Brief Report: CD109 Overexpression Ameliorates Skin Fibrosis in a Mouse Model of Bleomycin‐Induced Scleroderma

Objective

Transforming growth factor β (TGFβ) is a profibrotic cytokine, and its aberrant function is implicated in several types of fibrotic pathologies including scleroderma (systemic sclerosis [SSc]). Multiple lines of evidence show that increased TGFβ signaling contributes to progressive fibrosis in SSc by promoting fibroblast activation, excessive extracellular matrix (ECM) deposition, and dermal thickening. We have previously identified CD109 as a TGFβ coreceptor and have shown that it antagonizes TGFβ signaling and TGFβ‐induced ECM expression in vitro in human keratinocytes and fibroblasts. The aim of the present study was to examine the ability of CD109 to prevent skin fibrosis in a mouse model of bleomycin‐induced SSc.

Methods

Transgenic mice overexpressing CD109 in the epidermis and their wild‐type (WT) littermates were injected with bleomycin in phosphate buffered saline (PBS) or with PBS alone every other day for 21 days or 28 days. Dermal thickness and collagen deposition were determined histologically using Masson's trichrome and picrosirius red staining. In addition, collagen and fibronectin content was analyzed using Western blotting, and activation of TGFβ signaling was examined by determining phospho‐Smad2 and phospho‐Smad3 levels using Western blotting and immunohistochemistry.

Results

Transgenic mice overexpressing CD109 in the epidermis showed resistance to bleomycin‐induced skin fibrosis, as evidenced by a significant decrease in dermal thickness, collagen crosslinking, collagen and fibronectin content, and phospho‐Smad2/3 levels, as compared to their WT littermates.

Conclusion

Our findings suggest that CD109 inhibits TGFβ signaling and fibrotic responses in experimental murine scleroderma. They also suggest that CD109 regulates dermal–epidermal interactions to decrease extracellular matrix synthesis in the dermis. Thus, CD109 is a potential molecular target for therapeutic intervention in scleroderma.

     

No major cognitive impairment in young children with acute lymphoblastic leukemia using chemotherapy only: a prospective longitudinal study

PURPOSE: To study, using serial neuropsychological assessment and evaluation of school achievement, persistent neuropsychological late effects in children treated for acute lymphoblastic leukemia (ALL) at a young age with chemotherapy only. PATIENTS AND METHODS: Twenty consecutive patients underwent three evaluations, including 12 psychometric measures beside IQ. The authors applied strict methodology and a prospective-longitudinal design that started at diagnosis and extended to a median follow-up of 7 years. This report focuses on the outcome of the last evaluation. Test results were compared with healthy controls and to patients with ALL treated on a previous chemotherapy-only protocol. School achievement was evaluated in patients and their siblings. RESULTS: At the last evaluation, significantly lower test scores in patients compared with controls were found for only 2 of 14 cognitive measures (1 intelligence and 1 attention measure). No great differences were seen between school achievement of patients and siblings. Compared with the previous chemotherapy protocol, a better outcome was seen in the current study group on two measures (one memory and one attention measure). CONCLUSIONS: Children surviving ALL have no major cognitive impairment after chemotherapy, including intrathecal and high-dose intravenous methotrexate. The slightly better outcome in the current group may indicate possible adverse effects of more dexamethasone treatment in the previous group.     

Leydig cell development of pig testis in the early fetal period: An ultrastructural study

Leydig cell development in the pig testis occurs in three periods (an early fetal, the perinatal period, and the period from puberty onward). The earliest of these periods was investigated ultrastructurally. The early fetal period starts immediately after gonadal differentiation, approximately 27 days postcoitum (p.c.), and finishes at about 60 days postcoitum. Dates of observation were 35, 52, and 62 days p.c. At 42 days p.c. some animals were decapitated. Leydig cells at 35 days p.c. are characterized by an oval nucleus, vesicular or branched tubular smooth endoplasmic reticulum (SER), and a small quantity of rough endoplasmic reticulum (RER). The RER has two forms: a short and a long profile. The latter is closely coupled with mitochondria. The mitochondria mostly have tubular cristae. From 52 days p.c. onward the degree of coupling lessens, and it vanishes at 62 days p.c. At 52 and 62 days p.c. a very large amount of 10 nm filaments and a slight decrease in SER can be observed. The SER now has a branched tubular form, and the presence of polygonal dense bodies is also characteristic. Decapitation does not disturb normal development of the Leydig cells in the observation period. No obvious differences from controls can be observed.     

Topotecan distribution in an anephric infant with therapy resistant bilateral Wilms tumor with a novel germline WT1 gene mutation

The therapeutic strategy for bilateral Wilms tumor (WT) remains a challenge. Especially in cases with chemotherapy resistant disease, bilateral nephrectomy is sometimes inevitable. For optimal cure rates stage V WT patients benefit from adjuvant treatment; however, there are limited data available on chemotherapy pharmacokinetics in anephric children. In this report, we describe a 10-month old girl with bilateral Wilms tumor and a novel germline WT1 gene mutation. This patient hardly showed any response on preoperative chemotherapy, and ultimately, underwent sequential bilateral tumor-nephrectomy. Subsequently, during peritoneal dialysis, she received topotecan as adjuvant chemotherapy based on plasma levels, indicating that this is a reasonable option as adjuvant treatment in therapy-resistant Wilms tumor patients after bilateral nephrectomy. This case showed a novel germline WT1 gene mutation of which the correlation with resistant phenotype has to be confirmed in larger cohorts of WT patients.     

Healing,Inflammation, and Fibrosis: When Benign Becomes Cancer: Malignant Degeneration of Chronic Inflammation

Chronic inflammation, long implicated in the genesis of malignancy, is now understood to underlie an estimated 25% of all cancers. The most pertinent malignancies, to the plastic surgeon, associated with the degeneration of chronic inflammation include Marjolin''s ulcer, breast implant-associated large cell lymphoma, radiation-induced sarcoma, and Kaposi''s sarcoma. The cellular and genetic damage incurred by a prolonged inflammatory reaction is controlled by an increasingly understood cytokinetic system. Advances in understanding the chronic inflammatory cascade have yielded new therapeutics and therapeutic targets.     

Healing,Inflammation, and Fibrosis: Updates in Diabetic Wound Healing,Inflammation, and Scarring

Diabetic patients can sustain wounds either as a sequelae of their disease process or postoperatively. Wound healing is a complex process that proceeds through phases of inflammation, proliferation, and remodeling. Diabetes results in several pathological changes that impair almost all of these healing processes. Diabetic wounds are often characterized by excessive inflammation and reduced angiogenesis. Due to these changes, diabetic patients are at a higher risk for postoperative wound healing complications. There is significant evidence in the literature that diabetic patients are at a higher risk for increased wound infections, wound dehiscence, and pathological scarring. Factors such as nutritional status and glycemic control also significantly influence diabetic wound outcomes. There are a variety of treatments available for addressing diabetic wounds.     

Cytokine responses to repeated,prolonged walking in lean versus overweight/obese individuals

Objectives

Obesity is characterized by a pro-inflammatory state, which plays a role in the pathogenesis of metabolic and cardiovascular disease. An exercise bout causes a transient increase in pro-inflammatory cytokines, whilst training has anti-inflammatory effects. No previous study examined whether the exercise-induced increase in pro-inflammatory cytokines is altered with repeated prolonged exercise bouts and whether this response differs between lean and overweight/obese individuals.

Four-year follow-up of endoscopic gastroplication for the treatment of gastroesophageal reflux disease

AIM: To evaluate the long-term effect of Endocinch treatment for gastroesophageal reflux disease (GERD).METHODS: After unblinding and crossover, 50 patients (32 males, 18 females; mean age 46 years) with pH-proven chronic GERD were recruited from an initial randomized, placebo-controlled, single-center study, and included in the present prospective open-label follow-up study. Initially, three gastroplications using the Endocinch device were placed under deep sedation in a standardized manner. Optional retreatment was offered in the first year with 1 or 2 extra gastroplications. At baseline, 3 mo after (re) treatment and yearly proton pump inhibitor (PPI) use, GERD symptoms, quality of life (QoL) scores, adverse events and treatment failures (defined as: patients using > 50% of their baseline PPI dose or receiving alternative antireflux therapy) were assessed. Intention-to-treat analysis was performed.RESULTS: Median follow-up was 48 mo [interquartile range (IQR): 38-52]. Three patients were lost to follow-up. In 44% of patients retreatment was done after a median of 4 mo (IQR: 3-8). No serious adverse events occurred. At the end of follow-up, symptom scores and 4 out of 6 QoL subscales were improved (all P < 0.01 compared to baseline). However, 80% of patients required PPIs for their GERD symptoms. Ultimately, 64% of patients were classified as treatment failures. In 60% a post-procedural endoscopy was carried out, of which in 16% reflux esophagitis was diagnosed.CONCLUSION: In the 4-year follow-up period, the subset of GERD patients that benefit from endoscopic gastroplication kept declining gradually, nearly half opted for retreatment and 80% required PPIs eventually.