Miracle-dz/UniFAR-FTUs huggingface dataset:
BIOCHEMICAL AND GENETIC APPROACHES TO UNRAVEL MITOCHONDRIAL COMPLEX I DEFICIENCY

III TABLE of CONTENTS . V ABBREVIATIONS . VIII 1 INTRODUCTION . 1 1.1 Mitochondria and Mitochondrial Proteome . 1 1.2 Mitochondrial Respiratory Chain and Oxidative Phosphorylation System . 1 1.2.1 Complex I: NADH:ubiquinone oxidoreductase. 2 1.2.2 Complex II: Succinate CoQ Reductase . 3 1.2.3 Complex III: Ubiquinol-Cytochrome c Reductase . 3 1.2. 4 Complex IV: Cytochrome c Oxidase . 3 1.2. 5 Complex V: ATP Synthase . 3 1.3 Biochemical Assessment of Complex I Deficiency . 4 1.4 Complex I Function, Structure and Assembly . 4 1.5 Mitochondrial Disease . 12 1.6 Genetics of Complex I Deficiency . 14 1.6. 1 mtDNA mutations . 14 1.6. 2 Nuclear DNA Subunit Mutations . 15 1.6. 3 Assembly Factor Mutations . 15 1.7 Mouse Models for Nuclear DNA-encoded Mitochondrial Complex I Deficiency . 23 1.7. 1 The Harlequin mouse . 23 1.7. 2 The NDUFS4-knock out mouse . 24 1.8 Approaches to Treatment of Complex I Deficiency . 25 2 AIM OF THE THESIS . 29 3 MATERIALS and METHODS . 32 3.1 Patient Cohort . 32 3.2 Cell culture methods . 35 3.3 Biochemical studies . 35 3.3.1 Complex I/Complex IV microplate and dipstick assays . 35 3.3.2 Preparation of crude mitochondriaI pellets with digitonin (mitoplasts) . 36 3.3.3 Blue Native studies . 37 3.3.4 Western blot studies . 38 3.3.5 Submitochondrial fractionation . 38 ___________________________TABLE of CONTENTS____________________________ VI 3.4 Genetic studies . 40 3.4.1 DNA and RNA extraction . 40 3.4.2 Homozygosity Mapping and Bioinformatics analysis . 41 3.4.3 Sequencing of candidate genes . 43 3.5 Functional studies . 48 3.5.1 Preparation of lentiviral vectors . 48 3.5.2 Complementation and RNA interference studies . 49 4 RESULTS . 51 4.1 Biochemistry . 51 4.1.1 Complex I activity . 51 4.1.2 Blue Native studies . 52 4.2 Genetics studies . 56 4.2.1 Homozygosity Mapping and Bioinformatics Analysis . 56 4.2.2 Candidate Gene Approach . 59 4.3 Functional studies . 62 4.3.1 Family 1, Patients 1 and 2: NDUFS4 . 62 4.3.2 Family 4, Patient 5: FOXRED1 . 62 4.3.2.1 Lentiviral-mediated complementation and silencing studies . 62 4.3.2.2 Western blot analysis . 63 4.3.2.3 Subcellular and submitochondrial localization . 64 4.3.3 Patient 6: NDUFAF1 . 65 4.3.3.1 Western blot . 66 5 DISCUSSION . 69 5.1 NDUFS4 . 69 5.2 FOXRED1 . 70 5.3 NDUFAF1 . 72 5.4 Other Patients in the cohort . 73 5.5 Complex I assembly . 73 6 CONCLUSIONS . 79 REFERENCES . 82 APPENDIX . 102 ___________________________TABLE of CONTENTS____________________________
The Role of Oliguria and the Absence of Fluid Administration and Balance Information in Illness Severity Scores

Urinary examination has formed part of patient assessment since the earliest days of medicine. Current definitions of oliguria are essentially arbitrary, but duration and intensity of oliguria have been associated with an increased risk of mortality, and this risk is not completely attributable to the development of concomitant acute kidney injury (AKI) as defined by changes in serum creatinine concentration. The increased risk of death associated with the development of AKI itself may be modified by directly or indirectly by progressive fluid accumulation, due to reduced elimination and increased fluid administration. None of the currently extant major illness severity scoring systems or outcome prediction models use modern definitions of AKI or oliguria, or any values representative of fluid volumes variables. Even if a direct relationship with mortality is not observed, then it is possible that fluid balance or fluid volume variables mediate the relationship between illness severity and mortality in the renal and respiratory physiological domains. Fluid administration and fluid balance may then be an important, easily modifiable therapeutic target for future investigation. These relationships require exploration in large datasets before being prospectively validated in groups of critically ill patients from differing jurisdictions to improve prognostication and mortality prediction.
Detrimental Effects of Temperature on the Efficacy of the Universit of Wisconsin Solution When Used for Cardioplegia at Moderate Hypothermia: Comparison With the St. Thomas Hospital Solution at 4°C and 20°C

BackgroundWe have previously reported the superior protective properties of the University of Wisconsin (UW) solution compared with the St. Thomas solution (ST) in the rat heart subjected to the deep hypothermia (4°C), thus demonstrating its possible use in cardiac transplantation. We thought it was important to evaluate the potential of the UW solution as a cardioplegic solution under the moderately hypothermic (20°C) conditions of routine intraoperative myocardial protection. Methods and ResultsIsolated rat hearts were subjected to 60 minutes of ischemia at 4°C or 30 (or 60) minutes of ischemia at 20°C with UW, ST, and ST plus 100 mM K (ST+100) solutions. Coronary flow, mechanical function, endothelial function, and ultrastructure were observed. Mean time (seconds) to infuse 10 ml of cardioplegic solution under constant pressure, a measure of coronary vascular resistance at 4°C and 20°C, respectively, for each solution were ST, 69.2±6.9 and 64.7±3.8; UW, 142.2±8.8 and 187.2±10.0 (p<0.01); and ST+100, 78.2±8.0 and 176±8.1 (p.001). Mean recovery values of cardiac output (expressed as percentage of its preischemic value) after 60 minutes of ischemia at 4°C were ST, 95.5±2.1%; UW, 93.0±2.4%; and ST+100, 96.5±1.5%. After 30 minutes of ischemia at 20°C, values were ST, 88.0±1.3%; UW, 72.2±3.6% (p<0.005 versus ST); and ST+100, 53.3±1.8%o (p<0.001 versus ST). ConclusionsThe efficacies of UW and severely hyperkalemic cardioplegic solutions are affected by the degree of hypothermia under which they are used. Under moderate hypothermia (20°C), severe hyperkalemia induces a marked increase in coronary vascular resistance that is associated with impaired myocardial protection. These studies discourage the use of UW for routine intraoperative cardioplegic arrest where the degree of hypothermia cannot be readily controlled. The ST solution does not share this constraint.
Can laparoscopic liver resection for colorectal liver metastases provide early initiation of adjuvant chemotherapy

The long-term outcome of patients with colorectal liver metastases (CRLM) has improved because of advances in surgical technique and perioperative chemotherapy (1-3). Liver resection followed by adjuvant chemotherapy (AC) provides better recurrence-free survival in patients with CRLM than surgery alone (4,5).
Brief Report

The copy number aberrations (CNAs) deletion of 17p and gain of 1q21 are cytogenetic markers for high-risk multiple myeloma. Of these, the gain of the 1q21 region occurs most frequently, is found in about 40% of cases, and is often found in proliferative relapsed and/or refractory disease. Gains of 1q21 are most often associated with secondary aberrations involving jumping translocations of 1q12 (JT1q12). In patients with JT1q12s, we have shown that extra copies of 1q21 result from the formation of triradial chromosomes involving the 1q12 region.We and others have previously speculated that hypomethylation of the highly repetitive elements that make up the 1q12 pericentromeric region may be related to the origin and progression of CNAs of 1q21, suggesting epigenetic factors are involved. In fact, methylation studies in multiple myeloma (MM) have shown a gradual progression from overall global hypomethylation to DNA hypermethylation of specific genes and that hypomethylation of repetitive elements may contribute to tumor progression and genomic instability. It has previously been demonstrated that hypomethylation of the pericentromeric regions of metaphase chromosomes by 5-azacytidine can induce 1q12 chromosome decondensation and somatic associations in chromosome regions 1, 9, and 16 in human lymphocytes. The aim of this study was to test the hypothesis that hypomethylation of 1q12 pericentromeric heterochromatin by 5-azacytidine can initiate copy number (CN) gains of 1q21. Here we present evidence that the hypomethylation of the 1q12 region not only induces CN gains of 1q21, but also can induce novel CN gains of chromosome regions inverted or translocated next to hypomethylated 1q12 pericentromeric heterochromatin.
Mechanistic Insights Into Today’s (and Tomorrow’s) Treatments for Moderate-to-Severe Psoriasis

ABSTRACT Psoriasis is a chronic immune-mediated disease, and several cytokine pathways in the psoriatic cascade have been identified and investigated as clinical targets for systemic therapy. This review provides an overview of psoriasis, including discussion of clinical variants, environmental and genetic risk factors, known comorbidities, treatment strategies, and limitations in evaluating disease severity. The manuscript then focuses on addressing how existing biologics target the various pathways described in the pathogenesis of psoriasis, how modulating these mechanisms can improve outcomes over time, and how new insights have led to the development of agents that can target different pathways associated with the disease. Overall, biologics that target tumor necrosis factor-&agr; or interleukin-12/23 have established themselves as effective, well-tolerated treatment options for chronic plaque psoriasis that can quickly produce dramatic clinical improvement. Unlike topical, phototherapy, and conventional systemic therapies that do not specifically target the underlying pathogenesis of psoriasis, biologics have been, and continue to be, developed based on identifying therapeutic targets within the immune and inflammatory pathways associated with disease development and progression. Recently, interleukin-17A has been identified as a central cytokine driver in the pathogenesis of psoriasis, and biologic therapy targeting this cytokine has recently been approved.
Patient interviews, students writings

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Patient interviews, students writings Nicolas Lechopier, Xavier Mabire, Jennifer Bernard, Jean-Félix Gross, Paul-Fabien Groud, Agathe Camus, Geneviève Fourel
The Impact of Possible Clonal Spread of Acinetobacter baumannii Complex Bacteremia

September 2014 • Volume 42 • Number 9 (MLST) are currently two methods commonly used for this purpose (3). PFGE was applied in this study (2). Imipenem-susceptible A. baumannii complex isolates that caused 75.5% of all bloodstream infections were extremely diverse and each carried a different PFGE genotype. On the other hand, 68 imipenemresistant A. baumannii (IRAB) isolates showed 26 different PFGE genotypes. Thirty-five out of the 68 IRAB isolates (51.5%) actually belonged to PFGE genotype 1 and its seven subtypes (1a, 1b, 1c, 1d, 1e, 1f, and 1g; see Supplemental Table 5 in [2]). Different subtypes with at least two different fragments were not the same clone but only related (4). We have further examined the clonal relationship of IRAB isolates collected in 2010 by MLST using the Bartual’s PubMLST scheme (5). There were 11 different sequence types (ST), ST455, ST544, ST545, ST208, ST436, ST191, ST473, ST547, ST549, ST551, and ST456, identified among PFGE genotype 1 and its subtypes (C.-H. Chiu, unpublished data, 2013). The major clone identified was ST455, and the ST455 comprised 38.5% of the IRAB isolates tested by MLST. However, IRAB was the cause for only 22.8% of all ABC bacteremia. Taken together, there was no clonal spread or outbreaks in terms of ABC bloodstream infection during the study period in our hospital. We found in our study that imipenem-resistant A. baumannii complex bacteremia specifically showed a high mortality (69.9%) and was associated with prior use of broad-spectrum antibiotics for more than 5 days for treating ventilator-associated pneumonia before the occurrence of bacteremia. We have to reiterate that mortality was associated with inappropriate initial antimicrobial therapy which was correlated with imipenem resistance of ABC but not with any specific genospecies or any clone of a genospecies. In other words, even if there had been a single clone found to be associated with mortality, the predictive factor for mortality, namely, imipenem resistance and inappropriate early treatment, would not have been changed according to our analytical algorithm. Drs. Lee and Chiu received support for article research from grants from National Science Council and Chang Gung Memorial Hospital.
Circulation: Heart Failure's Editors' Picks: Most Important Papers in Epidemiology and Outcomes

The following are highlights from the new series, Circulation: Heart Failure Topic Review. This series will summarize the most important manuscripts, as selected by the editors, which have published in the Circulation portfolio. The objective of this new series is to provide our readership with a timely and comprehensive selection of important papers that are relevant to the heart failure audience, covering a variety of areas within the heart failure field. The studies included in this article represent the most noteworthy research in the areas of epidemiology and outcomes.
Clinical practice Endogenous Klebsiella pneumoniae endophthalmitis associated with intravenous drug abuse

DOI: 10.3760/cma.j.issn.0366-6999.20132985 Tianjin Eye Hospital; Tianjin Key Labrotary of Ophthalmology and Visual Science; Tianjin Eye Institute; Clinical College of Ophthalmology, Tianjin Medical University, Tianjin 300020, China (Kong YC, Tang X, Han QH and Jiang H) Correspondence to: Dr. Kong Yichun, Tianjin Eye Hospital; Tianjin Key Labrotary of Ophthalmology and Visual Science; Tianjin Eye Institute; Clinical College of Ophthalmology, Tianjin Medical University, Tianjin 300020, China (Email: kongyc1942@hotmail. com) Clinical practice
Recognizing Pathogens Toll-like receptors

Toll-like receptors (TLRs) comprise a family of cellular surface protein receptors present on numerous different cell types that function in mammals to recognize conserved molecular components of microorganisms that have been termed pathogen-associated molecular patterns (PAMPs). The TLRs are the major molecular mechanism by which the host recognizes that there is an invading microorganism present. This crucial information (i.e., a microbe is present in the body) is transmitted across the cell membrane, and the resulting signal is eventually transmitted into the nucleus so that specific gene sets can be activated to initiate an appropriate response. There are at least 11 different TLRs in mammals, of which ten are functional in humans. The component of the TLRs that recognize PAMPs consists of conserved repeating motifs of sequences that are rich in leucine. Despite this conservation of structure of the TLRs, these domains are able to recognize multiple ligands with different structures. The exact molecular mechanism underlying this process is not yet established. It has been difficult to document direct physical binding between the PAMP ligands and the TLRs, and in some cases efficient signaling by the PAMP ligands requires the presence of accessory molecules. For example, lipopolysaccharide (LPS) binding protein (LBP), CD14, and MD2 facilitate the binding of LPS to TLR4. Many TLRs have their recognition domains on the extracellular surface; however, some TLRs, such as those that recognize microbial nucleic acid structures as ligands (TLR7, TLR8, and TLR9), have these domains in an endosome within the cell. The cytoplasmic component of the TLRs is also highly conserved. Because the intracellular sequences of the TLRs were found to have homology with the cytoplasmic tail of the interleukin (IL)-1 receptor, this portion of the TLRs is known as the TLR/IL-1R (TIR) domain. After binding to a PAMP, the TLR dimerizes either with itself or, in some cases, with a different TLR in a way that induces an intracellular conformational shift so that certain additional proteins in the cytoplasm are recruited. These proteins (named MyD88, TIRAP/MAL, TRAM, and TRIF) serve as adaptors to translate the message that the TLR has been activated. All TLRs except TLR3 signal through MyD88 (although some TLRs require several of these adaptor molecules). The information is then transmitted via a molecular signaling cascade into the cell nucleus so that an appropriate cellular response, such as the induction of expression of chemokines and cytokines, can be initiated. A schematic diagram of the TLRs is shown in Figure 1, and a list of microbial ligands for each TLR is shown in Table 1.
Role of tamsulosin in the management of lower ureteric stone at tertiary care hospital in Western Rajasthan, India

Background: Many minimally invasive interventional techniques as well as expectant treatments exist for the management of lower ureteric calculi. Methods: 100 patients [group A (50 patients) patients given capsule tamsulosin 0.4mg, 1 daily up to 4 weeks while group B (50 patients) patients given regularly practiced treatment without Tamsulosin] with distal ureteric stone included in the study. Study duration was 6 months and study performed at S.P. Medical College. Bikaner, Rajasthan, India. Results: Group A showed a statistically significant advantage in terms of the stone expulsion rate. 41 patients (82%) in group A and 30 patients (60%) in group B expelled stones. Overall patients in group A had mean expulsion time of 7.86 days, whereas in group B mean expulsion time was 18.64 days. In group A stone expulsion rate was higher as compared to group B. In group A only 12 (24%) patients experienced pain relapses whereas in group B 32 (64%) patients reported pain relapses. The diclofenac dosage required in group A was observed to be 1.62 tablets whereas in group B it was 2.6 tablets. Conclusions: It is concluded that tamsulosin should be considered for uncomplicated distal ureteral calculi before ureteroscopy or extracorporeal lithotripsy. Tamsulosin has been found to increase and hasten stone expulsion rates, decrease acute attacks by acting as a spasmolytic, reduces mean days to stone expulsion and decreases analgesic dose usage.
Compassion Fatigue and Effects Upon Critical Care Nurses

Walker and Avant’s method of concept analysis was used to delve into the initial understanding of compassion fatigue, a relatively new concept being explored with critical care nurses and other health care professionals. The term was originally used in 1992 involving research exploring burnout experienced by critical care nurses when a trend emerged where nurses appeared to have lost their “ability to nurture. ” The term has since been used synonymously with secondary traumatic stress disorder. Two important goals exist for this article: First, theoretically to conduct a concept analysis of compassion fatigue, thereby providing information for critical care nurses to understand the concept as a universal human experience. Second, from a caring perspective, identifying the effects related to critical care nurses provides an opportunity to address physical and somatic consequences of compassion fatigue that will ultimately become important to nursing practice, education, and research.
Very late relapse metastatic renal cell carcinoma: Characteristics and outcomes of patients with a disease-free interval of greater than 10 years.

541 Background: Late relapse of renal cell carcinoma (RCC), or presentation with metastatic disease after a disease free interval of >5 years, is a known behavior of RCC. Recent studies have concluded that late relapse RCC is associated with favorable patient and tumor characteristics as well as an improved response to targeted therapy (TT) when compared to early relapse patients. Less studied are patients who relapse very late, with a disease free interval >10 years. We evaluated the clinical characteristics, response to TT and outcomes of this unique population. Methods: We collected data on consecutive patients with metastatic RCC who had disease recurrence >10 years after nephrectomy. Outcomes were tabulated using basic statistical techniques; adverse events were graded using CTCAE v4.0 and treatment response graded using RECIST 1.1. Results: Among 720 RCC patients treated with nephrectomy, we identified 8 who developed recurrent metastatic disease after a >10 year disease free interval (median: 16.7 .
Antagonistic interaction between adenosine A2A and dopamine D2 receptors modulates the social recognition memory in reserpine-treated rats

Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the control of motor activity. However, there are few studies investigating this interaction in other brain regions and its role in additional functions. In the present study, we evaluated whether reserpine-treated rats (1.0mg/kg, i.p.) exhibit altered social recognition memory abilities. The effects of acute administration of the dopamine receptor agonists 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine (SKF 38393, dopamine D1 receptor agonist) and quinpirole (dopamine D2 receptor agonist), together with the adenosine receptor antagonists caffeine (non-selective), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, adenosine A1 receptor antagonist) and 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a} {1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, adenosine A2A receptor antagonist), were also investigated. Twenty-four hours after treatment, reserpine-treated rats exhibited a significant disruption in the ability to recognize a juvenile rat after a short period of time. These animals did not show any motor deficit. The social recognition disruption induced by reserpine was reversed by acute treatment with quinpirole (0.05–0.1mg/kg, i.p.), caffeine (10.0–30.0mg/kg, i.p.) or ZM241385 (0.5–1.0mg/kg, i.p.), but not with SKF 38393 (0.5–3.0mg/kg, i.p.) or DPCPX (0.5–3.0mg/kg, i.p.). Moreover, a synergistic response was observed following the co-administration of ‘non-effective’ doses of ZM241385 (0.1mg/kg, i.p.) and quinpirole (0.01mg/kg, i.p.). These results reinforce and extend the notion of antagonistic interactions between adenosine and dopamine receptors, and demonstrate, for the first time, that the blockade of adenosine A2A receptors and the activation of dopamine D2 receptors can reverse the social recognition deficits induced by reserpine in rats. Behavioural Pharmacology 16:209–218 c 2005 Lippincott Williams & Wilkins.
Skolsköterskors hälsofrämjande arbete med psykisk hälsa hos ensamkommande flyktingbarn

Bakgrund: Forskning tyder pa att ett ensamkommande flyktingbarn loper en storre risk for psykiska halsoproblem. Skolskoterskors arbete ska praglas av ett salutogent perspektiv och att framja psykis .
Preventive psychiatry from public health perspectives

The focus in public health has been shifted to noncommunicable diseases (NCD) in last decade. Mental health is gaining momentum as fifth NCD. The concept of prevention in psychiatry is new, but an interesting area from public health perspectives. The concepts of primary, secondary, and tertiary prevention relevant to psychiatry are discussed. Among primary prevention interventions, universal, selective, and indicated prevention strategies in psychiatry are discussed with examples from published literature. Challenges in preventive psychiatric practice on issue of payments, available standard of evidence, and best health-care professionals for its delivery are also discussed. There is a need to focus on preventive psychiatric interventions, especially in developing countries.