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Influence of follicle stage on artificial ovary outcome using fibrin as a matrix.

Hum Reprod. 2015 Nov 30;

Authors: Chiti MC, Dolmans MM, Orellana R, Soares M, Paulini F, Donnez J, Amorim CA

Abstract
STUDY QUESTION: Do primordial-primary versus secondary follicles embedded inside a fibrin matrix have different capabilities to survive and grow after isolation and transplantation?
SUMMARY ANSWER: Mouse primordial-primary follicles showed a lower recovery rate than secondary follicles, but both were able to grow.
WHAT IS KNOWN ALREADY: Fresh isolated mouse follicles and ovarian stromal cells embedded in a fibrin matrix are capable of surviving and developing after short-term autografting.
STUDY DESIGN, SIZE, DURATION: In vivo experimental model using 11 donor Naval Medical Research Institute (NMRI) mice and 11 recipient severe combined immunodeficiency (SCID) mice. Both ovaries from all NMRI mice were mechanically disrupted and primordial-primary and secondary follicles were isolated with ovarian stromal cells. They were then encapsulated in a fibrin matrix composed of 12.5 mg/ml of fibrinogen (F12.5) and 1 IU/ml of thrombin (T1) (F12.5/T1), and grafted to the inner part of the peritoneum of SCID mice for 2 and 7 days.
PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted at the Gynecology Research Unit, Université Catholique de Louvain. All materials were used to conduct histological (H-E staining) and immunohistochemical (Ki67, TUNEL) analyses.
MAIN RESULTS AND THE ROLE OF CHANCE: Although all grafted fibrin clots were recovered, the follicle recovery rate on day 2 was 16 and 40% for primordial-primary and secondary follicles respectively, while on day 7, it was 6 and 28%. The secondary group showed a significantly higher recovery rate than the primordial-primary group (23%, P-value <0.001). Follicles found in both groups were viable, as demonstrated by live/dead assays, and no difference was observed in the apoptosis rate between groups, as evidenced by TUNEL. Their growth to further stages was confirmed by Ki67 immunostaining.
LIMITATIONS, REASONS FOR CAUTION: As demonstrated by our results, secondary follicles appear to be more likely to survive and develop than primordial-primary follicles in a fibrin matrix after both periods of grafting. These findings may also be attributed to the specific features of the fibrin matrix, which could benefit larger follicles, but not smaller follicles.
WIDER IMPLICATIONS OF THE FINDINGS: This study is essential to understanding possible impairment caused by factors such as the isolation procedure or fibrin matrix composition to the survival and development of different follicle stages. It therefore provides the basis for further investigations with longer periods of grafting.
STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (grant Télévie No. 7.4578.14 and 7.4627.13, grant 5/4/150/5 awarded to Marie-Madeleine Dolmans), Fonds Spéciaux de Recherche, Fondation St Luc, the Foundation Against Cancer, and the Region Wallone (Convention N°6519-OVART) and donations from Mr Pietro Ferrero, Baron Frère and Viscount Philippe de Spoelberch. None of the authors have any competing interests to declare.

PMID: 26628641 [PubMed – as supplied by publisher]

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Application of diagnostic and treatment criteria for common variable immunodeficiency disorder.

Expert Rev Clin Immunol. 2015 Dec 1;

Authors: Ameratunga R, Storey P, Barker R, Jordan A, Koopmans W, Woon ST

Abstract
Common variable immunodeficiency disorder (CVID) is the most frequent symptomatic primary immune deficiency disorder in adults. It probably comprises a spectrum of polygenic disorders with hypogammaglobulinemia being the overarching feature. While the majority of patients with CVID can be identified with relative ease, a significant proportion can present with minimal symptoms in spite of profound laboratory abnormalities. Here we discuss three patients who were presented to the Auckland Hospital Immunoglobulin treatment committee to determine if they qualified for immunoglobulin replacement. Two were asymptomatic with profound laboratory abnormalities while the third patient was severely ill with extensive bronchiectasis. The third patient had less severe laboratory abnormalities compared with the two asymptomatic patients. We have applied four sets of published diagnostic and treatment criteria to these patients to compare their clinical utility. We have chosen these patients from the broad phenotypic spectrum of CVID, as this often illustrates differences in diagnostic and treatment criteria.

PMID: 26623716 [PubMed – as supplied by publisher]

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Silvery Hair with Speckled Dyspigmentation: Chediak-Higashi Syndrome in Three Indian Siblings.

Int J Trichology. 2015 Jul-Sep;7(3):133-135

Authors: Raghuveer C, Murthy SC, Mithuna MN, Suresh T

Abstract
Silvery hair is a common feature of Chediak-Higashi syndrome (CHS), Griscelli syndrome, and Elejalde syndrome. CHS is a rare autosomal recessive disorder characterized by partial oculocutaneous albinism, frequent pyogenic infections, and the presence of abnormal large granules in leukocytes and other granule containing cells. A 6-year-old girl had recurrent respiratory infections, speckled hypo- and hyper-pigmentation over exposed areas, and silvery hair since early childhood. Clinical features, laboratory investigations, hair microscopy, and skin biopsy findings were consistent with CHS. Her younger sisters aged 4 and 2 years had similar clinical, peripheral blood picture, and hair microscopy findings consistent with CHS. This case is reported for its rare occurrence in all the three siblings of the family, prominent pigmentary changes, and absent accelerated phase till date. Awareness, early recognition, and management of the condition may prevent the preterm morbidity associated.

PMID: 26622160 [PubMed – as supplied by publisher]

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Severe infectious diseases of childhood as monogenic inborn errors of immunity.

Proc Natl Acad Sci U S A. 2015 Nov 30;

Authors: Casanova JL

Abstract
This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

PMID: 26621750 [PubMed – as supplied by publisher]

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How reliable is online diffusion of medical information targeting patients and families?

World J Exp Med. 2015 Nov 20;5(4):244-250

Authors: Xavier-Elsas P, Bastos SE, Gaspar-Elsas MI

Abstract
AIM: To determine whether online diffusion of the “Ten Warning Signs of Primary Immunodeficiency Diseases (PID)” adheres to accepted scientific standards.
METHODS: We analyzed how reproducible is online diffusion of a unique instrument, the “Ten Warning Signs of PID”, created by the Jeffrey Modell Foundation (JMF), by Google-assisted searches among highly visited sites from professional, academic and scientific organizations; governmental agencies; and patient support/advocacy organizations. We examined the diffusion, consistency of use and adequate referencing of this instrument. Where applicable, variant versions of the instrument were examined for changes in factual content that would have practical impact on physicians or on patients and their families.
RESULTS: Among the first 100 sites identified by Google search, 85 faithfully reproduced the JMF model, and correctly referenced to its source. By contrast, the other 15 also referenced the JMF source but presented one or more changes in content relative to their purported model and therefore represent uncontrolled variants, of unknown origin. Discrepancies identified in the latter included changes in factual content of the original JMF list (C), as well as removal (R) and introduction (I) of novel signs (Table 2), all made without reference to any scientific publications that might account for the drastic changes in factual content. Factual changes include changes in the number of infectious episodes considered necessary to raise suspicion of PID, as well as the inclusion of various medical conditions not mentioned in the original. Together, these changes will affect the way physicians use the instrument to consult or to inform patients, and the way patients and families think about the need for specialist consultation in view of a possible PID diagnosis.
CONCLUSION: The retrieved adaptations and variants, which significantly depart from the original instrument, raise concerns about standards for scientific information provided online to physicians, patients and families.

PMID: 26618111 [PubMed – as supplied by publisher]

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[Atopic dermatitis of the adult].

Rev Med Interne. 2015 Nov 23;

Authors: Hello M, Aubert H, Bernier C, Néel A, Barbarot S

Abstract
Atopic dermatitis (AD) of the adult is a common skin disease. Its prevalence has greatly increased during the past decades. AD is commonly associated with other atopic disorders. Its impact on quality of life is often underestimated. Various immunopathologic mechanisms are involved in AD: innate epidermal barrier dysfunction due to filaggrin gene mutations, innate and adaptative abnormalities of the immune system (an initial Th2 phase precedes a chronic Th1 phase), intestinal and cutaneous microbiomes dysbiosis, and environmental factors. Diagnosis of AD is clinical and there is no predictive biomarker of future severity. The main differential diagnoses are: scabies, psoriasis, cutaneous adverse reaction, cutaneous T cell lymphoma, primary immunodeficiency, and Netherton’s syndrome. Therapeutic management is challenging and should integrate a therapeutic education program. Topical corticosteroids are the first line treatment, including a preliminary assessment of possible topical corticosteroids phobia. Systemic treatments are recommended in severe, chronic and resistant AD, after careful evaluation in a reference centre. Dupilumab, an IL4/IL13 inhibitor, might be the first effective targeted therapy in AD, whereas therapies that specifically target the mechanisms of pruritus represent an exciting perspective.

PMID: 26617291 [PubMed – as supplied by publisher]

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Primary central nervous system lymphomas and related diseases: Pathological characteristics and discussion of the differential diagnosis.

Neuropathology. 2015 Nov 26;

Authors: Sugita Y, Muta H, Ohshima K, Morioka M, Tsukamoto Y, Takahashi H, Kakita A

Abstract
Although primary diffuse large B-cell lymphomas of the CNS are designated as primary CNS lymphomas according to the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue in 2008, a variety of other lymphomas (Burkitt lymphomas, EBV-positive diffuse large B-cell lymphoma of the elderly) and related diseases (lymphomatoid granulomatosis) that are also found in the CNS have been spotlighted in recent years. The histopathology of primary CNS Burkitt lymphomas mimics that of primary diffuse large B-cell lymphomas of the CNS after steroid administration. Therefore, for correct diagnosis of the involved lymphoma, comprehensive fluorescent in situ hybridization analysis for c-MYC and BCL2 is recommended in all primary CNS lymphoma cases with aggressive clinical course, multifocal involvement of the CNS, and a high proliferation index. The pathological characteristics of primary CNS EBV-positive diffuse large B-cell lymphoma of the elderly have similarities with those of the latency phenotype III, EBV lymphoproliferative disorders that arise in the setting of immunodeficiency. These age-related lymphomas usually occur in elderly immunocompetent patients, and the incidence of this disease was estimated to range from 4.0% to 13.6% of all primary CNS lymphomas. Shorter overall survival has been reported for patients with this disease. Lymphomatoid granulomatosis (LYG) is a systemic, EBV-driven, angiocentric and angiodestructive lymphoproliferative disorder. Primary LYG that shows distinct clinicopathological features compared with systemic LYG was recently reported. Finally, this review focuses on the relationship between primary CNS lymphomas and demyelinating diseases, and the concomitant use of intraoperative cytology and frozen sections that are helpful in rapid intraoperative diagnosis.

PMID: 26607855 [PubMed – as supplied by publisher]

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Genetics of inflammatory bowel disease from multifactorial to monogenic forms.

World J Gastroenterol. 2015 Nov 21;21(43):12296-310

Authors: Bianco AM, Girardelli M, Tommasini A

Abstract
Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn’s disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6(th) year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.

PMID: 26604638 [PubMed – in process]

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The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1.

J Clin Immunol. 2015 Nov 25;

Authors: Depner M, Fuchs S, Raabe J, Frede N, Glocker C, Doffinger R, Gkrania-Klotsas E, Kumararatne D, Atkinson TP, Schroeder HW, Niehues T, Dückers G, Stray-Pedersen A, Baumann U, Schmidt R, Franco JL, Orrego J, Ben-Shoshan M, McCusker C, Jacob CM, Carneiro-Sampaio M, Devlin LA, Edgar JD, Henderson P, Russell RK, Skytte AB, Seneviratne SL, Wanders J, Stauss H, Meyts I, Moens L, Jesenak M, Kobbe R, Borte S, Borte M, Wright DA, Hagin D, Torgerson TR, Grimbacher B

Abstract
PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients.
METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients’ peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients.
RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61 %). Out of 39 familial cases from 11 families, 26 patients (67 %) from 9 families and out of 18 sporadic cases, 9 patients (50 %) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients.
CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.

PMID: 26604104 [PubMed – as supplied by publisher]

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Subclinical intestinal inflammation in chronic granulomatous disease patients.

Immunol Res. 2015 Nov 24;

Authors: Broides A, Sagi O, Pinsk V, Levy J, Yerushalmi B

Abstract
Chronic granulomatous disease is a primary immunodeficiency caused by impaired neutrophil production of reactive oxygen species. Non-infectious colitis is common in chronic granulomatous disease, and high levels of antimicrobial antibodies that are associated with Crohn’s disease are common even without colitis. Fecal calprotectin concentration is a marker for intestinal inflammation. We sought to determine whether subclinical intestinal inflammation occurs in asymptomatic chronic granulomatous disease patients. Asymptomatic chronic granulomatous disease patients without overt gastrointestinal symptoms suggestive of colitis at the time of enrollment were studied for fecal calprotectin concentration, antibodies associated with Crohn’s disease and systemic inflammatory markers. Eight patients were included, aged 54-176 months. In 7/8 (87.5 %) fecal calprotectin concentration was normal (<50) and elevated (137 mg/kg) in only one patient. This patient later developed colitis. In 7/8 (87.5 %) anti-Saccharomyces cerevisiae antibody was positive. C-reactive protein, albumin, complete blood count and p-anti-neutrophil cytoplasmic antibody were normal in all 8 patients. Subclinical colitis is not evident in most asymptomatic chronic granulomatous disease patients; however, in some patients, fecal calprotectin concentration may be elevated, possibly indicating the presence of subclinical colitis and predicting the occurrence of clinically relevant colitis. Serum anti-Saccharomyces cerevisiae antibody concentrations do not seem to correlate with fecal calprotectin concentration in asymptomatic chronic granulomatous disease patients.

PMID: 26603166 [PubMed – as supplied by publisher]

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