Bone marrow mesenchymal stem cells undergo nemosis and induce keratinocyte wound healing utilizing the HGF/c-Met/PI3K pathway

We previously showed cell–cell contacts of human dermal fibroblasts to induce expression of the hepatocyte growth factor/scatter factor (HGF) in a process designated as nemosis. Now we report on nemosis initiation in bone marrow mesenchymal stem cells (BMSCs). Because BMSCs are being used increasingly in cell transplantation therapy we aimed to demonstrate a functional effect and benefit of BMSC nemosis for wound healing. Nemotic and monolayer cells were used to stimulate HaCaT keratinocyte migration in a scratch-wound healing assay. Both indicators of nemosis, HGF production and cyclooxygenase-2 expression, were induced in BMSC spheroids. When compared with a similar amount of cells as monolayer, nemotic cells induced keratinocyte in vitro scratch-wound healing in a concentration-dependent manner. The HGF receptor, c-Met, was rapidly phosphorylated in the nemosis-stimulated keratinocytes. Nemosis-induced in vitro scratch-wound healing was inhibited by an HGF-neutralizing antibody as well as the small molecule c-Met inhibitor, SU11274. HGF-induced in vitro scratch-wound healing was inhibited by PI3K inhibitors, wortmannin and LY294002, while LY303511, an inactive structural analogue of LY294002, had no effect. Inhibitors of the mitogen-activated protein kinases MEK/ERK1/2 (PD98059 and U0126), and p38 (SB203580) attenuated HGF-induced keratinocyte in vitro scratch-wound healing. We conclude that nemosis of BMSCs can induce keratinocyte in vitro scratch-wound healing, and that in this effect signaling via HGF/c-Met is involved.     

Increased incidence of Hirschsprung's disease in patients with hypoplastic left heart syndrome—a common neural crest-derived etiology?

Background

The enteric ganglions and the outflow tract of the heart originate from the neural crest. Impaired migration or differentiation of the neural crest cells causes Hirschsprung's disease (HD) and results in the development of cardiac outflow tract malformations. We hypothesize that the incidence of HD and bowel disorders associated with HD are increased in patients with hypoplastic left heart syndrome (HLHS) including left cardiac outflow tract obstruction.

Methods

All consecutive patients treated for HLHS at our institution during 1969 to 2005 were retrospectively reviewed. The number of patients with histologically confirmed HD or clinical findings characteristic of HD such as constipation and delayed meconium were recorded from the patient records.

Results

A total of 113 patients (65 males) were identified. At the time of survey, 57 patients (51%) were alive. Overall, there were 26 (23%) patients with constipation, and 9/23 (39%) had delayed passage of meconium after 48 hours. Despite frequent bowel disorders only 4 (3.5%) patients had undergone histologic examination of the rectum. Hirschsprung's disease was detected in 3 patients (95% confidence interval, 0.62-8.77). The expected number of HD cases in the study population was 0.026 giving 117-fold significant increase in the incidence of HD among patients with HLHS when compared to general Finnish population.

Conclusions

The incidence of HD is increased in patients with HLHS. These results point to a common neural crest-derived embryologic origin of HD and HLHS and warrant further studies.     

Medial unicompartmental knee arthroplasty with Miller-Galante II prosthesis: mid-term clinical and radiographic results

Aim  The purpose of our study was to evaluate retrospectively the mid-term results of the Miller-Galante II (Zimmer, Warsaw, USA) unicondylar knee arthoplasty (UKA). Method  The study included 46 patients with medial UKAs. Mean follow-up time was 7.0 years (range 2.7–13.1 years). Results  Survival rate of the prosthesis was 86.6% (95% CI 73.7–99.6) at 7 years. The mean clinical and functional Knee Society Scores had increased from 51 and 62 points preoperatively to 76 and 93 points (P < 0.001) postoperatively. Five of the 46 knees were revised because of excessive wear of the polyethylene liner, and three due to progression of the osteoarthritis in the lateral compartment of the knee. Conclusion  Survival of this fixed-bearing UKA was not as good as previously reported and polyethylene wear seems to be a more common problem than previously assumed.     

Selective inhibition of cyclooxygenase 2 induces p27kip1 and skp2 in oral squamous cell carcinoma

It has been shown that inhibition of cyclooxygenase 2 (COX-2) may cause growth arrest and reduced tumour formation in some human cancers; however, the mechanism is not fully known. In this study, we used an oral squamous cell carcinoma cell line to study growth inhibition and changes in critical cell cycle-regulating proteins induced by the selective COX-2 inhibitor celecoxib. Using cell viability assay, we established the optimal in vitro inhibitory dose of celecoxib and showed that inhibition of COX-2 markedly induces the expression of p27kip1, p21, waf1, and the F-box protein skp2. These results add new experimental data to our knowledge of the mechanism of cyclooxygenases on neoplastic cells.     

Occupational allergic contact dermatitis from lichens in present-day Finland

Lichens are abundant in forests, living on trees, soil, stones and rocks. They contain usnic acid and other lichen acids that are contact allergens. Lichens and liverworts cause woodcutter's dermatitis, eczema that appears in the forest on the bare skin areas, especially in cold and wet weather. Occupational allergic contact dermatitis from lichens occurs in forestry and horticultural workers and in lichen pickers. Lichens can cause immediate allergy, contact urticaria, rhinitis and asthma and probably also photoallergic contact dermatitis. Lichens are used for the manufacture of oak moss absolute, a fragrance constituent. Oak moss absolute contains lichen acids and is one of the commonest contact allergens. Lichen acid allergy develops either from contact with lichens or from fragrances. We describe 4 cases of occupational allergic contact dermatitis from lichens during the past decade: 2 were farmers and 2 gardeners. 3 of them had allergic reactions to fragrance mix and oak moss absolute. Lichen contact allergy is an old, partly forgotten, syndrome that should be remembered for symptoms in contact with barked wood or wood dust.     

Induction of Hyaluronan Cables and Monocyte Adherence in Epidermal Keratinocytes

Hyaluronan attached to cell surface can form at least two very different structures; a pericellular coat close to plasma membrane and hyaluronan chains coalesced into “cables” that can span several cell lengths. The hyaluronan in cables, induced by many inflammatory agents, can bind leukocytes, whereas that in the pericellular coat does not contribute to leukocyte binding. Therefore, this structural change seems to have a major role in inflammation. In the present study we checked whether cells of squamous epithelium, like epidermal keratinocytes, can form hyaluronan cables and bind leukocytes. In addition, we checked whether hyaluronan synthesis is affected during the induction of cables. Control keratinocytes expressed pericellular hyaluronan as small patches on plasma membrane. But when treated with inflammatory agents or stressful conditions (tunicamycin, interleukin-1β, tumor necrosis factor-α, and high glucose concentration), hyaluronan organization changed into cable-like structures that avidly bound monocytes. Simultaneously, the total amount of secreted hyaluronan was slightly decreased, and the expression levels of hyaluronan synthases (Has1–3) and CD44 were not significantly changed. The results show that epidermal keratinocytes can form cables and bind leukocytes under inflammatory provocation and that these effects are not dependent on stimulation of hyaluronan secretion.     

Complex evolution and epidemiology of Dobrava-Belgrade hantavirus: definition of genotypes and their characteristics

Dobrava-Belgrade virus (DOBV) is a human pathogen that has evolved in, and is hosted by, mice of several species of the genus Apodemus. We propose a subdivision of the species Dobrava-Belgrade virus into four related genotypes – Dobrava, Kurkino, Saaremaa, and Sochi – that show characteristic differences in their phylogeny, specific host reservoirs, geographical distribution, and pathogenicity for humans.     

The severity of individual obstruction events is related to increased mortality rate in severe obstructive sleep apnea

Obstructive sleep apnea (OSA) is linked to an increased mortality rate. However, the severity of individual obstruction events is rarely considered quantitatively in clinical practice. We hypothesized that OSA with especially severe obstruction events would predispose a patient to greater health risks than OSA with a similar apnea–hypopnea index (AHI), but lower severity of individual events. This hypothesis was tested in a follow‐up (198.2 ± 24.7 months) of a population of 1068 men referred for ambulatory polygraphic recording due to suspected OSA. The recordings were analysed according to the guidelines of the American Academy of Sleep Medicine. Furthermore, a novel obstruction severity parameter was determined; this was defined as the product of duration of the individual obstruction event and area of the related desaturation event. Patients treated with continuous positive airway pressure (CPAP) were omitted. We identified 125 deceased patients from our original population and for 113 of these a matching alive patient with similar AHI, age, body mass index (BMI), smoking habits and follow‐up time could be found. The deceased patients with severe OSA (based on conventional AHI) showed higher obstruction severity values than their AHI‐matched alive controls. Based on the multivariate logistic regression analysis, obstruction severity was the only parameter which was related statistically significantly to mortality in the severe OSA category. Furthermore, 59% of all deceased patients and 83% of those who had severe OSA displayed higher obstruction severity than the AHI‐matched alive counterparts. To conclude, the obstruction severity parameter provided valuable prognostic information supplementing AHI. The obstruction severity parameter might improve recognition of the patients with the highest risk.