Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.

Optimal progressive taxation in a model with endogenous skill supply.

This paper examines whether efficiency considerations require that optimal labour income taxation is progressive or regressive in a model with skill heterogeneity, endogenous skill acquisition and a production sector with capital-skill complementarity. We find that wage inequality driven by the resource requirements of skill-creation implies progressive labour income taxation in the steady-state as well as along the transition path from the exogenous to optimal policy steady-state. We find that these results are explained by a lower labour supply elasticity for skilled versus unskilled labour which results from the introduction of the skill acquisition technology.

Twenty-four-hour energy expenditure and thermogenesis: response to progressive carbohydrate overfeeding in man.

Short-term overfeeding with carbohydrate induced a marked stimulation of energy expenditure, amounting to 33 per cent of the excess energy intake on the 7th day of overfeeding. This value is larger than that previously reported in man. Stimulation of lipogenesis and increased activity of the sympathetic nervous system seem to be the two major mechanisms which account for the stimulation of energy expenditure during carbohydrate overfeeding.

Chronic experimental infection by Trypanosoma cruzi in Cebus apella monkeys

Twenty young male Cebus apella monkeys were infected with CAl Trypanosoma cruzi strain and reinfected with CA l or Tulahuen T.cruzi strains, with different doses and parasite source. Subpatent parasitemia was usually demonstrated in acute and chronic phases. Patent parasitemia was evident in one monkey in the acute phase and in four of them in the chronic phase after re-inoculations with high doses of CAl strain. Serological conversion was observed in all monkeys; titers were low, regardless of the methods used to investigate anti-T. cruzi specific antibodies. Higher titers were induced only when re-inoculations were perfomed with the virulent Tulahuén strain or high doses of CAl strain. Clinical electrocardiographic and ajmaline test evaluations did not reveal changes between infected and control monkeys. Histopathologically, cardiac lesions were always characterized by focal or multifocal mononuclear infiltrates and/or isolated fibrosis, as seen during the acute and chronic phases; neither amastigote nests nor active inflammation and fibrogenic processes characteristic of human acute and chronic myocarditis respectively, were observed. These morphological aspects more closely resemble those found in the "indeterminate phase" and contrast with the more diffuse and progressive pattern of the human chagasic myocarditis. All monkeys survived and no mortality was observed.

Glomérulonéphrite rapidement progressive: une urgence diagnostique et thérapeutique [Rapidly progressive glomerulonephritis: a diagnostic and therapeutic emergency]

Rapidly progressive glomerulonephritis (RPG) is a rare clinical syndrome characterized by kidney damage that can lead to irreversible kidney failure. RPG can be caused by primary glomerular disease or can be part of a systemic autoimmune disorder. All RPG have a similar pathophysiology (proliferation of cells in Bowman's capsule and formation of crescents) and clinical evolution (rapidly progressive kidney failure with proteinuria and an active urine sediment). Immunosuppressive therapy and sometimes plasma exchanges are required. Overall- and kidney survival are closely linked to the blood creatinine level at presentation, the percentage of damaged glomeruli, and to the underlying cause. RPG is therefore a diagnostic and therapeutic emergency that needs quick referral to a nephrologist.

"In vivo" imaging of atherosclerosis

Atherosclerosis is a systemic and multifocal disease, which starts early in life, and that usually takes decades before overt disease eventually appears as a consequence of progressive obstruction or abrupt thrombotic occlusion. This silent course makes necessary to develop predictors of disease long before symptomatic lesions develop. Besides several classical risk factors and new emerging humoral risk predictors, imaging may constitute a formidable diagnostic and prognostic tool in order to identify presence, extension, progression (or regression) of disease as well as vulnerability of atherosclerotic lesions. This review summarizes the rapidly growing clinical and research field in imaging atherosclerosis from different perspectives opening important opportunities for timely detection and treatment of atherosclerosis.

A progressive autosomal recessive cataract locus maps to chromosome 9q13-q22.

Cataracts are the leading cause of blindness in most countries. Although most hereditary cases appear to follow an autosomal dominant pattern of inheritance, autosomal recessive inheritance has been clearly documented and is probably underrecognized. We studied a large family-from a relatively isolated geographic region-whose members were affected by autosomal recessive adult-onset pulverulent cataracts. We mapped the disease locus to a 14-cM interval at a novel disease locus, 9q13-q22 (between markers D9S1123 and D9S257), with a LOD score of 4.7. The study of this progressive and age-related cataract phenotype may provide insight into the cause of the more common sporadic form of age-related cataracts.

Effect of epinephrine on oxygen consumption and delivery during progressive hemorrhage.

OBJECTIVE: To determine whether, during hemorrhagic shock, the effect of epinephrine on energy metabolism could be deleterious, by enhancing the oxygen requirement at a given level of oxygen delivery (DO2). DESIGN: Prospective, randomized, control trial. SETTING: Experimental laboratory. SUBJECTS: Two groups of seven mongrel dogs were studied. The epinephrine group received a continuous infusion of epinephrine (1 microgram/min/kg) while the control group received saline. INTERVENTION: Dogs were anesthetized with pentobarbital, and shock was produced by stepwise hemorrhage. MEASUREMENTS AND MAIN RESULTS: Oxygen consumption (VO2) was continuously measured by the gas exchange technique, while DO2 was independently calculated from cardiac output (measured by thermodilution) and blood oxygen content. A dual-lines regression fit was applied to the DO2 vs. VO2 plot. The intersection of the two regression lines defined the critical value of DO2. Values above critical DO2 belonged to phase 1, while phase 2 occurred below critical DO2. In the control group, VO2 was independent of DO2 during phase 1; VO2 was dependent on DO2 during phase 2. In the epinephrine group, the expected increase in VO2 (+19%) and DO2 (+50%) occurred under normovolemic conditions. During hemorrhage, VO2 immediately decreased, and the slope of phase 1 was significantly (p < .01) different from zero, and was significantly (p < .05) steeper than in the control group (0.025 +/- 0.005 vs. 0.005 +/- 0.010). However, the critical DO2 (8.7 +/- 1.7 vs. 9.7 +/- 2.4 mL/min/kg), the critical VO2 (5.6 +/- 0.5 vs. 5.5 +/- 0.9 mL/min/kg), and the slope of phase 2 (0.487 +/- 0.080 vs. 0.441 +/- 0.130) were not different from control values. CONCLUSIONS: The administration of pharmacologic doses of epinephrine significantly increased VO2 under normovolemic conditions due to the epinephrine-induced thermogenic effect. This effect progressively decreased during hemorrhage. The critical DO2 and the relationship between DO2 and VO2 in the supply-dependent phase of shock were unaffected by epinephrine infusion. These results suggest that during hemorrhagic shock, epinephrine administration did not exert a detrimental effect on the relationship between DO2 and VO2.

New-Generation Multifocal Intraocular Lens for Pediatric Cataract.

Background/Aims: To evaluate multifocal intraocular lens (MIOL) implantation in children. Methods: This is a retrospective study evaluating refractive, visual and safety results of MIOL in pediatric cataract surgery. Average follow-up was 25.73 ± 10.5 months. Surgery included 12 o'clock clear corneal incision, anterior capsulorhexis, lens material aspiration and MIOL implantation (SN6AD3; Alcon). Results: We included 34 cataract eyes of 26 pediatric patients aged 2-15 years, of which 14 (54%) were unilateral. Best near visual acuity (BNVA) and best distance visual acuity (BDVA) improved significantly in 100% of eyes (p = 0.0001). BDVA was above 0.8 in 31.25% (5/16) of bilateral cases. Significant stereopsis improvement was observed postoperatively in bilateral cases only (p = 0.01). Conclusion: MIOL implantation is a safe alternative to monofocal pseudophakia for pediatric cataract with a very low complication rate. Significant BNVA, BDVA and stereopsis improvement can be achieved, particularly in bilateral cases. Message: This study shows significant BDVA, BNVA and stereopsis improvement, especially in bilateral cases, after MIOL implantation for pediatric cataracts. © 2013 S. Karger AG, Basel.

Multifocal nodular episcleritis and scleritis with undiagnosed Hodgkin's lymphoma.

PURPOSE: To report the case of a patient with undiagnosed Hodgkin's lymphoma who presented with coexistent unilateral nodular episcleritis and scleritis. DESIGN: Interventional case report and literature review METHODS: Review of clinical history, laboratory findings, histology of episcleral and cervical lymph node biopsies, and follow-up. RESULTS: A 20-year-old female presented with a 5-month history of redness and pain in her left eye, with associated symptoms of dyspnea, malaise, and fever. The patient was found to have multifocal nodular episcleritis and scleritis that was not responsive to topical steroids or systemic nonsteroidal anti-inflammatory treatment. Laboratory tests subsequently revealed evidence of systemic inflammation, and radiologic studies showed extensive mediastinal and cervical adenopathy. A cervical lymph node biopsy showed Reed-Sternberg cells and a chronic lymphocytic infiltrate consistent with nodular sclerosing Hodgkin's lymphoma. Histopathologic analysis of an episcleral nodule revealed a necrotizing granuloma with vasculitis. Systemic chemotherapy was instituted for the Hodgkin's disease; this therapy abolished the nodular scleritis. CONCLUSIONS: This case raises the possibility of concurrent undiagnosed systemic vasculitis with only an ocular manifestation with Hodgkin's lymphoma, either as a coincidence or as a paraneoplastic syndrome. Moreover, it emphasizes the important role of tissue biopsy in establishing diagnosis and directing treatment.

Acquired oscillopsia: potential complication after multifocal IOL implantation

A healthy 60-year-old woman had uneventful bilateral sequential cataract surgery with diffractive multifocal intraocular lens (IOL) implantation. Immediately after surgery in the first eye, the patient complained of right monocular oscillopsia during motion. Surgery in the second eye was followed by the same symptoms. Ocular motility was normal. Any movement of head or eye was accompanied by oscillopsia, disappearing immediately upon cessation of movement. Slitlamp examination revealed pseudophacodonesis, without obvious zonular laxity. We postulate that the rapid oscillation of an unsteady multifocal IOL during head or eye movement caused the optical steps to pass in front of the visual axis. Cataract surgeons must be aware of this potential, but rare, complication before deciding to implant a multifocal IOL.