Non-erythroid Rh glycoproteins: a putative new family of mammalian ammonium transporters

The Rhesus (Rh) glycoproteins, originally described in human blood cells, are mostly recognized for their immunogenic characteristics and importance in pregnancy. The Rh proteins in the red blood cell are expressed as an "Rh complex" made up of one D-subunit, one CE-subunit and two Rh-associated glycoprotein (RhAG) subunits. In addition to its antigenic property, the Rh complex is thought to contribute to membrane stability and structure of red blood cells. The exact function is yet to be determined. Recently, two non-erythroid Rh glycoproteins were cloned from mice (Rhcg and Rhbg) and humans (RhCG and RhBG). RhCG is expressed at the membrane surface alone with no apparent need for heteromeric interaction with other glycoproteins. It is more similar to RhAG than to Rh CE/D, occurs late in development and is expressed abundantly and broadly in kidney and testis. In the kidney RhCG is localized to the apical cell membrane of the collecting duct. Rhbg and its human analog (RhBG) are expressed mainly in liver, skin and the kidney tubules. In the kidney collecting duct, Rhbg is localized to the basolateral membrane. Based on structural similarities to the methylammonium and ammonium permease/ammonium (MEP/Amt) transporters in yeast and their sequence homology, these proteins probably function as NH(4)(+) transporters. An initial study has indicated that RhAG or RhCG promote efflux of NH(4)(+), whereas another study has suggested that RhAG functions as an NH(4)(+)-H(+) exchanger. Evidence for such a function is still circumstantial and data indicating that Rh proteins function as NH(4)(+) transporters are indirect.     

Non‐invasive monitoring of muscle blood perfusion by photoplethysmography: evaluation of a new application

Aim: To evaluate a specially developed photoplethysmographic (PPG) technique, using green and near‐infrared light sources, for simultaneous non‐invasive monitoring of skin and muscle perfusion. Methods: Evaluation was based on assessments of changes in blood perfusion to various provocations, such as post‐exercise hyperaemia and hyperaemia following the application of liniment. The deep penetrating feature of PPG was investigated by measurement of optical radiation inside the muscle. Simultaneous measurements using ultrasound Doppler and the new PPG application were performed to elucidate differences between the two methods. Specific problems related to the influence of skin temperature on blood flow were highlightened, as well. Results: Following static and dynamic contractions an immediate increase in muscle perfusion was shown, without increase in skin perfusion. Liniment application to the skin induced a rapid increase in skin perfusion, but not in muscle. Both similarities and differences in blood flow measured by Ultrasound Doppler and PPG were demonstrated. The radiant power measured inside the muscle, by use of an optical fibre, showed that the near‐infrared light penetrates down to the vascular depth inside the muscle. Conclusions: The results of this study indicate the potentiality of the method for non‐invasive measurement of local muscle perfusion, although some considerations still have to be accounted for, such as influence of temperature on blood perfusion.     

Optically active polymers bearing side‐chain photochromic moieties: synthesis and chiroptical properties of methacrylic homopolymers with pendant trans‐azobenzene chromophores bound through L‐leucine,L‐valine and L‐proline amino acid spacers

Novel optically active monomers, based on different L ‐amino acid residues such as trans‐(S)‐4‐(2‐methacryloylamino‐3‐methylbutanoylamino)azobenzene, trans‐(S)‐4‐(2‐methacryloylamino‐4‐methylpentanoylamino)azobenzene and trans‐(S)‐4‐(N‐methacryloyl‐2‐pyrrolidinoylamino)azobenzene, have been prepared and homopolymerized by free radical initiation. Circular dichroism spectra of the resulting polymers, as compared with those of the corresponding low molecular weight analogues, purposely synthesized, allow one to suggest that the macromolecules assume in solution achiral or chiral conformations with a prevailing screw sense, depending on the bulkiness and rigidity of the L ‐amino acid residue present in the side chains. The role of intra‐ and/or inter‐molecular hydrogen bonding between side‐chain amido groups along the backbone and the structural requirements of the chiral groups in determining the macromolecular arrangement is also discussed.     

HLA‐B*38:55Q: a new alternatively expressed allele identified in a three‐generation Italian family

The new allelic variant HLA‐B*38:55Q differs from the closest related B*38:01:01 by one nucleotide substitution at position 373 in exon 3 (TGC>CGC). This results in a difference of one amino acid at residue 101 of the HLA‐B heavy chain, from a neutral‐polar Cys to a basic‐polar Arg, thus impairing disulphide bridge formation in the alpha‐2 domain. This alteration of the secondary structure probably affects the maturation of the heavy chain and the level of surface expression, making the HLA‐B*38:55Q undetectable by standard serological typing.     

Non‐clinical obsessions in a young adolescent population: Frequency and association with metacognitive variables

Objectives. Little is known about normal obsessions in adolescence. This study examined the frequency and content of intrusions in adolescence, and a number of process variables that have been associated with obsessions in adults. Design and methods. Sixty‐two adolescents (aged 12–14 years) participated. They completed measures of obsessions and metacognitive beliefs. They were interviewed about recent episodes of obsessional thought, including content, frequency, acceptability, distress, dismissibilty, interference, and avoidance. Results. Seventy‐seven per cent of participants reported obsessions. Frequency, distress, dismissibility, acceptability, interference, and avoidance, were associated with metacognitive appraisals. Conclusions. Obsessions are a normal experience in adolescence and are associated with metacognitive appraisals in the same way as for adults, indicating that adult models may be relevant for this younger population.     

Non‐pharmacological treatment of psychiatric disorders in individuals with 22q11.2 deletion syndrome; a systematic review

22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of anxiety disorders, psychotic disorders, and other psychiatric conditions. In the general population, psychiatric disorders are treated with proven pharmacological and non‐pharmacological therapies, such as cognitive behavioral therapy (CBT). To begin to assess the feasibility and efficacy of non‐pharmacological therapies in 22q11.2DS, we performed a systematic search to identify literature on non‐pharmacological interventions for psychiatric disorders in individuals with 22q11.2DS. Of 1,240 individual publications up to mid‐2016 initially identified, 11 met inclusion criteria. There were five literature reviews, five publications reporting original research (two originating from a single study), and one publication not fitting either category that suggested adaptations to an intervention without providing scientific evidence. None of the original research involved direct study of the evidence‐based non‐pharmacological therapies available for psychiatric disorders. Rather, these four studies involved computer‐based or group interventions aimed at improving neuropsychological deficits that may be associated with psychiatric disorders. Although the sample sizes were relatively small (maximum 28 participants in the intervention group), these reports documented the promising feasibility of these interventions, and improvements in domains of neuropsychological functioning, including working memory, attention, and social cognition. The results of this review underline the need for research into the feasibility and efficacy of non‐pharmacological treatments of psychiatric disorders in individuals with 22q11.2DS to inform clinical care, using larger samples, and optimally, standard randomized, placebo‐controlled, clinical trials methodology.

     

Brief problem‐solving training for family caregivers of persons with recent‐onset spinal cord injuries: a randomized controlled trial

Our objective was to examine the effectiveness of a brief individualized problem‐solving intervention for family with caregivers of persons with recent‐onset spinal cord injury (SCI). Family caregivers were randomly assigned to a usual care control group (N=30) or an intervention group (N=30) in which participants were to receive three face‐to‐face problem‐solving training sessions (PST), educational materials, and telephone contacts as requested over the first year of caregiving. The participants included 60 caregivers (49 women, 11 men). The Social Problem‐Solving Inventory‐Revised, the Inventory to Diagnose Depression, and the SF‐36 were administered at baseline, 6 months and 12 months. Caregivers in the intervention group reported a significant decrease in dysfunctional problem‐solving styles scores over time; there were no observable effects for PST on caregiver depression. There was also some indication that the intervention had beneficial effects on caregiver social and physical functioning. An intervention for new caregivers featuring brief PST, education, and contact may be associated with lower dysfunctional problem‐solving styles over time and may promote certain aspects of caregiver quality of life. We also discuss limitations and implications of the present study. © 2009 Wiley Periodicals, Inc. J Clin Psychol 65: 1–17, 2009.     

Facile Preparation of a Fluorine‐Free,Robust, Superhydrophobic Coating through Dip Coating Combined with Non‐Solvent Induced Phase Separation (Dip‐Coating‐NIPS) Method

Superhydrophobic surfaces based on non‐fluorinated materials and facile fabrication techniques are of great practical value with respect to environmental friendliness and industrial applications. In this work, a fluorine‐free, superhydrophobic coating with hierarchical surface structure and low surface energy is successfully fabricated on various substrates through a recently developed dip coating combined with non‐solvent induced phase separation (dip‐coating‐NIPS) method. A bio‐based polymer, poly(l ‐lactic acid), and commercially available hydrophobic SiO₂ nanoparticles, are used. The fabricated coating exhibits superhydrophobicity, with a static water contact angle (WCA) of 155.7° ± 1.4° and contact angle hysteresis (θ_Hys) of 5.2° ± 0.4°. The results from stability tests demonstrate excellent mechanical durability and chemical stability of the superhydrophobic coating. Finally, the fabricated coating is successfully applied in water–oil separation with superior efficiency. This simple, cost‐effective, and time‐efficient method may provide an effective way for the design of nonfluorine‐based environmentally friendly membranes for separation applications.     

A novel IL‐17‐dependent mechanism of cross protection: Respiratory infection with mycoplasma protects against a secondary listeria infection

Immune responses to pathogens occur within the context of current and previous infections. Cross protection refers to the phenomena where infection with a particular pathogen provides enhanced resistance to a subsequent unrelated pathogen in an antigen‐independent manner. Proposed mechanisms of antigen‐independent cross protection have involved the secretion of IFN‐γ, which activates macrophages, thus providing enhanced innate immunity against the secondary viral or bacterial pathogen. Here we provide evidence that a primary infection with the chronic respiratory pathogen, Mycoplasma pulmonis, provides a novel form of cross protection against a secondary infection with Listeria monocytogenes that is not mediated by IFN‐γ, but instead relies upon IL‐17 and mobilization of neutrophils. Mice infected with M. pulmonis have enhanced clearance of L. monocytogenes from the spleen and liver, which is associated with increased numbers of Gr‐1⁺CD11b⁺ cells and higher levels of IL‐17. This enhanced clearance of L. monocytogenes was absent in mice depleted of Gr‐1⁺ cells or in mice deficient in the IL‐17 receptor. Additionally, both the IL‐17 receptor and neutrophils were essential for optimal clearance of M. pulmonis. Thus, a natural component of the immune response directed against M. pulmonis was able to enhance clearance of L. monocytogenes.     

A quarter of patients with type 1 diabetes have co‐existing non‐islet autoimmunity: the findings of a UK population‐based family study

Individuals with type 1 diabetes (T1D) are at increased risk of coeliac disease (CD), autoimmune thyroiditis and autoimmune gastritis, but the absolute risks are unclear. The aim of this study was to investigate the prevalence of autoantibodies to tissue transglutaminase (TGA), thyroid peroxidase (TPOA) and gastric H⁺/K⁺‐ATPase (ATPA) and their genetic associations in a well‐characterized population‐based cohort of individuals with T1D from the Bart's–Oxford family study for whom islet autoantibody prevalence data were already available. Autoantibodies in sera from 1072 patients (males/females 604/468; median age 11·8 years, median T1D duration 2·7 months) were measured by radioimmunoassays; HLA class II risk genotype was analysed in 973 (91%) using polymerase chain reaction with sequence specific primers (PCR‐SSP). The prevalence of TGA (and/or history of CD), TPOA and ATPA in patients was 9·0, 9·6 and 8·2%, respectively; 3·1% had two or more autoantibodies. Females were at higher risk of multiple autoimmunity; TGA/CD were associated with younger age and TPOA with older age. ATPA were uncommon in patients under 5 years, and more common in older patients. Anti‐glutamate decarboxylase autoantibodies were predictive of co‐existing TPOA/ATPA. TGA/CD were associated with human leucocyte antigen (HLA) DR3‐DQ2, with the DR3‐DQ2/DR3‐DQ2 genotype conferring the highest risk, followed by DR4‐DQ8/DR4‐DQ8. ATPA were associated with DR3‐DQ2, DRB1*0404 (in males) and the DR3‐DQ2/DR4‐DQ8 genotype. TPOA were associated with the DR3‐DQ2/DR3‐DQ2 genotype. Almost one‐quarter of patients diagnosed with T1D aged under 21 years have at least one other organ‐specific autoantibody. HLA class II genetic profiling may be useful in identifying those at risk of multiple autoimmunity.     

Terminal osseous dysplasia with pigmentary defects: clinical description of a new family

Terminal osseous dysplasia with pigmentary defects is an extremely rare condition characterized by the triad of pigmentary anomalies of the skin, skeletal abnormalities of the limbs and recurring digital fibromatosis of childhood, with considerable interfamilial and intrafamilial variability of expression. It has recently been added to the small group of X-linked dominant disorder with prenatal male lethality on the basis of a four-generation pedigree in which only females were affected, male progeny was decreased and the number of spontaneous abortions was increased. In this clinical report, we describe a 2-year-old girl with full expression of the syndrome including skin defects, skeletal anomalies and recurrent fibromatosis of fingers and toes and her mother who presents with only multiple hypertrophic oral frenula. As previously demonstrated, our patients also show an extremely skewed X-inactivation on blood cells, strongly suggesting that there is selective disadvantage for cells carrying the mutated gene on their active X chromosome. Terminal osseous dysplasia with pigmentary defects could represent an additional example of extreme intrafamilial variability as already described for other X-linked dominant disorders.     

Chronic mucocutaneous candidiasis: characterization of a family with STAT‐1 gain‐of‐function and development of an ex‐vivo assay for Th17 deficiency of diagnostic utility

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent and persistent superficial infections, with Candida albicans affecting the mucous membranes, skin and nails. It can be acquired or caused by primary immune deficiencies, particularly those that impair interleukin (IL)?17 and IL‐22 immunity. We describe a single kindred with CMC and the identification of a STAT1 GOF mutation by whole exome sequencing (WES). We show how detailed clinical and immunological phenotyping of this family in the context of WES has enabled revision of disease status and clinical management. Together with analysis of other CMC cases within our cohort of patients, we used knowledge arising from the characterization of this family to develop a rapid ex‐vivo screening assay for the detection of T helper type 17 (Th17) deficiency better suited to the routine diagnostic setting than established in‐vitro techniques, such as intracellular cytokine staining and enzyme‐linked immunosorbent assay (ELISA) using cell culture supernatants. We demonstrate that cell surface staining of unstimulated whole blood for CCR6⁺CXCR3^–CCR4⁺CD161⁺ T helper cells generates results that correlate with intracellular cytokine staining for IL‐17A, and is able to discriminate between patients with molecularly defined CMC and healthy controls with 100% sensitivity and specificity within the cohort tested. Furthermore, removal of CCR4 and CD161 from the antibody staining panel did not affect assay performance, suggesting that the enumeration of CCR6⁺CXCR3^–CD4⁺ T cells is sufficient for screening for Th17 deficiency in patients with CMC and could be used to guide further investigation aimed at identifying the underlying molecular cause.     

Glycoprotein targeted therapeutics: a new era of anti‐herpes simplex virus‐1 therapeutics

Herpes simplex virus type‐1 (HSV‐1) is among the most common human pathogens worldwide. Its entry into host cells is an intricate process that relies heavily on the ability of the viral glycoproteins to bind host cellular proteins and to efficiently mediate fusion of the virus envelope with the cell membrane. Acquisition of HSV‐1 results in a lifelong latent infection. Because of the cycles of reactivation from a latent state, much emphasis has been placed on the management of infection through the use of DNA synthesis inhibitors. However, new methods are needed to provide more effective treatment at earlier phases of the viral infection and to prevent the development of drug resistance by the virus. This review outlines the infection process and the common therapeutics currently used against the fundamental stages of HSV‐1 replication and fusion. The remainder of this article will focus on a new approach for HSV‐1 infection control and management, the concept of glycoprotein‐receptor targeting. Copyright © 2013 John Wiley & Sons, Ltd.