Expression of epithelial matrix molecules collagen and laminin and corresponding integrins in chronic wounds

Re-epithelialization of cutaneous wounds is a coordinated process of proliferation and migration of keratinocytes at the wound edge. The study objective was to identify the differences in epidermal morphology, keratinocyte proliferation and matrix molecules (laminin 1, laminin 5, type IV collagen) and their specific integrin (α3, α6) expression in biopsies of meshed split thickness grafted and chronic wounds. The mean mitotic index of keratinocytes (ratio of cell cycle associated antigen Ki-67 expressing keratinocytes to basal keratinocytes) was highest in chronic wounds (38.7%) compared to acute wounds (22.25%, range 5.7% to 54%). The mean thickness of the hyper-proliferative epithelium at the wound edge of chronic wounds was 0.69 mm compared to 0.15 mm at the wound margin of split thickness grafted wounds. Both chronic wounds and skin grafted wounds exhibited strong laminin 5 immunoreactivity at the basal side of the epithelium, which extended under the most forward keratinocytes. Laminin 1 and type IV collagen immunoreactivity did not extend to the wound margin in either skin grafted or chronic wounds. In both transplanted skin and chronic wounds, the integrin sub-units α3 and α6 exhibited a strong pericellular immunoreactivity on the leading keratinocytes of the wound margin. Our data demonstrates that the proliferation of keratinocytes and the expression of associated integrins are not impaired in chronic wounds. Presented at the 33rd Congress of the Association of German Plastic Surgeons, Germany, 18–21 September, 2002.     

Personality disorders evident by early adulthood and risk for anxiety disorders during middle adulthood

Data from the Children in the Community Study, a prospective longitudinal investigation, were used to investigate the association of personality disorder (PD) traits, evident by early adulthood, with risk for development of anxiety disorders by middle adulthood. Individuals without a history of anxiety disorders who met diagnostic criteria for >or=1 PD by early adulthood were at markedly elevated risk for agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, and panic disorder by middle adulthood. Antisocial, avoidant, borderline, dependent, depressive, histrionic, obsessive-compulsive, passive-aggressive, and schizotypal PD traits, evident by early adulthood, were associated with elevated risk for >or=1 anxiety disorder during middle adulthood. These associations remained significant after a history of anxiety disorder and co-occurring Axis I psychiatric disorder was controlled statistically. Findings of this study suggest that some types of PD traits that become evident by early adulthood may contribute to increased risk for the development of anxiety disorders by middle adulthood.     

Finite element analysis performed on radius and tibia HR‐pQCT images and fragility fractures at all sites in men

Few studies have investigated bone microarchitecture and biomechanical properties in men. This study assessed in vivo both aspects in a population of 185 men (aged 71 ± 10 years) with prevalent fragility fractures, compared to 185 controls matched for age, height, and weight, from the Structure of the Aging Men's Bones (STRAMBO) cohort. In this case‐control study, areal BMD (aBMD) was measured by DXA, bone microarchitecture was assessed by high resolution (HR)‐pQCT, and finite element (µFE) analysis was based on HR‐pQCT images of distal radius and tibia. A principal component (PC) analysis (PCA) was used to study the association of synthetic PCs with fracture by computing their odds ratio (OR [95%CI]) per SD change. Specific associations with vertebral fracture (n = 100), and nonvertebral fracture (n = 85) were also computed. At both sites, areal and volumetric BMD, cortical thickness and trabecular number, separation, and distribution were significantly worse in cases than in controls, with differences ranging from ?6% to 15%. µFE‐derived stiffness and failure load were 8% to 9% lower in fractures (p < .01). No difference in load distribution was found between the two groups. After adjustment for aBMD, only differences of µFE‐derived stresses, stiffness, and failure load at the tibia remained significant (p < .05). PCA resulted in defining 4 independent PCs, explaining 83% of the total variability of bone characteristics. Nonvertebral fractures were associated with PC1, reflecting bone quantity and strength at the radius (tibia) with OR = 1.64 [1.27–2.12] (2.21 [1.60–3.04]), and with PC2, defined by trabecular microarchitecture, with OR = 1.27 [1.00–1.61]. Severe vertebral fractures were associated with PC1, with OR = 1.56 [1.16–2.09] (2.21 [1.59–3.07]), and with PC2, with OR = 1.55 [1.17–2.06] (1.45 [1.06–1.98]). In conclusion, microarchitecture and biomechanical properties derived from µFE were associated with all types of fractures in men, showing that radius and tibia mechanical properties were relatively representative of distant bone site properties. © 2011 American Society for Bone and Mineral Research.     

Medical epidemiology of patients surviving ten years after liver transplantation

Simo KA, Sereika S, Bitner N, Newton KN, Gerber DA. Medical epidemiology of patients surviving ten years after liver transplantation.
Clin Transplant 2011: 25: 360–367. © 2010 John Wiley & Sons A/S. Abstract: The transition into extended long‐term follow‐up after liver transplantation raises a new series of issues with respect to continuing care of this population. A retrospective study was performed, analyzing patients who underwent orthotopic liver transplant (OLT) and survived ≥10 yr at a single institution. Long‐term comorbidities such as diabetes mellitus (DM), hypertension (HTN), chronic kidney disease (CKD), coronary artery disease (CAD), and obesity were identified and standardized prevalence ratios ([SPR]) utilized to compare with the general US population. There was an increased prevalence of HTN ([SPR] = 2.25 ± 0.61), DM ([SPR] = 2.67 ± 0.72), and CKD ([SPR] = 15.3 ± 4.04) but not CAD or obesity. In multivariate analysis, non‐viral etiology of end‐stage liver disease was associated with CKD (OR 3.42 CI 1.11–10.53), and an initial glomerular filtration rate (GFR) <60 mL/min per 1.73 m² (CKD stages III–V) was associated with HTN (OR 4.62 CI 1.14–18.73) after OLT. Creatinine ≥1.5 mg/dL at 10 yr was associated with an initial GFR <60 mL/min per 1.73 m² (p = 0.000) and CAD after OLT (p = 0.012). Patients, 10 yr after OLT, have a significantly higher prevalence of HTN, DM, and CKD than the general population, which is not confounded by obesity. Increased vigilance and proactive management are required to further improve long‐term outcomes.     

Wnt5a as an Effector of TGFβ in Mammary Development and Cancer

Wnt5a is a member of the Wingless-related/MMTV-integration family of secreted growth factors, which are involved in a wide range of cellular processes. Wnt signaling can be broadly divided into two categories the canonical, ß-catenin-dependent pathway and the non-canonical ß-catenin-independent pathway. Wnt5a is a non-canonical signaling member of the Wnt family. Loss of Wnt5a is associated with early relapse of invasive breast cancer, increased metastasis, and poor survival in humans. It has been shown that TGF-ß directly regulates expression of Wnt5a in mammary gland and that Wnt5a mediates the effects of TGF-ß on branching during mammary gland development. Here we review the evidence suggesting Wnt5a acts as an effector of TGF-ß actions in breast cancer. It is suggested that the tumor suppressive functions of TGF-ß involve Wnt5a-mediated antagonism of Wnt/ß-catenin signaling and limiting the stem cell population. Interactions between TGF-ß and Wnt5a in metastasis appear to be more complex, and may depend on specific cues from the microenvironment as well as activation of specific intracellular signaling pathways.     

Postnatal HIV transmission in breastfed infants of HIV‐infected women on ART: a systematic review and meta‐analysis

Introduction : To systematically review the literature on mother‐to‐child transmission in breastfed infants whose mothers received antiretroviral therapy and support the process of updating the World Health Organization infant feeding guidelines in the context of HIV and ART. Methods : We reviewed experimental and observational studies; exposure was maternal HIV antiretroviral therapy (and duration) and infant feeding modality; outcomes were overall and postnatal HIV transmission rates in the infant at 6, 9, 12 and 18 months. English literature from 2005 to 2015 was systematically searched in multiple electronic databases. Papers were analysed by narrative synthesis; data were pooled in random effects meta‐analyses. Postnatal transmission was assessed from four to six weeks of life. Study quality was assessed using a modified Newcastle‐Ottawa Scale (NOS) and GRADE. Results and discussion : Eleven studies were identified, from 1439 citations and review of 72 abstracts. Heterogeneity in study methodology and pooled estimates was considerable. Overall pooled transmission rates at 6 months for breastfed infants with mothers on antiretroviral treatment (ART) was 3.54% (95% CI: 1.15–5.93%) and at 12 months 4.23% (95% CI: 2.97–5.49%). Postnatal transmission rates were 1.08 (95% CI: 0.32–1.85) at six and 2.93 (95% CI: 0.68–5.18) at 12 months. ART was mostly provided for PMTCT only and did not continue beyond six months postpartum. No study provided data on mixed feeding and transmission risk. Conclusions : There is evidence of substantially reduced postnatal HIV transmission risk under the cover of maternal ART. However, transmission risk increased once PMTCT ART stopped at six months, which supports the current World Health Organization recommendations of life‐long ART for all.     

Rapid response of facial vitiligo to 308nm excimer laser and topical calcipotriene

Objective: Vitiligo is a common depigmenting condition that carries a high psychosocial morbidity. Many of the current topical and light therapies aid in repigmentation but require extensive treatment periods and carry unwanted side effects. The excimer laser is a newer treatment option that can induce repigmentation in an abbreviated time frame without global exposure to radiation. This case series provides further evidence to support the use of excimer laser in treating vitiligo especially of the face. Design: Patients with extensive facial depigmentation were treated with excimer laser twice weekly and calcipotriene daily until they developed significant repigmentation. Setting: Evaluation and treatment was performed at the Veterans Affairs outpatient dermatology clinic in Tampa, Florida. Participants: Three patients with Fitzpatrick skin types IV to VI were selected. These patients had failed a variety of topical treatments including steroids and calcipotriene, but were light naïve prior to beginning the study. Measurements: The primary outcome measure employed was percent repigmentation by visual estimation. The average dose of radiation, number of treatments, and weeks of therapy were also recorded. Results: All three patients experienced greater than 75 percent repigmentation of their facial vitiligo over a treatment course from 10 to 20 weeks. Conclusion: The excimer laser is a viable treatment for vitiligo and may yield results more expeditiously than other commonly utilized therapies. The rapid response may be correlated with skin type, but a more extensive study needs to be undertaken to further evaluate this correlation.Vitiligo is believed to be an autoimmune disease that results in the destruction of melanocytes leading to depigmentation. The disease affects approximately one percent of the population worldwide. Studies have demonstrated that the disfiguring nature of vitiligo causes high psychosocial morbidity.^1–3 This is especially pronounced in populations with darker skin tone, likely due to the marked contrast.^1,4A variety of treatment regimens are currently employed to repigment the skin. However, many of these require a prolonged treatment course and may yield minimal results. Therapies such as topical steroids rarely achieve more than 50- to 75-percent repigmentation and are cumbersome, requiring multiple daily applications. Further, topical steroids may require a year or more to note significant improvement.^5,6 Less than 50 percent of patients achieve greater than 75-percent repigmentation after 10 months of therapy.⁷ Other topical therapies including tacrolimus and calcipotriene yield similar results to topical steroids.Patients with extensive depigmentation may prefer treatment with light therapy due to the large surface area affected. Light therapies include oral or topical psoralens plus ultraviolet A radiation (PUVA), narrowband ultraviolet B radiation (NB-UVB), and excimer laser.PUVA has long been a mainstay of treatment for vitiligo, but over the last decade NB-UVB has been increasing in use due to decreased incidence of phototoxic side effects.^8,9 However, with both therapies, treatment may take many months, a year, or longer to achieve results.^8–10 PUVA achieved a partial response in 60 percent of patients after a mean of 84.2 treatments.¹¹ Patients treated with NB-UVB experienced a partial response at four weeks, but mean repigmentation was still less than 50 percent by 12 weeks.¹² There is some evidence that light treatments used in combination with topical agents improve outcomes.¹³The 308nm excimer laser is a newer treatment option that can yield impressive results in an abbreviated timeframe.¹⁰ Nicolaidou et al¹⁰ reviewed the use of excimer laser and demonstrated that 15 to 50 percent of patients achieved greater than 75-percent repigmentation. Notably, excimer laser treatment periods were 15 weeks or less in the overwhelming majority of the studies analyzed.¹⁰ Additionally, there has been some evidence that excimer laser treatment causes faster, more complete repigmentation in patients with higher Fitzpatrick skin types.^13,14This case series examines three male patients with Fitzpatrick skin types IV to VI and their results after undergoing combination treatment utilizing excimer laser with calcipotriene.     

Histological osseointegration of Tutobone<Superscript>®</Superscript>: first results in human

The aim of this study was to evaluate the histological and radiological osseointegration characteristics of implanted solvent-preserved cancellous bovine bone substitution material Tutobone after opening-wedge osteotomy and hip arthroplasty in human. The baseline hypothesis connected to the usage of bovine bone substitute materials is the assumption of temporary structural support, integration in the surrounding bone, bioresorption and replacement with vital bone. This hypothesis is based on numerous studies evaluating sintered bovine grafts showing good osseointegration and stability. Studies analyzing cancellous bovine grafts such as Tutobone hardly exist. The only rabbit defect model showed 100% remodeling of Tutobone after 26 weeks. However, no histological data are available on application of this xenograft in patients. In this study, nine patients biopsies were collected about 11 months after application of Tutobone. Unlike animal studies, the results showed incorporated avital graft remnants (47%) as well as new bone formation (53%) of the total mineralized area. Radiological evaluation confirmed increasing signs of osseointegration and an incomplete resorption. In conclusion, degradation and replacement of bovine graft seems to be less accelerated in patients than the animal study indicated. Nevertheless, Tutobone shows an excellent biocompatibility, good osteoconductive characteristics and may represent a useful alternative to autogenous graft.     

Rapid closure of midgestational excisional wounds in a fetal mouse model is associated with altered transforming growth factor-β isoform and receptor expression

Background

Many pediatric diseases are characterized by excessive tissue contraction. Because of a poor understanding of contraction, few therapies exist. We developed a murine fetal excisional wound model of contraction and theorize that wound closure is associated with changes in transforming growth factor-β (TGF-β) expression.

Methods

Pregnant FVB mice underwent hysterotomy at midgestational (E15) or late-gestational (E18) ages. Three-millimeter excisional wounds were made in fetuses and harvested at 32 hours. Real-time polymerase chain reaction was performed for TGF-β1, TGF-β2, TGF-β3, TβR-1, and TβR-2 in wounds and normal skin and normalized to glyceraldehyde-3-phosphate dehydrogenase. Data were analyzed by paired t test (P < .05). H&E staining of wounds was performed.

Results

E15 wounds (80.5% ± 4.4%) were smaller than E18 wounds (10.4% ± 10.5%; P < .001) at 32 hours. E15 wounds expressed higher levels of TGF-β1 compared with normal skin (P = .001). TβR-2 levels were elevated in E15 and E18 wounds compared with their respective normal skin (P = .02, P = .01) and in E18 normal skin compared with E15 normal skin (P = .002).

Conclusion

This study demonstrates that rapid midgestational wound closure in a murine model is associated with increased TGF-β1 and TβR-2 expression. Elucidating the role of the TGF-β pathways may lead to an improved understanding of wound contraction.