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Absorciometria de Fóton , Anticorpos Monoclonais , Conservadores da Densidade Óssea , Densidade Óssea , Osso Esponjoso , Osteogênese Imperfeita , Humanos , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/diagnóstico por imagem , Absorciometria de Fóton/métodos , Feminino , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Osso Esponjoso/fisiopatologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Masculino , Adulto , Vértebras Lombares/fisiopatologia , Pessoa de Meia-IdadeRESUMO
Summary: Functioning gonadotroph tumors are rare neoplasms that can cause ovarian hyperstimulation syndrome (OHSS) in women of reproductive age. Here, we present a case of a follicle-stimulating hormone (FSH)-producing pituitary neuroendocrine tumor (PitNET) with irregular menstrual cycles and OHSS in a Japanese woman. A 34-year-old woman with bilateral multi-cystic ovarian mass was referred to our hospital for ovarian surgery. The imaging feature of magnetic resonance imaging (MRI) of the ovary and elevated estradiol levels with normal FSH and low luteinizing hormone (LH) levels led us to suspect the presence of a functioning gonadotroph PitNET. MRI revealed a 19-mm pituitary tumor, and increased tracer uptake was observed in the pituitary lesion on 111In-pentetreotide scintigraphy. Transsphenoidal tumor resection resulted in the resolution of the ovarian enlargement, normalization of her menstrual cycles, and spontaneous pregnancy. Immunohistochemistry (IHC) of the resected tumor for pituitary transcription factors, including steroidogenesis factor 1 (SF1) and estrogen receptor alpha, demonstrated positive immunoreactivity, whereas IHC for pituitary-specific positive transcription factor 1 was negative, suggesting that the tumor belonged to the SF1 lineage of PitNETs (gonadotroph tumor). The tumor cells showed positive expression of FSHß, while LHß was mostly negative. Consistent with the high pituitary tumor uptake observed on 111In-pentetreotide scintigraphy, the pituitary tumor showed positive expression of somatostatin receptor 2A. Detailed clinical and histological evaluations will provide useful information to understand these rare functioning gonadotroph tumors better. Learning points: Functioning gonadotroph tumors are very rare neuroendocrine tumors of pituitary origin. Women of reproductive age presenting with bilateral multi-cystic ovarian enlargement, irregular menstrual cycles, and hyperestrogenemia under unsuppressed follicle-stimulating hormone (FSH) levels should be evaluated for FSH-producing tumor. Raising awareness of OHSS due to functioning gonadotroph tumors is crucial to prevent unnecessary ovarian surgery. Comprehensive histological analysis may provide useful information to better understand the characteristics of functioning gonadotroph tumors.
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OBJECTIVES: We evaluated the feasibility of using deep learning with a convolutional neural network for predicting bone mineral density (BMD) and bone microarchitecture from conventional computed tomography (CT) images acquired by multivendor scanners. METHODS: We enrolled 402 patients who underwent noncontrast CT examinations, including L1-L4 vertebrae, and dual-energy x-ray absorptiometry (DXA) examination. Among these, 280 patients (3360 sagittal vertebral images), 70 patients (280 sagittal vertebral images), and 52 patients (208 sagittal vertebral images) were assigned to the training data set for deep learning model development, the validation, and the test data set, respectively. Bone mineral density and the trabecular bone score (TBS), an index of bone microarchitecture, were assessed by DXA. BMDDL and TBSDL were predicted by deep learning with a convolutional neural network (ResNet50). Pearson correlation tests assessed the correlation between BMDDL and BMD, and TBSDL and TBS. The diagnostic performance of BMDDL for osteopenia/osteoporosis and that of TBSDL for bone microarchitecture impairment were evaluated using receiver operating characteristic curve analysis. RESULTS: BMDDL and BMD correlated strongly (r = 0.81, P < 0.01), whereas TBSDL and TBS correlated moderately (r = 0.54, P < 0.01). The sensitivity and specificity of BMDDL for identifying osteopenia or osteoporosis were 93% and 90%, and 100% and 94%, respectively. The sensitivity and specificity of TBSDL for identifying patients with bone microarchitecture impairment were 73% for all values. CONCLUSIONS: The BMDDL and TBSDL derived from conventional CT images could identify patients who should undergo DXA, which could be a gatekeeper tool for detecting latent osteoporosis/osteopenia or bone microarchitecture impairment.
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Doenças Ósseas Metabólicas , Aprendizado Profundo , Osteoporose , Humanos , Densidade Óssea , Estudos de Viabilidade , Osteoporose/diagnóstico por imagem , Absorciometria de Fóton/métodos , Doenças Ósseas Metabólicas/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagemRESUMO
Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder that affects 6-7 per 100,000 populations, and pituitary stalk interruption syndrome (PSIS) is a rare congenital defect with varying degrees of pituitary hormone deficiency, affecting approximately 0.5 in every 100,000 births. Currently, only two cases of these complications have been reported. A 46-year-old male who had experienced more than 20 fractures (peripheral and vertebral) during adolescence visited our hospital for close examination. He presented with blue sclerae and long bone deformations. We suspected OI because his mother and sister, who were being treated for osteoporosis, also had blue sclerae. Genetic testing identified a heterozygous variant (c.757C > T, p.Arg253Ter) in the COL1A1 gene, leading to the diagnosis of OI. His mother and sister also had the same variant. Considering that he underwent GH replacement therapy for his short stature during his childhood, his pituitary hormone levels were also evaluated to know if GH deficiency impacted low bone density; hypopituitarism was then suspected. The pituitary function test results led to the diagnoses of hypothalamic GH deficiency, hypogonadism, hypothyroidism, and hypoadrenocorticism. Furthermore, magnetic resonance imaging showed anterior pituitary atrophy, pituitary stalk loss, and ectopic posterior pituitary, leading to the diagnosis of PSIS. The combination of OI and hypopituitarism may have caused further bone fragility. Therefore, although rare, clinicians should keep in mind that patients with OI can possibly have concomitant pituitary insufficiency, which can lead to developmental and growth retardation.
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Hipopituitarismo , Osteogênese Imperfeita , Doenças da Hipófise , Masculino , Adolescente , Humanos , Criança , Pessoa de Meia-Idade , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/patologia , Hipófise/diagnóstico por imagem , Hipófise/patologia , Hipopituitarismo/complicações , Hipopituitarismo/genética , Hipopituitarismo/diagnóstico , Hormônios HipofisáriosRESUMO
ABSTRACT: Blunt neck trauma is an uncommon condition in sports yet life-threatening if left untreated; hence, early diagnosis and management is necessary once suspected. We report a collegiate rugby player tackled around the neck during intersquad scrimmage. He broke his cricoid and thyroid cartilage, resulting in cervical subcutaneous emphysema and pneumomediastinum and eventually, airway obstruction. Thus, he underwent cricothyroidotomy and emergency tracheotomy. After 20 d, the emphysema disappeared. However, dilation failure of the vocal cord remained, thereby requiring laryngeal reconstruction. In conclusion, blunt neck trauma can cause airway obstruction in various sports.
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Obstrução das Vias Respiratórias , Lesões do Pescoço , Esportes , Ferimentos não Penetrantes , Masculino , Humanos , Rugby , Lesões do Pescoço/complicações , Lesões do Pescoço/diagnóstico , Ferimentos não Penetrantes/complicações , Ferimentos não Penetrantes/diagnóstico por imagem , Obstrução das Vias Respiratórias/diagnóstico , Obstrução das Vias Respiratórias/etiologia , Obstrução das Vias Respiratórias/cirurgiaRESUMO
PURPOSE: To evaluate left atrial (LA) function in patients with hypertrophic cardiomyopathy (HCM) by LA strain assessment using cardiac computed tomography (CT-derived LA strain). MATERIALS AND METHODS: This was a retrospective study of 34 patients with HCM and 31 non-HCM patients who underwent cardiac computed tomography (CT) using retrospective electrocardiogram-gated mode. CT images were reconstructed every 5% (0-95%) of the RR intervals. CT-derived LA strain (reservoir [LASr], conduit [LASc], and booster pump strain [LASp]) were semi-automatically analyzed using a dedicated workstation. We also measured the left atrial volume index (LAVI) and left ventricular longitudinal strain (LVLS) for the left atrial and ventricular functional parameters to assess the relationship with CT-derived LA strain. RESULTS: CT-derived LA strain significantly correlated with LAVI: r = - 0.69, p < 0.001 for LASr; r = - 0.70, p < 0.001 for LASp; and r = - 0.35, p = 0.004 for LASc. CT-derived LA strain also significantly correlated with LVLS: r = - 0.62, p < 0.001 for LASr; r = - 0.67, p < 0.001 for LASc; and r = - 0.42, p = 0.013 for LASp. CT-derived LA strain in patients with HCM was significantly lower than that in non-HCM patients: LASr (20.8 ± 7.6 vs. 31.7 ± 6.1%, p < 0.001); LASc (7.9 ± 3.4 vs. 14.2 ± 5.3%, p < 0.001); and LASp (12.8 ± 5.7 vs. 17.6 ± 4.3%, p < 0.001). Additionally, CT-derived LA strain showed high reproducibility; inter-observer correlation coefficients were 0.94, 0.90, and 0.89 for LASr, LASc, and LASp, respectively. CONCLUSION: CT-derived LA strain is feasible for quantitative assessment of left atrial function in patients with HCM.
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Fibrilação Atrial , Cardiomiopatia Hipertrófica , Humanos , Estudos Retrospectivos , Reprodutibilidade dos Testes , Átrios do Coração/diagnóstico por imagem , Cardiomiopatia Hipertrófica/diagnóstico por imagem , TomografiaRESUMO
The purpose of this study was to investigate the effects of neck and shoulder pain (NSP) and the position of the head and neck on the intramuscular circulation of the cervical muscles such as the trapezius and levator scapulae muscles in young females. Ten NSP subjects (mean age: 20.9 ± 0.5 years) and ten non-NSP subjects (mean age: 20.6 ± 0.7 years) were recruited to this study. Near-infrared spectroscopy (NIRS) was used to non-invasively measure total haemoglobin (Total-Hb), oxygenated haemoglobin (Oxy-Hb), and deoxygenated haemoglobin (Deoxy-Hb) of the trapezius and levator scapulae muscles. The measurements of Total-Hb, Oxy-Hb, and Deoxy-Hb were taken in the neutral position, immediately after the maximally flexed (extended) position, and after 30 s in the maximally flexed (extended) position. In flexion, no significant main effect or interaction was observed with Total-Hb and Oxy-Hb. A significant interaction was observed with Deoxy-Hb (p < 0.01). There was no significant difference in the changes over time in the NSP group (p = 0.91). However, in the non-NSP group, a significant increase was noted at the neutral position to immediately after the maximally flexed position (p < 0.01) and at the end of maintaining the maximally flexed position (p < 0.01). In extension, no significant main effect or interaction was observed with Total-Hb and Oxy-Hb. A significant interaction was observed with Deoxy-Hb (p < 0.01). In the NSP group, no significant difference was observed in the changes over time (p = 0.91). In the non-NSP group, however, a significant decrease was observed from the neutral position to immediately after the maximally extended position (p < 0.01). The results of this study indicate that maintaining either maximal cervical flexion or extension may affect venous blood flow on non-NSP group. However, no effect on NSP group was observed due to existing diminished intramuscular circulation.
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Músculos do Dorso , Músculos do Pescoço , Cervicalgia , Dor de Ombro , Adulto , Feminino , Humanos , Adulto Jovem , Hemodinâmica/fisiologia , Hemoglobinas/análise , Músculos/fisiopatologia , Oxiemoglobinas/análise , Dor de Ombro/fisiopatologia , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Cervicalgia/fisiopatologia , Fluxo Sanguíneo Regional/fisiologia , Músculos do Pescoço/irrigação sanguínea , Músculos do Pescoço/fisiopatologia , Músculos do Dorso/irrigação sanguínea , Músculos do Dorso/fisiopatologiaRESUMO
A deficiency in lumbar muscle blood circulation is considered to be a major risk factor for non-specific low back pain. The aim of this study was to investigate changes in relative circulation over time in the lumbar multifidus in different positions on sitting.Twelve healthy subjects (7 males, 5 females, average age: 20.9 years) without low back pain for the past 12 months were recruited. Near-infrared spectroscopy (NIRS) was used to non-invasively measure total haemoglobin (Total-Hb) and oxygenated haemoglobin (Oxy-Hb) in the lumbar multifidus at the L5-S1 segment. Subjects were asked to move into either 60-degree trunk-flexed or 20-degree trunk-extended position from the starting (standing in neutral) position in 3 s, timed by a metronome, and to maintain these positions for 30 s. The measurements of Total-Hb and Oxy-Hb were compared at -3 (neutral position), 0, 10, 20, and 30 s in each flexed and extended position on sitting.In flexion, Total-Hb and Oxy-Hb of the lumbar multifidus were significantly decreased from a neutral (-3 s) to flexed (0 s) position (Total-Hb: p = 0.002, Oxy-Hb: p = 0.004); however, there were no significant differences in the flexed position. In extension, Total-Hb and Oxy-Hb of the lumbar multifidus were significantly increased from 0 to 10 s (Total-Hb: p < 0.001, Oxy-Hb: p < 0.001); however, there were no significant differences from the neutral (-3 s) to extended (0 s) position, or from 10 to 30 s.The results of this study indicate that the intramuscular circulation of the lumbar multifidus decreases immediately once the trunk starts moving into a flexed position on sitting. On the other hand, the intramuscular circulation of the lumbar multifidus increases for up to 10 s once the trunk starts moving into an extended position.
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Dor Lombar , Oxiemoglobinas , Músculos Paraespinais , Posição Ortostática , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Dor Lombar/fisiopatologia , Região Lombossacral/fisiologia , Oxiemoglobinas/análise , Músculos Paraespinais/irrigação sanguínea , Músculos Paraespinais/fisiopatologiaRESUMO
SIGNIFICANCE STATEMENT: Due to its rarity, biochemical and histologic characteristics of androgen and glucocorticoid co-secreting adrenocortical adenomas are largely unknown. Herein, we report a case of adrenocortical adenoma that caused marked hyperandrogenemia and mild autonomous cortisol secretion. In this study, we investigated serum steroid profiles using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and histologic characteristics of the resected tumor. LC-MS/MS revealed highly elevated levels of 11-oxygenated androgens which have not been well studied in adrenal tumors. The expression patterns of steroidogenic enzymes determined by immunohistochemistry supported the results of steroid profiling and suggested the capacity of the tumor cells to produce 11-oxygenated androgens. Measurement of 11-oxygenated steroids should facilitate a better understanding of androgen-producing adrenocortical neoplasms.
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Neoplasias do Córtex Suprarrenal , Adenoma Adrenocortical , Humanos , Adenoma Adrenocortical/metabolismo , Glucocorticoides/metabolismo , Androgênios , Cromatografia Líquida , Hidrocortisona , Espectrometria de Massas em Tandem , Neoplasias do Córtex Suprarrenal/patologia , Esteroides , Hormônio AdrenocorticotrópicoRESUMO
Recent clinical practice guidelines for chronic pain indicate, with a high evidence level, that the combination of exercise and cognitive behavioral therapy (CBT) is effective. The purpose of this study was to evaluate the effectiveness of an exercise facilitation method in combination with CBT using the "Ikiiki Rehabilitation Notebook" for patients with intractable chronic pain. "Ikiiki" means active in Japanese. A total of 22 cases with chronic low back (n = 13), lower extremity (n = 8), or neck (n = 1) pain were treated using this notebook. Two cases dropped out, leaving 22 cases. Each case was evaluated in terms of the numerical rating scale (NRS) of the pain, activities of daily living (ADL), pain catastrophizing scale (PCS), and quality of life (QOL) at pretreatment and post-treatment. The endpoint of the method was to achieve the long-term goals set by the patients. The mean treatment period was 11.2 months. The outcomes were as follows: improvement of presenteeism: nine cases; enhanced participation in hobbies: seven cases; improved school attendance: two cases; return to work: one case; improvement of self-care and/or self-efficacy: three cases. The NRS, ADL, PCS, and QOL were significantly improved after the treatment. This method is possibly valuable for educating patients about the cause and treatment of chronic pain and actively facilitating exercise and social participation. Further studies are needed to investigate the effectiveness of using this notebook for the patient with intractable chronic pain.
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Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder whose causative gene encodes the fatty aldehyde dehydrogenase ALDH3A2. To date, the detailed molecular mechanism of the skin pathology of SLS has remained largely unclear. We generated double-knockout (DKO) mice for Aldh3a2 and its homolog Aldh3b2 (a pseudogene in humans). These mice showed hyperkeratosis and reduced fatty aldehyde dehydrogenase activity and skin barrier function. The levels of ω-O-acylceramides (acylceramides), which are specialized ceramides essential for skin barrier function, in the epidermis of DKO mice were about 60% of those in wild-type mice. In the DKO mice, levels of acylceramide precursors (ω-hydroxy ceramides and triglycerides) were increased, suggesting that the final step of acylceramide production was inhibited. A decrease in acylceramide levels was also observed in human immortalized keratinocytes lacking ALDH3A2. Differentiated keratinocytes prepared from the DKO mice exhibited impaired long-chain base metabolism. Based on these results, we propose that the long-chain-base-derived fatty aldehydes that accumulate in DKO mice and SLS patients attack and inhibit the enzyme involved in the final step of acylceramide production. Our findings provide insight into the pathogenesis of the skin symptoms of SLS, i.e., decreased acylceramide production, and its molecular mechanism.
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Aldeído Desidrogenase/metabolismo , Síndrome de Sjogren-Larsson/metabolismo , Pele/metabolismo , Aldeído Desidrogenase/genética , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Aldeídos/metabolismo , Animais , Diferenciação Celular , Ceramidas/metabolismo , Ceramidas/fisiologia , Modelos Animais de Doenças , Epiderme/metabolismo , Epiderme/fisiopatologia , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Feminino , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Sjogren-Larsson/fisiopatologiaRESUMO
[Purpose] The characteristics of neck and shoulder pain (NSP) in different age populations have not been sufficiently examined. Therefore, the purpose of this study was to compare and verify the cervicothoracic spinal alignment and neck flexor muscle endurance of young and older adult females with and without NSP. [Participants and Methods] We assessed 72 female participants (39 young participants, 33 elderly participants, 43 NSP, 29 non-NSP) aged 18-82â years who were recruited for this study. Cervicothoracic spinal alignment measurements were obtained with forward head alignment (FHA) along with the upper thoracic angle. The neck flexor endurance test was performed. [Results] There were no significant age-by-group interactions for any of the assessment variables. However, the upper thoracic angle and neck flexor muscle endurance showed significant effects in the groups. Age also had significant effects on FHA and upper thoracic angle. [Conclusion] These results suggested that the neck flexor muscle endurance was more appropriate as an evaluation tool for older adult females with NSP. It was also suggested that the cervical flexor muscle endurance and upper thoracic angle were more appropriate as evaluation tools for young adult females with NSP.
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The yeast protein Mpo1 belongs to a protein family that is widely conserved in bacteria, fungi, protozoa, and plants, and is the only protein of this family whose function has so far been elucidated. Mpo1 is an Fe2+-dependent dioxygenase that catalyzes the α-oxidation reaction of 2-hydroxy (2-OH) long-chain FAs (LCFAs) produced in the degradation pathway of the long-chain base phytosphingosine. However, several biochemical characteristics of Mpo1, such as its catalytic residues, membrane topology, and substrate specificity, remain unclear. Here, we report that yeast Mpo1 contains two transmembrane domains and that both its N- and C-terminal regions are exposed to the cytosol. Mutational analyses revealed that three histidine residues conserved in the Mpo1 family are especially important for Mpo1 activity, suggesting that they may be responsible for the formation of coordinate bonds with Fe2+ We found that, in addition to activity toward 2-OH LCFAs, Mpo1 also exhibits activity toward 2-OH very-long-chain FAs derived from the FA moiety of sphingolipids. These results indicate that Mpo1 is involved in the metabolism of long-chain to very-long-chain 2-OH FAs produced in different pathways. We noted that the growth of mpo1Δ cells is delayed upon carbon deprivation, suggesting that the Mpo1-mediated conversion of 2-OH FAs to nonhydroxy FAs is important for utilizing 2-OH FAs as a carbon source under carbon starvation. Our findings help to elucidate the as yet unknown functions and activities of other Mpo1 family members.
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Biocatálise , Carbono/metabolismo , Dioxigenases/metabolismo , Saccharomyces cerevisiae/enzimologia , Dioxigenases/química , Oxirredução , Domínios Proteicos , Especificidade por SubstratoRESUMO
BACKGROUND: Pedicled flaps are useful for reconstructive surgery. Previously, we often used vascularized supraclavicular flaps, especially for head and neck reconstruction, but then shifted to using thoracic branch of the supraclavicular artery (TBSA) flaps. However, limited research exists on the anatomy of TBSA flaps and on the use of indocyanine green (ICG) fluorescence videoangiography for supraclavicular artery flaps. We utilized ICG fluorescence videoangiography to harvest reliable flaps in reconstructive operations, and describe the results herein. METHODS: Data were retrospectively reviewed from six patients (five men and one woman: average age, 54 years; range, 48-60 years) for whom ICG videoangiography was performed to observe the skin perfusion of a supraclavicular flap after it was raised. Areas where the flap showed good enhancement were considered to be favorable for flap survival. The observation of ICG dye indicated good skin perfusion, which is predictive of flap survival; therefore, we trimmed any areas without dye filling and used the remaining viable part of the flap. RESULTS: The flaps ranged in size from 13×5.5 cm to 17×6.5 cm. One patient received a conventional supraclavicular flap, four patients received a TBSA flap, and one patient received a flap that was considered to be intermediate between a supraclavicular flap and a TBSA flap. The flaps completely survived in all cases, and no flap necrosis was observed. CONCLUSIONS: The TBSA flap is very useful in reconstructive surgery, and reliable flaps could be obtained by using ICG fluorescence videoangiography intraoperatively.
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Phytosphingosine (PHS) is the major long-chain base component of sphingolipids in Saccharomyces cerevisiae The PHS metabolic pathway includes a fatty acid (FA) α-oxidation reaction. Recently, we identified the novel protein Mpo1, which is involved in PHS metabolism. However, the details of the FA α-oxidation reaction and the role of Mpo1 in PHS metabolism remained unclear. In the present study, we revealed that Mpo1 is involved in the α-oxidation of 2-hydroxy (2-OH) palmitic acid (C16:0-COOH) in the PHS metabolic pathway. Our in vitro assay revealed that not only the Mpo1-containing membrane fraction but also the soluble fraction was required for the α-oxidation of 2-OH C16:0-COOH. The addition of Fe2+ eliminated the need for the soluble fraction. Purified Mpo1 converted 2-OH C16:0-COOH to C15:0-COOH in the presence of Fe2+, indicating that Mpo1 is the enzyme body responsible for catalyzing the FA α-oxidation reaction. This reaction was also found to require an oxygen molecule. Our findings indicate that Mpo1 catalyzes the FA α-oxidation reaction as 2-OH fatty acid dioxygenase, mediated by iron(IV) peroxide. Although numerous Mpo1 homologs exist in bacteria, fungi, protozoa, and plants, their functions had not yet been clarified. However, our findings suggest that these family members function as dioxygenases.
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Ácidos Palmíticos/metabolismo , Esfingolipídeos/metabolismo , Esfingosina/análogos & derivados , Catálise , Dioxigenases/metabolismo , Ácidos Graxos/metabolismo , Ferro/metabolismo , Oxirredução , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Esfingosina/metabolismoRESUMO
Insulation by myelin lipids is essential to fast action potential conductivity: changes in their quality or amount can cause several neurologic disorders. Sjögren-Larsson syndrome (SLS) is one such disorder, which is caused by mutations in the fatty aldehyde dehydrogenase ALDH3A2. To date, the molecular mechanism underlying SLS pathology has remained unknown. In this study, we found that Aldh3a2 is expressed in oligodendrocytes and neurons in the mouse brain, and neurons of Aldh3a2 knockout (KO) mice exhibited impaired metabolism of the long-chain base, a component of sphingolipids. Aldh3a2 KO mice showed several abnormalities corresponding to SLS symptoms in behavioral tests, including increased paw slips on a balance beam and light-induced anxiety. In their brain tissue, 2-hydroxygalactosylceramide, an important lipid for myelin function and maintenance, was reduced by the inactivation of fatty acid 2-hydroxylase. Our findings provide important new insights into the molecular mechanisms responsible for neural pathogenesis caused by lipid metabolism abnormalities.-Kanetake, T., Sassa, T., Nojiri, K., Sawai, M., Hattori, S., Miyakawa, T., Kitamura, T., Kihara, A. Neural symptoms in a gene knockout mouse model of Sjögren-Larsson syndrome are associated with a decrease in 2-hydroxygalactosylceramide.
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Comportamento Animal , Galactosilceramidas/deficiência , Síndrome de Sjogren-Larsson/fisiopatologia , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Animais , Ansiedade/metabolismo , Depressão/metabolismo , Galactosilceramidas/genética , Humanos , Luz , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Síndrome de Sjogren-Larsson/genética , Síndrome de Sjogren-Larsson/metabolismoRESUMO
NIPAL4 is one of the causative genes for autosomal recessive congenital ichthyosis. However, the role of NIPAL4 in skin barrier formation and the molecular mechanism of ichthyosis pathology caused by NIPAL4 mutations, have not yet been determined. Here, we found that Nipal4-knockout (KO) mice exhibited neonatal lethality due to skin barrier defects. Histological analyses showed several morphological abnormalities in the Nipal4-KO epidermis, including impairment of lipid multilayer structure formation, hyperkeratosis, immature keratohyalin granules, and developed heterochromatin structures. The levels of the skin barrier lipid acylceramide were decreased in Nipal4-KO mice. Expression of genes involved in skin barrier formation normally increases during keratinocyte differentiation, in which chromatin remodeling is involved. However, the induction of Krt1, Lor, Flg, Elovl1, and Dgat2 was impaired in Nipal4-KO mice. NIPAL4 is a putative Mg2+ transporter, and Mg2+ concentration in differentiated keratinocytes of Nipal4-KO mice was indeed lower than that of wild-type mice. Our results suggest that low Mg2+ concentration causes aberration in the proper chromatin remodeling process, which in turn leads to failure of differentiation-dependent gene induction in keratinocytes. Our findings provide insights into Mg2+-dependent regulation of gene expression and skin barrier formation during keratinocyte differentiation.
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DNA/genética , Epiderme/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Ictiose/genética , Metabolismo dos Lipídeos , Receptores de Superfície Celular/genética , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Epiderme/patologia , Proteínas Filagrinas , Ictiose/metabolismo , Ictiose/patologia , Camundongos , Camundongos Knockout , Permeabilidade , Receptores de Superfície Celular/metabolismoRESUMO
The use of antiplatelet therapy (APT) and/or anticoagulant therapy (ACT) continues to increase due to the aging population. Because the management of patients with acute cholecystitis receiving APT/ACT is still unclear, surgeons are sometimes faced with the difficult decision to delay surgery. We aimed to analyze characteristics and surgical risks of patients who underwent emergency cholecystectomy for acute cholecystitis without discontinuing APT. We conducted a retrospective review of 113 patients between 2006 and 2014. Treatment outcomes among 13 patients who underwent cholecystectomy without discontinuing APT (the cAPT group), 11 patients who discontinued APT and ACT (the D group), and 89 patients who did not receive preoperative APT and/or ACT (the No APT group) were compared. There were no significant differences in intraoperative blood loss, conversion to open surgery, and bleeding-related complications. However, the incidence of intraoperative blood transfusion was higher in the cAPT group (P = 0.04). They presented with severe local inflammation; thus, it was difficult to stop bleeding from the gallbladder bed. Hemostatic tools for liver surgery were used to control bleeding. Emergency cholecystectomy was tolerable for patients with acute cholecystitis while continuing APT. However, in case of severe local inflammation, there is a greater risk for massive hemorrhage.
Assuntos
Anticoagulantes/uso terapêutico , Colecistectomia , Colecistite Aguda/cirurgia , Inibidores da Agregação Plaquetária/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Emergências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Although normal fatty acids (FAs) are degraded via ß-oxidation, unusual FAs such as 2-hydroxy (2-OH) FAs and 3-methyl-branched FAs are degraded via α-oxidation. Phytosphingosine (PHS) is one of the long-chain bases (the sphingolipid components) and exists in specific tissues, including the epidermis and small intestine in mammals. In the degradation pathway, PHS is converted to 2-OH palmitic acid and then to pentadecanoic acid (C15:0-COOH) via FA α-oxidation. However, the detailed reactions and genes involved in the α-oxidation reactions of the PHS degradation pathway have yet to be determined. In the present study, we reveal the entire PHS degradation pathway: PHS is converted to C15:0-COOH via six reactions [phosphorylation, cleavage, oxidation, CoA addition, cleavage (C1 removal), and oxidation], in which the last three reactions correspond to the α-oxidation. The aldehyde dehydrogenase ALDH3A2 catalyzes both the first and second oxidation reactions (fatty aldehydes to FAs). In Aldh3a2-deficient cells, the unmetabolized fatty aldehydes are reduced to fatty alcohols and are incorporated into ether-linked glycerolipids. We also identify HACL2 (2-hydroxyacyl-CoA lyase 2) [previous name, ILVBL; ilvB (bacterial acetolactate synthase)-like] as the major 2-OH acyl-CoA lyase involved in the cleavage (C1 removal) reaction in the FA α-oxidation of the PHS degradation pathway. HACL2 is localized in the endoplasmic reticulum. Thus, in addition to the already-known FA α-oxidation in the peroxisomes, we have revealed the existence of FA α-oxidation in the endoplasmic reticulum in mammals.
Assuntos
Esfingosina/análogos & derivados , Aldeído Oxirredutases/metabolismo , Aldeído Oxirredutases/fisiologia , Animais , Células CHO , Cricetulus , Retículo Endoplasmático/metabolismo , Células HEK293 , Células HeLa , Humanos , Redes e Vias Metabólicas , Oxirredução , Proteólise , Esfingosina/metabolismoRESUMO
The fatty aldehyde dehydrogenase (FALDH) ALDH3A2 is the causative gene of Sjögren Larsson syndrome (SLS). To date, the molecular mechanism underlying the symptoms characterizing SLS has been poorly understood. Using Aldh3a2(-/-) mice, we found here that Aldh3a2 was the major FALDH active in undifferentiated keratinocytes. Long-chain base metabolism was greatly impaired in Aldh3a2(-/-) keratinocytes. Phenotypically, the intercellular spaces were widened in the basal layer of the Aldh3a2(-/-) epidermis due to hyperproliferation of keratinocytes. Furthermore, oxidative stress-induced genes were up-regulated in Aldh3a2(-/-) keratinocytes. Upon keratinocyte differentiation, the activity of another FALDH, Aldh3b2, surpassed that of Aldh3a2 As a result, Aldh3a2(-/-) mice were indistinguishable from wild-type mice in terms of their whole epidermis FALDH activity, and their skin barrier function was uncompromised under normal conditions. However, perturbation of the stratum corneum caused increased transepidermal water loss and delayed barrier recovery in Aldh3a2(-/-) mice. In conclusion, Aldh3a2(-/-) mice replicated some aspects of SLS symptoms, especially at the basal layer of the epidermis. Our results suggest that hyperproliferation of keratinocytes via oxidative stress responses may partly contribute to the ichthyosis symptoms of SLS.