Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies

Predictors of linkage to care following community-based HIV counseling and testing in rural Kenya

Despite innovations in HIV counseling and testing (HCT), important gaps remain in understanding linkage to care. We followed a cohort diagnosed with HIV through a community-based HCT campaign that trained persons living with HIV/AIDS (PLHA) as navigators. Individual, interpersonal, and institutional predictors of linkage were assessed using survival analysis of self-reported time to enrollment. Of 483 persons consenting to follow-up, 305 (63.2%) enrolled in HIV care within 3 months. Proportions linking to care were similar across sexes, barring a sub-sample of men aged 18–25 years who were highly unlikely to enroll. Men were more likely to enroll if they had disclosed to their spouse, and women if they had disclosed to family. Women who anticipated violence or relationship breakup were less likely to link to care. Enrolment rates were significantly higher among participants receiving a PLHA visit, suggesting that a navigator approach may improve linkage from community-based HCT campaigns.Vestergaard Frandse

The geography of recent genetic ancestry across Europe

The recent genealogical history of human populations is a complex mosaic formed by individual migration, large-scale population movements, and other demographic events. Population genomics datasets can provide a window into this recent history, as rare traces of recent shared genetic ancestry are detectable due to long segments of shared genomic material. We make use of genomic data for 2,257 Europeans (the POPRES dataset) to conduct one of the first surveys of recent genealogical ancestry over the past three thousand years at a continental scale. We detected 1.9 million shared genomic segments, and used the lengths of these to infer the distribution of shared ancestors across time and geography. We find that a pair of modern Europeans living in neighboring populations share around 10-50 genetic common ancestors from the last 1500 years, and upwards of 500 genetic ancestors from the previous 1000 years. These numbers drop off exponentially with geographic distance, but since genetic ancestry is rare, individuals from opposite ends of Europe are still expected to share millions of common genealogical ancestors over the last 1000 years. There is substantial regional variation in the number of shared genetic ancestors: especially high numbers of common ancestors between many eastern populations likely date to the Slavic and/or Hunnic expansions, while much lower levels of common ancestry in the Italian and Iberian peninsulas may indicate weaker demographic effects of Germanic expansions into these areas and/or more stably structured populations. Recent shared ancestry in modern Europeans is ubiquitous, and clearly shows the impact of both small-scale migration and large historical events. Population genomic datasets have considerable power to uncover recent demographic history, and will allow a much fuller picture of the close genealogical kinship of individuals across the world.Comment: Full size figures available from http://www.eve.ucdavis.edu/~plralph/research.html; or html version at http://ralphlab.usc.edu/ibd/ibd-paper/ibd-writeup.xhtm

Lycopene from two food sources does not affect antioxidant or cholesterol status of middle-aged adults

BACKGROUND: Epidemiological studies have reported associations between reduced cardiovascular disease and diets rich in tomato and/or lycopene. Intervention studies have shown that lycopene-containing foods may reduce cholesterol levels and lipid peroxidation, factors implicated in the initiation of cardiovascular disease. The objective of this study was to determine whether consumption of lycopene rich foods conferred cardiovascular protection to middle-aged adults as indicated by plasma lipid concentrations and measures of ex vivo antioxidants. METHODS: Ten healthy men and women consumed a low lycopene diet with no added lycopene (control treatment) or supplemented with watermelon or tomato juice each containing 20 mg lycopene. Subjects consumed each treatment for three weeks in a crossover design. Plasma, collected weekly was analyzed for total cholesterol, high density lipoprotein cholesterol (HDL-C) and triglyceride concentrations and for the antioxidant biomarkers of malondialdehyde formation products (MDA), plasma glutathione peroxidase (GPX) and ferric reducing ability of plasma (FRAP). Data were analyzed using Proc Mixed Procedure and associations between antioxidant and lipid measures were identified by Pearson's product moment correlation analysis. RESULTS: Compared to the control diet, the lycopene-containing foods did not affect plasma lipid concentrations or antioxidant biomarkers. Women had higher total cholesterol, HDL-C and triglyceride concentrations than did the men. Total cholesterol was positively correlated to MDA and FRAP while HDL-C was positively correlated to MDA and GPX. GPX was negatively correlated to triglyceride concentration. CONCLUSIONS: The inclusion of watermelon or tomato juice containing 20 mg lycopene did not affect plasma lipid concentrations or antioxidant status of healthy subjects. However, plasma cholesterol levels impacted the results of MDA and FRAP antioxidant tests

GSTT2 promoter polymorphisms and colorectal cancer risk

BACKGROUND: Glutathione S-transferases are a group of enzymes that participate in detoxification and defense mechanisms against toxic carcinogens and other compounds. These enzymes play an important role in human carcinogenesis. In the present study, we sought to determine whether GSTT2 promoter single nucleotide polymorphisms (SNPs) are associated with colorectal cancer risk. METHODS: A total of 436 colorectal cancer patients and 568 healthy controls were genotyped for three GSTT2 promoter SNPs (-537G>A, -277T>C and -158G>A), using real-time TaqMan assay and direct sequencing. An electrophoretic mobility shift assay (EMSA) was performed to determine the effects of polymorphisms on protein binding to the GSTT2 promoter. RESULTS: The -537A allele (-537G/A or A/A) was significantly associated with colorectal cancer risk (OR = 1.373, p = 0.025), while the -158A allele (-158G/A or A/A) was involved in protection against colorectal cancer (OR = 0.539, p = 0.032). Haplotype 2 (-537A, -277T, -158G) was significantly associated with colorectal cancer risk (OR = 1.386, p = 0.021), while haplotype 4 (-537G, -277C, -158A) protected against colorectal cancer (OR = 0.539, p = 0.032). EMSA data revealed lower promoter binding activity in the -537A allele than its -537G counterpart. CONCLUSION: Our results collectively suggest that SNPs and haplotypes of the GSTT2 promoter region are associated with colorectal cancer risk in the Korean population

Health and literacy in first- and second-generation Moroccan Berber women in the Netherlands: Ill literacy?

AIM: The present study was aimed at investigating the role of literacy and generation in the self-reported general health status of Moroccan Berber speaking women in the Netherlands. METHOD: Fifty women in our sample (N = 75) were first generation women, from which group 25 were literates and 25 illiterates. Another group of 25 literate women belonged to the second generation. The three groups were matched for demographic characteristics. Questionnaires were administered reflecting all concepts under study. We hypothesized that, within the first generation, illiterates compared with literates would report worse health. Our second hypothesis was that literates of the first generation compared with those of the second generation would have a similar health condition. RESULTS: After controlling for age, having a job, and having an employed partner, the first generation literates compared with the illiterates of the first generation indeed reported significantly better health. Additionally, we did not find any differences in health condition between both literate groups, even after controlling for age, number of children, and marital status. Health complaints that were most frequently reported by both groups, concerned pain in shoulders, back and head. CONCLUSIONS: Our results underline the importance of offering immigrants optimal access to opportunities and facilities that can improve their literacy and reading ability

Minimum detectable and minimal clinically important changes for pain in patients with nonspecific neck pain

<p>Abstract</p> <p>Background</p> <p>The minimal detectable change (MDC) and the minimal clinically important changes (MCIC) have been explored for nonspecific low back pain patients and are similar across different cultural settings. No data on MDC and MCIC for pain severity are available for neck pain patients. The objectives of this study were to estimate MDC and MCIC for pain severity in subacute and chronic neck pain (NP) patients, to assess if MDC and MCIC values are influenced by baseline values and to explore if they are different in the subset of patients reporting referred pain, and in subacute versus chronic patients.</p> <p>Methods</p> <p>Subacute and chronic patients treated in routine clinical practice of the Spanish National Health Service for neck pain, with or without pain referred to the arm, and a pain severity ≥ 3 points on a pain intensity number rating scale (PI-NRS), were included in this study. Patients' own "global perceived effect" over a 3 month period was used as the external criterion. The minimal detectable change (MDC) was estimated by means of the standard error of measurement in patients who self-assess as unchanged. MCIC were estimated by the mean value of change score in patients who self-assess as improved (mean change score, MCS), and by the optimal cutoff point in receiver operating characteristics curves (ROC). The effect on MDC and MCIC of initial scores, duration of pain, and existence of referred pain were assessed.</p> <p>Results</p> <p>658 patients were included, 487 of them with referred pain. MDC was 4.0 PI-NRS points for neck pain in the entire sample, 4.2 for neck pain in patients who also had referred pain, and 6.2 for referred pain. MCS was 4.1 and ROC was 1.5 for referred and for neck pain, both in the entire sample and in patients who also complained of referred pain. ROC was lower (0.5 PI-NRS points) for subacute than for chronic patients (1.5 points). MCS was higher for patients with more intense baseline pain, ranging from 2.4 to 4.9 PI-NRS for neck pain and from 2.4 to 5.3 for referred pain.</p> <p>Conclusion</p> <p>In general, improvements ≤ 1.5 PI-NRS points could be seen as irrelevant. Above that value, the cutoff point for clinical relevance depends on the methods used to estimate MCIC and on the patient's baseline severity of pain. MDC and MCIC values in neck pain patients are similar to those for low back pain and other painful conditions.</p

Superior Immunogenicity of Inactivated Whole Virus H5N1 Influenza Vaccine is Primarily Controlled by Toll-like Receptor Signalling

In the case of an influenza pandemic, the current global influenza vaccine production capacity will be unable to meet the demand for billions of vaccine doses. The ongoing threat of an H5N1 pandemic therefore urges the development of highly immunogenic, dose-sparing vaccine formulations. In unprimed individuals, inactivated whole virus (WIV) vaccines are more immunogenic and induce protective antibody responses at a lower antigen dose than other formulations like split virus (SV) or subunit (SU) vaccines. The reason for this discrepancy in immunogenicity is a long-standing enigma. Here, we show that stimulation of Toll-like receptors (TLRs) of the innate immune system, in particular stimulation of TLR7, by H5N1 WIV vaccine is the prime determinant of the greater magnitude and Th1 polarization of the WIV-induced immune response, as compared to SV- or SU-induced responses. This TLR dependency largely explains the relative loss of immunogenicity in SV and SU vaccines. The natural pathogen-associated molecular pattern (PAMP) recognized by TLR7 is viral genomic ssRNA. Processing of whole virus particles into SV or SU vaccines destroys the integrity of the viral particle and leaves the viral RNA prone to degradation or involves its active removal. Our results show for a classic vaccine that the acquired immune response evoked by vaccination can be enhanced and steered by the innate immune system, which is triggered by interaction of an intrinsic vaccine component with a pattern recognition receptor (PRR). The insights presented here may be used to further improve the immune-stimulatory and dose-sparing properties of classic influenza vaccine formulations such as WIV, and will facilitate the development of new, even more powerful vaccines to face the next influenza pandemic

Spiral-Wave Turbulence and Its Control in the Presence of Inhomogeneities in Four Mathematical Models of Cardiac Tissue

Regular electrical activation waves in cardiac tissue lead to the rhythmic contraction and expansion of the heart that ensures blood supply to the whole body. Irregularities in the propagation of these activation waves can result in cardiac arrhythmias, like ventricular tachycardia (VT) and ventricular fibrillation (VF), which are major causes of death in the industrialised world. Indeed there is growing consensus that spiral or scroll waves of electrical activation in cardiac tissue are associated with VT, whereas, when these waves break to yield spiral- or scroll-wave turbulence, VT develops into life-threatening VF: in the absence of medical intervention, this makes the heart incapable of pumping blood and a patient dies in roughly two-and-a-half minutes after the initiation of VF. Thus studies of spiral- and scroll-wave dynamics in cardiac tissue pose important challenges for in vivo and in vitro experimental studies and for in silico numerical studies of mathematical models for cardiac tissue. A major goal here is to develop low-amplitude defibrillation schemes for the elimination of VT and VF, especially in the presence of inhomogeneities that occur commonly in cardiac tissue. We present a detailed and systematic study of spiral- and scroll-wave turbulence and spatiotemporal chaos in four mathematical models for cardiac tissue, namely, the Panfilov, Luo-Rudy phase 1 (LRI), reduced Priebe-Beuckelmann (RPB) models, and the model of ten Tusscher, Noble, Noble, and Panfilov (TNNP). In particular, we use extensive numerical simulations to elucidate the interaction of spiral and scroll waves in these models with conduction and ionic inhomogeneities; we also examine the suppression of spiral- and scroll-wave turbulence by low-amplitude control pulses. Our central qualitative result is that, in all these models, the dynamics of such spiral waves depends very sensitively on such inhomogeneities. We also study two types of control schemes that have been suggested for the control of spiral turbulence, via low amplitude current pulses, in such mathematical models for cardiac tissue; our investigations here are designed to examine the efficacy of such control schemes in the presence of inhomogeneities. We find that a local pulsing scheme does not suppress spiral turbulence in the presence of inhomogeneities; but a scheme that uses control pulses on a spatially extended mesh is more successful in the elimination of spiral turbulence. We discuss the theoretical and experimental implications of our study that have a direct bearing on defibrillation, the control of life-threatening cardiac arrhythmias such as ventricular fibrillation

Avoidable costs of physical treatments for chronic back, neck and shoulder pain within the Spanish National Health Service: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Back, neck and shoulder pain are the most common causes of occupational disability. They reduce health-related quality of life and have a significant economic impact. Many different forms of physical treatment are routinely used. The objective of this study was to estimate the cost of physical treatments which, despite the absence of evidence supporting their effectiveness, were used between 2004 and 2007 for chronic and non-specific neck pain (NP), back pain (BP) and shoulder pain (SP), within the Spanish National Health Service in the Canary Islands (SNHSCI).</p> <p>Methods</p> <p>Chronic patients referred from the SNHSCI to private physical therapy centres for NP, BP or SP, between 2004 and 2007, were identified. The cost of providing physical therapies to these patients was estimated. Systematic reviews (SRs) and clinical practice guidelines (CPGs) for NP, BP and SP available in the same period were searched for and rated according to the Oxman and AGREE criteria, respectively. Those rated positively for ≥70% of the criteria, were used to categorise physical therapies as Effective; Ineffective; Inconclusive; and Insufficiently Assessed. The main outcome was the cost of physical therapies included in each of these categories.</p> <p>Results</p> <p>8,308 chronic cases of NP, 4,693 of BP and 5,035 of SP, were included in this study. Among prescribed treatments, 39.88% were considered Effective (physical exercise and manual therapy with mobilization); 23.06% Ineffective; 13.38% Inconclusive, and 23.66% Insufficiently Assessed. The total cost of treatments was € 5,107,720. Effective therapies accounted for € 2,069,932.</p> <p>Conclusions</p> <p>Sixty percent of the resources allocated by the SNHSCI to fund physical treatment for NP, BP and SP in private practices are spent on forms of treatment proven to be ineffective, or for which there is no evidence of effectiveness.</p