DFNB40, a recessive form of sensorineural hearing loss, maps to chromosome 22q11.21-12.1

We report on a novel localization for a recessive form of deafness (DFNB), by linkage analysis in an Iranian consanguineous family. Affected individuals suffer from prelingual profound sensorineural hearing loss. Genome-wide analysis led to the characterization of a new locus, DFNB40, which maps to an approximately 9 Mb interval between markers D22S427 and D22S1144 at chromosome 22q11.21-12.1. Maximum lod score of 3.09 was obtained with D22S1174. Since the Bronx waltzer (bv) mouse mutant, characterized by waltzing behavior, deafness, and degeneration of cochlear inner hair cells, has been mapped to the syntenic region on murine chromosome 5, we suggest that DFNB40 and bv may result from orthologous gene defects.     

Human microvasculature-on-a chip: anti-neovasculogenic effect of nintedanib in vitro

Idiopathic pulmonary fibrosis is characterized by a progressive scarring and stiffening of the peripheral lung tissue that decreases lung function. Over the course of the disease, the lung microvasculature undergoes extensive remodeling. There is increased angiogenesis around fibrotic foci and an absence of microvessels within the foci. To elucidate how the anti-fibrotic drug nintedanib acts on vascular remodeling, we used an in vitro model of perfusable microvessels made with primary endothelial cells and primary lung fibroblasts in a microfluidic chip. The microvasculature model allowed us to study the impact of nintedanib on permeability, vascularized area, and cell–cell interactions. The anti-vasculogenic impact of nintedanib was visible at the minimal concentrations of 10 nM, showing a significant increase in vessel permeability. Furthermore, nintedanib decreased microvessel density, diameter, and influenced fibroblast organization around endothelial microvessels. These results show that nintedanib acts on the endothelial network formation and endothelial–perivascular interactions. Advanced in vitro microvasculature models may thus serve to pinpoint the mechanistic effect of anti-fibrotic drugs on the microvascular remodeling in 3D and refine findings from animal studies.     

Ablation of Breast Cancer Cells Using Trastuzumab‐Functionalized Multi‐Walled Carbon Nanotubes and Trastuzumab‐Diphtheria Toxin Conjugate

Trastuzumab (Herceptin^®) is a monoclonal antibody (mAb) for specific ablation of HER2‐overexpressing malignant breast cancer cells. Intensification of antiproliferative activity of trastuzumab through construction of immunotoxins and nano‐immunoconjugates is a promising approach for treatment of cancer. In this study, trastuzumab was directly conjugated to diphtheria toxin (DT). Also, conjugates of trastuzumab and multiwalled carbon nanotubes (MWCNT) were constructed by covalent immobilization of trastuzumab onto MWCNTs. Then, antiproliferative activity of the fusion constructs against HER2‐overexpressing SK‐BR‐3 and also HER2‐negative MCF‐7 cancer cell lines were examined. Cells treated with trastuzumab‐MWCNT conjugates were irradiated with near‐infrared (NIR) light. Efficient absorption of NIR radiation and its conversion to heat by MWCNTs can be resulted to thermal ablation of cancerous cells. Our results strongly showed that both trastuzumab‐MWCNT and trastuzumab‐DT conjugates were significantly efficient in the specific killing of SK‐BR‐3 cells. Targeting of MWCNTs to cancerous cells using trastuzumab followed by exposure of cells to NIR radiation was more efficient in repression of cell proliferation than treatment for cancer cells with trastuzumab‐DT. Our results also showed that conjugation linkers can significantly affect the cytotoxicity of MWCNT‐immunoconjugates. In conclusion, our data demonstrated that trastuzumab‐MWCNT is a promising nano‐immunoconjugate for killing of HER2‐overexpressing cancerous cells.     

Endoscopic ultrasonography (EUS) in the localization of insulinoma

Objective Endoscopic ultrasonography has been accepted as a sensitive modality for preoperative tumor localization in pancreas. We have aimed to determine the performance characteristics of endoscopic ultrasonography in pancreatic insulinoma localization and evaluation of relationship between the tumor size and serum-c peptide level, lowest glucose level and insulin level. Methods Patients suspicious to insulinoma according to clinical and laboratory findings were included. Endoscopic ultrasonography was performed and if a tumor was identified, the patient was referred for surgery. Results A total of 52 patients (24 male and 28 female) with mean age of 42.4 years underwent EUS and 43 patients underwent surgery. In one patient, a tumor was identified both by transabdominal ultrasonography and abdominal CT scan. The overall sensitivity and accuracy of endoscopic ultrasonography for detection of insulinoma was 89.5% and 83.7% respectively. The sensitivity of endoscopic ultrasonography for detection of lesions in pancreatic head, body and tail was 92.6%, 78.9%, and 40.0%, respectively. There was no relationship between c-peptide, lowest blood glucose, insulin blood levels and tumor size in surgery. Conclusion EUS is an accurate method for detection of insulinoma. The accuracy depends on the location of the tumor and is greatest for tumors in the pancreatic head.     

Immunological and cytotoxicological characterization of tuberculin purified protein derivative (PPD) conjugated to single-walled carbon nanotubes

Tuberculosis (TB) represents one of the leading killers among all infectious disease. Protection against TB depends on the activation of T-helper type I (Th1) immune response. Carbon nanotubes (CNTs) have attracted considerable attention because of their potential applications as new nanovehicle. In the current study, tuberculin purified protein derivative (PPD) was conjugated to carboxylated single-walled carbon nanotubes (SWCNTs). Cytotoxicity of the carboxylated SWCNT and SWCNT-PPD conjugate was analyzed with MTT assay and by reactive oxygen species (ROS) and nitric oxide (NO) generation. Male BALB/c mice were immunized with BCG, PPD, SWCNT-PPD conjugate and PPD in complete Freund's adjuvant (CFA). Induction of cellular immune response was analyzed by measuring the levels of Th1 cytokines (IFN-γ and IL-12) and Th2 cytokines (IL-10 and IL-5). Immunization with non-conjugated PPD or PPD in Freund's adjuvant induced a Th2 cytokine response while immunization with BCG resulted to a mixed Th1/Th2 cytokine response. In contrast, PPD in conjugation with SWCNT generated preferentially a Th1-type cytokine response in the absence of potential cytotoxic effects.     

Heterotopic autotransplantation of vitrified mouse ovary

Purpose  

The aim of this study was to investigate the survival and development of premature follicles and oocytes from a vitrified-transplanted ovary in a murine experimental model.     

Dynamic iso-resistive trunk extension simulation: contributions of the intrinsic and reflexive mechanisms to spinal stability.

The effects of external resistance on the recruitment of trunk muscles and the role of intrinsic and reflexive mechanisms to ensure the spinal stability are significant issues in spinal biomechanics. A computational model of spine under the control of 48 anatomically oriented muscle actions was used to simulate iso-resistive trunk movements. Neural excitation of muscles was attained based on inverse dynamics approach along with the stability-based optimization. The effect of muscle spindle reflex response on the trunk movement stability was evaluated upon the application of a perturbation moment. In this study, the trunk extension movement at various resistance levels while extending from 60 degrees flexion to the upright posture was investigated. Incorporation of the stability condition as an additional constraint in the optimization algorithm increased antagonistic activities for all resistance levels demonstrating that the co-activation caused an increase in the intrinsic stiffness of the spine and its stability in a feed-forward manner. During the acceleration phase of the movement, extensors activity increased while flexors activity decreased in response to the higher resistance. The co-activation ratio noticed in the braking phase of the movement increased with higher resistance. In presence of a 30 Nm flexion perturbation moment, reflexive feed-back noticeably decreased the induced deviation of the velocity and position profiles from the desired ones at all resistance levels. The stability-generated co-activation decreased the reflexive response of muscle spindles to the perturbation demonstrating that both intrinsic and reflexive mechanisms contribute to the trunk stability. The rise in muscle co-activation can ameliorate the corruption of afferent neural sensory system at the expense of higher loading of the spine.     

In-hospital and mid-term adverse clinical outcomes of a direct stenting strategy versus stenting after predilatation for the treatment of coronary artery lesions

Background

Direct stenting without balloon dilatation may reduce procedural costs and duration, and hypothetically, the restenosis rate. This study was designed to compare the in-hospital and long-term outcomes of direct stenting (DS) versus stenting after pre-dilatation (PS) in our routine clinical practice.

Methods

The 1 603 patients treated with stenting for single coronary lesions were enrolled into a prospective registry. Patients with acute myocardial infarction (MI) within the preceding 48 hours, and those with highly calcified lesions, total occlusions, or a lesion in a saphenous graft were excluded. The baseline, angiographic and procedural data, inhospital outcomes and follow-up data were recorded in our database and analysed with appropriate statistical methods.

Results

Eight hundred and fifty-seven patients (53.5%) were treated with DS and 746 (46.5%) underwent PS. In the DS group, lesions were shorter in length, larger in diameter and had lower pre-procedural diameter stenosis. Type C and diffuse lesions and drug-eluting stents were found less often (p < 0.001). With univariate analysis, dissection and non-Q-wave MI occurred less frequently in this group (0.2 and 0.6% vs 3.9 and 2.1%, p < 0.001 and p = 0.01, respectively). However, the cumulative major adverse cardiac events (MACE) did not differ significantly (4.9 vs 4.6%, p = 0.79). With multivariate analysis, direct stenting reduced the risk of dissection (OR = 0.07, 95% CI: 0.01–0.33, but neither the cumulative endpoint of MACE (OR = 1.1, 95% CI = 0.58–2.11, p = 0.7) nor its constructing components were different between the groups.

Conclusions

Direct stenting in the real world has at least similar long-term outcomes in patients treated with stenting after pre-dilatation, and is associated with lower dissection rates.