane models of the human AF, and compared their performances against measurements (tissue level uniaxial and biaxial tests as well as whole disc experiments) and seven published hyperelastic models. The micromechanical model had a realistic non-homogenous distribution of collagen fiber networks within each lamella and elastic fiber network in the ILM. For small matrix linear moduli (<0.2 MPa), the ILM showed substantial anisotropy (>10%) due to the elastic fiber network. However, at moduli >0.2 MPa, the effects of the elastic fiber network on differences in stress-strain responses at different directions disappeared (<10%). Variations in sample geometry and boundary conditions (due to uncertainty) markedly affected stress-strain responses of the tissue in uniaxial and biaxial tests (up to 16 times). In tissue level tests, therefore, simulations should represent testing conditions (e.g., boundary conditions, specimen geometry, preloads) as closely as possible. Stress/strain fields estimated from the single equivalent layer approach (conventional method) yielded different results from those predicted by the anatomically more accurate apparoach (i.e., layerwise). In addition, in a disc under a compressive force (symmetric loading), asymmetric stress-strain distributions were computed when using a layerwise simulation. Although all developed and selected published AF models predicted gross compression-displacement responses of the whole disc within the range of measured data, some showed excessively stiff or compliant responses under tissue-level uniaxial/biaxial tests. This study emphasizes, when constructing and validating constitutive models of AF, the importance of the proper simulation of individual lamellae as distinct layers, and testing parameters (sample geometric dimensions/loading/boundary conditions)., Competing Interests: Declaration of Competing Interest None, (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: Resistance to anti-tuberculosis (anti-TB) drugs is becoming a major and alarming threat in most regions worldwide., Methods: This was a descriptive cross-sectional study at a tertiary hospital in Iran, using patient medical records for 2000-2003. The findings were analyzed following the same framework as that used for previous reports from this center., Results: Among 1556 TB patients, drug susceptibility testing (DST) was performed for 548 culture-positive cases. Anti-TB drug resistance to both isoniazid and rifampin was identified in 10 (2.8%) of the new TB cases (multidrug-resistant TB; MDR-TB). Any resistance was detected in 228 (41.6%), showing an increasing trend in both new and retreatment cases. The data analysis revealed that drug-resistant TB had a statistically significant association with Afghan ethnicity, age>65 years, and the type of disease (retreatment vs. new TB case) (p<0.05). Also, assessment of the drug resistance trends showed a significant increase in resistance to any anti-TB agent, to isoniazid, and to streptomycin in new cases, and to all of the first-line anti-TB drugs in retreatment patients., Conclusions: There has been an increasing trend in drug resistance in recent years, particularly in retreatment cases. Hence, revision of the national TB control program, reevaluation of the role of the World Health Organization category II (CAT II) regimen, as well as the conducting of a nationwide drug resistance survey, are recommended.

A cDNA sequence coding for the full-length human transforming growth factor alpha (TGF alpha) precursor protein was introduced into and transcribed in cultured human keratinocytes, using a high-titer, high-expression, murine amphotropic retrovirus. Keratinocytes were shown capable of post-translationally modifying the TGF alpha primary translation product, with the subsequent formation of several cell-associated and secreted forms of TGF alpha, at least five of which, including the 50 amino acid mature species, can potentially bind and activate the epidermal growth factor receptor. Cells overexpressing the TGF alpha gene assumed a spindled morphology with long, bipolar filamentous processes and displayed increased locomotion. The soluble, mature form of TGF alpha alone also could induce the observed changes in cell shape and motility when added to keratinocyte cultures exogenously. The effects were dose dependent, and up to fourfold increases in locomotion were caused by TGF alpha in the absence of bovine pituitary extract (BPE). The addition of BPE to high concentrations of TGF alpha further enhanced keratinocyte motility to eightfold over baseline, suggesting a synergistic interaction between the two factors. These experiments demonstrate that keratinocytes can synthesize several forms of TGF alpha and that TGF alpha, besides being mitogenic, may have other important regulatory functions in keratinocytes.