Symptoms and quality of life in late stage Parkinson syndromes: a longitudinal community study of predictive factors

BACKGROUND Palliative care is increasingly offered earlier in the cancer trajectory but rarely in Idiopathic Parkinson's Disease(IPD), Progressive Supranuclear Palsy(PSP) or Multiple System Atrophy(MSA). There is little longitudinal data of people with late stage disease to understand levels of need. We aimed to determine how symptoms and quality of life of these patients change over time; and what demographic and clinical factors predicted changes. METHODS We recruited 82 patients into a longitudinal study, consenting patients with a diagnosis of IPD, MSA or PSP, stages 3-5 Hoehn and Yahr(H&Y). At baseline and then on up to 3 occasions over one year, we collected self-reported demographic, clinical, symptom, palliative and quality of life data, using Parkinson's specific and generic validated scales, including the Palliative care Outcome Scale (POS). We tested for predictors using multivariable analysis, adjusting for confounders. FINDINGS Over two thirds of patients had severe disability, over one third being wheelchair-bound/bedridden. Symptoms were highly prevalent in all conditions - mean (SD) of 10.6(4.0) symptoms. More than 50% of the MSA and PSP patients died over the year. Over the year, half of the patients showed either an upward (worsening, 24/60) or fluctuant (8/60) trajectory for POS and symptoms. The strongest predictors of higher levels of symptoms at the end of follow-up were initial scores on POS (AOR 1.30; 95%CI:1.05-1.60) and being male (AOR 5.18; 95% CI 1.17 to 22.92), both were more predictive than initial H&Y scores. INTERPRETATION The findings point to profound and complex mix of non-motor and motor symptoms in patients with late stage IPD, MSA and PSP. Symptoms are not resolved and half of the patients deteriorate. Palliative problems are predictive of future symptoms, suggesting that an early palliative assessment might help screen for those in need of earlier intervention

L1TD1 Is a Marker for Undifferentiated Human Embryonic Stem Cells

Human embryonic stem cells (hESC) are stem cells capable of differentiating into cells representative of the three primary embryonic germ layers. There has been considerable interest in understanding the mechanisms regulating stem cell pluripotency, which will ultimately lead to development of more efficient methods to derive and culture hESC. In particular, Oct4, Sox2 and Nanog are transcription factors known to be important in maintenance of hESC. However, many of the downstream targets of these transcription factors are not well characterized. Furthermore, it remains unknown whether additional novel stem cell factors are involved in the establishment and maintenance of the stem cell state.Here we show that a novel gene, L1TD1 (also known as FLJ10884 or ECAT11), is abundantly expressed in undifferentiated hESC. Differentiation of hESC via embryoid body (EB) formation or BMP4 treatment results in the rapid down-regulation of L1TD1 expression. Furthermore, populations of undifferentiated and differentiated hESC were sorted using the stem cell markers SSEA4 and TRA160. Our results show that L1TD1 is enriched in the SSEA4-positive or TRA160-positive population of hESC. Using chromatin immunoprecipitation we found enriched association of Nanog to the predicted promoter region of L1TD1. Furthermore, siRNA-mediated knockdown of Nanog in hESC also resulted in downregulation of L1TD1 expression. Finally, using luciferase reporter assay we demonstrated that Nanog can activate the L1TD1 upstream promoter region. Altogether, these results provide evidence that L1TD1 is a downstream target of Nanog.Taken together, our results suggest that L1TD1 is a downstream target of Nanog and represents a useful marker for identifying undifferentiated hESC

Left ventricular free wall impeding rupture in post-myocardial infarction period diagnosed by myocardial contrast echocardiography: Case report

BACKGROUND: Left ventricular free wall rupture occurs in up to 10% of the in-hospital deaths following myocardial infarction. It is mainly associated with posterolateral myocardial infarction and its antemortem diagnosis is rarely made. Contrast echocardiography has been increasingly used for the evaluation of myocardial perfusion in patients with acute myocardial infarction, with important prognostic implications. In this case, we reported its use for the detection of a mechanical complication following myocardial infarction. CASE PRESENTATION: A 50-year-old man with acute myocardial infarction in the lateral wall underwent myocardial contrast echocardiography for the evaluation of myocardial perfusion in the third day post-infarction. A perfusion defect was detected in lateral and inferior walls as well as the presence of contrast extrusion from the left ventricular cavity into the myocardium, forming a serpiginous duct extending from the endocardium to the epicardial region of the lateral wall, without communication with the pericardial space. Magnetic resonance imaging confirmed the diagnosis of impending rupture of the left ventricular free wall. While waiting for cardiac surgery, patient presented with cardiogenic shock and died. Anatomopathological findings were consistent with acute myocardial infarction in the lateral wall and a left ventricular free wall rupture at the infarct site. CONCLUSION: This case illustrates the early diagnosis of left ventricular free wall rupture by contrast echocardiography. Due to its ability to be performed at bedside this modality of imaging has the potential to identify this catastrophic condition in patients with acute myocardial infarction and help to treat these patients with emergent surgery

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

The RNA Polymerase Dictates ORF1 Requirement and Timing of LINE and SINE Retrotransposition

Mobile elements comprise close to one half of the mass of the human genome. Only LINE-1 (L1), an autonomous non-Long Terminal Repeat (LTR) retrotransposon, and its non-autonomous partners—such as the retropseudogenes, SVA, and the SINE, Alu—are currently active human retroelements. Experimental evidence shows that Alu retrotransposition depends on L1 ORF2 protein, which has led to the presumption that LINEs and SINEs share the same basic insertional mechanism. Our data demonstrate clear differences in the time required to generate insertions between marked Alu and L1 elements. In our tissue culture system, the process of L1 insertion requires close to 48 hours. In contrast to the RNA pol II-driven L1, we find that pol III transcribed elements (Alu, the rodent SINE B2, and the 7SL, U6 and hY sequences) can generate inserts within 24 hours or less. Our analyses demonstrate that the observed retrotransposition timing does not dictate insertion rate and is independent of the type of reporter cassette utilized. The additional time requirement by L1 cannot be directly attributed to differences in transcription, transcript length, splicing processes, ORF2 protein production, or the ability of functional ORF2p to reach the nucleus. However, the insertion rate of a marked Alu transcript drastically drops when driven by an RNA pol II promoter (CMV) and the retrotransposition timing parallels that of L1. Furthermore, the “pol II Alu transcript” behaves like the processed pseudogenes in our retrotransposition assay, requiring supplementation with L1 ORF1p in addition to ORF2p. We postulate that the observed differences in retrotransposition kinetics of these elements are dictated by the type of RNA polymerase generating the transcript. We present a model that highlights the critical differences of LINE and SINE transcripts that likely define their retrotransposition timing

Characterization of LINE-1 Ribonucleoprotein Particles

The average human genome contains a small cohort of active L1 retrotransposons that encode two proteins (ORF1p and ORF2p) required for their mobility (i.e., retrotransposition). Prior studies demonstrated that human ORF1p, L1 RNA, and an ORF2p-encoded reverse transcriptase activity are present in ribonucleoprotein (RNP) complexes. However, the inability to physically detect ORF2p from engineered human L1 constructs has remained a technical challenge in the field. Here, we have employed an epitope/RNA tagging strategy with engineered human L1 retrotransposons to identify ORF1p, ORF2p, and L1 RNA in a RNP complex. We next used this system to assess how mutations in ORF1p and/or ORF2p impact RNP formation. Importantly, we demonstrate that mutations in the coiled-coil domain and RNA recognition motif of ORF1p, as well as the cysteine-rich domain of ORF2p, reduce the levels of ORF1p and/or ORF2p in L1 RNPs. Finally, we used this tagging strategy to localize the L1–encoded proteins and L1 RNA to cytoplasmic foci that often were associated with stress granules. Thus, we conclude that a precise interplay among ORF1p, ORF2p, and L1 RNA is critical for L1 RNP assembly, function, and L1 retrotransposition

Sex- and Age-Related Differences in Morbidity Rates of 2009 Pandemic Influenza A H1N1 Virus of Swine Origin in Japan

BACKGROUND: The objective of the present study was to determine whether the morbidity rates of the 2009 pandemic influenza A H1N1 virus (pdmH1N1) varied by age and/or sex. METHODS AND FINDINGS: Retrospective analysis of 2,024,367 cases of pdmH1N1 was performed using the national surveillance data from influenza sentinel points in Japan. The male-to-female morbidity ratios (M/F ratios) in nineteen age groups were estimated as the primary outcome. The M/F ratios for pdmH1N1 influenza were: >1 in age groups <20 years and ≥80 years (p<0.001); <1 in age groups 20-79 years (p<0.001). This data suggests that males <20 years of age may be more likely to suffer from pdmH1N1 influenza than females in the same age categories. When the infection pattern for pdmH1N1 was compared with that of seasonal influenza outbreaks between 2000 and 2008, the M/F ratio for pdmH1N1 influenza was higher in ages 3-29 years and lower in ages 40-79 years. Because the present study was based on the national surveillance, it was impossible to estimate the morbidity rate for the Japanese population. It is also likely that the data did not capture asymptomatic or mild infections. CONCLUSIONS: Although exposure to the pdmH1N1 virus is assumed to be similar in both boys and girls, M/F ratios were >1 in those younger than 20 years. The subsequent reversal of the M/F ratio in the adult generation could be due to several possibilities, including: greater immunity among adult males, more asymptomatic infections among males, less reporting of illness by males, or differences in exposure to the virus and probability of visiting a clinic. These results suggest that the infection and virulence patterns of pdmH1N1 are more complex than previously considered

Treatment delay of bone tumours, compilation of a sociodemographic risk profile: A retrospective study

<p>Abstract</p> <p>Background</p> <p>Bone tumours are comparatively rare tumours and delays in diagnosis and treatment are common. The purpose of this study was to analyse sociodemographic risk factors for bone tumour patients in order to identify those at risk of prolonged patients delay (time span from first symptoms to consultation), professional delay (from consultation to treatment) or symptom interval (from first symptoms to treatment). Understanding these relationships might enable us to shorten time to diagnosis and therapy.</p> <p>Methods</p> <p>We carried out a retrospective analysis of 265 patients with bone tumours documenting sociodemographic factors, patient delay, professional delay and symptom interval. A multivariate explorative Cox model was performed for each delay.</p> <p>Results</p> <p>Female gender was associated with a prolonged patient delay. Age under 30 years and rural living predisposes to a prolonged professional delay and symptom interval.</p> <p>Conclusion</p> <p>Early diagnosis and prompt treatment are required for successful management of most bone tumour patients. We succeeded in identifying the histology independent risk factors of age under 30 years and rural habitation for treatment delay in bone tumour patients. Knowing about the existence of these risk groups age under 30 years and female gender could help the physician to diagnose bone tumours earlier. The causes for the treatment delays of patients living in a rural area have to be investigated further. If the delay initiates in the lower education of rural general physicians, further training about bone tumours might advance early detection. Hence the outcome of patients with bone tumours could be improved.</p

Whole-Blood Flow-Cytometric Analysis of Antigen-Specific CD4 T-Cell Cytokine Profiles Distinguishes Active Tuberculosis from Non-Active States

T-cell based IFN-γ release assays do not permit distinction of active tuberculosis (TB) from successfully treated disease or latent M. tuberculosis infection. We postulated that IFN-γ and IL-2 cytokine profiles of antigen-specific T cells measured by flow-cytometry ex vivo might correlate with TB disease activity in vivo. Tuberculin (PPD), ESAT-6 and CFP-10 were used as stimuli to determine antigen-specific cytokine profiles in CD4 T cells from 24 patients with active TB and 28 patients with successfully treated TB using flow-cytometry. Moreover, 25 individuals with immunity consistent with latent M. tuberculosis infection and BCG-vaccination, respectively, were recruited. Although the frequency of cytokine secreting PPD reactive CD4 T cells was higher in patients with active TB compared to patients with treated TB (median 0.81% vs. 0.39% of CD4 T cells, p = 0.02), the overlap in frequencies precluded distinction between the groups on an individual basis. When assessing cytokine profiles, PPD specific CD4 T cells secreting both IFN-γ and IL-2 predominated in treated TB, latent infection and BCG-vaccination, whilst in active TB the cytokine profile was shifted towards cells secreting IFN-γ only (p<0.0001). Cytokine profiles of ESAT-6 or CFP-10 reactive CD4 T cells did not differ between the groups. Receiver operator characteristics (ROC) analysis revealed that frequencies of PPD specific IFN-γ/IL-2 dual-positive T cells below 56% were an accurate marker for active TB (specificity 100%, sensitivity 70%) enabling effective discrimination from non-active states. In conclusion, a frequency lower than 56% IFN-γ/IL-2 dual positive PPD-specific circulating CD4 T-cells is strongly indicative of active TB

The Neutrophil's Eye-View: Inference and Visualisation of the Chemoattractant Field Driving Cell Chemotaxis In Vivo

As we begin to understand the signals that drive chemotaxis in vivo, it is becoming clear that there is a complex interplay of chemotactic factors, which changes over time as the inflammatory response evolves. New animal models such as transgenic lines of zebrafish, which are near transparent and where the neutrophils express a green fluorescent protein, have the potential to greatly increase our understanding of the chemotactic process under conditions of wounding and infection from video microscopy data. Measurement of the chemoattractants over space (and their evolution over time) is a key objective for understanding the signals driving neutrophil chemotaxis. However, it is not possible to measure and visualise the most important contributors to in vivo chemotaxis, and in fact the understanding of the main contributors at any particular time is incomplete. The key insight that we make in this investigation is that the neutrophils themselves are sensing the underlying field that is driving their action and we can use the observations of neutrophil movement to infer the hidden net chemoattractant field by use of a novel computational framework. We apply the methodology to multiple in vivo neutrophil recruitment data sets to demonstrate this new technique and find that the method provides consistent estimates of the chemoattractant field across the majority of experiments. The framework that we derive represents an important new methodology for cell biologists investigating the signalling processes driving cell chemotaxis, which we label the neutrophils eye-view of the chemoattractant field