Role of vitrectomy for syphilitic uveitis in a tertiary hospital in Spain.

Diagnosis and treatment of ocular syphilis can be challenging due to the wide spectrum of clinical presentations of this sexually transmitted disease. In some cases of syphilitic panuveitis, pars plana vitrectomy (PPV) can be useful in management since it plays an important role in improving fundus examination allowing treatment of possible retinal associated lesions when vitreous inflammation is intense. We present 3 cases of patients with ocular syphilis that underwent a therapeutic PPV, vitreous sample was taken and analyzed in two of them.

Identification of differentially expressed genes profiles in a combined mouse model of Parkinsonism and colitis.

Different cellular mechanisms have been described as being potentially involved in the progression of neurodegeneration in Parkinson's disease, although their role is still unclear. The present study aimed to identify in detail, through differentially expressed genes analysis by bioinformatics approaches, the molecular mechanisms triggered after a systemic insult in parkinsonian mice. To address this objective, we combined a dextran sodium sulfate (DSS)-induced ulcerative colitis experimental mice model with an acute 1-methyl-4-phenyl-1,2,3,6-tetradropyridine (MPTP) intoxication. The animals were divided into four experimental groups based on the different treatments: (i) control, (ii) DSS, (iii) MPTP and (iv) MPTP + DSS. The data obtained by microarray and functional enrichment analysis point out the implication of different molecular mechanisms depending on the experimental condition. We see, in the striatum of animals intoxicated only with DSS, dysfunction processes related to the blood. On the other hand, oxidative stress processes are more prominent at the MPTP intoxicated mice. Finally, differentially expressed genes within the MPTP + DSS show functional enrichment in inflammation and programmed cell death. Interestingly, we identify a significant synergistic negative effect of both toxins since the expression of differentially expressed genes (DEGs) related to balanced cellular homeostasis was not enough to prevent processes associated with cell death. This work provides detailed insights into the involvement of systemic inflammation, triggered after an insult in the colon, in the progression of the degeneration in Parkinsonism. In this way, we will be able to identify promising therapeutic targets that prevent the contribution of inflammatory processes in the progression of Parkinson's disease.

Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.

The genetic basis of Alzheimer's disease (AD) is complex and heterogeneous. Over 200 highly penetrant pathogenic variants in the genes APP, PSEN1, and PSEN2 cause a subset of early-onset familial AD. On the other hand, susceptibility to late-onset forms of AD (LOAD) is indisputably associated to the ɛ4 allele in the gene APOE, and more recently to variants in more than two-dozen additional genes identified in the large-scale genome-wide association studies (GWAS) and meta-analyses reports. Taken together however, although the heritability in AD is estimated to be as high as 80%, a large proportion of the underlying genetic factors still remain to be elucidated. In this study, we performed a systematic family-based genome-wide association and meta-analysis on close to 15 million imputed variants from three large collections of AD families (~3500 subjects from 1070 families). Using a multivariate phenotype combining affection status and onset age, meta-analysis of the association results revealed three single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with AD risk: rs7609954 in the gene PTPRG (P-value=3.98 × 10-8), rs1347297 in the gene OSBPL6 (P-value=4.53 × 10-8), and rs1513625 near PDCL3 (P-value=4.28 × 10-8). In addition, rs72953347 in OSBPL6 (P-value=6.36 × 10-7) and two SNPs in the gene CDKAL1 showed marginally significant association with LOAD (rs10456232, P-value=4.76 × 10-7; rs62400067, P-value=3.54 × 10-7). In summary, family-based GWAS meta-analysis of imputed SNPs revealed novel genomic variants in (or near) PTPRG, OSBPL6, and PDCL3 that influence risk for AD with genome-wide significance.

Role of common and rare APP DNA sequence variants in Alzheimer disease.

OBJECTIVES: More than 30 different rare mutations, including copy number variants (CNVs), in the amyloid precursor protein gene (APP) cause early-onset familial Alzheimer disease (EOFAD), whereas the contribution of common APP variants to disease risk remains controversial. In this study we systematically assessed the role of both rare and common APP DNA variants in Alzheimer disease (AD) families. METHODS: Families with EOFAD genetically linked to the APP region were screened for missense mutations and locus duplications of APP. Further, using genome-wide DNA microarray data, we examined the APP locus for CNVs in a total of 797 additional early- and late-onset AD pedigrees. Finally, 423 single nucleotide polymorphisms (SNPs) in the APP locus, including 2 promoter polymorphisms previously associated with AD risk, were tested in up to 4,200 individuals from multiplex AD families. RESULTS: Analyses of 8 21q21-linked families revealed one family carrying a nonsynonymous mutation in exon 17 (Val717Leu) and another family with a partially penetrant 3.5-Mb locus duplication encompassing APP. CNV analysis in the APP locus revealed an additional family carrying a fully penetrant 380-kb duplication, merely spanning APP. Last, contrary to previous reports, association analyses of more than 400 different SNPs in or near APP failed to show significant effects on AD risk. CONCLUSION: Our study shows that APP mutations and locus duplications are a very rare cause of EOFAD and that the contribution of common APP variants to AD susceptibility is insignificant. Furthermore, duplications of APP may not be fully penetrant, possibly indicating the existence of hitherto unknown protective genetic factors.

Health-related direct-to-consumer genetic tests: a public health assessment and analysis of practices related to Internet-based tests for risk of thrombosis.

BACKGROUND: Recent years have seen increased concern about direct-to-consumer (DTC) genetic testing (i.e., the sale and use of genetic tests without involving a health care provider). Numerous professional organizations have developed policies in this area. However, little systematic evidence exists to inform public policy about these tests. METHODS: We conducted a systematic search to identify genetic tests that are sold DTC without involving a health care provider. We evaluated the practices of companies offering DTC genetic tests for risk of thrombosis using criteria from multiple sources and a minimal set of key practices. RESULTS: We identified 84 instances of currently available health-related DTC genetic tests sold on 27 Web sites; the most common were for pharmacogenomics (12), risk of thrombosis (10), and nutrigenomics (10). For the DTC genetic tests for risk of thrombosis, we found low adherence to recommendations. Online information was frequently incomplete and had low agreement with professional recommendations. CONCLUSION: Our findings document the rapid growth in the availability of health-related DTC genetic tests and highlight the need to improve the delivery of DTC genetic tests. A major implication of this study is the need for the scientific and medical community to develop consistent recommendations to increase their impact.

A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy.

BACKGROUND: Hereditary spastic paraplegia (HSP) are classified clinically as pure when progressive spasticity occurs in isolation or complicated when other neurologic abnormalities are present. At least 22 genetic loci have been linked to HSP, 8 of which are autosomal recessive (ARHSP). HSP complicated with the presence of thin corpus callosum (HSP-TCC) is a common subtype of HSP. One genetic locus has been identified on chromosome 15q13-q15 (SPG11) for HSP-TCC, but some HSP-TCC families have not been linked to this locus. METHODS: The authors characterized two families clinically and radiologically and performed a genome-wide scan and linkage analysis. RESULTS: The two families had complicated ARHSP. The affected individuals in Family A had thin corpus callosum and mental retardation, whereas in Family B two of three affected individuals had epilepsy. In both families linkage analysis identified a locus on chromosome 8 between markers D8S1820 and D8S532 with the highest combined lod score of 7.077 at marker D8S505. This 9 cM interval located on 8p12-p11.21 represents a new locus for ARHSP-TCC. Neuregulin and KIF13B genes, located within this interval, are interesting functional candidate genes for this HSP form. CONCLUSION: Two consanguineous families with complicated autosomal recessive hereditary spastic paraplegia were clinically characterized and genetically mapped to a new locus on 8p12-p11.21.

A second kindred linked to DFNA20 (17q25.3) reduces the genetic interval.

A family ascertained in the United States displays significant evidence of linkage to 17q25.3 (maximum two-point LOD score 6.32). The non-syndromic autosomal-dominant hearing-loss loci DFNA20 and DFNA26 map to this region. The 3-unit support interval and haplotype for this USA kindred falls within the interval for DFNA20 and DFNA26 and reduces the region to 6.05 cM, according to the deCode genetic map. The same gene is probably responsible for both DFNA20/DFNA26. In addition, the USH1G locus maps to this region and could be an allelic variant of the gene responsible for DFNA20/DFNA26. Clinical data is presented for this kindred, where hearing-impaired family members present with sloping audiograms with mid- and high-frequency hearing loss, which progresses to hearing loss that affects all frequencies. The mean age of onset of hearing impairment is 13.2 years of age (standard deviation: 4.6 years).

Retinoic acid receptor alpha1 variants, RARalpha1DeltaB and RARalpha1DeltaBC, define a new class of nuclear receptor isoforms.

Retinoic acid (RA) binds and activates retinoid X receptor (RXR)/retinoic acid receptor (RAR) heterodimers, which regulate the transcription of genes that have retinoic acid response elements (RARE). The RAR isotypes (alpha, beta and gamma) are comprised of six regions designated A-F. Two isoforms of RARalpha, 1 and 2, have been identified in humans, which have different A regions generated by differential promoter usage and alternative splicing. We have isolated two new splice variants of RARalpha1 from human B lymphocytes. In one of these variants, exon 2 is juxtaposed to exon 5, resulting in an altered reading frame and a stop codon. This variant, designated RARalpha1DeltaB, does not code for a functional receptor. In the second variant, exon 2 is juxtaposed to exon 6, maintaining the reading frame. This isoform, designated RARalpha1DeltaBC, retains most of the functional domains of RARalpha1, but omits the transactivation domain AF-1 and the DNA-binding domain. Consequently, it does not bind nor transactivate RARE on its own. Nevertheless, RARalpha1DeltaBC interacts with RXRalpha and, as an RXRalpha/RARalpha1DeltaBC heterodimer, transactivates the DR5 RARE upon all-trans-RA binding. The use of RAR- and RXR-specific ligands shows that, whereas transactivation of the DR5 RARE through the RXRalpha/RARalpha1 heterodimer is mediated only by RAR ligands, transactivation through the RXRalpha/RARalpha1DeltaBC heterodimer is mediated by RAR and RXR ligands. Whilst RARalpha1 has a broad tissue distribution, RARalpha1DeltaBC has a more heterogeneous distribution, but with significant expression in myeloid cells. RARalpha1DeltaBC is an infrequent example of a functional nuclear receptor which deletes the DNA-binding domain.

Retinoic acid receptor alpha (RAralpha) Mutations in Human Leukemia.

The retinoic acid receptor alpha (RARalpha) plays a central role in the biology of the myeloid cellular compartment. Chromosomal translocations involving the RARalpha locus probably represent the malignant initiating events in acute promyelocytic leukemia (APL). Recent studies that identify novel interactions between RARalpha and the nuclear receptor co-activators and co-repressors, new functions of the oncogenic RARalpha fusion proteins and their catabolism in retinoic acid-induced differentiation, and the availability of new transgenic mice models have provided important insights into our understanding of the mechanisms by which mutant forms of RARalpha can be implicated in the development of leukemia. Novel alterations of the RARalpha gene identified in hematopoietic malignant disorders other than APL, such as myelodysplastic syndromes, non-APL acute myeloid leukemias and B-chronic lymphocytic leukemias, suggest that disruption of the RARalpha gene might predispose to myeloid and lymphoid disorders.

Deregulated expression of promyelocytic leukemia zinc finger protein in B-cell chronic lymphocytic leukemias does not affect cyclin A expression.

INTRODUCTION: The promyelocytic leukemia zinc finger (PLZF) gene encodes a transcription factor expressed in myeloid, lymphoid and CD34(+) progenitor cells. Structurally related to BCL-6, which is involved in human lymphoma, PLZF may have a role in proliferation, differentiation and survival of hematopoietic cells, that could be mediated by transcriptional repression of the cyclin A gene. MATERIALS AND METHODS: Quantitative competitive reverse transcription-polymerase chain reaction was used to measure the levels of expression of PLZF and cyclin A in normal leukocyte subsets (including CD19(+) lymphocytes, n=21) and malignant B lymphocytes (including B-chronic lymphocytic leukemias [B-CLL], n=63). Results obtained with this method were confirmed by Western and Northern blot analysis. Transactivation assays were performed using an expression construct for PLZF and two cyclin A promoter luciferase reporters in an Epstein-Barr virus (EBV)-transformed B-cell line. Cyclin A expression, cell growth kinetics, and cell cycle were analysed in stable clones of the Burkitt lymphoma (BL) B-cell line DG75 with inducible expression of PLZF, generated using the tetracycline-regulated expression system. RESULTS: Expression of PLZF was 100-fold downregulated in 90% B-CLL (56/63) compared to normal B lymphocytes (P<0.001). B-CLL patients with the highest levels of PLZF had a poorer survival (P<0.013). In transactivation assays, PLZF inhibited the activity of the cyclin A reporters by 50%, demonstrating that PLZF can repress cyclin A expression in non-malignant B lymphocytes. However, in B-CLL patients, the level of cyclin A expression was found to be within the normal range. Altered PLZF function in B lymphoid malignancies was further corroborated in the PLZF-regulatable DG75 clones, where induction of PLZF expression did not significantly alter the levels of cyclin A expression, the cell growth kinetics, or the cell cycle phase distribution. CONCLUSION: The lower survival of patients with the highest levels of PLZF suggests that this protein may be a marker of progression in B-CLL. The absence of co-ordinated regulation of PLZF and cyclin A genes in B-CLL and in a malignant B-cell line may indicate a loss of cyclin A control by PLZF in B-CLL and other B-cell disorders. Deregulation of PLZF could thus play a role in B-cell malignancy.

Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation induction and degradation of AML1-ETO.

INTRODUCTION: Efficacy of differentiating agents requires that their specific cellular targets are still expressed and functional in the leukemic cells. One hypothesis to target sensitive cells is to select leukemic clones which harbor disrupted transcription factors. CBFalpha and CBFbeta are core-binding proteins which have been identified as transcription regulators of hematopoietic genes and shown to be altered in numerous leukemias. In M2 AML, the t(8;21) translocation, CBFalpha (AML1) is altered and produced as the AML1-ETO fusion protein. The fusion protein blocks transcription and differentiation mediated by G-CSF. Interestingly, AML1-ETO leukemic cell lines are sensitive to numerous cytokines in vitro and can be induced to differentiate in the presence of G-CSF and PMA. MATERIALS AND METHODS: As in the APL differentiation model, primary culture provides a useful tool for therapeutic screening of differentiation inducers, we analysed the in vitro sensitivity of 10 fresh M2 AML t(8;21) leukemic samples to G-CSF and the functionality of G-CSF intracellular pathways. In vitro data were compared with in vivo data from four patients treated with rhG-CSF at the dosage of 5 microg/kg/day i.v. for two to three weeks before the initiation of AML induction chemotherapy and immunophenotypic analysis performed weekly to monitor in vivo differentiation. RESULTS: In vitro, an increase in CD34+ cells expressing differentiation antigens (CD11b, CD13 or CD15) was noted along with a decrease of immature CD34+/differentiation antigen negative cells. After two weeks of a daily rhG-CSF administration in vivo, a significant, albeit transient, decrease of blast count was achieved, concomitant with an increase in differentiated leukemic cells suggesting that in vivo differentiation occurs. Fresh t(8;21) leukemic cells possess functional G-CSF signaling pathways as normal activity and kinetics of STAT1 and STAT3 binding was observed. Furthermore, differentiation induction leads to a subsequent degradation of the AML1-ETO oncoprotein. CONCLUSION: The data presented here supports the claim that G-CSF can induce in vitro and in vivo differentiation of M2 AML t(8;21) cells.

Alterations of the retinoic acid receptor alpha (RAR alpha) gene in myeloid and lymphoid malignancies.

The retinoic acid receptor alpha (RAR alpha) protein plays a central role in myeloid differentiation, and chromosomal translocations disrupting the RAR alpha gene are implicated in the development of acute myeloid leukaemia (AML). To identify haemopoietic malignant disorders which may also be linked to RAR alpha abnormalities, Southern blot analysis was performed in DNA from 153 patients with haematological malignancies other than AML FAB type M3 using RAR alpha cDNA probes. Alterations of RAR alpha were detected in 1/42 myelodysplastic syndromes (MDS), 2/24 AML, 3/47 B-chronic lymphocytic leukaemias (B-CLL), 0/40 lymphomas and 0/60 normal individuals. These data strongly suggest that alterations of RAR alpha might predispose for myeloid and lymphoid disorders.

[Second primary tumors in patients with pharyngo-laryngeal carcinoma]. / Segundos tumores primarios en pacientes con carcinoma faringolaríngeo.

The risk of second primary tumors of the respiratory and upper digestive tract developing in patients treated for head and neck cancer is well known. In these cases, the entire mucous membrane surface of the tract is affected and predisposed to metachronous or synchronous neoplasms. The mucosa of these patients is extremely susceptible to external carcinogenic stimuli. We report the results obtained in 83 patients with cancer of the oral cavity, pharynx, or larynx who experienced at least one second primary tumor. The most common site of the second primary was the lung (43.2%). We reviewed tobacco and alcohol use, treatments, and survival.

Repopulation of circulating T, B and NK lymphocytes following bone marrow and blood stem cell transplantation.

A variety of T, B and natural killer (NK) cell subsets defined by surface markers were analyzed by double immunofluorescence flow cytometry in the peripheral blood of patients following autologous bone marrow transplantation (ABMT, n = 14), autologous peripheral blood stem cell transplantation (PBSCT, n = 10) and allogeneic bone marrow transplantation (allo-BMT, n = 6). Patients following ABMT were divided in 2 groups, those who did not received G-CSF post-transplant (ABMT, n = 6) and those who did (ABMT + G, n = 8). All patients following PBSCT or allo BMT received G-CSF. In all the groups prolonged significant decreases with respect to normal numbers were observed for the T CD3+, CD2+ and CD25+ subsets, more profound for the CD4+ subset but less for the CD8+ subset, especially following PBSCT (only decreased at 1 month). A significant expansion of the CD3+CD57+ and CD8+CD57+ phenotypes was noticed between 9 and 12 months following ABMT, the group of longer follow-up. Long-lasting expansion of the NK-like CD3+CD56+ and CD3+CD16+ subsets was also observed. The B CD19+ and CD20+ subsets had a significant overexpression from 4 months after ABMT, showing a normally balanced Igk+:Ig1+ ratio. Concordantly, the HLA-DR+ and HLA-DQ+ subsets showed significant increases. The NK CD56+ and CD16+ subsets had a faster recovery than the T or B subsets in all the groups. However, the CD3-CD56+, CD3-CD16+, CD16+CD56+, CD3-CD8+, and especially the CD3-CD57+, CD16+CD57+, and CD56+CD57+ subsets had a slower recovery than the global CD56+, CD16+, or CD57+ subsets. The biological and clinical implications of these findings are discussed.

Central and peripheral actions of the NSAID ketoprofen on spinal cord nociceptive reflexes.

Ketoprofen is a non-steroidal antiinflammatory drug (NSAID) which provides effective analgesia in situations of pain provoked by tissue inflammation. However, the location of its analgesic effects, (peripheral tissues versus central nervous system), have not been clearly identified and separated. In the present study the effectiveness of ketoprofen was examined in two different types of experiments: (i) Open field behavioural tests in conscious rats, and (ii) spinal cord nociceptive reflexes (single motor units) activated by electrical and thermal stimulation in chloralose anaesthetised rats. The experiments were performed in rats with carrageenan-induced inflammation of one hindpaw, or of one knee joint. The administration of ketoprofen significantly inhibited the reduction of exploratory movements caused by inflammation in open field experiments. Ketoprofen was also effective in depressing reflex activity evoked by electrical and noxious thermal stimulation of the skin, either in inflamed tissue or in normal tissue of monoarthritic animals. It was also effective in the reduction of reflex wind-up; a phenomenon in which the activity of spinal cord neurones increases progressively with high frequency electrical stimulation. We therefore conclude that ketoprofen has central as well as peripheral analgesic activity.

Leukaemia of natural killer cell large granular lymphocyte type with HLA-DR-CD16-CD56bright+ phenotype.

The case is reported of a 45 year old woman with the rare leukaemia of natural killer cell large granular lymphocyte (NK/ LGL) type. Cytometric analysis of leukaemic blasts showed that they were positive for CD2, CD38, and CD56 antigens but negative for a series of antigens including CD3, CD7, CD16, and HLA-DR. Rearrangements of the beta T cell receptor, and heavy and kappa immunoglobulin genes were not detected and neither were chromosomal abnormalities. Leukaemic blasts developed NK cytotoxicity. The patient failed to respond to aggressive chemotherapy and died three months after diagnosis. The lack of expression of HLA-DR is an extraordinary characteristic of this case, as all cases of acute NK cell leukaemias described to date expressed HLA-DR. The immunophenotype observed in the NK cell leukaemic blasts may represent the counterpart of a hypothetical normal cell precursor in an early stage of ontogenic NK cell development.

[Differential diagnosis of neurinomas of the jugular foramen and glomus jugulare: a clinical case]. / Diagnóstico diferencial entre neurinomas de agujero rasgado posterior y glomus yugular: Caso clínco.

Neurinomas or schwannomas of the jugular foramen are rare tumors whose differentiation from tumors of the jugular body may be difficult because they share common symptoms. Since schwannomas at this site are less aggressive than tumors of the jugular body and certain elements of their treatment differ, it is important to make a correct diagnosis promptly. A well-documented case of schwannoma of the jugular foramen is reported and its differential diagnosis is discussed in the light of the literature.

[Orbital cellulitis and permanent amaurosis: clinical case]. / Celulitis orbitaria y amaurosis permanente: caso clínico.

Orbital cellulitis is a rare, potentially serious but complication of acute sinusitis. It is more frequent and benign in children, but in adults usually requieres surgical drainage of the affected sinus. We report a case of aggressive evolution with permanent blindness in an adult without general or local risk factors, in spite of adequate treatment. The literature is reviewed.

[Subdural empyema induced by frontal sinusitis]. / Empiema subdural inducido por sinusitis frontal.

Nowadays the complications arising from sinusitis are rare. However its seriousness can even cause death. Intracranial complications are much more uncommon than the orbital ones. However, slight symptoms can appear, which may disjunct the correlation between clinical-radiology and the severity of the infection. The diagnosis is fundamentally based on the TAC, and early treatment with intravenous anti-biotherapy should be implemented, being followed by drainage surgery of the sinus and empyema. We have presented a case which evolved favourably and revised all the literature pertaining to it.