Partial correction of sensitivity to oxidant stress in Friedreich ataxia patient fibroblasts by frataxin-encoding adeno-associated virus and lentivirus vectors

Peripheral nervous system (PNS) sensory neurons are directly involved in the pathophysiology of a number of debilitating inherited and acquired neurological conditions. The lack of effective treatments for many such conditions provides a strong rationale for exploring novel therapeutic approaches, including gene therapy. Friedreich ataxia (FRDA), a sensory neuropathy, is a progressive neurodegenerative disease associated with a loss of large sensory neurons from the dorsal root ganglia. Because a mouse model for this well-characterized disease has been generated, we elected to use FRDA as a model disease. In previous studies we achieved efficient and sustained delivery of a reporter gene to PNS sensory neurons, using recombinant adeno-associated viral (AAV) and lentiviral (LV) vectors. In the current study, AAV and LV vectors encoding the human frataxin cDNA were constructed and assessed for frataxin expression and function in primary FRDA patient fibroblast cell lines. FRDA fibroblasts have been shown to exhibit subtle biochemical changes, including increased mitochondrial iron and sensitivity to oxidant stress. Despite the inherent difficulty in working with primary cells, transduction of patient fibroblasts with either vector resulted in the expression of appropriately localized frataxin and partial reversal of phenotype.     

Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy: a meta-analysis

Investigations into the association between diabetic nephropathy (DN) and MTHFR C677T gene polymorphism in several case–control studies has yielded contradictory results. To shed light on these inconclusive findings, a meta-analysis of all available studies relating the C677T polymorphism to the risk of developing DN was conducted. The PubMed database was searched, and case–control studies investigating the association between MTHFR C677T gene polymorphism and DN were included in the meta-analysis. The meta-analysis included 15 studies, of which 8 involved Caucasians and 5 East Asians; 11 studies involved subjects with type 2 diabetes and 4 with type 1 diabetes. The main analysis (all studies) revealed significant heterogeneity between the studies (P _Q < 0.01) and a marginal association between the 677T allele and the risk of developing DN; the random effects (RE) pooled odds ratio (OR) was 1.30 (1.03–1.64). However, the sensitivity analysis (exclusion of studies not in Hardy–Weinberg equilibrium) produced non-significant results. The recessive model derived significant results in main analysis [fixed effects (FE) OR = 1.32 (1.10–1.58), P _Q = 0.27], and in type 2 diabetes [FE OR = 1.30 (1.06–1.60), P _Q = 0.38]. The additive model produced significant association in main analysis [RE OR = 1.65 (1.13–2.42), P _Q < 0.01] in Caucasians [FE OR = 1.48 (1.11–1.98), P _Q = 0.17] and in type 2 diabetes [RE OR = 1.65 (1.03–2.67), P _Q < 0.01]. However, sensitivity analysis diminished the significant results in type 2 diabetes. There is no differential magnitude of effect in large versus small studies. In conclusion, although there is some evidence of association between MTHFR C677T gene polymorphism and DN, the above findings reinforce the need for further and more rigorous association studies.     

Physical activity and mental well-being in older people participating in the Better Ageing Project

Increasing evidence suggests that physical activity can prevent some aspects of mental illness in older people such as depression, dementia and Alzheimer's disease. Additionally, limited research has shown that engagement in structured exercise can improve aspects of psychological well-being such as mood and self-perceptions in older adults. However, the relationship between incidental daily activity such as walking or time spent sedentary, with psychological well-being has not been investigated. The Better Ageing Project provided an opportunity to assess well-being and quality of life using standardised questionnaires with 176 adults aged 70 and over. Accelerometry was used to objectively assess daily energy expended in physical activity at different levels of intensity. In addition, an assessment of the impact of the 12-month Better Ageing structured group exercise programme was assessed through questionnaires and interviews. Total daily physical activity energy expenditure (joules/day) and amount of time spent in activity of at least moderate intensity were weakly related (r = 0.20-0.28) to quality of life, subjective well-being and physical self-perceptions. Time spent sedentary (min/day) was weakly and negatively related to several mental health indicators. The quantitative data showed only minor psychological benefits of the exercise intervention. In contrast, interviews with 27 research participants and 4 exercise leaders suggested that important improvements in perceived function and social benefits had been experienced.     

Can knowledge be promoted and values ignored? Implications for nursing education

This paper aims to reflect upon the educational task of the university, to consider whether knowledge can be promoted and values ignored, and thus to explore the implications for nursing education. The university is the cradle which nurtures intellectuals, professionals and scientists as whole human beings. Paced by the spirit and the ideals of paideia, it cannot be limited merely to developing the student's mind. It should also inspire the student with a belief in the higher values of life, as a compass in his profession. (Paideia is an ancient Greek conception of the ideal human education. It includes modern notions such as civilization, culture, tradition, literature, philosophy and education. It means formation of the human being of any age, as an independent, free and virtuous whole person.) Values, when transmitted by all teachers of all subjects within the educational structures of the university, can increase the student's respect for truth, for the worth and the rights of other persons, his appreciation of his own worth, assets and limitations, his love of wisdom and desire to serve humanity, his outlook about man's position in the world and his inquiring mind in order to discover higher perspectives of life. Only in this way does university become a worthy centre of paideia for educating nurses committed and aspiring to provide holistic, personalized, quality nursing care to people, as well as to determine and shape the future of nursing education in the midst of our technological, computerized, and some would say dehumanized era, propelling itself into the twenty-first century.     

In situ assessment of PI3K and PTEN alterations in mycosis fungoides: correlation with clinicopathological features

Deregulated signalling through phosphatidylinositol 3‐kinase (PI3K) pathway plays a critical role in tumour initiation and progression. We have already shown that AKT is activated in skin lesions in Mycosis Fungoides (MF) and we herein further investigate the frequency and clinical significance of PTEN and PI3K at the protein and at the DNA level as well as the presence of AKT1 mutations in skin lesions from 50 patients with MF clinical stages I‐IV in relation to clinicopathological features. Increased p‐AKT expression correlated with poor prognosis in plaques (P = 0.0198), whereas p‐AKT was an independent predictor of poor survival in the entire cohort (P = 0.017, HR = 1.012). PTEN cytoplasmic expression was found low or absent in all 77.3% of cases and inversely correlated with advanced clinical stages (P = 0.0744). Molecular analysis showed no AKT1 mutation, no PI3KCA copy number gain, only 1 case with PI3KCA mutation in exon 9 and 3 cases with PTEN mutations (7%) in exons 7, 8 and 5. The latter correlated with disease (P = 0.0253) and progression (P < 0.0001) free survival in tumour stage. Although activation of PI3K/AKT signalling pathway due to PTEN alterations is rarely attributed to abnormalities in PTEN, PI3K, and AKT1 genes, PTEN mutations exert a negative effect on patients’ prognosis with tumours.     

Arterial Stiffness Is Inversely Related to Plasma Adiponectin Levels in Young Normotensive Patients With Type 1 Diabetes

OBJECTIVE

This study investigated the association between arterial stiffness and plasma adiponectin in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Participants were normotensive patients with type 1 diabetes who were up to age 40 years. Subjects on statins with macrovascular disease or overt nephropathy were excluded. Large artery stiffness was assessed by measurement of carotid-femoral pulse wave velocity (PWV), whereas plasma adiponectin was measured by radioimmunoassay.

RESULTS

Data from 80 patients (age 27.1 ± 6.1 years, BMI 24.2 ± 3.1 kg/m², HbA_1c 7.5 ± 1.6%, 39 men, adiponectin 13.9 ± 6.7 μg/mL, and PWV 5.6 ± 0.9 m/s) were analyzed. Log adiponectin inversely correlated with age-adjusted PWV (r = −0.291, P = 0.009) and waist circumference (r = −0.427, P < 0.001). In a fully adjusted model, age, expiration/inspiration index, and log adiponectin were independently associated with PWV, explaining 39.6% of its variance.

CONCLUSIONS

Arterial stiffness is inversely related to adiponectin concentration in young patients with type 1 diabetes without major complications.Arterial stiffness, an independent predictor of total and cardiovascular mortality, can be assessed noninvasively by measurement of pulse wave velocity (PWV) (1), which is increased at early stages of type 1 diabetes (2,3). Plasma adiponectin, an adipocytokine with insulin-sensitizing, antiatherogenic, and anti-inflammatory properties (4), is high in patients with type 1 diabetes (5,6). Although adiponectin is inversely related to arterial stiffness in subjects with essential hypertension (7,8), no adiponectin-PWV relationship has been shown in children/adolescents with type 1 diabetes (9). This study investigated the association between adiponectin and PWV in young adults with type 1 diabetes.     

Repeated Episodes of Respiratory Failure Due to Bilateral Vocal Cord Paralysis

Background

Bilateral vocal cord paralysis can produce severe airway obstruction, leading to acute respiratory failure. Discriminating the pathology of the upper airway from chronic obstructive diseases of the lower airways often presents a challenge for clinicians in the Emergency Department.

Objectives

To underlie the value of clinical examination and flow-volume loops in the establishment of diagnosis of upper airway obstruction.

Case Report

We describe the case of a 55-year-old female ex-smoker who presented with a long history of hoarseness and progressive exertional dyspnea. The patient developed repeated episodes of acute respiratory failure and was supported with noninvasive ventilation. The diagnosis of bilateral vocal cord paralysis was finally established by patient’s symptoms and flow-volume loops demonstrating variable extrathoracic obstruction.

Conclusion

Vocal cord paralysis is a rare and often neglected condition, contributing to repeated episodes of acute respiratory failure. Flow-volume loop is a useful tool when symptoms are suggestive of upper airway obstruction.     

Complications of percutaneous stereotactic vacuum assisted breast biopsy system utilizing radio frequency

Objective

The Breast Lesion Excision System (BLES) is a novel, automatic breast biopsy device that utilizes radiofrequency to excise suspicious non-palpable mammographic lesions. The purpose of the present prospective study is to report and evaluate the complications of this new technique.

Materials and methods

In a two year period, we used the BLES device in 132 consecutive patients (134 procedures) with non-palpable mammographic lesions. The inclusion criteria consisted of suspicious microcalcifications, solid lesions and asymmetric density. In order to retrieve an intact biopsy specimen, we used the 12 mm, 15 mm or 20 mm tissue basket under local anesthesia, depending on the size of the lesion. Complications were recorded and classified as immediate if occurring during or shortly after the procedure, or late, if occurring in the post-procedure days.

Results

The procedure was considered successful in all cases, with mammographic confirmation of appropriate excision of the targeted lesion. Although, in a single case the basket initially failed to deploy. Immediate complications were encountered in 11 patients, with minor hemorrhage being the most common (n = 6). 17 patients suffered late complications, in seven of whom delayed wound healing was observed. Overall, 27 patients suffered Grade 1 complications (20.14%), one patient experienced a Grade 2 complication while no patients encountered Grade 3–5 complications.

Conclusions

According to our experience, the BLES device is an efficient and safe breast biopsy method, with low complication rates, which are minor in their majority. It appears to be a very promising alternative to other, minimally invasive, breast biopsy techniques.     

Diagnostic accuracy of the rapid shallow breathing index to predict a successful spontaneous breathing trial outcome in mechanically ventilated patients with chronic obstructive pulmonary disease

Objective

To evaluate the diagnostic accuracy of 2 threshold values (105 breaths per minute [bpm]/L and 130 bpm/L) of the rapid shallow breathing index (RSBI) to predict a successful weaning trial outcome in a homogenous group of patients with chronic obstructive pulmonary disease (COPD).

Methods

A consecutive population of patients with COPD who were intubated for hypercapnic respiratory failure during a 2-year period were studied prospectively. RSBI was measured by 2 investigators at minute 5 of the T-piece trial, whereas 2 other physicians evaluated the 30 minute T-piece trial as successful or unsuccessful, according to clinical criteria.

Results

Of 64 patients with COPD (53 male, 11 female) who constituted the study population, 42 patients (35 male, 7 female; aged 70 ± 9.2 years) completed the spontaneous breathing trial (SBT) and remained clinically stable (group 1). The remaining 22 patients (18 male, 4 female; aged 71.9 ± 4.7 years) had to return to ventilatory support by the end of the SBT because of clinical deterioration (group 2). The 2 threshold values that were evaluated had low specificity (38.1% for < 105 bpm/L and 66.7% for < 130 bpm/L), low sensitivity (63.6% for < 105 bpm/L and 54.5% for < 130 bpm/L), and low diagnostic accuracy (46.8% for < 105 bpm/L and 65.6% for < 130 bpm/L) in predicting a successful T-piece trial outcome.

Conclusion

RSBI measured early during an SBT cannot accurately predict the successful outcome of a T-piece trial in a homogenous population of patients with COPD.