Molecular and structural basis of the evolution of parvovirus tropism

Parvoviruses have small genomes and, consequently, are highly dependent on their host for various functions in their reproduction. Since these viruses generally use ubiquitous receptors, restrictions are usually intracellularly regulated. A lack of mitosis, and hence absence of enzymes required for DNA replication, is a powerful block of virus infection. Allotropic determinants have been identified for several parvoviruses: porcine parvovirus, canine parvovirus (CPV), feline parvovirus (feline panleukopenia virus), minute virus of mice, Aleutian disease virus, and GmDNV (an insect parvovirus). Invariably, these identifications involved the use of infectious clones of these viruses and the exchange of restriction fragments to create chimeric viruses, of which the resulting phenotype was then established by transfection in appropriate cell lines. The tropism of these viruses was found to be governed by minimal changes in the sequence of the capsid proteins and, often, only 2 or 3 critical amino acids are responsible for a given tropism. These amino acids are usually located on the outside of the capsid near or on the spike of the threefold axis for the vertebrate parvoviruses and on loops 2 or 3 for the insect parvoviruses. This tropism is not mediated via specific cellular receptors but by interactions with intracellular factors. The nature of these factors is unknown but most data point to a stage beyond the conversion of the single-stranded DNA genome by host cell DNA polymerase into monomeric duplex intermediates of the replicative form. The sudden and devastating emergence of mink enteritis virus (MEV) and CPV in the last 50 years, and the possibility of more future outbreaks, demonstrates the importance of understanding parvovirus tropism

The objective burden in partners of heart failure patients; development and initial validation of the Dutch objective burden inventory

BACKGROUND: Measures on objective caregiver burden in partners of Heart Failure patients are hardly available and never include HF specific aspects. AIM: The main objective of our study was to develop an inventory that assesses the objective caregiver burden of partners of HF patients, including the full range of potential care giving demands. METHODS: To develop the inventory, six domains of caregiving demands were identified. Items for the domains were generated from the literature, expert opinion and existing scales. The original 50-items self-report inventory was administered to 321 partners of HF patients. Demographic data of HF partners were collected by questionnaire. Clinical data of the HF patients were collected by chart review. RESULTS: Component analysis led to exclusion of 12 original items and to a meaningful four-factor solution with a total explained variance of 43%. The components reflected four different kinds of care giving tasks; personal care, emotional, motivational and practical (treatment related) support. They demonstrated good internal consistency and initial validity was supported by a pattern of meaningful associations with external variables. CONCLUSION: The Objective Burden Inventory is a promising inventory to assess objective care giving tasks performed by HF partners, including emotional and motivational support. It provides information on the caregiver situation that may help to develop effective intervention

Automatic hoof-on and -off detection in horses using hoof-mounted inertial measurement unit sensors

For gait classification, hoof-on and hoof-off events are fundamental locomotion characteristics of interest. These events can be measured with inertial measurement units (IMUs) which measure the acceleration and angular velocity in three directions. The aim of this study was to present two algorithms for automatic detection of hoof-events from the acceleration and angular velocity signals measured by hoof-mounted IMUs in walk and trot on a hard surface. Seven Warmblood horses were equipped with two wireless IMUs, which were attached to the lateral wall of the right front (RF) and hind (RH) hooves. Horses were walked and trotted on a lead over a force plate for internal validation. The agreement between the algorithms for the acceleration and angular velocity signals with the force plate was evaluated by Bland Altman analysis and linear mixed model analysis. These analyses were performed for both hoof-on and hoof-off detection and for both algorithms separately. For the hoof-on detection, the angular velocity algorithm was the most accurate with an accuracy between 2.39 and 12.22 ms and a precision of around 13.80 ms, depending on gait and hoof. For hoof-off detection, the acceleration algorithm was the most accurate with an accuracy of 3.20 ms and precision of 6.39 ms, independent of gait and hoof. These algorithms look highly promising for gait classification purposes although the applicability of these algorithms should be investigated under different circumstances, such as different surfaces and different hoof trimming conditions

Automatic detection of break-over phase onset in horses using hoof-mounted inertial measurement unit sensors

A prolonged break-over phase might be an indication of a variety of musculoskeletal disorders and can be measured with optical motion capture (OMC) systems, inertial measurement units (IMUs) and force plates. The aim of this study was to present two algorithms for automatic detection of the break-over phase onset from the acceleration and angular velocity signals measured by hoof-mounted IMUs in walk and trot on a hard surface. The performance of these algorithms was evaluated by internal validation with an OMC system and a force plate separately. Seven Warmblood horses were equipped with two wireless IMUs which were attached to the lateral wall of the right front (RF) and hind (RH) hooves. Horses were walked and trotted over a force plate for internal validation while simultaneously the 3D position of three reflective markers, attached to lateral heel, lateral toe and lateral coronet of each hoof, were measured by six infrared cameras of an OMC system. The performance of the algorithms was evaluated by linear mixed model analysis. The acceleration algorithm was the most accurate with an accuracy between -9 and 23 ms and a precision around 24 ms (against OMC system), and an accuracy between -37 and 20 ms and a precision around 29 ms (against force plate), depending on gait and hoof. This algorithm seems promising for quantification of the break-over phase onset although the applicability for clinical purposes, such as lameness detection and evaluation of trimming and shoeing techniques, should be investigated more in-depth

Hyperammonemic encephalopathy as a manifestation of Reye syndrome in a previously-healthy 14-year-old girl: A case report

Reye syndrome is seldom considered in the older child presenting with acute encephalopathy. The paucity of literature on Reye syndrome in the past 30 years highlights the importance of sharing new observations of this less-commonly considered disease. This case details an atypical presentation of Reye syndrome in an adolescent girl whose course was unexpectedly complicated by dialysis disequilibrium syndrome, occurring as a result of rapid metabolic shifts in the setting of urgent hemodialysis. A 14-year-old, previously healthy girl born to non-consanguineous Pakistani parents presented with acute-onset encephalopathy characterized by aggressive behaviour and altered level of consciousness. This was preceded by frequent vomiting and weeks of disordered eating. Laboratory findings included high anion-gap [30 (normal range, \u3c14)] metabolic acidosis [pH 7.23 (normal range, 7.35-7.45), bicarbonate 10 mmol/L (normal range, 22-29 mmol/L)] with markedly elevated peak levels of lactate [13.6 mmol/L (normal range, 0.5-2.2 mmol/L)] and ammonia [573 μmol/L (normal range, 11-48 μmol/L)]. Emergent hemodialysis was undertaken for management of severe hyperammonemia, with subsequent worsening of cerebral edema, elevated intracranial pressure, and consequent uncal and tonsillar herniation, in keeping with the development of dialysis disequilibrium syndrome. The patient was ultimately diagnosed with Reye syndrome after extensive biochemical and molecular testing including exome sequencing were non-contributory. This diagnosis would be consistent with her poor nutritional state, depleted carnitine levels, mild liver dysfunction and hyperammonemia. Two weeks of intensive care were required. The patient was ultimately discharged to a rehabilitation facility with ongoing fatigue and regression in motor and cognitive domains. Hyperammonemic encephalopathy should prompt consideration for Reye syndrome. Hyperammonemia is a medical emergency; the extremely time-sensitive nature of hyperammonemia management mandates that ammonia level testing be undertaken for any unexplained encephalopathy. Severe elevations can result in neurological impairment, cerebral edema, and are acutely life-threatening. Hemodialysis may be indicated for levels \u3e150 μmol/L; the urgency of ammonia clearance must be balanced against the risk of developing dialysis disequilibrium syndrome

Deep Brain Stimulation of the Pallidum is Effective and Might Stabilize Striatal D2 Receptor Binding in Myoclonus–Dystonia

Purpose: To assess clinical efficacy of deep brain stimulation (DBS) of the pallidum in Myoclonus–Dystonia (M–D) patients, and to compare pre- and post-operative striatal dopamine D2 receptor availability. Methods: Clinical parameters were scored using validated rating scales for myoclonus and dystonia. Dopamine D2 receptor binding of three patients was studied before surgery and approximately 2 years post-operatively using 123-I-iodobenzamide Single Photon Emission Computed Tomography. Two patients who did not undergo surgery served as controls. Results: Clinically, the three M–D patients improved 83, 17, and 100%, respectively on the myoclonus rating scale and 78, 23, and 65% on the dystonia rating scale after DBS. Dopamine D2 receptor binding did not change after surgery. In the two control subjects, binding has lowered further. Conclusion: These findings confirm that DBS of the pallidum has beneficial effects on motor symptoms in M–D and suggest this procedure might stabilize dopamine D2 receptor binding

The relationships between university IP regimes and scientists´ motivations and their engagement with research commercialisation in Europe

Many policy makers regard Technology Transfer Offices as a vehicle for Intellectual Property regimes and a main driver for research commercialisation. The involvement of scientists in the process of research commercialisation is often taken for granted. National regulations can determine the IP regimes at universities and their decisions about the ownership of scientific research results. This paper describes the relationships between four university IP regimes and identifies three driving forces, which motivate individual scientists to engage with the commercialisation of their own research, and the real involvement of scientists with research commercialisation. A representative survey of approximately 2,660 scientists working in all disciplines at some 150 universities in 30 European countries, covering a time frame from 2010 till 2015, shows that around 32% of the scientists are engaged in various pathways of research commercialisation. We found significantly higher percentages of scientists who are involved in research commercialisation at universities that hold IP ownership on research results and that have obligatory Technology Transfer Office services. The individual driving forces are positively associated with significantly higher levels of engagement with research commercialisation, double the amount of patenting and a threefold higher involvement with spin-off companies. Involvement with a spin-off formation was only positively correlated with scientists-related driving forces, not with the intellectual property regime of the university where they work. We conclude that the driving forces of scientists and university IP regimes are both factors that can contribute to increased levels of research commercialisation. Our data suggest that the former factor is by far the more important.Merit, Expertise and Measuremen

Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome

Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G>A mutation in the donor splice site of exon 4 (c.500+1G>A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsense-mediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma