Depicting the inner and outer nose: The representation of the nose and the nasal mucosa on the human primary somatosensory cortex (SI)

The nose is important not only for breathing, filtering air, and perceiving olfactory stimuli. Although the face and hands have been mapped, the representation of the internal and external surface of the nose on the primary somatosensory cortex (SI) is still poorly understood. To fill this gap functional magnetic resonance imaging (fMRI) was used to localize the nose and the nasal mucosa in the Brodman areas (BAs) 3b, 1, and 2 of the human postcentral gyrus (PG). Tactile stimulation during fMRI was applied via a customized pneumatically driven device to six stimulation sites: the alar wing of the nose, the lateral nasal mucosa, and the hand (serving as a reference area) on the left and right side of the body. Individual representations could be discriminated for the left and right hand, for the left nasal mucosa and left alar wing of the nose in BA 3b and BA 1 by comparing mean activation maxima and Euclidean distances. Right‐sided nasal conditions and conditions in BA 2 could further be separated by different Euclidean distances. Regarding the alar wing of the nose, the results concurred with the classic sensory homunculus proposed by Penfield and colleagues. The nasal mucosa was not only determined an individual and bilateral representation, its position on the somatosensory cortex is also situated closer to the caudal end of the PG compared to that of the alar wing of the nose and the hand. As SI is commonly activated during the perception of odors, these findings underscore the importance of the knowledge of the representation of the nasal mucosa on the primary somatosensory cortex, especially for interpretation of results of functional imaging studies about the sense of smell. Hum Brain Mapp 35:4751–4766, 2014. © 2014 Wiley Periodicals, Inc .     

Genomic characterization of small cell carcinomas of the uterine cervix

Small cell carcinoma (SCC) of the uterine cervix is a rare and aggressive form of neuroendocrine carcinoma, which resembles small cell lung cancer (SCLC) in its histology and poor survival rate. Here, we sought to define the genetic underpinning of SCCs of the uterine cervix and compare their mutational profiles with those of human papillomavirus (HPV)‐positive head and neck squamous cell carcinomas, HPV‐positive cervical carcinomas, and SCLCs using publicly available data. Using a combination of whole‐exome and targeted massively parallel sequencing, we found that the nine uterine cervix SCCs, which were HPV18‐positive (n = 8) or HPV16‐positive (n = 1), harbored a low mutation burden, few copy number alterations, and other than TP53 in two cases no recurrently mutated genes. The majority of mutations were likely passenger missense mutations, and only few affected previously described cancer‐related genes. Using RNA‐sequencing, we identified putative viral integration sites on 18q12.3 and on 8p22 in two SCCs of the uterine cervix. The overall nonsilent mutation rate of uterine cervix SCCs was significantly lower than that of SCLCs, HPV‐driven cervical adeno‐ and squamous cell carcinomas, or HPV‐positive head and neck squamous cell carcinomas. Unlike SCLCs, which are reported to harbor almost universal TP53 and RB1 mutations and a dominant tobacco smoke‐related signature 4, uterine cervix SCCs rarely harbored mutations affecting these genes (2/9, 22% TP53; 0% RB1) and displayed a dominant aging (67%) or APOBEC mutational signature (17%), akin to HPV‐driven cancers, including cervical adeno‐ and squamous cell carcinomas and head and neck squamous cell carcinomas. Taken together, in contrast to SCLCs, which are characterized by highly recurrent TP53 and RB1 alterations, uterine cervix SCCs were positive for HPV leading to inactivation of the suppressors p53 and RB, suggesting that these SCCs are convergent phenotypes.     

New Clamp-PID Algorithm for Automated Glucose Clamps Improves Clamp Quality

Background:In automated glucose clamp experiments, blood glucose (BG) concentrations are kept close to a predefined target level using variable glucose infusion rates (GIRs) determined by implemented algorithms. Clamp quality (ie, the ability to keep BG close to target) highly depends on the quality of these algorithms. We developed a new Clamp algorithm based on the proportional-integral-derivative (PID) approach and compared clamp quality between this and the established Biostator (BS) algorithm.Methods:In numerical simulations, the PID-based algorithm was optimized in silico. The optimized Clamp-PID algorithm was tested in in vitro experiments and finally validated in vivo in a small (n = 5) clinical study.Results:In silico, in vitro, and in vivo experiments showed better clamp quality for the new Clamp-PID algorithm compared with the BS algorithm: precision and absolute control deviation (ACD) decreased from 3.7% to 1.1% and from 2.9 mg/dL to 0.6 mg/dL, respectively, in the numerical simulation. The in vitro validation demonstrated reductions in precision (from 3.3% ± 0.1% (mean ± SD) to 1.4% ± 0.4%) and in ACD (from 2.3 mg/dL ± 0.4 mg/dL to 0.8 mg/dL ± 0.2 mg/dL), respectively. In the clinical study, precision and ACD improved from 6.5% ± 1.3% to 4.0% ± 1.1% and from 3.6 mg/dL ± 0.9 mg/dL to 2.2 mg/dl ± 0.6 mg/dl, respectively. The quality parameter utility did not change.Conclusions:The new Clamp-PID algorithm improves the clamp quality parameters precision and ACD versus the BS algorithm.     

Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation

Because of the perception that depleting hematopoietic grafts of T cells will result in poorer immune recovery and in increased risk of graft rejection, pure hematopoietic stem cells (HSC), which avoid the potentially lethal complication of graft-versus-host disease (GVHD), have not been used for allogeneic hematopoietic cell transplantation (HCT) in humans. Ideal grafts should contain HSC plus mature cells that confer only the benefits of protection from pathogens and suppression of malignancies. This goal requires better understanding of the effects of each blood cell type and its interactions during engraftment and immune regeneration. Here, we studied hematopoietic reconstitution post-HCT, comparing grafts of purified HSC with grafts supplemented with T cells in a minor histocompatibility antigen (mHA)-mismatched mouse model. Cell counts, composition, and chimerism of blood and lymphoid organs were evaluated and followed intensively through the first month, and then subsequently for up to 1 yr. Throughout this period, recipients of pure HSC demonstrated superior total cell recovery and lymphoid reconstitution compared with recipients of T cell-containing grafts. In the latter, rapid expansion of T cells occurred, and suppression of hematopoiesis derived from donor HSC was observed. Our findings demonstrate that even early post-HCT, T cells retard donor HSC engraftment and immune recovery. These observations contradict the postulation that mature donor T cells provide important transient immunity and facilitate HSC engraftment.     

The Roll of Toll-like Receptors in the Antiphospholipid Syndrome

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis, recurrent fetal loss, and the presence of antiphospholipid antibodies (aPL). Recent data support the idea that the thrombotic activity in APS patients is attributed to enhanced cytokine release via activation of certain Toll-like receptors. To investigate these mechanisms more precisely, different experimental approaches were used to investigate this connection in detail. IgG fractions and/or monoclonal aPL, either generated from murine or human B cells were intensely used for stimulation experiments of monocytes, endothelial cells, or dendritic cells. All these stimuli induced an enhanced expression and secretion of cytokines, especially tumor necrosis factor (TNF)-α, caused by specific regulation or activation of Toll-like receptors. Using specific agonists or inhibitors could confirm the causal connection of these stimulatory effects. This review focuses on these recent developments, connecting the binding of aPL with the activity of Toll-like receptors, especially in monocytes, endothelial cells, and dendritic cells.     

Proapoptotic and redox state-related signaling of reactive oxygen species generated by transformed fibroblasts

Oncogenic transformed fibroblasts are characterized by extracellular superoxide anion generation through a membrane-associated NADPH oxidase. After cellular glutathione depletion, extracellular reactive oxygen species (ROS) generated by transformed fibroblasts exhibit a strong apoptosis-inducing potential. As apoptosis induction under glutathione depletion is inhibited by catalase, the NADPH oxidase inhibitor apocynin, superoxide dismutase, the hydroxyl radical scavenger terephthalate and the iron chelator deferoxamine, the metal-catalysed Haber-Weiss reaction seems to be the responsible signaling mechanism. In contrast to extracellular ROS, intracellular ROS play no role for apoptosis induction in glutathione-depleted transformed fibroblasts initially, since a high level of intracellular catalase scavenges intracellular hydrogen peroxide. Intracellular catalase seems to be induced by extracellular hydrogen peroxide, as pretreatment of transformed fibroblasts with exogenous catalase downmodulates endogenous catalase and renders glutathione-depleted transformed cells susceptible for the effect of endogenous hydrogen peroxide. In contrast to transformed fibroblasts, nontransformed glutathione-depleted fibroblasts do not generate substantial extracellular ROS, but apoptosis is efficiently induced in these cells by intracellular ROS. Our data show that extracellular ROS of transformed fibroblasts exhibit redox-related signaling and at the same time represent a potential apoptosis-inducing hazard through the metal-catalysed Haber-Weiss reaction.     

Activation of the peripheral endocannabinoid system in human obesity

Obesity is the main risk factor for the development of type 2 diabetes. Activation of the central endocannabinoid system increases food intake and promotes weight gain. Blockade of the cannabinoid type 1 (CB-1) receptor reduces body weight in animals by central and peripheral actions; the role of the peripheral endocannabinoid system in human obesity is now being extensively investigated. We measured circulating endocannabinoid concentrations and studied the expression of CB-1 and the main degrading enzyme, fatty acid amide hydrolase (FAAH), in adipose tissue of lean (n = 20) and obese (n = 20) women and after a 5% weight loss in a second group of women (n = 17). Circulating levels of anandamide and 1/2-arachidonoylglycerol were increased by 35 and 52% in obese compared with lean women (P < 0.05). Adipose tissue mRNA levels were reduced by -34% for CB-1 and -59% for FAAH in obese subjects (P < 0.05). A strong negative correlation was found between FAAH expression in adipose tissue and circulating endocannabinoids. Circulating endocannabinoids and CB-1 or FAAH expression were not affected by 5% weight loss. The expression of CB-1 and FAAH was increased in mature human adipocytes compared with in preadipocytes and was found in several human tissues. Our findings support the presence of a peripheral endocannabinoid system that is upregulated in human obesity.     

Cyclooxygenase-2 inhibitors suppress the growth of human hepatocellular carcinoma implants in nude mice

Cyclooxygenase (COX)-2 is expressed in hepatocellular carcinomas (HCCs) and HCC cell lines. COX-2 inhibition strongly suppresses growth of HCC cells in vitro by inducing apoptosis and reducing proliferation. Here, we evaluate the in vivo effects and mechanism of COX-2 inhibition of human HCC cell line derived xenotransplanted tumors in nude mice. Firstly, nude mice were treated with a COX-2 specific inhibitor (meloxicam) or a non-specific inhibitor (sulindac) starting 5 days prior to tumor cell injection. After 35 days mice were killed and tumors were analyzed morphologically and assayed for proliferation (Ki67), apoptosis (M30) and COX-2 expression. Secondly, mice were treated with meloxicam or sulindac after tumors had reached a diameter of at least 0.2 cm. COX-2 expression was maintained in implant tumors at levels comparable with parental cells. Selective COX-2 inhibition led to a significant reduction of tumor growth and weight. COX-2 inhibition had a significant anti-proliferative and pro-apoptotic effect on tumor cells. These results demonstrate that under experimental conditions selective COX-2 inhibition suppresses solid HCC growth in vivo and, therefore may have preventive and therapeutic potential for human HCCs.