RESUMEN
Dyssegmental dysplasia (DD) is a severe skeletal dysplasia comprised of two subtypes: lethal Silverman-Handmaker type (DDSH) and nonlethal Rolland-Desbuquois type (DDRD). DDSH is caused by biallelic pathogenic variants in HSPG2 encoding perlecan, whereas the genetic cause of DDRD remains undetermined. Schwartz-Jampel syndrome (SJS) is also caused by biallelic pathogenic variants in HSPG2 and is an allelic disorder of DDSH. In SJS and DDSH, 44 and 8 pathogenic variants have been reported in HSPG2, respectively. Here, we report that five patients with DDRD carried four pathogenic variants in HSPG2: c.9970 G > A (p.G3324R), c.559 C > T (p.R187X), c7006 + 1 G > A, and c.11562 + 2 T > G. Two patients were homozygous for p.G3324R, and three patients were heterozygous for p.G3324R. Haplotype analysis revealed a founder haplotype spanning 85,973 bp shared in the five patients. SJS, DDRD, and DDSH are allelic disorders with pathogenic variants in HSPG2.
Asunto(s)
Haplotipos , Proteoglicanos de Heparán Sulfato , Osteocondrodisplasias , Femenino , Humanos , Masculino , Alelos , Enfermedades del Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/patología , Efecto Fundador , Proteoglicanos de Heparán Sulfato/genética , Mutación , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Enfermedades FetalesRESUMEN
A 67-year-old man with type 1 diabetes, Cronkhite-Canada syndrome, and membranous nephropathy who received insulin therapy was admitted to our hospital with right hemiplegia and dysarthria. Brain magnetic resonance imaging revealed a lesion with a high diffusion-weighted imaging signal and low apparent diffusion coefficient signal in the posterior limb of the left internal capsule. He was hypoglycemic with a blood glucose level of 56 mg/dL (3.1 mmol/L). Following glucose administration, the patient's symptoms resolved within several hours. The patient experienced similar transient hypoglycemic hemiplegia at midnight, three times within 10 days. In a literature review of 170 cases of hypoglycemic hemiplegia, 26 cases of recurrent hemiplegia were investigated. Recurrent hypoglycemic hemiplegia occurs more frequently on the right side than on the left side, and most recurrences occur within approximately a week, almost exclusively at midnight and in the early morning. We speculate that hypoglycemia-associated autonomic failure may be involved in the nocturnal recurrence of episodes. In our patient, depleted endogenous insulin secretion and lipodystrophy at the injection site, may have acted as additional factors, leading to severe hypoglycemia despite the absence of apparent autonomic neuropathy. Clinically, it is important to recognize hypoglycemia as a cause of hemiplegia to avoid unnecessary intervention and to maintain an appropriate blood glucose level at midnight and early in the morning to prevent recurrent hypoglycemic hemiplegia.
Asunto(s)
Hemiplejía , Hipoglucemia , Recurrencia , Humanos , Masculino , Hemiplejía/etiología , Anciano , Hipoglucemia/etiología , Diabetes Mellitus Tipo 1/complicaciones , Glucemia/metabolismo , Insulina/uso terapéutico , Insulina/administración & dosificaciónRESUMEN
A long-standing question in sentence processing research concerns the online parsing process in clause-boundary garden-path sentences, such as After Mary dressed John bathed. In this sentence, "John" must be parsed as the matrix subject DP but can be locally analysed as the object of the embedded verb. There is considerable evidence that the parser misanalyses these garden-path sentences. However, the controversy lies in whether the parser revises them during the online parsing process. The present study investigated this revision process through two self-paced reading experiments utilising grammatical constraints on reflexives and subject or object relative clauses embedded within the locally ambiguous DP. The results provided evidence of revision when a subject relative clause was embedded but not when an object relative clause was embedded. These findings suggest that the parser assigns grammatical structures that correspond to input strings during the revision of clause-boundary ambiguities but that object relative clauses affect the online revision process.
Asunto(s)
Lenguaje , Lectura , Humanos , ComprensiónRESUMEN
The chemical and physical properties of amides change substantially when the electron-withdrawing groups attached to the nitrogen are varied. Herein, we report the superior performance of N-diphenylphosphinyl 1,2,3-triazolium amidate as a photoinduced hydrogen-atom transfer catalyst compared to its N-benzoyl analog. A binary catalyst system of the phosphinyl amidate and an Ir-based photocatalyst enables the alkylation of unbiased C-H bonds.
RESUMEN
In online language comprehension, the parser incrementally builds hierarchical syntactic structures. The predictive nature of this structure-building process has been the subject of extensive debate. A previous study observed that when a wh-phrase indicates parallelism between the upcoming wh-clause and a preceding clause (e.g., John told some stories, but we couldn't remember which stories ), the parser predictively constructs the wh-clause. This observation demonstrates predictive structure building. However, the study also suggests that the parser does not make a prediction when the wh-phrase indicates that parallelism does not hold (e.g., John told some stories with which stories ), a potential limit to the prediction of syntactic structures. Crucially, these findings are controversial because the study did not observe processing difficulty when disambiguating input indicated that the predicted continuation was inconsistent with the globally grammatical structure (garden-path effects). The controversial results may be due to a lack of statistical power. Therefore, the present study conducted a large-scale replication study (324 participants and 24 sets of materials). The results revealed that the parser predicts the clausal structure, irrespective of the type of wh-phrase. There was also evidence of garden-path effects, supporting the finding that the parser makes a prediction. These observations suggest that the prediction algorithm inherent in the human parser is more powerful than assumed by the previous study and that the parser attempts to construct globally grammatical structures during revision.
Asunto(s)
Comprensión , Lenguaje , Humanos , Recuerdo Mental , Programas InformáticosRESUMEN
Natriuresis is closely linked to glomerular hemodynamics in diabetic kidney disease (DKD), and is known to be influenced by inhibition of sodium-glucose cotransporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4). In the present study, we investigated whether dual inhibition of SGLT2 and DPP-4 exerts an additive effect on promoting natriuresis and how it ameliorates glomerular hemodynamic abnormalities via the natriuretic effect in DKD. Eight-week-old male KK/Ta-Ins2Akita (KK/Ta-Akita) mice which develop progressive DKD were orally once-daily given either SGLT2 inhibitor empagliflozin (30 mg/kg) alone, DPP-4 inhibitor linagliptin (5 mg/kg) alone or a combination of empagliflozin (30 mg/kg) plus linagliptin (5 mg/kg) for 6 weeks. In vehicle-treated control KK/Ta-Akita mouse group, markedly enhanced glomerular albumin filtration and glomerular filtration rate (GFR) were observed. These renal alterations were dramatically attenuated in KK/Ta-Akita mouse group treated with a combination of empagliflozin plus linagliptin. Notably, the combination therapy provided greater reduction in glomerular albumin filtration and GFR along with higher urinary excretion of sodium and a potential afferent arteriolar vasoconstrictor adenosine than the empagliflozin monotherapy. Significant reduction in urinary excretion levels of a potential afferent arteriolar vasodilator prostaglandin E2 (PGE2) relative to the baseline values was observed after the combination therapy but not the monotherapy. These results suggest that dual inhibition of SGLT2 and DPP-4 highly promotes a distal tubular sodium delivery and thereby contributes to the appropriate modulation of preglomerular arteriolar tone and intraglomerular pressure via an increase in adenosine release and a reduction in PGE2 secretion from macula densa in DKD.
Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Linagliptina , Animales , Masculino , Ratones , Adenosina , Albúminas , Dinoprostona , Hemodinámica , Insulina , Linagliptina/farmacología , Linagliptina/uso terapéutico , Natriuresis , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéuticoRESUMEN
The embryonic development times, spawning timing and hatching rates of the black sea bream Acanthopagrus schlegelii were examined to investigate the potential effect of seawater temperature, tides and photoperiod on the reproductive rhythm of this species in Hiroshima Bay, Japan. Low temperatures decreased hatching rates and extended the hatching time, and the minimum temperature threshold for hatching was 15°C. Back-calculated spawning times indicated that the peak of spawning occurred just before sunset and the reduction in diurnal light intensity around the oyster rafts acted as a trigger for spawning. In contrast, no correlation was found between spawning rhythms and tidal cycle. The results highlight the important role of oyster farms in the reproductive cycle and population dynamics of A. schlegelii in Hiroshima Bay, the main spawning ground for this species in Japan. The study findings provide insights for the sustainable management of this important sparid species.
Asunto(s)
Ostreidae , Perciformes , Dorada , Animales , Reproducción , AcuiculturaRESUMEN
BACKGROUND: Rigid equinovarus foot deformities are seen in patients with cerebral palsy (CP). This retrospective study was undertaken to evaluate flexor hallucis longus tendon (FHL) transfer with gastrocsoleus recession (GSR) using motion analyses and quantitative measurement, and to investigate postoperative complications. METHODS: This study included 10 hemiplegic CP patients who underwent FHL transfer with GSR, and were evaluated by motion analyses consisting of weight distribution in static standing position and three-dimensional gait analysis, both pre and post-operatively. They were assessed in terms of kinematic data, Gait Variable Scores (GVS), and Gait Profile Score (GPS). RESULTS: The mean age at operation was 7.3 years (range, 4-13 years), and mean follow-up duration was 35 months (range, 25-64 months) post-operatively. Weight distribution at surgical site significantly rose from 34.3% pre-operatively to 47.3% post-operatively, and abnormal asymmetry of weight distribution between surgical site and contralateral site disappeared post-operatively. Maximum ankle dorsiflexion (ADF) at initial contact rose from -20.9° to -6.28°. Similarly, Maximum ADF at both stance and swing phase rose from -13.8° to 17.7° (P = 0.0003), and from -19.5° to 1.35° (P = 0.001), respectively. Although mean GPS decreased from 15.6° pre-operatively to 11.8°, which corresponded to 2.38 times the minimal clinically important difference (MCID = 1.6°), three cases manifested talipes calcaneus at final follow-up. CONCLUSION: Although quantitative assessment showed that the potential value of FHL transfer with GSR was to obtain initial heel contact and maintain sufficient clearance from the ground in swing, it also revealed a risk of leading to talipes calcaneus. In the near future, we should establish accurate criteria for determination of transfer site, and consider the possibility of modification of this procedure in order to balance between recurrent equinus and significant talipes calcaneus. STUDY DESIGN: Clinical comparison between preoperative and postoperative.
Asunto(s)
Pie Equinovaro , Hemiplejía , Niño , Pie , Marcha , Hemiplejía/etiología , Humanos , Estudios Retrospectivos , Transferencia TendinosaRESUMEN
Superoxide dismutase (SOD) is a major antioxidant enzyme for superoxide removal, and cytoplasmic SOD (SOD1) is expressed as a predominant isoform in all cells. We previously reported that renal SOD1 deficiency accelerates the progression of diabetic nephropathy (DN) via increasing renal oxidative stress. To evaluate whether the degree of SOD1 expression determines regeneration capacity and sarcopenic phenotypes of skeletal muscles under incipient and advanced DN conditions, we investigated the alterations of SOD1 expression, oxidative stress marker, inflammation, fibrosis, and regeneration capacity in cardiotoxin (CTX)-injured tibialis anterior (TA) muscles of two Akita diabetic mouse models with different susceptibility to DN, DN-resistant C57BL/6-Ins2Akita and DN-prone KK/Ta-Ins2Akita mice. Here, we report that KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, exhibit delayed muscle regeneration after CTX injection, as demonstrated by the finding indicating significantly smaller average cross-sectional areas of regenerating TA muscle myofibers relative to KK/Ta-wild-type mice. Furthermore, we observed markedly reduced SOD1 expression in CTX-injected TA muscles of KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, along with increased inflammatory cell infiltration, prominent fibrosis and superoxide overproduction. Our study provides the first evidence that SOD1 reduction and the following superoxide overproduction delay skeletal muscle regeneration through induction of overt inflammation and fibrosis in a mouse model of progressive DN.
Asunto(s)
Nefropatías Diabéticas/complicaciones , Músculo Esquelético/efectos de los fármacos , Regeneración Nerviosa/efectos de los fármacos , Sarcopenia/etiología , Superóxido Dismutasa-1/efectos de los fármacos , Animales , Cardiotoxinas/toxicidad , Colágeno Tipo I/biosíntesis , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Nefropatías Diabéticas/enzimología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , Progresión de la Enfermedad , Inducción Enzimática/efectos de los fármacos , Fibrosis , Regulación Enzimológica de la Expresión Génica , Predisposición Genética a la Enfermedad , Mesangio Glomerular/patología , Inflamación , Insulina/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Músculo Esquelético/fisiología , Estrés Oxidativo/efectos de los fármacos , Superóxido Dismutasa-1/biosíntesis , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/fisiología , Superóxidos/metabolismoRESUMEN
In Hiroshima Bay, parasitic isopods of the genus Mothocya infest the black sea bream Acanthopagrus schlegelii (Bleeker, 1854) and the Japanese halfbeak Hyporhamphus sajori (Temminck and Schlegel, 1846), two fish species that are abundant and commercially important in the Seto Inland Sea of Japan. Immature and mature Mothocya individuals can infect both juveniles and adults of H. sajori, while immature Mothocya are known to parasitize juveniles of A. schlegelii; i.e., no Mothocya parasites are found in adult A. schlegelii. The identification of the immature Mothocya parasitizing juveniles of A. schlegelii remains uncertain, because Mothocya species are morphologically identifiable only based on adult females. Also, the biological/ecological relationship between the hosts and parasites has not been studied. Here, we identified the parasites on A. schlegelii as Mothocya parvostis Bruce, 1986 by molecular sequence analyses along with other parasites obtained from H. sajori, the latter being morphologically confirmed by comparison with paratype materials of M. parvostis as well as the similar congener Mothocya sajori Bruce, 1986. The growth rates of the infected A. schlegelii juveniles from June to September in the years 2013-2015 and 2018 were significantly lower than those of the uninfected ones, suggesting a negative effect of the infection on the hosts. Our data on the prevalence and duration of the infection, as well as the body size gain of the hosts and parasites, corroborate a hypothesis that M. parvostis would utilize A. schlegelii as an optional intermediate host before it reaches the final host, H. sajori.
Asunto(s)
Enfermedades de los Peces/parasitología , Isópodos/clasificación , Isópodos/genética , Animales , Beloniformes/parasitología , Infestaciones Ectoparasitarias/parasitología , Complejo IV de Transporte de Electrones/genética , Isópodos/anatomía & histología , Japón , ARN Ribosómico 16S/genética , Dorada/crecimiento & desarrollo , Dorada/parasitología , Análisis de Secuencia de ADNRESUMEN
AIMS/INTRODUCTION: Caloric restriction (CR) promotes longevity and exerts anti-aging effects by increasing Sirtuin production and activation. Gastric inhibitory polypeptide (GIP), a gastrointestinal peptide hormone, exerts various effects on pancreatic ß-cells and extra-pancreatic tissues. GIP promotes glucose-dependent augmentation of insulin secretion and uptake of nutrients into the adipose tissue. MATERIALS AND METHODS: Gipr-/- and Gipr+/+ mice were used for lifespan analysis, behavior experiments and gene expression of adipose tissue and muscles. 3T3-L1 differentiated adipocytes were used for Sirt1 and Nampt expression followed by treatment with GIP and α-lipoic acid. RESULTS: We observed that GIP receptor-knockout (Gipr-/-) mice fed normal diet showed an extended lifespan, increased exploratory and decreased anxiety-based behaviors, which are characteristic behavioral changes under CR. Moreover, Gipr-/- mice showed increased Sirt1 and Nampt expression in the adipose tissue. GIP suppressed α-lipoic acid-induced Sirt1 expression and activity in differentiated adipocytes. CONCLUSIONS: Although maintenance of CR is difficult, food intake and muscle endurance of Gipr-/- mice were similar to those of wild-type mice. Inhibition of GIP signaling may be a novel strategy to extend the lifespan of diabetic patients.
Asunto(s)
Restricción Calórica , Polipéptido Inhibidor Gástrico/antagonistas & inhibidores , Longevidad/fisiología , Transducción de Señal/fisiología , Células 3T3-L1 , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Animales , Citocinas/metabolismo , Ratones , Ratones Noqueados , Nicotinamida Fosforribosiltransferasa/metabolismo , Receptores de la Hormona Gastrointestinal/genética , Sirtuina 1/metabolismoRESUMEN
Mitotic arrest deficient 2-like protein 2 (MAD2L2), also termed MAD2B or REV7, is involved in multiple cellular functions including translesion DNA synthesis (TLS), signal transduction, transcription, and mitotic events. MAD2L2 interacts with chromosome alignment-maintaining phosphoprotein (CAMP), a kinetochore-microtubule attachment protein in mitotic cells, presumably through a novel "WK" motif in CAMP. Structures of MAD2L2 in complex with binding regions of the TLS proteins REV3 and REV1 have revealed that MAD2L2 has two faces for protein-protein interactions that are regulated by its C-terminal region; however, the mechanisms underlying the MAD2L2-CAMP interaction and the mitotic role of MAD2L2 remain unknown. Here we have determined the structures of human MAD2L2 in complex with a CAMP fragment in two crystal forms. The overall structure of the MAD2L2-CAMP complex in both crystal forms was essentially similar to that of the MAD2L2-REV3 complex. However, the residue interactions between MAD2L2 and CAMP were strikingly different from those in the MAD2L2-REV3 complex. Furthermore, structure-based interaction analyses revealed an unprecedented mechanism involving CAMP's WK motif. Surprisingly, in one of the crystal forms, the MAD2L2-CAMP complex formed a dimeric structure in which the C-terminal region of MAD2L2 was swapped and adopted an immature structure. The structure provides direct evidence for the dynamic nature of MAD2L2 structure, which in turn may have implications for the protein-protein interaction mechanism and the multiple functions of this protein. This work is the first structural study of MAD2L2 aside from its role in TLS and might pave the way to clarify MAD2L2's function in mitosis.
Asunto(s)
Puntos de Control del Ciclo Celular/fisiología , Proteínas Cromosómicas no Histona , Proteínas Mad2 , Complejos Multiproteicos , Fosfoproteínas , Secuencias de Aminoácidos , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Cristalografía por Rayos X , Células HeLa , Humanos , Proteínas Mad2/química , Proteínas Mad2/genética , Proteínas Mad2/metabolismo , Complejos Multiproteicos/química , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Dominios Proteicos , Estructura Cuaternaria de Proteína , Relación Estructura-ActividadRESUMEN
The role of stromal cell-derived factor-1 (SDF-1) in the pathogenesis of diabetic nephropathy and its modification by dipeptidyl peptidase-4 (DPP-4) inhibition are uncertain. Therefore, we studied this independent of glucagon-like peptide-1 receptor (GLP-1R) signaling using two Akita diabetic mouse models, the diabetic-resistant C57BL/6-Akita and diabetic-prone KK/Ta-Akita. Increased SDF-1 expression was found in glomerular podocytes and distal nephrons in the diabetic-prone mice, but not in kidneys from diabetic-resistant mice. The DPP-4 inhibitor linagliptin, but not the GLP-1R agonist liraglutide, further augmented renal SDF-1 expression in both Glp1r(+/+) and Glp1r(-/-) diabetic-prone mice. Along with upregulation of renal SDF-1 expression, the progression of albuminuria, glomerulosclerosis, periglomerular fibrosis, podocyte loss, and renal oxidative stress was suppressed in linagliptin-treated Glp1r(+/+) diabetic-prone mice. Linagliptin treatment increased urinary sodium excretion and attenuated the increase in glomerular filtration rate which reflects glomerular hypertension and hyperfiltration. In contrast, selective SDF-1 receptor blockade with AMD3100 reduced urinary sodium excretion and aggravated glomerular hypertension in the Glp1r(+/+) diabetic-prone mice. Thus, DPP-4 inhibition, independent of GLP-1R signaling, contributes to protection of the diabetic kidney through SDF-1-dependent antioxidative and antifibrotic effects and amelioration of adverse renal hemodynamics.
Asunto(s)
Quimiocina CXCL12/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipoglucemiantes/uso terapéutico , Riñón/patología , Linagliptina/uso terapéutico , Albuminuria/tratamiento farmacológico , Albuminuria/orina , Animales , Bencilaminas , Ciclamas , Diabetes Mellitus Tipo 1/genética , Nefropatías Diabéticas/orina , Modelos Animales de Enfermedad , Femenino , Fibrosis , Tasa de Filtración Glomerular , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/genética , Compuestos Heterocíclicos/farmacología , Humanos , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Riñón/metabolismo , Liraglutida/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Receptores CXCR4/antagonistas & inhibidores , Regulación hacia ArribaRESUMEN
Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that has an antioxidative protective effect on various tissues. Here, we determined whether GLP-1 has a role in the pathogenesis of diabetic nephropathy using nephropathy-resistant C57BL/6-Akita and nephropathy-prone KK/Ta-Akita mice. By in situ hybridization, we found the GLP-1 receptor (GLP-1R) expressed in glomerular capillary and vascular walls, but not in tubuli, in the mouse kidney. Next, we generated C57BL/6-Akita Glp1r knockout mice. These mice exhibited higher urinary albumin levels and more advanced mesangial expansion than wild-type C57BL/6-Akita mice, despite comparable levels of hyperglycemia. Increased glomerular superoxide, upregulated renal NAD(P)H oxidase, and reduced renal cAMP and protein kinase A (PKA) activity were noted in the Glp1r knockout C57BL/6-Akita mice. Treatment with the GLP-1R agonist liraglutide suppressed the progression of nephropathy in KK/Ta-Akita mice, as demonstrated by reduced albuminuria and mesangial expansion, decreased levels of glomerular superoxide and renal NAD(P)H oxidase, and elevated renal cAMP and PKA activity. These effects were abolished by an adenylate cyclase inhibitor SQ22536 and a selective PKA inhibitor H-89. Thus, GLP-1 has a crucial role in protection against increased renal oxidative stress under chronic hyperglycemia, by inhibition of NAD(P)H oxidase, a major source of superoxide, and by cAMP-PKA pathway activation.
Asunto(s)
Nefropatías Diabéticas/etiología , Receptores de Glucagón/fisiología , Transducción de Señal/fisiología , Animales , AMP Cíclico/análisis , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón , Glomérulos Renales/inmunología , Glomérulos Renales/patología , Liraglutida , Masculino , Ratones Endogámicos C57BL , NADPH Oxidasas/antagonistas & inhibidores , Óxido Nítrico/análisis , Estrés Oxidativo , Receptores de Glucagón/agonistasRESUMEN
Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which exerts its glucose-lowering action by suppressing the degradation of a gut incretin hormone glucagon-like peptide-1 (GLP-1). To elucidate whether treatment with stronger DPP-4 inhibitor on top of angiotensin II type 1 receptor blocker (ARB) provides greater renal protective effects, we performed a crossover study with two DPP-4 inhibitors, sitagliptin and alogliptin, in twelve type 2 diabetic patients with incipient nephropathy taking ARBs. This study consisted of three treatment periods: sitagliptin 50 mg/day for 4 weeks (first period), alogliptin 25 mg/day for 4 weeks (second period), and sitagliptin 50 mg/day for 4 weeks (third period). Significant changes in body mass index, blood pressure, serum lipids, serum creatinine, estimated glomerular filtration rate, and HbA1c were not observed among the three treatment periods. Reduced urinary levels of albumin and an oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased urinary cAMP levels, and elevated plasma levels of stromal cell-derived factor-1α (SDF-1α) which is a physiological substrate of DPP-4 were observed after the switch from sitagliptin to a stronger DPP-4 inhibitor alogliptin. Given a large body of evidence indicating anti-oxidative action of cAMP and up-regulation of cellular cAMP production by SDF-1α, the present results suggest that more powerful DPP-4 inhibition on top of angiotensin II type 1 receptor blockade would offer additional protection against early-stage diabetic nephropathy beyond that attributed to glycemic control, via reduction of renal oxidative stress by SDF-1α-cAMP pathway activation.
Asunto(s)
Albuminuria/tratamiento farmacológico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Nefropatías Diabéticas/prevención & control , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Piperidinas/uso terapéutico , Uracilo/análogos & derivados , 8-Hidroxi-2'-Desoxicoguanosina , Anciano , Quimiocina CXCL12/sangre , Estudios Cruzados , AMP Cíclico/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/orina , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pirazinas/uso terapéutico , Receptor de Angiotensina Tipo 1 , Fosfato de Sitagliptina , Triazoles/uso terapéutico , Regulación hacia Arriba , Uracilo/uso terapéuticoRESUMEN
Objectives: Lumbar spondylolysis is a common condition; nonetheless, its cause in patients with spastic cerebral palsy (CP) remains unknown. Furthermore, examination of children with CP may not accurately capture complaints, thus causing diseases to be overlooked. Understanding the clinical features and gait patterns of lumbar spondylolysis in CP can aid in diagnosis. This study aimed to identify the clinical features and specific gait patterns of lumbar spondylolysis in ambulatory children with CP. Methods: Seventy-three children with CP were divided into two groups according to the presence or absence of lumbar spondylolysis on X-ray and magnetic resonance imaging. Three-dimensional gait analysis (3DGA) was performed to evaluate the kinematic data of the lower limbs. Results: Eight participants (11.4%) had lumbar spondylolysis primarily affecting the L5 vertebra. The lumbar spondylolysis group had a higher body weight and Body Mass Index, along with a smaller left popliteal angle on the spastic side. In 3DGA, detailed kinematic data indicated significant group differences in the mean angles of hip internal rotation (39.6° vs. 20.2°) during an entire gait cycle. The gait profile score was 19.7° in the lumbar spondylolysis group and 14.9° in the spinal uninvolved group; the difference in gait profile score between the two groups showed a minimal clinically important difference of 2.75. Conclusions: The overall gait profile score revealed that the gait of the lumbar spondylolysis group was deteriorated. Excessive internal rotation of the hip during gait might be a contributing factor to lumbar spondylolysis in children with CP.
RESUMEN
Avascular necrosis, a serious slipped capital femoral epiphysis (SCFE) complication, is difficult to treat. We report a rare case of revascularization of the necrotic femoral head in a 12-year-old male patient with a severe SCFE (posterior tilting angle, 87°). We performed the modified Dunn procedure (MDP), followed by long-term unloading therapy. Blood flow to the epiphysis had partially resumed 2.3 years postoperatively. At the final 4.5-year follow-up, blood flow had been restored, leading to epiphyseal closure without significant femoral head deformity or hip pain. The patient could walk unassisted, with a flexion range of 120°. These findings support the use of the MDP with long-term unloading therapy as a potential treatment option for severe SCFE.
RESUMEN
Introduction: Synovial chondromatosis (SC) is very rare among children. We are aware of no reports of patients with SC accompanied by leg length discrepancy (LLD). Case Report: We describe a case of synovial osteochondromatosis of a 7-year-old boy complicated by LLD. We performed epiphysiodesis of the distal femur and arthroscopic resection of loose bodies and total synovectomy. Three years after surgery, LLD had been corrected and there was no sign of recurrence. Conclusion: Physicians should be aware of synovial osteochondromatosis complicated by LLD in childhood and take radiographs of the whole length of lower legs when this condition is suspected.
RESUMEN
Obg-like ATPase 1 (OLA1) is a binding protein of Breast cancer gene 1 (BRCA1), germline pathogenic variants of which cause hereditary breast cancer. Cancer-associated variants of BRCA1 and OLA1 are deficient in the regulation of centrosome number. Although OLA1 might function as a tumor suppressor, the relevance of OLA1 deficiency to carcinogenesis is unclear. Here, we generated Ola1 knockout mice. Aged female Ola1+/- mice developed lymphoproliferative diseases, including malignant lymphoma. The lymphoma tissues had low expression of Ola1 and an increase in the number of cells with centrosome amplification. Interestingly, the proportion of cells with centrosome amplification in normal spleen from Ola1+/- mice was higher in male mice than in female mice. In human cells, estrogen stimulation attenuated centrosome amplification induced by OLA1 knockdown. Previous reports indicate that prominent centrosome amplification causes cell death but does not promote tumorigenesis. Thus, in the current study, the mild centrosome amplification observed under estrogen stimulation in Ola1+/- female mice is likely more tumorigenic than the prominent centrosome amplification observed in Ola1+/- male mice. Our findings provide a possible sex-dependent mechanism of the tumor suppressor function of OLA1.
Asunto(s)
Proteína BRCA1 , Centrosoma , Estrógenos , Ratones Noqueados , Animales , Femenino , Humanos , Masculino , Ratones , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Centrosoma/metabolismo , Estrógenos/metabolismo , Linfoma/metabolismo , Linfoma/genética , Linfoma/patologíaRESUMEN
Cymothoid parasitic isopods infest a wide range of fish of different taxa living in marine, brackish, and freshwater environments. Most research on the reproductive season of Cymothoidae has been done by collecting or monitoring host fish afflicted with cymothoid parasites. However, collecting ecological data on cymothoid species that infest non-commercial or endangered fishes is complex and challenging. We used a quatrefoil light trap to investigate the seasonal change in species composition of cymothoid free-swimming stages in the Seto Inland Sea, Japan. We also collected preliminary data for efficient light-trap sampling and showed its effectiveness in cymothoid-related research. From October 2020 to December 2021, 613 cymothoid free-swimming stages were sampled monthly. All obtained individuals were identified as Mothocya parvostis (596), Ceratothoa verrucosa (12), and Ceratothoa carinata (5) by DNA barcoding using cytochrome c oxidase subunit I and 16S rRNA gene sequences. Based on the number of M. parvostis mancae collected each month, M. parvostis was anticipated to reproduce from June to December, with two reproduction peaks each year, and C. verrucosa and C. carinata were expected to reproduce in June, July, and September, and September and October, respectively. In addition, free-swimming juveniles were captured, presumably after they had left their optional intermediate hosts. Furthermore, the most effective time to harvest cymothoids with light traps may be during high tide on the night of the new moon. This study serves as a methodological framework for future research on cymothoids using light traps.