Primary Follicular Lymphoma of the Duodenum with Erosions as Atypical Macroscopic Features

A 52-year-old Japanese woman who was eventually diagnosed with primary follicular lymphoma of the duodenum showed atypical endoscopic features, namely, erosions with peripheral whitish edematous mucosa. Initial biopsy specimens taken from the erosions revealed insufficient numbers of lymphoma cells for histological diagnosis. Subsequent biopsy specimens from the peripheral mucosa containing the whitish enlarged villi showed infiltration of the lymphoma cells forming lymphoid follicles, which led us to the appropriate diagnosis. This case indicates that endoscopists should take biopsy samples from the peripheral mucosa with whitish enlarged villi rather than erosions in the rare instances that erosions appear as the main macroscopic feature of intestinal follicular lymphoma

Therapeutic regimen of l-arginine for MELAS: 9-year, prospective, multicenter, clinical research

ObjectiveTo examine the efficacy and safety of the therapeutic regimen using oral and intravenous l-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).MethodsIn the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous l-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral l-arginine was the MELAS scale, while that for intravenous l-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined.ResultsOral l-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous l-arginine improved the rates of four major symptoms—headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 μmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of l-arginine were well tolerated.ConclusionsThe systematic administration of oral and intravenous l-arginine may be therapeutically beneficial and clinically useful for patients with MELAS

Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome

BACKGROUND: Cockayne syndrome (CS) is a rare, autosomal recessive multisystem disorder characterised by prenatal or postnatal growth failure, progressive neurological dysfunction, ocular and skeletal abnormalities and premature ageing. About half of the patients with symptoms diagnostic for CS show cutaneous photosensitivity and an abnormal cellular response to UV light due to mutations in either the ERCC8/CSA or ERCC6/CSB gene. Studies performed thus far have failed to delineate clear genotype-phenotype relationships. We have carried out a four-centre clinical, molecular and cellular analysis of 124 patients with CS

Quality of life of children with neurodevelopmental disorders and their parents during the COVID-19 pandemic : a 1-year follow-up study

This study aimed to reveal changes in the quality of life (QOL) of children with neurodevelopmental disorders and their parents, and the interaction between their QOL and parental mental state during the coronavirus 2019 (COVID-19) pandemic. Eighty-nine school-aged children and parents participated in surveys in May 2020 (T1) and May 2021 (T2). The parents completed questionnaires that assessed their QOL, depression, parenting stress, and living conditions. Children's temporary mood status was evaluated using the self-reported visual analog scale (VAS). Children's QOL and VAS at T2 were higher than their QOL at T1. Parents' QOL at T2 was lower than their QOL at T1. Severe parental depression at T1 had a synergistic effect on severe parenting stress and severe depressive state at T2. Additionally, children's high QOL at T1 had a synergistic effect on low parenting stress and children's high QOL at T2. Furthermore, children's low VAS scores and parents' low QOL at T2 were associated with deterioration of family economic status. Children and parents' QOL changed during the prolonged COVID-19 pandemic. Improvement in children's QOL was influenced by reduced maternal depressive symptoms. Public support for parental mental health is important to avoid decreasing QOL.Peer reviewe

Pyridoxal in the Cerebrospinal Fluid May Be a Better Indicator of Vitamin B6–dependent Epilepsy Than Pyridoxal 5′-Phosphate

Background We aimed to demonstrate the biochemical characteristics of vitamin B6–dependent epilepsy, with a particular focus on pyridoxal 5′-phosphate and pyridoxal in the cerebrospinal fluid. Methods Using our laboratory database, we identified patients with vitamin B6–dependent epilepsy and extracted their data on the concentrations of pyridoxal 5′-phosphate, pyridoxal, pipecolic acid, α-aminoadipic semialdehyde, and monoamine neurotransmitters. We compared the biochemical characteristics of these patients with those of other epilepsy patients with low pyridoxal 5′-phosphate concentrations. Results We identified seven patients with pyridoxine-dependent epilepsy caused by an ALDH7A1 gene abnormality, two patients with pyridoxal 5′-phosphate homeostasis protein deficiency, and 28 patients with other epilepsies with low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. Cerebrospinal fluid pyridoxal and pyridoxal 5′-phosphate concentrations were low in patients with vitamin B6–dependent epilepsy but cerebrospinal fluid pyridoxal concentrations were not reduced in most patients with other epilepsies with low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. Increase in 3-O-methyldopa and 5-hydroxytryptophan was demonstrated in some patients with vitamin B6–dependent epilepsy, suggestive of pyridoxal 5′-phosphate deficiency in the brain. Conclusions Low cerebrospinal fluid pyridoxal concentrations may be a better indicator of pyridoxal 5′-phosphate deficiency in the brain in vitamin B6–dependent epilepsy than low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. This finding is especially helpful in individuals with suspected pyridoxal 5′-phosphate homeostasis protein deficiency, which does not have known biomarkers

De Novo Mutations in GNAO1, Encoding a Gαo Subunit of Heterotrimeric G Proteins, Cause Epileptic Encephalopathy

Heterotrimeric G proteins, composed of α, β, and γ subunits, can transduce a variety of signals from seven-transmembrane-type receptors to intracellular effectors. By whole-exome sequencing and subsequent mutation screening, we identified de novo heterozygous mutations in GNAO1, which encodes a Gαo subunit of heterotrimeric G proteins, in four individuals with epileptic encephalopathy. Two of the affected individuals also showed involuntary movements. Somatic mosaicism (approximately 35% to 50% of cells, distributed across multiple cell types, harbored the mutation) was shown in one individual. By mapping the mutation onto three-dimensional models of the Gα subunit in three different complexed states, we found that the three mutants (c.521A>G [p.Asp174Gly], c.836T>A [p.Ile279Asn], and c.572_592del [p.Thr191_Phe197del]) are predicted to destabilize the Gα subunit fold. A fourth mutant (c.607G>A), in which the Gly203 residue located within the highly conserved switch II region is substituted to Arg, is predicted to impair GTP binding and/or activation of downstream effectors, although the p.Gly203Arg substitution might not interfere with Gα binding to G-protein-coupled receptors. Transient-expression experiments suggested that localization to the plasma membrane was variably impaired in the three putatively destabilized mutants. Electrophysiological analysis showed that Gαo-mediated inhibition of calcium currents by norepinephrine tended to be lower in three of the four Gαo mutants. These data suggest that aberrant Gαo signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements

C57BL/KsJ-db/db-ApcMin/+ Mice Exhibit an Increased Incidence of Intestinal Neoplasms

The numbers of obese people and diabetic patients are ever increasing. Obesity and diabetes are high-risk conditions for chronic diseases, including certain types of cancer, such as colorectal cancer (CRC). The aim of this study was to develop a novel animal model in order to clarify the pathobiology of CRC development in obese and diabetic patients. We developed an animal model of obesity and colorectal cancer by breeding the C57BL/KsJ-db/db (db/db) mouse, an animal model of obesity and type II diabetes, and the C57BL/6J-ApcMin/+ (Min/+) mouse, a model of familial adenomatous polyposis. At 15 weeks of age, the N9 backcross generation of C57BL/KsJ-db/db-ApcMin/+ (db/db-Min/+) mice developed an increased incidence and multiplicity of adenomas in the intestinal tract when compared to the db/m-Min/+ and m/m-Min/+ mice. Blood biochemical profile showed significant increases in insulin (8.3-fold to 11.7-fold), cholesterol (1.2-fold to 1.7-fold), and triglyceride (1.2-fold to 1.3-fold) in the db/db-Min/+ mice, when compared to those of the db/m-Min/+ and m/m-Min/+ mice. Increases (1.4-fold to 2.6-fold) in RNA levels of insulin-like growth factor (IGF)-1, IRF-1R, and IGF-2 were also observed in the db/db- Min/+ mice. These results suggested that the IGFs, as well as hyperlipidemia and hyperinsulinemia, promoted adenoma formation in the db/db-Min/+ mice. Our results thus suggested that the db/db-Min/+ mice should be invaluable for studies on the pathogenesis of CRC in obese and diabetes patients and the therapy and prevention of CRC in these patients

Nutraceutical Approach for Preventing Obesity-Related Colorectal and Liver Carcinogenesis

Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and liver carcinogenesis. Further, branched-chain amino acids (BCAA), which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic liver diseases, might be also effective for the suppression of obesity-related carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals