Acceleration of Amphibian Forelimb Regeneration By Polypeptide Growth Factors

Growth factors are potentially important modulators of epimorphic regeneration. This study examined effects of intraperitoneal administration of selected growth factors on limb regeneration of adult newts, Notophthalmus viridescens. These agents stimulated regeneration, producing overlapping but nonidentical effects. Fibroblast growth factor-2 (FGF-2) and insulin-like growth factor I (IGF-I) stimulated bud emergence (8.3 ± 0.6 and 8.3 ± 0.7 days, respectively, vs 11.4 ± 1.1 days for controls). Progression to the cone stage was enhanced by both FGF-2 and transforming growth factor beta 5 ( TGF-~ 5) ; 14.6 ± 0.5 and 15.4 ± 0.4 days with FGF-2 and TGF-~5 , respectively, vs 16.5 ± 0.5 days in controls. Insulin accelerated attainment of the palette stage, 17.0 ± 0.7 days vs 19.0 ± 0.4 days for controls. No treatments affected attaining the digital stage; means between 22.4 and 23.4 days. Histological analysis revealed changes consistent with gross observations. In addition, regenerates from newts treated with FGF-2, TGF-~5. and insulin displayed signs of greater (or earlier) histogenesis than did control animals. These results are consistent with the notion that FGF-2, TGF-~5. and possibly lGF-I stimulate proliferation of blastema cells and that insulin, FGF-2, and TGF-~5 promote differentiation and histogenesis during forelimb regeneration. In conclusion, these results demonstrate that several polypeptide growth factors positively affect the progress of forelimb regeneration, that different growth factors influence the same or similar events of epimorphic regeneration, and that diverse growth factors have nonidentical effects on regeneration

Apoptosis of Rat Myoblasts Is Induced In Vitro by Late, but Not Early, Wound Fluids

Interstitial fluids from late wound repair environments are not regeneration permissive as judged by their inability to promote either proliferation or differentiation of myoblasts in vitro. This irwestigation considered whether apoptosis (induced death) was an alternative fate for myoblasts exposed to these interstitial fluids. Myoblast fate was assessed by cell counts, tritiated thymidine release, and propidium iodide staining. Fluids from early wounds increased mean cell counts and induced little thymidine release or propidium iodide labeling. In contrast, fluids from late wounds reduced cell counts and induced both thymidine release and propidium iodide labeling. These data suggest that interstitial fluids from late wounds might trigger apoptosis. It is presently unclear how death is induced in these environments. Further study is required to ascertain whether these effects represent an impediment to skeletal muscle regeneration only or if they reflect a previously unidentified role for late wound fluids in postinjury resolution

Wound Repair

Following injury, a series of events is initiated that includes global and local reactions. Global reactions, such as inflammatory and immunological responses as well as adjustments in neural and endocrine status, are directed at marshaling the organism\u27s resources for dealing with changes in its integrity and the potential threat of infection or other complications. Injury entails cell and tissue damage and often a physical breach in the barrier against the outside world (e.g., skin). Local reactions are exemplified by immediate hemostatic (e.g., blood clotting) events followed by changes in local cellular composition created by the inflammatory infiltrate and adjustments in resident cell function. These are accompanied by local metabolic adjustments. These events are directed at restoring local integrity and establishing a relevant steady-state. The typical events of wound repair are extensively documented and well characterized. In recent years, research has explored regulation of wound repair at the cellular level and has sought alternative modes for correcting tissue damage that yield more efficient restoration of preinjury conditions (e.g., regeneration). Since repair typically leads to replacement of damaged tissues with connective tissue, reduction in function invariably accompanies wound healing. Where tissue damage is slight, this causes little or no problem for the individual. However, when tissue damage is great, as for example when a finger or limb is lost, the compromise of wound repair carries a noticeable price (both in actual costs and in quality of life for the affected individual)

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Regeneration - The Road Not Taken

Regeneration and repair are mutually-exclusive, adaptive responses to injury. The events associated with each process are well characterized. However, cellular and molecular mechanisms for their regulation are only now beginning to be defined. Moreover, full appreciation for factors that predispose to these contrasting pathways is not yet available. This article presents a perspective on regeneration and repair that suggests specific relationships between these modes of responding to injury. Injury provokes a coordinated pattern of response to tissue damage. At the wound site, local events determine whether tissue restoration or replacement occurs. Interplay among parenchymal and stromal cells at the site of injury, elements of the inflammatory infiltrate, and components of the immediate wound environment contribute to selecting an effector population for activation. The proposed model suggests that selecting parenchymal cells over stroma favors regeneration while the opposite favors repair. In addition, this model indicates that an integral aspect of both processes is the reintegration of effector cells into the damaged tissue or organ. Numerous illustrations suggest that regeneration and repair share common roots but diverge after injury. Viewing regeneration and repair as two equivalent pathways along the same continuum provides an integrative approach to resolving the apparent contrasts between these two means of responding to injury. Focusing on their parallels should facilitate defining means through which crossover from one process to the other might be achieved

Basic Fibroblast Growth Factor And Hepatocyte Growth Factor Content Of Wound, Repair, And Muscle Regeneration Fluids

Injury produces marked changes to the local environment. Changes in both diversity and availability of bioactive substances at wound sites might discriminate between repair and regeneration microenvironments and selectively drive events leading to final resolution. Among factors with potential relevance to wound repair and regeneration are basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF). In this study, concentrations of these factors were determined in fluids derived from wound, repair, and regeneration-conditioned models using enzyme-linked immunosorbent assays. All fluids contained substantial concentrations of bFGF which rose 5- to I 5-fold as resolution to injury was achieved. Mean bFGF content in regeneration fluid was three times greater than in wound fluid (645.5 vs 224.2 pg/mL) early after injury (days I - 3). Maximal bFGF content of regeneration fluids did not differ from that of wound fluids (3454.0 vs 3565.5 pg/mL), but was achieved about 5 days earlier (i.e., 9 - II days rather than (mathematical symbol) 5 days postinjury). In contrast, HGF was not consistently detected and was at much lower levels in wound, repair, or regeneration fluids . HGF content does not correlate either with repair or regeneration or with time postinjury. Basic FGF appears to provide a convenient index of postinjury age but is a poor discriminator for wound repair and regeneration