Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features.

Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor β (TGF-β) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P<0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-β1 (P=0.009), TGF-β2 (P=0.004) and additional inflammatory markers, and increased TGF-β1 (P=0.0009) and TGF-β2 (P=0.0001) secretion in dermal fibroblast cell lines from subjects with FMD compared to age- and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-β signaling and offers TGF-β as a marker of FMD.

Patient-centered outcomes after subepithelial connective tissue grafts and coronally advanced flaps

The use of a coronally advanced flap (CAF) and connective tissue graft (CTG) is a well-established procedure to cover single and multiple recessions and improve soft tissue esthetics. However, until now, there are still limited data evaluating patient morbidity, the fear of imminent tooth loss, and modification of sensitivity in surgical areas. The aim of the present study was to evaluate the patient-centered outcomes associated with CAF + CTG.

Temporal sequence of hard and soft tissue healing around titanium dental implants.

The objective of the present review was to summarize the evidence available on the temporal sequence of hard and soft tissue healing around titanium dental implants in animal models and in humans. A search was undertaken to find animal and human studies reporting on the temporal dynamics of hard and soft tissue integration of titanium dental implants. Moreover, the influence of implant surface roughness and chemistry on the molecular mechanisms associated with osseointegration was also investigated. The findings indicated that the integration of titanium dental implants into hard and soft tissue represents the result of a complex cascade of biological events initiated by the surgical intervention. Implant placement into alveolar bone induces a cascade of healing events starting with clot formation and continuing with the maturation of bone in contact with the implant surface. From a genetic point of view, osseointegration is associated with a decrease in inflammation and an increase in osteogenesis-, angiogenesis- and neurogenesis-associated gene expression during the early stages of wound healing. The attachment and maturation of the soft tissue complex (i.e. epithelium and connective tissue) to implants becomes established 6-8 weeks following surgery. Based on the findings of the present review it can be concluded that improved understanding of the mechanisms associated with osseointegration will provide leads and targets for strategies aimed at enhancing the clinical performance of titanium dental implants.

Plakins, a Versatile Family of Cytolinkers: Roles in Skin Integrity and in Human Diseases

The plakin family consists of giant proteins involved in the cross-linking and organization of the cytoskeleton and adhesion complexes. They further modulate several fundamental biological processes, such as cell adhesion, migration, and polarization or signaling pathways. Inherited and acquired defects of plakins in humans and in animal models potentially lead to dramatic manifestations in the skin, striated muscles, and/or nervous system. These observations unequivocally demonstrate the key role of plakins in the maintenance of tissue integrity. Here we review the characteristics of the mammalian plakin members BPAG1 (bullous pemphigoid antigen 1), desmoplakin, plectin, envoplakin, epiplakin, MACF1 (microtubule-actin cross-linking factor 1), and periplakin, highlighting their role in skin homeostasis and diseases.

The immunomodulator FTY720 and its phosphorylated derivative activate the Smad signalling cascade and upregulate connective tissue growth factor and collagen type IV expression in renal mesangial cells

1.--The immunomodulating agent FTY720 is a substrate for the sphingosine kinase and the phosphorylated form is able to bind to sphingosine 1-phosphate (S1P) receptors. In this study, we show that exposure of renal mesangial cells to phospho-FTY720 leads to a rapid and transient activation of several protein kinase cascades, including the mitogen- and stress-activated protein kinases. The nonphosphorylated FTY720 also increased MAPK phosphorylation, but with a reduced potency and a more delayed time course. In addition, phospho-FTY720 and FTY720 are able to increase phosphorylation of Smad proteins which are classical members of the transforming growth factor-beta (TGF-beta) signalling device, thus suggesting a crosstalk between FTY720 and TGF-beta signalling. 2.--Pretreatment with the S1P(3) receptor antagonist suramin inhibits FTY720 and phospho-FTY720-induced Smad phosphorylation, whereas pertussis toxin pretreatment, which blocks G(i/0) proteins, has no effect on Smad phosphorylation. 3.--Since TGF-beta is a potent profibrotic cytokine in mesangial cells and upregulates the connective tissue growth factor (CTGF) and collagen as important hallmarks in the fibrotic sequelae, we investigated whether FTY720 and phospho-FTY720 are able to mimic these effects of TGF-beta. Indeed, FTY720 and phospho-FTY720 markedly upregulate CTGF and collagen type IV protein expressions. In addition, the tissue inhibitor of metalloproteinase-1 is transcriptionally activated by FTY720, whereas cytokine-induced matrix metalloproteinase-9 is down-regulated by FTY720. 4.--Depletion of the TGF-beta receptor type II by the siRNA transfection technique blocks not only Smad phosphorylation but also CTGF upregulation. Similarly, Smad-4 depletion by siRNA transfection also abrogates CTGF upregulation induced by FTY720 and phospho-FTY720. 5.--In summary, our data show that FTY720 and phospho-FTY720 not only activate the Smad signalling cascade in mesangial cells, but also upregulate the expression of CTGF and collagen. These findings suggest that FTY720 may have additional effects besides the established immunomodulatory action and, importantly, a profibrotic activity has to be considered in future experimental approaches.

Connective tissue growth factor, steatosis and fibrosis in patients with chronic hepatitis C

BACKGROUND/AIM: Both steatosis and insulin resistance have been linked to accelerated fibrosis in chronic hepatitis C. Connective tissue growth factor (CTGF) plays a major role in extracellular matrix production in fibrotic disorders including cirrhosis, and its expression is stimulated in vitro by insulin and glucose. We hypothesized that CTGF may link steatosis, insulin resistance and fibrosis. METHODS: We included 153 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study and for whom a liver biopsy and plasma samples were available. CTGF expression was assessed quantitatively by immunohistochemistry. In 94 patients (57 with genotypes non-3), plasma levels of glucose, insulin and leptin were also measured. CTGF synthesis was investigated by immunoblotting on LX-2 stellate cells. RESULTS: Connective tissue growth factor expression was higher in patients with steatosis (P=0.039) and in patients with fibrosis (P=0.008) than those without these features. CTGF levels were neither associated with insulinaemia or with glycaemia, nor with inflammation. By multiple regression analysis, CTGF levels were independently associated with steatosis, a past history of alcohol abuse, plasma leptin and HCV RNA levels; when only patients with genotypes non-3 were considered, CTGF levels were independently associated with a past history of alcohol abuse, plasma leptin levels and steatosis. Leptin stimulated CTGF synthesis in LX-2 cells. CONCLUSIONS: In patients with chronic hepatitis C and steatosis, CTGF may promote fibrosis independently of inflammation. CTGF may link steatosis and fibrosis via increased leptin levels.

Treatment of multiple adjacent Miller class I and II gingival recessions with a Modified Coronally Advanced Tunnel (MCAT) technique and a collagen matrix or palatal connective tissue graft: a randomized, controlled clinical trial

BACKGROUND A newly developed collagen matrix (CM) of porcine origin has been shown to represent a potential alternative to palatal connective tissue grafts (CTG) for the treatment of single Miller Class I and II gingival recessions when used in conjunction with a coronally advanced flap (CAF). However, at present it remains unknown to what extent CM may represent a valuable alternative to CTG in the treatment of Miller Class I and II multiple adjacent gingival recessions (MAGR). The aim of this study was to compare the clinical outcomes following treatment of Miller Class I and II MAGR using the modified coronally advanced tunnel technique (MCAT) in conjunction with either CM or CTG. METHODS Twenty-two patients with a total of 156 Miller Class I and II gingival recessions were included in this study. Recessions were randomly treated according to a split-mouth design by means of MCAT + CM (test) or MCAT + CTG (control). The following measurements were recorded at baseline (i.e. prior to surgery) and at 12 months: Gingival Recession Depth (GRD), Probing Pocket Depth (PD), Clinical Attachment Level (CAL), Keratinized Tissue Width (KTW), Gingival Recession Width (GRW) and Gingival Thickness (GT). GT was measured 3-mm apical to the gingival margin. Patient acceptance was recorded using a Visual Analogue Scale (VAS). The primary outcome variable was Complete Root Coverage (CRC), secondary outcomes were Mean Root Coverage (MRC), change in KTW, GT, patient acceptance and duration of surgery. RESULTS Healing was uneventful in both groups. No adverse reactions at any of the sites were observed. At 12 months, both treatments resulted in statistically significant improvements of CRC, MRC, KTW and GT compared with baseline (p < 0.05). CRC was found at 42% of test sites and at 85% of control sites respectively (p < 0.05). MRC measured 71 ± 21% mm at test sites versus 90 ± 18% mm at control sites (p < 0.05). Mean KTW measured 2.4 ± 0.7 mm at test sites versus 2.7 ± 0.8 mm at control sites (p > 0.05). At test sites, GT values changed from 0.8 ± 0.2 to 1.0 ± 0.3 mm, and at control sites from 0.8 ± 0.3 to 1.3 ± 0.4 mm (p < 0.05). Duration of surgery and patient morbidity was statistically significantly lower in the test compared with the control group respectively (p < 0.05). CONCLUSIONS The present findings indicate that the use of CM may represent an alternative to CTG by reducing surgical time and patient morbidity, but yielded lower CRC than CTG in the treatment of Miller Class I and II MAGR when used in conjunction with MCAT.

Familial occurrence and heritable connective tissue disorders in cervical artery dissection

OBJECTIVE In a large series of patients with cervical artery dissection (CeAD), a major cause of ischemic stroke in young and middle-aged adults, we aimed to examine frequencies and correlates of family history of CeAD and of inherited connective tissue disorders. METHODS We combined data from 2 large international multicenter cohorts of consecutive patients with CeAD in 23 neurologic departments participating in the CADISP-plus consortium, following a standardized protocol. Frequency of reported family history of CeAD and of inherited connective tissue disorders was assessed. Putative risk factors, baseline features, and 3-month outcome were compared between groups. RESULTS Among 1,934 consecutive patients with CeAD, 20 patients (1.0%, 95% confidence interval: 0.6%-1.5%) from 17 families (0.9%, 0.5%-1.3%) had a family history of CeAD. Family history of CeAD was significantly more frequent in patients with carotid location of the dissection and elevated cholesterol levels. Two patients without a family history of CeAD had vascular Ehlers-Danlos syndrome with a mutation in COL3A1. This diagnosis was suspected in 2 additional patients, but COL3A1 sequencing was negative. Two patients were diagnosed with classic and hypermobile Ehlers-Danlos syndrome, one patient with Marfan syndrome, and one with osteogenesis imperfecta, based on clinical criteria only. CONCLUSIONS In this largest series of patients with CeAD to date, family history of symptomatic CeAD was rare and inherited connective tissue disorders seemed exceptional. This finding supports the notion that CeAD is a multifactorial disease in the vast majority of cases.

The modified coronally advanced tunnel combined with an enamel matrix derivative and subepithelial connective tissue graft for the treatment of isolated mandibular Miller Class I and II gingival recessions: a report of 16 cases.

OBJECTIVES To clinically evaluate the healing of mandibular Miller Class I and II isolated gingival recessions treated with the modified coronally advanced tunnel (MCAT) in conjunction with an enamel matrix derivative (EMD) and subepithelial connective tissue graft (SCTG). METHOD AND MATERIALS Sixteen healthy patients (13 women and 3 men) exhibiting one isolated mandibular Miller Class I and II gingival recessions of a depth of ≥ 3 mm, were consecutively treated with the MCAT in conjunction with EMD and SCTG. Treatment outcomes were assessed at baseline and at 12 months postoperatively. The primary outcome variable was complete root coverage (CRC) (eg, 100% root coverage). RESULTS Postoperative pain and discomfort were low and no complications such as postoperative bleeding, allergic reactions, abscesses, or loss of SCTG were observed. At 12 months, statistically significant (P < .0001) root coverage was obtained in all 16 defects. CRC was measured in 12 out of the 16 cases (75%) while in the remaining 4 defects root coverage amounted to 90% (in two cases) and 80% (in two cases), respectively. Mean root coverage was 96.25%. Mean keratinized tissue width increased from 1.98 ± 0.8 mm at baseline to 2.5 ± 0.9 mm (P < .0001) at 12 months, while mean probing depth did not show any statistically significant changes (ie, 1.9 ± 0.3 mm at baseline vs 1.8 ± 0.2 mm at 12 months). CONCLUSION Within their limits, the present results indicate that the described treatment approach may lead to predictable root coverage of isolated mandibular Miller Class I and II gingival recessions.

Transforming growth factor β2 (TGF-β2)-induced connective tissue growth factor (CTGF) expression requires sphingosine 1-phosphate receptor 5 (S1P5) in human mesangial cells

Transforming growth factor β2 (TGF-β2) is well known to stimulate the expression of pro-fibrotic connective tissue growth factor (CTGF) in several cell types including human mesangial cells. The present study demonstrates that TGF-β2 enhances sphingosine 1-phosphate receptor 5 (S1P5) mRNA and protein expression in a time and concentration dependent manner. Pharmacological and siRNA approaches reveal that this upregulation is mediated via activation of classical TGF-β downstream effectors, Smad and mitogen-activated protein kinases. Most notably, inhibition of Gi with pertussis toxin and downregulation of S1P5 by siRNA block TGF-β2-stimulated upregulation of CTGF, demonstrating that Gi coupled S1P5 is necessary for TGF-β2-triggered expression of CTGF in human mesangial cells. Overall, these findings indicate that TGF-β2 dependent upregulation of S1P5 is required for the induction of pro-fibrotic CTGF by TGF-β. Targeting S1P5 might be an attractive novel approach to treat renal fibrotic diseases.

Linear sclerodermic lupus erythematosus, a distinct variant of linear morphea and chronic cutaneous lupus erythematous

Overlap syndromes represent disorders that combine diagnostic criteria of two or more different connective tissue diseases.

Combined bone and soft-tissue augmentation surgery in temporo-orbital contour reconstruction

Temporal hollowing due to temporal muscle atrophy after standard skull base surgery is common. Various techniques have been previously described to correct the disfiguring defect. Most often reconstruction is performed using freehand molded polymethylmethacrylate cement. This method and material are insufficient in terms of aesthetic results and implant characteristics. We herein propose reconstruction of such defects with a polyetheretherketone (PEEK)-based patient-specific implant (PSI) including soft-tissue augmentation to preserve normal facial topography. We describe a patient who presented with a large temporo-orbital hemangioma that had been repaired with polymethylmethacrylate 25 years earlier. Because of a toxic skin atrophy fistula, followed by infection and meningitis, this initial implant had to be removed. The large, disfiguring temporo-orbital defect was reconstructed with a PEEK-based PSI. The lateral orbital wall and the temporal muscle atrophy were augmented with computer-aided design and surface modeling techniques. The operative procedure to implant and adopt the reconstructed PEEK-based PSI was simple, and an excellent cosmetic outcome was achieved. The postoperative clinical course was uneventful over a 5-year follow-up period. Polyetheretherketone-based combined bony and soft contour remodeling is a feasible and effective method for cranioplasty including combined bone and soft-tissue reconstruction of temporo-orbital defects. Manual reconstruction of this cosmetically delicate area carries an exceptional risk of disfiguring results. Augmentation surgery in this anatomic location needs accurate PSIs to achieve satisfactory cosmetic results. The cosmetic outcome achieved in this case is superior compared with previously reported techniques.

Occurrence of Chlamydiaceae, Mycoplasma conjunctivae, and pestiviruses in Alpine chamois (Rupicapra r. rupicapra) of Grisons, Switzerland

Because interactions between livestock and chamois occur on Alpine pastures, transmission of infectious diseases is considered possible. Thus, the occurrence of Chlamydiaceae, Mycoplasma conjunctivae, and pestiviruses in Alpine chamois (Rupicapra r. rupicapra) of the Surselva region (eastern Swiss Alps) was investigated. In total, 71 sera, 158 eye swabs, 135 tissue samples, and 23 fecal samples from 85 chamois were analyzed. The sera were tested by 2 enzyme-linked immunosorbent assay (ELISA) kits specific for Chlamydophila abortus. Eye swabs, tissue, and fecal samples were examined by a Chlamydiaceae-specific real-time polymerase chain reaction (PCR). Positive cases were further investigated by microarray method. One serum sample (1.4%) was positive in 1 of the ELISAs. Eye swabs of 3 chamois (3.8%) were positive for Chlamydiaceae. The microarray method revealed the presence of Chlamydophila abortus, C pecorum, and C pneumoniae. All tissue and fecal samples were negative. With real-time PCR, 3.9% of the chamois tested positive for Mycoplasma conjunctivae. One chamois had a simultaneous infection with Al. conjunctivae and 2 chlamydial species (C abortus, C. pecorum). Skin and tongue tissue samples of 35 chamois were negative for pestivirus antigen by immunohistochemistry. It was concluded that in contrast to the findings in Pyrenean chamois (Capra p. pyrenaica) of Spain, the occurrence of Chlamydiaceae in Alpine chamois of the Surselva region is low, and the transmission between domestic and wild Caprinae seems not to be frequent. Comparably, persistent pestiviral infections do not seem to be common in chamois of the Surselva region.

Management of aortic aneurysms in patients with connective tissue disease

Acute dissection and rupture of aortic aneurysms comprise for 1-2% of all deaths in developed countries. Dilation of the aorta is caused by several different mechanisms including inherited disorders of connective tissue. Recent reports estimate that 20% of patients presenting with thoracic aortic disease do have an underlying genetic basis of disease.