Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2

Degeneration of the cerebrum, cerebellum, and retina in infancy is part of the clinical spectrum of lysosomal storage disorders, mitochondrial respiratory chain defects, carbohydrate glycosylation defects, and infantile neuroaxonal dystrophy. We studied eight individuals from two unrelated families who presented at 2-6 months of age with truncal hypotonia and athetosis, seizure disorder, and ophthalmologic abnormalities. Their course was characterized by failure to acquire developmental milestones and culminated in profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Despite their debilitating state, the disease was compatible with survival of up to 18 years. Laboratory investigations were normal, but the oxidation of glutamate by muscle mitochondria was slightly reduced. Serial brain MRI displayed progressive, prominent cerebellar atrophy accompanied by thinning of the corpus callosum, dysmyelination, and frontal and temporal cortical atrophy. Homozygosity mapping followed by whole-exome sequencing disclosed a Ser112Arg mutation in ACO2, encoding mitochondrial aconitase, a component of the Krebs cycle. Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded, indicating that this mutation is pathogenic. Thus, a defect in mitochondrial aconitase is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. In the absence of noninvasive biomarkers, determination of the ACO2 sequence or of aconitase activity in lymphoblasts are warranted in similarly affected individuals, based on clinical and neuroradiologic grounds.     

Endoplasmic Reticulum Stress Induces a Caspase-dependent N-terminal Cleavage of RBX1 Protein in B Cells

Endoplasmic reticulum (ER) stress develops when the ER is overloaded with too many proteins to fold. This elicits a signaling pathway called the unfolded protein response. The unfolded protein response is physiologically required for the terminal development of B cells into antibody-secreting plasma cells. Ring Box Protein 1 (RBX1) is a 14-kDa protein necessary for ubiquitin ligation activity of the multimeric cullin ring ubiquitin ligases (CRLs). As RBX1 is shared by a large number of CRLs, alterations in its activity may lead to global changes in protein stability. We discovered that RBX1 is cleaved in the course of LPS-induced plasma cell differentiation and in multiple myeloma cell lines upon induction of pharmacological ER stress. The cleavage is executed by several caspase proteases that cleave RBX1 eight amino acids from the N terminus. To address the possible implication of RBX1 cleavage for CRL activity, we replaced the endogenous RBX1 homolog of the yeast Saccharomyces cerevisiae, Roc1, with the wild type or the N-terminal Δ8 mutant human RBX1. We show that yeast expressing the cleaved RBX1 are hypersensitive to ER stress and are impaired in CRL-mediated ubiquitination and degradation. We propose a model by which N-terminal cleavage of RBX1 impairs its activity and promotes susceptibility to ER stress induction.     

Contagious sterility in the parasitoid wasp Eretmocerus mundus (Hymenoptera: Aphelinidae)

The parasitoid wasp Eretmocerus mundus (Hymenoptera: Aphelinidae) is used commercially to control the sweet potato whitefly Bemisia tabaci (Homoptera: Aleyrodidae). Recently, a rapid deterioration of E. mundus populations has been documented under mass-rearing conditions. We found that deteriorating cultures consist of increasing proportions of sterile individuals, up to 90% within 6 months. Microscopic examination revealed that the gonads of wasps from both sexes are severely underdeveloped. Preliminary screening for potential pathogen candidates by means of polymerase chain reaction and denaturating-gradient gel electrophoresis did not provide any indication of possible causative agents.     

Defensive medicine in Israel - a nationwide survey

Background

Defensive medicine is the practice of diagnostic or therapeutic measures conducted primarily as a safeguard against possible malpractice liability. We studied the extent, reasons, and characteristics of defensive medicine in the Israeli health care system.

Methods and Findings

Cross-sectional study performed in the Israeli health care system between April and July 2008 in a sample (7%) of board certified physicians from eight medical disciplines (internal medicine, pediatrics, general surgery, family medicine, obstetrics and gynecology, orthopedic surgery, cardiology, and neurosurgery). A total of 889 physicians (7% of all Israeli board certified specialists) completed the survey. The majority [60%, (95%CI 0·57–0·63)] reported practicing defensive medicine; 40% (95%CI 0·37–0·43) consider every patient as a potential threat for a medical lawsuit; 25% (95%CI 0·22–0·28) have previously been sued at least once during their career. Independent predictors for practicing defensive medicine were surgical specialty [OR = 1.6 (95%CI 1·2–2·2), p = 0·0004], not performing a fellowship abroad [OR = 1·5 (95%CI 1·1–2), p = 0·027], and previous exposure to lawsuits [OR = 2·4 (95%CI 1·7–3·4), p<0·0001]. Independent predictors for the risk of being sued during a physician''s career were male gender [OR = 1·6 (95%CI 1·1–2·2), p = 0·012] and surgery specialty [OR = 3·2 (95%CI 2·4–4·3), p<0·0001] (general surgery, obstetrics and gynecology, orthopedic surgery, and neurosurgery).

Conclusions

Defensive medicine is very prevalent in daily physician practice in all medical disciplines. It exposes patients to complications due to unnecessary tests and procedures, affects quality of care and costs, and undermines doctor-patient relationships. Further studies are needed to understand how to minimize defensive medicine resulting from an increased malpractice liability market.     

ATP-induced allostery in the eukaryotic chaperonin CCT is abolished by the mutation G345D in CCT4 that renders yeast temperature-sensitive for growth

Saccharomyces cerevisiae yeast cells containing the chaperonin CCT (chaperonin-containing t-complex polypeptide 1 (TCP-1)) with the G345D mutation in subunit CCT4 (anc2-1) are temperature-sensitive for growth and display defects in organization of actin structure, budding and cell shape. In this first structure-function analysis of CCT, we show that this mutation abolishes both intra- and inter-ring cooperativity in ATP binding by CCT. The finding that a single mutation in only one subunit in each CCT ring has such drastic effects highlights the importance of allostery for its in vivo function. These results, together with other kinetic data for wild-type CCT reported in this study, provide support for the sequential model for ATP-dependent allosteric transitions in CCT.     

Regulatory T cells and immune tolerance

Regulatory T cells (Tregs) play an indispensable role in maintaining immunological unresponsiveness to self-antigens and in suppressing excessive immune responses deleterious to the host. Tregs are produced in the thymus as a functionally mature subpopulation of T cells and can also be induced from naive T cells in the periphery. Recent research reveals the cellular and molecular basis of Treg development and function and implicates dysregulation of Tregs in immunological disease.     

Physical control of leafhoppers

In 2000, a severe outbreak of phytoplasma-caused disease in Limonium spp. flowers devastated the industry in Israel; insecticides were not able to knock down and kill leafhopper vectors before they could transmit the pathogen. Nonchoice laboratory studies were conducted to determine the effect of UV-absorbing plastics on the movement of leafhoppers toward light; UV-absorbing plastic significantly reduced leafhopper movement. In choice trials conducted in sunlight, significantly more leafhoppers moved into the cage covered with regular plastic as opposed to the cage covered with UV-absorbing plastic. Field studies were conducted to determine at what height leafhoppers enter 2.5-3-m high walk-in tunnels; the majority enter the tunnels low to the ground, up to 1 m. Finally, field studies were conduced to compare leafhopper population levels in walk-in tunnels covered with UV-absorbing plastic or screening, and with ventilation holes at different heights above the ground. Elevated ventilation holes and UV-absorbing tunnel covering significantly reduced Orosius orientalis entrance into tunnels. Ramifications of these finding for leafhopper control are discussed.     

Evaluation of the parasitoid Copidosoma koehleri for biological control of the potato tuber moth,Phthorimaea operculella,in Israeli potato fields

The potato tuber moth Phthorimaea operculella (Zeller) (Lepidoptera: Gelechiidae) is a major agricultural pest of solaneceous crops in warm countries worldwide. The encyrtid polyembryonic parasitoid Copidosoma koehleri (Blanchard) has been successfully introduced for biological control of the moth in potato fields in South Africa and Australia; however, augmentative releases of the parasitoid in trial plots and in commercial potato fields in Israel did not reduce pest populations or infestation levels more than chemical treatment. Copidosoma koehleri accounted for 4–5% of parasitism on tuber moth caterpillars, while most parasitism was due to local species of larval parasitoids. The abundance and composition of local parasitoids did not differ between C. koehleri release plots and conventionally treated control plots. These findings can be interpreted as failure of the introduced parasitoids to survive and locate their hosts, or as mortality of C. koehleri within hosts in the field. Sentinel hosts, placed in trial plots and collected after 24 h, were rarely parasitised by C. koehleri, supporting the first interpretation. To test the second hypothesis, hosts parasitised by C. koehleri were placed in field plots for a week, collected, and reared out in the laboratory. The emergence rates of C. koehleri from these hosts resembled those of lab-reared controls, suggesting that mortality within hosts in the field is not a major cause of C. koehleri's poor biocontrol performance.