Treatment of keloid scars with intralesional triamcinolone and 5-fluorouracil injections - a randomized controlled trial.

Keloids have high recurrence rates. Current first-line therapy is triamcinolone (TAC) injection, but it has been suggested that approximately 50% of keloids are steroid resistant. We compared the efficacy of intralesional 5-fluorouracil (5-FU) and triamcinalone injections in a double-blind randomized controlled trial. Forty-three patients with 50 keloid scars were treated with either intralesional TAC or 5-FU-injections over 6 months. There was no statistically significant difference in the remission rate at 6 months between the 5-FU and TAC groups (46% vs 60%, respectively). Local adverse effects were higher in the TAC group compared to the 5-FU group. Occurrence of skin atrophy in TAC group was 44% and in the 5-FU group 8% (p < 0.05). Also the occurrence of telangiectasia in the TAC group was 50% and in the 5-FU 21% (p < 0.05). Vascularity of the keloids, assessed by spectral imaging and immunohistochemical staining for blood vessels, after treatment decreased in the TAC group, but not in the 5-FU group (p < 0.05). Fibroblast proliferation evaluated by Ki-67 staining significantly decreased in the TAC group (p < 0.05) but increased in the 5-FU group (p < 0.05). TAC and 5-FU injections did not differ in their clinical effectivity in this randomized study, but 5-FU injections lead to increased proliferation rate and did not affect vascular density in histological assessment. Due to the greater number of adverse effects observed after TAC treatment, 5-FU injections may be preferable for cosmetically sensitive skin areas.

On-chip integrated vertically aligned carbon nanotube based super- and pseudocapacitors.

On-chip energy storage and management will have transformative impacts in developing advanced electronic platforms with built-in energy needs for operation of integrated circuits driving a microprocessor. Though success in growing stand-alone energy storage elements such as electrochemical capacitors (super and pseusocapacitors) on a variety of substrates is a promising step towards this direction. In this work, on-chip energy storage is demonstrated using architectures of highly aligned vertical carbon nanotubes (CNTs) acting as supercapacitors, capable of providing large device capacitances. The efficiency of these structures is further increased by incorporating electrochemically active nanoparticles such as MnOx to form pseudocapacitive architectures thus enhancing device capacitance areal specific capacitance of 37 mF/cm2. The demonstrated on-chip integration is up and down-scalable, compatible with standard CMOS processes, and offers lightweight energy storage what is vital for portable and autonomous device operation with numerous advantages as compared to electronics built from discrete components.

Mechanical symptoms as an indication for knee arthroscopy in patients with degenerative meniscus tear: a prospective cohort study.

OBJECTIVE: According to prevailing consensus, patients with mechanical symptoms are those considered to most likely benefit from arthroscopic surgery. The aim of this study was to determine the value of using patients' pre-operative self-reports of mechanical symptoms as a justification surgery in patients with degenerative meniscus tear/knee disease. DESIGN: Pragmatic prospective cohort of 900 consecutive patients with symptomatic degenerative knee disease and meniscus tear undergoing arthroscopic partial meniscectomy (APM) was collected from one public orthopedic referral center specialized in arthroscopic surgery during 2007-2011. The patients' subjective satisfaction, self-rated improvement, change in Western Ontario Meniscal Evaluation Tool (WOMET) score, and patients' ratings of the knee using a numerical rating scale (NRS) was assessed at 1 year postoperatively. Multivariable regression models, adjusted for possible confounders and intermediates, were used to compare the outcomes in those with and without preoperative mechanical symptoms. RESULTS: The proportion of patients satisfied with their knee 12 months after arthroscopy was significantly lower among those with preoperative mechanical symptoms than among those without (61% vs 75%, multivariable adjusted risk ratio [RR] 0.84; 95% confidence interval [CI] 0.76, 0.92). Similarly, the proportion reporting improvement was lower (RR 0.91; 95% CI 0.85, 0.97). No statistically significant difference was found in change in WOMET or NRS between the two groups. Of those with preoperative mechanical symptoms, 47% reported persistent symptoms at 12 months postoperatively. CONCLUSIONS: Our observational data contradicts the current tenet of using patients' self-report of mechanical symptoms as a justification for performing arthroscopic surgery on patients with degenerative meniscus tear.

A New Surgical Model of Skeletal Muscle Injuries in Rats Reproduces Human Sports Lesions.

Skeletal muscle injuries are the most common sports-related injuries in sports medicine. In this work, we have generated a new surgically-induced skeletal muscle injury in rats, by using a biopsy needle, which could be easily reproduced and highly mimics skeletal muscle lesions detected in human athletes. By means of histology, immunofluorescence and MRI imaging, we corroborated that our model reproduced the necrosis, inflammation and regeneration processes observed in dystrophic mdx-mice, a model of spontaneous muscle injury, and realistically mimicked the muscle lesions observed in professional athletes. Surgically-injured rat skeletal muscles demonstrated the longitudinal process of muscle regeneration and fibrogenesis as stated by Myosin Heavy Chain developmental (MHCd) and collagen-I protein expression. MRI imaging analysis demonstrated that our muscle injury model reproduces the grade I-II type lesions detected in professional soccer players, including edema around the central tendon and the typically high signal feather shape along muscle fibers. A significant reduction of 30% in maximum tetanus force was also registered after 2 weeks of muscle injury. This new model represents an excellent approach to the study of the mechanisms of muscle injury and repair, and could open new avenues for developing innovative therapeutic approaches to skeletal muscle regeneration in sports medicine.

Osteoporosis: the emperor has no clothes.

Current prevention strategies for low-trauma fractures amongst older persons depend on the notions that fractures are mainly caused by osteoporosis (pathophysiology), that patients at high risk can be identified (screening) and that the risk is amenable to bone-targeted pharmacotherapy (treatment). However, all these three notions can be disputed. PATHOPHYSIOLOGY: Most fracture patients have fallen, but actually do not have osteoporosis. A high likelihood of falling, in turn, is attributable to an ageing-related decline in physical functioning and general frailty. SCREENING: Currently available fracture risk prediction strategies including bone densitometry and multifactorial prediction tools are unable to identify a large proportion of patients who will sustain a fracture, whereas many of those with a high fracture risk score will not sustain a fracture. TREATMENT: The evidence for the viability of bone-targeted pharmacotherapy in preventing hip fracture and other clinical fragility fractures is mainly limited to women aged 65-80 years with osteoporosis, whereas the proof of hip fracture-preventing efficacy in women over 80 years of age and in men at all ages is meagre or absent. Further, the antihip fracture efficacy shown in clinical trials is absent in real-life studies. Many drugs for the treatment of osteoporosis have also been associated with increased risks of serious adverse events. There are also considerable uncertainties related to the efficacy of drug therapy in preventing clinical vertebral fractures, whereas the efficacy for preventing other fractures (relative risk reductions of 20-25%) remains moderate, particularly in terms of the low absolute risk reduction in fractures with this treatment.

Comparison of modified Kessler tendon suture at different levels in the human flexor digitorum profundus tendon and porcine flexors and porcine extensors: an experimental biomechanical study.

This study compared the biomechanical behaviour of repairs in the human flexor digitorum profundus tendon in zones I, II and III with repairs of different segments of the porcine flexor tendon of the second digit and the extensor digiti quarti proprius tendon, in order to assess the validity of porcine tendons as models for human flexor tendon repairs. These porcine tendons were selected after comparing their size with the human flexor digitorum profundus tendon. The tendon repairs were done in three segments of each porcine tendon and repairs in the human tendons were done in zones I,II and III. Ten tendons in each group yielded a total of 90 specimens. A modified Kessler repair was done with 3-0 coated braided polyester suture and subjected to uniaxial tensile testing. In human flexor tendons, the ultimate force was higher in zones I and II than in zone III. The porcine flexor digitorum profundus tendon from the second digit and the proximal segment of the extensor digiti quarti proprius tendon behaved similarly to the human flexor tendon in zone III and can be considered as surrogates for the human flexor tendon.

3D visualization and quantification of rat cortical bone porosity using a desktop micro-CT system: a case study in the tibia.

Although micro-computed tomography (micro-CT) has become the gold standard for assessing the 3D structure of trabecular bone, its extension to cortical bone microstructure has been relatively limited. Desktop micro-CT has been employed to assess cortical bone porosity of humans, whereas that of smaller animals, such as mice and rats, has thus far only been imaged using synchrotron-based micro-CT. The goal of this study was to determine if it is possible to visualize and quantify rat cortical porosity using desktop micro-CT. Tibiae (n = 10) from 30-week-old female Sprague-Dawley rats were imaged with micro-CT (3 µm nominal resolution) and sequential ground sections were then prepared. Bland-Altman plots were constructed to compare per cent porosity and mean canal diameter from micro-CT (3D) versus histology (2D). The mean difference or bias (histology-micro-CT; ±95% confidence interval) for per cent porosity was found to be -0.15% (±2.57%), which was not significantly different from zero (P= 0.720). Canal diameter had a bias (±95% confidence interval) of -5.73 µm (±4.02 µm) which was found to be significantly different from zero (P < 0.001). The results indicated that cortical porosity in rat bone can indeed be visualized by desktop micro-CT. Quantitative assessment of per cent porosity provided unbiased results, whereas direct analysis of mean canal diameter was overestimated by micro-CT. Thus, although higher resolution, such as that available from synchrotron micro-CT, may ultimately be required for precise geometric measurements, desktop micro-CT--which is far more accessible--is capable of yielding comparable measures of porosity and holds great promise for assessment of the 3D arrangement of cortical porosity in the rat.

Clinical and laboratory characteristics of Finnish lupus erythematosus patients with cutaneous manifestations.

Our objective was to characterize clinical features, laboratory findings, concomitant autoimmune diseases, and smoking habits of lupus erythematosus subgroups in genetically homogeneous patients from two Dermatology Departments of Finnish University hospitals. One hundred and seventy eight discoid lupus erythematosus, 55 subacute cutaneous lupus erythematosus, and 77 systemic lupus erythematosus patients were enrolled using patients' charts from institutional database (1995-2006) and during routine control visits. Clustering analysis was performed to reveal natural groupings. Smoking at the onset of disease was significantly more common in all subgroups (57% for discoid lupus erythematosus, 35% for subacute cutaneous lupus erythematosus, and 34% for systemic lupus erythematosus) compared with the age/gender-matched prevalence in the Finnish population, suggesting smoking to be a trigger factor for cutaneous lupus. Leukopenia (38%) and lymphopenia (52%) were observed more often in patients with systemic lupus erythematosus than reported previously. Photosensitivity characterized all groups, especially patients with subacute cutaneous lupus erythematosus (87%). Of the autoimmune diseases, Sjögren's syndrome was the most common (22% of patients with systemic lupus erythematosus), followed by autoimmune thyroid disease (13% of patients with subacute cutaneous lupus erythematosus). The clustering analysis showed environmental factors (smoking) to be more involved in disease development in discoid lupus erythematosus, whereas immunological factors were more significant in initiating systemic lupus erythematosus. The high prevalence of autoimmune thyroid disease, together with photosensitivity, and the clustering profiles suggest that lupus erythematosus subtypes, especially discoid lupus erythematosus, are heterogeneic in their pathomechanisms.

A population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 is associated with high birthweight in Finnish diabetic families.

Children with type 1 diabetes (T1D) susceptibility HLA genotypes are shown to have an increased birthweight. We investigated to what extent T1D-predisposing HLA haplotypes were associated with increased birthweight. A total of 1255 Finnish children comprising those with T1D and their non-diabetic siblings were investigated. A total of 342 children and their non-diabetic parents were HLA genotyped. Birthweight data were obtained from the national Medical Birth Registry. The population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 was associated with high birthweight (P=0.0280) in families with a diabetic offspring. Other T1D-predisposing HLA haplotypes showed nonsignificant tendency with high birthweight. More infants with a birthweight >or=4000 g were born in families with a T1D offspring than in the general Finnish population (P=0.0139). The previously observed direct association between birthweight and T1D risk may be mediated through the modulating effects that T1D susceptibility HLA genes have on weight. High birthweight and subsequent weight gain may accelerate the ongoing pancreatic autoimmune process in genetically susceptible individuals. The high proportion of infants having a birthweight >or=4000 g in families with a diabetic offspring raises a concern of potential adverse health outcomes that high birthweight can have.

Matrix metalloproteinases as mediators of tissue injury in different forms of cutaneous lupus erythematosus.

BACKGROUND: Matrix metalloproteinases (MMPs) contribute to tissue destruction, regeneration, inflammation and apoptosis and several of them are upregulated by ultraviolet (UV) radiation in skin. Although some MMPs associate with organ manifestations of systemic lupus erythematosus (SLE), their role in cutaneous lupus erythematosus (LE) is elusive. OBJECTIVES: Our aim was to evaluate the expression of MMPs in SLE, subacute cutaneous LE (SCLE) and discoid LE (DLE) skin lesions and their relation to apoptosis and epidermal changes. METHODS: Lesional skin biopsies from 20 patients with SLE, 20 with DLE and 17 with SCLE, and from UVA/UVB-photoprovoked skin of healthy volunteers were immunostained using antibodies to multiple MMPs and tissue inhibitors of metalloproteinases (TIMPs). The TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling) method was used for detection of apoptosis. RESULTS: MMP-3, -10, -19 and -26 were abundantly expressed by keratinocytes in SLE, DLE and SCLE skin samples. MMP-7 was detected in keratinocytes in regions of oedema and vacuolization especially in SLE and SCLE, while MMP-14 was only occasionally observed in keratinocytes. Photoprovocation did not induce MMP-10 or -26 expression in skin of healthy volunteers. Epithelial TIMP-1 expression was low while occasional positive fibroblasts were seen in the dermis. TIMP-3 was abundantly expressed in the epidermis, endothelial cells and macrophages. CONCLUSIONS: Different subtypes of cutaneous LE are fairly similar in their MMP expression profile. MMP-3 and -10 mediate both epidermal changes and dermal tissue remodelling but are not present in lymphocytes. Low expression of TIMP-1 suggests that lupus skin is characterized by proteolytic events, and targeted action using selective MMP inhibitors may reduce lupus-induced damage in inflamed tissues.

In vitro evaluation of the effect of cyclodextrin complexation on pulmonary deposition of a peptide, cyclosporin A.

The effect of hydroxypropyl-alpha-cyclodextrin (HP-alpha-CD) complexation on in vitro pulmonary deposition of a cyclic peptide cyclosporin A (CsA) was studied. In addition, the effect of storage (32 days, 40 degrees C, 75% RH) on CsA/HP-alpha-CD complexes was studied. The complexation of CsA with CDs was evaluated by a phase-solubility method. Solid CsA/HP-alpha-CD complexes were prepared by freeze drying. Three inhalation formulations were prepared: CsA/lactose reference formulation (LF) (drug:carrier 1:364, w/w), CsA/HP-alpha-CD complex formulation (CDF) (drug:CD 1:269, w/w) and CsA/HP-alpha-CD complex/lactose formulation (CDLF) (complex:carrier 100:114, w/w). The inhalation studies were performed in vitro using Andersen Sampler (Ph. Eur.) and Taifun multi-dose dry powder inhalers (DPIs). Before the storage, the respirable fraction value (RF%) of CsA was 19.8+/-0.7%, 33.0+/-7.0% and 34.6+/-1.1% (mean+/-S.D., n=4 x 20) with LF, CDF and CDLF, respectively. When exposed to moisture (storage in a permeable polystyrene tube), the RF% values of CsA from formulations containing CsA/HP-alpha-CD complexes were lower than before the storage. However, when stored in the Taifun DPI, the RF% value of CsA from any of the formulations did not decrease. In conclusion, an acceptable RF% value of a peptide CsA from freeze-dried, simply micronized CsA/HP-alpha-CD complex powder was achieved before and after storage in the DPI.

Targeting the cannabinoid CB2 receptor: mutations, modeling and development of CB2 selective ligands.

Since the discovery of the cannabinoid CB2 receptor in 1993, there has been a growing interest to clarify the importance of this G-protein coupled receptor (GPCR) for human physiology, and to investigate it as a possible target for current and future drug development. Several mutation studies have examined the receptor activation and structure of the receptor binding cavity. Additionally, 3D models for the CB2 receptor have been constructed to aid in perceiving important ligand-receptor interactions. In recent years, many research groups have succeeded in synthesizing new CB2 selective ligands. This review focuses on (i) important features for ligand recognition and/or receptor activation at CB2, derived from mutation and modeling studies, and (ii) recent advances in the field of CB2 selective ligands.

Villous tip intraepithelial lymphocytes as markers of early-stage coeliac disease.

BACKGROUND: An investigation was conducted to determine whether the density of small-intestinal villous tip intraepithelial lymphocytes would be of value in clinical practice in uncovering early-stage coeliac disease. METHODS: Villous tip, CD3+ and gammadelta+ intraepithelial lymphocytes were counted in patients with definite early-stage coeliac disease without villous atrophy, in classic coeliac disease with manifest mucosal lesion and in non-coeliac controls with normal mucosal structure. Villous tip analysis was made of haematoxylin-eosin specimens and CD3+ and gammadelta+ of immunohistochemical stainings from frozen samples. RESULTS: The villous tip intraepithelial lymphocyte count was statistically significantly higher in patients with early-stage coeliac disease than in non-coeliac controls. The sensitivity of this method to detect untreated coeliac disease with normal villous architecture was 0.84; the specificity was 0.88. This method proved superior to CD3+ analysis and was at least as good as gammadelta+ analysis in detecting early-stage coeliac disease. In detecting classic coeliac disease, villous tip analysis also reached a higher sensitivity than CD3+ and gammadelta+ cells. CONCLUSIONS: Villous tip analysis seems to distinguish early coeliac from non-specific changes, thus providing a valuable tool in routine practice, especially when borderline findings are involved. Its value appears to be similar to counting of gammadelta+ cells, which, however, requires frozen biopsy samples.

Chemical and enzymatic stability evaluation of lipoamino acid esters of idebenone.

Lipophilic conjugates of idebenone (IDE) with short-chain alkylamino acids were previously synthesized and evaluated in vitro for their antioxidant properties. In this study, their susceptibility to chemical and enzymatic hydrolysis was evaluated. Results indicated that these derivatives release the parent drug quantitatively via enzymatic hydrolysis by serum and liver esterases, with a cleavage rate related to the length of the alkyl side chain. Consequently, the present lipoamino acid conjugates of IDE are prodrugs and their in vivo effects are mediated through the parent compound released in the body.

Topoisomerase IIalpha gene (TOP2A) amplification and deletion in cancer--more common than anticipated.

In solid tumours the predominant genetic mechanism for oncogene activation is through amplification of genes. The HER-2 (also known as ErbB2/c-erbB2/HER-2/neu) oncogene is the most frequently amplified oncogene in breast cancer and is also commonly amplified in other forms of cancer. The HER-2 amplicon also contains other biologically relevant genes with altered copy numbers, among these genes is the topoisomerase IIalpha (TOP2A). TOP2A gene is located adjacent to the HER-2 oncogene at the chromosome location 17q12-q21 and is either amplified or deleted, with equal frequency, in almost 90% of HER-2 amplified primary breast tumours. Recent data suggest that amplification and deletion of TOP2A may account for both sensitivity and resistance to topoII-inhibitor-chemotherapy, depending on the specific genetic defect at the TOP2A locus. In this issue of the Cytopathology, Bofin et al. present preliminary evidence for high prevalance of TOP2A amplification and deletion not only in the HER-2 amplified breast tumours, but also in the primary breast tumours without the HER-2 amplification. This finding together with the concept that TOP2A gene amplification and deletion seem to account for both relative chemosensitivity and resistance to topoII-inhibitor therapy further highlights the importance of screening for TOP2A gene copy number aberrations when topoII-inhibitors are considered either alone or in combination of other chemotherapeutic drugs for the treatment of cancer patients.

Estrogen deposits extra mineral into bones of female rats in puberty, but simultaneously seems to suppress the responsiveness of female skeleton to mechanical loading.

To first test the possible effect of gender on the responsiveness of growing rat skeleton to mechanical loading, 5-week-old littermates of 25 male and 25 female rats were subjected to either free-cage activity or treadmill training for a period of 14 weeks (experiment 1). Using peripheral quantitative computed tomography (pQCT) and mechanical testing of the femoral neck, we observed female rats exhibiting a clearly lower responsiveness to external loading than male rats (+3.0% vs +25% in cross-sectional area (CSA), +4.2% vs +27% in the bone mineral content (BMC), -0.6% vs +10% in volumetric bone mineral density (BMD), and +4.7% vs +28% in fracture strength (F(max)) of the femoral neck). Also, relative to the mechanical demands placed on the skeleton, the bones of the young female rats were considerably denser (>50%) than those of the males. In the subsequent experiment 2, we repeated the above-noted first experiment with 33-week-old rats and observed virtually identical exercise-induced benefits (+2.1% vs +10% in CSA, +3.4% vs +18% in BMC, +2.5% vs +23% in BMD, and -1.1% vs +27% in F(max) in females vs males, respectively) and the growth/puberty-related condensation of mineral into female bones. Finally, in experiment 3, 60 littermates of 3-week-old female rats were first subjected to sham operation or ovariectomy and then further randomized to exercise or control groups, respectively, to study whether the condensation of mineral into female bones and their lower responsiveness to loading were attributable to the effects of estrogen. At the end of the 16-week intervention, our pQCT and mechanical testing analysis showed not only the anticipated effect of reduced bone density in the ovariectomized rats ( approximately -20%) but also the hypothesized better responsiveness to mechanical loading in these estrogen-depleted rats (-3.5% vs +9.1% in CSA, -0.4% vs +12% in BMC, +4.4% vs +9.6% in BMD, and -4.2% vs +16% in F(max) in SHAM vs OVX, respectively). In conclusion, the results of our series of three experiments suggest that as such estrogen seems to have very little primary effect on the sensitivity of female bone to respond to external loading, but rather deposits extra stock of mineral into female bones in puberty. This estrogen-driven extra condensation of the female skeleton seems to persist into adulthood, simultaneously damping the responsiveness of the female skeleton to mechanical loading.

Basic science and clinical studies coincide: active treatment approach is needed after a sports injury.

The basic response to injury at the tissue level is well known and consists of acute inflammatory phase, proliferative phase, and maturation and remodeling phase. Knowing these phases, the treatment and rehabilitation program of athletes' acute musculoskeletal injuries should use a short period of immobilization followed by controlled and progressive mobilization. Both experimental and clinical trials have given systematic and convincing evidence that this program is superior to immobilization - a good example where basic science and clinical studies do coincide - and therefore active approach is needed in the treatment of these injuries.