Angiogenesis induction and regression in human surgical wounds

Angiogenesis in human wound healing is not well characterized, with only sparse information available regarding the maturation and fate of vessels formed as a consequence of human tissue repair. Therefore, this study aimed to establish the temporal profile of angiogenesis in human dermal wounds. Punch biopsies were obtained under local anesthesia from 45 patients following breast surgery. Scars were predominantly between 2 and 52 weeks after surgery but in five patients were > 52 weeks. Control samples were taken from breast skin peroperatively (n = 24). Quantification of vascular density was performed using the Chalkley grid, following antibody staining for platelet endothelial cell adhesion molecule. Vascular patterns, wound cellularity and morphology were also determined. Cumulative microvessel density was increased in all samples when compared to controls (p < 0.05). This was greatest 2 to 24 weeks following surgery 17 (15-21) median (range), decreased thereafter, but remained elevated compared to controls even in the mature scars > 52 weeks. Control tissue showed an ordered morphological arrangement of dermal structures, collagen, and elastic fibers. However, wounding resulted in marked structural distortion for up to 15 weeks. In conclusion, this study shows for the first time the prolonged persistence of both microvessels and cellularity (fibroblastic cells), in addition to structural distortion in human dermal wounds, which is in contrast to previous in vitro and in vivo studies.     

Adaptations in the Microarchitecture and Load Distribution of Maternal Cortical and Trabecular Bone in Response to Multiple Reproductive Cycles in Rats

Pregnancy, lactation, and weaning result in dramatic changes in maternal calcium metabolism. In particular, the increased calcium demand during lactation causes a substantial degree of maternal bone loss. This reproductive bone loss has been suggested to be largely reversible, as multiple clinical studies have found that parity and lactation history have no adverse effect on postmenopausal fracture risk. However, the precise effects of pregnancy, lactation, and post‐weaning recovery on maternal bone structure are not well understood. Our study aimed to address this question by longitudinally tracking changes in trabecular and cortical bone microarchitecture at the proximal tibia in rats throughout three cycles of pregnancy, lactation, and post‐weaning using in vivo μCT. We found that the trabecular thickness underwent a reversible deterioration during pregnancy and lactation, which was fully recovered after weaning, whereas other parameters of trabecular microarchitecture (including trabecular number, spacing, connectivity density, and structure model index) underwent a more permanent deterioration, which recovered minimally. Thus, pregnancy and lactation resulted in both transient and long‐lasting alterations in trabecular microstructure. In the meantime, multiple reproductive cycles appeared to improve the robustness of cortical bone (resulting in an elevated cortical area and polar moment of inertia), as well as increase the proportion of the total load carried by the cortical bone at the proximal tibia. Taken together, changes in the cortical and trabecular compartments suggest that whereas rat tibial trabecular bone appears to be highly involved in maintaining calcium homeostasis during female reproduction, cortical bone adapts to increase its load‐bearing capacity, allowing the overall mechanical function of the tibia to be maintained. © 2017 American Society for Bone and Mineral Research.     

Continuous Acquisition of MHC:Peptide Complexes by Recipient Cells Contributes to the Generation of Anti‐Graft CD8+ T Cell Immunity

Understanding the evolution of the direct and indirect pathways of allorecognition following tissue transplantation is essential in the design of tolerance‐promoting protocols. On the basis that donor bone marrow–derived antigen‐presenting cells are eliminated within days of transplantation, it has been argued that the indirect response represents the major threat to long‐term transplant survival, and is consequently the key target for regulation. However, the detection of MHC transfer between cells, and particularly the capture of MHC:peptide complexes by dendritic cells (DCs), led us to propose a third, semidirect, pathway of MHC allorecognition. Persistence of this pathway would lead to sustained activation of direct‐pathway T cells, arguably persisting for the life of the transplant. In this study, we focused on the contribution of acquired MHC‐class I on recipient DCs during the life span of a skin graft. We observed that MHC‐class I acquisition by recipient DCs occurs for at least 1 month following transplantation and may be the main source of alloantigen that drives CD8⁺ cytotoxic T cell responses. In addition, acquired MHC‐class I:peptide complexes stimulate T cell responses in vivo, further emphasizing the need to regulate both pathways to induce indefinite survival of the graft.     

Secondary thyroidectomy: A twenty-year experience

Secondary thyroidectomy is an operation generally considered to be associated with a significantly increased risk of damage to the recurrent laryngeal nerves and parathyroid glands. During a 20-year period, to December, 1986, a total of 408 secondary thyroidectomies were performed. The majority (n=227) were for recurrent nodular goiter, followed by reoperations for thyroid cancer (n=151), and operations for secondary thyrotoxicosis (n=30). The incidence of operative recurrent laryngeal palsy was 1.5% over the 20-year period, while the incidence of permanent hypoparathyroidism fell from 3.5% during the first 15 years to 1.6% over the last 5 years, with a similar fall in the incidence of transient hypocalcemia (8.4% down to 4.8%). The risk of complications can be minimized by careful attention to operative detail, employing the technique of capsular dissection with preservation of the vascular supply to the parathyroid glands while protecting the recurrent laryngeal nerve.

---

Resumen La tiroidectomía secundaria es una operación generalmente considerada como de riesgo significativamente mayor en cuanto a lesión de los nervios recurrentes laríngeos y de las glándulas paratiroideas. En el curso de un periodo de 20 años, hasta diciembre de 1986, se realizaron 408 tiroidectomías secundarias. La mayoría (n=227) fueron realizadas por bocio nodular recurrente, seguidas de reoperaciones por cáncer tiroideo (n=151), y de operaciones por tirotoxicosis secundaria (n=30). La incidencia de parálisis del nervio recurrente laríngeo fue de 1.5% en este periodo de 20 años, en tanto que la incidencia de hipoparatiroidismo permanente descendió de 3.5% en los primeros 15 años a 1.6% en los últimos 5 años, con un descenso similar en la incidencia de hipocalcemia transitoria (8.4% a 4.8%). El riesgo de complicaciones puede ser reducido al mínimo mediante cuidadosa atención al detalle de la técnica quirúrgica, el empleo de la técnica de disección capsular con preservación de la vascularización de las glándulas paratiroides mientras se protege el nervio recurrente laríngeo.

---

Résumé On considére que le risque de lésions des nerfs récurrents et des parathyroïdes est augmenté dans la thyroïdectomie secondaire. Dans les 20 ans avant décembre 1986, nous avons effectué 408 thyroïdectomies secondaires. La plupart (n=227) étaient indiquées pour goitre nodulaire récidivant, suivi de cancer (n= 151), et ensuite de thyréotoxicose (n=30). L'incidence de paralysie laryngée récurrente était de 1.5% pendant ces 20 ans, alors que l'incidence d'hypoparathyroïdie permanente était de 3.5% pendant les 15 premières années et de 1.6% pour les 5 dernières années. Parallèlement, le taux d'hypocalcémie transitoire tombe de 8.4% à 4.8% pendant la même période. On réduit le risque de complications grâce à une technique rigoureuse et en restant intracapsulaire pour conserver la vascularisation des glandes parathyroïdiennes et protéger les nerfs récurrents.

---

---

Presented at the International Association of Endocrine Surgeons in Sydney, Australia, September, 1987.     

Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection

Because CD4+ T cells play a key role in aiding cellular immune responses, we wanted to assess whether increasing numbers of gene-engineered antigen-restricted CD4+ T cells could enhance an antitumor response mediated by similarly gene-engineered CD8+ T cells. In this study, we have used retroviral transduction to generate erbB2-reactive mouse T-cell populations composed of various proportions of CD4+ and CD8+ cells and then determined the antitumor reactivity of these mixtures. Gene-modified CD4+ and CD8+ T cells were shown to specifically secrete Tc1 (T cytotoxic-1) or Tc2 cytokines, proliferate, and lyse erbB2+ tumor targets following antigen ligation in vitro. In adoptive transfer experiments using severe combined immunodeficient (scid) mice, we demonstrated that injection of equivalent numbers of antigen-specific engineered CD8+ and CD4+ T cells led to significant improvement in survival of mice bearing established lung metastases compared with transfer of unfractionated (largely CD8+) engineered T cells. Transferred CD4+ T cells had to be antigen-specific (not just activated) and secrete interferon gamma (IFN-gamma) to potentiate the antitumor effect. Importantly, antitumor responses in these mice correlated with localization and persistence of gene-engineered T cells at the tumor site. Strikingly, mice that survived primary tumor challenge could reject a subsequent rechallenge. Overall, this study has highlighted the therapeutic potential of using combined transfer of antigen-specific gene-modified CD8+ and CD4+ T cells to significantly enhance T-cell adoptive transfer strategies for cancer therapy.     

A Systematic Review of the Patient- and Carer-Related Factors Affecting the Experience of Pain for Advanced Cancer Patients Cared for at Home

Context

Effective pain management is a priority in the palliative care of advanced cancer patients. A body of research is emerging examining the factors that influence the management and experience of pain for such individuals. Identifying such factors should allow for the development of targeted interventions to improve pain management in the home while ultimately reducing unnecessary suffering for the patient.

COVID-19 and biomarkers of thrombosis: focus on von Willebrand factor and extracellular vesicles

Journal of Thrombosis and Thrombolysis - COVID-19, caused by the SARS-CoV-2 virus, is responsible for a pandemic of unparalleled portion over the past century. While the acute phase of infection...     

A cross-sectional comparison of three self-reported functional indices in scleroderma

OBJECTIVES: In scleroderma, outcome measures such as skin score provide only limited information about the functional impact of the disease. The requirement for validated and convenient instruments that reliably reflect disease morbidity is now recognized. This study compares the Disability Index of the Health Assessment Questionnaire (HAQ-DI) with two more recently developed scleroderma-specific tools: scleroderma-visual analogue scales (scleroderma-VAS) and the UK scleroderma Functional Score (UKFS). In addition, the use of clinical and laboratory measures as predictors of disease severity have been examined. METHODS: One hundred and fifteen consecutive patients were studied. Subjects completed the 20-item HAQ-DI, the scleroderma-VAS and a questionnaire related to hand and muscle function (UKFS). Clinical details, measurement of maximal hand-spread, fist-closure and investigations for internal organ involvement were recorded. RESULTS: Over 68% of patients with diffuse disease had moderate to severe disease on the UKFS, compared with 44% with limited disease. The mean UKFS in diffuse disease was 14.7 (s.d. 9.1) and 10.6 (s.d. 8.5) in the limited subset (P=0.02). The mean HAQ-DI in diffuse disease was 1.23 (s.d. 0.77) and 0.79 (s.d. 0.75) in the limited subset (P=0.005). The HAQ-DI showed significant correlation with UKFS (r=0.9; P < 0.001). Several clinical and laboratory measures were associated with higher HAQ-DI and UKFS. CONCLUSIONS: This is the first comparative study of the UKFS and the HAQ-DI. These data show a strong correlation between assessment methods. Higher scores correlated with clinical and laboratory indicators of severe disease. Used together, these inexpensive tools assess general and organ-specific symptoms, as well as functional limitation.