Mitochondrial neurogastrointestinal encephalomyopathy: Clinical and biochemical impact of allogeneic stem cell transplantation in a Greek patient with one novel TYMP mutation.

We describe the case of a Greek female patient with the Classic form of the ultra- rare and fatal autosomal recessive disorder Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and the impact of allogeneic hematopoietic stem cell transplantation on the biochemical and clinical aspects of the disease. The patient presented at the age of 15 years with severe gastrointestinal symptoms, cachexia, peripheral neuropathy and diffuse leukoencephalopathy. The diagnosis of MNGIE disease was established by the increased levels of thymidine and deoxyuridine in plasma and the complete deficiency of thymidine phosphorylase activity. The novel c.[978dup] (p.Ala327Argfs*?) variant and the previously described variant c.[417 + 1G > A] were identified in TYMP. The donor for the allogeneic hematopoietic stem cell transplantation was her fully compatible sister, a carrier of the disease. The patient had a completely uneventful post- transplant period and satisfactory PB chimerism levels. A marked and rapid decrease in thymidine and deoxyuridine plasma levels and an increase of the thymidine phosphorylase activity to the levels measured in her donor sister was observed and is still present sixteen months post-transplant. Disease symptoms stabilized and some improvement was also observed both in her neurological and gastrointestinal symptoms. Follow up studies will be essential for determining the long term impact of allogeneic hematopoietic stem cell transplantation in our patient.

Relaxin as a potential diagnostic biomarker for ovarian cancer- A prospective study.

Ovarian cancer is a leading cause of female mortality worldwide. Although novel approaches on this disease have been developed, overall survival rates remain moderate due to the lack of scientific evidence promoting screening at early stages of the disease. A number of biomarkers have been suggested as predictive for this type of cancer. The role of relaxin in endometrial cancer is well documented but the scientific evidence is lacking with regards to ovarian cancer. We studied patients with ovarian cancer, benign ovarian cyst and healthy patients too. The levels of relaxin have been found to be an adequate diagnostic biomarker for ovarian cancer. We also presented the different range of Ca125, HE4 and ROMA in these three groups. Randomised control trials need to be conducted though, in order to elucidate the true role of relaxin in these cases.

Nitrogen loading and natural pressures on the water quality of a shallow Mediterranean lake.

The water quality of Koumoundourou Lake, a heavily modified, peri-urban, brackish and shallow lake near Athens, Greece, is under multiple stressors due to the industrial activities in the catchment area and natural pollution pressures. Although the broader area has undergone significant land use changes since the beginning of the 20th century converting it from rural to heavily industrialized, Koumoundourou Lake remained as one of the few habitats in Attica Region, for large numbers of aquatic birds. The water quality of the lake has been recently improved, which contributed to the increase of aquatic birds' population in the area and to the higher, in relation to the past, nitrogen inputs from natural sources. Therefore, a monitoring program has been implemented to assess the pollution pressure factors in the lake. A water quality model has been also used to simulate the lake's processes and estimate the nutrient mass budget focusing on the various nitrogen loading mechanisms (natural and anthropogenic). Based on the model output, the main polluting factor of the lake is the groundwater inflows. Aquatic birds affect slightly the lake's water quality, while the dry and wet atmospheric deposition contributes insignificantly to the total nitrogen loading.

Historical trends and the long-term changes of the hydrological cycle components in a Mediterranean river basin.

Identifying the historical hydrometeorological trends in a river basin is necessary for understanding the dominant interactions between climate, human activities and local hydromorphological conditions. Estimating the hydrological reference conditions in a river is also crucial for estimating accurately the impacts from human water related activities and design appropriate water management schemes. In this effort, the output of a regional past climate model was used, covering the period from 1660 to 1990, in combination with a dynamic, spatially distributed, hydrologic model to estimate the past and recent trends in the main hydrologic parameters such as overland flow, water storages and evapotranspiration, in a Mediterranean river basin. The simulated past hydrologic conditions (1660-1960) were compared with the current hydrologic regime (1960-1990), to assess the magnitude of human and natural impacts on the identified hydrologic trends. The hydrological components of the recent period of 2008-2016 were also examined in relation to the impact of human activities. The estimated long-term trends of the hydrologic parameters were partially assigned to varying atmospheric forcing due to volcanic activity combined with spontaneous meteorological fluctuations.

Determination of environmental flows in rivers using an integrated hydrological-hydrodynamic-habitat modelling approach.

We propose the novel integrated modelling procedure 3H-EMC for the determination of the environmental flow in rivers and streams; 3H-EMC combines Hydrological, Hydrodynamic and Habitat modelling with the use of the Environmental Management Classes (EMCs) that are defined by the Global Environmental Flow Calculator. We apply 3H-EMC in the Sperchios River in Central Greece, in which water abstractions for irrigation cause significant environmental impacts. Calculations of the hydrodynamic-habitat model, in which the large and the small chub are the main fish species, suggest discharge values that range from 1.0 m3/s to 4.0 m3/s. However, hydrological modelling indicates that it is practically difficult to achieve discharges that are higher than approximately 1.0-1.5 m3/s. Furthermore, legislation suggests significantly lower values (0.4-0.5 m3/s) that are unacceptable from the ecological point of view. This behaviour shows that a non-integrated approach, which is based only on hydrodynamic-habitat modelling does not necessarily result in realistic environmental flows, and thus an integrated approach is required. We propose the value of 1.0 m3/s as the "optimum" environmental flow for Sperchios River, because (a) it satisfies the habitat requirements, as expressed by the values of weighted useable area that are equal to 2180 and 1964 m2 for the large and small chub, respectively, and correspond to 82 and 95% of their respective maximum values, (b) it is consistent with the requirements of Environmental Classes A and B, whose percentiles are higher than 75% for discharge (77.2%) and for habitat availability (>83.5% for the large chub and >85.0% for the small chub), (c) it is practically achievable from the hydrological point of view, and (d) it is higher than the value proposed by the Greek legislation. The proposed modelling approach can be applied to any river or stream using the same or similar modelling tools, which should be linked via suitable coupling algorithms.

Neuroradiological, neurophysiological and molecular findings in infantile Krabbe disease: two case reports.

Krabbe disease is an autosomal recessive neurodegenerative disorder due to a defect of the lysosomal enzyme ß-galactocerebrosidase (ß-GALC). Depending on the age of onset, the disease is classified into infantile and later-onset forms. We report neuroradiological, neurophysiological and molecular findings in two Greek patients with the infantile form of Krabbe disease. The index patients presented at the age of 3.5 and 6 months, respectively, due to developmental delay. Magnetic resonance imaging (MRI) of the first patient's brain demonstrated signs of leukodystrophy, while nerve conduction velocities (NCVs) were significantly decreased. The second patient's MRI at the age of 4 months was initially normal, but at 18 months demonstrated leukodystrophic alterations as well, whereas NCVs were also significantly delayed. In both patients, a severe decrease in ß-GALC, activity supported the diagnosis of Krabbe disease, while the final diagnosis was confirmed by molecular genetic testing. Two homozygous mutations of the GALC gene, the c.411_413delTAA [p.K139del] mutation in the first patient, and the c.749T>C [p.I250T] mutation in the second patient, were identified. At their last follow-up visit at the age of 4 and 6 years, respectively, both patients were bedridden and quadri-plegic, suffering from frequent respiratory tract infections and fed through a gastrostomy. Both mutations found in homozygosity in these two unrelated patients of Greek ancestry, could pinpoint a common origin. Genotyping of patients with Krabbe disease is important, in order to contribute to the creation of a European mutation database and to further study possible genotype-phenotype correlations of the disease.

Water quality monitoring and assessment of an urban Mediterranean lake facilitated by remote sensing applications.

Degradation of water quality is a major problem worldwide and often leads to serious environmental impacts and concerns about public health. In this study, the water quality monitoring and assessment of the Koumoundourou Lake, a brackish urban shallow lake located in the northeastern part of Elefsis Bay (Greece), were evaluated. A number of water quality parameters (pH, temperature, dissolved oxygen concentration, electrical conductivity, turbidity, nutrients, and chlorophyll-a concentration) were analyzed in water samples collected bimonthly over a 1-year period from five stations throughout the lake. Moreover, biological quality elements were analysed seasonally over the 1-year period (benthic fauna). Statistical analysis was performed in order to evaluate the water quality of the lake and distinguish sources of variation measured in the samples. Furthermore, the chemical and trophic status of the lake was evaluated according to the most widely applicable classification schemes. Satellite images of Landsat 5 Thematic Mapper were used in order for algorithms to be developed and calculate the concentration of chlorophyll-a (Chl-a). The trophic status of the lake was characterized as oligotrophic based on phosphorus and as mesotrophic-eutrophic based on Chl-a concentrations. The results of the remote sensing application indicated a relatively high coefficient of determination (R (2)) among point sampling results and the remotely sensed data, which implies that the selected algorithm is reliable and could be used for the monitoring of Chl-a concentration in the particular water body when no field data are available.

Niemann-Pick type C disease: a novel NPC1 mutation segregating in a Greek island.

Niemann-Pick type C (NPC) disease is a rare autosomal recessive lysosomal storage disease, exhibiting an extremely heterogeneous clinical phenotype. It is a cellular lipid trafficking disorder characterized by the accumulation in the lysosomal/late endosomal system of a variety of lipids, especially unesterified cholesterol. So far two genes, NPC1 or NPC2, have been linked to the disorder. It is a panethnic disease for which two isolates have been described. We present a novel NPC1 mutation (p.A1132P; c.3394G>C) identified in homozygosity in two patients originating from the same small town of an Aegean Sea island and the results of the broad screening of their extended families. Overall 153 individuals have so far been investigated and a total of 64 carriers were identified. Moreover a common descent of the individuals tested was revealed and all carriers could be traced back to a common surname, apparently originating from a common ancestor couple six generations back. The mutation was found associated with an uncommon haplotype in the island that is also present in other populations.

The thickness and volume of LLETZ specimens can predict the relative risk of pregnancy-related morbidity.

OBJECTIVE: The aim of this study was to determine if the individual physical characteristics of the extirpated transformation zone after large loop excision of the transformation zone (LLETZ) might predict the relative risk of adverse obstetric outcome, specifically preterm labour (PTL). DESIGN: A retrospective observational study. SETTING: University teaching hospital in Dublin (Coombe Women & Infants University Hospital, CWIUH). POPULATION: Women who had LLETZ treatment for cervical intraepithelial neoplasia (CIN) in the colposcopy service between 1999 and 2002, and who subsequently had a pregnancy at the CWIUH. METHODS: Case records and histology reports for eligible women were examined. Age, parity, smoking history, pregnancy complications and CIN grade were recorded. Exclusion criteria were age >42 years, previous treatment for CIN, previous premature labour or twin pregnancies. The Student's t-test, Mann-Whitney U-test, analysis of variants (ANOVA) and logistic regression were employed to analyse the data. MAIN OUTCOME MEASURES: Gestational age at birth, PTL (i.e. <37 weeks of gestation) and miscarriage rate (<24 weeks of gestation). RESULTS: Out of 1808 women who underwent LLETZ treatment, a total of 353 women were identified who subsequently had a pregnancy at the CWIUH, with 321 being eligible for inclusion in the study. Of these, 76.3% delivered at term, 9.1% delivered at <37 weeks of gestation and 14.6% miscarried at <24 weeks of gestation. There was a three-fold increase in the risk of PTL if the excision volume exceeded 6 cm(3) (RR = 3.00; 95% CI 1.45-5.92), or when the thickness of the excised tissue was greater than 12 mm (RR = 2.98; 95% CI 1.27-7.01). The time interval between LLETZ and pregnancy did not appear to have an effect on PTL rates. We found no association between the grade of CIN and the risk of PTL. CONCLUSIONS: This study reveals that the thickness and the total volume of the excised transformation zone are associated with an increased risk of PTL. Excisions thicker than 1.2 cm and larger than 6 cm(3) carry a three times greater risk for PTL.

Prevalence of attention deficit hyperactivity disorder in schoolchildren in Athens, Greece. Association of ADHD subtypes with social and academic impairment.

The aim of this study was to explore the prevalence of attention deficit hyperactivity disorder (ADHD) and social and academic impairment in 6- to 11-year-old children residents of Athens, Greece. We screened 603 elementary schoolchildren following grades first to sixth. A two-stage screening process was employed including a standardized ADHD test for teachers and the Teacher Report Form (TRF). Among the 603 children, 36 (6.0%) met the study criteria for ADHD. The estimated prevalence was 8% for boys and 3.8% for girls. The most prevalent subtype of ADHD was the combined type (3.8%), followed by the ADHD inattentive (1.7%) and the ADHD hyperactive-impulsive type (0.5%). The ADHD-combined type was strongly associated with clinical impairment in both areas of functioning (academic and social), where the ADHD inattentive subtype was found to be strongly associated with academic problems. The ADHD hyperactive-impulsive type was the less prevalent and the less impaired subtype in this study. None of the 36 children had been previously diagnosed as having ADHD or other primary disorder. In conclusion, the prevalence of ADHD among schoolchildren in Athens and the risk factors were found to be comparable to those reported in other countries worldwide. Additionally, impairment in social and academic functioning was strongly associated with the subtypes of the disorder.

Chitotriosidase plasma activity in nephropathic cystinosis.

Chitotriosidase is a fully active chitinase produced and secreted by activated phagocytes. Plasma chitotriosidase activity is a well-established marker of total disease burden in Gaucher disease that has proved useful in monitoring the response to both enzyme replacement and substrate reduction therapies in patients with Gaucher disease. Increased chitotriosidase plasma activity has also been observed in several other lysosomal and non lysosomal disorders. Cystinosis, a rare multisystemic lysosomal storage disease, is characterized by the intralysosomal accumulation of free cystine in many cell types including phagocytes. We here report on plasma chitotriosidase activity in a child with nephropathic cystinosis. Increased plasma chitotriosidase activity (481 nmol/h per ml; normal range 0-150 units) was found on diagnosis and prior to the initiation of oral cysteamine (Cystagon) treatment. Serial estimations of plasma chitotriosidase activity showed that it correlated with leukocyte cystine content and decreased to 100 nmol/h per ml following 14 months' treatment. This novel observation suggests that cystinosis should be included in the differential diagnosis of disorders associated with increased plasma chitotriosidase activity. Furthermore, it suggests that serial estimations of plasma chitotriosidase activity could be of value in monitoring the response to oral cysteamine treatment in cystinosis.

Serum S100B levels in X-linked adrenoleukodystrophy and Gaucher disease.

S100B, a small acidic protein, is a member of a multigenic family of calcium-modulated proteins. It is mainly produced by astrocytes and the secreted protein, depending on its concentration, can exert either trophic or toxic effects. In humans increased S100B levels have been detected in brain trauma and ischaemia, and neurodegenerative, neurometabolic, inflammatory and psychiatric disease. Serum S100B concentrations have been used as markers of brain disease. In the present study S100B serum levels were determined in patients with the neuroinflammatory disease X-linked adrenoleukodystrophy (X-ALD) and in patients with both the acute neuronopathic (type II) and the non-neuronopathic (type I) types of Gaucher disease (GD). Sixteen X-ALD patients (10 with the childhood, 4 with the adult cerebral forms, 2 asymptomatic) and 22 Gaucher disease patients (19 type I, 3 type II) were studied. No statistically significant differences were observed between the X-ALD (median 0.13 microg/L, p=0.191) or Gaucher type I patients (median 0.07 microg/L, p=0.095) and controls of similar age (median 0.10 microg/L, n=22). Serum S100B levels of type II Gaucher disease patients were also within the normal for their age range (patients 0.2, 0.22, 0.65; control median 0.81 microg/L, n=44). Lack of clinical symptoms and/or MRI findings in X-ALD patients was not associated with lower S100B values. Our results indicate that serum S100B levels cannot serve as peripheral marker in the evaluation of brain disease in X-ALD and GD.

Chitotriosidase in neonates with fungal and bacterial infections.

Increased plasma and/or urine chitotriosidase activity was found in neonates with fungal infection changing in parallel with their clinical condition. Increased levels were also found in neonates with bacterial infection. Chitotriosidase activity increase is not a response specific to fungi, but serial assays could monitor the course of neonatal fungal infection.

Elevated plasma chemokine CCL18/PARC in beta-thalassemia.

Plasma CCL18/PARC, a member of the CC chemokine family, has been found to be several ten-fold increased in symptomatic Gaucher type I patients. Elevated plasma chitotriosidase levels are a well-known abnormality in Gaucher patients, however, its diagnostic use is limited by the frequent genetic deficiency in the protein. Like the situation in Gaucher disease, lipids accumulate in macrophages of patients suffering from beta-thalassemia, and, in both conditions, increased chitotriosidase levels occur. We here report that plasma CCL18/PARC is also significantly increased in patients with beta-thalassemia major (range 76.8-4977.8, median=650.8 ng/ml, n=36 and control range 10-72, median=33 ng/ml n=36 respectively, P<0.001). The CCL18/PARC levels are lower than in Gaucher patients (range 174.8-10798.7, median 2538.2 ng/ml, n=28, P<0.001). In our cohort of beta-thalassemic patients, CCL18/PARC showed a significant negative correlation to iron chelation therapy and a significant positive correlation to ferritin and chitotriosidase levels, the latter only in the patients with the wild type genotype for the enzyme. Our study demonstrates that beta-thalassemic patients have increased CCL18/PARC levels that could be of value in monitoring iron overload and compliance to therapy.

Sanfilippo B syndrome: molecular defects in Greek patients.

Sanfilippo syndrome type B [mucopolysaccharidosis IIIB (MPS IIIB] is the most prevalent type of MPS III in Greece, accounting for 81% of all MPS III cases diagnosed at the Institute of Child Health (Athens) over the last 20 years. The majority of the patients originated from East Central/Central Greece, Thessaly, and Macedonia. We present the results of mutation analysis in 21 Greek patients from 18 different families, all of whom had the severe form of the disorder. Patients were initially screened for five previously known mutations by restriction enzyme digestion of polymerase chain reaction products. Unknown mutations were identified by single-strand conformation polymorphism analysis and DNA sequencing and were confirmed by restriction enzyme analysis. Seven previously described mutations (Y140C, R626X, 503-512del, H414R, G292R, 334del25, and E452K) and four novel mutations (P516L, L242P, E446K, and R482Q) were identified. Expression of the latter and H414R showed that they were all null activity mutations. Considerable genetic heterogeneity has been described in MPS IIIB patients of different origins. In our population, Y140C, H414R, and R626X account for approximately 70% of the studied alleles. Our findings, especially in combination with the origin of individual patients, can improve carrier detection and genetic counseling in affected families.

The expanding spectrum of disorders with elevated plasma chitotriosidase activity: an update.

A striking elevation of plasma chitotriosidase activity, greater than 150 times the normal median value, was found in two galactosialidosis patients. Furthermore, increased plasma chitotriosidase activity, 10-53 times the normal median value, was also observed in fucosidosis, glycogen storage disease type IV, Alagille syndrome and hydrops fetalis due to congenital herpes virus infection.

Developing sustainable water management scenarios by using thorough hydrologic analysis and environmental criteria.

Wetlands constitute a significant source of life since they incorporate unique habitats with endemic and migrant species. They also contribute to the preservation of high global biodiversity and they are under protection according to EU legislation. Nevertheless, during the last century, significant degradation has been observed in wetlands, mainly due to intensification of agriculture and poor water management practices. Calcareous fens habitat with the endangered species Cladium mariscus and Carex spp. is an ecologically significant wetland that undergoes great ecological stresses globally, due to the irrational use of water resources. In Trichonis lake, Western Greece, this habitat has been under deterioration during the last 50 years due to the lack of a sustainable water management plan that has caused destabilization of the hydrologic balance and high water level fluctuations. This human induced hydrologic regime has led to seasonal shifting between drought and flooding which constitute unfavorable conditions for this fen habitat and as a result significant elimination of this ecosystem extent has occurred. This study has adopted technologically advanced scientific methods such as GIS applications and remote sensing techniques to quantify the existing water resources and formulate a sustainable management scheme by considering both anthropogenic water uses and environmental protection.

Early-onset severe neurological involvement and D409H homozygosity in Gaucher disease: outcome of enzyme replacement therapy.

Gaucher disease, in most cases, is the result of mutations in the beta-glucocerebrosidase gene. More than 150 such mutations have been identified so far. Mutation D409H is the second most frequent in Greek patients, accounting for 15.5% of all identified mutated alleles. D409H homozygosity has, so far, been associated with a unique type III subtype of Gaucher disease that is characterized by the presence of devastating valvular heart disease, oculomotor apraxia, and, sometimes, features normally associated with mucopolysaccharidoses or oligosaccharidoses. Common manifestations of Gaucher disease tend to be less evident or even absent. We report the first Greek patient bearing the D409H/D409H genotype with onset of the disease in the first months of life and a phenotype dominated by severe neurological involvement. Enzyme replacement therapy, while improving the hematological parameters and organomegaly, failed to improve or even arrest the neurological condition.