Pulmonary embolism in intensive care unit: Predictive factors, clinical manifestations and outcome

<b>Objective</b> :<b> </b> To determine predictive factors, clinical and demographics characteristics of patients with pulmonary embolism (PE) in ICU, and to identify factors associated with poor outcome in the hospital and in the ICU. <b> Methods</b> :<b> </b> During a four-year prospective study, a medical committee of six ICU physicians prospectively examined all available data for each patient in order to classify patients according to the level of clinical suspicion of pulmonary thromboembolism. During the study periods, all patients admitted to our ICU were classified into four groups. The first group includes all patients with confirmed PE; the second group includes some patients without clinical manifestations of PE; the third group includes patients with suspected and not confirmed PE and the fourth group includes all patients with only deep vein thromboses (DVTs) without suspicion of PE. The diagnosis of PE was confirmed either by a high-probability ventilation/perfusion (V/Q) scan or by a spiral computed tomography (CT) scan showing one or more filling defects in the pulmonary artery or in its branches. The diagnosis was also confirmed by echocardiography when a thrombus in the pulmonary artery was observed. <b> Results</b> :<b> </b> During the study periods, 4408 patients were admitted in our ICU. The diagnosis of PE was confirmed in 87 patients (1.9&#x0025;). The mean delay of development of PE was 7.8 &#177; 9.5 days.<b> </b> On the day of PE diagnosis, clinical examination showed that 50 patients (57.5&#x0025;) were hypotensive, 63 (72.4&#x0025;) have SIRS, 15 (17.2&#x0025;) have clinical manifestations of DVT and 71 (81.6&#x0025;) have respiratory distress requiring mechanical ventilation. In our study, intravenous unfractionated heparin was used in 81 cases (93.1&#x0025;) and low molecular weight heparins were used in 4 cases (4.6&#x0025;).<b> </b> The mean ICU stay was 20.2 &#177; 25.3 days and the mean hospital stay was 25.5 &#177; 25 days. The mortality rate in ICU was 47.1&#x0025; and the in-hospital mortality rate was 52.9&#x0025;.<b> </b> Multivariate analysis showed that factors associated with a poor prognosis in ICU are the use of norepinephrine and epinephrine<b> . </b> Furthermore, factors associated with in-hospital poor outcome in multivariate analysis were a number of organ failure associated with PE &#8805; 3. Moreover, comparison between patients with and without pe showed that predictive factors of pe are: acute medical illness, the presence of meningeal hemorrhage, the presence of spine fracture, hypoxemia with PaO₂ /FiO₂ ratio &#60; 300 and the absence of pharmacological prevention of venous thromboembolism. <b>Conclusion</b> :<b> </b> Despite the high frequency of DVT in critically ill patients, symptomatic PE remains not frequently observed, because systematic screening is not performed. Pulmonary embolism is associated with a high ICU and in-hospital mortality rate. Predictive factors of PE are acute medical illness, the presence of meningeal hemorrhage, the presence of spine fracture, hypoxemia with PaO₂ /FiO₂ &lt; 300 and the absence of pharmacological prevention of venous thromboembolism

Paroxysmal Dyskinesias Revealing 3-Hydroxy-Isobutyryl-CoA Hydrolase (HIBCH) Deficiency

International audienceParoxysmal dyskinesias (PD) are rare movement disorders characterized by recurrent attacks of dystonia, chorea, athetosis, or their combination, with large phenotypic and genetic heterogeneity. 3-Hydroxy-isobutyryl-CoA hydrolase (HIBCH) deficiency is a neurodegenerative disease characterized in most patients by a continuous decline in psychomotor abilities or a secondary regression triggered by febrile infections and metabolic crises.We describe two PD patients from two pedigrees, both carrying a homozygous c.913A > G, p.Thr305Ala mutation in the HIBCH gene, associated with an unusual clinical presentation. The first patient presented in the second year of life with right paroxysmal hemidystonia lasting for 30 minutes, without any loss of consciousness and without any triggering factor. The second patient has presented since the age of 3 recurrent exercise-induced PD episodes which have been described as abnormal equinovarus, contractures of the lower limbs, lasting for 1 to 4 hours, associated with choreic movements of the hands. Their neurological examination and metabolic screening were normal, while brain magnetic resonance imaging showed abnormal signal of the pallidi.We suggest that HIBCH deficiency, through the accumulation of metabolic intermediates of the valine catabolic pathway, leads to a secondary defect in respiratory chain activity and pyruvate dehydrogenase (PDH) activity and to a broad phenotypic spectrum ranging from Leigh syndrome to milder phenotypes. The two patients presented herein expand the spectrum of the disease to include unusual paroxysmal phenotypes and HIBCH deficiency should be considered in the diagnostic strategy of PD to enable adequate preventive treatment

Protein Kinase A deregulation in the medial prefrontal cortex impairs working memory in murine Oligophrenin1 deficiency

Classical and systems genetics have identified wide networks of genes associated with cognitive and neurodevelopmental diseases. In parallel to deciphering the role of each of these genes in neuronal or synaptic function, evaluating the response of neuronal and molecular networks to gene loss-of-function could reveal some pathophysiological mechanisms potentially accessible to non-genetic therapies. Loss of function of the Rho-GAP Oligophrenin-1 is associated with cognitive impairments in both human and mouse. Up-regulation of both PKA and ROCK has been reported in Ophn1-/y mice, but it remains unclear if kinase hyperactivity contributes to the behavioural phenotypes. In this study, we thoroughly characterized a prominent perseveration phenotype displayed by Ophn1 deficient mice using a Y-maze spatial working memory (SWM) test. We report that Ophn1 deficiency in the mouse generated severe cognitive impairments, characterized by both a high occurrence of perseverative behaviours and a lack of deliberation during SWM test. In vivo and in vitro pharmacological experiments suggest that PKA dysregulation in the mPFC underlies cognitive dysfunction in Ophn1 deficient mice, as assessed using a delayed spatial alternation task results. Functionally, mPFC neuronal networks appeared to be affected in a PKA-dependent manner, whereas hippocampal-PFC projections involved in SWM were not affected in Ophn1-/y mice. Thus, we propose that discrete gene mutations in intellectual disability might generate "secondary" pathophysiological mechanisms, which are prone to become pharmacological targets for curative strategies in adult patients.SIGNIFICANCE STATEMENTHere we report that Ophn1 deficiency generates severe impairments in performance at spatial working memory tests, characterized by a high occurrence of perseverative behaviours and a lack of decision making. This cognitive deficit is consecutive to PKA deregulation in the mPFC that prevents Ophn1 KO mice to exploit a correctly acquired rule. Functionally, mPFC neuronal networks appear to be affected in a PKA-dependent manner, whereas behaviourally important hippocampal projections were preserved by the mutation. Thus, we propose that discrete gene mutations in intellectual disability can generate "secondary" pathophysiological mechanisms prone to become pharmacological targets for curative strategies in adults

Homozygous truncating variants in TBC1D23 cause pontocerebellar hypoplasia and alter cortical development

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.PMC559084