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Critical COVID-19 patients admitted to the intensive care unit (ICU) frequently suffer from severe multiple organ dysfunction with underlying widespread cell death. Ferroptosis and pyroptosis are two detrimental forms of regulated cell death that could constitute new therapeutic targets. We enrolled 120 critical COVID-19 patients in a two-center prospective cohort study to monitor systemic markers of ferroptosis, iron dyshomeostasis, pyroptosis, pneumocyte cell death and cell damage on the first three consecutive days after ICU admission. Plasma of 20 post-operative ICU patients (PO) and 39 healthy controls (HC) without organ failure served as controls. Subsets of COVID-19 patients displayed increases in individual biomarkers compared to controls. Unsupervised clustering was used to discern latent clusters of COVID-19 patients based on biomarker profiles. Pyroptosis-related interleukin-18 accompanied by high pneumocyte cell death was independently associated with higher odds at mechanical ventilation, while the subgroup with high interleuking-1 beta (but limited pneumocyte cell death) displayed reduced odds at mechanical ventilation and lower mortality hazard. Meanwhile, iron dyshomeostasis with a tendency towards higher ferroptosis marker malondialdehyde had no association with outcome, except for the small subset of patients with very high catalytic iron independently associated with reduced survival. Forty percent of patients did not have a clear signature of the cell death mechanisms studied in this cohort. Moreover, repeated moderate levels of soluble receptor of advanced glycation end products and growth differentiation factor 15 during the first three days after ICU admission are independently associated with adverse clinical outcome compared to sustained lower levels. Altogether, the data point towards distinct subgroups in this cohort of critical COVID-19 patients with different systemic signatures of pyroptosis, iron dyshomeostasis, ferroptosis or pneumocyte cell death markers that have different outcomes in ICU. The distinct groups may allow ‘personalized’ treatment allocation in critical COVID-19 based on systemic biomarker profiles.

Les ateliers d’harmonisation de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC) ont pour but d’établir des recommandations pratiques établies, d’une part, à partir des données de la littérature et des recommandations internationales et, d’autre part, par consensus en l’absence de données formellement prouvées. La vie sexuelle et affective des patients allogreffés de cellules souches hématopoïétiques (CSH) est souvent très impactée et reste un sujet relativement peu abordé par les patients comme les soignants. Cet article est une actualisation d’un précédent atelier et s’accompagne d’un livret destiné aux patients qui sera inclus dans le classeur de suivi post-allogreffe édité par la SFGM-TC. Ces deux documents ont pour but de faciliter les échanges entre patients/soignants sur le sujet et de présenter des propositions de suivi et d’outils pour mieux prendre en charge la vie sexuelle et affective des patients allogreffés de CSH.

IMPORTANCE: Experimental evidence suggests that cyclosporine prevents postcardiac arrest syndrome by attenuating the systemic ischemia reperfusion response. OBJECTIVE: To determine whether early administration of cyclosporine at the time of resuscitation in patients with out-of-hospital cardiac arrest (OHCA) would prevent multiple organ failure. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, single-blind, randomized clinical trial was conducted from June 22, 2010, to March 13, 2013 (Cyclosporine A in Out-of-Hospital Cardiac Arrest Resuscitation [CYRUS]). Sixteen intensive care units in 7 university-affiliated hospitals and 9 general hospitals in France participated. A total of 6758 patients who experienced nonshockable OHCA (ie, asystole or pulseless electrical activity) were assessed for eligibility. Analyses were performed according to the intention-to-treat analysis. INTERVENTIONS: Patients received an intravenous bolus injection of cyclosporine, 2.5 mg/kg, at the onset of advanced cardiovascular life support (cyclosporine group) or no additional intervention (control group). MAIN OUTCOMES AND MEASURES: The primary end point was the Sequential Organ Failure Assessment (SOFA) score, assessed 24 hours after hospital admission, which ranges from 0 to 24 (with higher scores indicating more severe organ failure). Secondary end points included survival at 24 hours, hospital discharge, and favorable neurologic outcome at discharge. RESULTS: Of the 6758 patients screened, 794 were included in intention-to-treat analysis (cyclosporine, 400; control, 394). The median (interquartile range [IQR]) ages were 63.0 (54.0-71.8) years for the cyclosporine group and 66.0 (57.0-74.0) years for the control group. The cohorts included 293 men (73.3%) in the treatment group and 288 men (73.1%) in the control group. At 24 hours after hospital admission, the SOFA score was not significantly different between the cyclosporine (median, 10.0; IQR, 7.0-13.0) and the control (median, 11.0; IQR, 7.0-15.0) groups. Survival was not significantly different between the 98 (24.5%) cyclosporine vs 101 (25.6%) control patients at hospital admission (adjusted odds ratio [aOR], 0.94; 95% CI, 0.66-1.34), at 24 hours for 67 (16.8%) vs 62 (15.7%) patients (aOR, 1.08; 95% CI, 0.71-1.63), and at hospital discharge for 10 (2.5%) vs 5 (1.3%) patients (aOR, 2.00; 95% CI, 0.61-6.52). Favorable neurologic outcome at discharge was comparable between the cyclosporine and control groups: 7 (1.8%) vs 5 (1.3%) patients (aOR, 1.39; 95% CI, 0.39-4.91). CONCLUSION AND RELEVANCE: In patients presenting with nonshockable cardiac rhythm after OHCA, cyclosporine does not prevent early multiple organ failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01595958; EudraCT Identifier: 2009-015725-37

Genital chronic graft-versus-host disease (GVHD) is a frequent but underdiagnosed complication of allogeneic stem-cell transplantation impairing quality of life.

Background.The strength of the association between intensive care unit (ICU)-acquired nosocomial infections (NIs) and mortality might differ according to the methodological approach taken.Objective.TO assess the association between ICU-acquired NIs and mortality using the concept of population-attributable fraction (PAF) for patient deaths caused by ICU-acquired NIs in a large cohort of critically ill patients.Setting.Eleven ICUs of a French university hospital.Design.We analyzed surveillance data on ICU-acquired NIs collected prospectively during the period from 1995 through 2003. The primary outcome was mortality from ICU-acquired NI stratified by site of infection. A matched-pair, case-control study was performed. Each patient who died before ICU discharge was defined as a case patient, and each patient who survived to ICU discharge was denned as a control patient. The PAF was calculated after adjustment for confounders by use of conditional logistic regression analysis.Results.Among 8,068 ICU patients, a total of 1,725 deceased patients were successfully matched with 1,725 control Patients. The adjusted PAF due to ICU-acquired NI for patients who died before ICU discharge was 14.6% (95% confidence interval [CI], 14.4%—14.8%). Stratified by the type of infection, the PAF was 6.1% (95% CI, 5.7%–6.5%) for pulmonary infection, 3.2% (95% CI, 2.8%–3.5%) for central venous catheter infection, 1.7% (95% CI, 0.9%–2.5%) for bloodstream infection, and 0.0% (95% CI, –0.4% to 0.4%) for urinary tract infection.Conclusions.ICU-acquired NI had an important effect on mortality. However, the statistical association between ICU-acquired NI and mortality tended to be less pronounced in findings based on the PAF than in study findings based on estimates of relative risk. Therefore, the choice of methods does matter when the burden of NI needs to be assessed.

Monocationic bis‐allyl complexes [Ln(η3‐C3H5)2(thf)3]+[B(C6X5)4]−(Ln=Y, La, Nd; X=H, F) and dicationic mono‐allyl complexes of yttrium and the early lanthanides [Ln(η3‐C3H5)(thf)6]2+[BPh4]2−(Ln=La, Nd) were prepared by protonolysis of the tris‐allyl complexes [Ln(η3‐C3H5)3(diox)] (Ln=Y, La, Ce, Pr, Nd, Sm; diox=1,4‐dioxane) isolated as a 1,4‐dioxane‐bridged dimer (Ln=Ce) or THF adducts [Ln(η3‐C3H5)3(thf)2] (Ln=Ce, Pr). Allyl abstraction from the neutral tris‐allyl complex by a Lewis acid, ER3(Al(CH2SiMe3)3, BPh3) gave the ion pair [Ln(η3‐C3H5)2(thf)3]+[ER3(η1‐CH2CHCH2)]−(Ln=Y, La; ER3=Al(CH2SiMe3)3, BPh3). Benzophenone inserts into the LaCallylbond of [La(η3‐C3H5)2(thf)3]+[BPh4]−to form the alkoxy complex [La{OCPh2(CH2CHCH2)}2(thf)3]+[BPh4]−. The monocationic half‐sandwich complexes [Ln(η5‐C5Me4SiMe3)(η3‐C3H5)(thf)2]+[B(C6X5)4]−(Ln=Y, La; X=H, F) were synthesized from the neutral precursors [Ln(η5‐C5Me4SiMe3)(η3‐C3H5)2(thf)] by protonolysis. For 1,3‐butadiene polymerization catalysis, the yttrium‐based systems were more active than the corresponding lanthanum or neodymium homologues, giving polybutadiene with approximately 90 % 1,4‐cisstereoselectivity.

Openers of K+ATPchannels protect the myocardium from I/R injury. Sulfonylureas are known as potent blockers of KATPchannels. We investigated whether 1) mitochondrial permeability transition pore may be involved in the protection afforded by the mitoK+ATPopener nicorandil and 2) whether sulfonylureas may prevent this beneficial effect. Anesthetized New Zealand White rabbits underwent 30 min of coronary artery occlusion, followed by 60 (isolated mitochondria) or 240 min (infarct size) of reperfusion. They received an administration of either saline (control) or nicorandil (0.5 mg kg−1, i.v.) 15 min before ischemia. Each control and nicorandil group was divided in four subgroups pretreated by either saline, glibenclamide (Glib; 1 mg kg−1), gliclazide (Glic; 1 mg kg−1), or glimepiride (Glim; 5 g kg−1) 10 min before this. Infarct size was assessed by triphenyltetrazolium chloride staining. Mitochondria were isolated from the area at risk for further assessment of the calcium retention capacity. Glibenclamide (35 ± 8), but neither Glic (61 ± 9) nor Glim (48 ± 7), reversed the improvement in calcium retention capacity due to nicorandil (58 ± 10 vs. 27 ± 8 nmoles CaCl2mg−1proteins in control). Infarct size reduction by nicorandil (32% ± 6% vs. 65% ± 6% of area at risk) was abolished by Glib (55 ± 5) but not by Glic (37 ± 3) or Glim (31 ± 5). These data suggest that 1) the protective effect of nicorandil involves the inhibition of the mitochondrial permeability transition pore and 2) that unlike Glib, second-generation sulfonylureas preserve this cardioprotection.

Mitochondrial permeability transition pore (mPTP) opening is a crucial event in cardiomyocyte death after I/R. We questioned whether preconditioning (PC) may inhibit mPTP opening during ischemia and/or during reperfusion and whether this effect would persist as reperfusion evolves. Anesthetized New Zealand white rabbits underwent a test ischemia followed by reperfusion. Ischemia lasted either 10 or 30 min, whereas reperfusion duration varied from 5 to 20, 60 and up to 240 min. For each duration of ischemia and reperfusion, animals were randomized as either control or PC. Preconditioning was induced by 5 min of ischemia followed by 5 min of reperfusion. Mitochondria were isolated from myocardium at risk for assessment of the calcium retention capacity (CRC) (potentiometric technique) used here as an index of sensitivity of the mPTP to Ca2+loading. In controls, the CRC was moderately reduced after ischemia alone, but reperfusion severely and time-dependently accelerated further CRC reduction. Preconditioning failed to modify mPTP opening during ischemia alone, but significantly improved CRC during reperfusion. This protective effect persisted as reperfusion evolved. These data suggest that (a) reperfusion strikingly increases the susceptibility to Ca2+-induced mPTP opening, and that (b) PC inhibits mPTP opening at reflow and throughout the first hours of reperfusion.

Trimethylsilylmethyl complexes of the type [Ln(η5-C5Me4CH2SiMe2NC6H4R-4-κN)(CH2SiMe3)(thf)n] containing a dianionic ligand [C5Me4CH2SiMe2NC6H4R-4]2–with a para-substituted anilido group and a CH2SiMe2link were prepared. The yttrium complex [Y(η5-C5Me4CH2SiMe2NPh-κN)(CH2SiMe3)(thf)2] (2a) reacts with H2to generate the corresponding dimeric hydride [Y(η5-C5Me4CH2SiMe2NPh-κN)(μ-H)(thf)]2(5a). Pyridine inserts into the Y–H bond in a 1,2-fashion to afford the stable 2-hydropyridyl complex [Y(η5-C5Me4CH2SiMe2NPh-κN)(η1-NC5H6)(py)2] (6a). Upon reaction with tBuC≡CH, protonolysis takes place to give the dimeric alkynyl complex [Y(η5-C5Me4CH2SiMe2NPh-κN)(μ-C≡CtBu)(thf)]2(7a).(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Half-sandwich rare-earth metal tetramethylaluminate complexes [Ln(η5-C5Me4SiMe3){(μ-Me)2(AlMe2)}2] (Ln = Y, La, Nd, Sm, Gd, Lu) were obtained by reaction of the neutral homoleptic tetramethylaluminate complex [Ln{(μ-Me)2(AlMe2)}3] with tetramethyl(trimethylsilyl)cyclopentadiene, (C5Me4H)SiMe3. Protonolysis reaction of the neutral mono(cyclopentadienyl) complexes with the Brønsted acid [NEt3H]+[BPh4]–in thf led to the formation of the monocationic methyl complexes [Ln(η5-C5Me4SiMe3)Me(thf)3]+[BPh4]–(Ln = Y, La, Nd, Sm, Lu). Single-crystal X-ray diffraction study on the Y, Sm, and Lu derivatives showed a four-legged piano-stool configuration. Upon activation with [Ph3C]+[B(C6F5)4]–, the neutral half-sandwich tetramethylaluminate complex [La(η5-C5Me4SiMe3){(μ-Me)2(AlMe2)}2] catalyzed the polymerization of butadiene in the presence of [AliBu3] to give trans-1,4-polybutadiene with narrow polydispersities (Mn/Mw= 1.05–1.09).(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Noninvasive positive ventilation has undergone a remarkable evolution over the past decades and is assuming an important role in the management of both acute and chronic respiratory failure. Long-term ventilatory support should be considered a standard of care to treat selected patients following an intensive care unit (ICU) stay. In this setting, appropriate use of noninvasive ventilation can be expected to improve patient outcomes, reduce ICU admission, enhance patient comfort, and increase the efficiency of health care resource utilization. Current literature indicates that noninvasive ventilation improves and stabilizes the clinical course of many patients with chronic ventilatory failure. Noninvasive ventilation also permits long-term mechanical ventilation to be an acceptable option for patients who otherwise would not have been treated if tracheostomy were the only alternative. Nevertheless, these results appear to be better in patients with neuromuscular/-parietal disorders than in chronic obstructive pulmonary disease. This clinical review will address the use of noninvasive ventilation (not including continuous positive airway pressure) mainly in diseases responsible for chronic hypoventilation (that is, restrictive disorders, including neuromuscular disease and lung disease) and incidentally in others such as obstructive sleep apnea or problems of central drive.

The alkyl abstraction reaction of [YR3(thf)2] (R = CH2SiMe3) with group-13 trialkyl complexes [(ER3)n] (E = B, Ga, In: n = 1; E = Al: n = 2) forming cationic yttrium species [YR2(thf)4]+[ER4]– (E = Al, Ga, In) shows a strong dependence on the Lewis acidic metal centre E and on the solvent basicity. Whilst the boron compound does not react with [YR3(thf)2], the heavier homologues form the ion pairs [YR2(thf)4]+[ER4]– (E = Al, Ga, In) which dissociate to give the neutral compounds in apolar solvents such as benzene. Single-crystal structure analysis of the gallate [YR2(thf)4]+[GaR4]– shows the presence of an ion pair with cis-arranged alkyl ligands in the octahedral yttrium cation and a tetrahedral gallate anion. Group-13 trialkyl compounds [(ER3)n] (E = B, Al, Ga), all liquids at room temperature, and [Li(12-crown-4)2]+[AlR4]– were characterised by single-crystal X-ray diffraction and NMR spectroscopy. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Pure red-cell aplasia (PRCA) after erythropoietin (Epo) administration due to the appearance of neutralizing anti-Epo antibodies has been reported in over 200 cases between 1998 and 2002. However, large intercountry disparities were observed in the occurrence of this syndrome.

Studies reveal that people under correctional supervision suffer from health problems in proportionally greater numbers than the general population and that their use of health services is extensive. However, very few studies shed light on this phenomenon. The poor health status of inmates is neither the only nor the most important factor in the understanding of health services utilization in custody. Organization of services, health professional practices, and users' perceptions are all important variables in understanding health care consumption. This review of the literature, mostly Canadian studies, aims at documenting some factors that could help us understand the practices of health care utilization behind the walls.

To analyze the outcome of acuterespiratory failure (ARF) in patients with idiopathic pulmonaryfibrosis (IPF), and to evaluate the benefits of invasive andnoninvasive mechanical ventilation (MV).

We report two patients undergoing maintenance hemodialysis who presented with sleep apnea syndrome (SAS). The first patient is a 36-year-old man with a terminal Berger's glomerulopathy and associated obstructive sleep apnea syndrome (OSAS) (apnea-hypopnea index [AHI]=80). He was receiving home hemodialysis and was treated by nasal continuous positive airway pressure (CPAP). After successful renal transplantation, his symptoms completely disappeared, and control polysomnography greatly improved (AHI=9). The second patient had hypokalemic nephropathy with severe, uncontrolled hypertension and hypertensive myocardopathy. He was receiving home dialysis and showed a central sleep apnea syndrome with an AHI of 51. He also was successfully treated by nasal CPAP. After renal transplantation, his sleep improved, insomnia disappeared, and polysomnography showed great improvement (AHI=5). We discuss the role of periodic breathing related to end-stage renal disease associated metabolic abnormalities, as a pathogenetic factor of these SASs. Respiratory correction of chronic metabolic acidosis, “uremic toxins,” “middle molecules,” and hemodialysis are all evoked as etiologic factors and their own roles are discussed.

Retroviral RNA‐dependent DNA polymerase (reverse transcriptase or RT) uses the 3'OH end of a cellular tRNA as primer to initiate DNA synthesis. Previous work with avian retrovirus has shown that reverse transcriptase is implicated in the selection of cellular virion‐encapsidated tRNAs and has shown that the primer tRNA is positioned on the primer binding site near the 5' end of the viral RNA. These mechanisms support the idea that the retroviral polymerase should form complexes with primer tRNA and the specific encapsidated ones. The genomic sequence of human immunodeficiency virus (HIV) allows the prediction that tRNALys3is the natural primer. In this article we show, using the mobility shift assay, that recombinant HIV reverse transcriptase is able to form a complex with bovine tRNALys. By fluorescence studies and α‐chymotrypsin analysis we have observed a modification of the enzyme conformation when reverse transcriptase is bound to the putative primer tRNA. This structural change is specific for tRNALysalthough the retroviral polymerase is able to interact with other tRNAs.

Intermittent positive pressure ventilation (IPPV) delivered via nasal access can normalize alveolar ventilation for individuals with chronic alveolar hypoventilation (CAH) due to neuromuscular disease, spinal cord injury, or skeletal deformity. The purpose of this study was to evaluate the effect of nasal IPPV (NIPPV) air leakage-associated oxyhemoglobin desaturations (dSATs) on the sleep efficiency of kyphoscoliotic individuals with severe pretreatment nocturnal dSATs. Only individuals using nocturnal NIPPV without supplemental oxygen therapy were studied. Seven such individuals were able to maintain PaO2greater than 60 mm Hg without supplemental oxygen therapy (five had been using oxygen therapy in the pretreatment period), had fewer hospitalizations, and had improvements in symptoms, arterial blood gas values, and nocturnal oxyhemoglobin saturation (SAT) by nocturnal NIPPV. This occurred despite polysomnographically observed sleep disruption and sleep stage changes associated with frequent transient dSATs and massive insufflation leakage. Arousals and dSATs were most frequent during rapid eye movement (REM) sleep with the latter occurring at a frequency of 10/h. The dSATs resulted in brief arousals or lightening of sleep stage 76% of the time. With or without arousal, central nervous system mediated reflex muscular activity occurred to diminish leak and normalize SAT. We conclude that the effectiveness of nocturnal NIPPV is dependent in part on central mediated muscular activity.

Retroviral RNA-dependent DNA polymerase (reverse transcriptase or RT) uses the 3'OH end of a cellular tRNA as primer to initiate DNA synthesis. Previous work with avian retrovirus has shown that reverse transcriptase is implicated in the selection of cellular virion-encapsidated tRNAs and has shown that the primer tRNA is positioned on the primer binding site near the 5' end of the viral RNA. These mechanisms support the idea that the retroviral polymerase should form complexes with primer tRNA and the specific encapsidated ones. The genomic sequence of human immunodeficiency virus (HIV) allows the prediction that tRNA Lys3is the natural primer. In this article we show, using the mobility shift assay, that recombinant HIV reverse transcriptase is able to form a complex with bovine tRNA Lys. By fluorescence studies and α-chymotrypsin analysis we have observed a modification of the enzyme conformation when reverse transcriptase is bound to the putative primer tRNA. This structural change is specific for tRNA Lysalthough the retroviral polymerase is able to interact with other tRNAs.

Nasal continuous positive airway pressure (N-CPAP) is now the treatment of choice for patients with sleep apnea syndrome (SAS). Side effects and adverse reactions have been described with this device. We have therefore systematically studied side effects of N-CPAP in 193 patients recruited consecutively from two French sleep centers (Lyon and Grenoble). Patients were followed up with repeated polysomnography, clinical assessment, and a formal questionnaire about subjective benefits and side effects of treatment. The patients (mean age, 59±12 years) were obese (body mass index, 32±7 kg/m2) and had been using N-CPAP for 19±17 months for moderate to severe SAS (respiratory disturbance index [RDI] =53±25/h). The clinical presentation was the same in the two sleep centers. Fifty percent of the patients complained of at least one side effect due to the nasal mask (allergy to the face, air leaks, abrasions of the ridge of the nose). Using individually molded masks, the patients exhibited fewer abrasions of the bridge of the nose (p<0.01) and had red eyes every morning in only 9% of cases vs 24% for the patients using industrial silicone nasal masks (p<0.025). Patients with silicone nasal masks also had more allergic reaction to the face (13% vs 5%), but this difference did not reach significance. Dry nose or mouth in the morning affected 65% of the patients. Sneezing and nasal drip were present in more than 35% of the subjects and nasal congestion in 25%. When the patients were separated in two groups, whether or not using a humidifier, no difference was found for any of the side effects described. The clinical presentation as to the clinical benefits obtained from N-CPAP were different when comparing mild vs moderate-to-severe SAS. However, no differences were shown in the two subgroups regarding the side effects due to the nasal mask. The discomfort of the N-CPAP apparatus in terms of noise was described more frequently in the subgroup with mild SAS. We did not observe any correlation between the side effects and the level of pressure used during N-CPAP. The rate of compliance remains high with a daily use of 6.5±3 h, with 88% of the patients using their device every night. This could be explained by the clinical benefit obtained: only 1% of the patients had no subjective benefit induced by their therapy. Snoring and daytime sleepiness were relieved in more than 65% of the subjects and sleep quality improved in 75%. In the present study, we have confirmed in two different centers in France that side effects were frequent during N-CPAP treatment. From this study, it also appears that the incidence of nasal side effects can be reduced with appropriate follow-up.

Prior studies have shown that nasal intermittent positive pressure ventilation (NIPPV) can improve arterial blood gas values, prevent symptoms resulting from alveolar hypoventilation, and decrease hospitalization in patients with chronic respiratory failure. Most studies have involved small samples of patients followed up for a limited time. This study reviews our experience during 5 years use of NIPPV in 276 patients with kyphoscoliosis, posttuberculosis sequelae, Duchenne-type muscular dystrophy, COPD, and bronchiectasis followed up for ≥3 years while receiving NIPPV. Outcomes were compared for patients who survived short term, eg, died or converted to management with a tracheostomy and intermittent positive ventilation (TIPPV) during year 1 or year 2 on a regimen of NIPPV and long term, eg, survived more ≥2 years on a regimen of NIPPV. Ihe most favorable outcome was achieved by patients with kyphoscoliosis and posttubenculous sequelae with improvement in PaO2 and PaCO2 (p<0.0001) and a reduction in days of hospitalization for respiratory illness (p<0.0001) for ≥2 years while receiving NIPPV. Patients with Duchenne-type muscular dystrophy also had fewer hospital days during NIPPV (p<0.003) but only 9 of 16 patients (56 percent) continued using NIPPV for the duration of followup. Benefit was also more short term for patients with COPD and bronchiectasis. NIPPV can sustain improvement in gas exchange, while reducing hospitalization for substantial periods of time. NIPPV can be an attractive and effective alternative to other methods of assisted ventilation such as TIPPV.

A high molecular weight mitochondrial DNA (mtDNA) replication complex, associated with the mitochondrial membrane, was isolated by sucrose gradient centrifugation from purified wheat embryo mitochondria. This complex comprised the mtDNA as well as enzyme activities involved in the replication and transcription of the organelle genome, such as DNA polymerase, RNA polymerase and topoisomerase type I. The isolated complex is active in mtDNA and mtRNA synthesis in vitro. Electron microscopy and lipid analysis confirmed the membrane origin of this complex. Enzyme activities are resistant to physiological ionic strengths, 0.1–0.2 M KCl, while the membrane-mtDNA association is resistant up to 1 M KCl. DNase treatment of the complex released the DNA polymerase activity while protease treatment solubilized mtDNA, suggesting the direct interaction of mtDNA with membrane protein(s). The use of a novel approach to detect mtDNA fragments specifically retained by the mitochondrial membranes after Sal I digestion of the complex suggests that specific mtDNA sequences anchor mtDNA to mitochondrial membranes.

Over the past three decades, the use of noninvasive ventilation or “NIV” to assuage symptoms of hypoventilation for patients with early onset or mild ventilatory pump failure has been extended to up to the use of continuous noninvasive ventilatory support (CNVS) at full ventilatory support settings as a definitive alternative to tracheostomy mechanical ventilation. NVS, along with mechanical insufflation-exsufflation, now provides a noninvasive option for the management of both chronic and acute respiratory failure for these patients. The most common diagnoses for which these methods are useful include chest wall deformities, neuromuscular diseases, morbid obesity, high level spinal cord injury and idiopathic, primary or secondary disorders of the ventilatory control. Thus, NVS is being used in diverse settings: critical care units, medical wards, at home, and in extended care. The aim of this review is to examine the techniques used for daytime support.

Supplemental Digital Content is available in the text.

We present a case of a 3-year-old boy with neurodegeneration. Family history reveals Rendu-Osler-Weber disease. Magnetic resonance imaging (MRI) of the spinal cord and spinal angiography showed a spinal arteriovenous fistula with venous aneurysm, causing compression of the lumbar spinal cord. Embolisation of the fistula was executed, resulting in clinical improvement. A week after discharge he was readmitted with neurologic regression. A second MRI scan revealed an intraspinal epidural haematoma and increase in size of the aneurysm with several new arterial feeders leading to it. Coiling of the aneurysm and fistulas was performed. Postoperative, the spinal oedema increased despite corticoids, causing more extensive paraplegia of the lower limbs and a deterioration of his mental state. A laminectomy was performed and the aneurysm was surgically removed. Subsequently, the boy recovered gradually. A new MRI scan after two months showed less oedema and a split, partly affected spinal chord. This case shows the importance of excluding possible arteriovenous malformations in a child presenting with progressive neurodegeneration. In particular when there is a family history for Rendu-Osler-Weber disease, scans should be performed instantly to rule out this possibility. The case also highlights the possibility of good recovery of paraplegia in paediatric Rendu-Osler-Weber patients.

The cover picture showsthe reactivity of half-sandwich bis(aluminate) complexes of the rare-earth metals that can be converted either into cationic methyl species by protonolysis or into dimeric dimethyl species by donor-induced cleavage of the aluminate moieties. Details are discussed in the article by J. Okuda et al. on p. 2801 ff.

Human immunodeficiency virus (HIV) reverse transcriptase (RT) uses host tRNALys partially annealed to the primer binding site (PBS) as primer for the initiation of cDNA synthesis. When assaying cDNA synthesis with a template-primer complex formed by an RNA fragment carrying the PBS site and bovine tRNALys we noticed that an excess of primer tRNA inhibited strongly the DNA polymerase activity of a recombinant HIV RT (p66-p51 heterodimeric form) produced in transformed yeast cells. The same inhibitory effect was observed with animal DNA polymerase α, while avian retrovirus RT was neither affected by tRNALys nor by its specific primer tRNATrp. Although the strongest inhibition was observed with tRNALys, other tRNas like tRNAPhe and tRNATrP inhibited also the HIV RT, whereas tRNAs specific for valine, proline and glycine had no effect on enzyme activity. Digestion of tRNALys with pancreatic RNase abolished the inhibition ; on the other hand T1 RNase digestion had no effect on the inhibition suggesting a role of the anticodon region in this effect. The 12- and 14-mers corresponding to the anticodon regions of the three bovine tRNALys isoacceptors inhibited RT activity, indicating that at least an important part of the inhibitory effect could be ascribed to this tRNA region. A strong stimulation of DNA polymerase activity was observed when the effect of tRNALys was assayed on a recombinant HIV reverse transcriptase produced in a protease deficient yeast strain, which leads to the production of an active p66 enzyme. The same tRNAs that inhibited strongly the heterodimeric form stimulated the p66 form of HIV reverse transcriptase. The results suggest that although both enzymatic forms are able to interact with tRNALys the topography, as well as the functional implications of the interaction between the precursor and the mature form of HIV reverse transcriptase with the tRNALys primer, are different.