NIR-Triggered Thermosensitive Nanoreactors for Dual-Guard Mechanism-Mediated Precise and Controllable Cancer Chemo-Phototherapy.

Thermosensitive nanoparticles can be activated by externally applying heat, either through laser irradiation or magnetic fields, to trigger the release of drug payloads. This controlled release mechanism ensures that drugs are specifically released at the tumor site, maximizing their effectiveness while minimizing systemic toxicity and adverse effects. However, its efficacy is limited by the low concentration of drugs at action sites, which is caused by no specific target to tumor sties. Herein, hyaluronic acid (HA), a gooey, slippery substance with CD44-targeting ability, was conjugated with a thermosensitive polymer poly(acrylamide-co-acrylonitrile) to produce tumor-targeting and thermosensitive polymeric nanocarrier (HA-P) with an upper critical solution temperature (UCST) at 45 °C, which further coloaded chemo-drug doxorubicin (DOX) and photosensitizer Indocyanine green (ICG) to prepare thermosensitive nanoreactors HA-P/DOX&ICG. With photosensitizer ICG acting as the "temperature control element", HA-P/DOX&ICG nanoparticles can respond to temperature changes when receiving near-infrared irradiation and realize subsequent structure depolymerization for burst drug release when the ambient temperature was above 45 °C, achieving programmable and on-demand drug release for effective antitumor therapy. Tumor inhibition rate increased from 61.8 to 95.9% after laser irradiation. Furthermore, the prepared HA-P/DOX&ICG nanoparticles possess imaging properties, with ICG acting as a probe, enabling real-time monitoring of drug distribution and therapeutic response, facilitating precise treatment evaluation. These results provide enlightenment for the design of active tumor targeting and NIR-triggered programmable and on-demand drug release of thermosensitive nanoreactors for tumor therapy.

Constructing Oxygen-Related Defects in Carbon Nanodots with Janus Optical Properties: Noninvasive NIR Fluorescent Imaging and Effective Photocatalytic Therapy.

Noninvasive fluorescence (FL) imaging and high-performance photocatalytic therapy (PCT) are opposing optical properties that are difficult to combine in a single material system. Herein, a facile approach to introducing oxygen-related defects in carbon dots (CDs) via post-oxidation with 2-iodoxybenzoic acid is reported, in which some nitrogen atoms are substituted by oxygen atoms. Unpaired electrons in these oxygen-related defects rearrange the electronic structure of the oxidized CDs (ox-CDs), resulting in an emerging near-infrared (NIR) absorption band. These defects not only contribute to enhanced NIR bandgap emission but also act as trappers for photoexcited electrons to promote efficient charge separation on the surface, leading to abundant photo-generated holes on the ox-CDs surface under visible-light irradiation. Under white LED torch irradiation, the photo-generated holes oxidize hydroxide to hydroxyl radicals in the acidification of the aqueous solution. In contrast, no hydroxyl radicals are detected in the ox-CDs aqueous solution under 730 nm laser irradiation, indicating noninvasive NIR FL imaging potential. Utilizing the Janus optical properties of the ox-CDs, the in vivo NIR FL imaging of sentinel lymph nodes around tumors and efficient photothermal enhanced tumor PCT are demonstrated.

A Randomized Controlled Trial for Audiovisual Multisensory Perception in Autistic Youth.

Differences in audiovisual integration are commonly observed in autism. Temporal binding windows (TBWs) of audiovisual speech can be trained (i.e., narrowed) in non-autistic adults; this study evaluated a computer-based perceptual training in autistic youth and assessed whether treatment outcomes varied according to individual characteristics. Thirty autistic youth aged 8-21 were randomly assigned to a brief perceptual training (n = 15) or a control condition (n = 15). At post-test, the perceptual training group did not differ, on average, on TBWs for trained and untrained stimuli and perception of the McGurk illusion compared to the control group. The training benefited youth with higher language and nonverbal IQ scores; the training caused widened TBWs in youth with co-occurring cognitive and language impairments.

The effect of calcium supplementation in people under 35 years old: A systematic review and meta-analysis of randomized controlled trials.

Background: The effect of calcium supplementation on bone mineral accretion in people under 35 years old is inconclusive. To comprehensively summarize the evidence for the effect of calcium supplementation on bone mineral accretion in young populations (≤35 years). Methods: This is a systematic review and meta-analysis. The Pubmed, Embase, ProQuest, CENTRAL, WHO Global Index Medicus, Clinical Trials.gov, WHO ICTRP, China National Knowledge Infrastructure (CNKI), and Wanfang Data databases were systematically searched from database inception to April 25, 2021. Randomized clinical trials assessing the effects of calcium supplementation on bone mineral density (BMD) or bone mineral content (BMC) in people under 35 years old. Results: This systematic review and meta-analysis identified 43 studies involving 7,382 subjects. Moderate certainty of evidence showed that calcium supplementation was associated with the accretion of BMD and BMC, especially on femoral neck (standardized mean difference [SMD] 0.627, 95% confidence interval [CI] 0.338-0.915; SMD 0.364, 95% CI 0.134-0.595; respectively) and total body (SMD 0.330, 95% CI 0.163-0.496; SMD 0.149, 95% CI 0.006-0.291), also with a slight improvement effect on lumbar spine BMC (SMD 0.163, 95% CI 0.008-0.317), no effects on total hip BMD and BMC and lumbar spine BMD were observed. Very interestingly, subgroup analyses suggested that the improvement of bone at femoral neck was more pronounced in the peripeak bone mass (PBM) population (20-35 years) than the pre-PBM population (<20 years). Conclusions: Our findings provided novel insights and evidence in calcium supplementation, which showed that calcium supplementation significantly improves bone mass, implying that preventive calcium supplementation before or around achieving PBM may be a shift in the window of intervention for osteoporosis. Funding: This work was supported by Wenzhou Medical University grant [89219029].

Osteoporosis and bone fractures are common problems among older people, particularly older women. These conditions cause disability and reduce quality of life. Progressive loss of bone mineral density is usually the culprit. So far, strategies to prevent bone weakening with age have produced disappointing results. For example, taking calcium supplements in later life only slightly reduces the risk of osteoporosis or fracture. New approaches are needed. Bone mass increases gradually early in life and peaks and plateaus around 20-35 years of age. After that period, bone mass slowly declines. Some scientists suspect that increasing calcium intake during this period of peak bone mass may reduce osteoporosis or fracture risk later in life. A meta-analysis by Liu, Le et al. shows that boosting calcium intake in young adulthood strengthens bones. The researchers analyzed data from 43 randomized controlled trials that enrolled 7,382 participants. About half the studies looked at the effects of taking calcium supplements and the other half analyzed the effects of a high calcium diet. Boosting calcium intake in people younger than age 35 improved bone mineral density throughout the body. It also increased bone mineral density at the femoral neck, where most hip fractures occur. Calcium supplementation produced larger effects in individuals between the ages of 20 and 35 than in people younger than 20. Both high calcium diets and calcium supplements with doses less than 1000 mg/d boosted bone strength. Higher dose calcium supplements did not provide any extra benefits. The analysis suggests people should pay more attention to bone health during early adulthood. Large randomized clinical trials are needed to confirm the long-term benefits of boosting calcium intake during early adulthood. But if the results are validated, taking calcium supplements, or eating more calcium-rich foods between the ages of 20 and 35 may help individuals build healthier bones and prevent fractures and osteoporosis later in life.

A water-dependent reversible photoacidity strategy for cancer treatment.

In the reported mechanisms of reversible photoacidity, protons were dissociated from compounds which contained hydroxyl, indazole or formed hydroxyl via intramolecular hydrogen abstraction under irradiation. Herein, a water-dependent reversible photoacidity (W-RPA) mechanism mediated by a thiadiazoloquinoxaline compound (TQs-Th-PEG5) has been found, in which the proton is not dissociated from TQs-Th-PEG5 itself but from a water locked by TQs-Th-PEG5 under the irradiation of a 660 nm laser. After turning off the laser, the produced acid will disappear quickly. This process is repeatable with no consumption of TQs-Th-PEG5. More importantly, water is indispensable. Furthermore, it is confirmed that there is no other element involved in the process except TQs-Th-PEG5, light and water. Excitingly, W-RPA therapy mediated by TQs-Th-PEG5 nanoparticle exhibits remarkable antitumor effect both in vitro and in vivo, especially in hypoxic tumors with diameter larger than 10 mm owing to its oxygen-independent feature. This study not only discovers a W-RPA mechanism but also provides a novel phototherapy strategy for cancer treatment.

Relations Between the McGurk Effect, Social and Communication Skill, and Autistic Features in Children with and without Autism.

Children with autism show alterations in multisensory integration that have been theoretically and empirically linked with the core and related features of autism. It is unclear, however, to what extent multisensory integration maps onto features of autism within children with and without autism. This study, thus, evaluates relations between audiovisual integration and core and related autism features across children with and without autism. Thirty-six children reported perceptions of the McGurk illusion during a psychophysical task. Parents reported on participants' autistic features. Increased report of illusory percepts tended to covary with reduced autistic features and greater communication skill. Some relations, though, were moderated by group. This work suggests that associations between multisensory integration and higher-order skills are present, but in some instances vary according to diagnostic group.

Portulaca oleracea L. polysaccharides enhance the immune efficacy of dendritic cell vaccine for breast cancer.

Previous studies have reported that Portulaca oleracea L. polysaccharides (POL-P3b) is an immunoregulatory agent. However, few studies exist on POL-P3b as a novel immune adjuvant in combination with the DC vaccine for breast cancer treatment. In this work, a DC vaccine loaded with mouse 4T1 tumor cell antigen was prepared to evaluate the properties of POL-P3b in inducing the maturation and function of DC derived from mouse bone marrow, and then to investigate the effect of the DC vaccine combined with POL-P3b on breast cancer in vivo and in vitro. Morphological changes of DC were observed using scanning electron microscopy. Phenotypic and functional analyses of DC were detected by flow cytometry and allogeneic lymphocyte reaction. Cytokine levels in the DC culture supernatant were detected by ELISA. Western blotting analysis was used for the protein expression of TLR4, MyD88 and NF-κB. Apoptosis detection and protein expression of the tumor tissue were analyzed by TUNEL staining and immunohistochemistry, respectively. The security of POL-P3b was evaluated by the detection of hematological and blood biochemical indicators and pathological analysis for tissues. POL-P3b can induce DC activation and maturation, which is attributed to increasing the specific anti-tumor immune response, and the mechanism of action involved in the TLR4/MyD88/NF-κB signaling pathway. Experimental results in vivo further suggested that the administration of POL-P3b-treated antigen-primed DC achieved remarkable tumor growth inhibition through inducing apoptosis and enhancing immune responses. Moreover, the POL-P3b-treated DC vaccine was able to inhibit lung metastases. The results proved the feasibility of POL-P3b as an edible adjuvant of the DC vaccine for anti-breast cancer therapy.

Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency.

OBJECTIVE: To analyze the clinical characteristics of patients with hydrocephalus secondary to cobalamin C (cblC) deficiency and to discuss the optimal strategies for assessing and treating such patients by performing clinical and laboratory studies in 70 patients. METHODS: A total of 1,211 patients were clinically diagnosed with methylmalonic acidemia (MMA) from 1998 to 2019. Among them, cblC deficiency was confirmed in 70 patients with hydrocephalus by brain imaging and biochemical and genetic analysis. RESULTS: Of the 70 patients, 67 (95.7%) had early-onset MMA and homocystinuria. The patients typically had high blood propionylcarnitine and total homocysteine, low methionine, and methylmalonic aciduria. Signs of intracranial hypertension were relatively rare. We measured ventricular dilatation early in the disease by cranial ultrasound and MRI and/or CT. Eighteen different MMACHC mutations, including 4 novel mutations (c.427C>T, c.568insT, c.599G>A, and c.615C>A), were identified biallelically in all 70 patients. c.609G>A was the most frequent mutation, followed by c.658_660del, c.217C>T, and c.567dupT. Three cases were diagnosed by postmortem study. Metabolic therapy, including cobalamin injections supplemented with oral l-carnitine and betaine, was administered in the remaining 67 cases. A ventriculoperitoneal shunt was performed in 36 cases. During the follow-up, psychomotor development, nystagmus, impaired vision, and sunset eyes improved gradually. CONCLUSION: Hydrocephalus is a severe condition with several different causes. In this study, ventriculomegaly was found in 70 patients with cblC deficiency. Early diagnosis, etiologic treatment, and prompt surgical intervention are crucial to improve the prognosis of patients.

Enhancing Drug Delivery for Overcoming Angiogenesis and Improving the Phototherapy Efficacy of Glioblastoma by ICG-Loaded Glycolipid-Like Micelles.

BACKGROUND: Phototherapy is a potential new candidate for glioblastoma (GBM) treatment. However inadequate phototherapy due to stability of the photosensitizer and low target specificity induces the proliferation of neovascular endothelial cells for angiogenesis and causes poor prognosis. METHODS: In this study, we constructed c(RGDfk)-modified glycolipid-like micelles (cRGD-CSOSA) encapsulating indocyanine green (ICG) for dual-targeting neovascular endothelial cells and tumor cells, and cRGD-CSOSA/ICG mediated dual effect of PDT/PTT with NIR irradiation. RESULTS: In vitro, cRGD-CSOSA/ICG inhibited cell proliferation and blocked angiogenesis with NIR irradiation. In vivo, cRGD-CSOSA/ICG exhibited increased accumulation in neovascular endothelial cells and tumor cells. Compared with that of CSOSA, the accumulation of cRGD-CSOSA in tumor tissue was further improved after dual-targeted phototherapy pretreatment. With NIR irradiation, the tumor-inhibition rate of cRGD-CSOSA/ICG was 80.00%, significantly higher than that of ICG (9.08%) and CSOSA/ICG (42.42%). Histological evaluation showed that the tumor vessels were reduced and that the apoptosis of tumor cells increased in the cRGD-CSOSA/ICG group with NIR irradiation. CONCLUSION: The cRGD-CSOSA/ICG nanoparticle-mediated dual-targeting phototherapy could enhance drug delivery to neovascular endothelial cells and tumor cells for anti-angiogenesis and improve the phototherapy effect of glioblastoma, providing a new strategy for glioblastoma treatment.

Efficient Biotransformation of Phytosterols to Dehydroepiandrosterone by Mycobacterium sp.

In this study, a method for the efficient production of dehydroepiandrosterone (DHEA) from phytosterols in a vegetable oil/aqueous two-phase system by Mycobacterium sp. was developed. After the 3-hydroxyl group of phytosterols was protected, they could be converted into DHEA with high yield and productivity by Mycobacterium sp. NRRL B-3683. In a shake flask biotransformation, 15.05 g l-1 of DHEA and a DHEA yield of 85.39% (mol mol-1) were attained after 7 days with an initial substrate concentration of 25 g l-1. When biotransformation was carried out in a 30-l stirred bioreactor with 25 g l-1 substrate, the DHEA concentration and yield was 16.33 g l-1 and 92.65% (mol mol-1) after 7 days, respectively. The results of this study suggest that inexpensive phytosterols could be utilized for the efficient production of DHEA.

Gynura divaricata attenuates tumor growth and tumor relapse after cisplatin therapy in HCC xenograft model through suppression of cancer stem cell growth and Wnt/ß-catenin signalling.

ETHNOPHARMACOLOGICAL RELEVANCE: Gynura divaricata subsp. formosana is a widely used traditional herbal medicine for treating liver disorders such as hepatitis and liver cancer in Taiwan. AIM OF THE STUDY: This study was aimed to evaluate the anti-cancer and cancer stabilization effect of water extract of the aerial part of G. divaricata (GD extract) both in vitro and in vivo. MATERIALS AND METHODS: Cytotoxicity and anti-proliferative effects of GD extract alone and in combination with cisplatin were determined by alamarBlue and clonogenic assay. Cancer stem cell (CSC) inhibition and the expression of CSC markers were revealed by sphere formation assay and real-time PCR (qPCR). The in vivo anti-cancer effect of GD extract was evaluated in Huh7 xenograft mice model and Ki-67 expression were also measured. The activity of Wnt signalling and the expression level of Wnt target genes and ß-catenin were determined by luciferase reporter assay, qPCR, immunoblotting and IHC. RESULTS: Moderate cytotoxicity of GD extract in liver cancer cells was observed. GD extract sensitized Huh7 cells to cisplatin treatment. Interestingly, GD extract inhibited cancer sphere formation and reduced the expression of CSC markers. Importantly, GD extract suppressed Huh7 tumor growth, Ki-67 expression and prolonged the anti-liver cancer effect of cisplatin in vivo. Treatment of GD extract resulted in reductions of Wnt reporter activity and the expression of Wnt target genes. Moreover, suppression of ß-catenin were observed in both GD extract treated Huh7 spheres and xenograft tumors. CONCLUSION: Accordingly, our findings suggest that G. divaricata may target liver CSC by suppressing the Wnt pathway and the combination of G. divaricata and cisplatin could be a candidate regimen for treating HCC.

[Acute encephalopathy induced by vaccination in an infant with methylmalonic aciduria cblA].

OBJECTIVE: We report the first case of acute encephalopathy induced by vaccination in an infant with methylmalonic aciduria cblA in China. METHOD: The clinical presentation, blood acylcarnitines analysis, urine organic acids analysis and gene studies of the patient were summarized. RESULT: The proband, a boy, was admitted at the age of 15 months because of recurrent vomiting, acidosis and development delay for 8 months. The previously healthy boy presented vomiting and coma just one hour after hepatitis B vaccination at the age of seven months. Moderate dehydration, electrolyte disturbance and metabolic acidosis had been found. Although his acute metabolic crisis had been corrected soon after intravenous transfusion, psychomotor retardation and recurrent vomiting had been observed. When he was 15 months old, vomiting and lethargy occurred again 3 hours after DTaP vaccination. He was weakened as the illness became worse and got coma with dyspnea 7 days later. He was hospitalized with the suspected diagnosis of viral encephalitis. Blood acylcarnitines analysis, urine organic acids analysis and gene study had been performed for the etiologic investigation.His blood propionylcarnitine (16.3 µmol/L vs. normal range 1.0-5.0 µmol/L) and propionylcarnitine/free carnitine ratio (0.27 vs. normal range 0.03 to 0.25) increased. Markedly elevated urinary methylmalonic acid (388.21 mmol/mol creatinine vs. normal range 0.2 to 3.6 mmol/mol creatinine) and normal plasma total homocysteine supported the diagnosis of isolated methylmalonic aciduria. Two mutations, c.650 T>A (p.L217X) and c.742 C>T (p.Q248X), were identified in his MMAA gene, confirmed the diagnosis of cblA. Each parent carried one of the two mutations. Progressive clinical and biochemical improvement has been observed after hydroxylcobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine. He is currently 2 years and 7 months old with normal development and general condition. CONCLUSION: A boy with cblA was firstly detected after the acute encephalopathy induced by vaccination in China. It is important to pay more attention to the patients with metabolic crisis or organ damage after vaccination. Metabolic studies are keys to the diagnosis of potential diseases and improve the outcome.

Very long-chain acyl-coenzyme A dehydrogenase deficiency in Chinese patients: eight case reports, including one case of prenatal diagnosis.

OBJECTIVE: Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) is a rare mitochondrial fatty acid ß-oxidation disorder. We aimed to explore the clinical, biochemical, and genetic findings, treatments and outcomes in eight Chinese VLCADD patients. METHODS: Eight patients from six unrelated Chinese families with symptomatic VLCADD were diagnosed in the past 4 years. The clinical features and ACADVL gene mutations were analyzed. RESULTS: One patient underwent newborn screening and has been treated timely, she hardly had any symptoms. The remaining seven patients were found because of edema, diarrhea, coma, liver damage and psychomotor retardation. Seven patients had fatty liver. Five had myopathy. All patients had elevated blood tetradecanoylcarnitine. Nine heterozygous mutations of the ACADVL gene were found. Three (c.1102C > T, c.1795G > A and IVS10, +6T > A) were novel. Seven patients completely recovered after treatment. One patient died before diagnosis due to cardiomyopathy. His mother underwent amniocentesis for prenatal diagnosis. The fetus had the same gene mutation of the proband and markedly elevated tetradecanoylcarnitine in amniotic fluid. The boy has been treated after birth and he is healthy now. CONCLUSIONS: Dietary treatment usually leads to good outcomes to VLCADD patients. Amniocytes ACADVL mutations and amniotic fluid tetradecanoylcarnitine analysis are useful for the prenatal diagnosis.

Natural phosphodiesterase-4 inhibitors from the leaf skin of Aloe barbadensis Miller.

The ethanolic extract of Aloe barbadensis Miller leaf skin showed inhibitory activity against phosphodiesterase-4D (PDE4D), which is a therapeutic target of inflammatory disease. Subsequent bioassay-guided fractionation led to the isolation of two new anthrones, 6'-O-acetyl-aloin B (9) and 6'-O-acetyl-aloin A (11), one new chromone, aloeresin K (8), together with thirteen known compounds. Their chemical structures were elucidated by spectroscopic methods including UV, IR, 1D and 2D NMR, and HRMS. All of the isolates were screened for their inhibitory activity against PDE4D using tritium-labeled adenosine 3',5'-cyclic monophosphate ((3)H-cAMP) as substrate. Compounds 13 and 14 were identified as PDE4D inhibitors, with their IC50 values of 9.25 and 4.42 µM, respectively. These achievements can provide evidences for the use of A. barbadensis leaf skin as functional feed additives for anti-inflammatory purpose.

The first Chinese case report of hereditary folate malabsorption with a novel mutation on SLC46A1.

BACKGROUND: Hereditary folate malabsorption is a rare, autosomal recessive disorder of proton-coupled folate transporter deficiency resulting in folate deficiency. Left untreated, the condition can cause severe brain damage and megaloblastic anemia, leading to progressive psychomotor retardation, seizures and other neurological problems. Early diagnosis and treatment are crucial. No case has been documented yet in Mainland China until now. METHODS: A Chinese girl affected by hereditary folate malabsorption was studied. The girl presented with recurrent megaloblastic anemia from the age of 7 months. Paroxysmal limbs trembling and seizures were presented from the age of three years. Intracranial calcification was noted by CT. At her age of 5 years, mental regression, lower-extremity weakness and sleeping problems were observed. Her plasma folate decreased to 4.49 nmol/L (normal control>6.8nmol/L). Plasma total homocysteine elevated to 28.11 µmol/L (normal control<15 µmol/L). Folate and 5-methylterahydrofolate in cerebrospinal fluid were significantly decreased to undetectable level. RESULTS: On SLC46A1 gene, a novel mutation, c.1A>T (M1L), and a reported mutation c.194-195 insG (p.Cys66LeufsX99) were identified, supported the diagnosis of hereditary folate malabsorption. Each parent carries one of two mutations. Folinic calcium supplement resulted in rapid clinical improvement. She is currently 6 years old with normal development and routine blood features. CONCLUSION: Hereditary folate malabsorption is one of the few easily-treatable inherited metabolic diseases. Measurements of folate and 5-methyltetrahydrofolate in cerebrospinal fluid are keys for the diagnosis of the patients.

Jolkinolide B inhibits RANKL-induced osteoclastogenesis by suppressing the activation NF-κB and MAPK signaling pathways.

Osteoclasts together with osteoblasts play pivotal roles in bone remodeling. The unique function and ability of osteoclasts to resorb bone makes them critical in both normal bone homeostasis and pathologic bone diseases such as osteoporosis and rheumatoid arthritis. Thus, new compounds that may inhibit osteoclastogenesis and osteoclast function may be of great value in the treatment of osteoclast-related diseases. In the present study, we examined the effect of jolkinolide B (JB), isolated from the root of Euphorbia fischeriana Steud on receptor activator of NF-κB ligand (RANKL)-induced osteoclast formation. We found that JB inhibited RANKL-induced osteoclast differentiation from bone marrow macrophages (BMMs) without cytotoxicity. Furthermore, the expression of osteoclastic marker genes, such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (CtsK), and calcitonin receptor (CTR), was significantly inhibited. JB inhibited RANKL-induced activation of NF-κB by suppressing RANKL-mediated IκBα degradation. Moreover, JB inhibited RANKL-induced phosphorylation of mitogen-activated protein kinases (p38, JNK, and ERK). This study thus identifies JB as an inhibitor of osteoclast formation and provides evidence that JB might be an alternative medicine for preventing and treating osteolysis.

[Intrahepatic cholestasis due to mitochondrial respiratory chain complex I deficiency in a Chinese boy].

Mitochondrial respiratory chain deficiency is a common cause of mitochondrial disease in children. This study aimed to review the clinical, enzymatic and genetic characteristics of a Chinese boy with progressive intrahepatic cholestasis due to mitochondrial respiratory chain complex I deficiency. The boy developed diarrhea from the age of 13 months, followed by progressive body weight loss, jaundice and weakness. His urine organic acids, blood amino acids and acylcarnitines profiles were normal. Mitochondrial respiratory chain complexes I to V activities in peripheral leukocytes were measured using spectrophotometric assay. Complex I activity was reduced. 5821G>A mutation was indentified by gene sequencing on tRNA-cys of mitochondrial gene in the patient and his mother. Vitamin supplements, liver protection, antibiotics and plasma infusion were not effective in the patient. Unfortunately, the boy died at the age of 17 months. Mitochondrial respiratory chain complex I deficiency is the most common mitochondrial respiratory chain disorder. This was the first case of intrahepatic cholestasis due to complex I deficiency confirmed by mitochondrial respiratory chain enzyme activity assay and gene analysis in China. It was concluded that mitochondrial hepatopathy is one of major causes of metabolic hepatopathy. Biochemical assay, mitochondrial respiratory chain complex activities assay and genetic analysis are crucial for the etiological diagnosis of metabolic hepatopathy.

Nutritional and metabolic findings in patients with Prader-Willi syndrome diagnosed in early infancy.

OBJECTIVE: Early treatment (growth hormone and nutritional support) improves development in infants with Prader-Willi syndrome. This study aimed to evaluate the nutritional and metabolic condition of nine patients who were diagnosed and treated in early infancy. METHODS: Nine patients were hospitalized at the age of \xe2\u20ac\xa810 days to 11 months because of severe feeding difficulties, failure to thrive, or developmental delay. The diagnosis of Prader-Willi syndrome was confirmed by fluorescence in situ hybridization or other molecular genetic techniques. Nutritional and metabolic investigations including urinary organic acid analysis, blood amino acid, and acylcarnitine profiles were performed. RESULTS: The diagnosis was made at the mean age of 6.3 months. A deletion of the paternal gene in the 15q11-13 region was detected in all patients. Eight patients had ketosis, seven had malnutrition, five had hyperammonemia, three had liver dysfunction, three had low blood cholesterol level, and two had hypoglycemia. All patients had reduction of serum multiple amino acids and free carnitine. Significant arginine deficiency was found in all patients. Six patients had mildly elevated blood long-chain and very long-chain acylcarnitine. After supplementation with l-arginine, medium-chain fatty acids, l-carnitine, and vitamins, all patients responded with improvement of motor development and nutritional conditions. Four patients were almost caught up on physical and psychomotor development. CONCLUSIONS: Patients with Prader-Willi syndrome are in bad metabolic condition in the early period. Early diagnosis and individual nutritional interventions may improve the nutritional and developmental progress and decrease death rate in infancy.

Reduced somatostatin in hypothalamus of young male mouse increases local but not circulatory GH.

The release of growth hormone (GH) from the pituitary gland is primarily inhibited by somatostatin (SRIF) from the hypothalamus via interactions with five types of SRIF receptors (SSTRs). However, the inhibition mechanism of SRIF on GH has not been fully examined. In this study, we repressed the hypothalamic SRIF in young male mice by stereotaxic injection of the lentiviral-shRNA against SRIF to investigate the role of hypothalamic SRIF on hormone secretion in the GH/IGF-1 axis. We found that the reduction of SRIF in hypothalamus was associated with an increase in the protein, but not the mRNA level, of the GH in the pituitary where SSTR 2 and SSTR 5 act importantly. Interestingly, the level of blood circulatory SRIF, GH, IGF-1 and the body weight were not significantly influenced by the downregulation of hypothalamic SRIF. Our findings provide insights into the mechanisms underlying the inhibition of SRIF on GH secretion.

Inhibition of cadmium-induced oxidative injury in rat primary astrocytes by the addition of antioxidants and the reduction of intracellular calcium.

Exposure of the brain to cadmium ions (Cd(2+)) is believed to lead to neurological disorders of the central nervous system (CNS). In this study, we tested the hypothesis that astrocytes, the major CNS-supporting cells, are resistant to Cd(2+)-induced injury compared with cortical neurons and microglia (CNS macrophages). However, treatment with CdCl(2) for 24 h at concentrations higher than 20 microM substantially induced astrocytic cytotoxicity, which also resulted from long-term exposure to 5 microM of CdCl(2). Intracellular calcium levels were found to rapidly increase after the addition of CdCl(2) into astrocytes, which led to a rise in reactive oxygen species (ROS) and to mitochondrial impairment. In accordance, preexposure to the extracellular calcium chelator EGTA effectively reduced ROS production and increased survival of Cd(2+)-treated astrocytes. Adenovirus-mediated transfer of superoxide dismutase (SOD) or glutathione peroxidase (GPx) genes increased survival of Cd(2+)-exposed astrocytes. In addition, increased ROS generation and astrocytic cell death due to Cd(2+) exposure was inhibited when astrocytes were treated with the polyphenolic compound ellagic acid (EA). Taken together, Cd(2+)-induced astrocytic cell death resulted from disrupted calcium homeostasis and an increase in ROS. Moreover, our findings demonstrate that enhancement of the activity of intracellular antioxidant enzymes and supplementation with a phenolic compound, a natural antioxidant, improves survival of Cd(2+)-primed astrocytes. This information provides a useful approach for treating Cd(2+)-induced CNS neurological disorders.