Miracle-dz/UniFAR-FTUs huggingface dataset:
Phenotypic variation within European carriers of the Y-chromosomal gr/gr deletion is independent of Y-chromosomal background

Background: Previous studies have compared sperm phenotypes between men with partial deletions within the AZFc region of the Y chromosome and non-carriers, with variable results. In this study, a separate question was investigated, the basis of the variation in sperm phenotype within gr/gr deletion carriers, which ranges from normozoospermia to azoospermia. Differences in the genes removed by independent gr/gr deletions, the occurrence of subsequent duplications or the presence of linked modifying variants elsewhere on the chromosome have been suggested as possible causal factors. This study set out to test these possibilities in a large sample of gr/gr deletion carriers with known phenotypes spanning the complete range. Results: In total, 169 men diagnosed with gr/gr deletions from six centres in Europe and one in Australia were studied. The DAZ and CDY1 copies retained, the presence or absence of duplications and the Y-chromosomal haplogroup were characterised. Although the study had good power to detect factors that accounted for ⩾5.5% of the variation in sperm concentration, no such factor was found. A negative effect of gr/gr deletions followed by b2/b4 duplication was found within the normospermic group, which remains to be further explored in a larger study population. Finally, significant geographical differences in the frequency of different subtypes of gr/gr deletions were found, which may have relevance for the interpretation of case control studies dealing with admixed populations. Conclusions: The phenotypic variation of gr/gr carriers in men of European origin is largely independent of the Y-chromosomal background.
House dust mite allergic airway inflammation facilitates neosensitization to inhaled allergen in mice

The mechanism by which many monosensitized allergic individuals progress to polysensitization over time remains to be elucidated. Mouse models have contributed greatly to the understanding of sensitization to inhaled allergens in healthy airways but hardly any studies have addressed sensitization during established allergy. We hypothesized that an allergic inflammatory milieu might facilitate sensitization to inhaled allergens by the presence of mature dendritic cells (DCs) and IL‐4.
Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy

Introduction: Autosomal dominant optic atrophy (ADOA) is considered as the most common form of hereditary optic neuropathy. Although genetic linkage studies point to the OPA1 locus on chromosome 3q28–q29 as by far the most common gene locus, previous screening studies—based on sequencing of the coding exons—detected OPA1 mutations in only 32–70% of ADOA patients. We therefore hypothesised that larger deletions or duplications that remained undetected in previous screening approaches may substantially contribute to the prevalence of OPA1 mutations in ADOA. Methods: 42 independent ADOA patients were analysed for the presence of genomic rearrangements in OPA1 by means of multiplex ligation probe amplification (MLPA). Deletions or duplications were confirmed either by long distance polymerase chain reaction (PCR) and breakpoint sequencing or loss of heterozygosity analyses with flanking microsatellite markers. Patients underwent ophthalmological examination including visual acuity, colour vision testings, perimetry and funduscopy. Results: We identified genomic rearrangements in 8 of 42 patients, including single exon deletions of exon 9 and exon 24, respectively, a deletion of exons 1–5, two different deletions of the complete OPA1 gene as well as a duplication of the exons 7–9, with the latter being present in three unrelated families. Patients’ phenotypes were highly variable, similar to patients with point mutation in OPA1. Discussion: Our findings show that gross genomic aberrations at the OPA1 gene locus are frequent in ADOA and substantially contribute to the spectrum and prevalence of OPA1 mutations in ADOA patients. They further strengthen the hypothesis that haploinsufficiency is a major pathomechanism in OPA1 associated ADOA.
Modèles animaux d'ostéoporose post-ménopausique

Osteoporosis is a disease characterized by low bone mass, microarchitectural deterioration of bone tissue leading to enhanced bone fragility, and a consequent increase in fracture risk. In humans estrogen deficiency following menopause is associated with a more or less intense osteopenia. In some subjects, such a decrease in bone mass induces osteoporosis. Several animal models (ovariectomized female dogs, pigs and monkeys) are used to study the etiology, prophylaxis and treatment for osteoporosis. Nevertheless, the changes in bone metabolism following estrogen deficiency are very similar in rats and humans. Thus, the ovariectomized rat is the most frequently used model for such studies.
Association of IL18RAP and CCR3 with coeliac disease in the Spanish population

Background and aims: Genome-wide association studies in coeliac disease (CD) have resulted in the finding of eight new genetic regions associated with disease susceptibility. However, a replication study performed in the Italian population could not confirm two of those new regions: 2q12 (IL18RAP) and 3p21 (CCR3). The aim of this study was to investigate the role of those regions in CD risk in a different Mediterranean population, the Spanish population. Methods: A case–control study with 722 patients with CD and 794 ethnically matched healthy controls was performed. Two single-nucleotide polymorphisms, rs917997 (2q12) and rs6441961 (3p21), were genotyped and their genetic frequencies were compared between both groups using the χ2 test. Results: An association was found with rs6441961 (p = 0.0004, OR = 1.32, 95% CI 1.13 to 1.54). A non-significant result (but concordant with the initial study) was obtained for rs917997. Conclusion: The association of the 3p21 genetic region with CD susceptibility in the Spanish population was confirmed. In 2q12, the initially described OR is most probably overestimated and therefore the real situation may be the existence of a genuine but weak risk factor, which generates statistical power limitations.
A reappraisal of the blood supply of the pectoralis minor muscle

Recently the pectoralis minor muscle has been introduced as a free muscle transplant for facial reanimation in peripheral facial paralysis. However, reports on the vascular supply of this muscle are incomplete or contradictory. Therefore the pectoral region was examined in 57 human cadavers. A complex pattern of variations in the arterial supply was found: it was, however, systematically arranged and limited to a small part of the arterial tree. A topographical classification was made, based on the dominant muscle artery, to provide a useful orientation during reconstructive surgery. Related to the origin of this dominant artery, three main patterns are distinguished. In the most frequent pattern a major role is played by an artery not mentioned in Nomina Anatomica (Edinburgh: Churchill Livingstone, 1989). This artery usually arises directly from the axillary artery, accompanies the medial pectoral nerve, and supplies the major lateral part of the muscle from its deep surface. For topographical reasons we propose the name “lateral pectoral artery. ” The classification, presented in this study, may provide a better insight for the reconstructive surgeon working in this area. © 1994 Wiley‐Liss, Inc.
Diabetes in pregnancy: influence of genetic background and maternal diabetic state on the incidence of skeletal malformations in the fetal rat.

Female Sprague-Dawley rats from two different substrains (denoted U and H rats) were made manifest diabetic (MD) with a single iv injection of streptozotocin 2-4 weeks before mating. In some MD animals insulin treatment was started 1-3 weeks before mating (denoted MDI rats) and in a majority of these animals the treatment was interrupted during two days of pregnancy, i.e. gestational days 2 + 3, 4 + 5, 6 + 7, 8 + 9 or 10 + 11. The pregnant rats were killed on gestational day 20. The offspring of MD and MDI rats of the U substrain showed skeletal malformations (micrognathia and sacral dysgenesis) at a rate up to 19%, whereas the MD and MDI fetuses of the H strain did not display any skeletal malformations. Offspring of the U strain with sacral dysgenesis exhibited lack of a tail and no staining of osseous and cartilagenous tissue in the sacral-caudal region, suggesting total absence of vertebrae. The offspring of the diabetic U rats tended to be more readily resorbed, were smaller and tended to have slightly larger placentae than those of the diabetic H rats. The severity of the diabetic state in pregnant and nonpregnant female rats--as reflected by body and kidney weights, blood levels of HbA1c, carbohydrate and lipid metabolites--did not differ significantly between the U and H rats. These results are in concert with the notion that congenital malformations result from a teratogenic insult in a genetically predisposed organism. The described malformation-prone rat strain (U) may be a suitable model for the future elucidation of teratological mechanisms in diabetic pregnancy.
Improvement and retardation of wound healing: effects of pharmacological agents in laboratory animal studies.

Impaired wound healing is an important problem; retardation of healing may be induced by endogenous and/or exogenous factors and treatments capable of ameliorating these effects are needed. The effects of solutions containing light ichthyol or povidone iodine, of ointments containing zinc oxide (ZO) and/or cod liver oil (CLO), and of a polyurethane-hydrogel foam wound dressing were examined on healing of full-thickness murine skin wounds impaired by systemic dexamethasone. The effects of the ointments were also studied on murine skin ulceration induced by subcutaneous sodium dodecyl sulphate solution. Light ichthyol at 1% and 2% but not at 5% and 10%, povidone iodine at 1% and the foam accelerated impaired healing. The ointments containing ZO or CLO accelerated healing of impaired full-thickness wounds and of ulcerated skin; ZO and CLO were synergistic. These studies demonstrate the value of murine models in the evaluation of agents employed in veterinary wound dressings.
Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair

Background The frequency of cancer, neurologic degeneration and mortality in xeroderma pigmentosum (XP) patients with defective DNA repair was determined in a four decade natural history study. Methods All 106 XP patients admitted to the National Institutes of Health from 1971 to 2009 were evaluated from clinical records and follow-up. Results In the 65 per cent (n=69) of patients with skin cancer, non-melanoma skin cancer (NMSC) was increased 10 000-fold and melanoma was increased 2000-fold in patients under age 20. The 9 year median age at diagnosis of first non-melanoma skin cancer (NMSC) (n=64) was significantly younger than the 22 year median age at diagnosis of first melanoma (n=38)—a relative age reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. XP patients with pronounced burning on minimal sun exposure (n=65) were less likely to develop skin cancer than those who did not. This may be related to the extreme sun protection they receive from an earlier age, decreasing their total ultraviolet exposure. Progressive neurologic degeneration was present in 24% (n=25) with 16/25 in complementation group XP-D. The most common causes of death were skin cancer (34%, n=10), neurologic degeneration (31%, n=9), and internal cancer (17%, n=5). The median age at death (29 years) in XP patients with neurodegeneration was significantly younger than those XP patients without neurodegeneration (37 years) (p=0.02). Conclusion This 39 year follow-up study of XP patients indicates a major role of DNA repair genes in the aetiology of skin cancer and neurologic degeneration.
Chemokine axes in breast cancer: factors of the tumor microenvironment reshape the CCR7‐driven metastatic spread of luminal‐A breast tumors

Chemokine axes have been shown to mediate site‐specific metastasis in breast cancer, but their relevance to different subtypes has been hardly addressed. Here, with the focus on the CCR7‐CCL21 axis, patient datasets demonstrated that luminal‐A tumors express relatively low CCR7 levels compared with more aggressive disease subtypes. Furthermore, lymph node metastasis was not associated with high CCR7 levels in luminal‐A patients. The metastatic pattern of luminal‐A breast tumors may be influenced by the way luminal‐A tumor cells interpret signals provided by factors of the primary tumor microenvironment. Thus, CCR7‐expressing human luminal‐A cells were stimulated simultaneously by factors representing 3 tumor microenvironment arms typical of luminal‐A tumors, hormonal, inflammatory, and growth stimulating: estrogen + TNF‐α + epidermal growth factor. Such tumor microenvironment stimulation down‐regulated the migration of CCR7‐expressing tumor cells toward CCL21 and inhibited the formation of directional protrusions toward CCL21 in a novel 3‐dimensional hydrogel system. CCL21‐induced migration of CCR7‐expressing tumor cells depended on PI3K and MAPK activation; however, when CCR7‐expressing cancer cells were prestimulated by tumor microenvironment factors, CCL21 could not effectively activate these signaling pathways. In vivo, pre‐exposure of the tumor cells to tumor microenvironment factors has put restraints on CCL21‐mediated lymph node‐homing cues and shifted the metastatic pattern of CCR7‐expressing cells to the aggressive phenotype of dissemination to bones. Several of the aspects were also studied in the CXCR4‐CXCL12 system, demonstrating similar patient and in vitro findings. Thus, we provide novel evidence to subtype‐specific regulation of the CCR7‐CCL21 axis, with more general implications to chemokine‐dependent patterns of metastatic spread, revealing differential regulation in the luminal‐A subtype.
FOXN1 mutation abrogates prenatal T-cell development in humans

Background The transcription factor FOXN1 is implicated in the differentiation of thymic and skin epithelial cells, and alterations in it are responsible for the Nude/SCID phenotype. During a genetic counselling programme offered to couples at risk in a community where a high frequency of mutated FOXN1 had been documented, the identification of a human FOXN1−/− fetus gave the unique opportunity to study T cell development in utero. Results Total blockage of CD4+ T cell maturation and severe impairment of CD8+ cells were documented. Evaluation of the variable-domain β-chain (Vβ) families' usage among T lymphocytes revealed that the generation of T cell receptor (TCR) diversity occurred to some extent in the FOXN1−/− fetus, although it was impaired compared with the control. A few non-functional CD8+ cells, mostly bearing TCRγδ in the absence of CD3, were found. Discussion FOXN1 is crucial for in utero T cell development in humans. The identification of a limited number of CD8+ cells suggests an extrathymic origin for these cells, implying FOXN1-independent lymphopoiesis.
Lack of the programmed death‐1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules

The programmed death‐1 receptor is expressed on a wide range of immune effector cells, including T cells, natural killer T cells, dendritic cells, macrophages, and natural killer cells. In malignancies and chronic viral infections, increased expression of programmed death‐1 by T cells is generally associated with a poor prognosis. However, its role in early host microbial defense at the intestinal mucosa is not well understood. We report that programmed death‐1 expression is increased on conventional natural killer cells but not on CD4+, CD8+ or natural killer T cells, or CD11b+ or CD11c+ macrophages or dendritic cells after infection with the mouse pathogen Citrobacter rodentium. Mice genetically deficient in programmed death‐1 or treated with anti–programmed death‐1 antibody were more susceptible to acute enteric and systemic infection with Citrobacter rodentium. Wild‐type but not programmed death‐1–deficient mice infected with Citrobacter rodentium showed significantly increased expression of the conventional mucosal NK cell effector molecules granzyme B and perforin. In contrast, natural killer cells from programmed death‐1–deficient mice had impaired expression of those mediators. Consistent with programmed death‐1 being important for intracellular expression of natural killer cell effector molecules, mice depleted of natural killer cells and perforin‐deficient mice manifested increased susceptibility to acute enteric infection with Citrobacter rodentium. Our findings suggest that increased programmed death‐1 signaling pathway expression by conventional natural killer cells promotes host protection at the intestinal mucosa during acute infection with a bacterial gut pathogen by enhancing the expression and production of important effectors of natural killer cell function.
miRNA‐155 controls mast cell activation by regulating the PI3Kγ pathway and anaphylaxis in a mouse model

Mast cells (MCs) play a central role in allergic and inflammatory disorders by rapid degranulation and release of inflammatory mediators upon antigen‐driven engagement of the FcεRI. Receptor‐mediated MC responses are controlled by the activation of different isoforms of phosphoinositide‐3‐kinase (PI3K) and the downstream signaling processes. Recent evidence suggests that miRNAs are important molecular players regulating the PI3K/Akt pathway.
Systematic Review of Sonographic Measurements of the Ulnar Nerve at the Elbow

A systematic review was performed to identify studies reporting summary data (mean, standard deviation) of sonographic cross-sectional measurements of the ulnar nerve at the elbow. Comparisons of measurements were performed to determine whether statistical differences existed between groups of individuals symptomatic and asymptomatic of ulnar nerve entrapment at the elbow (UNE). Across the four studies meeting the selection criteria of the search, five sample groups were identified and compared: three asymptomatic of UNE and two symptomatic of UNE. There were significant differences between measurements of people with and without UNE (P < .0001—.041). Significant differences also existed between the two symptomatic populations (P < .0001—.0062) and between the three asymptomatic populations (P < .0001—.41). This systematic review demonstrates that significant differences exist between sonographic measurements of ulnar nerve dimension between people with and without UNE, confirming that these measurements are potential discriminators of UNE. The demonstration of significant differences between measurements of ulnar nerve size within sample populations with similar symptomatic status suggests that further studies are required to confirm the effect of ulnar nerve pathologies, measurement protocols, and anthropometric factors.
Host lung immunity is severely compromised during tropical pulmonary eosinophilia: role of lung eosinophils and macrophages

Eosinophils play a central role in the pathogenesis of tropical pulmonary eosinophilia, a rare, but fatal, manifestation of filariasis. However, no exhaustive study has been done to identify the genes and proteins of eosinophils involved in the pathogenesis of tropical pulmonary eosinophilia. In the present study, we established a mouse model of tropical pulmonary eosinophilia that mimicked filarial manifestations of human tropical pulmonary eosinophilia pathogenesis and used flow cytometry‐assisted cell sorting and real‐time RT‐PCR to study the gene expression profile of flow‐sorted, lung eosinophils and lung macrophages during tropical pulmonary eosinophilia pathogenesis. Our results show that tropical pulmonary eosinophilia mice exhibited increased levels of IL‐4, IL‐5, CCL5, and CCL11 in the bronchoalveolar lavage fluid and lung parenchyma along with elevated titers of IgE and IgG subtypes in the serum. Alveolar macrophages from tropical pulmonary eosinophilia mice displayed decreased phagocytosis, attenuated nitric oxide production, and reduced T‐cell proliferation capacity, and FACS‐sorted lung eosinophils from tropical pulmonary eosinophilia mice upregulated transcript levels of ficolin A and anti‐apoptotic gene Bcl2, but proapoptotic genes Bim and Bax were downregulated. Similarly, flow‐sorted lung macrophages upregulated transcript levels of TLR‐2, TLR‐6, arginase‐1, Ym‐1, and FIZZ‐1 but downregulated nitric oxide synthase‐2 levels, signifying their alternative activation. Taken together, we show that the pathogenesis of tropical pulmonary eosinophilia is marked by functional impairment of alveolar macrophages, alternative activation of lung macrophages, and upregulation of anti‐apoptotic genes by eosinophils. These events combine together to cause severe lung inflammation and compromised lung immunity. Therapeutic interventions that can boost host immune response in the lungs might thus provide relief to patients with tropical pulmonary eosinophilia.
HIV and HIV‐Tat inhibit LPS‐induced IL‐27 production in human macrophages by distinct intracellular signaling pathways

Monocyte‐derived Mϕs (MDMs) from HIV‐infected patients and MDM infected in vitro with HIV exhibit a reduced ability to secrete various cytokines, including IL‐12. Recently, IL‐27, an IL‐12 family cytokine, was shown to inhibit HIV replication in Mϕ. Whether HIV infection or HIV accessory protein(s) impact IL‐27 production in Mϕs remains unknown. Herein, we show that in vitro HIV infection, as well as intracellular HIV‐Tat (Tat) and Tat peptides, inhibit LPS‐induced IL‐27 production in human MDMs, suggesting impairment of the TLR4 signaling pathway. To understand the signaling pathways governing HIV or Tat‐mediated inhibition of LPS‐induced IL‐27 production, we first demonstrated that p38 MAPK, PI3K, Src‐homology region 2 domain‐containing tyrosine phosphatase 1 (SHP‐1), and Src kinases regulate LPS‐induced IL‐27 production in MDMs. Tat caused down‐regulation of TNFR‐associated factor (TRAF)‐6 and inhibitor of apoptosis 1 (cIAP‐1) and subsequently decreased phosphorylation of downstream PI3K and p38 MAPKs, which were implicated in LPS‐induced IL‐27 production. Whereas SHP‐1 and Src kinases regulated LPS‐induced IL‐27 production, Tat did not inhibit these kinases, suggesting that they were not involved in Tat‐mediated inhibition of LPS‐induced IL‐27 production. In contrast to Tat, in vitro HIV infection of MDM inhibited LPS‐induced IL‐27 production via inhibition of p38 MAPK activation. Overall, HIV and Tat inhibit LPS‐induced IL‐27 production in human macrophages via distinct mechanisms: Tat through the inhibition of cIAP‐1–TRAF‐6 and subsequent inhibition of PI3K and p38 MAPKs, whereas HIV through the inhibition of p38 MAPK activation.
Standardized testing with chlorhexidine in perioperative allergy – a large single‐centre evaluation

Perioperative allergic reactions to chlorhexidine are often severe and easily overlooked. Although rare, the prevalence remains unknown. Correct diagnosis is crucial, but no validated provocation model exists, and other diagnostic tests have never been evaluated. The aims were to estimate (i) the prevalence of chlorhexidine allergy in perioperative allergy and (ii) the specificity and sensitivity for diagnostic tests for chlorhexidine allergy.