Transposable elements contribute to the establishment of the glycine shuttle in Brassicaceae species.

C3 -C4 intermediate photosynthesis has evolved at least five times convergently in the Brassicaceae, despite this family lacking bona fide C4 species. The establishment of this carbon concentrating mechanism is known to require a complex suite of ultrastructural modifications, as well as changes in spatial expression patterns, which are both thought to be underpinned by a reconfiguration of existing gene-regulatory networks. However, to date, the mechanisms which underpin the reconfiguration of these gene networks are largely unknown. In this study, we used a pan-genomic association approach to identify genomic features that could confer differential gene expression towards the C3 -C4 intermediate state by analysing eight C3 species and seven C3 -C4 species from five independent origins in the Brassicaceae. We found a strong correlation between transposable element (TE) insertions in cis-regulatory regions and C3 -C4 intermediacy. Specifically, our study revealed 113 gene models in which the presence of a TE within a gene correlates with C3 -C4 intermediate photosynthesis. In this set, genes involved in the photorespiratory glycine shuttle are enriched, including the glycine decarboxylase P-protein whose expression domain undergoes a spatial shift during the transition to C3 -C4 photosynthesis. When further interrogating this gene, we discovered independent TE insertions in its upstream region which we conclude to be responsible for causing the spatial shift in GLDP1 gene expression. Our findings hint at a pivotal role of TEs in the evolution of C3 -C4 intermediacy, especially in mediating differential spatial gene expression.

KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia.

BACKGROUND AND PURPOSE: Despite recent advances in neurogenetics that have facilitated the identification of a number of dystonia genes, many familial dystonia syndromes remain without known cause. The aim of the study was to identify the cause of autosomal dominant tremulous myoclonus-dystonia in a UK kindred with affected individuals in three generations. METHODS: Known genetic causes of myoclonus-dystonia were excluded. We combined clinical and electrophysiological phenotyping with whole-exome sequencing and Sanger sequencing to identify candidate causal variants in a family with tremulous myoclonus-dystonia. RESULTS: The core phenotype consisted of childhood-onset dystonia predominantly affecting hands and neck, with a fast tremor with superimposed myoclonus and, in some individuals, subtle cerebellar signs. We identified a novel missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) [NM_021614:c.1112G>A:p.(Gly371Glu)], which was the only variant that we were able to identify as segregating with the phenotype over three generations. This variant, which is absent from the most recent version of gnomAD, was predicted to be deleterious by SIFT and PolyPhen-2 and had an overall CADD score of 29.7. CONCLUSIONS: KCNN2, a member of the KCNN family of potassium channel genes, is highly conserved across species and in humans is highly expressed in the brain, particularly the cerebellum. KCNN2 mutations have never been described as pathological in human disease, but are recognized abnormalities in two rodent models of fast, jerky tremor. Segregation, absence of the variant in the normal population and in-silico prediction of a deleterious effect together with animal models compatible with the clinical phenotype are all in line with KCNN2 mutations being a plausible cause underlying myoclonus-dystonia.

Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease.

AIM: Late-onset Alzheimer's disease (LOAD) accounts for 95% of all Alzheimer's cases and is genetically complex in nature. Overlapping clinical and neuropathological features between AD, FTD and Parkinson's disease highlight the potential role of genetic pleiotropy across diseases. Recent genome-wide association studies (GWASs) have uncovered 20 new loci for AD risk; however, these exhibit small effect sizes. Using NGS, here we perform association analyses using exome-wide and candidate-gene-driven approaches. METHODS: Whole-exome sequencing was performed on 132 AD cases and 53 control samples. Exome-wide single-variant association and gene burden tests were performed for 76 640 nonsingleton variants. Samples were also screened for known causative mutations in familial genes in AD and other dementias. Single-variant association and burden analysis was also carried out on variants in known AD and other neurological dementia genes. RESULTS: Tentative single-variant and burden associations were seen in several genes with kinase and protease activity. Exome-wide burden analysis also revealed significant burden of variants in PILRA (P = 3.4 × 10-5 ), which has previously been linked to AD via GWAS, hit ZCWPW1. Screening for causative mutations in familial AD and other dementia genes revealed no pathogenic variants. Variants identified in ABCA7, SLC24A4, CD33 and LRRK2 were nominally associated with disease (P < 0.05) but did not withstand correction for multiple testing. APOE (P = 0.02) and CLU (P = 0.04) variants showed significant burden on AD. CONCLUSIONS: In addition, polygenic risk scores (PRS) were able to distinguish between cases and controls with 83.8% accuracy using 3268 variants, sex, age at death and APOE ε4 and ε2 status as predictors.

Primary familial brain calcification linked to deletion of 5' noncoding region of SLC20A2.

OBJECTIVES: Primary familial brain calcification (PFBC) is a rare neurological disease often inherited as a dominant trait. Mutations in four genes (SLC20A2, PDGFB, PDGFRB, and XPR1) have been reported in patients with PFBC. Of these, point mutations or small deletions in SLC20A2 are most common. Thus far, only one large deletion covering entire SLC20A2 and several smaller, exonic deletions of SLC20A2 have been reported. The aim of this study was to identify the causative gene defect in a Finnish PFBC family with three affected patients. MATERIALS AND METHODS: A Finnish family with three PFBC patients and five unaffected subjects was studied. Sanger sequencing was used to exclude mutations in the coding and splice site regions of SLC20A2, PDGFRB, and PDGFB. Whole-exome (WES) and whole-genome sequencing (WGS) were performed to identify the causative mutation. A SNP array was used in segregation analysis. RESULTS: Copy number analysis of the WGS data revealed a heterozygous deletion of ~578 kb on chromosome 8. The deletion removes the 5' UTR region, the noncoding exon 1 and the putative promoter region of SLC20A2 as well as the coding regions of six other genes. CONCLUSIONS: Our results support haploinsufficiency of SLC20A2 as a pathogenetic mechanism in PFBC. Analysis of copy number variations (CNVs) is emerging as a crucial step in the molecular genetic diagnostics of PFBC, and it should not be limited to coding regions, as causative variants may reside in the noncoding parts of known disease-associated genes.

Pseudohypoparathyroidism type I-b with neurological involvement is associated with a homozygous PTH1R mutation.

Pseudohypoparathyroidism type 1b (PHP1b) is characterized by hypocalcemia, hyperphosphatemia, increased levels of circulating parathyroid hormone (PTH), and no skeletal or developmental abnormalities. The goal of this study was to perform a full characterization of a familial case of PHP1b with neurological involvement and to identify the genetic cause of disease. The initial laboratory profile of the proband showed severe hypocalcemia, hyperphosphatemia and normal levels of PTH, which was considered to be compatible with primary hypoparathyroidism. With disease progression the patient developed cognitive disturbance, PTH levels were found to be slightly elevated and a picture of PTH resistance syndrome seemed more probable. The diagnosis of PHP1b was established after the study of family members and blunted urinary cAMP results were obtained in a PTH stimulation test. Integration of whole genome genotyping and exome sequencing data supported this diagnosis by revealing a novel homozygous missense mutation in PTH1R (p.Arg186His) completely segregating with the disease. Here, we demonstrate segregation of a novel mutation in PTH1R with a phenotype of PHP1b presenting with neurological symptoms, but no bone defects. This case represents the extreme end of the spectrum of cognitive impairment in PTH dysfunction and defines a possible novel form of PHP1b resulting from the impaired interaction between PTH and PTH1R.

The heritability and genetics of frontotemporal lobar degeneration.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder. METHODS: We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease. RESULTS: A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1). CONCLUSION: These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation.

Extended tracts of homozygosity identify novel candidate genes associated with late-onset Alzheimer's disease.

Large tracts of extended homozygosity are more prevalent in outbred populations than previously thought. With the advent of high-density genotyping platforms, regions of extended homozygosity can be accurately located allowing for the identification of rare recessive risk variants contributing to disease. We compared measures of extended homozygosity (greater than 1 Mb in length) in a population of 837 late-onset Alzheimer's disease (LOAD) cases and 550 controls. In our analyses, we identify one homozygous region on chromosome 8 that is significantly associated with LOAD after adjusting for multiple testing. This region contains seven genes from which the most biologically plausible candidates are STAR, EIF4EBP1, and ADRB3. We also compared the total numbers of homozygous runs and the total length of these runs between cases and controls, showing a suggestive difference in these measures (p-values 0.052-0.062). This research suggests a recessive component to the etiology of LOAD.

Whole genome analysis in a consanguineous family with early onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) is a clinically and genetically heterogeneous condition in which the typical features appear significantly earlier in life (before 65 years). Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in autosomal dominant forms of EOAD. However, in about 50% of Mendelian cases and in most of the sporadic EOAD patients, no mutations have been found. We present clinical characteristics of an Israeli family comprising two affected siblings with EOAD born to neurologically healthy parents who were first cousins (both parents died after 90 years old). Sequence analysis of PSEN1, PSEN2, APP, TAU, PGRN, and PRNP failed to reveal any mutations in the affected siblings. Because the disease in this family is consistent with an autosomal recessive mode of inheritance we identified all homozygous regions identical by descent (IBD) in both siblings, by high-density SNP genotyping. We provide here the first catalog of autozygosity in EOAD and suggest that the regions identified are excellent candidate loci for a recessive genetic lesion causing this disease.

Abscesos cerebrales múltiples de etiología micótica en un individuo inmunocompetente / Multiple brain abscesses of a mycotic origin in an immunocompetent individual

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Síndrome de Balint por hematomas bilaterales secuenciales / Balint's syndrome due to sequential bilateral haematomas

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[Mechanical ventilation near large centers. The experience of a perinatal care unit]. / Ventilação mecânica próximo dos grandes centros. Experiência de uma unidade de apoio perinatal.

A retrospective study of the newborns who were submitted to mechanical ventilation at the Neonatal Intermediate Care Unit was made between July 1991 and June 1994. Mechanical ventilation in such a unit should be transitory and not exceed 24 hours. Information concerning pregnancy, labour, neonates, type of ventilation and its problems was gathered. Forty seven neonates were ventilated. The average ventilation time was six hours (1-20 hours). The main cause of ventilation was hyaline membrane disease which occurred in 24% of all cases. Mortality observed was 16.6% and some sequellae were registered which were related not only to ventilation but also to the basic pathology in 26% of cases.

Influence of ambroxol on lung tissue penetration of amoxicillin.

Lung amoxicillin levels were assessed in tissue obtained from 16 patients who underwent lung resection due to different pulmonary diseases. In this double-blind placebo controlled study patients were allocated to two groups in randomized order; one group received amoxicillin 1000 mg t.i.d. (n = 8) and the other amoxicillin 1000 mg + ambroxol 60 mg t.i.d. (n = 8). A trend towards higher antibiotic lung tissue levels was observed in patients who received the antibiotic together with the mucolytic agent. The ratio pulmonary tissue/serum amoxicillin levels reached a significant difference being higher in the amoxicillin plus ambroxol group than in the other one (0.411 +/- 0.04 vs 0.672 +/- 0.07; p less than 0.01), even if the amoxicillin plasma levels were lower. A possible effect of ambroxol on lung tissue penetration of amoxicillin is suggested and discussed.

Influence of ambroxol on amoxicillin levels in bronchoalveolar lavage fluid.

Amoxicillin levels were measured in bronchoalveolar lavage (BAL) fluid samples obtained from patients who after randomization were treated in double-blind fashion either with amoxicillin 1000 mg p.o.t.i.d. or with amoxicillin 1000 mg + ambroxol 60 mg p.o.t.i.d. Antibiotic levels were higher in the group receiving ambroxol (0.32 +/- 0.02 micrograms/ml; n = 8) than in the other one (0.19 +/- 0.02 micrograms/ml; n = 6). This difference was statistically significant (p less than 0.001). Comparisons of protein concentrations in BAL fluid samples and of amoxicillin plasma levels did not show significant differences in the two groups. These results seem to prove that ambroxol is able to increase the antibiotics concentration in the lungs, although the mechanism of action is still unclear. In addition it could be shown that the BAL technique is suitable for exploring the lung concentration of antibiotics.

Ambroxol plus amoxicillin in the treatment of exacerbations of chronic bronchitis.

Twenty-three patients with exacerbations of chronic bronchitis were divided in two groups in a randomized fashion receiving either amoxicillin 1500 mg/d (n = 13) or amoxicillin 1500 mg/d associated with the mucolytic drug ambroxol 90 mg/d (n = 10). The improvement in cough, expectoration difficulties and sputum purulence was statistically more evident and occurred earlier in the ambroxol + amoxicillin group than in the amoxicillin only group. Although amoxicillin plasma and sputum levels were similar in both groups, the differences in daily sputum volume, which was also statistically greater in patients receiving ambroxol, suggests that this drug favours the bronchial mucus clearance of the antibiotic which could be related to the more favourable clinical evolution. No changes were observed in lung function tests and blood gases.

Experimental findings on the estrogenic activity of estradiol enantate.

In a first attempt to find out the estrogenic activity of the monthly injectable contraceptive composed of dihydroxyprogesterone acetophenide 150 mg + estradiol enantate 10 mg (Perlutal, Topasel), estradiol enantate (estra-1,3,5(10)-triene-3-ol-17 beta-heptanoat), estradiol benzoate and ethinylestradiol were compared in rats of the Chbb: THOM species. Estradiol benzoate potency was significantly higher than that of estradiol enantate: 20.34 (15.57-26.31) times in the vaginal cornification test in castrated females; 2.21 (1.63-2.98) times in the uterine weight test also in castrated rats and 2.91 (1.86-4.54) times in the vaginal opening test in immature rats. Ethinylestradiol, orally administered in the first two tests, was less active than the other two parenterally given substances; it overcame them in the vaginal opening test, when all substances were perivaginally administered. The duration of action of equivalent doses on the vaginal smear in castrated females resulted higher for estradiol enantate: 2.52 times more than estradiol benzoate and 5.2 times more than ethinylestradiol. Based on these results and on preexistent literature, the estradiol enantate dosis which would be sufficient to obtain the endometrial proliferation in women was extrapolated and compared with those already established of estradiol benzoate and ethinylestradiol. Finally, the possibility that the estrogenic potency of the injectable contraceptive treatment can be similar or lower than the oral one with pills containing ethinylestradiol 0.030-0.050 mg is discussed.