Impact of nutritional guidance on various clinical parameters in patients with moderate obesity: A retrospective study.

Context: This study aims to investigate whether there is adequate provision of nutritional guidance through interventions by registered dietitians, especially for patients with moderate obesity. This is particularly important as such interventions may prove to be more effective for Japanese patients. Methods: In Japan, since there is a system of nutritional guidance with a registered dietitian for patients with a BMI over 30 kg/m2, we recruited 636 patients with obesity who had a BMI over 30 kg/m2 admitted to the Kawasaki Medical School General Medical Center between April 2018 and March 2020 through a review of their medical records. Second, we recruited 153 patients who underwent a blood examination before receiving nutritional guidance and at least one time every 3 to 6 months thereafter after receiving it. We aimed to evaluate whether continued nutritional guidance and follow-up interventions for patients with obesity were effective. We compared the BMI and metabolic markers of the patients who received nutritional guidance from a registered dietitian against those who did not. Results: A total of 636 patients with obesity who have a BMI over 30 kg/m2 were included in this study. A total of 164 patients with obesity received nutritional guidance from a registered dietitian at least one time, but 472 patients did not. Most interventions on nutritional guidance conducted by a registered dietitian were ordered from internal medicine (81.1%). However, internal medicine was the most common department that did not perform these interventions; however, less than half of the (49.2%) received them. In the second analysis, we compared two groups of patients with obesity. The first group (n = 70) who underwent blood examinations received nutritional guidance from a registered dietitian, while the second group (n = 54) did not receive such guidance. We found that there was no significant difference in body weight and BMI between the two groups of patients. We observed a significant decrease in dyslipidemia-associated metabolic markers among the patients who received nutritional guidance compared to those who did not [total cholesterol, -9.7 ± 29.3 vs. 2.3 ± 22.0 mg/dL (p = 0.0208); low-density lipoprotein cholesterol, -10.4 ± 30.5 vs. -2.0 ± 51.0 mg/dL (p = 0.0147), respectively]. Other metabolic markers also tended to decrease, although they did not reach statistical significance. Conclusion: It is rare for patients with only obesity to receive nutritional guidance. However, when nutritional guidance from a registered dietitian is provided, improvements in BMI and metabolic parameters can be expected.

Identification of gibberellin-regulated protein as a new allergen in orange allergy.

BACKGROUND: To date, three orange allergens have been reported. However, it is still unclear whether gibberellin-regulated proteins (GRPs), identified as new allergens in other fruit allergies, are also involved in orange allergy. OBJECTIVE: To investigate the allergenicity of orange GRP and to determine the clinical characteristics of patients with orange allergy who are sensitized to orange GRP. METHODS: We enrolled 14 patients (four men, 10 women, mean age: 29.6 years) who were diagnosed with orange allergy based on relevant clinical history, positive skin test, and/or positive challenge test. Orange GRP (molecular weight: 6941.6 Da) was purified by ion-exchange column chromatography. To test for orange GRP-specific IgE, we performed ELISA, basophil activation tests, and skin prick tests. Cross-reactivity of orange GRP with native peach allergen nPru p 7 and Japanese apricot nPru m 7 was analysed by ELISA inhibition assays. IgE specific for orange, grapefruit, and peach allergens rPru p 1, rPru p 3, and rPru p 4 was measured using ImmunoCAP. RESULTS: Twelve of the 14 patients (85.7%) were positive for orange GRP allergy in at least one test: 71.4% (10/14) were positive by ELISA, 50% (3/6) were positive in the basophil activation test, and 100% (4/4) were positive in the skin prick test. ELISA inhibition assays revealed cross-reactivity of orange GRP with both nPru p 7 and nPru m 7. The patients showed variable positivity for specific IgE against orange, grapefruit, rPru p 1, rPru p 3, and rPru p 4 (57.1%, 71.4%, 7.1%, 0%, and 21.4%, respectively). The most frequent symptoms of orange GRP allergy were facial swelling and oropharyngeal symptoms. CONCLUSIONS AND CLINICAL RELEVANCE: Orange GRP may be involved in orange allergy and may be a cross-reactive allergen between citrus fruits and the Rosaceae family of fruits.

Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations.

Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.

Hyperthermia and chemotherapy using Fe(Salen) nanoparticles might impact glioblastoma treatment.

We previously reported that µ-oxo N,N'-bis(salicylidene)ethylenediamine iron [Fe(Salen)], a magnetic organic compound, has direct anti-tumor activity, and generates heat in an alternating magnetic field (AMF). We showed that Fe(Salen) nanoparticles are useful for combined hyperthermia-chemotherapy of tongue cancer. Here, we have examined the effect of Fe(Salen) on human glioblastoma (GB). Fe(Salen) showed in vitro anti-tumor activity towards several human GB cell lines. It inhibited cell proliferation, and its apoptosis-inducing activity was greater than that of clinically used drugs. Fe(Salen) also showed in vivo anti-tumor activity in the mouse brain. We evaluated the drug distribution and systemic side effects of intracerebrally injected Fe(Salen) nanoparticles in rats. Further, to examine whether hyperthermia, which was induced by exposing Fe(Salen) nanoparticles to AMF, enhanced the intrinsic anti-tumor effect of Fe(Salen), we used a mouse model grafted with U251 cells on the left leg. Fe(Salen), BCNU, or normal saline was injected into the tumor in the presence or absence of AMF exposure. The combination of Fe(Salen) injection and AMF exposure showed a greater anti-tumor effect than did either Fe(Salen) or BCNU alone. Our results indicate that hyperthermia and chemotherapy with single-drug nanoparticles could be done for GB treatment.

Transient receptor potential cation 3 channel regulates melanoma proliferation and migration.

Melanoma has an extremely poor prognosis due to its rapidly progressive and highly metastatic nature. Several therapeutic drugs have recently become available, but are effective only against melanoma with specific BRAF gene mutation. Thus, there is a need to identify other target molecules. We show here that Transient receptor potential, canonical 3 (TRPC3) is widely expressed in human melanoma. We found that pharmacological inhibition of TRPC3 with a pyrazole compound, Pyr3, decreased melanoma cell proliferation and migration. Similar inhibition was observed when the TRPC3 gene was silenced with short-hairpin RNA (shRNA). Pyr3 induced dephosphorylation of signal transducer and activator of transcription (STAT) 5 and Akt. Administration of Pyr3 (0.05 mg/kg) to mice implanted with human melanoma cells (C8161) significantly inhibited tumor growth. Our findings indicate that TRPC3 plays an important role in melanoma growth, and may be a novel target for treating melanoma in patients.

Negative Correlation between Serum Cytokine Levels and Cognitive Abilities in Children with Autism Spectrum Disorder.

Evidence suggests that cytokines may be one of the major factors influencing cognitive development in those with autism spectrum disorder (ASD). To shed light on the neural and cognitive mechanisms of ASD, we investigated the association between peripheral cytokine levels and cognitive profiles in children with ASD. The serum levels of 10 cytokines (granulocyte macrophage colony-stimulating factor, interferon (IFN)-γ, interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and tumor necrosis factor-α) were examined in 14 children with ASD using the Human Ultrasensitive Cytokine Magnetic 10-Plex Panel for the Luminex platform. The Wechsler Intelligence Scale for Children (WISC) was administered to each subject, and the relationships between WISC scores and serum levels of the cytokines were examined. The full-scale intelligence quotient (IQ) was significantly negatively correlated with the levels of IL-6 (Spearman's rank, p < 0.0001, false discovery rate q < 0.01). The levels of IL-6 and IFN-γ showed significant negative correlations with the verbal comprehension index (p < 0.001, q < 0.01) and working memory index (p < 0.01, q < 0.05), respectively. No other cytokines were significantly correlated with full-scale IQ or with any of the subscale scores of the WISC. The present results suggest negative correlations of IL-6 and IFN-γ levels with cognitive development of children with ASD. Our preliminary findings add to the evidence that cytokines may play a role in the neural development in ASD.

Hyperthermia generated with ferucarbotran (Resovist®) in an alternating magnetic field enhances cisplatin-induced apoptosis of cultured human oral cancer cells.

Hyperthermia is a promising anti-cancer treatment in which the tissue temperature is increased to 42-45 °C, and which is often used in combination with chemotherapy or radiation therapy. Our aim in the present work was to examine the feasibility of combination therapy for oral cancer with cisplatin and hyperthermia generated with ferucarbotran (Resovist(®); superparamagnetic iron oxide) in an alternating magnetic field (AMF). First, we established that administration of ferucarbotran at the approved dosage for magnetic resonance imaging provides an iron concentration sufficient to increase the temperature to 42.5 °C upon exposure to AMF. Then, we examined the effect of cisplatin combined with ferucarbotran/AMF-induced hyperthermia on cultured human oral cancer cells (HSC-3 and OSC-19). Cisplatin alone induced apoptosis of cancer cells in a dose-dependent manner, as is well known. However, the combination of cisplatin with ferucarbotran/AMF was significantly more effective than cisplatin alone. This result suggests that it might be possible to reduce the clinically effective dosage of cisplatin by administering it in combination with ferucarbotran/AMF-induced hyperthermia, thereby potentially reducing the incidence of serious cisplatin-related side effects. Further work seems justified to evaluate simultaneous thermo-chemotherapy as a new approach to anticancer therapy.

Store-operated Ca2+ entry (SOCE) regulates melanoma proliferation and cell migration.

Store-operated Ca(2+) entry (SOCE) is a major mechanism of Ca(2) (+) import from extracellular to intracellular space, involving detection of Ca(2+) store depletion in endoplasmic reticulum (ER) by stromal interaction molecule (STIM) proteins, which then translocate to plasma membrane and activate Orai Ca(2+) channels there. We found that STIM1 and Orai1 isoforms were abundantly expressed in human melanoma tissues and multiple melanoma/melanocyte cell lines. We confirmed that these cell lines exhibited SOCE, which was inhibited by knockdown of STIM1 or Orai1, or by a pharmacological SOCE inhibitor. Inhibition of SOCE suppressed melanoma cell proliferation and migration/metastasis. Induction of SOCE was associated with activation of extracellular-signal-regulated kinase (ERK), and was inhibited by inhibitors of calmodulin kinase II (CaMKII) or Raf-1, suggesting that SOCE-mediated cellular functions are controlled via the CaMKII/Raf-1/ERK signaling pathway. Our findings indicate that SOCE contributes to melanoma progression, and therefore may be a new potential target for treatment of melanoma, irrespective of whether or not Braf mutation is present.