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Agócs M M (Division of Environmental Hazards and Health Effects, Centers for Disease Control, 1600 Clifton Rd. Atlanta, GA 30333, USA), Markowitz L E, Straub I and Dömök I. The 1988–1989 measles epidemic in Hungary: Assessment of vaccine failure. 1992; 21: 1007–1013. Hungary has had a successful measles vaccination programme, achieving over 93% coverage in targeted groups. However, from September 1988 until December 1989, 17 938 measles cases were reported among the civilian populalion (attack rate [AR] = 169 per 100 000 population) with the majority of cases occurring in vaccinated people. National surveillance data were analysed to determine reasons for the outbreak and risk factors for vaccine failure. People born during 1971 and 1972 had been targeted for vaccination during campaigns in April and September of 1973 and had the highest AR (1332 and 1632 per 100 000, respectively). Epidemiological studies of vaccine efficacy conducted among secondary school students corroborated these findings. Among 754 secondary school students, those vaccinated during the April 1973 campaign were at highest risk compared with those vaccinated at routine health care after 1974 (relative risk = 10.9, 95% confidence interval [CI] : 2.5–47.9). Among 341 primary school students, one-dose recipients were at higher risk compared with two-dose recipients controlling for age at and time elapsed since vaccination ( = 0.04). [ABSTRACT FROM PUBLISHER]

Piccolo, a presynaptic active zone protein, is best known for its role in the regulated assembly and function of vertebrate synapses. Genetic studies suggest a further link to several psychiatric disorders as well as Pontocerebellar Hypoplasia type 3 (PCH3). We have characterized recently generated Piccolo KO ( Pclo gt/gt ) rats. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT ( Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Analysis of the cerebellum and brainstem revealed a reduced granule cell layer and a reduction in size of pontine nuclei. Moreover, the maturation of mossy fiber afferents from pontine neurons and the expression of the α6 GABA A receptor subunit at the mossy fiber-granule cell synapse are perturbed, as well as the innervation of Purkinje cells by cerebellar climbing fibers. Ultrastructural and functional studies revealed a reduced size of mossy fiber boutons, with fewer synaptic vesicles and altered synaptic transmission. These data imply that Piccolo is required for the normal development, maturation, and function of neuronal networks formed between the brainstem and cerebellum. Consistently, behavioral studies demonstrated that adult Pclo gt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Together, these data suggest that loss of Piccolo function in patients with PCH3 could be involved in many of the observed anatomical and behavioral symptoms, and that the further analysis of these animals could provide fundamental mechanistic insights into this devastating disorder. SIGNIFICANCE STATEMENT Pontocerebellar Hypoplasia Type 3 is a devastating developmental disorder associated with severe developmental delay, progressive microcephaly with brachycephaly, optic atrophy, seizures, and hypertonia with hyperreflexia. Recent genetic studies have identified non-sense mutations in the coding region of the PCLO gene, suggesting a functional link between this disorder and the presynaptic active zone. Our analysis of Piccolo KO rats supports this hypothesis, formally demonstrating that anatomical and behavioral phenotypes seen in patients with Pontocerebellar Hypoplasia Type 3 are also exhibited by these Piccolo deficient animals., (Copyright © 2020 the authors.)

Cerebellar granule cells (GCs) make up the majority of all neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs in mice. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs than GCs closer to the Purkinje cell layer (outer-zone GCs). Dynamic Clamp experiments showed that inner- and outer-zone GCs preferentially respond to high- and low-frequency mossy fiber inputs, respectively, enabling dispersion of the mossy fiber input into its frequency components as performed by a Fourier transformation. Furthermore, inner-zone GCs have faster axonal conduction velocity and elicit faster synaptic potentials in Purkinje cells. Neuronal network modeling revealed that these gradients improve spike-timing precision of Purkinje cells and decrease the number of GCs required to learn spike-sequences. Thus, our study uncovers biophysical gradients in the cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs., Competing Interests: IS, LW, AE, MH, NB, SM, ID, KD, ES, IB, MK, PI, SH No competing interests declared, (© 2020, Straub et al.)

Deleterious variants in the same gene present in two or more families with overlapping clinical features provide convincing evidence of a disease-gene association; this can be a challenge in the study of ultrarare diseases. To facilitate the identification of additional families, several groups have created "matching" platforms. We describe four individuals from three unrelated families "matched" by GeneMatcher and MatchMakerExchange. Individuals had microcephaly, developmental delay, epilepsy, and recessive mutations in TRIT1. A single homozygous mutation in TRIT1 associated with similar features had previously been reported in one family. The identification of these individuals provides additional evidence to support TRIT1 as the disease-causing gene and interprets the variants as "pathogenic." TRIT1 functions to modify mitochondrial tRNAs and is necessary for protein translation. We show that dysfunctional TRIT1 results in decreased levels of select mitochondrial proteins. Our findings confirm the TRIT1 disease association and advance the phenotypic and molecular understanding of this disorder., (© 2017 Wiley Periodicals, Inc.)

The melastatin-related transient receptor potential (TRP) channel TRPM3 is a nonselective cation channel expressed in nociceptive neurons and activated by heat. Because TRPM3-deficient mice show inflammatory thermal hyperalgesia, pharmacological inhibition of TRPM3 may exert antinociceptive properties. Fluorometric Ca influx assays and a compound library containing approved or clinically tested drugs were used to identify TRPM3 inhibitors. Biophysical properties of channel inhibition were assessed using electrophysiological methods. The nonsteroidal anti-inflammatory drug diclofenac, the tetracyclic antidepressant maprotiline, and the anticonvulsant primidone were identified as highly efficient TRPM3 blockers with half-maximal inhibition at 0.6 to 6 μM and marked specificity for TRPM3. Most prominently, primidone was biologically active to suppress TRPM3 activation by pregnenolone sulfate (PregS) and heat at concentrations markedly lower than plasma concentrations commonly used in antiepileptic therapy. Primidone blocked PregS-induced Cai influx through TRPM3 by allosteric modulation and reversibly inhibited atypical inwardly rectifying TRPM3 currents induced by coapplication of PregS and clotrimazole. In vivo, analgesic effects of low doses of primidone were demonstrated in mice, applying PregS- and heat-induced pain models, including inflammatory hyperalgesia. Thus, applying the approved drug at concentrations that are lower than those needed to induce anticonvulsive effects offers a shortcut for studying physiological and pathophysiological roles of TRPM3 in vivo.

This study is the first to evaluate the potential of Calligonum azel Maire as a food ingredient. The plant materials flowers, leaves, stems and roots were analyzed by wet-chemical and instrumental methods for major and minor composition. The highest protein and sugar contents were recorded in the flowers (17.8% and 1.6% respectively), while the fat content was most abundant in the leaves (2.9%). Hexane extracts screened by gas chromatography (GC) for fatty acid composition showed 14 major compounds such as oleic acid, linoleic acid and palmitic acid, but also ω3 and ω6 unsaturated fatty acids. The essential oils extracted by hydrodistillation were screened by GC/MS and 31 compounds were identified including estragole, naphthalene, anethole, phytol and curcumene. The HPLC-DAD screening revealed that the methanolic extracts do not contain any pharmacologically active compound with adverse properties, but quercetin, hordenine and vanillin were abundant in the flowers, leaves and roots. Proton nuclear magnetic resonance ( 1 H NMR) spectroscopy showed that glucose, sucrose and fructose were abundant in acetone and methanol extracts, while urea and glycerol were abundant in the aqueous extracts. A sensory evaluation of the aqueous infusions showed properties of the flowers reminiscent of other herbal teas. In conclusion, our results corroborate the suitability of the traditionally described use of Calligonum azel Maire as food and feed. The further study of this plant as a sustainable nutritional ingredient appears to be worthwhile., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Cerebellar granule cells (GCs), the smallest neurons in the brain, have on average four short dendrites that receive high-frequency mossy fiber inputs conveying sensory information. The short length of the dendrites suggests that GCs are electrotonically compact allowing unfiltered integration of dendritic inputs. The small average diameter of the dendrites (~0.7 µm), however, argues for dendritic filtering. Previous studies based on somatic recordings and modeling indicated that GCs are electrotonically extremely compact. Here, we performed patch-clamp recordings from GC dendrites in acute brain slices of mice to directly analyze the electrotonic properties of GCs. Strikingly, the input resistance did not differ significantly between dendrites and somata of GCs. Furthermore, spontaneous excitatory postsynaptic potentials (EPSP) were similar in amplitude at dendritic and somatic recording sites. From the dendritic and somatic input resistances we determined parameters characterizing the electrotonic compactness of GCs. These data directly demonstrate that cerebellar GCs are electrotonically compact and thus ideally suited for efficient high-frequency information transfer.

Transient receptor potential melastatin 3 (TRPM3) is a calcium-permeable nonselective cation channel that is expressed in a subset of dorsal root (DRG) and trigeminal ganglia sensory neurons. TRPM3 can be activated by the neurosteroid pregnenolone sulfate (PregS) and heat. TRPM3⁻/⁻ mice display an impaired sensation of noxious heat and thermal hyperalgesia. We have previously shown that TRPM3 is blocked by the citrus fruit flavanones hesperetin, naringenin, and eriodictyol as well as by ononetin, a deoxybenzoin from Ononis spinosa. To further improve the tolerability, potency, and selectivity of TRPM3 blockers, we conducted a hit optimization procedure by rescreening a focused library that was composed of chemically related compounds. Within newly identified TRPM3 blockers, isosakuranetin and liquiritigenin displayed favorable properties with respect to their inhibitory potency and a selective mode of action. Isosakuranetin, a flavanone whose glycoside is contained in blood oranges and grapefruits, displayed an IC₅₀ of 50 nM and is to our knowledge the most potent inhibitor of TRPM3 identified so far. Both compounds exhibited a marked specificity for TRPM3 compared with other sensory TRP channels, and blocked PregS-induced intracellular free Ca²⁺ concentration signals and ionic currents in freshly isolated DRG neurons. Furthermore, isosakuranetin and previously identified hesperetin significantly reduced the sensitivity of mice to noxious heat and PregS-induced chemical pain. Because the physiologic functions of TRPM3 channels are still poorly defined, the development and validation of potent and selective blockers is expected to contribute to clarifying the role of TRPM3 in vivo.

Neurogenesis requires the balance between the proliferation of newly formed progenitor cells and subsequent death of surplus cells. RT-PCR and immunocytochemistry demonstrated the presence of P2X7 receptor mRNA and immunoreactivity in cultured neural progenitor cells (NPCs) prepared from the adult mouse subventricular zone (SVZ). Whole-cell patch-clamp recordings showed a marked potentiation of the inward current responses both to ATP and the prototypic P2X7 receptor agonist dibenzoyl-ATP (Bz-ATP) at low Ca(2+) and zero Mg(2+) concentrations in the bath medium. The Bz-ATP-induced currents reversed their polarity near 0 mV; in NPCs prepared from P2X7(-/-) mice, Bz-ATP failed to elicit membrane currents. The general P2X/P2Y receptor antagonist PPADS and the P2X7 selective antagonists Brilliant Blue G and A-438079 strongly depressed the effect of Bz-ATP. Long-lasting application of Bz-ATP induced an initial current, which slowly increased to a steady-state response. In combination with the determination of YO-PRO uptake, these experiments suggest the dilation of a receptor-channel and/or the recruitment of a dye-uptake pathway. Ca(2+)-imaging by means of Fura-2 revealed that in a Mg(2+)-deficient bath medium Bz-ATP causes [Ca(2+)](i) transients fully depending on the presence of external Ca(2+). The MTT test indicated a concentration-dependent decrease in cell viability by Bz-ATP treatment. Correspondingly, Bz-ATP led to an increase in active caspase 3 immunoreactivity, indicating a P2X7-controlled apoptosis. In acute SVZ brain slices of transgenic Tg(nestin/EGFP) mice, patch-clamp recordings identified P2X7 receptors at NPCs with pharmacological properties identical to those of their cultured counterparts. We suggest that the apoptotic/necrotic P2X7 receptors at NPCs may be of particular relevance during pathological conditions which lead to increased ATP release and thus could counterbalance the ensuing excessive cell proliferation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Vitamin D testing is increasing worldwide. Recently several diagnostic manufacturers including Abbott and Siemens have launched automated 25-hydroxy vitamin D (25OH-D) immunoassays. Furthermore, preexisting assays from DiaSorin and Roche have recently been modified. We compared the performance of 5 automated immunoassays, an RIA and 2 liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods., Methods: Aliquots of 170 randomly selected patient samples were prepared and 25OH-D was measured by 2 LC-MS/MS methods, an RIA (DiaSorin), and automated immunoassays from Abbott (Architect), DiaSorin (LIAISON), IDS (ISYS), Roche (E170, monoclonal 25OH-D(3) assay), and Siemens (Centaur). Within-run and between-run imprecision were evaluated by measurement of 5 replicates of 2 serum pools on 5 consecutive days., Results: The LC-MS/MS methods agreed, with a concordance correlation coefficient (CCC) of 0.99 and bias of 0.56 μg/L (1.4 nmol/L). The RIA assay showed a performance comparable to LC-MS/MS, with a CCC of 0.97 and a mean bias of 1.1 μg/L (2.7 nmo/L). All immunoassays measured total 25OH-D (including D(3) and D(2)), with the exception of the Roche assay (D(3) only). Among the immunoassays detecting total 25OH-D, the CCCs varied between 0.85 (Abbott) to 0.95 (LIAISON). The mean bias ranged between 0.2 μg/L (0.5 nmol/L) (LIAISON) and 4.56 μg/L (11.4 nmol/L) (Abbott). The Roche 25OH-D(3) assay demonstrated small mean bias [-2.7 μg/L (-6.7 nmol/L)] [-2.7 μg/L (-6.7 nmol/L)] but a low CCC of just 0.66. Most assays demonstrated good intra- and interassay precision, with CV <10%., Conclusions: Automated immunoassays demonstrated variable performance and not all tests met our minimum performance goals. It is important that laboratories be aware of the limitations of their assay.

Background and Purpose: Fenamates are N-phenyl-substituted anthranilic acid derivatives clinically used as non-steroid anti-inflammatory drugs in pain treatment. Reports describing fenamates as tools to interfere with cellular volume regulation attracted our attention based on our interest in the role of the volume-modulated transient receptor potential (TRP) channels TRPM3 and TRPV4., Experimental Approach: Firstly, we measured the blocking potencies and selectivities of fenamates on TRPM3 and TRPV4 as well as TRPC6 and TRPM2 by Ca(2+) imaging in the heterologous HEK293 cell system. Secondly, we further investigated the effects of mefenamic acid on cytosolic Ca(2+) and on the membrane voltage in single HEK293 cells that exogenously express TRPM3. Thirdly, in insulin-secreting INS-1E cells, which endogenously express TRPM3, we validated the effect of mefenamic acid on cytosolic Ca(2+) and insulin secretion., Key Results: We identified and characterized mefenamic acid as a selective and potent TRPM3 blocker, whereas other fenamate structures non-selectively blocked TRPM3, TRPV4, TRPC6 and TRPM2., Conclusions and Implications: This study reveals that mefenamic acid selectively inhibits TRPM3-mediated calcium entry. This selectivity was further confirmed using insulin-secreting cells. K(ATP) channel-dependent increases in cytosolic Ca(2+) and insulin secretion were not blocked by mefenamic acid, but the selective stimulation of TRPM3-dependent Ca(2+) entry and insulin secretion induced by pregnenolone sulphate were inhibited. However, the physiological regulator of TRPM3 in insulin-secreting cells remains to be elucidated, as well as the conditions under which the inhibition of TRPM3 can impair pancreatic β-cell function. Our results strongly suggest mefenamic acid is the most selective fenamate to interfere with TRPM3 function., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Background: In the WHO region Europe, the average unrecorded adult per capita alcohol consumption was 2.67 L pure ethanol in 2005, which is 22% of the total consumption of 12.20 L. Despite concerns about potential health harms from the chemical composition of unrecorded alcohol, there are surprisingly few data on the problem in the European Region. This study reports the results from the Alcohol Measures for Public Health Research Alliance (AMPHORA) project, which assessed the quality of unrecorded alcohol in a Europe-wide study., Methods: Samples of unrecorded alcohol were collected in 16 European countries and chemically analyzed for potentially health-relevant parameters. Thresholds for parameters were defined based on potential health hazards of daily drinking., Results: The average alcoholic strength of unrecorded wine products was 14.9% vol, and 47.8% vol in unrecorded spirits. One half of the samples (n=57) showed acceptable alcohol quality. The other half (n=58) showed one or several deficits with the most prevalent problem being ethyl carbamate contamination (n=29). Other problems included copper (n=20), manganese (n=16) and acetaldehyde (n=12). All other parameters (including methanol, higher alcohols, phthalates) were only seldom problematic (limit exceedance in less than 10 samples). The price of unrecorded alcohol was approximately 45% of the price of recorded alcohol., Conclusions: The major problem regarding unrecorded alcohol appears to be ethanol itself, as it is often higher in strength and its lower price may further contribute to higher drinking amounts. Compared to the health effects of ethanol, the contamination problems detected may be of minor importance as exposure will only in worst-case scenarios reach tolerable daily intakes of these substances.

Transient receptor potential (TRP) cation channels are renowned for their ability to sense diverse chemical stimuli. Still, for many members of this large and heterogeneous protein family it is unclear how their activity is regulated and whether they are influenced by endogenous substances. On the other hand, steroidal compounds are increasingly recognized to have rapid effects on membrane surface receptors that often have not been identified at the molecular level. We show here that TRPM3, a divalent-permeable cation channel, is rapidly and reversibly activated by extracellular pregnenolone sulphate, a neuroactive steroid. We show that pregnenolone sulphate activates endogenous TRPM3 channels in insulin-producing beta cells. Application of pregnenolone sulphate led to a rapid calcium influx and enhanced insulin secretion from pancreatic islets. Our results establish that TRPM3 is an essential component of an ionotropic steroid receptor enabling unanticipated crosstalk between steroidal and insulin-signalling endocrine systems.

Two novel biostable polyurethanes, designated EV3.34 and EV3.35, were used to manufacture a flexible trileaflet heart valve. The valves were implanted in the mitral position in young adult (18 month) sheep. Six valves were electively explanted at 6 months and the remaining six valves at 9 months follow-up. The leaflet material was examined by surface Fourier transform infrared spectrometry (ATR/FTIR) and scanning electron microscopy (SEM). The leaflet material was also subjected to cyclic mechanical testing and, compared with unimplanted control material, to demonstrate any change in mechanical properties during implantation. There was no degradation of functional groups detected by ATR/FTIR, although there was a slight surface enrichment of siloxane soft segment. Surface morphology of the explanted leaflet material was similar to unimplanted control material. EV3.34 demonstrated similar inelastic energy loss behavior, with no significant change in residual strain in explanted compared with control material. EV3.35 demonstrated a reduction in inelastic energy and residual strain in explanted compared with control material. There is no evidence of biodegradation of these siloxane-based polyurethanes, in functional valves up to 9 months implantation in sheep. The FTIR and SEM findings are supported by the retention of mechanical properties of the materials., (Copyright 2002 Wiley Periodicals, Inc.)

Tick-borne encephalitis (TBE) has been registered in Hungary since 1977. In the last four years a moderate decrease of cases was observed. Most cases belong to the age group of 30-39 years, and the number of males is twice as high as that of the females among the TBE cases. The efficacy of TBE vaccination was proven also in field trials. The use of the specific hyperimmune gamma-globulins for postexposure prophylaxis is effective. The need to create an international standard for TBE vaccine is discussed.

Shigellae were isolated from 32 399 persons in the bacteriological laboratories of the Public Health Stations between 1972-1976. The number of isolations ranged between 5325 and 8237 yearly. As S. dysenteriae and S. boydii serotypes occurred only in about 1.5% of all isolations, the epidemiological situation was determined by the incidence of S. flexneri and S. sonnei. Except in 1973, S. sonnei constituted the majority in every year. S. sonnei predominance, observed first in the western regions of the country, showed a gradual eastward spread and became characteristic of all localities in 1975-1976. The July-September peak of shigella isolations was associated with S. sonnei, as S. flexneri was distributed practically evenly in every season. The incidence of shigella isolations per 100 000 inhabitants was the lowest in the middle and the highest in the northern parts of the country. Sporadic cases were somewhat more frequent than epidemic outbreaks. Shigellae were isolated in 64.1% from patients and in 35.9% from asymptomatic excreters. The patient : excreter ratio was higher for S. sonnei (70.2 : 29.8) than for S. flexneri (54.6 : 45.4). In the survey period, 14 692 isolations were made in the course of 3278 epidemics; out of these, 11 171 cases were involved in 574 extensive outbreaks. S. sonnei was responsible mainly for school and nursery outbreaks, whereas S. flexneri dysentery predominated in mental wards and in homes for the aged and for mentally retarded children. The prevalent types of S. flexneri were (serological/phage type): 2a/69, 3a/5, 3a/19, 4a/81, 4a/89d and 6/85. The prevalent epidemiological subunits of S. sonnei were (phage/colicin type): 2/0, 2/6, 2/12, 3/12, 6/0, 7/0, 65/0, 65/6 and 65/12.