Isolated paracetamol-induced acute kidney injury: a systematic review.

AIM: We sought to characterise the syndrome of isolated paracetamol-induced acute kidney injury (AKI), whose incidence and mechanisms are poorly understood. METHODS: Using systematic review methodology, fifty-six papers relating to paracetamol-induced AKI were identified. RESULTS: 24 cases of isolated paracetamol-induced AKI were identified and compared to 87 identified cases of concurrent renal and hepatic injury. Paracetamol-induced AKI became detectable 3-4 days after exposure; liver injury, where it occurred, preceded AKI detection by 1 day. Risk factors affecting hepatotoxicity risk do not appear to influence isolated AKI, with no clear associated factors except younger age (mean 18.8 versus 33.1 years). CONCLUSIONS: Isolated paracetamol-induced AKI appears commoner in younger patients. Paracetamol-induced AKI occurs late and may go undetected by current treatment guidelines.

A novel accelerometer-based method to describe day-to-day exposure to potentially osteogenic vertical impacts in older adults: findings from a multi-cohort study.

This observational study assessed vertical impacts experienced in older adults as part of their day-to-day physical activity using accelerometry and questionnaire data. Population-based older adults experienced very limited high-impact activity. The accelerometry method utilised appeared to be valid based on comparisons between different cohorts and with self-reported activity. INTRODUCTION: We aimed to validate a novel method for evaluating day-to-day higher impact weight-bearing physical activity (PA) in older adults, thought to be important in protecting against osteoporosis, by comparing results between four cohorts varying in age and activity levels, and with self-reported PA levels. METHODS: Participants were from three population-based cohorts, MRC National Survey of Health and Development (NSHD), Hertfordshire Cohort Study (HCS) and Cohort for Skeletal Health in Bristol and Avon (COSHIBA), and the Master Athlete Cohort (MAC). Y-axis peaks (reflecting the vertical when an individual is upright) from a triaxial accelerometer (sampling frequency 50 Hz, range 0-16 g) worn at the waist for 7 days were classified as low (0.5-1.0 g), medium (1.0-1.5 g) or higher (≥1.5 g) impacts. RESULTS: There were a median of 90, 41 and 39 higher impacts/week in NSHD (age 69.5), COSHIBA (age 76.8) and HCS (age 78.5) participants, respectively (total n = 1512). In contrast, MAC participants (age 68.5) had a median of 14,322 higher impacts/week. In the three population cohorts combined, based on comparison of beta coefficients, moderate-high-impact activities as assessed by PA questionnaire were suggestive of stronger association with higher impacts from accelerometers (0.25 [0.17, 0.34]), compared with medium (0.18 [0.09, 0.27]) and low impacts (0.13 [0.07,0.19]) (beta coefficient, with 95 % CI). Likewise in MAC, reported moderate-high-impact activities showed a stronger association with higher impacts (0.26 [0.14, 0.37]), compared with medium (0.14 [0.05, 0.22]) and low impacts (0.03 [-0.02, 0.08]). CONCLUSIONS: Our new accelerometer method appears to provide valid measures of higher vertical impacts in older adults. Results obtained from the three population-based cohorts indicate that older adults generally experience very limited higher impact weight-bearing PA.

Circulating levels of dickkopf-1, osteoprotegerin and sclerostin are higher in old compared with young men and women and positively associated with whole-body bone mineral density in older adults.

Bone mineral density declines with increasing older age. We examined the levels of circulating factors known to regulate bone metabolism in healthy young and older adults. The circulating levels of dickkopf-1, osteocalcin, osteoprotegerin and sclerostin were positively associated with whole-body bone mineral density (WBMD) in older adults, despite the average WBMD being lower and circulating dickkopf-1, osteoprotegerin and sclerostin being higher in old than young. INTRODUCTION: This study aims to investigate the relationship between whole-body bone mineral density (WBMD) and levels of circulating factors with known roles in bone remodelling during 'healthy' ageing. METHODS: WBMD and fasting plasma concentrations of dickkopf-1, fibroblast growth factor-23, osteocalcin, osteoprotegerin, osteopontin and sclerostin were measured in 272 older subjects (69 to 81 years; 52% female) and 171 younger subjects (18-30 years; 53% female). RESULTS: WBMD was lower in old than young. Circulating osteocalcin was lower in old compared with young, while dickkopf-1, osteoprotegerin and sclerostin were higher in old compared with young. These circulating factors were each positively associated with WBMD in the older adults and the relationships remained after adjustment for covariates (r values ranging from 0.174 to 0.254, all p < 0.01). In multivariate regression, the body mass index, circulating sclerostin and whole-body lean mass together accounted for 13.8% of the variation with WBMD in the older adults. In young adults, dickkopf-1 and body mass index together accounted for 7.7% of variation in WBMD. CONCLUSION: Circulating levels of dickkopf-1, osteocalcin, osteoprotegerin and sclerostin are positively associated with WBMD in community-dwelling older adults, despite the average WBMD being lower and circulating dickkopf-1, osteoprotegerin and sclerostin being higher in old than young.

Dose-response relationships in aluminium toxicity in humans.

INTRODUCTION: Aluminium exposure is associated with bone disease (an elevated bone content of aluminium and reduced bone formation on bone biopsy) and neurotoxicity (features of altered brain functions and/or typical spike and slow wave waveforms on electroencephalogram) in patients with elevated blood aluminium concentrations. OBJECTIVES: To critically analyse the literature to determine the dose-toxicity relationships between aluminium exposure and related bone disease and aluminium neurotoxicity. METHODS: A systematic review of the literature with collation and analysis of individual data of human cases of aluminium exposure was conducted between 1 January 1966 and 30 December 2020. Embase, MEDLINE (OVID MEDLINE), PubMed and TOXNET were searched with the following strategies: "Aluminium AND toxicity OR aluminium AND poisoning OR aluminium AND dialysis OR aluminium AND chronic renal failure OR aluminium AND intravenous" limited to "(human)". Inclusion criteria required individual data relating to aluminium exposure in humans. Papers in which features of aluminium toxicity and analytical confirmation of aluminium exposure could not be determined in individual patients were excluded. RESULTS: Thirty-seven papers were identified, which included data on 179 individuals exposed to aluminium. The sources of aluminium exposure (median duration of exposure) were: dialysis fluid (48 months) in 110 cases; oral aluminium hydroxide (20 months) in 20 cases; plasma exchange (2 months) in 16 cases; infant formula feed (minimal duration of 2 weeks) in 14 cases; intravesical exposures (2 days) in 13 oncology patients and potable water exposure in six cases. EXPOSURE TO DIALYSIS FLUID: Of the 110 patients exposed to dialysis fluid, 99 were adults and 11 children, who were analysed separated. Of the adults, 50 with aluminium neurotoxicity had a median aluminium concentration of 467 µg/L (IQR 230 - 752), 28 with aluminium bone disease had a median aluminium concentration of 142 µg/L (IQR 46-309) and 21 with asymptomatic aluminium overload had a median aluminium concentration of 35 µg/L (IQR 26-51). Median aluminium concentrations were significantly greater in patients with aluminium neurotoxicity compared to those with aluminium bone disease (p < 0.0001) or asymptomatic aluminium overload (p < 0.0001). ORAL ALUMINIUM HYDROXIDE: Of the 20 cases, 11 were adults and nine were children. Of the 11 adults, eight with aluminium neurotoxicity had a median aluminium concentration of 682 µg/L (IQR 438-770) and three with aluminium bone disease had a median aluminium concentration of 100 µg/L (IQR 62-138) (p = 0.007). Of the nine children, five had aluminium neurotoxicity with a median aluminium concentration of 335 µg/L (IQR 229-601), one had aluminium bone disease and an aluminium concentration of 1030 µg/L and three had asymptomatic aluminium overload with a median aluminium concentration 98 µg/L (IQR 65-365). PLASMA EXCHANGE: Three patients with stage 5 chronic kidney disease developed aluminium bone disease during plasma exchange; their median blood or serum aluminium concentration was 73 µg/L (IQR 59-81). Asymptomatic aluminium overload was reported in six patients receiving outpatient plasma exchange who had a median creatinine clearance of 71 mL/min (IQR 40-106) and a median aluminium concentration of 49 µg/L (IQR 34-116), and in seven intensive care patients with acute kidney injury whose median aluminium concentration was 30 µg/L (IQR 17-35); (p = 0.02). INTRAVESICAL EXPOSURES: All 13 intravesical exposures developed aluminium neurotoxicity and had a median aluminium concentration of 157 µg/L (IQR 45-276). POTABLE WATER: All six patients developed aluminium bone disease and their median blood aluminium concentration was 17 µg/L (IQR 13-100). CONCLUSIONS: Toxic aluminium exposure can result in neurotoxicity and bone disease, especially in patients with chronic kidney disease. Adults with stage 5 chronic kidney disease chronically exposed to aluminium developed aluminium neurotoxicity at higher concentrations than those with aluminium bone disease or with asymptomatic aluminium overload. Aluminium neurotoxicity was reported at lower concentrations following acute exposure to intravesical aluminium. Extrapolating the relevance of these concentrations to the general population is problematic in that the data were derived from oncology patients, however, the possibility that aluminium neurotoxicity may occur at concentrations lower that those reported historically in patients with stage 5 chronic kidney disease cannot be excluded.

Civilian exposure to chlorine gas: A systematic review.

INTRODUCTION: Halogen pulmonary irritants (HPIs) are volatile liquids that directly damage the respiratory mucosa. Chlorine is readily available in large volumes as an industrial chemical and has a significant potential for accidental or deliberate release. We conducted a systematic review to determine the clinical features; treatment and long-term sequelae of civilian chlorine gas exposure. METHODS: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. Medline; Ovid and Google Scholar databases were searched from 1966 to January 2017. A database of relevant papers was compiled and descriptive statistics used to summarise the data. RESULTS: Thirty-six papers describing 37 incidents involving 1566 individual acute exposers to chlorine gas were identified. The most common reported features were cough (29%), dyspnoea (22%), sore throat (16%), eye features (12%) and excessive sputum or haemoptysis (7%). Acute management included high-flow oxygen (32.8%); steroids (28.4%); bronchodilators (28.2%) and ventilation (2.3%). Nine deaths (0.6%) were reported. Follow-up data available in 60% of cases; full recovery was reported in 90% of cases where data was available. DISCUSSION: Acute chlorine gas exposure in civilian incidents presented with acute respiratory features and irritation of the eyes and throat. The development of pulmonary oedema or ARDS was relatively rare when compared to military experience in the First World War.

Altered Nuclear Expression of the Deubiquitylase BAP1 Cannot be Used as a Prognostic Marker for Canine Melanoma.

BRCA1-associated protein-1 (BAP1) is a nuclear localized deubiquitylating enzyme that belongs to the ubiquitin c-terminal hydrolase subfamily. The encoded protein is highly homologous between man and dogs, suggesting a functional significance preserved by evolution. BAP1 has multiple properties, including tumour suppressor activity. Loss of BAP1 function is implicated in the oncogenesis of several types of cancers including uveal, mucosal and some cutaneous melanomas in humans, as well as in mesothelioma. In this study we investigate the significance of BAP1 in canine melanoma. Nuclear BAP1 protein was detected in five canine oral melanoma cell lines using an antibody commonly used for analysis of human tissues. BAP1 loss of function mutations often lead to loss of nuclear BAP1 (nBAP1) expression in humans; this is associated with a poorer prognosis in uveal and mucosal melanoma. Therefore, as a prelude to a study evaluating the prognostic significance of nBAP1 expression in dogs, immunohistochemistry (IHC) was used to assess cases of canine melanoma for nBAP1 expression. In 89 cases where tumour cells were identified by melan-A labelling, 100% of tumour cells were positive for nBAP1 expression, including eight uveal tract and 29 oral mucosal melanomas. This finding indicates that BAP1 IHC cannot be used as a prognostic marker in canine uveal and mucosal melanoma. Moreover, this observation suggests that either BAP1 has a different functional significance in canine melanoma or that loss of BAP1 function is achieved by a different route. This is a novel finding that warrants further investigation to determine the comparative biological relevance.

A splice variant of the neuron-restrictive silencer factor repressor is expressed in small cell lung cancer: a potential role in derepression of neuroendocrine genes and a useful clinical marker.

The neuron-restrictive silencer factor [NRSF (RE-1 silencing transcription factor/X box repressor)] is a transcriptional silencer, which we have previously implicated in deregulation of the vasopressin promoter in small cell lung cancer (SCLC). Here we describe a novel splice variant of the NRSF transcript, which is highly expressed in SCLCs. The variant was detected in both established cell lines and primary SCLC cultures as well as in some primitive neuroectodermal tumor biopsies. It was present at very low levels in human brain tissue, non-SCLC tumors, and normal bronchial epithelium. This human splice variant, which is massively overexpressed in SCLCs, incorporates a 50-bp insert between exons 5 and 6, introducing a stop codon and predicting translation of a truncated NRSF isoform. We propose that the encoded isoform may antagonize repression of the vasopressin promoter and other "neuronal" genes with neuron-restrictive silencer elements in SCLCs. Thus, up-regulated expression of this NRSF isoform may be a key early factor in defining the neuroendocrine phenotype of these tumors. The NRSF splice variant represents a specific clinical marker that could prove useful in detection of the majority of SCLCs.

Arginine vasopressin promoter regulation is mediated by a neuron-restrictive silencer element in small cell lung cancer.

Arginine vasopressin (AVP) is often expressed in small cell lung cancer (SCLC), and a 65-bp AVP minimal promoter fragment is sufficient to restrict activity to SCLC in vitro. We now describe a motif with homology to the neuron-restrictive silencer element (NRSE) within this fragment. Electrophoretic mobility shift analysis demonstrated that multiple specific complexes are bound by this motif. These complexes are cross-competed with a characterized SCG10 NRSE probe and do not bind to the AVP probe with a specific mutation in the NRSE. The complexes vary in mobility between lung tumor cell lines, showing different levels of AVP expression, and some are differentially bound in SCLC. Overexpression of a neuron-restrictive silencer factor expression construct can silence reporter gene expression supported by the AVP promoter in SCLC, although this was dependent on both the level of endogenous AVP expression in the cells and putative enhancer elements in larger promoter constructs. Activation of the proximal AVP promoter in SCLC is therefore proposed to, at least partially, rely on modulation of normal repressor activity at the NRSE.

The relationship between blood pressure variability and catecholamine metabolites: a pilot study.

Ambulatory blood pressure variability (ABPV) is a predictor of cardiovascular risk in hypertensives. Factors that contribute to ABPV are not well described. This pilot study aimed to investigate the relationship between ABPV and urine catecholamine metabolites in order to rationalise further therapeutic intervention in the management of hypertension. Twenty individuals (14 female), aged from 23 to 71 years, with primary hypertension were identified from referrals to a regional hypertension clinic. Individuals had a 24-h ambulatory blood pressure recording (Del Mar Reynolds), and a 24-h urine collection was analysed for metadrenaline and normetadrenaline by reverse-phase chromatography (Spherisorb ODS2) and electrochemical detection (Coulochem II). Normetadrenaline concentration correlated with systolic blood pressure (SBP) variability, r=0.493, P=0.02, and with SBP coefficient of variability, r=0.490, P=0.02. Metadrenaline concentration did not correlate with either SBP variability, r=0.177, P=0.43, or coefficient of variability, r=0.185, P=0.42. A correlation was observed between 24 h urinary normetadrenaline and measures of SBP variability but not 24 h urinary metadrenaline and blood pressure variability. It is hypothesised that sympathetic activity may influence SBP variability.

Correlation between baseline blood pressure and the brainstem FMRI response to isometric forearm contraction in human volunteers: a pilot study.

It has been shown previously that changes in brainstem neural activity correlate with changes in both mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA) during static handgrip (SHG). However, the relationship between baseline MAP and brainstem neural activity is unclear. We investigated changes in blood oxygen level-dependent (BOLD) signal induced by SHG in 12 young adults using BOLD functional magnetic resonance imaging (FMRI). An estimation of the blood pressure response to SHG was obtained in seven subjects during a session outside the MRI scanner and was used to model the blood pressure response to SHG inside the scanner. SHG at 40% of maximum grip increased MAP (mean ± s.d.) at the end of the 180-s squeeze from 85 ± 6 mm Hg to 108 ± 15 mm Hg, P = 0.0001. The brainstem BOLD signal change associated with SHG was localised to the ventrolateral medulla. This regional BOLD signal change negatively correlated with baseline MAP, r = -0.61, P = 0.01. This relationship between baseline MAP and brainstem FMRI responses to forearm contraction is suggestive of a possible role for brainstem activity in the control of MAP and may provide mechanistic insights into neurogenic hypertension.

Right subscapular artery catheterization for balloon valvuloplasty of critical aortic stenosis in infants.

This study was performed to evaluate the utility and safety of catheterizing the right subscapular artery for balloon valvuloplasty of critical aortic stenosis in infants. Twenty-one patients, age 20 days to 17 months, underwent attempted valvuloplasty through the surgically exposed right subscapular artery. Five or 7Fr catheters with balloon diameters of 7 to 10 mm were used. Valvuloplasty was successfully performed using this approach in 11 patients. In 2 other patients, the subscapular artery would not accommodate the balloon angioplasty catheter (7Fr), and the arteriotomy was extended into the axillary artery. In these 13 patients, the peak systolic pressure gradient across the aortic valve was decreased from 85 +/- 23 to 33 +/- 7 mm Hg. Moderate aortic regurgitation developed in 3 patients. In the remaining 8 patients, valvuloplasty could not be performed through the right subscapular artery. In 2 patients, the right subclavian artery was anomalous and led to the descending aorta. In 6 small patients, no catheter could be advanced across the aortic valve. In 1 of these patients, a guidewire perforated a coronary sinus of Valsalva causing death. Overall, valvuloplasty using the right subscapular arterial approach was successful in 13 of 19 infants (68%) with normal right subclavian arteries, including all 10 such patients weighing > or = 5.5 kg. No clinically significant peripheral vascular complications or brachial plexus injuries occurred. Thus, the right subscapular arterial approach is an alternative route to be considered when planning balloon aortic valvuloplasty in infants.

Use of RT-PCR to detect co-expression of neuropeptides and their receptors in lung cancer.

Small-cell lung cancer (SCLC) synthesises a wide range of neuropeptides and their corresponding receptors. Together, these can form autocrine growth loops. Non-small-cell lung cancer (NSCLC) does not generally share this neuroendocrine phenotype. In this study, we tested the hypothesis that multiple neuropeptides and their receptors are co-expressed in SCLC, constituting potential autocrine loops. Expression of mRNA for arginine vasopressin, gastrin, cholecystokinin, gastrin-releasing peptide, endothelin and neurotensin, together with their cognate receptors, was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) in a panel of human lung cancer cell lines. We have assessed those neuropeptides and neuropeptide receptors that could be used as potential early markers to detect lung cancer cells both as micrometastases in blood and within dysplasia in bronchial biopsies. We establish that although no cell line expressed all neuropeptides, co-expression of neuropeptides and their receptors is common in SCLC but not in NSCLC. We conclude that mRNA for the neuropeptides gastrin-releasing peptide and arginine vasopressin and the cholecystokinin receptor B were most SCLC-specific and RT-PCR for these markers could be used to distinguish between SCLC and NSCLC.

Neuron restrictive silencer factor as a modulator of neuropeptide gene expression.

We hypothesize that the transcription factor neuron restrictive silencer factor (NRSF) is an important determinant of the expression of the preprotachykinin (PPTA) gene (encoding substance P and Neurokinin A) and arginine vasopressin (AVP) both in neuronal and nonneuronal cells. NRSF, a zinc finger repressor protein, binds the NRSE motif found in many neuronal specific genes at a variety of promoter locations. However, it is found in a similar location at the major transcriptional start site, within both PPTA and AVP peptide promoters. We have correlated modulation of NRSF activity with expression of AVP and PPTA in a variety of cell types, indicating the general mechanism by which this protein may regulate expression. Specifically, they are as follows:(1). Expression of NRSF dramatically represses PPTA promoter activity in reporter gene constructs in primary cultures of DRG neurons.(2). The PPTA promoter activity is regulated differentially in osteoarthritic compared to normal chondrocytes. This regulation correlates with the region containing the NRSE site.(3). We have correlated a splice variant of NRSF with the establishment and progression of small cell lung carcinoma (SCLC) and demonstrated that NRSF variants can directly affect the activity of the AVP promoter in reporter gene constructs. If the deregulated expression of peptides in these diseases point to the mechanism determining the pathology, then perhaps targeting protocols that correct this deregulation may also reverse the specific disease phenotypes. Our data would indicate that modulation of NRSF activity would be a target for such intervention.

Overexpression of cyclooxygenase-2 in non-small cell lung cancer.

Evidence is accumulating to suggest that the inducible isoenzyme of cyclooxygenase (COX)-2 is up-regulated in human cancers and epidemiological studies indicate that COX inhibitors may have a protective effect on the development of lung cancer. We used immunohistochemistry and Western blotting to investigate COX expression in lung tumour specimens and three lung cancer cell lines. Sixty-five archival lung tissue samples, including 46 squamous cell and 6 adenocarcinoma lung resections, and 13 small cell lung cancer (SCLC) biopsies were studied. Dense and intense cytoplasmic COX-2 staining was found in all 52 resections from non-small cell lung cancer (NSCLC). The staining was diffuse and much stronger than adjacent respiratory epithelium. COX-2 staining was relatively weak in the majority of the SCLC samples. The bronchial and bronchiolar epithelium in the surrounding normal lung structures showed uniform COX immunoreactivity with apical concentration of the stain. There was no increase in COX-1 staining in any tumour type. Western blot analysis of the cancer lines revealed significantly higher expression of COX-1 in CORL23 line and COX-2 in two NSCLC cell lines (MOR/P; A549) compared with the expression of COX-1 and COX-2 in cultured normal bronchial epithelial cells. Our findings demonstrated COX-2 overexpression in NSCLC.

Neonatal mitral valve endocarditis: diagnosis and successful management.

Although still considered to be a rare and mostly fatal illness, the reported incidence of neonatal bacterial endocarditis has increased during the past decade. This parallels the establishment of intensive supportive management of severely ill newborns with multiple medical problems. An extremely difficult diagnostic problem with protean manifestations, the presence of neonatal endocarditis should be vigorously sought in the at risk neonate. The authors report the first known case in America of successfully diagnosed and treated neonatal endocarditis involving the mitral valve.

Guidelines for Introducing Beneficial Insect-parasitic Nematodes into the United States.

Guidelines are suggested to implement the introduction of beneficial insect-parasitic nematodes into the United States from abroad. These suggestions result from experiences and research with these and other biological control agents and from the current need for procedures to import nematodes. Subjects considered are need to import, foreign exploration, taxonomy, shipment, quarantine facilities, permits, host range tests, release, and documentation. Nematodes covered under these suggested guidelines include entomopathogenic species of mermithids, sphaerulariids, aphelenchids, steinernematids, and heterorhabditids. Host specificity and safety tests are discussed. Concern over the possible concomitant introduction of plant-parasitic nematodes, insects, or other pests is expressed. Current information on the treatment of insect-parasitic nematodes by the Environmental Protection Agency and USDA's Animal and Plant Health Inspection Service is presented. These suggested guidelines are presented to stimulate the development of workable protocols for safe introduction of beneficial insect-parasitic nematodes into the United States from aboard.

The deubiquitylase Ataxin-3 restricts PTEN transcription in lung cancer cells.

The phosphatidylinositol-3-kinase (PI3K) pathway is commonly hyperactivated in cancer. One mechanism by which this occurs is by silencing of the phosphatase and tensin homolog (PTEN), a tumor suppressor and major antagonist of the pathway, through genetic, epigenetic or posttranscriptional mechanisms. Here, we used an unbiased siRNA screen in non-small-cell lung cancer cells to identify deubiquitylases (DUBs) that have an impact on PI3K signaling by regulating the abundance of PTEN. We found that PTEN expression was induced by depleting any of three members of the Josephin family DUBs: ataxin 3 (ATXN3), ataxin 3-like (ATXN3L) and Josephin domain containing 1 (JOSD1). However, this effect is not mediated through altered PTEN protein stability. Instead, depletion of each DUB increases expression of both the PTEN transcript and its competing endogenous RNA, PTENP1. In ATXN3-depleted cells, under conditions of transcriptional inhibition, PTEN and PTENP1 mRNAs rapidly decay, suggesting that ATXN3 acts primarily by repressing their transcription. Importantly, the PTEN induction observed in response to ATXN3 siRNA is sufficient to downregulate Akt phosphorylation and hence PI3K signaling. Histone deacetylase inhibitors (HDACi) have been suggested as potential mediators of PTEN transcriptional reactivation in non-small-cell lung cancer. Although PTEN exhibits a very limited response to the broad-spectrum HDACi Vorinostat (SAHA) in A549 cells, we find that combination with ATXN3 depletion enhances PTEN induction in an additive manner. Similarly, these interventions additively decrease cell viability. Thus, ATXN3 provides an autonomous, complementary therapeutic target in cancers with epigenetic downregulation of PTEN.

Health-care utilization and respiratory morbidities in preterm infants with pulmonary hypertension.

OBJECTIVE: To assess health-care utilization and risk of respiratory morbidities in preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). STUDY DESIGN: Retrospective data were obtained from subjects (n=109) attending a BPD clinic. Subjects were stratified by the presence or absence of PH before and after 2 months of age. Analytic methods included t-tests, χ(2) tests and regression. RESULT: Subjects with BPD and PH present after 2 months of age were hospitalized for 2.2 months longer than those without PH (P=0.02). These subjects were 4.5 times more likely to receive home supplemental oxygen or mechanical ventilation (P=0.03). No difference in the risk of respiratory morbidities after initial hospital discharge was seen with PH. CONCLUSION: PH in preterm infants is associated with longer initial hospitalizations and a higher likelihood of requiring home respiratory support. This has implications for counseling families and reducing the medical, psychosocial, and economic burden of BPD and PH.