Cofilin peptide homologs interfere with immunological synapse formation and T cell activation

The formation of supramolecular activation clusters within the immunological synapse, crucial for sustained signaling and T lymphocyte activation, requires costimulation-dependent reorganization of the actin cytoskeleton. Here we have identified the actin-remodeling protein cofilin as a key player in this process. Cell-permeable peptides that block costimulation-induced cofilin/F-actin interactions in untransformed human T lymphocytes impair receptor capping and immunological synapse formation at the interface between T cells and antigen-presenting cells. As a consequence, T cell activation, as measured by cytokine production and proliferation, is inhibited.     

Proportion and extent of manifestation of molar‐incisor‐hypomineralizations according to different phenotypes

Objective: This epidemiological study aimed to assess the proportion and extent of manifestation of enamel hypomineralization, including molar‐incisor‐hypomineralization (MIH), in the permanent and primary dentition. Methods: A total of 693 children enrolled in an ongoing birth cohort study (GINIplus‐10) were examined at their 10‐year follow‐up. Enamel hypomineralization was scored in the primary and permanent dentition on a tooth‐ and surface‐related level based on the criteria of the European Academy of Paediatric Dentistry (EAPD). Children were grouped according to their distribution pattern of enamel hypomineralization: children with a minimum of one hypomineralized tooth in the primary dentition (ht ≥ 1) and permanent dentition (HT ≥ 1); with a minimum of one hypomineralization on at least one first permanent molar (MIH); and with hypomineralization on at least one first permanent molar and permanent incisor (M + IH). For each group, the mean values of hypomineralized primary teeth (ht), permanent teeth (HT), and permanent surfaces (HS) were calculated. Results: The proportion of affected children was 36.5 percent (HT ≥ 1), 14.7 percent (MIH), and 9.4 percent (M + IH); 6.9 percent of the subjects had a minimum of one affected primary tooth (ht ≥ 1). The mean number of hypomineralized permanent teeth and surfaces were 2.3HT/2.9HS (HT ≥ 1), 3.4HT/4.8HS (MIH), and 4.2HT/5.9HS (M + IH). The mean number of hypomineralized primary teeth amounted to 0.1ht in the entire study population. Conclusions: Enamel hypomineralization can be detected frequently in this study sample. Children with M + IH showed the highest number of affected teeth and surfaces followed by those with MIH.     

Development of volume‐stable adipose tissue constructs using polycaprolactone‐based polyurethane scaffolds and fibrin hydrogels

Adipose tissue engineering aims at the restoration of soft tissue defects and the correction of contour deformities. It is therefore crucial to provide functional adipose tissue implants with appropriate volume stability. Here, we investigate two different fibrin formulations, alone or in combination with biodegradable polyurethane (PU) scaffolds as additional support structures, with regard to their suitability to generate volume‐stable adipose tissue constructs. Human adipose‐derived stem cells (ASCs) were incorporated in a commercially available fibrin sealant as well as a stable fibrin hydrogel previously developed by our group. The composite constructs made from the commercially available fibrin and porous poly(ε‐caprolactone)‐based polyurethane scaffolds exhibited increased volume stability as compared to fibrin gels alone; however, only constructs using the stable fibrin gels completely maintained their size and weight for 21 days. Adipogenesis of ASCs was not impaired by the additional PU scaffold. After induction with a common hormonal cocktail, for constructs with either fibrin formulation, strong adipogenic differentiation of ASCs was observed after 21 days in vitro. Furthermore, upregulation of adipogenic marker genes was demonstrated at mRNA (PPARγ, C/EBPα, GLUT4 and aP2; qRT–PCR) and protein (leptin; ELISA) levels. Stable fibrin/PU constructs were further evaluated in a pilot in vivo study, resulting in areas of well‐vascularized adipose tissue within the implants after only 5 weeks. Copyright © 2013 John Wiley & Sons, Ltd.     

Pemphigus vulgaris localized to the nose and cheeks

Pemphigus vulgaris is an autoimmune blistering disease characterized by disseminated bullae and erosions of the mucosal surfaces and skin. Cases of pemphigus vulgaris with localized lesions on glabrous skin have been reported, and most of them have been attributed to the Koebner phenomenon. Lesions limited to the nose have mostly been described in pemphigus foliaceus, but the nose has also been the initial site of pemphigus vulgaris in a few patients. We report 4 cases of localized pemphigus vulgaris: one case with lesions limited to the nose and cheeks and 3 cases with isolated lesions on the nose. Recurrent episodes in these patients also occurred on the nose. None of them showed mucosal involvement or dissemination during a follow-up period of 2 to 9 years. Three patients had autoantibodies against desmoglein-3 as detected by immunoblot. In the other patient, antibodies against desmoglein-3 were detected by enzyme-linked immunosorbent assay. These localized lesions may represent a subgroup of pemphigus vulgaris or a period of limited activity during this chronic disease.     

Assessment of cardiac output,intravascular volume status,and extravascular lung water by transpulmonary indicator dilution in critically ill neonates and infants

OBJECTIVE: To assess cardiac output, intrathoracic blood volume, global end-diastolic volume, and extravascular lung water in critically ill neonates and small infants using transpulmonary indicator dilution. DESIGN: Prospective, observational, clinical study. SETTING: Pediatric intensive care unit in a university hospital. PARTICIPANTS: Critically ill neonates and small infants suffering from severe heart failure, respiratory failure, or sepsis (n = 10). INTERVENTIONS: A total of 194 transpulmonary indicator dilution measurements were done. Global end-diastolic volume, intrathoracic blood volume, and stroke volume were measured and compared with standard hemodynamic parameters during the clinical course and before and after volume loading (16 +/- 3.7 mL/kg of 10% albumin solution) in 8 of 10 patients. MEASUREMENTS AND MAIN RESULTS: A positive correlation was found for stroke volume index versus global end-diastolic volume (r = 0.76, p < 0.001) and intrathoracic blood volume (r = 0.56, p < 0.001). In contrast, no correlation was observed for stroke volume index versus central venous pressure. Volume loading resulted in significant increases in stroke volume index (p < 0.01), global end-diastolic volume (p < 0.01), and intrathoracic blood volume (p < 0.01); whereas central venous pressure, heart rate, mean arterial pressure, and extravascular lung water remained unchanged. CONCLUSION: Transpulmonary indicator dilution enables measurement of cardiac output and intravascular volume status in critically ill neonates and infants at the bedside. The effects of volume loading on cardiac preload and effective change in stroke volume can be monitored by this technique, whereas central venous pressure was not indicative of changes in intravascular volume status.     

Temozolomide Combined with Irradiation as Postoperative Treatment of Primary Glioblastoma Multiforme

BACKGROUND AND PURPOSE: The role of radiochemotherapy in the treatment of primary glioblastoma multiforme is still discussed controversially. To evaluate the feasibility and toxicity of irradiation and concomitant administration of 50 mg/m(2) temozolomide in patients with primary malignant glioma, this phase I/II study was conducted. PATIENTS AND METHODS: 53 Patients with histologically confirmed WHO grade IV malignant glioma were enrolled into the study. All patients were treated with radiation therapy up to a total dose of 60 Gy using conventional fractionation of 5 x 2.0 Gy/week. Temozolomide was administered orally each therapy day at a dose of 50 mg/m(2). RESULTS: Prior to radiochemotherapy, complete resection (n = 14), subtotal resection (n = 22) or a biopsy (n = 17) of the tumor was performed. The median time interval between surgery and radiochemotherapy was 21 days. Treatment-related toxicity was very mild. Acute toxicity > grade 2 was observed in one patient who developed grade 4 hemotoxicity. Minor side effects of chemotherapy included nausea and vomiting. No severe late effects were observed. Median progression-free and overall survival were 8 and 19 months, respectively. The overall survival rate was 72% at 1 and 26% at 2 years. Age and extent of surgery significantly influenced survival. CONCLUSION: The combination of temozolomide plus radiation therapy is feasible and safe in terms of toxicity. Overall survival times were relatively long compared to survival times reported for radiotherapy alone. The application of 50 mg/m(2) of temozolomide can be performed throughout the whole time course without interruption due to side effects and might largely contribute to the prolonged overall survival. Further evaluation is warranted as to which dose of temozolomide is optimal with regard to tumor response and toxicity.     

Identification of a novel urokinase receptor splice variant and its prognostic relevance in breast cancer

The cellular receptor for urokinase-type plasminogen activator, uPAR, plays a central role in both cell surface-associated proteolysis and cellular adhesion. In the present study, we systematically searched for splice variants of uPAR mRNA in human cells and tumor tissues by qualitative RT-PCR using specific primers for uPAR exons 1 and 6. Beside the wild-type (wt) uPAR mRNA and the previously described splice variant lacking exon 5 (uPAR-del5), a novel splice variant lacking both exons 4 and 5 (uPAR-del4/5) was found predominantly in various cancer cell lines. To elucidate whether alternatively spliced uPAR mRNA may be translated and post-translationally processed, we generated stably transfected Chinese hamster ovary cells, which harbor expression plasmids of wt uPAR and various uPAR variants including uPAR-del5 and uPAR-del4/5. By ELISA, flow cytofluorometry, and Western blot analysis, we confirmed synthesis and secretion of wt uPAR and the uPAR variants by the use of domain-specific monoclonal antibodies against uPAR. For quantification of uPAR mRNA variants, we established two highly sensitive real-time RT-PCR assays based on LightCycler technology. Study of their expression in a representative set of breast cancer tissues indicated that the novel mRNA variant uPAR-del4/5 was expressed very frequently and independently of uPAR mRNA variants covering exon 4 (uPAR-wt and uPAR-del5). Higher uPAR-del4/5 expression was significantly associated with shorter disease-free survival (p = 0.0004) of breast cancer patients. These results suggest that uPAR-del4/5 mRNA may serve as a novel prognostic marker in breast cancer.     

Fixation instability and oculomotor abnormalities in Friedreich's ataxia

Eye movements were studied in 13 patients with Friedreich's ataxia and correlated with MRI findings to investigate whether oculomotor abnormalities can be traced to cerebellar disturbances in this disease. One of the most prominent eye signs was fixation instability (square-wave jerks, SWJ.). Besides SWJ the patients showed various combinations of cerebellar, vestibular and brain-stem oculomotor signs. Our patients did not comprise a homogeneous group with regard to their oculomotor findings. There was no correlation between the severity of any of the so-called cerebellar oculomotor disturbances and the number of SWJ. We tried to correlate the extent of oculomotor disturbances with floccular atrophy and atrophy of the dorsal vermis on MRI in seven of the patients. None of the oculomotor features (including SWJ) correlated with flocculus or dorsal vermis size. Furthermore, floccular and vermal measurements on MRI were normal. Accordingly, we think it unlikely that the oculomotor disturbances, including SWJ, are attributable to cerebellar pathology per se.     

Results of the treatment of first carpometacarpal joint osteoarthritis: trapeziectomy alone versus trapeziectomy associated with suspensionplasty

Backgrounds

The goal of this study was to compare trapeziectomy alone to trapeziectomy associated with a technique of suspensionplasty using the abductor pollicis longus with a minimum of 6 years of follow-up in the treatment of osteoarthritis of the first carpometacarpal joint.

Methods

Our series included 46 trapeziectomies in 35 patients, aged 69 years in average, among which 27 were women. In 27 cases group I, a trapeziectomy alone was performed, and in 19 cases group II, a trapeziectomy associated with an abductor pollicis longus suspensionplasty was performed.

Results

At the last follow-up, the difference between pre- and postoperative Quick DASH was ??36.104 in average in group I and ??38.877 in average in group II p?=?0.7717. The difference between pre- and postoperative pain was ??3.926 in average in group I and ??4.368 in average in group II p?=?0.35. The difference of pre- and postoperative thumb opposition was 0.630 in group I and 0.421 in group II p?=?0.3033. The average difference of pre- and postoperative key pinch was 0.389 in group I and 0.842 in group II p?=?0.3303. No complication was reported.

Conclusions

Our results suggest that it is unnecessary to perform a ligamentoplasty when a trapeziectomy is indicated.