Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease

OBJECTIVE: To determine the prevalence and characteristics of moderate to severe pulmonary hypertension (PH) in patients with systemic sclerosis (SSc) with and without interstitial lung disease (ILD). METHODS: We retrospectively studied clinical and functional characteristics of 197 consecutive patients with SSc who had undergone a screening echocardiography to detect PH. RESULTS: Moderate to severe PH was suspected in 36 patients (18.3%) and confirmed in 32 who underwent right heart catheterization. The prevalence of PH did not differ between patients with limited and patients with diffuse cutaneous SSc. PH was detected in 12/67 (17.9%) patients without ILD vs 24/110 (21.8%) patients with ILD (p not significant). In patients with ILD, a lower PaO2 appeared as the unique independent factor significantly associated with PH, regardless of the extent of fibrosis. In 3 patients out of 9 (33.3%) with ILD and significantly restrictive disease, PH was out of proportion to the degree of fibrosis. In patients with no ILD, a higher grade of dyspnea appeared as the unique independent factor associated with PH. In patients with no ILD, altered DLCO was the sole indicator of the pulmonary function tests associated with PH (best cutoff value 72%). DLCO correlated with systolic pulmonary arterial pressure only in patients with no ILD. CONCLUSION: Prevalence of moderate to severe PH was similar in SSc patients with and those without ILD. In patients with ILD, a lower PaO2 was the unique independent indicator associated with PH. In some patients with severe ILD, PH was out of proportion to the degree of fibrosis. A linear correlation between DLCO and systolic pulmonary arterial pressure was observed only in patients without ILD. All these indicators should assist identification of patients with or without ILD requiring diagnostic procedures for PH before annual screening.     

Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms

Overexpression of the amyloid precursor protein (APP) in hippocampal neurons leads to elevated beta-amyloid peptide (Abeta) production and consequent depression of excitatory transmission. The precise mechanisms underlying APP-induced synaptic depression are poorly understood. Uncovering these mechanisms could provide insight into how neuronal function is compromised before cell death during the early stages of Alzheimer's disease. Here we verify that APP up-regulation leads to depression of transmission in cultured hippocampal autapses; and we perform whole-cell recording, FM imaging, and immunocytochemistry to identify the specific mechanisms accounting for this depression. We find that APP overexpression leads to postsynaptic silencing through a selective reduction of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated currents. This effect is likely mediated by Abeta because expression of mutant APP incapable of producing Abeta did not depress transmission. In addition, although we eliminate presynaptic silencing as a mechanism underlying APP-mediated inhibition of transmission, we did observe an Abeta-induced presynaptic deficit in vesicle recycling with sustained stimulation. These findings demonstrate that APP elevation disrupts both presynaptic and postsynaptic compartments.     

Early Psychosis Prevention and Intervention Centre long-term follow-up study of first-episode psychosis: methodology and baseline characteristics

Aim: This paper reports the rationale, methodology and baseline characteristics of a large long‐term follow‐up study of first‐episode psychosis from a geographically defined catchment area. Method: A total of 723 first‐episode psychosis patients were recruited from a specialized early psychosis service between 1989 and 2001 and prospectively followed up at a median of 7.4 years after initial presentation. Participants’ baseline demographic, clinical and functional characteristics are described. Sampling bias at study recruitment was assessed by comparison with a more complete sample of Early Psychosis Prevention and Intervention Centre (EPPIC) cases rated directly from the medical records. Results: At baseline, 57% of the sample were diagnosed with schizophrenia or schizophreniform disorder, whereas the full range of psychotic disorders was represented. Statistical analysis confirmed that the sample recruited was representative of total EPPIC‐treated incident cases. Conclusions: The EPPIC long‐term follow‐up study is a large and epidemiologically representative first‐episode psychosis cohort that has been subsequently prospectively followed up over a long period. Such a sample provides a rare opportunity to study the course and outcome of psychotic disorders.     

Accuracy and reliability of MRI vs. laboratory measurements in an ex vivo porcine model of arthritic cartilage loss

PURPOSE: To quantify the accuracy of magnetic resonance imaging (MRI) measurement of change in cartilage volume due to thin linear excisions, simulating arthritic cartilage losses, by comparison with laboratory volume measurements in an ex vivo porcine model. MATERIALS AND METHODS: We scanned 15 porcine patellae by T1-weighted spoiled gradient echo (SPGR) MRI at baseline and after excision of up to three thin layers of articular cartilage. Excised fragment volume was determined from density and weight. Postexcision scans were "fused" to the baseline scan by three-dimensional (3D) registration. This allowed automated recalculation of the remaining cartilage volume within a baseline region of interest (ROI) following each excision. We compared MRI estimates of change in cartilage volume to direct laboratory measurement of fragment volume. RESULTS: Our 38 excised fragments averaged 0.16 mL, or approximately 7% of cartilage volume. MRI and laboratory estimates of total cartilage volume loss differed by 1.6% +/- 13.2% (mean, coefficient of variation [CV]). Accuracy was +/-0.1 mL for 95% of scans. CONCLUSION: MRI estimates of small changes in porcine patellar cartilage volume were unbiased, reliable, and accurate to 0.1 mL. Despite a proportionately high error in the very thin fragments tested, achievement of similar accuracy in vivo would be adequate to detect approximately two years of osteoarthritic cartilage loss.     

The encapsulation of DNA molecules within biomimetic lipid nanocapsules

Most of DNA synthetic complexes result from the self-assembly of DNA molecules with cationic lipids or polymers in an aqueous controlled medium. However, injection of such self-assembled complexes in medium like blood that differ from that of their formulation leads to strong instability. Therefore, DNA vectors that have physico-chemical properties and structural organisation that will not be sensitive to a completely different medium in terms of ionic and protein composition are actively sought. To this end, the goal here was to discover and optimize a nanostructured system where DNA molecules would be encapsulated in nanocapsules consisting in an oily core and a shell covered by PEG stretches obtained through a nanoemulsion process in the absence of organic solvent. This encapsulation form of DNA molecules would prevent interactions with external hostile biological fluid. The results show the entrapment of lipoplexes into lipid nanocapsules, leading to the formation of neutral 110 nm-DNA nanocapsules. They were weakly removed by the immune system, displaying an increased blood half-life, and improved carcinoma cell transfection, in comparison to the parent lipoplexes. Our results demonstrate that the fabrication of nanocapsules encapsulating hydrophilic DNA in an oily core that meet criteria for blood injection is possible.     

Human papillomavirus 16 E6 variants differ in their dysregulation of human keratinocyte differentiation and apoptosis

L83V-related variants of human papillomavirus (HPV) 16 E6, exemplified by the Asian-American variant Q14H/H78Y/L83V, were shown to be more prevalent than E6 prototype in progressing lesions and cervical cancer. We evaluated functions relevant to carcinogenesis for the E6 variants L83V, R10/L83V and Q14H/H78Y/L83V as well as the prototype in a model of human normal immortalized keratinocytes (NIKS). All E6 expressing NIKS equally abrogated growth arrest and DNA damage responses. Organotypic cultures derived from these keratinocytes demonstrated hyperplasia and aberrantly expressed keratin 5 in the suprabasal compartment. In contrast, differentiation and induction of apoptosis varied. The E6 variant rafts expressed keratin 10 in nearly all suprabasal cells while the prototype raft showed keratin 10 staining in a subset of suprabasal cells only. In addition, E6 variant NIKS expressing R10G/L83V and Q14H/H78Y/L83V were more prone to undergo cell-detachment-induced apoptosis (anoikis) than NIKS expressing E6 prototype. The combined differentiation and apoptosis pattern of high-risk E6 variants, especially of Q14H/H78Y/L83V, may reflect a phenotype beneficial to carcinogenesis and viral life cycle.     

Subchronic infusion of the product of inflammation prostaglandin J2 models sporadic Parkinson's disease in mice

Background  

Chronic neuroinflammation is implicated in Parkinson's disease (PD). Inflammation involves the activation of microglia and astrocytes that release high levels of prostaglandins. There is a profound gap in our understanding of how cyclooxygenases and their prostaglandin products redirect cellular events to promote PD neurodegeneration. The major prostaglandin in the mammalian brain is prostaglandin D2, which readily undergoes spontaneous dehydration to generate the bioactive cyclopentenone prostaglandins of the J2 series. These J2 prostaglandins are highly reactive and neurotoxic products of inflammation shown in cellular models to impair the ubiquitin/proteasome pathway and cause the accumulation of ubiquitinated proteins. PD is a disorder that exhibits accumulation of ubiquitinated proteins in neuronal inclusions (Lewy bodies). The role of J2 prostaglandins in promoting PD neurodegeneration has not been investigated under in vivo conditions.