Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual ...disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
Aim
The objective of this study was to describe the use of COVID‐19‐related medicines during pregnancy and their evolution between the early/late periods of the pandemic.
Methods
Pregnant women who ...tested positive for SARS‐CoV‐2 from March 2020 to July 2021 were included using the COVI‐PREG registry. Exposure to the following COVID‐19‐related medicines was recorded: antibiotics, antivirals, hydroxychloroquine, corticosteroids, anti‐interleukin‐6 and immunoglobulins. We described the prevalence of medicines used, by trimester of pregnancy, maternal COVID‐19 severity level and early/late period of the pandemic (before and after 1 July 2020).
Findings
We included 1964 pregnant patients who tested positive for SARS‐CoV‐2. Overall, 10.4% (205/1964) received at least one COVID‐19‐related medicine including antibiotics (8.6%; 169/1694), corticosteroids (3.2%; 62/1964), antivirals (2.0%; 39/1964), hydroxychloroquine (1.4%; 27/1964) and anti‐interleukin‐6 (0.3%; 5/1964). The use of at least one COVID‐19‐related medicine was 3.1% (12/381) in asymptomatic individuals, 4.2% (52/1233) in outpatients, 19.7% (46/233) in inpatients without oxygen, 72.1% (44/61) in those requiring standard oxygen, 95.7% (22/23) in those requiring high flow oxygen, 96.2% (25/26) in patients who required intubation and 57.1% (4/7) among patients who died. The proportion who received medicines to treat COVID‐19 was higher before than after July 2020 (16.7% vs. 7.7%). Antibiotics, antivirals and hydroxychloroquine had lower rates of use during the late period.
Conclusion
Medicine use in pregnancy increased with disease severity. The trend towards increased use of corticosteroids seems to be aligned with changing guidelines. Evidence is still needed regarding the effectiveness and safety of COVID‐19‐related medicines in pregnancy.
...their suggestion that lowering of fecal butyrate in a majority of individuals is beneficial should be viewed with caution. ...we believe that in light of the scientific literature available today, ...the existence of an optimal range of intestinal butyrate concentrations that support health cannot be excluded. The impact of the level of the intestinal short chain fatty acids in inflammatory bowel disease patients versus healthy subjects.
Epidemiological studies have identified increased colorectal cancer (CRC) risk with high red meat (HRM) intakes, whereas dietary fibre intake appears to be protective. In the present study, we ...examined whether a HRM diet increased rectal O
6
-methyl-2-deoxyguanosine (O
6
MeG) adduct levels in healthy human subjects, and whether butyrylated high-amylose maize starch (HAMSB) was protective. A group of twenty-three individuals consumed 300 g/d of cooked red meat without (HRM diet) or with 40 g/d of HAMSB (HRM+HAMSB diet) over 4-week periods separated by a 4-week washout in a randomised cross-over design. Stool and rectal biopsy samples were collected for biochemical, microbial and immunohistochemical analyses at baseline and at the end of each 4-week intervention period. The HRM diet increased rectal O
6
MeG adducts relative to its baseline by 21 % (
P
< 0·01), whereas the addition of HAMSB to the HRM diet prevented this increase. Epithelial proliferation increased with both the HRM (
P
< 0·001) and HRM+HAMSB (
P
< 0·05) diets when compared with their respective baseline levels, but was lower following the HRM+HAMSB diet compared with the HRM diet (
P
< 0·05). Relative to its baseline, the HRM+HAMSB diet increased the excretion of SCFA by over 20 % (
P
< 0·05) and increased the absolute abundances of the
Clostridium coccoides
group (
P
< 0·05), the
Clostridium
leptum
group (
P
< 0·05),
Lactobacillus
spp. (
P
< 0·01),
Parabacteroides distasonis
(
P
< 0·001) and
Ruminococcus bromii
(
P
< 0·05), but lowered
Ruminococcus torques
(
P
< 0·05) and the proportions of
Ruminococcus gnavus
,
Ruminococcus torques
and
Escherichia coli
(
P
< 0·01). HRM consumption could increase the risk of CRC through increased formation of colorectal epithelial O
6
MeG adducts. HAMSB consumption prevented red meat-induced adduct formation, which may be associated with increased stool SCFA levels and/or changes in the microbiota composition.
Epidemiological studies have identified increased colorectal cancer (CRC) risk with high red meat (HRM) intakes, whereas dietary fibre intake appears to be protective. In the present study, we ...examined whether a HRM diet increased rectal O super(6)-methyl-2-deoxyguanosine (O super(6)MeG) adduct levels in healthy human subjects, and whether butyrylated high-amylose maize starch (HAMSB) was protective. A group of twenty-three individuals consumed 300 g/d of cooked red meat without (HRM diet) or with 40 g/d of HAMSB (HRM+HAMSB diet) over 4-week periods separated by a 4-week washout in a randomised cross-over design. Stool and rectal biopsy samples were collected for biochemical, microbial and immunohistochemical analyses at baseline and at the end of each 4-week intervention period. The HRM diet increased rectal O super(6)MeG adducts relative to its baseline by 21 % (P< 0.01), whereas the addition of HAMSB to the HRM diet prevented this increase. Epithelial proliferation increased with both the HRM (P< 0.001) and HRM+HAMSB (P< 0.05) diets when compared with their respective baseline levels, but was lower following the HRM+HAMSB diet compared with the HRM diet (P< 0.05). Relative to its baseline, the HRM+HAMSB diet increased the excretion of SCFA by over 20 % (P< 0.05) and increased the absolute abundances of the Clostridium coccoides group (P< 0.05), the Clostridium leptum group (P< 0.05), Lactobacillus spp. (P< 0.01), Parabacteroides distasonis (P< 0.001) and Ruminococcus bromii (P< 0.05), but lowered Ruminococcus torques (P< 0.05) and the proportions of Ruminococcus gnavus, Ruminococcus torques and Escherichia coli (P< 0.01). HRM consumption could increase the risk of CRC through increased formation of colorectal epithelial O super(6)MeG adducts. HAMSB consumption prevented red meat-induced adduct formation, which may be associated with increased stool SCFA levels and/or changes in the microbiota composition.
3(S)-(6-Methoxypyridin-3-yl)-3-{2-oxo-3-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propylimidazolidin-1-yl}propionic acid 6 was identified as a potent and selective antagonist of the αvβ3 receptor. ...This compound has an excellent in vitro profile (IC50 = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.
Red meat may increase promutagenic lesions in the colon. Resistant starch (RS) can reduce these lesions and chemically induced colon tumours in rodents. Msh2 is a mismatch repair (MMR) protein, ...recognising unrepaired promutagenic adducts for removal. We determined if red meat and/or RS modulated DNA adducts or oncogenesis in Msh2-deficient mice. A total of 100 Msh2-/- and 60 wild-type mice consumed 1 of 4 diets for 6 months: control, RS, red meat and red meat+RS. Survival time, aberrant crypt foci (ACF), colon and small intestinal tumours, lymphoma, colonic O6-methyl-2-deoxyguanosine (O6MeG) adducts, methylguanine methyltransferase (MGMT) and cell proliferation were examined. In Msh2-/- mice, red meat enhanced survival compared to control (p<0.01) and lowered total tumour burden compared to RS (p<0.167). Msh2-/- mice had more ACF than wild-type mice (p<0.014), but no colon tumours developed. Msh2-/- increased cell proliferation (p<0.001), lowered DNA O6MeG adducts (p<0.143) and enhanced MGMT protein levels (p<0.001) compared to wild-type mice, with RS supplementation also protecting against DNA adducts (p<0.01). No link between red meat-induced promutagenic adducts and risk for colorectal cancer was observed after 6 months' feeding. Colonic epithelial changes after red meat and RS consumption with MMR deficiency will differ from normal epithelial cells.
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