Alterations of oral microbiota and impact on the gut microbiome in type 1 diabetes mellitus revealed by integrated multi-omic analyses.

BACKGROUND: Alterations to the gut microbiome have been linked to multiple chronic diseases. However, the drivers of such changes remain largely unknown. The oral cavity acts as a major route of exposure to exogenous factors including pathogens, and processes therein may affect the communities in the subsequent compartments of the gastrointestinal tract. Here, we perform strain-resolved, integrated meta-genomic, transcriptomic, and proteomic analyses of paired saliva and stool samples collected from 35 individuals from eight families with multiple cases of type 1 diabetes mellitus (T1DM). RESULTS: We identified distinct oral microbiota mostly reflecting competition between streptococcal species. More specifically, we found a decreased abundance of the commensal Streptococcus salivarius in the oral cavity of T1DM individuals, which is linked to its apparent competition with the pathobiont Streptococcus mutans. The decrease in S. salivarius in the oral cavity was also associated with its decrease in the gut as well as higher abundances in facultative anaerobes including Enterobacteria. In addition, we found evidence of gut inflammation in T1DM as reflected in the expression profiles of the Enterobacteria as well as in the human gut proteome. Finally, we were able to follow transmitted strain-variants from the oral cavity to the gut at the individual omic levels, highlighting not only the transfer, but also the activity of the transmitted taxa along the gastrointestinal tract. CONCLUSIONS: Alterations of the oral microbiome in the context of T1DM impact the microbial communities in the lower gut, in particular through the reduction of "mouth-to-gut" transfer of Streptococcus salivarius. Our results indicate that the observed oral-cavity-driven gut microbiome changes may contribute towards the inflammatory processes involved in T1DM. Through the integration of multi-omic analyses, we resolve strain-variant "mouth-to-gut" transfer in a disease context. Video Abstract.

Integration of absolute multi-omics reveals dynamic protein-to-RNA ratios and metabolic interplay within mixed-domain microbiomes.

While the field of microbiology has adapted to the study of complex microbiomes via modern meta-omics techniques, we have not updated our basic knowledge regarding the quantitative levels of DNA, RNA and protein molecules within a microbial cell, which ultimately control cellular function. Here we report the temporal measurements of absolute RNA and protein levels per gene within a mixed bacterial-archaeal consortium. Our analysis of this data reveals an absolute protein-to-RNA ratio of 102-104 for bacterial populations and 103-105 for an archaeon, which is more comparable to Eukaryotic representatives' humans and yeast. Furthermore, we use the linearity between the metaproteome and metatranscriptome over time to identify core functional guilds, hence using a fundamental biological feature (i.e., RNA/protein levels) to highlight phenotypical complementarity. Our findings show that upgrading multi-omic toolkits with traditional absolute measurements unlocks the scaling of core biological questions to dynamic and complex microbiomes, creating a deeper insight into inter-organismal relationships that drive the greater community function.

High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis.

BACKGROUND/AIMS: Wilson disease is caused by a large number of different mutations in the ATP7B gene. Wilson disease patients from a homogeneous ethnical background (Saxonia) were studied for distribution and phenotypes of ATP7B mutations. METHODS: Eighty-two patients were analyzed. The H1069Q mutation was assayed by a polymerase chain reaction-based restriction fragment length polymorphism test. Exons 8 and 15 were sequenced in all, and the entire gene in 30, non-H1069Q-homozygotes. RESULTS: Four novel and 12 known mutations were found. Thirty-two (39%) Wilson disease patients were homozygous and 39 (48%) heterozygous for the H1069Q mutation (allele frequency 63%). Together with sequence analysis of exons 8 and 15 mutations in both alleles were identified in 65% of patients. Only one patient had both mutations at other locations. In H1069Q homozygotes symptoms started later (21.3+/-7.2 years) than in H1069Q compound heterozygotes (14.6+/-5.8, P<0.001) or H1069Q negatives (10+/-4.4, P<0.001), and they had more frequently neurologic symptoms (93 vs. 47%, P<0.001) and Kayser-Fleischer rings (82 vs. 51%, P<0.001). Mutation status did not correlate with liver biopsy findings, serum ceruloplasmin levels or (64)Cu-assay results. CONCLUSIONS: In spite of many known ATP7B mutations, only few occur in this homogeneous population. Limited genetic testing is useful to confirm Wilson disease in this population.

Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel.

KCNQ2 and KCNQ3 are two homologous K(+) channel subunits that can combine to form heterotetrameric channels with properties of neuronal M channels. Loss-of-function mutations in either subunit can lead to benign familial neonatal convulsions (BFNC), a generalized, idiopathic epilepsy of the newborn. We now describe a syndrome in which BFNC is followed later in life by myokymia, involuntary contractions of skeletal muscles. All affected members of the myokymia/BFNC family carried a mutation (R207W) that neutralized a charged amino acid in the S4 voltage-sensor segment of KCNQ2. This substitution led to a shift of voltage-dependent activation of KCNQ2 and a dramatic slowing of activation upon depolarization. Myokymia is thought to result from hyperexcitability of the lower motoneuron, and indeed both KCNQ2 and KCNQ3 mRNAs were detected in the anterior horn of the spinal cord where the cells of the lower motoneurons arise. We propose that a difference in firing patterns between motoneurons and central neurons, combined with the drastically slowed voltage activation of the R207W mutant, explains why this particular KCNQ2 mutant causes myokymia in addition to BFNC.

Direct molecular analysis of myotonic dystrophy in the German population: important considerations in genetic counselling.

Myotonic dystrophy (DM) is associated with the expansion and instability of a trinucleotide (CTG) repeat at the DM locus on chromosome 19. Direct genomic analysis in the German population was carried out on 18 DM families, six families with equivocal diagnosis, 69 subjects with equivocal clinical diagnosis, and 100 controls using the polymerase chain reaction (PCR) and a refined Southern protocol. In the majority of the cases molecular analysis confirmed the clinical diagnosis. These included seven cases of congenital DM (CDM) with widely differing gene expansions and instabilities. In most DM families the expanded fragment became larger in successive generations, but we also identified four families with contractions and two families that showed stability of the enlarged fragment during transmission. In four clinically defined DM patients we were unable to detect enlarged CTG repeats. Sequencing of each exon of the DM gene in two of these patients failed to show any mutations. Our cases have important implications for genetic counselling of DM families, highlighting both the diagnostic value of direct genomic analysis and its limitations.

[Magnetic resonance of brain involvement in progressive facial hemiatrophy (Romberg's disease). Reconsideration of a syndrome]. / Ressonância magnética do envolvimento cerebral na hemiatrofia facial progressiva (doença de Romberg). Reconsideração de uma síndrome.

UNLABELLED: Progressive facial hemiatrophy (PFH) is a sporadic disease of unclear etiology, characterized by shrinking and deformation of one side of the face. Reports and interpretations of CNS involvement in PFH, as deduced from the occurrence of seizures in some patients and documented by pneumoencephalography and CT findings in small series of patients, are contradictory. We examined three female patients with PFH, one with partial epilepsy, with the view to gaining further insight into the pathogenesis of the disease. METHODS: Routine MR examinations of the head and face were performed. RESULTS: Only the patient with epilepsy showed pathological findings, confined to the cerebral hemisphere homolateral to the facial hemiatrophy, and including monoventricular enlargement, meningo-cortical dysmorphia and white matter changes. CONCLUSIONS: The MR morphology, and corresponding neuroradiological and histopathological findings disclosed by a review of the literature, indicate that homolateral hemiatrophy is a typical finding for a subgroup of PFH patients, but do not support the model of a simple or nutritive atrophic process. We reconsider chronic localized meningo-encephalitis with vascular involvement as possible underlying cause of the occasional brain involvement in PFH.

Ressonância magnética do envolvimento cerebral na hemiotrofia facial progressiva (doença de Romberg): reconsideraçäo de uma síndrome / Magnetic resonance of brain involvement in progressive facial hemiatrophy (Romberg's disease): reconsideration of a syndrome

A hemiatrofia facial progressiva (HFP) é doença esporádica de etiologia näo esclarecida, caracterizada por progressiva atrofia e deformaçäo de um dos lados da face. Os relatos e interpretaçöes de comprometimento do sistema nervoso central HFP, conforme deduzido pela ocorrência de crises epilépticas em alguns pacientes e pela documentaçäo por pneumencefalografia e CT em pequenas séries de pacientes, säo contraditórios. Examinamos tres pacientes do sexo feminino com HFP, uma com epilepsia, com o objetivo de obter mais informaçöes sobre patogênese da doença. Métodos: Realizamos exames de ressonância magnética nuclear (RMN) de rotina da cabeça e face. Resultados: Apenas a paciente com epilepsia apresentou achados patológicos no cérebro. Estes eram confinados ao hemisfério homolateral à hemiatrofia facial: dilataçäo monoventricular, dismorfismo maningo-cortical e alteraçöes na substância branca. Conclusöes: As alteraçöes morfológicas verificadas à RMN assim como os achados neurorradiológicos e histopatológicos mostrados em revisäo da literatura indicaram que a hemiatrofia homolateral é achado típico para um subgrupo de pacientes com HFP, mas näo indica um modelo de simples processo atrófico. Reconsideramos a possibilidade de uma meningoencefalite crônica com acometimento vascular como possível causa do ocasional envolvimento cerebral na HFP

MR of brain involvement in progressive facial hemiatrophy (Romberg disease): reconsideration of a syndrome.

PURPOSE: To gain further insight into the pathogenesis of progressive facial hemiatrophy, a sporadic disease of unclear etiology characterized by shrinking and deformation of one side of the face. METHODS: We investigated possible brain involvement. MR of the head and face was performed in three female patients with progressive facial hemiatrophy. The central-nervous-system findings were correlated to a clinical protocol and a review of the literature. RESULTS: One patient with epilepsy had abnormal brain findings confined to the cerebral hemisphere homolateral to the facial hemiatrophy. These consisted of monoventricular enlargement, meningocortical dysmorphia, and white-matter changes. CONCLUSIONS: These MR findings, and corresponding neuroradiologic data disclosed by the review, indicate that homolateral hemiatrophy occasionally occurs in a subgroup of patients with progressive facial hemiatrophy. The MR features do not seem consistent with an underlying simple or nutritive atrophic process. We propose chronic localized meningoencephalitis with vascular involvement as a possible underlying cause of the occasional brain involvement in progressive facial hemiatrophy.

[Cerebral manifestations of progressive facial hemiatrophy (Romberg's disease). Nuclear spin tomographic findings and literature review]. / Zerebrale Manifestation der progressiven fazialen Hemiatrophie (Romberg-Erkrankung). Kernspintomographische Befunde und Literaturübersicht.

Progressive facial hemiatrophy (PFH) is a sporadic disease of unknown etiology. It is characterized by shrinking and deformation of one side of the face. Potential CNS involvement has repeatedly been suspected in some patients, but is still a matter of controversy. In this article we describe the clinical and MR imaging findings of the CNS in three female patients with PFH and present a comprehensive review of the literature. One of three PFH patients had partial epilepsy. MRI showed ventricular enlargement, white matter lesions, flattening of the cortical surface and meningeal adhesions homolateral to the facial hemiatrophy. Two other patients had completely normal intracranial findings. These findings confirm that cerebral hemiatrophy occurs in a subgroup of PFH patients. The MRI pattern, however, does not seem to be consistent with a simple atrophic or malnutritional process. We consider chronic localized meningoencephalitis with vascular involvement as a possible underlying mechanism for the occasional CNS involvement in PFH.

Long-term care and management of Wilson's disease in the GDR.

Diagnosis, long-term management and family investigations of Wilson's disease are provided by selected clinical institutions in the GDR. From 187 patients detected since 1949, 111 are alive. In spite of the principal effectiveness of penicillamine treatment, confirmed by the disappearance of most of the central nervous system symptoms and successful professional rehabilitation of many patients, insufficient therapeutic discipline, psychosocial disturbances and penicillamine side-effects forcing its substitution by zinc or triethylenetetramine dihydrochloride in 14 cases need our further attention.

[Islet cell adenoma with acute neuropsychiatric symptoms]. / Das Inselzelladenom mit akuter neurologisch-psychiatrischer Symptomatik.

The author, by reference to observations made on two cases of islet cell adenoma with cerebral symptoms, describes the most important symptoms of this multifaceted disease picture. Diagnostic possibilities are discussed, and surgical treatment as the method of choice is pointed out.

[Extrapyramidal syndromes as side-effects of metoclopramide (Cerucal) medication]. / Extrapyramidale Syndrome als Nebenwirkungen bei Metoclopramid-(Cerucal-)Medikation

The authors, by describing their own observations made on eight patients showing extrapyramidal syndromes as side effects of metoclopramide (Cerucal) medication, report the various kinds of possible side effects, discussing their conformity with side effects produced by conventional neuroleptics and showing methods of treatment. Metoclopramide is known to produce three froms of extrapyramidal and motor side effects, namely: 1. Dyskinetic syndrome; 2. acathisia; and 3. Parkinson's syndrome. Therapy is in the following form regardless of the particular side effect produced by the said drug: 1. Administration of antiparkinsonian remedies; 2. administration of coffein; and 3. discontinuation or drastic reduction, respectively, of the daily dose of Cerucal.

[The effect of carbocromen on the ST segment of the epicardial electrocardiogram in a model of intermitting myocardial ischemia (author's transl)]. / Die Wirkung von Carbocromen auf die ST-Strecke des epikardialen Elektrokardiogramms im Modell einer intermittierenden myokardialen Ischämie

3-(2-Diethylaminoethyl)-4-methyl-7-(carbethoxy-methoxy)-2-oxo-1,2-chromene-hydrochloride (carbocromen, Intensaïn) was studied on a model of a brief intermittent myocardial ischemia in dogs. At doses which did not affect blood pressure and heart rate, carbocromen markedly improved the ischemic reaction as measured by the ST segment of the epicardial ECG. Higher doses--increasing heart rate--did not, however, aggravate ischemic reaction, although as a rule increasing heart rate enhances ischemic reaction. When keeping the heart rate constant by means of a pace maker, carbocromen even at higher dosage caused a clear-cut improvement. In order to exclude any influence of the experimental and time conditions of the model on the results, identical tests were performed with a placebo. The results proved the carbocromen effects to be independent of the model chosen and its duration. The effects of propranolol, nitroglycerin and isoproterenol observed in our experiments are in agreement with the results frequently described in literature. Considering the changes in ST segment of the epicardial ECG a criterion of myocardial injury, our findings permit the statement that carbocromen clearly reduces the negative sequelae of brief intermittent disturbance of coronary blood flow.