SAM syndrome is characterized by extensive phenotypic heterogeneity

Severe skin dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a rare life‐threatening inherited condition caused by bi‐allelic mutations in DSG1 encoding desmoglein 1. The disease was initially reported to manifest with severe erythroderma, failure to thrive, atopic manifestations, recurrent infections, hypotrichosis and palmoplantar keratoderma. We present 3 new cases of SAM syndrome in 2 families and review the cases published so far. Whole exome and direct sequencing were used to identify SAM syndrome‐causing mutations. Consistent with previous data, SAM syndrome was found in all 3 patients to result from homozygous mutations in DSG1 predicted to result in premature termination of translation. In contrast, as compared with patients previously reported, the present cases were found to display a wide range of clinical presentations of variable degrees of severity. The present data emphasize the fact that SAM syndrome is characterized by extensive phenotypic heterogeneity, suggesting the existence of potent modifier traits.     

IGF1R-directed targeted therapy enhances the cytotoxic effect of chemotherapy in endometrial cancer

This study evaluated the potential ability of MK-0646 to inhibit IGF1-mediated biological actions and cell signaling events in Type 1 and Type 2 endometrial cancer. We found that MK-0646 treatment significantly decreased IGF1R expression. In addition, pretreatment with MK-0646 decreased the IGF1-induced phosphorylation of IGF1R, AKT and ERK. Apoptosis analyses showed that MK-0646 abolished the anti-apoptotic effect of IGF1. Furthermore, MK-0646 treatment abolished the IGF1-stimulatory effect on proliferation and enhanced the cytotoxic effect of cisplatin. These findings indicate that specific inhibition of IGF1R could be a useful therapeutic approach for Type 1 and Type 2 endometrial cancer.     

The association between poor ovarian response and thrombophilia in assisted reproduction

Objective

To investigate the association between thrombophilic risk factors and poor ovarian response in an assisted reproductive technologies (ART) setting.

Study design

This is a preliminary prospective cohort study in a university affiliated reproductive medicine unit. Eighty-nine infertile women undergoing IVF-ET treatment were recruited. Following IVF-ET treatment, the 28 women that had ≤3 oocytes on retrieval were the study group, and the 61women that had ≥ 4 oocytes on retrieval were the control group. All women underwent ovarian reserve testing and thrombophilia work-up prior to treatment.

Results

Patients’ characteristics, except for chronological age, were similar between the two groups. Women in the study group had clear manifestations of low ovarian reserve, evident by ovarian reserve testing, controlled ovarian hyper-stimulation and IVF-ET treatment results, as compared to the control group. The incidence of all thrombophilias tested was similar between the study and control group. Moreover, the incidence of any single or combined thrombophilia was also similar between the two groups. Logistic regression model analysis and Pearson correlation tests did not show significant correlation between number of oocytes retrieved and thrombophilia. Furthermore, basal ovarian reserve tests did not differ between women with and without thrombophilia. When only the 48 women ≤ 35 years of were analyzed, the five women in the study group had significantly higher incidence of a single as well as combined thrombophilia as compared to the 43 controls.

Conclusions

Thrombophilic risk factors have no correlation with poor ovarian response in the general infertile population undergoing ART. Whether premature low ovarian reserve is linked to thrombophilia remains to be established.     

Comparison of different dose regimens of enoxaparin in deep vein thrombosis therapy in pregnancy

INTRODUCTION: Pregnant women have a higher risk of developing deep vein thrombosis (DVT) and consequent thrombogenic events, including pulmonary embolisms. Low-molecular-weight heparin (LMWH) products have been shown to successfully treat DVT with few significant side effects. The purpose of this study was to compare the effects of two dose regimens of enoxaparin (a LMWH) in the management of DVT in pregnancy. METHODS: A total of 35 pregnant patients with DVT were enrolled in this study. As first-line anticoagulation therapy, patients were administered an intravenous unfractionated heparin infusion for 5 days, followed by a subcutaneous injection of enoxaparin 1 mg/kg twice a day until discharge. The enoxaparin therapy continued at home with 1 mg/kg twice a day for 18 patients (group I) and 1.5 mg/kg once a day for the other 17 patients (group II). Enoxaparin was discontinued 12-24 hours before delivery and restarted within 8-12 hours after delivery. Warfarin was given as adjuvant therapy along with enoxaparin in the post-partum period. Enoxaparin was discontinued when an international normalised ratio of 2 or above was reached. Differences between the two groups in terms of therapy response, complications and efficacy were recorded. RESULTS: Thrombophilic disease was observed in three patients in each group. The iliac vein had the highest incidence of DVT in both groups. During therapy, two patients in group I were diagnosed with a mild haemorrhage; one patient (in group II) had abortion. There were no significant differences between groups in terms of recanalisation (measured by venous ultrasonography examination), post-thrombotic symptoms or safety parameters. CONCLUSION: Enoxaparin can be used safely in DVT therapy during pregnancy. Our results indicate that therapy consisting of a single daily dose of 1.5 mg/kg enoxaparin is as effective as twice-daily administration.     

Antibacterial properties of an oligo-acyl-lysyl hexamer targeting gram-negative species

Toward developing new tools for fighting resistance to antibiotics, we investigated the antibacterial properties of a new decanoyl-based oligo-acyl-lysyl (OAK) hexamer, aminododecanoyl-lysyl-[aminodecanoyl-lysyl](5) (α(12)-5α(10)). The OAK exhibited preferential activity against Gram-negative bacteria (GNB), as determined using 36 strains, including diverse species, with an MIC(90) of 6.2 μM. The OAK's bactericidal mode of action was associated with rapid membrane depolarization and cell permeabilization, suggesting that the inner membrane was the primary target, whereas the observed binding affinity to lipoteichoic acid suggested that inefficacy against Gram-positive species resulted from a cell wall interaction preventing α(12)-5α(10) from reaching internal targets. Interestingly, perturbation of the inner membrane structure and function was preserved at sub-MIC values. This prompted us to assess the OAK's effect on the proton motive force-dependent efflux pump AcrAB-TolC, implicated in the low sensitivity of GNB to various antibiotics, including erythromycin. We found that under sub-MIC conditions, wild-type Escherichia coli was significantly more sensitive to erythromycin (the MIC dropped by >10-fold), unlike its acr-deletion mutant. Collectively, the data suggest a useful approach for treating GNB infections through overcoming antibiotic efflux.     

Inflammatory peeling skin syndrome caused a novel mutation in <Emphasis Type="Italic">CDSN</Emphasis>

Generalized peeling skin syndrome (PSS) is a rare autosomal recessive dermatosis manifesting with continuous exfoliation of the stratum corneum. The inflammatory (type B) subtype of PSS was recently found to be caused by deleterious mutations in the CDSN gene encoding corneodesmosin, a major component of desmosomal junctions in the uppermost layers of the epidermis. In the present study, we assessed a 10-month-old baby, who presented with generalized superficial peeling of the skin. Using PCR amplification and direct sequencing, we identified the third PSS-associated mutation in CDSN, a homozygous 4 bp duplication in the second exon of the gene (c.164_167dup GCCT; p.Thr57ProfsX6). These data further support the notion that corneodesmosin deficiency impairs cell–cell adhesion in the upper epidermis, paving the way for an abnormal inflammatory response due to epidermal barrier disruption.     

Targeted inactivation of Dp71, the major non-muscle product of the DMD gene: differential activity of the Dp71 promoter during development

The dystrophin gene, which is defective in Duchenne muscular dystrophy (DMD), also encodes a number of smaller products controlled by internal promoters. Dp71, which consists of the two C-terminal domains of dystrophin, is the most abundant product of the gene in non-muscle tissues and is the major product in adult brain. To study the possible function of Dp71 and its expression during development, we specifically inactivated the expression of Dp71 by replacing its first and unique exon and a part of the concomitant intron with a beta-galactosidase reporter gene. X-Gal staining of Dp71-null mouse embryos and tissues revealed a very stage- and cell type-specific activity of the Dp71 promoter during development and during differentiation of various tissues, including the nervous system, eyes, limb buds, lungs, blood vessels, vibrissae and hair follicles. High activity of the Dp71 promoter often seemed to be associated with morphogenic events and terminal differentiation. In some tissues the activity greatly increased towards birth.      

Pseudoaneurysm formation in surgically treated Behçet's syndrome--a case report

Beh?et's syndrome is a multisystem disorder with unknown etiology. Clinically it is mostly seen as a systemic vasculitis; almost 30% of the patients have vascular involvements, and most of these are venous thrombosis and arterial aneurysms. Obstructions of the femoral and tibial arteries have also been reported in the literature. The authors present here a patient with Beh?et's syndrome who had pseudoaneurysms on both femoral arteries after aortobifemoral bypass surgery.