Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C‐terminal amino acid sequence

Defects in the gene encoding synaptotagmin 2 (SYT2) have been linked to a presynaptic congenital myasthenic syndrome (CMS) and motor neuropathies. However, to date only dominant forms of the disease have been described. We report here a consanguineous patient with a severe recessive form of presynaptic CMS and denervation atrophy caused by the homozygous mutation c.1191delG, p.Arg397Serfs*37 in SYT2. The affected 2‐year‐old girl had profound weakness and areflexia with moderate bulbar deficit. Repetitive nerve stimulation revealed an extreme reduction of compound muscle action potential amplitudes at rest, with a striking facilitation followed by a progressive decline at fast stimulation rates. These findings were reminiscent, but not identical to those seen in the Lambert–Eaton myasthenic syndrome. 3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle fatigue, but albuterol was ineffective. Modeling of the mutation using the rat Syt1 C2B x‐ray structure revealed that Arg397Serfs*37 disrupts a highly conserved amino acid sequence at the bottom face of the C2B domain not directly involved in calcium binding, but crucial for synaptotagmin‐SNARE interaction and exocytosis. Thus, this report describes a recessive form of synaptotagmin 2‐CMS and highlights the importance of the synaptotagmin C‐terminal on synaptic vesicle fusion and exocytosis.     

MHC class II and CD40 play opposing roles in dendritic cell survival

In contrast to very immature dendritic cells (DC), mature DC are largely resistant to death by CD95 (CD95/APO-1) ligation. Investigation of other potential death-inducing ligands showed that mature DC were instead highly susceptible to apoptosis induced by cross-linking of MHC class II. Thus, increasing DC maturity correlates with increased resistance to CD95 killing, but an increased susceptibility to class II-mediated killing. Anti-I-A/I-E monoclonal antibodies (mAb) induced rapid (<2 h) apoptotic cell death in mature epidermal, spleen and bone marrow-derived DC, as determined by annexin/propidium iodide staining, morphological changes, decreased diploidy and loss in mitochondrial membrane potential. Although full class II-mediated killing required DC cytoskeletal motion, divalent cations and phosphatase activity, neither caspase activation, respiration, RNA or protein synthesis, NO production, nor CD95:CD95L interactions were required. Strikingly, DC pretreated by CD40 mAb cross-linking, but not by lipopolysaccharide or TNF-alpha, were completely resistant to class II-mediated killing. CD40-mediated protection was reduced in the presence of the SB202190 inhibitor of the mitogen-activated protein kinase p38 pathway, but appeared to be independent of p42/44 extracellular signal-related kinase or NF-KB activation. Our findings show that in addition to its role as an activator of antigen-presenting cell function, CD40 provides an important counter-signal against class II-induced apoptosis. Thus, these data point to an important role of the T cell in regulating DC survival.     

Determination of serum bactericidal activity against Escherichia coli by an automated photometric method

The resistance of gram-negative bacteria to complement-mediated serum activity is supposedly an important virulence factor. However, the lack of standardization in the methods used to determine serum activity and the many definitions applied make the comparisons between studies very difficult. We developed a rapid photometric method that we compared with a classical killing one. Escherichia coli in the exponential phase of growth in brain heart infusion broth (final inoculum, 10(7) CFU/ml) at 35 degrees C was added to 50% human serum in Veronal buffer. Viable counts and automatic recording of the variations in the optical densities were obtained for 40 E. coli strains isolated from the stools of healthy adults. With the viable count method, 17 (42.5%) were susceptible (at least a 1 log CFU/ml decrease), 17 (42.5%) were resistant (a 0.6 log CFU/ml increase), 4 (10%) were intermediate (poorly growing inoculum or a decrease of less than 1 log CFU/ml), and 2 could not be classified (nonreproducible results). Agreement between both methods was observed for 87.5% of the stool strains. Eight reference strains of known susceptibilities were classified identically by both methods, leading to a final concordance rate of 89.6%. A total of 129 blood isolates were tested by the photometric method: 64 (49.6%) were resistant, 50 (38.8%) were susceptible 5 (3.9%) showed early regrowth, and 10 (7.7%) were not perfectly reproducible. Of these 129 blood isolates, 5 were also tested by the killing method: 37 (49%) were resistant, 32 (43%) were susceptible, and 6 (8%) were intermediate. The concordance rate between both assays was 89% for the blood isolates; when the minor discordances were ruled out, it was 97%. This automated method could be a useful screening tool for detecting resistance to serum in clinical trials and for studying the in vitro variations of this property.     

L1 knockout mice show dilated ventricles, vermis hypoplasia and impaired exploration patterns

L1 is a neural cell adhesion molecule mainly involved in axon guidance and neuronal migration during brain development. Mutations in the human L1 gene give rise to a complex clinical picture, with mental retardation, neurologic abnormalities and a variable degree of hydrocephalus. Recently, a transgenic mouse model with a targeted null mutation in the L1 gene was generated. These knockout (KO) mice show hypoplasia of the corticospinal tract. Here we have performed further studies of these KO mice including magnetic resonance imaging of the brain, neuropathological analysis and behavioral testing. The ventricular system was shown to be abnormal with dilatation of the lateral ventricles and the 4th ventricle, and an altered shape of the Sylvius aqueduct. Additionally, the cerebellar vermis of the KO mice is hypoplastic. Their exploratory behavior is characterized by stereotype peripheral circling reminiscent of that of rodents with induced cerebellar lesions.      

Computerized Cardiovascular Monitoring: Method and Data

This paper describes the development of a digitized, real-time, microcomputer-based signal processing system which records the following variables: systolic and diastolic blood pressure, heart rate, pulse transit time, blood volume pulse, and R-, S-, and T-wave amplitudes of EKG signals. Forty-eight healthy subjects participated in a three-task stress response study in order to gather initial data for evaluating the reliability and validity of this monitoring system. The three tasks represented replications of earlier studies: 1) reading aloud of a monotonous neutral text (Reading Only, RO); 2) mental arithmetic without vocalization (Arithmetic Quiet, AQ); and 3) mental arithmetic with vocalization (Arithmetic Aloud, AA). The findings provided support for the reliability and validity of the new monitoring system given that few data were lost, and resting values as well as differential task responses were found to be comparable with earlier data sets derived via similar experimental protocols.     

Selective decline in protein F1 phosphorylation in hippocampus of senescent rats

Certain forms of neuronal plasticity have been found to be expressed through alterations in brain protein phosphorylation, and its regulation by protein kinase activity. Of interest in this regard is the possibility that the decline in neuronal plasticity and cognitive function that occurs in advanced age may result in part from altered phosphorylation of specific proteins. As a first attempt to identify age-related changes in phosphoproteins, we assayed in vitro phosphorylation of proteins in hippocampus, cerebellum, entorhinal cortex, and frontal cortex from Fischer-344 rats of 5 months, 11 months, and 25 months of age. Compared to the middle-aged animals, the aged rats showed a selective 46% decline in phosphorylation of the 47 kDa protein (F1) in hippocampus, with no change in the phosphorylation of other proteins measured in this structure. Aged animals also showed decreased phosphorylation relative to young animals. No age-related change was observed in any protein band for the other brain areas examined. Since protein F1 is phosphorylated by protein kinase C (PKC), the cytosolic and membrane distribution of this enzyme was compared across age groups. The activity of PKC in hippocampus did not change across age. The explanation of this age-related decline in protein F1 phosphorylation is likely to be a decline in the substrate protein itself. The results are discussed in terms of protein F1's possible role in age-related decline of hippocampal synaptic plasticity.     

A reflex increase in heart rate from distension of the junction between the superior vena cava and the right atrium

1. Localized distension of the junction between the superior vena cava and the right atrium without obstructing venous return caused an increase in heart rate.2. This increase in heart rate was a reflex response; the afferent path was in the vagi and the efferent solely in the sympathetic nerves.3. The receptors most likely to be stimulated by the distension of the junction between the superior vena cava and the right atrium are the right atrial receptors located on the endocardial surface of the intrapericardial portion of the superior vena caval-right atrial junction.     

Yohimbine: a new street drug

Following the ingestion of an alleged aphrodisiac known as "yo-yo," a 16-year-old girl experienced an acute dissociative reaction accompanied by weakness, paresthesias, and incoordination. Subsequent symptoms included anxiety, headache, nausea, palpitations, and chest pain. Hypertension, tachycardia, tachypnea, diaphoresis, pallor, tremors, and an erythematous rash were noted on physical examination. Serum epinephrine and norepinephrine levels were found to be elevated. Symptoms resolved spontaneously but lasted approximately 36 hours. The ingested substance was identified as yohimbine. The pharmacology of yohimbine and the treatment of yohimbine poisoning are discussed.     

Dental curriculum in Nijmegen

The dental curriculum at the University of Nijmegen is based on what the dentist should know and be able to do after his graduation. The programme is divided up into cognitive, behavioural and motoric modules. These modules are vertically connected through subsequent course years by thematically related lines. For every module, the general objectives and general contents have been formulated. Moreover, all subcomponents have been specified as instructional objectives. Half of the study hours is reserved for practical dentistry, by means of preclinically laboratory courses or patient treatment. The curriculum is based on a scientific approach of dentistry and emphasis is placed on patient related instructional situations.