Relationship of MTHFR gene polymorphisms with renal and cardiac disease.

AIM: To investigate the effects of different methylenetetrahydrofolate reductase (MTHFR) 677C>T gene polymorphism and hyperhomocysteinemia for the development of renal failure and cardiovascular events, which are controversial. METHODS: We challenged the relationship, if any, of MTHFR 677C>T and MTHFR 1298A>C polymorphisms with renal and heart function. The present article is a reappraisal of these concepts, investigating within a larger population, and including a subgroup of dialysis patients, if the two most common MTHFR polymorphisms, C677T and A1298C, as homozygous, heterozygous or with a compound heterozygous state, show different association with chronic renal failure requiring hemodialysis. MTHFR polymorphism could be a favorable evolutionary factor, i.e., a protective factor for many ominous conditions, like cancer and renal failure. A similar finding was reported in fatty liver disease in which it is suggested that MTHFR polymorphisms could have maintained and maintain their persistence by an heterozygosis advantage mechanism. We studied a total of 630 Italian Caucasian subject aged 54.60 ± 16.35 years, addressing to the increased hazard of hemodialysis, if any, according to the studied MTHFR genetic polymorphisms. RESULTS: A favorable association with normal renal function of MTHFR polymorphisms, and notably of MTHFR C677T is present independently of the negative effects of left ventricular hypertrophy, increased Intra-Renal arterial Resistance and hyperparathyroidism. CONCLUSION: MTHFR gene polymorphisms could have a protective role on renal function as suggested by their lower frequency among our dialysis patients in end-stage renal failure; differently, the association with left ventricular hypertrophy and reduced left ventricular relaxation suggest some type of indirect, or concurrent mechanism.

Perceived agricultural runoff impact on drinking water.

Agricultural runoff into surface water is a problem in Australia, as it is in arguably all agriculturally active countries. While farm practices and resource management measures are employed to reduce downstream effects, they are often either technically insufficient or practically unsustainable. Therefore, consumers may still be exposed to agrichemicals whenever they turn on the tap. For rural residents surrounded by agriculture, the link between agriculture and water quality is easy to make and thus informed decisions about water consumption are possible. Urban residents, however, are removed from agricultural activity and indeed drinking water sources. Urban and rural residents were interviewed to identify perceptions of agriculture's impact on drinking water. Rural residents thought agriculture could impact their water quality and, in many cases, actively avoided it, often preferring tank to surface water sources. Urban residents generally did not perceive agriculture to pose health risks to their drinking water. Although there are more agricultural contaminants recognised in the latest Australian Drinking Water Guidelines than previously, we argue this is insufficient to enhance consumer protection. Health authorities may better serve the public by improving their proactivity and providing communities and water utilities with the capacity to effectively monitor and address agricultural runoff.

A dose of our own therapy: using research findings to challenge mental health nurses to embrace contemporary practice realities.

This paper explores the effects of mental policy changes and the curtailment of mental health nursing education on the realities of working as a mental health nurse in rural and remote locations in New South Wales, Australia. Using the twin lenses of mental health nursing and the sociology of work and social change, the experiences of mental health nurses are explored and set in the context of the evolution of the mental health nurse into non-specialist mental health worker. At the same time, mental health nurses are challenged to adapt to new practice realities.

Renal insufficiency in non-diabetic subjects: relationship of MTHFR C677t gene polymorphism and left ventricular hypertrophy.

BACKGROUND: Association of methylenetetrahydrofolate reductase (MTHFR) 677C>T gene polymorphism with hyperhomocysteinemia, renal failure, and cardiovascular events is controversial. We investigated the relationship of MTHFR 677C>T polymorphisms with left ventricular hypertrophy (LVH) and renal insufficiency. METHODS: Glomerular filtration rate (GFR) and left myocardial ventricular mass/m2 were assessed in 138 non-diabetic subjects (age, 50.93 ± 14.85 years; body mass index, 27.95 ± 5.98 kg/m(2)), 38 no-mutation wild MTHFR C677CC, 52 heterozygous MTHFR C677CT, and 48 homozygous MTHFR C677TT, all with adequate adherence to current international healthy dietary guidelines. Serum homocysteine, insulin resistance, high-sensitivity C-reactive-protein (hsCRP), parathyroid hormone, and renal artery resistive index (RRI) were challenged by odds ratio analysis and multiple linear regression models. RESULTS: MTHFR 677C>T polymorphism showed higher GFR (73.8 ± 27.99 vs. 58.64 ± 29.95; p= 0.001) and lower renal failure odds (OR, 0.443; 95% confidence interval, 0.141-1.387) in comparison with wild MTHFR genotype. A favorable effect on GFR of MTHFR polymorphism is presented independently by the negative effects of LVH, increased intra-renal arterial resistance, and hyperparathyroidism; GFR is the significant predictive factor to LVH. CONCLUSIONS: Renal insufficiency in non-diabetic subjects is explained by interactions of MTHFR C677T polymorphism mutation with LVH, hsCRP, intact parathyroid hormone (iPTH), and RRI. Sign of these predictive effects is opposite: subjects with MTHFR 677C>T polymorphism have lower likelihood of renal insufficiency; differently, wild-type MTHFR genotype subjects have lower GFR and greater hsCRP, iPTH, RRI, and LVH.

Rural Australian women's legal help seeking for intimate partner violence: women intimate partner violence victim survivors' perceptions of criminal justice support services.

Intimate partner violence (IPV) is a widespread, ongoing, and complex global social problem, whose victims continue to be largely women. Women often prefer to rely on friends and family for IPV help, yet when informal support is unavailable they remain hesitant to contact formal services, particularly legal support for many reasons. This study applies a sociological lens by framing the IPV and legal help-seeking experiences of rural Australian women gained from 36 in-depth face-to-face interviews as socially contextualized interactions. Findings reveal police and court responses reflect broader social inequalities and rurality exacerbates concerns such as anonymity and lack of service. Cultural differences and power imbalances between survivors and formal support providers are manifested to inform future research seeking to improve survivors' willingness to engage and satisfaction with formal services. Finally, the important role police and the criminal justice system play in de-stigmatizing IPV and legitimating its unacceptability is argued a crucial, yet unrecognized, key to social change.

Chemosensitivity of nonleukemic clonogenic precursors in AML patients in complete remission: association with CD34(+) mobilization and with disease-free survival.

A high number of CD34(+) cells in the peripheral blood during mobilization in patients with acute myeloid leukemia (AML) in complete remission (CR) is associated with a high relapse rate. The variability in chemoresistance of normal bone marrow precursors has been hypothesized as explanation for the variable CD34 mobilization in AML. In 37 patients with AML in CR, we determined the chemosensitivity of bone marrow clonogenic precursors to maphosphamide and etoposide, which was then correlated with the degree of CD34(+) mobilization. In an enlarged set of 49 patients, we also studied the importance of chemosensitivity of marrow precursors for disease-free survival and relapse incidence. Significant correlations were demonstrated between the peak number of CD34(+) cells and residual growth of colony-forming unit granulocyte-macrophage (CFU-GM) after maphosphamide (R = 0.550; p = 0.0003) and after etoposide (R = 0.793; p = 0.0003). It was possible to identify three groups of AML patients based on chemosensitivity. The mean CD34(+) peak was 33 × 10(6)/L in the hyperchemosensitive group, 141 × 10(6)/L in the normochemosensitive (p = 0.03), and 379 × 10(6)/L in the chemoresistant group (p = 0.002). Failed CD34(+) mobilization was observed in 72% of the hyperchemosensitive group, 23% of the normochemosensitive group, and 0% of the chemoresistant group (p = 0.001). Hyperchemosensitivity of CFU-GM, together with a low platelet count, were independent factors important in the failure of CD34(+) cell mobilization. A disease-free survival significantly inferior to that of all other patients was associated with chemoresistance of CFU-GM (log rank, p = 0.030) and with chemoresistance of burst-forming unit erythroid (BFU-E) (log rank, p = 0.033). Chemoresistance of CFU-GM (p = 0.048) and BFU-E (p = 0.017) was also associated with increase relapse incidence. Nonleukemic nature of these precursors was demonstrated studying minimal residual disease from single colony cells. In conclusion, we found that hyperchemosensitivity of normal nonleukemic CFU-GM is associated with a high risk of CD34(+) cell mobilization failure, while a chemoresistant pattern in CFU-GM and BFU-E is associated with poor disease-free survival and increased cumulative incidence of relapse.

Realities of mental health nursing practice in rural Australia.

Mental health nursing as a distinct speciality has been in decline in New South Wales (NSW), Australia, for two decades. Arguably, this decline has worsened both consumer outcomes and the workplace experiences of mental health nurses. This article reports on a study designed to ascertain the nature of contemporary mental health nursing practice in New South Wales. The study utilised focus group research methodology, with participants recounting the realities of their day-to-day professional practice and perceptions of their professional identity. The findings indicate a contracting, if not moribund, profession; a decrease in the value attached to mental health nursing; and a pattern of persistent underfunding by successive governments of mental health services. An analysis of present and historical trends reveals there is a pressing need for a restructure and re-formation of mental health nursing in rural areas. This article links the shortage of mental health nurses in NSW to the closure of the mental health nursing register, a shift to comprehensive/generalist nurse education models, a perceived lack of nurses' professional standing, and natural attrition without suitably qualified replacements. Mental health nurses in this study perceived that they were not valued by other health professionals or by their own managers. Participants in this study reported mental health nursing in rural areas was an unattractive career choice. These findings are important to the understanding of recruitment and retention issues in rural mental health nursing in Australia.

Decreased expression of GRAF1/OPHN-1-L in the X-linked alpha thalassemia mental retardation syndrome.

BACKGROUND: ATRX is a severe X-linked disorder characterized by mental retardation, facial dysmorphism, urogenital abnormalities and alpha-thalassemia. The disease is caused by mutations in ATRX gene, which encodes a protein belonging to the SWI/SNF DNA helicase family, a group of proteins involved in the regulation of gene transcription at the chromatin level. In order to identify specific genes involved in the pathogenesis of the disease, we compared, by cDNA microarray, the expression levels of approximately 8500 transcripts between ATRX and normal males of comparable age. METHODS: cDNA microarray was performed using total RNA from peripheral blood mononuclear cells of ATRX and normal males. Microarray results were validated by quantitative real-time polymerase chain reaction. RESULTS: cDNA microarray analysis showed that 35 genes had a lower expression (30-35% of controls) while 25 transcripts had a two-fold higher expression in comparison to controls. In the microarray results the probe for oligophrenin-1, a gene known for its involvement in mental retardation, showed a decreased hybridization signal. However, such gene was poorly expressed in blood mononuclear cells and its decrease was not confirmed in the quantitative real-time RT-PCR assay. On the other hand, the expression of an homologous gene, the GTPase regulator associated with the focal adhesion kinase 1/Oligophrenin-1-like (GRAF1/OPHN-1-L), was relatively high in blood mononuclear cells and significantly decreased in ATRX patients. The analysis of the expression pattern of the GRAF1/OPHN-1-L gene in human tissues and organs revealed the predominant brain expression of a novel splicing isoform, called variant-3. CONCLUSIONS: Our data support the hypothesis of a primary role for altered gene expression in ATRX syndrome and suggest that the GRAF1/OPHN-1-L gene might be involved in the pathogenesis of the mental retardation. Moreover a novel alternative splicing transcript of such gene, predominantly expressed in brain tissues, was identified.

Screening of subtelomeric rearrangements in autistic disorder: identification of a partial trisomy of 13q34 in a patient bearing a 13q;21p translocation.

Within the framework of a FISH screening protocol to detect cryptic subtelomeric rearrangements in autistic disorder (AD), a patient bearing three copies of the subtelomeric portion of the q arm of chromosome 13 has been identified. Beside AD, the patient also has severe mental retardation and displays several dysmorphic features. Further FISH analyses revealed that the trisomy was caused by the translocation of a 13q subtelomeric fragment to the acrocentric tip of one chromosome 21 [46,XY.ish der(21) t(13;21) (q34;p13)(D13S1825+)]. Gene dosage experiments carried out with three multiallelic polymorphisms of the subtelomeric region of chromosome 13q showed that the putative length of the triplicate region does not exceed 300 kb about, that is, the distance from telomere to the first normally inherited marker. In addition, gene dosage analysis performed on the derivative chromosome 21, did not reveal loss of the most telomeric protein-encoding genes on 21p. The potential relationship between a postulated increased expression of genes on 13q34 and the complex phenotype in this trisomic patient is discussed.

Asymptomatic and mild beta-thalassemia in homozygotes and compound heterozygotes for the IVS2+1G-->A mutation: role of the beta-globin gene haplotype.

BACKGROUND AND OBJECTIVES: We report on two families in which the beta(0)-thalassemia mutation IVS2+1G-->A occurs either in the homozygous or compound heterozygous condition with other beta-thalassemia determinants. In the first family the proband, homozygous for the IVS2+1 determinant, is asymptomatic and was detected by chance during a screening program for beta-thalassemia. In the second family, the proband is a 43-year old female with a very mild thalassemia intermedia due to compound heterozygosity for the IVS2+1G>A and IVS1+110G>A mutations. Her father was diagnosed as having a thalassemic disorder only during the family studies carried out because of the proband's condition. He is a compound heterozygote for the Sicilian type deltabeta(0)-thalassemia and the IVS2+1 mutation and has a normal level of hemoglobin. DESIGN AND METHODS: In both families, the heterozygous carriers of the IVS2+1G>A have unusually elevated levels of fetal hemoglobin (HbF), and the homozygotes showed 98% HbF, reflecting an increased production of well hemoglobinized F-cells not associated with a significant erythroid expansion. RESULTS: The high HbF levels co-segregate with the beta-thalassemia mutation; the size and structure of both pedigrees do not allow the contribution of unlinked genes to the elevated production of HbF to be assessed. INTERPRETATION AND CONCLUSIONS: We propose that the unusual phenotypes resulting from homozygosity and compound heterozygosity for IVS2+1 are, against the background of a polygenic quantitative control of HbF expression, principally due to elements, such as repetitive sequences or single nucleotide polymorphisms, within or closely linked to the beta-gene cluster. These are potentially implicated in chromatin environment modifications, and could, therefore, be responsible for sustained HbF synthesis during development.

Mutational analysis of the ATRX gene by DGGE: a powerful diagnostic approach for the ATRX syndrome.

Molecular defects affecting the ATRX gene lead to the ATRX syndrome (alpha thalassemia/mental retardation syndrome, X-linked), characterized by severe mental retardation, microcephaly, distinct facial dysmorphism, and genital abnormalities, as well as a wide spectrum of other pathological features. Alpha thalassemia is frequent but does not represent a constant characteristic of the syndrome. An expanding phenotype of the ATRX gene (a RAD54 homologue encoding a putative zinc-finger helicase) has been demonstrated as a result of the association of single mutations with specific X-linked mental retardation syndromes. To date, mutational analysis of the gene has been based on direct DNA sequencing or using methods with a lower detection rate. In this paper, we present a broad-range DGGE method for single-step mutation scanning of the entire open reading frame (ORF) and canonical splice sites of the gene. Using this method, we successfully identified five novel sequence changes in the ATRX gene, including four missense mutations (K1733E, R2085C, D2136N, T2169A) and one polymorphism (IVS5+35G>A).

Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation.

The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)-gene clusters are located close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms in the evolution and pathology of the human genome.