Single- and multiple-dose pharmacokinetics of sotalol hydrochloride in healthy cats.

INTRODUCTION/OBJECTIVES: The objective of this study was to describe the single- and multiple-dose pharmacokinetics and urinary elimination of sotalol in healthy cats. ANIMALS: Six adult purpose-bred cats MATERIALS AND METHODS: Cats were administered 2 mg sotalol/kg body weight as a single intravenous bolus and as a single oral dose in a randomized crossover study with a two-week washout period. The same cats then received 3 mg sotalol/kg orally every 12 h for two weeks. Blood samples were collected at predetermined time points for 48 h postdose for quantification of sotalol using ultra-high-pressure liquid chromatography with mass spectrometry. Non-compartmental analysis was used to obtain pharmacokinetic parameters. Data are presented as median (min-max). RESULTS: Following intravenous administration, plasma clearance and volume of distribution were 9.22 mL/min/kg (5.69-10.89 mL/min/kg) and 2175.56 mL/kg (1961-2341.57 mL/kg), respectively. Bioavailability was 88.41% (62.75-130.29) following a single oral dose. Peak plasma concentration (Cmax) and time to Cmax were 0.94 µg/mL (0.45-1.17 µg/mL) and 1.5 h (0.5-4 h) after a single oral dose (2 mg/kg), and 2.29 µg/mL (1.91-2.48 µg/mL) and 1.0 h (0.5-1.5 h) with chronic oral dosing (3 mg/kg), respectively. Elimination half-life was 2.75 h (2.52-4.10 h) and 4.29 h (3.33-5.53 h) for single and chronic oral dosing, respectively. Accumulation index was 1.17 (1.09-1.29) after chronic dosing. Urinary sotalol recovery was 81-108% of the intravenous dose. CONCLUSIONS: Oral sotalol administration resulted in plasma concentrations reportedly efficacious in other species, with good to excellent oral bioavailability. Urinary excretion appears to be a major route of elimination. Following repeated oral dosing, minimal drug accumulation was estimated. Additional studies in cats are recommended due to the possibility of nonlinear kinetics.

National hospital readiness for COVID-19 in Lesotho: evidence for oxygen ecosystem strengthening.

SETTING: Sub-Saharan African country, Lesotho, during the SARS-CoV-2 COVID-19 pandemic. OBJECTIVE: To evaluate COVID-19 hospital capacity in Lesotho. DESIGN: We conducted a pragmatic assessment of all public hospitals in Lesotho using a WHO COVID-19 hospital assessment tool during July 2020 (baseline), with targeted follow-up in December 2020. We adapted the WHO tool into a questionnaire with a focus on hospital services and included oxygen ecosystem elements (pulse oximeters, oxygen, and advanced respiratory care). We converted qualitative questionnaire answers into quantitative ordinal variables and used standard statistics for analysis. RESULTS: At baseline, we found all 12 questionnaire domains demonstrate both hospital preparedness and weakness in infection prevention and control. Key baseline gaps were lack of a dedicated team, and insufficient personal protective equipment and space for donning and doffing. Substantial limitations were noted in hypoxemia diagnosis and treatment; information management and care coordination pathways were also suboptimal. Targeted follow-up after 5 months revealed improvement in the availability of pulse oximetry, oxygen capacity, and heated high-flow nasal cannula devices. CONCLUSION: Our baseline findings may reflect uneven early pandemic care quality; targeted follow-up suggests strengthening of the oxygen ecosystem.

LIEU: Pays d'Afrique subsaharienne, Lesotho, pendant la pandémie de COVID-19 due au SARS-CoV-2. OBJECTIF: Évaluer les capacités hospitalières relatives à la COVID-19 au Lesotho. MÉTHODE: Nous avons réalisé une évaluation pragmatique de tous les hôpitaux publics du Lesotho en utilisant un outil d'évaluation hospitalière de l'OMS pour la COVID-19 pendant le mois de juillet 2020 (point de référence), avec un suivi ciblé en décembre 2020. Nous avons adapté l'outil de l'OMS en un questionnaire se concentrant sur les services hospitaliers. Nous y avons inclus les éléments relatifs à l'écosystème de l'oxygène (oxymètres de pouls, oxygène et soins respiratoires avancés). Nous avons converti les réponses au questionnaire qualitatif en variables ordinales quantitatives et avons utilisé des méthodes statistiques standards pour l'analyse. RÉSULTATS: Au point de référence, nous avons observé que l'ensemble des 12 thèmes abordés par le questionnaire a indiqué une certaine capacité de réaction et des faiblesses en matière de prévention et de contrôle des infections des hôpitaux. Les lacunes clés initiales étaient l'absence d'une équipe dédiée, un équipement de protection individuelle insuffisant et un manque d'espace dédié pour enfiler et enlever cet équipement. Des limites conséquentes ont été observées pour le diagnostic et le traitement de l'hypoxémie. La gestion de l'information et la coordination des soins étaient également sous-optimales. Le suivi ciblé après 5 mois a révélé une amélioration en matière de disponibilité des oxymètres de pouls, des capacités en oxygène et des canules nasales chauffées à haut débit. CONCLUSION: Nos résultats au point de référence peuvent refléter une qualité des soins inégale au début de la pandémie. Le suivi ciblé suggère qu'il conviendrait de renforcer l'écosystème de l'oxygène.

Development of tuberculosis infection control guidelines in a pediatric HIV clinic in sub-Saharan Africa.

SETTING: A well-established pediatric human immunodeficiency virus (HIV) clinic in Lesotho with initial infection control (IC) measures prioritizing blood-borne disease. In line with international recommendations, services have been expanded to include the management of patients with tuberculosis (TB). The creation of comprehensive IC guidelines with an emphasis on TB has become a priority. OBJECTIVE: To provide a model for developing and implementing IC guidelines in ambulatory care facilities in limited-resource settings with high HIV and TB prevalence. Activities: An IC plan that includes guidance covering both general IC measures and TB-specific guidelines was created by integrating local and international recommendations and emphasizing the importance of administrative measures, environmental controls, and disease-specific precautions. An interdisciplinary committee was established to oversee its implementation, monitoring, and evaluation. DISCUSSION: Development and implementation of IC guidelines in resource-limited settings are feasible and should be a priority in high HIV and TB prevalence areas. Education should be the cornerstone of such endeavors. Many interventions can be implemented with minimal expertise and material resources. Administrative support and institutional investment are essential to the sustainability of an effective IC program.

Contexte : Une consultation pour le virus de l'immunodéficience humaine (VIH) pédiatrique bien établie au Lesotho avec des mesures de lutte initialement dirigées en priorité contre les maladies à transmission sanguine. En accord avec les recommandations internationales, les services se sont élargis pour inclure la prise en charge des patients tuberculeux. L'élaboration de directives complètes de lutte contre les infections (IC), avec un accent particulier sur la tuberculose (TB), est devenue une priorité.Objectif : Fournir un modèle d'élaboration et de mise en œuvre de directives d'IC dans des structures de soins ambulatoires aux ressources limitées mais dans un contexte de prévalence élevée du VIH et de la TB.Activités : Un plan d'IC, qui inclut une guidance couvrant à la fois les mesures d'IC en général et les directives spécifiques à la TB, a été élaboré en intégrant les recommandations locales et internationales et en mettant l'accent sur l'importance des mesures administratives, du contrôle de l'environnement et des précautions spécifiques aux différentes maladies. Un comité interdisciplinaire a été établi afin de superviser sa mise en œuvre, son suivi et son évaluation.Discussion : L'élaboration et la mise en œuvre de directives d'IC dans un contexte de ressources limitées sont faisables et devraient être une priorité dans des zones de prévalence élevée de la TB et du VIH. L'éducation devrait être la pierre angulaire de tels projets. De nombreuses interventions peuvent être mises en œuvre avec une expertise et des ressources matérielles minimales. Le soutien administratif et l'investissement des institutions sont essentiels à la pérennité d'un programme efficace d'IC.

Marco de referencia: Un consultorio reconocido de atención de la infección por el virus de la inmunodeficiencia humana (VIH) en los niños en Lesoto, cuyas medidas de control de las infecciones (IC) daban prelación a las enfermedades transmitidas por vía sanguínea. En concordancia con las recomendaciones internacionales, se ampliaron los servicios a fin de incluir el tratamiento de los pacientes con diagnóstico de tuberculosis (TB). En este contexto, la elaboración de directrices exhaustivas de IC con una atención especial en la TB se convirtió en una prioridad.Objetivo: Aportar un modelo que facilite la elaboración y la ejecución de directrices sobre el IC en los establecimientos de atención ambulatoria cuyos recursos son limitados, en entornos con una alta prevalencia de infección por el VIH y TB.Método: Se elaboró un plan de IC con orientaciones sobre las medidas generales de control además de las medidas específicas de la TB, mediante la integración de las recomendaciones locales e internacionales y destacando la importancia de las medidas administrativas, los controles medioambientales y las precauciones específicas de determinadas enfermedades. Se estableció un comité interdisciplinario que supervisó la ejecución, el seguimiento y la evaluación del plan.Conclusión: Es factible elaborar directrices sobre el IC y ponerlas en práctica en los entornos con recursos limitados. Esta iniciativa debe constituir una prioridad en las regiones con alta prevalencia de infección por el VIH y TB. La educación debe constituir la piedra angular de este tipo de iniciativas. Se pueden llevar a cabo muchas intervenciones con un mínimo de conocimientos técnicos y recursos materiales. El respaldo administrativo y la inversión institucional son elementos primordiales en la sostenibilidad de un programa eficaz de IC.

Allogeneic hematopoietic cell transplantation for neuroblastoma: the CIBMTR experience.

Although the role of autologous hematopoietic cell transplantation (auto-HCT) is well established in neuroblastoma (NBL), the role of allogeneic HCT (allo-HCT) is controversial. The Center for International Blood and Marrow Transplant Research conducted a retrospective review of 143 allo-HCT for NBL reported in 1990-2007. Patients were categorized into two different groups: those who had not (Group 1) and had (Group 2) undergone a prior auto-HCT (n=46 and 97, respectively). One-year and five-year OS were 59% and 29% for Group 1 and 50% and 7% for Group 2, respectively. Among donor types, disease-free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not at 5 years post HCT. Patients in CR or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared with those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared with those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.

Modulation of gene expression using electrospun scaffolds with templated architecture.

The fabrication of biomimetic scaffolds is a critical component to fulfill the promise of functional tissue-engineered materials. We describe herein a simple technique, based on printed circuit board manufacturing, to produce novel templates for electrospinning scaffolds for tissue-engineering applications. This technique facilitates fabrication of electrospun scaffolds with templated architecture, which we defined as a scaffold's bulk mechanical properties being driven by its fiber architecture. Electrospun scaffolds with templated architectures were characterized with regard to fiber alignment and mechanical properties. Fast Fourier transform analysis revealed a high degree of fiber alignment along the conducting traces of the templates. Mechanical testing showed that scaffolds demonstrated tunable mechanical properties as a function of templated architecture. Fibroblast-seeded scaffolds were subjected to a peak strain of 3 or 10% at 0.5 Hz for 1 h. Exposing seeded scaffolds to the low strain magnitude (3%) significantly increased collagen I gene expression compared to the high strain magnitude (10%) in a scaffold architecture-dependent manner. These experiments indicate that scaffolds with templated architectures can be produced, and modulation of gene expression is possible with templated architectures. This technology holds promise for the long-term goal of creating tissue-engineered replacements with the biomechanical and biochemical make-up of native tissues.

The quality of life of adult survivors of childhood hematopoietic cell transplant.

Survival rates after myeloablative hematopoietic cell transplantation (HCT) in childhood have improved. We conducted a cross-sectional study evaluating the quality of life (QOL) of 214 adult survivors of a childhood HCT compared with controls using standardized self-report measures with strong psychometric properties to evaluate physical function, psychological function and cognitive symptoms. From these results we conducted a multivariate analysis of risk factors. This analysis for physical functioning showed poorer function among myeloid disease survivors compared with patients with all other diagnoses (P=0.02), men functioned better than women (P=0.05) and those >18 years after transplant functioned more poorly than those <18 years after transplant (P=0.05). Psychological functioning showed that those who received more therapy and females were more likely to be depressed (P=0.03) and (P=0.005). Perceived cognitive symptoms showed that female survivors had more symptoms than male survivors (P=0.01), and those receiving more preceding therapy compared with those with less preceding therapy (P=0.001) or cranial irradiation compared with those without cranial irradiation (P=0.002) had more perceived cognitive symptoms. Overall, these data indicate that the majority of adult survivors of a childhood transplant are functioning well, but some have problems that need to be addressed.

Growth and development after hematopoietic cell transplant in children.

Hematopoietic cell transplantation (HCT) following high-dose chemotherapy or chemoradiotherapy for children with malignant or nonmalignant hematologic disorders has resulted in an increasing number of long-term disease-free survivors. The preparative regimens include high doses of alkylating agents, such as CY with or without BU, and may include TBI. These agents impact the neuroendocrine system in growing children and their subsequent growth and development. Children receiving high-dose CY or BUCY have normal thyroid function, but those who receive TBI-containing regimens may develop thyroid function abnormalities. Growth is not impacted by chemotherapy-only preparative regimens, but TBI is likely to result in growth hormone deficiency and decreased growth rates that need to be treated with synthetic growth hormone therapy. Children who receive high-dose CY-only have normal development through puberty, whereas those who receive BUCY have a high incidence of delayed pubertal development. Following fractionated TBI preparative regimens, approximately half of the patients have normal pubertal development. These data demonstrate that the growth and development problems after HCT are dependent upon the preparative regimen received. All children should be followed for years after HCT for detection of growth and development abnormalities that are treatable with appropriate hormone therapy.

Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia.

Although haematopoietic cell transplantation (HCT) is curative for sickle cell anaemia (SCA), concerns about its short- and long-term toxicities limit its application. A potential toxicity is an adverse effect on growth. To identify an HCT growth effect, serial height and weight measurements from 53 children and adolescents with SCA after receiving a transplant were compared to historical controls. Hierarchical Linear Models for longitudinal data were used for analysis. In general growth was not impaired by HCT for SCA in young children; however, diminished growth may occur if HCT is carried out near or during the adolescent growth spurt.

Effects of fluid insert volume changes on socket pressures and shear stresses: case studies from two trans-tibial amputee subjects.

Fluid inserts potentially help to overcome prosthetic fit problems resulting from stump volume change. The purpose of this investigation was to add fluid to fluid inserts positioned on the inner socket walls of trans-tibial prostheses and to assess their influence on socket stresses. Pressures and shear stresses were measured at 13 sites on the sockets of two trans-tibial amputee subjects while they ambulated at their self-selected walking speeds. Stresses at the transducer sites generally increased with greater fluid addition and, interestingly, both subjects found relatively high fluid insert volumes most comfortable. The magnitudes of stress change were larger than those resulting from alignment, cadence, and componentry changes as reported in the literature. Possible explanations for why subjects found settings that induced higher measured socket stresses more comfortable than those that induced lower measured stresses include: A reduced shear: pressure ratio; the short duration of the study; and reduced stresses at sites not monitored with transducers.

A unique device for controlled electrospinning.

The purpose of this research was to develop a system for controlled electrospinning of fibro-porous scaffolds for tissue engineering applications and to use this system to assess mesh architecture sensitivity to manufacturing parameters. The intent was to achieve scaffolds with well-controlled fiber diameters and inter-fiber spacing. To accomplish these objectives, a custom, closed-loop controlled, electrospinning system was built. The system was unique in that it had a collection surface that was independent of the electrodes. The system allowed independent manipulation and analysis of a number of manufacturing parameters: distance between the electrodes, distance from the nozzle to the collection surface, applied voltage, temperature of the melt, collection surface dielectric strength, and collection surface area. Morphological analysis of fabricated meshes showed that all test parameters significantly affected fiber diameter and inter-fiber spacing. Further, contrary to what is generally accepted in the electrospinning literature, voltage and temperature (inversely related to viscosity) were not the most significant parameters. Features of the collection surface, including dielectric strength and surface area, were more significant. This dominance is, in part, a reflection of the unique electrospinning system used. The collection surface, which was not connected to either of the electrodes, substantially altered the electric field between the electrodes. Using the developed controlled electrospinning system, thermoplastic polyurethane meshes with fiber diameters ranging from 5 to 18 microm with variability less than 1.8% were made; inter-fiber spacing ranged from 4 to 90 microm with variability less than 20.2%. The system has potential use in biomedical applications where meshes with controlled fiber diameter and inter-fiber spacing are of interest.

Changes in interface pressures and shear stresses over time on trans-tibial amputee subjects ambulating with prosthetic limbs: comparison of diurnal and six-month differences.

For trans-tibial amputees maintenance over time of a quality fit of the prosthesis to the residual limb is an important clinical challenge. The purpose of this research was to compare diurnal and long-term (5 weeks to 6 months) interface stress changes as well as variance in the change in cross-sectional area down the length of the residual limb. If long-term changes were simply accentuated diurnal fluctuations then this result would suggest similar treatment methods should be used for both conditions. Interface pressures and shear stresses at 13 sites and residual limb shape were measured on eight trans-tibial amputee subjects using patellar-tendon-bearing prostheses. Data were collected at diurnal intervals (within the same day at least 5 h apart) as well as at long-term intervals (5, 10, 15, 20, and 25 weeks apart). Absolute diurnal interface stress changes were not significantly different from those at 5-weeks intervals but were significantly smaller than those at 15, 20, and 25-weeks intervals. Mean interface stress changes increased significantly (p<0.05) for increased session-to-session intervals. Variance of the change in cross-sectional area down the length of the residual limb was significantly smaller for diurnal intervals than for 6-months intervals, indicating that long-term changes were more localized than diurnal changes. These results indicate that long-term changes are not simply accentuated diurnal fluctuations, suggesting that different treatment methods should be used to treat each condition.

Small fiber diameter fibro-porous meshes: tissue response sensitivity to fiber spacing.

The purpose of this research was to determine if fiber spacing for small fiber diameter fibro-porous meshes affected tissue response in vivo. Disk-shaped polyurethane meshes, with mean fiber diameters of 7.6 microm and fiber spacing between 6 and 68 microm, were implanted in rat subcutaneous dorsum for 5-week intervals and then prepared for light microscopy and morphological analysis. Results showed that implants with 12- to 68-microm spacing had no histologically apparent fibrous capsule around the perimeter, a result different from that for 6-microm spacing samples that had a capsule around a mean of 34.2% of the perimeter. For the 12- to 68-microm spacing range, a mean of 21.0% of individual fibers within the meshes were encapsulated. Qualitatively, it appeared that larger fibers were encapsulated more frequently than smaller ones. When nodeless or baggy meshes were implanted, cells tended to cluster three or more fibers into groups and then encapsulate each group. Over the 6- to 68-microm spacing range, cell nuclei volume fraction within the meshes increased from the 6- to the 29-microm spacing (p = 0.000) and then decreased from the 29- to the 68-microm spacing (p = 0.015). There was a trend of an increase in local vessel volume fraction with spacing over the 6- to 68-microm range, though the relationship was weak. The results indicate that the reason for the lack of encapsulation of small-fiber fibro-porous meshes is not exclusively a pore boundary explanation, as is proposed for small-pore porous meshes.

Outcome of allogeneic bone marrow transplantation for children with advanced acute myeloid leukemia.

Allogeneic bone marrow transplantation (BMT) may offer the only chance of cure for children with acute myeloid leukemia (AML) in second complete remission (CR2) or with relapsed disease, but the outcome of these patients has not been clearly defined. We conducted a retrospective study of 58 children, median age 7.4 years (range 0.8-17.3), who received matched related or unrelated BMT at our institution for AML in CR2 (n = 12), in untreated first relapse (n = 11) or with refractory disease (n = 35), to identify risk factors associated with disease-free survival (DFS). Life threatening to fatal regimen-related toxicity was observed in 22% of patients. Estimates of DFS at 5 years (95% confidence interval) for patients in CR2, with untreated first relapse and refractory disease were 58% (27-80%), 36% (11-63%) and 9% (2-21%), respectively. Non-relapse mortality estimates were 0%, 27% (0-54%) and 17% (5-30%), and relapse estimates were 42% (14-70%), 36% (8-65%) and 74% (60-89%), respectively. Advanced disease phase and cytogenetic abnormalities at the time of transplantation were each associated with decreased DFS and increased relapse in multivariable regression models. Survival for children transplanted in CR2 or untreated first relapse is higher than that previously reported, but relapse remains the major cause of treatment failure regardless of disease stage.

Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience.

The purpose of this study was to evaluate the role of allogeneic bone marrow transplantation (BMT) in children with myelodysplastic syndrome (MDS). In total, 94 consecutive pediatric patients with MDS received an allogeneic BMT from 1976 to 2001 for refractory anemia (RA) (n=25), RA with ringed sideroblasts (RARS) (n=2), RA with excess blasts (RAEB) (n=20), RAEB in transformation (RAEB-T) (n=14), juvenile myelomonocytic leukemia (JMML) (n=32) or chronic myelomonocytic leukemia (CMML) (n=1). The estimated 3-year probabilities of survival, event-free survival (EFS), nonrelapse mortality and relapse were 50, 41, 28 and 29%, respectively. Patients with RA/RARS had an estimated 3-year survival of 74% compared to 68% in those with RAEB and 33% in patients with JMML/CMML. In multivariable analysis, patients with RAEB-T or JMML were 3.9 and 3.7 times more likely to die compared to those with RA/RARS and RAEB (P=0.005 and 0.004, respectively). Patients with RAEB-T were 5.5 times more likely to relapse (P=0.01). The median follow-up among the 43 surviving patients is 10 years (range 1-25). We conclude that allogeneic BMT for children with MDS is well tolerated and can be curative.

Biomaterial mesh seeded with vascular remnants from a quail embryo has a significant and fast vascular templating effect on host implant tissue.

Seeding biomaterial implants with vascular remnants has the potential to facilitate host vessel ingrowth via a vascular templating effect. Vessels from quail embryo were grown into a polyurethane fibroporous mesh and the samples were frozen-thawed and then implanted in rat subcutaneous dorsum. Results show that the process of revascularization, using the quail vessel remnants, occurred over the first 3 days after implantation and resulted in functional vessels. Rat endothelial cells were found in the quail templates on day 1. On day 2 the endothelial cells formed a confluent layer and started producing laminin. By this time approximately 70% of the rat vessel tissue in the implant had grown into quail vascular remnants, indicating that the quail vessels were extensively used as templates for host vessel ingrowth. Laminin production was increased and collagen production started by day 3, at which time the vessels were functional in that rat blood flowed through them. At 2 weeks host vessel density was approximately twice that of control samples; thus the implant substantially enhanced the size of the vascular network. For meshes that additionally received vascular endothelial growth factor (VEGF) seeding before implantation, vessel density at 2 weeks was enhanced over samples with quail embryo alone. However, the quail was found to have the greatest angiogenic effect above any of the implant components-quail, VEGF, and collagen. Tissue engineering of vessel templates may thus be a realistic solution to effective fast vascularization of biomaterials.

Fibrous encapsulation of single polymer microfibers depends on their vertical dimension in subcutaneous tissue.

The purpose of this research was to investigate possible explanations for why small-diameter microfiber implants do not experience encapsulation in subcutaneous tissue as do large-diameter fiber implants. Single polypropylene microfibers of approximately rectangular cross-section with rounded edges were twisted about their longitudinal axes and affixed at their ends to polycarbonate frames. The frames were implanted in rat subcutaneous dorsum for a 5-week period, then removed and processed for light microscopy analysis. Fibrous capsule presence/absence and thickness around the implants were assessed, and their relationships to geometric features of the fibers investigated. A logistic regression analysis between presence/absence of a fibrous capsule and geometric features of interest demonstrated strong predictive ability (92.4% correct predictions) for implant height and a well-defined threshold separating the presence and absence of a fibrous capsule at 5.9 microm (p < 0.001). Implant height was defined as the vertical distance between the most superficial and deepest level of the implant. This 5.9-microm threshold value of implant height is comparable to the 6.0-microm diameter threshold for capsule presence/absence in fibers of circular cross-section [Sanders et al. J Biomed Mater Res 2000; 52(1):231-237]. Fiber major axis length, minor axis length, aspect ratio, surface area per unit length, implant width, and implant angle did not show similar predictive ability or a well-defined threshold separating the presence and absence of a fibrous capsule. It is reasoned that for fibers greater than the threshold height of 5.9 microm, separation of collagen fibers in the extracellular matrix creates dead space regions adjacent to the fibers that attract inflammatory cells and stimulate fibrous capsule formation.

Polymer microfiber mechanical properties: a system for assessment and investigation of the link with fibrous capsule formation.

A novel microtensile testing instrument was developed to assess the mechanical properties of small-diameter polyethylene, polyurethane, and polyester microfibers. The instrument had a root-mean-square error of 2.96 microN for force measurement and 1.91 microm for displacement measurement. Microfibers ranging in diameter from 1.0 to 10.9 microm were strained at 2 mm/s in the device, and the slopes of their stress-strain curves (material moduli) were determined. Correlations between material modulus and previously published data on fibrous capsule presence and thickness for implanted polyethylene, polyurethane, and polyester microfibers were investigated. Results for the 1.0-5.9-microm microfiber diameter range showed that neither the percentage of unencapsulated fibers nor the capsule thickness correlated well with modulus. Correlation coefficients were 0.04 and 0.09, respectively. However, for the 6.0-10.9 microm diameter range the correlations were strong, 1.00 for both percentage of unencapsulated fibers and capsule thickness. It is suggested that the results reflect the greater attachment and mechanical interaction of cells with microfibers for the 6.0-10.9 microm-diameter range than for the 1.0-5.9 microm-diameter range.

Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation.

The incidence, etiology, outcome, and risk factors for developing pneumonia late after hematopoietic stem cell transplantation (SCT) were investigated in 1359 patients transplanted in Seattle. A total of 341 patients (25% of the cohort) developed at least one pneumonic episode. No microbial or tissue diagnosis (ie clinical pneumonia) was established in 197 patients (58% of first pneumonia cases). Among the remaining 144 patients, established etiologies included 33 viral (10%), 31 bacterial (9%), 25 idiopathic pneumonia syndrome (IPS, 7%), 20 multiple organisms (6%), 19 fungal (6%), and 16 Pneumocystis carinii pneumonia (PCP) (5%). The overall cumulative incidence of first pneumonia at 4 years after discharge home was 31%. The cumulative incidences of pneumonia according to donor type at 1 and 4 years after discharge home were 13 and 18% (autologous/syngeneic), 22 and 34% (HLA-matched related), and 26 and 39% (mismatched related/unrelated), respectively. Multivariate analysis of factors associated with development of late pneumonia after allografting were increasing patient age (RR 0.5 for <20 years, 1.2 for >40 years, P=0.009), donor HLA-mismatch (RR 1.6 for unrelated/mismatched related, P=0.01), and chronic graft-versus-host disease (GVHD; RR 1.5, P=0.007). Our data suggest that extension of PCP prophylaxis may be beneficial in high-risk autograft recipients. Further study of long-term anti-infective prophylaxis based on patient risk factors after SCT appear warranted.

How does skin adapt to repetitive mechanical stress to become load tolerant?

Skin breakdown from mechanical stress application is a difficult health care problem for lower-limb amputees using prosthetic limbs. Post-operative treatments to encourage skin adaptation do exist, but are largely unsuccessful. Potentially, by understanding skin adaptation on a molecular level, appropriate biomolecules can be identified and then delivered to skin to encourage adaptation in at-risk patients. Based from a critical review of the literature, it is expected that adaptation occurs by forming new collagen fibrils with larger diameters as opposed to increasing diameters of existing fibrils. Small collagen fibril breakdown by stress activated metalloproteinases is expected to be followed by increased expressions of decorin, biglycan, fibromodulin, lumican, thrombospondin-2, and collagens I and III, facilitating formation of new fibrils with larger diameters. After remodeling, total collagen fibril cross-sectional area is expected to return to baseline values since increased collagen content would increase mass and be redundant towards the purpose of adaptation.