Primary immunodeficiencies are potentially life-threatening diseases. Over the last years, the clinical phenotype and the molecular basis of an increasing number of immunological defects have been ...characterized. However, in daily practice primary immunodeficiencies are still often diagnosed too late. Considering that an early diagnosis may reduce morbidity and mortality of affected patients, an interdisciplinary guideline for the diagnosis of primary immunodeficiencies was developed on behalf of the Arbeitsgemeinschaft Pädiatrische Immunologie (API) and the Deutsche Gesellschaft für Immunologie (DGfI).
The guideline is based on expert opinion and on knowledge from other guidelines and recommendations from Germany and other countries, supplemented by data from studies that support the postulated key messages (level of evidence III). With the contribution of 20 representatives, belonging to 14 different medical societies and associations, a consensus-based guideline with a representative group of developers and a structured consensus process was created (S2k). Under the moderation of a representative of the Association of the Scientific Medical Societies in Germany (AWMF) the nominal group process took place in April 2011.
The postulated key messages were discussed and voted on following a structured consensus procedure. In particular, modified warning signs for primary immunodeficiencies were formulated and immunological emergency situations were defined.
Conserved from fish to mammals, renal proximal tubule organic anion secretion plays an important role in drug and xenobiotic elimination. Studies with the model substrate p-aminohippurate (PAH) have ...suggested that a basolateral PAH/alpha-ketoglutarate exchanger imports diverse organic substrates into the proximal tubule prior to apical secretion. cDNAs encoding PAH transporters have been cloned recently from rat and flounder. Here we report the cloning of a highly similar human PAH transporter (hPAHT) from human kidney. By Northern blot analysis and EST database searching, hPAHT mRNA was detected in kidney and brain. PCR-based monochromosomal somatic cell hybrid mapping placed the hPAHT gene on chromosome 11. When expressed transiently in vitro, hPAHT catalyzed time-dependent and saturable 3HPAH uptake (Km of approximately 5 microM). Preincubation with unlabeled alpha-ketoglutaric or with glutaric acid stimulated tracer PAH uptake, and preincubation with unlabeled PAH stimulated tracer alpha-ketoglutarate uptake, results that are consistent with PAH/alpha-ketoglutarate exchange. Several structurally diverse organic anions cis-inhibited PAH uptake. Like rat OAT1 organic anion transporter, hPAHT was inhibited by furosemide, indomethacin, probenecid, and alpha-ketoglutarate. Unlike OAT1, hPAHT was not inhibited by prostaglandins or methotrexate (MTX). Moreover, tracer PGE2 and MTX were not transported, indicating that the substrate specificity for transport by hPAHT is not broad. PAH uptake was inhibited by phorbol 12-myristate 13-acetate (PMA) in a dose- and time-dependent fashion, but not by the inactive 4alpha-phorbol-12,13 didecanoate. PMA-induced inhibition was blocked by staurosporine. Thus the protein kinase C-mediated inhibition of basolateral organic anion entry previously reported in intact tubules is likely due, at least in part, to direct modulation of the PAH/alpha-ketoglutarate exchanger.
A recently cloned cDNA encodes the so-called "organic anion-transporting polypeptide" (i.e., oatp), which is expressed in rat liver and in the kidney S3 proximal tubule. functional characterization ...of the cloned transporter indicates that estradiol 17 beta-D-glucuronide is a major substrate. Because the urinary excretion of glucuronidated steroids differs between males and females, we hypothesized that renal oatp expression may be under sex hormone control. Total RNA was isolated from male or female kidneys and probed with a digoxigenin-labeled oatp antisense riboprobe. Expression of oatp mRNA expression was quantitated by densitometry from Northern blots. Male kidneys expressed at least six distinct oatp transcripts (approximately 4.0, 3.2, 2.9, 2.6, 1.7, and 1.2 kb). Of these, the 3.2-kb band was consistently the strongest. In female rats, renal oatp mRNA expression was markedly less, such that only the 3.2-kb band was consistently detectable. Administering testosterone to female rats increased, and administering estradiol (E2) to male rats decreased, the steady-state levels of renal oatp mRNA. Gonadectomized male and female rats, as well as adrenalectomized male rats, were given pharmacological hormone replacement (testosterone, E2, or dexamethasone, respectively) by subcutaneous osmotic minipump. Castration of male rats produced a dramatic drop in the steady-state level of all six renal oatp transcripts. These were returned to normal by testosterone replacement. In contrast, there was no regulation of hepatic oatp mRNA expression by testosterone. Renal oatp mRNA expression in female rats was mildly increased by oophorectomy. Administration of E2 to oophorectomized females moderately suppressed renal oatp mRNA expression. Adrenalectomy produced a small decrease in oatp expression, but dexamethasone replacement failed to return expression to normal. We conclude that renal oatp mRNA expression is under strong (stimulatory) testosterone control and perhaps weaker (inhibitory) estrogen control. We speculate that this regulation of renal oatp expression is important in modulating the renal tubular secretion of conjugated E2.
Background.
An analysis was conducted out to establish the boundaries of the Kurrachi-Dolomite formation reservoir (Jihar field, Hayan block, Palmyra fold belt). In the process of research, data from ...geophysical surveys of wells were used and statistical processing of the obtained data was carried out. Currently, due to the difficult situation in Syria, scientific research in this area is extremely limited.
Aim
. To conduct a combined processing of geophysical well data (GWD), including by using a correlation matrix, and to assess the applicability the results obtained as an express method for interpreting geophysical data and identifying the boundaries of the Kurrachine-Dolomite formation within the Hayan block and adjacent areas.
Materials and methods
. The well data for the empirical study was provided by the Syrian Petroleum Company. Correlation matrices were obtained between the following logging data: CAL, AC, GR, RD, RS, RHOB, and PE. This allowed a good correlation to be determined between their numerical values and the results of core studies, which were carried out to establish lithological characteristics and reservoir properties of the area under study (northwestern part of the Hayan block).
Results.
The processed materials made it possible to select the most effective GWD combination for identifying the boundaries and fringe zones of sediments in the Kurrachine-Dolomite formation, considered as a mega reservoir, and to identify priority development objects similar in geological structure and reservoir properties.
Conclusion.
The proposed method for processing field geophysical materials (construction of correlation matrices and statistical processing of geological and field data) can be used in selecting an optimal combination of GWD for establishing the reservoir boundaries of the Kurrachine-Dolomite formation, quantifying the reservoir properties, and increasing the efficiency of the Jihar field development (mega reservoir of the Hayan block).
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency, which most often manifests itself after Epstein-Barr virus (EBV) infection. The main clinical phenotypes include fulminant or ...fatal infectious mononucleosis, dysgammaglobulinaemia and malignant lymphoma. We have recently cloned the SH2D1A gene, which has been shown to be mutated in ∼70% of XLP patients. Now we report five novel SH2D1A mutations in patients from five unrelated XLP families. No mutations were found in another three XLP families. In three boys with early onset non-Hodgkin lymphoma (NHL) from two unrelated families a deletion of SH2D1A exon 1 and a splice site mutation were found, respectively. These patients did not show any laboratory or clinical signs of a previous EBV infection. A fourth EBV-uninfected and unrelated boy with a stop mutation in the SH2D1Agene shows only signs of dysgammaglobulinaemia. Development of dysgamma-globulinaemia and lymphoma without evidence of prior EBV infection in four of our patients suggests that EBV is unrelated to these phenotypes, in contrast to fulminant or fatal infectious mononucleosis. The role of SH2D1A as a putative tumour suppressor gene remains to be investigated.
The cDNA for the rat liver organic anion-transporting polypeptide "oatp" has been shown to encode transport of bromosulfophthalein (BSP) and bile salts in Xenopus oocytes (E. Jacquemin, B. Hagenbuch, ...B. Stieger, A. W. Wolkoff, and P. J. Meier. Proc. Natl. Acad. Sci. USA 91: 133-137, 1994). Because oatp mRNA is expressed strongly in the kidney, we sought to determine whether renal oatp might play a role in the known secretion of a large variety of organic anions by the kidney. We transiently expressed a full-length oatp cDNA, cloned in pSPORT, in HeLa cell monolayers using the recombinant vaccinia virus vtf7-3. We tested an array of organic anions as candidate substrates by determining their ability to compete with tracer BSP for transport. HeLa cell monolayers transfected with the oatp cDNA transported tracer BSP and taurocholate at rates substantially higher than monolayers transfected with a control plasmid. Thus good expression can be obtained with the vaccinia-HeLa system using a standard plasmid cloning vector. BSP transport varied as a function of the medium albumin, ionic conditions, and pH in a fashion similar to that in Xenopus oocytes. Several organic anions known to be secreted by the classic secretory pathway, including p-aminohippurate (PAH), phenol red, and indigo carmine (10 microM) failed to inhibit oatp-mediated BSP transport. Direct testing using tracers revealed no oatp-mediated transport of sulfate, urate, PAH, several eicosanoids, or unconjugated or conjugated bilirubin. On the other hand, BSP transport was inhibited by approximately 50% by 10 microM corticosterone sulfate, spironolactone, and several other steroids. We conclude that the functional properties of oatp expressed in the HeLa cell/vaccinia transient expression system are comparable to those following expression in Xenopus oocytes and that steroids are likely to represent high-affinity endogenous oatp substrates. The latter hypothesis is addressed in greater detail in a companion paper.
Ligneous conjunctivitis Schuster, Volker; Seregard, Stefan
Survey of Ophthalmology,
07/2003, Letnik:
48, Številka:
4
Book Review, Journal Article
Recenzirano
Ligneous conjunctivitis (McKusick 217090) is a rare form of chronic conjunctivitis characterized by the development of firm fibrin-rich, woody-like pseudomembraneous lesions mainly on the tarsal ...conjunctivae. Less frequently, similar lesions may occur on other mucous membranes of the body indicating that these manifestations are part of a systemic disease. Histopathological findings from affected humans and (plasminogen-deficient) mice indicate that wound healing, mainly of injured mucosal tissue, is impaired due to markedly decreased (plasmin-mediated) extracellular fibrinolysis. Pseudomembraneous lesions of the eyes and other mucosal tissue mainly contain clotted fibrin(ogen). Actually, systemic plasminogen deficiency has been linked to ligneous conjunctivitis in humans and mice. In one case, ligneous conjunctivitis has been induced by antifibrinolytic treatment with tranexamic acid. Further rare associated disorders of ligneous conjunctivitis are congenital occlusive hydrocephalus and juvenile colloid milium. This review outlines the historical background, clinical characteristics of ligneous conjunctivitis and its associated complications, histological abnormalities of pseudomembraneous lesions, inheritance, hemostasiologic and molecular genetic findings in affected patients, current treatment approaches, and the plasminogen-deficient mouse as an animal model.
We examined the longitudinal impact of self-reported exposure to pro- and anti-tobacco media on adolescents' susceptibility to smoking, using in-school surveys from a culturally diverse sample. ...Ethnicity and acculturation also were examined as potential moderators. Middle-school students (N=2,292) completed self-report questionnaires during the 6th, 7th, and 8th grades. Chi-square analyses were conducted to determine whether reported exposure to pro- and anti-tobacco media varied according to ethnicity, acculturation, and immigration status. Logistic regression models were used to examine whether pro- and anti-tobacco media exposure in 6th grade was associated with susceptibility to smoking by later grades. Recall of people smoking in television programs and pro-tobacco advertisements in stores was associated with adolescent smoking susceptibility. Exposure to anti-tobacco advertisements on television protected against susceptibility. No significant interaction effects between pro- and anti-tobacco media exposure on smoking susceptibility were found. Ethnicity and acculturation did not moderate these associations. Our longitudinal study provides evidence that pro-tobacco media and advertising increases susceptibility to smoking over time. More important, anti-tobacco advertisements are not sufficient to reduce the harmful effects of adolescent exposure to pro-tobacco media. Policy-level interventions such as restrictions in tobacco advertising may be necessary to prevent adolescent smoking.
Summary
Severe type I plasminogen deficiency has been recently linked to ligneous conjunctivitis, a rare and uncommon form of chronic conjunctivitis. In this study, eight unrelated ligneous ...conjunctivitis patients living in different parts of the world were examined. All affected subjects from which plasma was available displayed absent or markedly reduced plasminogen antigen and plasminogen functional activity. Molecular genetic studies of seven patients identified a Lys
19
→ Glu mutation in two boys in a homozygous state, and in two girls in a compound-heterozygous state in which the second plasminogen gene carried a missense (Arg
134
→ Lys) and a nonsense mutation (Cys
133
→ Stop), respectively. A fifth patient was shown to be homozygous for a frameshift mutation in plasminogen exon 14 (Gly
565
ins-G). In two unrelated subjects with ligneous conjunctivitis no mutations in the plasminogen gene were identified. Our results suggest that the Lys
19
→ Glu mutation is the most prevalent mutation in the plasminogen gene of patients with ligneous conjunctivitis.
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