Optical coherence tomography represents a sensitive and reliable tool for routine monitoring of idiopathic intracranial hypertension with and without papilledema.

BACKGROUND AND PURPOSE: We previously reported that certain optical coherence tomography (OCT) measures were sensitive and reliable in identifying idiopathic intracranial hypertension (IIH). This prospective study aimed to define OCT measures that allow differentiation of IIH with and without papilledema, thereby helping clinical decision-making. METHODS: Eight patients with IIH with papilledema, nine without papilledema and 19 with other neurological diseases were included. OCT measures were obtained before lumbar puncture and within 2 h, 1, 3 and 6 months after lumbar puncture with cerebrospinal fluid (CSF) removal. RESULTS: All patients with papilledema had increased retinal nerve fiber layer (RNFL) thickness and elevated CSF pressure. All patients without papilledema had normal RNFL but elevated CSF pressure. After CSF removal, reduced RNFL thickness was registered in all eight patients with IIH with papilledema. No significant change in RNFL thickness after CSF removal was observed in IIH without papilledema or in patients with other neurological diseases, although reduced CSF pressure was documented. RNFL thickness tended to be normal in patients with IIH with papilledema at 3-6 months after CSF removal. All patients with IIH showed increased rim area and rim thickness, but reduced optic cup volume regardless of RNFL thickness or papilledema. CONCLUSIONS: Retinal nerve fiber layer thickness is sensitive for monitoring acute IIH and evaluating treatment effect. Increased rim area and rim thickness and decreased optic cup volume are reliable parameters that indicate persistently increased CSF pressure and risk of relapse. OCT measures are sensitive and reliable for diagnosing subtle IIH even in the absence of papilledema.

Long-term changes in the structure of benthic communities: Revisiting a sampling transect in Crete after 24 years.

A bathymetric transect in the north coast of Crete first studied in 1989, was revisited 24 years later. Identical sampling design, season, techniques and protocols were followed in both studies in order to minimize bias in the long-term comparisons. This comprehensive macrofaunal dataset (4 stations, 2 sampling seasons, 7 replicates in each study) revealed changes in benthic diversity and community composition between the sampling periods. The recorded changes were higher at the stations located close to the coastal zone. In addition, while benthic communities showed lower total abundance during the recent sampling period, species abundances were more evenly distributed indicating that some species dominated the historical communities. In spite of these changes, the ecological status remained above the threshold values for good ecological status. The results indicated that changes in the benthic community seem to have been driven by local anthropogenic factors and natural variability rather than by large-scale factors such as nutrients influxes in the entire Mediterranean Basin.

International network on endocrine complications in thalassaemia (I-CET): an opportunity to grow.

Most of the endocrine complications in thalassaemia are attributable to iron overload which may be the result of economic circumstances (expense of the chelation therapy), late onset of chelation therapy or poor compliance with the iron chelation therapy. The major difficulties reported by hematologists or pediatric endocrinologists experienced in thalassaemias or thalassaemia syndromes in following growth disorders and endocrine complications were: lack of familiarity with medical treatment of endocrine complications (40%), interpretation of endocrine tests (30%), costs (65%), absence of paediatric endocrinologist for consultation on growth disorders and endocrine complications (27%), facilities (27%), other (e.g. lack of collaboration and on-time consultation between thalassaemic Centers supervised by hematologists and endocrinologists) (17%). Because any progress we make in research into growth disorders and endocrine complications in thalassaemia should be passed on to all those suffering from it, guaranteeing them the same therapeutic benefits and the same quality of life, on the 8th of May, 2009 in Ferrara (Italy), the International Network on Endocrine Complications in Thalassemia (I-CET) was founded. The I-CET group is planning to conduct, in Ferrara in May 2012, a workshop, "MRI and Endocrine Complications in Thalassaemia", and in Doha (Qatar) in September 2012, a 3-day intensive course entitled, "Growth disorders and Endocrine Complications in Thalassaemia", to provide interested pediatricians, physicians and hematologists from all over the world with an in-depth approach to the diagnosis and management of growth and endocrine disorders in thalassaemic patients.

Surveillance of HIV in the army of the Republic of Cyprus (SHARC); rationale, design, and implementation of an inexpensive system.

OBJECTIVES: To design and implement an HIV surveillance system using periodic cross sectional prevalence surveys in National Guard recruits of the Republic of Cyprus. METHODS: HIV infection surveillance used unlinked anonymous screening (UAS) methodology, which tested residual blood originally collected for other purposes. Residual blood from samples collected for ABO blood group typing at intake and samples from blood collected for hepatitis testing at discharge was used. Screening was unlinked and anonymous. RESULTS: The system operated for four semiannual recruitment seasons: summer 1998 to the end of winter 2000. No recruits screened at entry into the ranks tested positive. CONCLUSIONS: This was the first large scale HIV surveillance project in Cyprus. Without nationwide HIV surveys, periodic measurements of prevalence could lead to estimates of HIV incidence and provide insights on temporal changes in HIV infection rates. The prevalence data collected provide useful epidemiological information about the status of the HIV epidemic in this segment of the population in Cyprus.

Polycystic ovarian syndrome and thrombophilia.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is associated with insulin-induced plasminogen activator inhibitor-1 (PAI-1) elevations. Since thrombophilic states correlate with high miscariage rates, as does PCOS, this study aimed at looking for thrombophilic predisposition in PCOS women compared with non-PCOS controls. METHODS: The prevalence of antithrombin III, protein S and protein C deficiencies, as well as factor V Leiden, prothrombin G20210A factor and methylene tetrahydrofolate reductase (MTHFR) mutations, was compared between two different groups of women, one with PCOS (n = 30) and one without PCOS (n = 45). RESULTS: Median proportions of activated protein C, S and antithrombin III as well as the activated protein C ratios were within normal ranges in both samples. There was no evidence that the genetic analysis for factor V Leiden or prothrombin factor differed between the two samples. The odds ratio (OR) of bearing a mutation on the MTHFR gene was 1.2-fold higher [95% confidence interval (CI) 0.470-3.065] in women with PCOS than in women without (P = 0.83). Although this difference is not statistically significant, it might indicate a slightly higher prevalence of heterozygous genotypes in women with PCOS (OR = 1.197, 95% CI 0.473-3.034). CONCLUSIONS: Molecular risk factors of hereditary thrombophilia do not show increased prevalence in women with PCOS in comparison with women in the general population. The existence of a possible trend towards higher prevalence of MTHFR mutation in women with PCOS needs further study, particularly regarding homocysteine levels.

ARM domain-dependent nuclear import of adenomatous polyposis coli protein is stimulated by the B56 alpha subunit of protein phosphatase 2A.

Inactivating mutations in the adenomatous polyposis coli (APC) gene correlate with progression of colon cancer and familial adenomatous polyposis. The APC tumor suppressor contributes to chromosome segregation and turnover of the oncogenic transcriptional activator beta-catenin, and these activities are impaired by truncating cancer mutations. APC was recently identified as a shuttling protein whose subcellular distribution is regulated by two nuclear localization signals (NLSs) and multiple nuclear export signals (NESs). Here, we show that mutant disease-linked truncated forms of APC, most of which lack the two central NLSs and certain NES sequences, retain nuclear-cytoplasmic shuttling activity. Nuclear export of truncated APC is mediated by a dominant N-terminal NES. Nuclear import of NLS-deficient APC mutants is facilitated by the N-terminal ARM domain. Furthermore, co-expression of the ARM-binding protein, B56 alpha, increased the nuclear localization of mutant and wild-type APC. The minimal B56 alpha-responsive sequence mapped to APC amino acids 302-625. B56 alpha is a regulatory subunit of protein phosphatase 2A; however, its ability to shift APC to the nucleus was independent of phosphatase activity. We conclude that APC nuclear import is regulated by the ARM domain through its interaction with B56 alpha and postulate that APC/B56 alpha complexes target the dephosphorylation of specific proteins within the nucleus.

Nuclear export of human beta-catenin can occur independent of CRM1 and the adenomatous polyposis coli tumor suppressor.

beta-Catenin is a mediator of the Wnt-signaling pathway. In many cancers, beta-catenin is stabilized and accumulates in the nucleus where it associates with lymphoid-enhancing factor 1/ T-cell transcription factors to activate genes involved in cell transformation. Previously, we showed that adenomatous polyposis coli (APC) protein can regulate beta-catenin localization by nuclear export. In this study, we used in vitro transport assays to test whether cellular beta-catenin can exit the nucleus independent of APC and the CRM1 export receptor. In digitonin-permeabilized SW480 (APC(mut/mut)) tumor cells, nuclear beta-catenin decreased >60% in export reactions in the absence of exogenous factors. Under similar conditions, nuclear c-ABL was only exported after the addition of cytosolic extract, and the export was blocked by the CRM1-specific inhibitor, leptomycin B. The nuclear export of beta-catenin was not blocked by leptomycin B treatment, revealing a CRM1- and APC-independent pathway. The export of beta-catenin was sensitive to lower temperatures and the removal of ATP, indicating an active process. Ectopically expressed yellow fluorescent protein-beta-catenin also displayed CRM1-independent export. Conversely, the overexpression of the CRM1 transporter moderately stimulated export of nuclear beta-catenin, confirming that beta-catenin exits the nucleus by at least two distinct pathways. The shuttling ability of tumor cell beta-catenin has implications for its regulation and its role in transferring signals between the nucleus and plasma membrane.

Combined genetic defect (homogeneity for factor V Leiden and heterogeneity for prothrombin G20210A allele), in a young patient, with recurrent deep vein thrombosis and serious postphlebitic syndrome--a case report.

Just a few years ago, resistance to activated protein C (APCR) was reported to be of high significance representing a strong predisposing factor in the development of venous thrombosis (VT). A little while later, APCR was established to be the result of a point mutation of the factor V gene (factor V Leiden: a G-to-A transition at position 1691). Up to today, it is not certain whether factor V Leiden is in itself able to lead to VT, or whether it acts in synergy with other factors. Nevertheless, heterozygous subjects have a tenfold increase in the risk of VT when compared to general population, whereas the risk is 80 times greater in homozygous individuals. In 1996, a prothrombin gene mutation (prothrombin G20210A allele), which is a single-nucleotide G-to-A transition at position 20210 in the sequence of the 3'-untranslated region (3'UTR) on chromosome 11, was discovered. The presence of this mutant gene results in elevated plasma prothrombin concentrations, increasing the possibility for the development of VT. However, the coexistence of these two abnormalities, as well as the clinical consequence, have not yet been studied. So far, only a few reports are found in the literature describing the coexistence of both mutations. The authors present a 25-year-old patient with a simultaneous double mutation of the FV and F II gene. The patient was homozygous for the factor V Leiden and heterozygous for the prothrombin G20210A allele. It is unclear whether the coexistence of the two predisposes more to the development of VT than the summation of the two as independent factors.

A comparison of the activity, sequence specificity, and CRM1-dependence of different nuclear export signals.

Nuclear export sequences (NESs) have been identified in many cellular proteins, but it remains unclear how different NESs compare in activity. We describe a sensitive new in vivo export assay which we have used to assess the relative export activity of different types of NES. The most common type of export sequence resembles that first identified in the HIV-1 Rev protein and typically comprises a core of large hydrophobic amino acids that specify recognition by the CRM1 export receptor. We compared 10 previously identified Rev-type NESs in our assay, and whereas all were functional, the relative export activities of these signals varied considerably. We further identified 3 new Rev-type NESs from a computer database search, and each export signal was assigned a score of 1 to 9 and ranked in order of activity (e.g., PKI > c-ABL > Ran-BP1 > FMRP > PML > IkappaB-alpha > hdm2). The weakest NESs were found in the p53 tumor suppressor and the p53-regulated proteins p21 and hdm2, which are all normally localized to the nucleus. All of the Rev-type NESs were inactivated by mutation of key hydrophobic residues and by treatment with the CRM1-specific export inhibitor, leptomycin B. In contrast, a different type of export signal, the KNS shuttling element derived from hnRNP K, exhibited a modest export activity that was insensitive to leptomycin B treatment. KNS thus appears to mediate export via a CRM1-independent pathway. Mutagenesis of the KNS sequence identified, for the first time, specific serines and acidic residues necessary for its export activity, thereby distinguishing KNS from other types of nuclear transport signal. We have shown that different nuclear export signals can vary profoundly in activity and therefore conclude that the nuclear export rate of a specific shuttling protein largely depends on both the strength and the accessibility of its NES.

Autosomal dominant polycystic kidney disease-type 2. Ultrasound, genetic and clinical correlations.

BACKGROUND: Ultrasound, genetic and clinical correlations are available for ADPKD-1, but lacking for ADPKD-2. The present study was carried out to address: (i) the age-related diagnostic usefulness of ultrasound compared with genetic linkage studies; (ii) the age-related incidence and prevalence of relevant symptoms and complications; and (iii) the age and causes of death in patients with ADPKD-2. METHODS: Two hundred and eleven alive subjects, from three ADPKD-2 families at 50% risk, were evaluated by physical examination, consultation of hospital records, biochemical parameters, ultrasound and with genetic linkage and DNA mutation analyses. Nineteen deceased and affected family members were also included in the study. RESULTS: Of the 211 alive members, DNA linkage studies and direct mutation analyses showed that 106 were affected and 105 were not. Ultrasound indicated 94 affected, 108 not affected and nine equivocal results in nine children under the age of 15. For all ages, the false-positive diagnostic rate for ultrasound was 7.5% and the false-negative rate was 12.9%. The difference between ultrasound and DNA findings was most evident in children aged 5-14 years where the ultrasound was correct in only 50% and wrong or inconclusive in the remaining 50%. The mean age of the 106 alive, ADPKD-2 genetically affected patients was 37.9 years (range: 6-66 years). Among them, 23.5% had experienced episodes of renal pain, 22.6% were treated for hypertension, 22.6% had experienced at least one urinary tract infection, 19.8% had nephrolithiasis, 11.3% had at least one episode of haematuria, 9.4% had asymptomatic liver cysts, 7.5% had developed chronic renal failure and 0.9% had reached end-stage renal failure. Of the 19 deceased members, nine died before reaching end-stage renal failure at a mean age of 58.7 years (range: 40-68 years), mainly due to vascular complications, while the remaining 10 died on haemodialysis at a mean age of 71.4 years (range: 66-82 years). CONCLUSIONS: DNA analysis is the gold standard for the diagnosis of ADPKD-2, especially in young people. Ultrasound diagnosis is highly dependent on age. Under the age of 14, ultrasound is not recommended as a routine diagnostic procedure, but ultrasound becomes 100% reliable in excluding ADPKD-2 in family members at 50% risk, over the age of 30. ADPKD-2 represents a mild variant of polycystic kidney disease with a low prevalence of symptoms and a late onset of end-stage renal failure.

The prevalence of factor V Leiden as a risk factor for venous thromboembolism in the population of North-Western Greece.

BACKGROUND: Many predisposing factors have been associated with the development of venous thromboembolism. Recently, Factor V Leiden has been described as a common genetic risk factor. The geographic distribution of this genetic abnormality in the general population greatly varies. The prevalence of the Factor V Leiden mutation in Europe is high, particularly in Greece, where according to some authors it is especially high. The purpose of this study was to estimate the prevalence of the Factor V Leiden mutation in patients presenting with at least one episode of venous thromboembolism and to compare it with that of the general population. METHODS: Blood samples were drawn from 388 subjects. 240 healthy blood donors (controls) and 148 unselected patients with a history of one or more episodes of venous thrombosis. DNA analysis was performed using the polymerase chain reaction to amplify the factor V gene exon 10, and to detect the Factor V Leiden point mutation. RESULTS: DNA analysis revealed Factor V Leiden mutations in eight (3.3%) control subjects (seven heterozygous and one homozygous) and in twenty-four (16.2%) patients, (twenty-two heterozygous and two homozygous). The difference between the two groups is statistically significant (p<0.0001; chi2 test). CONCLUSIONS: The prevalence of the Factor V Leiden mutation in the general population of North-Western Greece is 3.3%, which is within the same range as that reported for other European countries. The Factor V Leiden mutation is one of the most important predisposing genetic factors in the development of venous thrombosis and was present in 16.2% of our patients.

Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease.

There is a group of inherited cystic nephropathies that are characterized by juvenile onset recessive inheritance (familial juvenile nephronophthisis, FJN) or by adult onset dominant inheritance (medullary cystic disease, MCD) and share similar clinico-pathological presentation to the extent that they are usually grouped together under the term FJN/MCD complex. The main symptoms consist of renal cyst formation in the medulla or the corticomedullary junction and salt wasting. Although earlier reports had suggested that one single gene may be responsible for this pathology, recent reports have shown that the FJN complex itself comprises a genetically heterogeneous group. Here we are presenting two large Cypriot families that segregate autosomal dominant medullary cystic kidney disease (ADMCKD) with hyperuricemia and gout and with very late age of onset (mean 62.2 and 51.5 years). We performed DNA linkage mapping using highly polymorphic microsatellite markers and found linkage to marker locus D1S1595 at 1q21 with a two-point lod score of 6.45 at Theta = 0.00. Analysis of haplotypes and of critical recombinants enabled confinement of the disease locus within an approximately 8 cM region between marker loci D1S498 and D1S2125. FISH mapping with a large P1 clone confirmed the physical localization within 1q21. The two families share the same disease haplotype, thus suggesting their relationship through a common ancestor and the possible existence of a single ADMCKD-causing mutation within these families. To our knowledge this is the first genetic locus identified to cause FJN/MCD pathology of the dominant adult type.

Transfusional transmitted viruses in pregnancy.

Blood has long been recognized as a vehicle for transmission of infectious organisms and as molecular laboratory technology has advanced, a seemingly endless array of infectious agents has occasionally been documented to be blood transmitted. Transfusion associated hepatitis (TAH) has been the most common serious consequence of blood transfusion although in recent years this has been significantly reduced (blood donor screening, blood processing, etc.). Thalassaemia major is classically associated with increased susceptibility to infections caused by those agents that are blood transmitted such as HBV, HCV, HIV, CMV, HPV B-19 (frequency rates vary from country to country). Monitoring the prevalence of transfusion transmitted infections in thalassaemics has been in recent years an indispensable part of their clinical management protocol. As a number of these viruses have been documented to be efficiently transmitted through the vertical route, the issue of blood transmitted viral infection monitoring becomes particularly important in order to provide protection or treatment both to the pregnant thalassaemic patient herself and to her foetus/newborn. Hepatitis (mainly B and C) and HIV in the obstetric thalassaemic is what the clinician is faced with most frequently. Although preventative measures have been very successful in the case of HBV infection and recently to an encouraging extent in the case of HIV (recommendations have been constructed), the mechanisms and frequency of HCV vertical transmission as well as the clinical outcome of children born to HCV carriers are not yet completely clarified. No vaccines are available and HIGB or antivirals do not appear to offer protection to the foetus against infection with HCV. Thalassaemics are frequently seropositive to markers of other transfusion transmitted viruses, such as CMV and HPV B-19, particularly by the age of pregnancy. Infection with a second or multiple strains as well as reactivation of existing CMV strain(s) are possible events in thalassaemics. However, the frequency of "recurrency" episodes, their implication in vertical transmission and clinical outcome for the foetus/newborn are issues requiring further investigation.

Viral meningitis in Cyprus and England : summer 1996.

An outbreak of viral meningitis began in Cyprus on 5 July 1996. By 28 August a total of 316 cases had been admitted to hospital, most of whom were infants and young children; 55 (17%) were less than 1 year of age, 117 (37%) were aged 1 to 4 years, 103 (33