Randomized controlled phase I trial for a novel peripheral parenteral nutrition formula containing dextrose, amino acids, fat emulsion, electrolytes, and FDA2000 recommendation-based vitamins.

BACKGROUND & AIMS: We developed the world's first all-in-one type peripheral parenteral nutrition product containing dextrose, amino acids, fat emulsion, electrolytes and vitamins, according to the FDA 2000 recommendation. This phase I trial examined the safety and changes in nutritional parameters in healthy participants. METHODS: A single-center, randomized, open-label, active-controlled trial was performed in single ascending dose (SAD: Step 1-3) and multiple dose (Step 4) studies. Participants were administered a single dose of OPF-105 (test solution: 150 g of dextrose, 60 g of amino acids, 40 g of fat, 1240 kcal of total energy per 2200 mL, and 106 NPC/N ratio, with multivitamins, n = 17) or BFI (control solution: 150 g of dextrose, 60 g of amino acids, 840 kcal of total energy per 2000 mL, and 64 NPC/N ratio, with vitamin B1, n = 18) with three ascending doses (Step 1: 550 mL, Step 2: 1100 mL, and Step 3: 2200 mL) in the SAD study, or received multiple doses with Step 3 amount of OPF-105 (n = 5) or BFI (n = 6) for 3 days (Step 4) via peripherally inserted venous catheters. The safety and nutritional parameters were assessed. RESULTS: There were no serious adverse events or events requiring discontinuation of the solution administration in either group. Blood urea nitrogen (BUN) levels remained within the normal range in both groups (Step 1-4). However, they gradually increased during the time course of the study in the BFI group but not in the OPF group (Step 4), suggesting the prevention of body protein breakdown. Blood triglyceride (TG) levels increased after administration in the OPF group but promptly returned to the pre-administration level (Step 1-4). Blood total ketone body levels increased the day after administration in both groups, which may imply a lower degree of starvation (Step 1-3), but the increase in the OPF group was milder than that in the BFI group (Step 4). Blood vitamin B6 and folic acid levels were maintained within the normal ranges in the OPF group but were near the lower limit in the BFI group (Step 1-4). Blood vitamin C levels showed almost lower limit in the two groups (Step 1-3), but increased only in the OPF group (Step 4). Blood vitamin K levels in the BFI group remained near the lower limit of the normal range, but those in the OPF group were higher than the upper limit at the end of administration and quickly returned to the pre-administration level (Step 1-4). CONCLUSIONS: This trial suggests that the newly developed formula (OPF-105) improves fat metabolism, maintains vitamin profiles, and may prevent body protein and fat breakdown and can be safely administered to healthy participants. Registration number of Clinical Trial: UMIN000046915; https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000053479.

Postoperative Vitamin Profile after Receiving a Novel Peripheral Parenteral Nutrition Solution: Multicenter Randomized Controlled Phase III Trial.

INTRODUCTION: We assessed the efficacy and safety of OPF-105, a novel all-in-one peripheral parenteral nutrition (PPN) solution containing multivitamins by the U.S. Food and Drug Administration in 2000 (FDA2000 recommendation). METHODS: We conducted a phase III trial administering OPF-105 or BFL (combination of a commercially available PPN solution and fat emulsion) to patients after gastrointestinal (GI) tract surgery from postoperative day (POD) 1 up to POD14. Until POD7, nutrients were provided only with OPF-105 or BFL. After blood sampling on POD8, oral food intake was permitted. PPN was administered according to the amount of food intake. RESULTS: Efficacy endpoints were assessed in 99 subjects (OPF group: 52; BFL group: 47). The levels of blood proteins and fatty acids in the two groups were similar on POD8. The transition of these mean levels was similar in both groups from POD1 or 2 to POD9 to 15. The mean preoperative blood vitamin levels were within reference intervals (RIs). On POD1 (before administration), the mean levels of most blood vitamins decreased compared to those of the preoperative levels. In the BFL group, the mean blood levels of vitamin B2, B6, pantothenic acid (PA), folic acid (FA), biotin, and C decreased below or near the lower limit of RIs on POD8, and the mean blood levels of vitamin B6 and C remained low from POD9 to 15. In the OPF group, the mean blood levels of vitamins, excluding vitamin K, were within RIs on POD8 and POD9 to 15. The mean levels of blood vitamin K increased over the upper limit of RIs on POD8 but within RIs from POD9 to 15. There was no obvious difference in the incidence of adverse events between the two groups, which is common after GI tract surgeries. CONCLUSION: Blood vitamin levels decreased when patients were administered PPN without vitamin supplementation during the first week after surgery. The novel PPN formula containing multivitamins recommended by FDA2000 can be safely administered to postoperative patients to maintain blood vitamin levels.

A novel method to estimate changes in stress-induced salivary α-amylase using heart rate variability and respiratory rate, as measured in a non-contact manner using a single radar attached to the back of a chair.

The authors have developed a non-contact system which estimates changes in salivary α-amylase (sAA ratio) induced by stress. Before and after stressful sound exposure, a single 24 GHz compact radar which is attached to the back of a chair measures the low frequency (LF) component of heart rate variability and respiratory rate, α-amylase in the subjects' buccal secretions was measured by using an α-amylase assay kit. Using multiple regression analysis, sAA ratio was estimated using stress-induced LF change (LF ratio) and stress-induced respiratory rate change (respiratory rate ratio). Twelve healthy subjects were tested (12 males, 22 ± 2 years), who were exposed to audio stimuli with a composite tone of 2120 Hz and 2130 Hz sine waves at a sound pressure level of 95 dB after a silent period through a headphone. The result showed that sAA ratio estimated using multiple regression analysis significantly correlated with measured sAA ratio (R = 0.76, p < 0.01). This indicates that the system may serve for a stress management in the future.

Proteomic analysis of native hepatocyte nuclear factor-4α (HNF4α) isoforms, phosphorylation status, and interactive cofactors.

Hepatocyte nuclear factor-4α (HNF4α, NR2A1) is a nuclear receptor that has a critical role in hepatocyte differentiation and the maintenance of homeostasis in the adult liver. However, a detailed understanding of native HNF4α in the steady-state remains to be elucidated. Here we report the native HNF4α isoform, phosphorylation status, and complexes in the steady-state, as shown by shotgun proteomics in HepG2 hepatocarcinoma cells. Shotgun proteomic analysis revealed the complexity of native HNF4α, including multiple phosphorylation sites and inter-isoform heterodimerization. The associating complexes identified by label-free semiquantitative proteomic analysis include the following: the DNA-dependent protein kinase catalytic subunit, histone acetyltransferase complexes, mRNA splicing complex, other nuclear receptor coactivator complexes, the chromatin remodeling complex, and the nucleosome remodeling and histone deacetylation complex. Among the associating proteins, GRB10 interacting GYF protein 2 (GIGYF2, PERQ2) is a new candidate cofactor in metabolic regulation. Moreover, an unexpected heterodimerization of HNF4α and hepatocyte nuclear factor-4γ was found. A biochemical and genomewide analysis of transcriptional regulation showed that this heterodimerization activates gene transcription. The genes thus transcribed include the cell death-inducing DEF45-like effector b (CIDEB) gene, which is an important regulator of lipid metabolism in the liver. This suggests that the analysis of the distinctive stoichiometric balance of native HNF4α and its cofactor complexes described here are important for an accurate understanding of transcriptional regulation.

Improved recovery of exfoliated colonocytes from feces using newly developed immunomagnetic beads.

We demonstrated the feasibility of a new methodology for isolating colonocytes from feces. To reduce costs and improve the recovery rate of colonocytes from feces, we attempted to develop new immunomagnetic beads. Several sizes of magnetic beads were prepared and tagged with a monoclonal antibody against EpCAM. We made several new monoclonal antibodies against EpCAM, and each monoclonal antibody was tagged to the magnetic beads. In the simulation, the most efficient recovery of HT-29 cells was obtained using the smallest size of beads. Also, beads tagged with a monoclonal antibody with a higher affinity against EpCAM had a higher recovery rate. Similar results were obtained when the smallest size of beads with the highest-affinity monoclonal antibody was applied to clinical samples. The newly developed immunomagnetic beads may be useful for isolating colorectal cancer cells from feces, enabling the cytological or molecular biological diagnosis of CRC.

Development of real-time detection direct test for hepatitis B virus and comparison with two commercial tests using the WHO international standard.

AIMS: A highly reproducible and sensitive hepatitis B virus real-time detection direct (HBV RTD-direct) test using DNA extraction by magnetic beads coated with polyclonal anti-HBsAg, followed by the real-time detection polymerase chain reaction (PCR) method, was developed for the detection of HBV DNA. METHODS: The HBV DNA could be extracted from the HBsAg positive viral particles without resulting in viral DNA fragmentation. The HBV RTD-direct test was validated using a serial dilution panel of the WHO standard HBV DNA 97/746 I. RESULTS: The test had a dynamic range of 0.7-8.0 log10 international units (IU) per mL and the results were shown to be comparable to those obtained with two commercially available tests: the HBV DNA transcription-mediated amplification-hybridization protection assay and the Amplicor HBV Monitor test. In addition, the HBV RTD-direct test, based on magnetic extraction, successfully eliminated PCR inhibitors in clinical specimens. CONCLUSION: We conclude that the HBV RTD-direct test is an excellent alternative for monitoring patients undergoing antiviral treatment or for screening various clinical specimens.