Phenotypic variability of CADASIL and novel morphologic findings

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a non-arterio-atherosclerotic, non-amyloidotic arteriopathy affecting preferentially the small arteries and arterioles of the brain. The morphologic hallmark is the presence of a characteristic granular alteration of the arterial media that ultrastructurally corresponds to the accumulation of electron-dense material surrounding the smooth muscle cells. Although the presence of this granular osmiophilic material (GOM) was originally described as limited to brain vessels, identical electron microscopic findings have been demonstrated in the media of peripheral tissue arteries, allowing for a pathologic diagnosis of the disease by a simple skin, muscle or nerve biopsy. We report some atypical features identified in our CADASIL patients that broaden the phenotypic expression of this disease. Firstly, we identified a cortical infarct in an otherwise typical CADASIL patient. Secondly, we observed GOM in skin arteries of a 30-year-old man with hemiplegic migraine, the son of a woman who had died with CADASIL. This confirms that it may be possible to diagnose the disease at a preclinical stage by the ultrastructural evaluation of peripheral tissue biopsy material, particularly for individuals for whom there is a supporting family history. Thirdly, ultrastructural examination of the skin, and subcutaneous and striated muscle of an unrelated and apparently sporadic patient with neuropathologic and neuroradiologic evidence of CADASIL in meningeal and cerebral vessels failed to reveal diagnostic lesions in peripheral arteries. Thus, the possibility of a false-negative pathologic diagnosis in patients with a clinicoradiologic diagnosis of CADASIL, if one relies solely on a peripheral tissue biopsy, does exist. Additionally, we have identified heat shock proteins (Hsp70 and αB crystallin) and ubiquitin in the vascular myocytes of affected arteries. αB crystallin also seemed to be deposited extracellularly, which suggests that GOM also might be immunoreactive for αB crystallin. Received: 9 December 1996 / Revised, accepted: 21 February 1997     

Auditory evoked phosphenes in optic nerve disease

Five patients with optic neuropathy, four vascular and one demyelinating, are described who each complained of an unusual symptom. Bright flashes of light (phosphenes) occurred in the affected eyes and were evoked by sudden unexpected sounds. Movement of the eye alone did not reproduce the symptom. In all patients the phenomenon was sufficiently prominent to interfere with sleep and was the main complaint of one patient. An anticonvulsant (phenytoin) greatly reduced the frequency and intensity of the phosphene in one patient.     

Cryopreservation of all prezygotes in patients at risk of severe hyperstimulation does not eliminate the syndrome, but the chances of pregnancy are excellent with subsequent frozen-thaw transfers

In-vitro fertilization patients (n = 15) at risk of ovarian hyperstimulation syndrome (OHSS) (oestradiol > or =4500 pg/ml on the day of human chorionic gonadotrophin administration and 25 or more follicles of intermediate or large size) underwent aspiration of all follicles and cryopreservation of all fertilized oocytes at the pronuclear stage. Patients were monitored for up to 2 weeks post- retrieval. Subsequent transfer of cryopreserved-thawed embryos was performed in programmed cycles using exogenous oestrogen and progesterone for endometrial preparation. Two patients (13%) developed OHSS necessitating hospitalization and vaginal aspiration of ascitic fluid. Two other patients (13%) developed moderate OHSS requiring ascitic fluid vaginal aspiration in the office setting, with dramatic improvement of the condition. Subsequent transfer of cryopreserved- thawed embryos yielded a clinical pregnancy rate of 58% per transfer and ongoing or delivery rates of 42 and 67% per transfer and per patient respectively. By eliminating pregnancy potential with cryopreservation of all prezygotes and examining the pregnancy potential with subsequent cryopreserved-thawed transfers, it is concluded that OHSS is reduced, but not eliminated for patients at risk. Subsequent transfer of cryopreserved-thawed prezygotes in a programmed cycle with exogenous steroids yields an excellent pregnancy rate.      

Attenuated virulence of a Burkholderia cepacia type III secretion mutant in a murine model of infection

Type III secretion systems are utilized by a number of gram-negative bacterial pathogens to deliver virulence-associated proteins into host cells. Using a PCR-based approach, we identified homologs of type III secretion genes in the gram-negative bacterium Burkholderia cepacia, an important pulmonary pathogen in immunocompromised patients and patients with cystic fibrosis. One of the genes, designated bscN, encodes a member of a family of ATP-binding proteins believed to generate energy driving virulence protein secretion. Genetic dissection of the regions flanking the bscN gene revealed a locus consisting of at least 10 open reading frames, predicted to encode products with significant homology to known type III secretion proteins in other bacteria. A defined null mutation was generated in the bscN gene, and the null strain and wild-type parent strain were examined by use of a murine model of B. cepacia infection. Quantitative bacteriological analysis of the lungs and spleens of infected C57BL/6 mice revealed that the bscN null strain was attenuated in virulence compared to the parent strain, with significantly lower bacterial recovery from the lungs and spleens at 3 days postinfection. Moreover, histopathological changes, including an inflammatory cell infiltrate, were more pronounced in the lungs of mice infected with the wild-type parent strain than in those of mice infected with the isogenic bscN mutant. These results implicate type III secretion as an important determinant in the pathogenesis of B. cepacia.     

Environmental heat stress, hyperammonemia and nucleotide metabolism during intermittent exercise

This study investigated the influence of environmental heat stress on ammonia (NH₃) accumulation in relation to nucleotide metabolism and fatigue during intermittent exercise. Eight males performed 40 min of intermittent exercise (15 s at 306±22 W alternating with 15 s of unloaded cycling) followed by five 15 s all-out sprints. Control trials were conducted in a 20°C environment while heat stress trials were performed at an ambient temperature of 40°C. Muscle biopsies and venous blood samples were obtained at rest, after 40 min of exercise and following the maximal sprints. Following exercise with heat stress, the core and muscle temperatures peaked at 39.5±0.2 and 40.2±0.2°C to be ~ 1°C higher (P<0.05) than the corresponding control values. Mean power output during the five maximal sprints was reduced from 618±12 W in control to 558±14 W during the heat stress trial (P<0.05). During the hot trial, plasma NH₃ increased from 31±2 μM at rest to 93±6 at 40 min and 151±15 μM after the maximal sprints to be 34% higher than control (P<0.05). In contrast, plasma K⁺ and muscle H⁺ accumulation were lower (P<0.05) following the maximal sprints with heat stress compared to control, while muscle glycogen, CP, ATP and IMP levels were similar across trials. In conclusion, altered levels of “classical peripheral fatiguing agents” does apparently not explain the reduced capacity for performing repeated sprints following intermittent exercise in the heat, whereas the augmented systemic NH₃ response may be a factor influencing fatigue during exercise with superimposed heat stress.     

The Effect of Telephone-Administered Psychotherapy on Symptoms of Depression and Attrition: A Meta-Analysis

Increasingly, the telephone is being used to deliver psychotherapy for depression, in part as a means to reduce barriers to treatment. Twelve trials of telephone-administered psychotherapies, in which depressive symptoms were assessed, were included. There was a significant reduction in depressive symptoms for patients enrolled in telephone-administered psychotherapy as compared to control conditions ( d  = 0.26, 95% confidence interval [CI] = 0.14–0.39, p  < .0001). There was also a significant reduction in depressive symptoms in analyses of pretreatment to posttreatment change ( d  = 0.81, 95% CI = 0.50–1.13, p  < .0001). The mean attrition rate was 7.56% (95% CI = 4.23–10.90). These findings suggest that telephone-administered psychotherapy can produce significant reductions in depressive symptoms. Attrition rates were considerably lower than rates reported in face-to-face psychotherapy.     

Common genetic variants do not associate with CAD in familial hypercholesterolemia

In recent years, multiple loci dispersed on the genome have been shown to be associated with coronary artery disease (CAD). We investigated whether these common genetic variants also hold value for CAD prediction in a large cohort of patients with familial hypercholesterolemia (FH). We genotyped a total of 41 single-nucleotide polymorphisms (SNPs) in 1701 FH patients, of whom 482 patients (28.3%) had at least one coronary event during an average follow up of 66 years. The association of each SNP with event-free survival time was calculated with a Cox proportional hazard model. In the cardiovascular disease risk factor adjusted analysis, the most significant SNP was rs1122608:G>T in the SMARCA4 gene near the LDL-receptor (LDLR) gene, with a hazard ratio for CAD risk of 0.74 (95% CI 0.49–0.99; P-value 0.021). However, none of the SNPs reached the Bonferroni threshold. Of all the known CAD loci analyzed, the SMARCA4 locus near the LDLR had the strongest negative association with CAD in this high-risk FH cohort. The effect is contrary to what was expected. None of the other loci showed association with CAD.     

A nonstop variant in REEP1 causes peripheral neuropathy by unmasking a 3′UTR‐encoded,aggregation‐inducing motif

Single‐nucleotide variants that abolish the stop codon (“nonstop” alterations) are a unique type of substitution in genomic DNA. Whether they confer instability of the mutant mRNA or result in expression of a C‐terminally extended protein depends on the absence or presence of a downstream in‐frame stop codon, respectively. Of the predicted protein extensions, only few have been functionally characterized. In a family with autosomal dominant Charcot‐Marie‐Tooth disease type 2, that is, an axonopathy affecting sensory neurons as well as lower motor neurons, we identified a heterozygous nonstop variant in REEP1. Mutations in this gene have classically been associated with the upper motor neuron disorder hereditary spastic paraplegia (HSP). We show that the C‐terminal extension resulting from the nonstop variant triggers self‐aggregation of REEP1 and of several reporters. Our findings support the recently proposed concept of 3′UTR‐encoded “cryptic amyloidogenic elements.” Together with a previous report on an aggregation‐prone REEP1 deletion variant in distal hereditary motor neuropathy, they also suggest that toxic gain of REEP1 function, rather than loss‐of‐function as relevant for HSP, specifically affects lower motor neurons. A search for similar correlations between genotype, phenotype, and effect of mutant protein may help to explain the wide clinical spectra also in other genetically determined disorders.     

Diagnosis of autoimmune pancreatitis by core needle biopsy: application of six microscopic criteria

Autoimmune pancreatitis (AIP) has been established as a special entity of chronic pancreatitis (CP). However, its clinical distinction from pancreatic cancer and other types of CP is still difficult. The aim of this study was to evaluate the efficacy of pancreatic core needle biopsy for the diagnosis of AIP. In 44 core needle biopsy specimens, we assessed the following microscopic features: granulocytic epithelial lesions (GELs), more than ten IgG4-positive plasma cells/HPF, more than ten eosinophilic granulocytes/HPF, cellular fibrosis with inflammation, lymphoplasmacytic infiltration, and venulitis. All biopsies that showed four or more of the six features (22 of 44) were obtained from 21 of 26 patients whose clinical diagnosis and follow-up were consistent with AIP. All non-AIP CP patients (n = 14) showed three or less than three of the features in their biopsies. GELs were only observed in biopsy specimens from AIP patients. In conclusion, our data indicate that the six criteria we applied were able to recognize AIP in 76% of biopsy specimens using a cut-off level of four. When the specimens that revealed only three features but showed GELs were added, the sensitivity rose to 86%. Pancreatic core needle biopsy can therefore make a significant contribution to the diagnosis of AIP.