The Special Issue On Attachment: Overreaching Theory And Data

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92050/1/j.1744-1617.2012.01464.x.pd

Stability effects on results of diffusion tensor imaging analysis by reduction of the number of gradient directions due to motion artifacts: an application to presymptomatic Huntington's disease.

In diffusion tensor imaging (DTI), an improvement in the signal-to-noise ratio (SNR) of the fractional anisotropy (FA) maps can be obtained when the number of recorded gradient directions (GD) is increased. Vice versa, elimination of motion-corrupted or noisy GD leads to a more accurate characterization of the diffusion tensor. We previously suggest a slice-wise method for artifact detection in FA maps. This current study applies this approach to a cohort of 18 premanifest Huntington's disease (pHD) subjects and 23 controls. By 2-D voxelwise statistical comparison of original FA-maps and FA-maps with a reduced number of GD, the effect of eliminating GD that were affected by motion was demonstrated.We present an evaluation metric that allows to test if the computed FA-maps (with a reduced number of GD) still reflect a "true" FA-map, as defined by simulations in the control sample. Furthermore, we investigated if omitting data volumes affected by motion in the pHD cohort could lead to an increased SNR in the resulting FA-maps.A high agreement between original FA maps (with all GD) and corrected FA maps (i.e. without GD corrupted by motion) were observed even for numbers of eliminated GD up to 13. Even in one data set in which 46 GD had to be eliminated, the results showed a moderate agreement

Incidence of Rejection in Renal Transplant Surgery in the LVHN Population Leading to Graft Failure: 6 Year Review

Incidence of Rejection in Renal Transplant Surgery in the LVHN Population Leading to Graft Failure: 6 Year Review Jessica Ludolph1 Lynsey Biondi, MD1,2 and Michael Moritz, MD1,2 1Department of Surgery, Lehigh Valley Health Network 2Research Scholar Program Mentor Abstract To obtain optimal outcomes, it is vital to continually investigate variables potentially effecting rejection and graft failures. 407 renal transplant recipients who were transplanted at The Transplant Center of the Lehigh Valley from January 2009 to December 2014 were analyzed using descriptive statistics. Variables potentially influencing graft survival, including delayed graft function, and cell mediated and antibody mediated rejection, were compared. Demographic information, donor characteristics, and cold ischemic time were also investigated. Rejection of one or more types occurred in 39% of patients. Cellular rejection (35% of total patients) occurred more commonly than antibody mediated rejection (8% of total patients), with borderline cellular rejection the most common (40% of rejections). Antibody mediated rejection negatively impacted graft survival (p=0.0917) whereas cellular rejection did not show a statistically significant effect. Delayed graft function was common (29% of patients), but patients with delayed graft function have similar rejection rates as patients without delayed graft function (29% for both). Delayed graft function was associated with significantly lower graft survival. Background Typical solid organs transplanted are the kidneys, heart, liver, pancreas, and lungs. Kidneys are the most common solid organ transplant performed. The Transplant Center of the Lehigh Valley performs a large volume of kidney transplant surgeries and maintains a large database with the details of these procedures. This project will quantify recent outcomes data related to incidences of the different types of rejection as compared to other variables. These variables include transplant type, cause of renal failure, and time on dialysis prior to transplantation. Currently, there is debate about the impact of acute rejection episodes on graft survival. More recent studies demonstrate a reduction in incidences of rejection over time, but not a similar reduction in renal graft failure.5 Further studies have also seen that graft failures are less dependent on the acute rejection episode itself but rather that an acute rejection can initiate a chronic pathological process that ultimately leads to graft failure.8 Rejection can be broken down into two major types; cell-mediated and antibody mediated rejection. Severity is graded on the Banff ’97 scale. This scale is broken down into seven different categories, in order of increasing severity: Borderline, Grade 1A, Grade 1B, Grade 2A, Grade 2B, Grade 3, and Grade 4, aimed at providing a standard classification system for the varying pathologies seen on histological examination. In addition to the Banff scale, clinical vs. subclinical rejection becomes an important metric for evaluating the ultimate outcome of the allograft. An incidence of subclinical rejection is diagnosed from biopsies performed routinely based on protocol rather than for a change in transplant function. LVHN performs protocol biopsies at 1, 6, and 12 months post-transplant. Additional biopsies are performed when clinically indicated, usually a negative change in transplant function. In some studies, rejection episodes that do not cause a decrease in renal function have a lesser impact on graft survival.5 It can be postulated then, that subclinical rejection episodes do not have as significant of an impact on graft survival as clinical rejection episodes. The occurrence of cell mediated versus antibody mediated rejection can have vastly different effects on outcomes. These two types of rejection should not be thought of as completely separate entities, but rather overlapping, where an episode of unresolved cell-mediated rejection can lead to antibody mediated rejection.8 This study aims to further investigate the relationships between the different types of rejection and the graft failure as well as look at other compounding factors that might also show correlation with either the incidence of rejection or the ultimate outcome of the graft. Methods A retrospective study was conducted at the Transplant Center of the Lehigh Valley in Allentown, Pennsylvania. The 407 patients that underwent renal transplantation from January 2009 to December 2014 were included in the study. During this period, a uniform protocol for immunosuppression, post-transplant care, and biopsy by protocol and clinical indication was in place. Patient data was collected from the Organ Transplant Tracking Record (OTTR) database and included transplant date, graft survival time, patient survival time, donor type, types of rejections, treatments received, and demographic information. Those patients who experienced one or more episodes of rejection were then further analyzed to see if there is a correlation between the other factors including, transplant type (living vs. deceased donor, PHS higher risk), demographics (age, sex), delayed graft function (defined as the patient needing dialysis within 7 days of transplant), time on dialysis prior to transplant, cold ischemic time, and the ultimate outcome of the graft. Data from the OTTR was coded so it could be statistically analyzed. Primary disease category was done based on the categories used by the Scientific Registry of Transplant Recipients (SRTR): Glomerular diseases, Tubular and Interstitial diseases, Polycystic Kidneys, congenital/familial/metabolic, Diabetes, Renovascular and Vascular diseases, Neoplasms, and Hypertensive Nephrosclerosis. Most of the data was coded using 0=No and 1=Yes for types or rejection, delayed graft function, and whether or not the patient received a particular treatment. Cell mediated rejection and antibody mediated rejection were compared for history of delayed graft function and graft survival. Descriptive statistics were performed on age, gender, type of donor (living vs. deceased), graft failure, delay of graft function, time on dialysis, cold ischemic time, and incidence of rejection and the proportion of each type of rejection. Patients who died with a functioning graft were excluded in graft survival. Survival analysis was used to analyze cell mediated rejection, antibody mediated rejection, and delayed graft function, versus graft survival time. Results Of 407 total patients included in the study, 159 experienced at least one episode of rejection (39%) and 248 experienced no rejection (61%). (See Table 1) Of those who experienced rejection, the mean age was 57 years old, 32% were female, 19% had a living donor, 23% had graft failure (p=.0254), 29% had delay of graft function. The mean time on dialysis was 1401 days, and the mean cold ischemic time was 712 minutes. Looking at those who experienced no rejection, the mean age was 58 years old, 30% were female, 23% had a living donor, 16% had graft failure, 29% had a delay in graft function, the mean time on dialysis was 925 days, and the mean cold ischemic time was 719 minutes. Only graft failure was statistically significantly different. Regarding all types of rejection, cell mediated borderline rejection was the most common encompassing 40% of all rejections, followed by Acute Cellular Rejection Banff Grade 1B (20%), Acute Cellular Rejection Banff Grade 1A (19%), Antibody mediated rejection (17%), and Grade 2A and 2B (2%). Antibody mediated rejection is associated with a statistically higher incidence (p Delayed graft function was also shown to have an influence on graft survival time (p Discussion In the LVHN population of renal transplant patients, less severe types of cellular rejection are more common (i.e. Borderline, Grade 1B). Overall, there were fewer instances of antibody mediated rejection compared to cell mediated rejection; 31% of the antibody mediated rejections ended in graft failure while only 10% of cell mediated rejections ended in graft failure. While there was a correlation between antibody mediated rejection and graft survival time, the same correlation was not as strong for cell mediated rejection with a p value of (\u3e0.05). Antibody mediated rejection appears to have a greater negative effect on graft survival than cell mediated rejection. In addition to examining the impact of rejection on the outcome of the graft, it is important to also consider factors that can impact episodes of rejection. In this study, delayed graft function and the presence and type of rejection were examined. For all patients, cell mediated rejection was more common than antibody mediated rejection. The incidence of all types of rejection was similar for delayed graft function and non-delayed graft function patients. Previous studies show delayed graft function after Donation after Cardiac Death (DCD) donors does not have the same negative influence on survival as delayed graft function after brain death. Further investigation into delayed graft function patients and types of donors is warranted. When analyzing graft survival as a continuous variable delayed graft function had a large impact, with the lowest mean graft survival time with a standard error of 53, and cell mediated rejection had the second lowest graft survival time with a similar standard error of 51. Interestingly, antibody mediated rejection had the highest mean graft survival time, but it also had the largest standard error of 114, indicating that its mean is not as well-known as the other two. This can be due to the smaller number of individuals experiencing antibody mediated rejection (36) compared to 118 with delayed graft function and 143 with cell mediated rejection. Late rejections may also influence this data. A survival analysis would have to be run on this data to determine the true relationship between these conditions and graft survival time. Comparing low level (Borderline/1A) with high level cellular rejection may also be useful. This study serves to provide a brief overview of the characteristics of the LVHN Renal transplant population. It is a springboard for future investigation of the rejection process and graft survival. Conclusions Acute cellular rejection (particularly borderline) is more common than antibody mediated rejection. Antibody mediated rejection has a statistically significant (p References Controversial Issues. (n.d.) West\u27s Encyclopedia of American Law, edition 2. (2008). Retrieved February 23 2015 from http://legal-dictionary.thefreedictionary.com/Controversial+Issues Lamb, K.E., Lodhi, S., & Meier-Kriesche, H.U. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant 2011, 11:450-462. Racusen, L.C., Colvin, R.B., Solez, K., et al. Antibody-Mediated Rejection Criteria-an Addition to the Banff ’97 Classification of Renal Allograft Rejection. American Journal of Transplantation 2003, 3: 708-714. Gaber, L.W., Moore, L.W., Alloway, R.R., et al. Correlation between Banff classification, acute renal rejection scores and reversal of rejection. Kidney International 1996, 49: 481-487. Meier-Kriesche, H.U., Schold, J.D., Srinivas, T.R., & Kaplan, B. Lack of Improvement in Renal Allograft Survival Despite a Marked Decrease in Acute Rejection Rates Over the Most Recent Era. American Journal of Transplantation 2004, 4:378-383. El-Zoghby, Z.M., Stegall, M.D., Lager, D.J., et al. Identifying Specific Causes of Kidney Allograft Loss. American Journal of Transplantation 2009, 9:527-535. Wu, K., Budde K., Lu, H., et al. The Severity of Acute Cellular Rejection Defined by Banff Classification Is Associated With Kidney Allograft Outcomes. Transplantation 2014, 97:1146-1154. El Terse, M., Grande, J.P., Keddis, M.T., Rodrigo, E., et al. Kidney Allograft Survival After Acute Rejection, the Value of Follow-Up Biopsies. American Journal of Transplantation 2013, 13:2334-2341. Appendix Table 1: Characteristics of patients with at least one incidence of rejection vs. those with none (n=407) *Influence of rejection as the independent variable. All other variables show incidence of rejection as the dependent variable. Graft failure only includes those who had graft failure unrelated to patient death. Figure 1: Includes types of cell mediated rejections Banff Scale (Grade 1A, 1B, 2A, 2B, 3, 4, Borderline) Figure 2: Delayed graft function is defined as anyone receiving dialysis within 7 days post-transplant. {Mean graft survival time in days} Delayed Graft Function (DGF) Figure 3: Graft failure only included patients who had graft failure unrelated to patient death. Effect of antibody mediated rejection on graft failure p\u3c0.0001 Figure 4: Delayed Graft Function p Cell Mediated Rejection p=.053

CSF SerpinA1 in Creutzfeldt\u2013Jakob disease and frontotemporal lobar degeneration

Objective: SerpinA1 (alpha-1 antitrypsin) is an acute inflammatory protein, which seems to play a role in neurodegeneration and neuroinflammation. In Alzheimer\u2019s disease and synucleinopathies, SerpinA1 is overexpressed in the brain and the cerebrospinal fluid (CSF) showing abnormal patterns of its charge isoforms. To date, no comprehensive studies explored SerpinA1 CSF isoforms in Creutzfeldt\u2013Jakob disease (CJD) and frontotemporal lobar degeneration (FTLD). Methods: Using a capillary isoelectric focusing immunoassay, we analyzed CSF SerpinA1 isoforms in control cases (n = 31) and patients with a definite or probable diagnosis of CJD (n=77) or FTLD (n = 30), belonging to several disease subtypes. Results: The overall SerpinA1 signal was significantly higher than in controls in CJD subtypes linked to abnormal prion protein (PrPSc) type 1, such as sporadic CJD (sCJD) MM(V)1, and in FTLD-TDP. Moreover, CJD linked to PrPSc type 1 and FTLD-TAU groups showed a significant relative increase of acidic and basic isoforms in comparison with controls, thereby forming two distinct SerpinA1 isoform profiles. Interpretation: CJD linked to PrPSc type 1 and FTLD show a differential upregulation and post-translational modifications of CSF SerpinA1. Further studies are needed to clarify whether these findings may reflect a common, albeit disease-specific, pathogenetic mechanism related to neurodegeneration

Assessing the health benefits of development interventions

Biomedical interventions, such as therapeutics, vaccines and insecticides, are alone insufficient to achieve Sustainable Development Goal (SDG) 3—healthy lives and wellbeing for all ages. We also need development interventions to tackle the underlying determinants of ill-health by reducing deprivation and improving living conditions and the environment. This recognition formed the bedrock of early public health, from housing improvements and clean water provision in 19th century Europe and North America, to house screening for malaria elimination in the USA and water management for historical vector control in Italy, Sri Lanka, Panama and Zambia. Today, development interventions are a basic human right and ever more critical in response to rapid population growth, urbanisation and climate change

Pattern of paresis in ALS is consistent with the physiology of the corticomotoneuronal projections to different muscle groups

OBJECTIVE: A recent neuroanatomical staging scheme of amyotrophic lateral sclerosis (ALS) indicates that a cortical lesion may spread, as a network disorder, both at the cortical level and via corticofugal tracts, including corticospinal projections providing direct monosynaptic input to α-motoneurons. These projections are involved preferentially and early in ALS. If these findings are clinically relevant, the pattern of paresis in ALS should primarily involve those muscle groups that receive the strongest direct corticomotoneuronal (CM) innervation. METHODS: In a large cohort (N=436), we analysed retrospectively the pattern of muscle paresis in patients with ALS using the UK Medical Research Council (MRC) scoring system; we subsequently carried out two independent prospective studies in two smaller groups (N=92 and N=54). RESULTS: The results indicated that a characteristic pattern of paresis exists. When pairs of muscle groups were compared within patients, the group known to receive the more pronounced CM connections was significantly weaker. Within patients, there was greater relative weakness (lower MRC score) in thumb abductors versus elbow extensors, for hand extensors versus hand flexors and for elbow flexors versus elbow extensors. In the lower limb, knee flexors were relatively weaker than extensors, and plantar extensors were weaker than plantar flexors. CONCLUSIONS: These findings were mostly significant (p<0.01) for all six pairs of muscles tested and provide indirect support for the concept that ALS may specifically affect muscle groups with strong CM connections. This specific pattern could help to refine clinical and electrophysiological ALS diagnostic criteria and complement prospective clinicopathological correlation studies

H1N1 influenza pandemic in Italy revisited : has the willingness to get vaccinated suffered in the long run?

Background. The aim of the study is to assess the long-term secondary effects of personal experience with the H1N1 pandemic of 2009/2010 and the perception of the institutional reaction to it on Italians\u2019 willingness to get vaccinated in case of a novel influenza pandemic. Design and Methods. We conducted 140 face-to-face interviews in the Registry Office of the Municipality of Milan, Italy, from October to December 2012. Results. Willingness to get vaccinated during a novel influenza pandemic was best predicted by having been vaccinated against the seasonal flu in the past (OR=5.18; 95%CI: 1.40 to 19.13) and fear of losing one\u2019s life in case of an infection with H1N1 (OR=4.09; 95%CI: 1.68 to 9.97). It was unaffected by the assessment of institutional performance. Conclusions. The findings of this study do not point to long-term secondary effects of the institutional handling of the H1N1 pandemic. The results highlight the fact that behavioural intention is not the same as behaviour, and that the former cannot simply be taken as an indicator of the latter

Long-term survival analysis of masitinib in amyotrophic lateral sclerosis

Background: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001. Methods: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity. Results: A significant survival benefit of 25 months (p = 0.037) and 47% reduced risk of death (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo (n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31–0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001. Conclusions: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality.Fil: Mora, Jesus S.. No especifíca;Fil: Bradley, Walter G.. University of Miami; Estados UnidosFil: Chaverri, Delia. No especifíca;Fil: Hernández Barral, María. No especifíca;Fil: Mascias, Javier. No especifíca;Fil: Gamez, Josep. Universitat Autònoma de Barcelona; EspañaFil: Gargiulo Monachelli, Gisella Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Moussy, Alain. No especifíca;Fil: Mansfield, Colin D.. No especifíca;Fil: Hermine, Olivier. No especifíca;Fil: Ludolph, Albert C.. Universitat Ulm; Alemani

Implementation of a population-based epidemiological rare disease registry: study protocol of the amyotrophic lateral sclerosis (ALS) - registry Swabia

BACKGROUND: The social and medical impact of rare diseases is increasingly recognized. Amyotrophic lateral sclerosis (ALS) is the most prevalent of the motor neuron diseases. It is characterized by rapidly progressive damage to the motor neurons with a survival of 2–5 years for the majority of patients. The objective of this work is to describe the study protocol and the implementation steps of the amyotrophic lateral sclerosis (ALS) registry Swabia, located in the South of Germany. METHODS/DESIGN: The ALS registry Swabia started in October 2010 with both, the retrospective (01.10.2008-30.09.2010) and prospective (from 01.10.2010) collection of ALS cases, in a target population of 8.6 million persons in Southern Germany. In addition, a population based case–control study was implemented based on the registry that also included the collection of various biological materials. Retrospectively, 420 patients (222 men and 198 women) were identified. Prospectively data of ALS patients were collected, of which about 70% agreed to participate in the population-based case–control study. All participants in the case–control study provided also a blood sample. The prospective part of the study is ongoing. DISCUSSION: The ALS registry Swabia has been implemented successfully. In rare diseases such as ALS, the collaboration of registries, the comparison with external samples and biorepositories will facilitate to identify risk factors and to further explore the potential underlying pathophysiological mechanisms

Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS

Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for independent verification. This review considers the potential routes to the discovery of neurochemical markers in ALS, and provides a consensus statement on standard operating procedures that will facilitate multicenter collaboration, validation and ultimately clinical translation