Gelsolin amyloid angiopathy causes severe disruption of the arterial wall

Hereditary gelsolin amyloidosis (HGA) is a dominantly inherited systemic disease reported worldwide. HGA is characterized by ophthalmological, neurological, and dermatological manifestations. AGel amyloid accumulates at basal lamina of epithelial and muscle cells, thus amyloid angiopathy is encountered in nearly every organ. HGA patients have cardiovascular, hemorrhagic, and potentially vascularly induced neurological problems. To clarify pathomechanisms of AGel angiopathy, we performed histological, immunohistochemical, and electron microscopic analyses on facial temporal artery branches from 8 HGA patients and 13 control subjects. We demonstrate major pathological changes in arteries: disruption of the tunica media, disorganization of vascular smooth muscle cells, and accumulation of AGel fibrils in arterial walls, where they associate with the lamina elastica interna, which becomes fragmented and diminished. We also provide evidence of abnormal accumulation and localization of collagen types I and III and an increase of collagen type I degradation product in the tunica media. Vascular smooth muscle cells appear to be morphologically and semi‐quantitatively normal, only their basal lamina is often thickened. In conclusion, angiopathy in HGA results in severe disruption of arterial walls, characterized by prominent AGel deposition, collagen derangement and severe elastolysis, and it may be responsible for several, particularly hemorrhagic, disease manifestations in HGA.     

Peptide derivatives specific for a Plasmodium falciparum proteinase inhibit the human erythrocyte invasion by merozoites

A specific proteinase of P. falciparum merozoites has been detected by using hydrosoluble fluorogenic peptidic substrates synthesized by classical peptide chemistry; their N-terminal end was acylated by a gluconoyl group that protects them from aminopeptidase degradation and increases their hydrosolubility, and their carboxylic end was substituted by a 3-amino-9-ethylcarbazole group. The sequence Val-Leu-Gly-Lys was found to be the most specific substrate. On this basis, reversible peptidic inhibitors were synthesized by substituting the C-terminal lysyl residue, at the proteolytic site, by different alkylamines and amino alcohols. The activity of these compounds, studied on the P. falciparum proteinase and in in vitro cultures, strongly suggests a specific effect of this peptidic sequence on the reinvasion process. The peptidic inhibitors do not impair the release of merozoites from schizonts, but selectively inhibit the invasion step leading to the formation of rings. Although the natural target of this enzyme is not yet known, these specific peptide inhibitors could lead to a new antimalarial approach.     

Intracranial dural arteriovenous fistula with spinal venous drainage]

Two cases of intracranial dural arteriovenous fistulae draining into the medullary veins are reported. One patient was a 68-year old man who experienced brief and repeated episodes of paraplegia, followed by a permanent spinal cord syndrome. The other patient was a 74-year-old woman who rapidly developed a syndrome of the medulla and spinal cord. In both cases spinal cord angiography failed to show vascular malformations, but myelography revealed venous imprints and magnetic resonance imaging of the cervical spinal cord disclosed a pre-medullary signal. Cerebral angiography showed an intracranial arteriovenous fistula fed by the external carotid artery and draining into the veins of the posterior fossa and the spinal venous network. Complete occlusion of the fistula was achieved by embolization with microparticles. Intracranial dural arteriovenous fistulae draining into the medullary veins are rare: to our knowledge, only 4 cases have been reported. Such lesions must be considered whenever a spinal cord syndrome has no detectable cause.     

Proposal for a numerical prognostic evaluation in intracerebral hematoma

From 300 cases of spontaneous intracerebral hematomas, 5 parameters are extracted they are: Age, sex, level of consciousness, localisation of hematomas and risk factors. A value, varying from 1 to 5 is attributed to each parameter, the sum of values give a score for each patient. This score allows the clinician to predict, within the early 48 hours, the vital prognosis. Survival chances are: 80% if score between 5 and 8; 60% if score between 9 and 13; 40% if score between 14 and 17; 20% if score equal or superior to 18.     

Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease

BACKGROUND: Vascular risk factors play a role in the development of dementia, including Alzheimer disease (AD). However, little is known about the effect of body mass index and clustering of vascular risk factors on the development of dementia. OBJECTIVE: To investigate the relation between midlife body mass index and clustering of vascular risk factors and subsequent dementia and AD. DESIGN AND SETTING: Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population-based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1449 individuals (73%) aged 65 to 79 years participated in the reexamination in 1998. MAIN OUTCOME MEASURES: Dementia and AD. RESULTS: Obesity at midlife (body mass index>30 kg/m2) was associated with the risk of dementia and AD even after adjusting for sociodemographic variables (odds ratio [OR], 2.4 [95% confidence interval (CI), 1.2-5.1]). The association was somewhat modified by further adjusting for midlife blood pressure, total cholesterol level, and smoking (OR, 2.1 [95% CI, 1.0-4.6]) and also for apolipoprotein E genotype and history of vascular disorders (OR, 1.9 [95% CI, 0.8-4.6]). Midlife obesity, high total cholesterol level, and high systolic blood pressure were all significant risk factors for dementia with ORs of around 2 for each factor, and they increased the risk additively (OR, 6.2 for the combination). CONCLUSIONS: Obesity at midlife is associated with an increased risk of dementia and AD later in life. Clustering of vascular risk factors increases the risk in an additive manner. The role of weight reduction for the prevention of dementia needs to be further investigated.     

Implementation of antimicrobial peptides for sample preparation prior to nucleic acid amplification in point-of-care settings

Background: A variety of sample preparation techniques are used prior to nucleic acid amplification. However, their efficiency is not always sufficient and nucleic acid purification remains the preferred method for template preparation. Purification is difficult and costly to apply in point-of-care (POC) settings and there is a strong need for more robust, rapid, and efficient biological sample preparation techniques in molecular diagnostics.

Methods: Here, the authors applied antimicrobial peptides (AMPs) for urine sample preparation prior to isothermal loop-mediated amplification (LAMP). AMPs bind to many microorganisms such as bacteria, fungi, protozoa and viruses causing disruption of their membrane integrity and facilitate nucleic acid release.

Results: The authors show that incubation of E. coli with antimicrobial peptide cecropin P1 for 5 min had a significant effect on the availability of template DNA compared with untreated or even heat treated samples resulting in up to six times increase of the amplification efficiency.

Conclusion: These results show that AMPs treatment is a very efficient sample preparation technique that is suitable for application prior to nucleic acid amplification directly within biological samples. Furthermore, the entire process of AMPs treatment was performed at room temperature for 5 min thereby making it a good candidate for use in POC applications.     

Two sisters with Silver-Russell phenotype

Silver-Russell syndrome (SRS) is a well recognizable syndrome, but the etiology of SRS seems to be heterogeneous. SRS is listed in Mendelian Inheritance in Man as an autosomal dominant disorder because most described cases have been of sporadic occurrence, and most likely were caused by de novo autosomal dominant mutation, and because families with apparent dominant transmission of a SRS phenotype have been described. Still, in a few families, autosomal recessive inheritance has been suggested. We describe two sisters who meet the criteria for SRS proposed by Price et al. [1999]. The parents had normal facial features, normal height, and normal post-natal growth. This is the second well-documented case of familial recurrence of SRS that resembles an autosomal recessive inheritance pattern. Since sib recurrence is so rare in SRS, other modes of inheritance should be considered. The finding of maternal uniparental disomy 7 (mUPD7) in 10% of SRS cases suggests that lack of paternally expressed imprinted gene(s) or overexpression of maternal imprinted gene(s) on chromosome 7 cause SRS. The recurrence in sibs could be caused by a mutation in the imprinted gene or imprinting center carried by one parent. Alternatively, recurrence in sibs could represent germ line mosaicism for a dominant mutation in one of the parents.     

Sports drug testing and the athletes' exposome

Similar to the general population, elite athletes are exposed to a complex set of environmental factors including chemicals and radiation and also biological and physical stressors, which constitute an exposome that is, unlike for the general population, subjected to specific scrutiny for athletes due to applicable antidoping regulations and associated (frequent) routine doping controls. Hence, investigations into the athlete's exposome and how to distinguish between deliberate drug use and different contamination scenarios has become a central topic of antidoping research, as a delicate balance is to be managed between the vital and continually evolving developments of sensitive analytical techniques on the one hand, and the risk of the athletes' exposome potentially causing adverse analytical findings on the other.     

A functional NOS1 promoter polymorphism interacts with adverse environment on functional and dysfunctional impulsivity

Rationale  

Neuronal nitric oxide synthase (NOS1) knockout results in increased impulsive aggression in mice under adverse housing conditions. In line with this, we have previously shown that a functional promoter polymorphism of NOS1, termed NOS1 ex1f-VNTR, is associated with impulsivity-related traits and related disorders.