An Extraperitoneal Technique for Murine Heterotopic Cardiac Transplantation

The mouse heterotopic cardiac transplantation model has been used extensively by investigators in the field of organ transplantation to study the rejection process, test new antirejection treatments, tolerance induction protocols or to understand basic immunological principles. Due to its extensive use, any small refinement of the technique would have a major impact on replacement, reduction and refinement (commonly known as the 3Rs). Here, we describe a novel approach to refine this model. The donor aorta and pulmonary artery are anastomosed peripherally to the femoral artery and vein of the recipient, respectively. The technical success rate is comparable to the conventional abdominal site, but it avoids a laparotomy and handling of the bowels making it less invasive method. As a result, recipients recover faster and require less postoperative analgesia. It is a major refinement under one of the 3Rs and would represent an advance in animal welfare in scientific research.     

Does <Emphasis Type="Italic">Dientamoeba fragilis</Emphasis> cause diarrhea? A systematic review

It remains controversial whether Dientamoeba fragilis is a commensal parasite or a pathogen. The objective of this systematic review was to establish the strength of the evidence that Dientamoeba fragilis would cause diarrhea. A search was performed for studies that reported either the association between D. fragilis detection in stools and diarrhea or diarrhea outcomes with D. fragilis therapy or challenge. Data from seven studies of specific populations reported that 22% had D. fragilis in stools of which only 23% had diarrhea. Eleven studies of stool samples submitted to laboratories reported that 4.3% of individuals had D. fragilis of which 54% had diarrhea. Twelve studies reported that D. fragilis was detected from 1.6% of individuals with diarrhea and 9.6% of diarrheal stools. Five studies analyzed the prevalence of D. fragilis in individuals with and without diarrhea; the two with a statistically significant difference between groups had discordant results. The only cohort study with an appropriate control group reported diarrhea in a higher proportion of children with D. fragilis than in controls. No D. fragilis treatment studies included diarrhea as an outcome. There were only two challenge studies involving one person each. In conclusion, the evidence that D. fragilis would cause diarrhea or that treatment would hasten diarrhea resolution is inconclusive.     

Respiratory syncytial virus prophylaxis in cystic fibrosis: the Canadian registry of palivizumab data (2005–2016)

Respiratory syncytial virus (RSV) may cause severe illness in cystic fibrosis (CF) children, but recommendations vary on prophylaxis. CARESS is a prospective registry of children who received palivizumab in 32 Canadian sites from 2005 to 2016. Demographic data were collected at enrollment and respiratory illness-related events recorded monthly. We reviewed respiratory illness hospitalization (RIH) and RSV hospitalization (RSVH) in CF children aged <?24 months versus those prophylaxed for standard indications (SI; prematurity, chronic lung disease [CLD] and congenital heart disease [CHD]), and complex medical disorders (CM). Of 23,228 children analyzed, 19,452 (83.8%) were SI, 3349 (14.4%) were CM, and 427 (1.8%) were CF. CF children were more likely to be Caucasian, heavier at birth and enrollment, and less likely to have a sibling or live in crowded conditions. CF children were similar to the other groups in daycare attendance, history of atopy, and exposure to smoking. RIH incidences were 4.3% (premature), 13.8% CLD, 11.5% CHD, 11.7% CM, and 6.8% CF. RSVH incidence in CF children was similar to that in the SI and CM groups: 1.1, 1.5, and 2.0% groups respectively. Cox regression analyses showed that compared to CF children, the HRs for RSVH in SI (HR 2.0 95% CI 0.5–8.3, p?=?0.3) and CM (HR 2.4, 95% CI 0.6–9.8, p?=?0.2) did not differ. CF children are equally at risk for RSVH relative to those prophylaxed for other indications. Pending robust evidence from prospective trials, palivizumab could perhaps be considered in the interim, for young CF patients born early during the RSV season with evidence of serious lung disease.     

In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer’s dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.The consensus statement on concussions from the Fourth International Conference on Concussion in Sports (Zurich 2012) (1) defines acute mild traumatic brain injury (mTBI) or cerebral concussion as a brain injury with a complex pathophysiological process induced by biomechanical forces. Cerebral concussion causes white matter axonal injury due to axonal shearing and stretching (2), typically resulting in the rapid onset of short-lived impairment of neurological function that resolves spontaneously and largely reflects a functional disturbance rather than a structural injury. As such, no abnormality is seen on standard structural neuroimaging determinations (1).A number of early literature reports described a neurodegenerative disease associated with a history of repetitive TBI in retired professional boxers (3, 4), with a prevalence rate of up to 47% among retired professional boxers aged 50 y and older who boxed for more than 10 y (5). Initially named “punch drunk syndrome” (3) and dementia pugilistica (4), this syndrome is now known as chronic traumatic encephalopathy (CTE) in the current literature (6, 7).Compelling autopsy evidence (6–8) and neurobehavioral determinations (9) of retired professional American football athletes indicate that a subgroup develops neurodegenerative and clinical changes typical of CTE, a progressive syndrome distinctively different from Alzheimer’s disease (AD), which is the most common form of dementia in the elderly (10). The connection between multiple concussions and subconcussive head impacts (2) and CTE is compelling, because history of repetitive concussions is the strongest risk factor for development of CTE in numerous contact sports (e.g., American football, rugby, boxing, ice hockey, soccer, and professional wrestling), in war veterans with a history of blast or blunt force TBI, and in conditions where trauma to the head occurs for various reasons (e.g., falls during seizures, head-banging in autistic children, motor vehicle and domestic accidents, domestic violence and abuse) (6, 8, 11–14). As with most neurodegenerative diseases, clinical diagnosis remains elusive due to the lack of specificity of CTE clinical symptomatology criteria, and histopathological examination of brain at autopsy is the most definitive diagnostic modality (6, 8, 11).The novel imaging approaches leading to the in vivo characterization of CTE brain neuropathology premortem (e.g., PET) are complementary to structural imaging modalities [e.g., diffusion tensor imaging MRI (DTI MRI)] and offer a specific and sensitive strategy to facilitate diagnosis of CTE. Neuronal and glial fibrillar hyperphosphorylated microtubule-associated protein tau deposits composed of paired helical filament (PHF)-tau are the primary brain proteinopathy of CTE based on autopsy determinations, and their 3R/4R tau isoform ratio is similar to that of AD (11). Their topographically predictable pattern of distribution was used as a basis for a severity staging system of CTE neuropathology (7), ranging from mild (neuropathology stages I and II) to advanced (neuropathology stages III and IV) (7) (Tables S1 and S2). In addition, more than 80% of analyzed pathologically confirmed CTE cases also show transactive response (TAR) DNA-binding protein of ∼43 kDa (TDP-43) either as inclusions in sparse neurites in cortex, medial temporal lobe structures, and brainstem in CTE neuropathology stages I–III, as widespread neuronal and glial inclusions in severe CTE cases (neuropathology stage IV), or in CTE cases with motor neuron disease (7, 15) (Tables S1 and S2). CTE cases also can exhibit the presence of other fibrillar protein aggregates. McKee et al. (7) and Omalu et al. (8) reported that in autopsy determinations, less than half of all CTE cases and less than one third of “pure” CTE cases show amyloid-β (Aβ) deposits, predominantly as scattered cortical diffuse plaques in low density (Tables S1 and S2). Of note is that subjects with Aβ deposits were significantly older than those without. Moreover, their neuropathology was more severe than that in cases without Aβ deposits and was often combined with α-synuclein deposits (7). As an example, as reported by McKee et al. (7), of 30 CTE cases with at least some cortical Aβ deposits (of 68 confirmed CTE cases), 29 brains were from subjects who died in their seventh decade of life and one from a subject who died in his sixth decade.Subsequent to our preliminary report (16), in this work we use [F-18]FDDNP, an imaging agent for fibrillar insoluble protein aggregates (16–20), and PET imaging with the aim of establishing (i) topographic brain localization of [F-18]FDDNP PET signals indicative of fibrillar neuroaggregates in retired professional American football players with suspected CTE (mTBI group) vs. controls (CTRL); (ii) determination of [F-18]FDDNP PET signal patterns in the mTBI group; (iii) presence of [F-18]FDDNP PET signal as a measure of neuropathology in the brain areas involved in mood disorders related neurocircuits; (iv) correlation of [F-18]FDDNP PET results with neuropathology distributions in confirmed CTE cases; (v) differential patterns of [F-18]FDDNP PET signals, and thus deposition of fibrillar neuroaggregates, in the mTBI group with respect to the AD group; and (vi) preliminary demonstration of differences in [F-18]FDDNP PET signal patterns in mTBI cases with different etiology, i.e., contact-sport–related mTBI in retired professional American football players vs. blast-induced mTBI in war veterans. We further intended to demonstrate that tau (vs. Aβ) specificity of high affinity PET molecular imaging probes may not be a necessary requirement when used in CTE subjects with primary proteinopathy in the form of PHF-tau (8): PET imaging probes potentially sensitive to TDP-43 aggregates and Aβ deposits, which are present in higher densities almost exclusively in older CTE cases with more advanced neuropathology (e.g., stage IV), could better define disease progression based on quantification of differences in regional loads of combined neuropathologies because additional neuropathologies appear in predictable topographical and temporal patterns.