Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60

SPG13, an autosomal dominant form of pure hereditary spastic paraplegia, was recently mapped to chromosome 2q24-34 in a French family. Here we present genetic data indicating that SPG13 is associated with a mutation, in the gene encoding the human mitochondrial chaperonin Hsp60, that results in the V72I substitution. A complementation assay showed that wild-type HSP60 (also known as "HSPD1"), but not HSP60 (V72I), together with the co-chaperonin HSP10 (also known as "HSPE1"), can support growth of Escherichia coli cells in which the homologous chromosomal groESgroEL chaperonin genes have been deleted. Taken together, our data strongly indicate that the V72I variation is the first disease-causing mutation that has been identified in HSP60.     

Saprolegnia strains isolated from river insects and amphipods are broad spectrum pathogens

Saprolegnia species are destructive pathogens to many aquatic organisms and are found in most parts of the world. Reports based on phylogenetic analysis suggest that Saprolegnia strains isolated from aquatic animals such as crustaceans and frogs are close to Saprolegnia strains isolated from infected fish or fish eggs and vice versa. However, it has often been assumed that host specificity occurs for each individual isolate or strain. Here we demonstrate that Saprolegnia spp. can have multiple hosts and are thus capable of infecting different aquatic organisms. Saprolegnia delica, Saprolegnia hypogyna, and 2 strains of Saprolegnia diclina were isolated from aquatic insects and amphipods while S. delica, Saprolegnia ferax, Pythium pachycaule, and a Pythium sp. were isolated from the water of a medium to fast flowing river. The ITS region of the rRNA gene was sequenced for all isolates. In challenge experiments, all four isolates from insects were found to be highly pathogenic to eggs of Atlantic salmon (Salmo salar) and embryos of the African clawed frog (Xenopus laevis). We found that Saprolegnia spp. isolated from salmon eggs were also able to successfully establish infection in nymphs of stonefly (Perla bipunctata) and embryos of X. laevis). These results suggest that Saprolegnia spp. are capable of infecting multiple hosts, which may give them an advantage during seasonal variation in their natural environments.     

Spatio‐temporal gradients in food supply help explain the short‐term colonisation dynamics of the critically endangered central rock‐rat (Zyzomys pedunculatus)

Currently, the impact of introduced predators on small mammal population decline is a focal research direction in the Australian desert literature. In all likelihood though, single‐factor explanation of population dynamics is inadequate, leaving gaps in our knowledge of the multitude of potential influences on small mammal abundance and occupancy patterns in time and space. Here, we investigated floristic gradients across four potential refuge sites of the central rock‐rat, Zyzomys pedunculatus, a granivore rodent (50–120 g) that is endemic to central Australia and is categorised as critically endangered. The study took place in Tjoritja/West MacDonnell National Park in the MacDonnell Ranges bioregion. Floristic sampling was allocated across the four sites, the locations of which were predetermined by an established monitoring and management programme for the central rock‐rat. Our aim was to examine the relationship between environmental gradients and floristic composition across the four sites, and thereby test the extent to which the patterns of food type and food availability can inform central rock‐rat spatio‐temporal dynamics. We found high site‐scale floristic patterning that related foremost to elevation and then to antecedent rainfall and time‐since‐fire and fire‐severity effects. To interpret these results, we applied the principles of refuge theory and we described a gradient from core refuge habitat to intermittent and then marginal habitat within the current central rock‐rat stronghold area. Overall, our results implied a strong floristic basis to central rock‐rat site occurrence, and they thus compel us to take explicit account of spatial (elevation) and temporal (rainfall–productivity and fire‐disturbance) influences on the food axis of potential refuge sites of this critically endangered species.     

In vivo osteopontin-induced macrophage accumulation is dependent on CD44 expression

In order to assess the role of osteopontin (OPN) in leukocyte accumulation in inflammatory conditions, native OPN and its thrombin cleaved form (OPN + Thr) were studied in vivo using a rodent subcutaneous air pouch model (AP). Both forms of OPN-induced macrophage infiltration into the AP in wild-type mice. In animals lacking CD44, macrophage numbers were significantly reduced within the cavity, but cells still accumulated along the subcutaneous lining. In animals lacking endogenous OPN, no differences were found in exogenous OPN-induced macrophage accumulation, although macrophage exhibited increased α4 integrin expression. These studies reveal that both OPN and OPN + Thr attract macrophages in vivo through CD44.     

Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species

An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.     

Social, psychological and existential well-being in patients with glioma and their caregivers: a qualitative study

Background:

Cerebral glioma has a devastating impact on cognitive, physical, social, psychological and spiritual well-being. We sought to understand the multidimensional experience of patients with this form of cancer as they progressed from receiving a diagnosis to the terminal phase of the disease.

Methods:

We recruited patients with a suspected brain tumour from a tertiary referral centre in the United Kingdom. We interviewed patients and their caregivers at key stages of the illness: before receiving a formal diagnosis, at the start of initial treatment, after initial treatment was completed and at six months’ follow-up; caregivers were also interviewed postbereavement. We interviewed the patients’ general practitioners once, after treatment had been completed. We transcribed the interviews and analyzed them thematically using the constant comparative method of a grounded theory approach.

Results:

We conducted in-depth interviews with 26 patients, 23 of their relatives and 19 general practitioners. We saw evidence of physical, social, psychological and existential distress even before a diagnosis was confirmed. Social decline followed a similar trajectory to that of physical decline, whereas psychological and existential distress were typically acute around diagnosis and again after initial treatment. Each patient’s individual course varied according to other factors including the availability of support and individual and family resources (e.g., personal resilience and emotional support).

Interpretation:

There are practical ways that clinicians can care for patients with glioma and their caregivers, starting from before a diagnosis is confirmed. Understanding the trajectories of physical, social, psychological and existential well-being for these patients allows health care professionals to predict their patients’ likely needs so they can provide appropriate support and sensitive and effective communication.Cerebral glioma (hereafter glioma) is a rare but devastating cancer.¹ Despite increased treatment options, average survival for the most aggressive form, glioblastoma multiforme, is less than one year.² In addition to physical decline and increasing social isolation,³ patients may undergo a shattering of preconscious assumptions about their life and its meaning,⁴ causing existential anxiety.^5–7 Fear around death and dying are not always verbalized, but may be expressed in other ways, such as concern for relatives or a desire to get one’s affairs in order.⁸ Anxiety related to shock, anger, fear and uncertainty may, with time, be replaced by acceptance.⁸ However, little is known about how these issues interact and vary dynamically as the tumour progresses.We sought to explore qualitatively whether patients with glioma follow archetypal trajectories of physical, social, psychological and existential well-being as their illness progresses. We investigated how people experience and deal with a diagnosis of glioma and the associated transition toward death in an effort to understand the issues patients and caregivers face and the support they need.     

ADH1B and ADH1C Genotype,Alcohol Consumption and Biomarkers of Liver Function: Findings from a Mendelian Randomization Study in 58,313 European Origin Danes

Background

The effect of alcohol consumption on liver function is difficult to determine because of reporting bias and potential residual confounding. Our aim was to determine this effect using genetic variants to proxy for the unbiased effect of alcohol.

Methods

We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on alanine aminotransferase (ALT), γ-glutamyl-transferase (γ-GT), alkaline phosphatase (ALP), bilirubin and prothrombin action. Analyses were undertaken on 58,313 Danes (mean age 56).

Results

In both confounder adjusted multivariable and genetic-IV analyses greater alcohol consumption, amongst those who drank any alcohol, was associated with higher ALT [mean difference per doubling of alcohol consumption: 3.4% (95% CI: 3.1, 3.7) from multivariable analyses and 3.7% (−4.5, 11.9) from genetic-IV analyses] and γ-GT [8.2% (7.8, 8.5) and 6.8% (−2.8, 16.5)]. The point estimates from the two methods were very similar and statistically the results from the two methods were consistent with each other for effects with ALT and γ-GT (both p_diff>0.3). Results from the multivariable analyses suggested a weak inverse association of alcohol with ALP [−1.5% (−1.7, −1.3)], which differed from the strong positive effect found in genetic-IV analyses [11.6% (6.8, 16.4)] (p_diff<0.0001). In both multivariable and genetic-IV analyses associations with bilirubin and protrombin action were weak and close to the null.

Conclusions

Our results suggest that greater consumption of alcohol is related to poorer liver function as indicated by higher ALT, γ-GT and ALP, but not to clotting or bilirubin.