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1.
Diabetes Technol Ther ; 25(1): 50-61, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36326825

RESUMO

Objective: Stepped-care has been suggested in the management of patients with problematic hypoglycemia and impaired awareness of hypoglycemia (IAH), initially with psychoeducational programs based on blood glucose awareness training, progressing to diabetes technology in those with persisting need. We examined the clinical effectiveness of stepped-care starting with HypoAware and adding continuous glucose monitoring (CGM) as needed, versus immediate CGM in type 1 diabetes patients with problematic hypoglycemia despite previous structured education in insulin adjustment. Research Design and Methods: A randomized controlled trial (N = 52, mean age 53, 56% females). The stepped-care group attended HypoAware. If a severe hypoglycemic event (SHE) had occurred or IAH was still present after 6 months, CGM was initiated. The control group started immediate CGM. Primary endpoint was the number of participants with self-reported SHE. Secondary outcomes, evaluated at 6 and 12 months, were glycated hemoglobin (HbA1c), the number of participants with IAH time below range (TBR; <54 mg/dL), and patient-reported outcomes (PROs). Results: At 6 months, the number of patients reporting SHE had decreased significantly more in the CGM group: -39% (P < 0.05). HbA1c decreased more in the CGM group (-0.47 percentage-points, P < 0.05). IAH was restored in 31% of patients in both groups. TBR (<54 mg/dL) was lower in the CGM group (-2.4 percentage-points, P < 0.05). In the stepped-care group, 93% started CGM/intermittently scanned CGM. At 12 months, the number of patients reporting SHE was still higher in the stepped-care group. No differences were found in PROs. Conclusions: Immediate start of CGM is more effective than a hypoglycemia-focused reeducation program in reducing SHE risk and attaining glycemic targets in individuals with problematic hypoglycemia and IAH despite previous education in insulin dose adjustment. Trial registration: Netherlands Trial Register, NL64474.029.18.


Assuntos
Diabetes Mellitus Tipo 1 , Hipoglicemia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glicemia , Automonitorização da Glicemia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas , Hipoglicemia/etiologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Insulina Regular Humana
2.
ACS Biomater Sci Eng ; 7(6): 2198-2203, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34043314

RESUMO

Biomedical adhesives have been found to be an attractive alternative to suturing in several circumstances. However, to date most of the clinically approved formulations are based on synthetic and highly reactive toxic chemicals. In this work, we aimed to combine for the first time the bioactive properties of the cationic polysaccharide chitosan and its intrinsic electrostatic binding to negatively charged tissues with the biocompatible and clinically compliant enzymatic cross-linking scheme of fibrin glue. This synergistic activity led to the generation of a transglutaminase Factor XIII cross-linkable chitosan formulation with fast gelation kinetics, tunable mechanical properties, antibacterial activity, and strong adhesion to cartilage.


Assuntos
Quitosana , Adesivos Teciduais , Adesivos , Fator XIII , Hidrogéis
3.
DNA Repair (Amst) ; 91-92: 102870, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470850

RESUMO

By combining mutations in DNA repair genes, important and unexpected interactions between different repair pathways can be discovered. In this study, we identified a novel link between mismatch repair (MMR) genes and postreplication repair (PRR) in Saccharomyces cerevisiae. Strains lacking Rad5 (HLTF in mammals), a protein important for restarting stalled replication forks in the error-free PRR pathway, were supersensitive to the DNA methylating agent methyl methanesulfonate (MMS). Deletion of the mismatch repair genes, MSH2 or MSH6, which together constitutes the MutSα complex, partially suppressed the MMS super-sensitivity of the rad5Δ strain. Deletion of MSH2 also suppressed the MMS sensitivity of mms2Δ, which acts together with Rad5 in error-free PRR. However, inactivating the mismatch repair genes MSH3 and MLH1 did not suppress rad5Δ, showing that the suppression was specific for disabling MutSα. The partial suppression did not require translesion DNA synthesis (REV1, REV3 or RAD30), base excision repair (MAG1) or homologous recombination (RAD51). Instead, the underlying mechanism was dependent on RAD52 while independent of established pathways involving RAD52, like single-strand annealing and break-induced replication. We propose a Rad5- and Rad51-independent template switch pathway, capable of compensating for the loss of the error-free template-switch subpathway of postreplication repair, triggered by the loss of MutSα.


Assuntos
Dano ao DNA , DNA Helicases/metabolismo , Reparo de Erro de Pareamento de DNA , Replicação do DNA , Proteínas de Ligação a DNA/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , DNA Helicases/genética , DNA Fúngico/efeitos dos fármacos , DNA Fúngico/metabolismo , Proteínas de Ligação a DNA/genética , Deleção de Genes , Metanossulfonato de Metila/toxicidade , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 3 Homóloga a MutS/genética , Proteína 3 Homóloga a MutS/metabolismo , Proteína Rad52 de Recombinação e Reparo de DNA , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
4.
PLoS Genet ; 10(2): e1004106, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24516398

RESUMO

Meiotic recombination ensures the correct segregation of homologous chromosomes during gamete formation and contributes to DNA diversity through both large-scale reciprocal crossovers and very localised gene conversion events, also known as noncrossovers. Considerable progress has been made in understanding factors such as PRDM9 and SNP variants that influence the initiation of recombination at human hotspots but very little is known about factors acting downstream. To address this, we simultaneously analysed both types of recombinant molecule in sperm DNA at six highly active hotspots, and looked for disparity in the transmission of allelic variants indicative of any cis-acting influences. At two of the hotspots we identified a novel form of biased transmission that was exclusive to the noncrossover class of recombinant, and which presumably arises through differences between crossovers and noncrossovers in heteroduplex formation and biased mismatch repair. This form of biased gene conversion is not predicted to influence hotspot activity as previously noted for SNPs that affect recombination initiation, but does constitute a powerful and previously undetected source of recombination-driven meiotic drive that by extrapolation may affect thousands of recombination hotspots throughout the human genome. Intriguingly, at both of the hotspots described here, this drive favours strong (G/C) over weak (A/T) base pairs as might be predicted from the well-established correlations between high GC content and recombination activity in mammalian genomes.


Assuntos
Troca Genética , Meiose/genética , Recombinação Genética , Espermatozoides/crescimento & desenvolvimento , Alelos , Animais , Genoma Humano , Células Germinativas/crescimento & desenvolvimento , Histona-Lisina N-Metiltransferase/genética , Humanos , Masculino , Ácidos Nucleicos Heteroduplexes/genética , Polimorfismo de Nucleotídeo Único , Espermatozoides/metabolismo
5.
Proc Natl Acad Sci U S A ; 108(30): 12378-83, 2011 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-21750151

RESUMO

PRDM9 is a major specifier of human meiotic recombination hotspots, probably via binding of its zinc-finger repeat array to a DNA sequence motif associated with hotspots. However, our view of PRDM9 regulation, in terms of motifs defined and hotspots studied, has a strong bias toward the PRDM9 A variant particularly common in Europeans. We show that population diversity can reveal a second class of hotspots specifically activated by PRDM9 variants common in Africans but rare in Europeans. These African-enhanced hotspots nevertheless share very similar properties with their counterparts activated by the A variant. The specificity of hotspot activation is such that individuals with differing PRDM9 genotypes, even within the same population, can use substantially if not completely different sets of hotspots. Each African-enhanced hotspot is activated by a distinct spectrum of PRDM9 variants, despite the fact that all are predicted to bind the same sequence motif. This differential activation points to complex interactions between the zinc-finger array and hotspots and identifies features of the array that might be important in controlling hotspot activity.


Assuntos
População Negra/genética , Variação Genética , Histona-Lisina N-Metiltransferase/genética , Alelos , Sequência de Aminoácidos , Sequência de Bases , Troca Genética , DNA/genética , Conversão Gênica , Frequência do Gene , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Desequilíbrio de Ligação , Masculino , Meiose/genética , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Recombinação Genética , Espermatozoides/metabolismo , População Branca/genética
6.
Nat Genet ; 42(10): 859-63, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20818382

RESUMO

PRDM9 has recently been identified as a likely trans regulator of meiotic recombination hot spots in humans and mice. PRDM9 contains a zinc finger array that, in humans, can recognize a short sequence motif associated with hot spots, with binding to this motif possibly triggering hot-spot activity via chromatin remodeling. We now report that human genetic variation at the PRDM9 locus has a strong effect on sperm hot-spot activity, even at hot spots lacking the sequence motif. Subtle changes within the zinc finger array can create hot-spot nonactivating or enhancing variants and can even trigger the appearance of a new hot spot, suggesting that PRDM9 is a major global regulator of hot spots in humans. Variation at the PRDM9 locus also influences aspects of genome instability-specifically, a megabase-scale rearrangement underlying two genomic disorders as well as minisatellite instability-implicating PRDM9 as a risk factor for some pathological genome rearrangements.


Assuntos
Variação Genética/genética , Instabilidade Genômica , Histona-Lisina N-Metiltransferase/genética , Meiose/genética , Recombinação Genética/genética , Alelos , Animais , Rearranjo Gênico , Genoma Humano , Homozigoto , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Espermatozoides
7.
Proc Natl Acad Sci U S A ; 105(30): 10471-6, 2008 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-18650392

RESUMO

Population diversity data have recently provided profound, albeit inferential, insights into meiotic recombination across the human genome, revealing a landscape dominated by thousands of cross-over hotspots. However, very few of these putative hotspots have been directly analyzed for cross-over activity. We now describe a search for very active hotspots, by using extreme breakdown of marker association as a guide for high-resolution sperm cross-over analysis. This strategy has led to the isolation of the most active cross-over hotspots yet described. Their morphology, sequence attributes, and cross-over processes are very similar to those seen at less active hotspots, but their activity in sperm is poorly predicted from population diversity information. Several of these hotspots showed evidence for biased gene conversion accompanying cross-over, in some cases associated with variation between men in cross-over activity and with two hotspots showing complete presence/absence polymorphism in different men. Hotspot polymorphism is very common at less active hotspots but curiously was not seen at any of the most active hotspots. This contrasts with the prediction that extreme hotspots should be the most vulnerable to attenuation by meiotic drive in favor of mutations that suppress recombination and should therefore show rapid rate evolution and thus variation in activity between men. Finally, these very intense hotspots provide a valuable resource for dissecting meiotic recombination processes and pathways in humans.


Assuntos
Troca Genética , Marcadores Genéticos , Genoma Humano , Espermatozoides/fisiologia , Evolução Molecular , Variação Genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Modelos Genéticos , Polimorfismo Genético , Recombinação Genética
8.
Am J Hum Genet ; 72(6): 1436-47, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12748906

RESUMO

Minisatellite MS1 (locus D1S7) is one of the most unstable minisatellites identified in humans. It is unusual in having a short repeat unit of 9 bp and in showing somatic instability in colorectal carcinomas, suggesting that mitotic replication or repair errors may contribute to repeat-DNA mutation. We have therefore used single-molecule polymerase chain reaction to characterize mutation events in sperm and somatic DNA. As with other minisatellites, high levels of instability are seen only in the germline and generate two distinct classes of structural change. The first involves large and frequently complex rearrangements that most likely arise by recombinational processes, as is seen at other minisatellites. The second pathway generates primarily, if not exclusively, single-repeat changes restricted to sequence-homogeneous regions of alleles. Their frequency is dependent on the length of uninterrupted repeats, with evidence of a hyperinstability threshold similar in length to that observed at triplet-repeat loci showing expansions driven by dynamic mutation. In contrast to triplet loci, however, the single-repeat changes at MS1 exclusively involve repeat deletion, and can be so frequent--as many as 0.7-1.3 mutation events per sperm cell for the longest homogeneous arrays--that alleles harboring these long arrays must be extremely ephemeral in human populations. The apparently impossible existence of alleles with deletion-prone uninterrupted repeats therefore presents a paradox with no obvious explanation.


Assuntos
Deleção de Genes , Mutação em Linhagem Germinativa/genética , Repetições Minissatélites/genética , Alelos , Carcinoma/genética , Neoplasias Colorretais/genética , DNA Satélite/análise , Frequência do Gene , Genoma Humano , Células Germinativas , Heterozigoto , Homozigoto , Humanos , Masculino , Deleção de Sequência , Espermatozoides/fisiologia
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