Correction: Equilibrium gels of low-valence DNA nanostars: a colloidal model for strong glass formers

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Metallothioneins as dynamic markers for brain disease in lysosomal disorders

Objective: To facilitate development of novel disease-modifying therapies for lysosomal storage disorder (LSDs) characterized by nervous system involvement such as metachromatic leukodystrophy (MLD), molecular markers for monitoring disease progression and therapeutic response are needed. To this end, we sought to identify blood transcripts associated with the progression of MLD. Methods: Genome-wide expression analysis was performed in primary T lymphocytes of 24 patients with MLD compared to 24 age- and sex-matched healthy controls. Genes associated with MLD were identified, confirmed on a quantitative polymerase chain reaction platform, and replicated in an independent patient cohort. mRNA and protein expression of the prioritized gene family of metallothioneins was evaluated in postmortem patient brains and in mouse models representing 6 other LSDs. Metallothionein expression during disease progression and in response to specific treatment was evaluated in 1 of the tested LSD mouse models. Finally, a set of in vitro studies was planned to dissect the biological functions exerted by this class of molecules. Results: Metallothionein genes were significantly overexpressed in T lymphocytes and brain of patients with MLD and generally marked nervous tissue damage in the LSDs here evaluated. Overexpression of metallothioneins correlated with measures of disease progression in mice and patients, whereas their levels decreased in mice upon therapeutic treatment. In vitro studies indicated that metallothionein expression is regulated in response to oxidative stress and inflammation, which are biochemical hallmarks of lysosomal storage diseases. Interpretation Metallothioneins are potential markers of neurologic disease processes and treatment response in LSDs

Lamin A/C Missense Mutation R216C Pinpoints Overlapping Features Between Brugada Syndrome and Laminopathies

A 31-year-old man experienced at-rest cardiac arrest. After successful resuscitation, the baseline ECG demonstrated sinus rhythm with concave ST segment elevation in right precordial leads (V1–V3) followed by a negative and symmetrical T-wave. Neither coronary artery disease nor electrolytes’ imbalances were detected. In the following days, ECG showed a spontaneous type 1 Brugada ECG pattern (Figure [A1]), more evident with right precordial leads in II and III intercostal spaces. Transthoracic echocardiography (Figure [A2]) failed to show any cardiomyopathy. Cardiac MRI showed normal chambers dimension, wall thickness, volume, and function (left ventricular end diastolic volume, 67.7 mL/m2; IVS, 1 cm; left ventricular end fraction, 59.7%). Late gadolinium enhancement sequences were negative; adipose and fibrous tissue infiltration were excluded. The patient was implanted with a transvenous single chamber cardioverter defibrillator (Medtronic). Several appropriate ICD interventions on VT and ventricular fibrillation were recorded in the following years. Family history (Figure [B]) was positive for sudden cardiac death: the maternal grandfather died at age 45 years, aII degree maternal cousin died during sleep at age 40 years. The proband’s mother showed a first degree atrioventricular block (PR interval=280 ms) and right bundle branch block (Figure [A3]). A neurological examination in the index case and his mother was negative and creatine phosphokinase levels were normal in both. Informed written consent was obtained from all family members. Study was approved by the Local Ethics Committee (152/2013/O/Oss, June 1, 2013). Molecular genetic analysis was performed by next generation sequencing using PED MASTR Plus assay comprising 52 cardiac electrical disorders related genes, SCN5A included (www.agilent.com)

The increased risk of stroke/transient ischemic attack in women with a cardiac implantable electronic device is not associated with a higher atrial fibrillation burden

To evaluate if the increased thromboembolic risk in female patients may be related to a higher burden of atrial fibrillation (AF)

Unpredictability of Intravenous Busulfan Pharmacokinetics in Children Undergoing Hematopoietic Stem Cell Transplantation for Advanced Beta Thalassemia: Limited Toxicity with a Dose-Adjustment Policy

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Effectiveness of Pre-Hospital Tourniquet in Emergency Patients with Major Trauma and Uncontrolled Haemorrhage: A Systematic Review and Meta-Analysis

: Trauma is one of the leading causes of uncontrolled haemorrhage, death, and disability. Use of a tourniquet can be considered an optimal anti-haemorrhagic resource, in pre-hospital and emergency settings, and its lifesaving effect is clinically contradictory. This review aims to assess the clinical efficacy of the tourniquet in the emergency pre-hospital care setting for the management of haemorrhage. We conducted the systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, the PRISMA statement. We searched the following electronic databases: EMBASE, MEDLINE, and Cochrane-CENTRAL. All studies included were appraised for risk of bias. Prevalent primary outcomes were mortality and use of blood products. Secondary outcomes were related to adverse effects. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE). Four studies were involved (1762 trauma patients). The adjusted odds ratio (aOR) of 0.47 (95% confidence Interval (CI) 0.19-1.16; three studies; 377 patients) for overall mortality estimates did not give a clear indication of the benefits of emergency pre-hospital tourniquets (PH-TQ) versus no pre-hospital tourniquet (NO PH-TQ) placement. The adjusted mean difference for blood product use was -3.28 (95% CI -11.22, 4.66) for packed red blood cells (pRBC) and -4.80 (95% CI -5.61, -3.99) for plasma, respectively. The certainty of evidence was downgraded to very low for all outcomes. Our results suggest an unclear effect of emergency pre-hospital tourniquet placement on overall mortality and blood product use. However, this systematic review highlights the availability of only observational studies and the absence of high quality RCTs assessing the efficacy of PH-TQs. Randomized controlled trials are needed

Preoperative bi-fractionated accelerated radiation therapy for combined treatment of locally advanced rectal cancer in a consectutive series of unselected patients

Background: although preoperative RT (Radiation Therapy) is becoming the preferred approach for combined treatment of locally advanced rectal adenocarcinoma, no regimen can be now considered as a standard. Since the toxicity of preoperative RT isn't yet completely known, and the advantages of preoperative RT could be counterbalanced by increased postoperative morbidity and mortality, a monocentre series of preoperative bifractionated accelerated RT was retrospectively reviewed to clarify toxicity and outcomes after a prolonged follow up. Methods: patients were screened following these eligibility criteria: histology-proven adenocarcinoma of the rectum; distal tumour extent at 12 cm or less from the anal verge; clinical stage T3-4/anyN, or anyT/ N1-2; ECOG Performance Status 0-2. A total dose of 41.6 Gy (26 twice daily fractions of 1.6 Gy) was delivered. Surgery was carried out 17 \ub1 2 days after RT completion, adopting the total mesorectal excision technique. Results: 24 men and 23 women were enrolled; median age was 55 years (r.: 39-77). Twenty-eight patients were stage II and 19 stage III. 9 patients suffered from a recurrent tumour. 2 patients experienced a severe grade 4 gastrointestinal toxicity (a colo-vaginal fistula and an intestinal obstruction, both successfully treated). Operative mortality was nil; postoperative early complications occurred in 13 cases; mean length of hospital stay was 15 days. After a mean follow up of 44 months (r.: 18-84) 8 patients had deceased for recurrent disease, 15 were alive with a disease progression (2 pelvic recurrences and 13 pure distant deposits) and 24 were alive, without disease. The 5-year actuarial overall survival was 74.2%, the disease-free survival 62.9% and the regional control rate 84.7%. Long-term complications included 1 case of radiation enteritis requiring surgery, 2 cases of anastomotic stricture and 3 cases of bladder incontinence. Conclusion: bifractionated accelerated RT administered in the preoperative setting to patients bearing locally advanced rectal cancer is reliable and safe, as its immediate and late toxicity (mainly infectious) is acceptably low and long-term survivals are achievable. These findings support the increasing use of preoperative RT for treatment of this malignancy in experienced centres. Ongoing multicentric trials are expected to address still unsolved issues, including the benefit of CT adjunct to preoperative RT

Operative blood loss and use of blood products after full robotic and conventional low anterior resection with total mesorectal excision for treatment of rectal cancer

To date, no studies have investigated the estimated blood loss (EBL) after full robotic low anterior resection (R-LAR) in a case-matched model, comparing it with the conventional open approach (O-LAR). Forty-nine patients in the R-LAR and 105 in the O-LAR group were matched for age, gender, BMI (body mass index), ASA (American Society of Anesthesiology) class, tumor–node–metastasis (TNM) classification and UICC (Union for International Cancer Control) stage, distance of the lower edge of the tumor from the anal verge, presence of comorbidities, and preoperative hemoglobin (Hb). EBL was significantly higher in the O-LAR group (P < 0.001); twelve units of packed red blood cells were globally transfused in the O-LAR group, compared to one unit only in the R-LAR (P = 0.051). A significantly higher postoperative Hb drop (3.0 vs. 2.4 g/dL, P = 0.015) was registered in the O-LAR patients. The length of hospital stay was much lower for the R-LAR group (8.4 vs. 12.4 days, P < 0.001). The number of harvested lymph nodes (17.4 vs. 13.5, P = 0.006) and extent of distal margin (2.9 vs. 1.9 cm, P < 0.001) were significantly higher in the R-LAR group. Open surgery was confirmed as the sole variable significantly associated (P < 0.001) with blood loss (odds ratio = 4.41, 95% CI 2.06–9.43). It was a confirmed prognosticator of blood loss (P = 0.006) when a preoperative clinical predictive model was built, using multivariate analysis (odds ratio = 3.95, 95% CI 1.47–10.6). In conclusion, R-LAR produced less operative blood loss and less drop in postoperative hemoglobin when compared to O-LAR. Other clinically relevant outcomes were similar or superior to O-LAR

Burden of Risk Alleles for Hypertension Increases Risk of Intracerebral Hemorrhage

Background and Purpose-Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. Methods-We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. Results-No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score. Conclusion-Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN. (Stroke. 2012; 43: 2877-2883.