Synthesis and structure determination of a synthetic cannabinoid CUMYL-THPINACA metabolite with differentiation between the ortho-, meta-, and para-hydroxyl positions of the cumyl moiety.

Synthetic cannabinoids, a type of new psychoactive substances, are likely to be rapidly metabolized; thus, the detection of their metabolites, rather than the parent compound, is a common method used to prove drug consumption. Although the analysis of metabolites is generally performed by mass spectrometry, it is limited to structural estimation because of few commercially available standards. In particular, distinguishing between positional isomers is difficult. Synthetic cannabinoids with a cumyl moiety can be hydroxylated at the cumyl moiety during metabolism, but it remains unclear whether the hydroxylation occurs at the ortho, meta, or para position. This study determined the structures of a metabolite formed by mono-hydroxylation at the cumyl moiety of the synthetic cannabinoid CUMYL-THPINACA, used as a model compound. Chemical synthesis was performed to create possible metabolites with one hydroxyl group at the ortho, meta, or para positions of the cumyl moiety. Using the synthesized metabolites and liquid chromatography-quadrupole time-of-flight mass spectrometry, the metabolite detected in the microsomal reaction of CUMYL-THPINACA was identified as a compound mono-hydroxylated at the para position based on retention time and product ion spectra. Moreover, the rapid metabolism of CUMYL-THPINACA was demonstrated with an in vitro half-life of 4.9 min and the identified metabolite could be detected for a relatively long time in vitro. The synthesized metabolite may be utilized as a good reference standard for proof of CUMYL-THPINACA consumption. These findings have potential applications in the synthesis of metabolites of other synthetic cannabinoids bearing a cumyl moiety.

Acute kidney injury is an unfavorable prognostic factor in acute liver failure and is associated with tumor necrosis factor-alpha.

Acute kidney injury (AKI) is a common complication of acute liver failure (ALF); but its pathogenesis is unknown. ALF was divided into 2 subgroups; ALF with hepatic coma, which corresponds to ALF in the US and Europe, and ALF without hepatic coma. AKI has been shown to worsen the prognosis of ALF patients with hepatic coma; however, its prognostic significance in ALF without hepatic coma remains unknown. A single-center retrospective study of 174 patients with ALF was performed. AKI was defined according to KDIGO criteria. AKI developed in 29 (66.0%) of 44 ALF patients with hepatic coma and 27 (38.5%) of 130 ALF patients without hepatic coma. Systemic inflammatory response syndrome (SIRS) was found to be significantly associated with AKI incidence in ALF patients (P < .001). Tumor necrosis factor-alpha (TNF-α) was found to be significantly associated with the presence and severity of AKI (P = .0039 and P = .0140, respectively). On multivariate analysis, TNF-α was an independent risk factor linked with AKI (P = .0103). Even in the absence of hepatic coma, the transplant-free survival rate of ALF was significantly associated with the presence and severity of AKI. Even when hepatic coma is absent, AKI complicated in ALF is strongly associated with TNF-α and worsens the transplant-free survival rate. Before the onset of hepatic coma, plasma exchange, or extracorporeal blood purification to remove inflammatory cytokines should be considered in ALF patients.

Efficacy of Naldemedine on Intestinal Hypomotility and Adhesions in Rodent Models of Postoperative Ileus.

Postoperative ileus (POI) often decreases patients' QOL because of prolonged hospitalization and readmission. Alvimopan, a peripheral µ-opioid receptor antagonist, is currently the only therapeutic drug for POI. The aim of this study was to examine the efficacy of naldemedine (a peripheral µ-opioid receptor antagonist with a non-competitive pharmacological profile different from that of alvimopan) on postoperative intestinal hypomotility and adhesion in rodent models, and compare it with the effects of alvimopan. Oral administration of naldemedine (0.3 mg/kg) and alvimopan (3 mg/kg) significantly inhibited the decrease in intestinal motility induced by mechanical irritation in mice (p < 0.01, for both). Naldemedine (1 mg/kg) significantly shortened the adhesion length in chemical-induced postoperative adhesion model rats (p < 0.05). Alvimopan (3 mg/kg) also significantly reduced the adhesion ratio (p < 0.01). These findings suggest that naldemedine is effective for postoperative intestinal hypomotility and adhesions in rodents (i.e., as for alvimopan). Thus, naldemedine may be a useful option for the treatment of POI.

Synthetic symbiosis between a cyanobacterium and a ciliate toward novel chloroplast-like endosymbiosis.

Chloroplasts are thought to have co-evolved through endosymbiosis, after a cyanobacterial-like prokaryote was engulfed by a eukaryotic cell; however, it is impossible to observe the process toward chloroplasts. In this study, we constructed an experimental symbiosis model to observe the initial stage in the process from independent organisms to a chloroplast-like organelle. Our system of synthetic symbiosis is capable of long-term coculture of two model organisms: a cyanobacterium (Synechocystis sp. PCC6803) as a symbiont and a ciliate (Tetrahymena thermophila) as a host with endocytic ability. The experimental system was clearly defined, because we used a synthetic medium and the cultures were shaken to avoid spatial complexity. We determined the experimental conditions for sustainable coculture, by analyzing population dynamics using a mathematical model. We experimentally demonstrated that the coculture was sustainable for at least 100 generations, through serial transfers. Moreover, we found that cells isolated after the serial transfer improved the probability of coexistence of both species without extinction in re-coculture. The constructed system will be useful for understanding the initial stage of primary endosymbiosis from cyanobacteria to chloroplasts, i.e., the origin of algae and plants.

Rapid Determination of Preservatives in Cosmetics Using a Core-Shell Column.

Preservatives are frequently added to cosmetics to maintain product quality. Our laboratory quantifies 11 preservatives in cosmetics each year for regulatory purposes. In laboratories, many manufactures also analyze the preservatives in their products for quality control. To analyze many cosmetic samples, a rapid analysis method is required for efficiency. In this study, we developed a rapid method for the simultaneous determination of 11 regulated preservatives in cosmetics using a core-shell column by high-performance liquid chromatography. In this method, the 11 preservatives were separated within 17 min, which was approximately half the time reported in the previous study. The peak resolution for each preservative was >2.6, the correlation coefficients of the calibration curves were >0.9988, the percent recoveries were 92.0-111.9% and the relative standard deviations were <3.5% (n = 3). The relative standard deviations among 6 researchers were <4.7%. Thus, it is an effective rapid determination method for the analysis of preservatives in cosmetics.

A Formula for the Estimation of 24-Hour Urinary Creatinine Excretion: A Derivation and Validation Study.

OBJECTIVE: Twenty-four-hour urinary creatinine (Cr) excretion (24h-uCr) is the basis of Cr clearance and urinary protein-Cr ratio, and it is related to frailty, worsening kidney function, and mortality in patients with chronic kidney disease. Although subjects with lower estimated glomerular filtration rate (eGFR) tend to have lower 24h-uCr, previous formulae for the estimation of 24h-uCr did not include Cr as a predictor. METHODS: This retrospective study included patients admitted to the Department of Nephrology at our hospital (derivation cohort and validation cohort: patients admitted between April 2016 and March 2020). The prediction formula of 24h-uCr was calculated using a multivariate linear regression model with the bootstrap method. Age, height, weight, sex, Cr, and cystatin C were used as predictors. RESULTS: The derivation and validation cohorts included 187 and 63 patients, respectively. The characteristics of the derivation and validation cohorts were as follows: age 73 (61-79.5) years and 70 (58.5-79) years; males, 61.5% and 60.3%; eGFRCr 27.0 (13.7-48.6) mL/min/1.73 m2 and 26.3 (14.0-51.5) mL/min/1.73 m2; and 24-hour urinary protein excretion 0.79 (0.17-2.12) g/day and 1.08 (0.26-2.55) g/day, respectively. Seven prediction formulae were derived. In all models, the Pearson's correlation coefficient was relatively high and statistically significant. However, previous models tended to overestimate the 24h-uCr. Furthermore, the predicted 24h-uCr calculated by the models that do not include Cr as a predictor fluctuates depending on the eGFRCr. CONCLUSION: The best formula for predicting 24h-uCr (mg/day) in a wide range of eGFR populations is a Cr-containing formula: [-9.04 × age (years) + 8.03 × weight (kg) + 0.66 × height (cm) + 188.59 (if male) - 32.11 × Cr (mg/dL) + 779.14].

[Current status of breast cancer undetected by mammography in population-based breast cancer screening and associated factors].

Objective　This study aimed to promote the application of mammography (MMG) screening without performing a clinical breast examination (CBE). It examined population-based screening data, including history taking findings, to elucidate the status of breast cancer cases, detected solely by CBE, and to reveal the factors associated with breast cancer. Through this, it explored alternative methods for evaluating breast cancer cases, undetected by MMG, when CBE is omitted.Methods　The linked anonymized data from women, who underwent breast cancer screening in 2014, 2016, or 2017, were prepared. The data were obtained from the Nishinomiya City database. Breast cancer, undetected by MMG, were defined as breast cancer cases diagnosed by close examination based on CBE only (MMG findings were category 2 or lower, with no abnormalities). To assess the quality of breast cancer screening, process indices were calculated for the overall population, and for patients indicated for close examination based on CBE but not MMG. The association of breast cancer with each factor was statistically analyzed (χ2 test, etc.).Results　In total, 13,504 women underwent breast cancer screening. Close examination was required in 1,247 women (9.2%). Breast cancer was diagnosed in 44 women (3.5%), including four, who had breast cancer undetected by MMG. All of the process indices satisfied the acceptable values. Three of the four women with breast cancer, undetected by MMG, noticed a lump. Breast cancer was significantly associated with "subjective symptoms". The presence of a "lump" and "nipple discharge" were significantly more common in breast cancer patients.Conclusion　Three of the four breast cancer cases, undetected by MMG screening, had a subjective symptom (lump). There was a significant association between subjective symptoms (lump and nipple discharge) and breast cancer. To avoid missing breast cancer, undetected by MMG alone, these symptoms should be especially evaluated in women to compensate for the omission of a CBE. This can be achieved by encouraging women experiencing symptoms to seek consult, performing a thorough history-taking and observation, engaging in multidisciplinary collaboration (communication from medical staff to physicians), and promoting breast awareness.

Endoscopically unobservable appendiceal adenoma treated using laparoscopically assisted surgery.

INTRODUCTION: Primary benign adenomas of the appendix occur rarely. According to appendectomy and autopsy reports, benign adenomas of the appendix are sporadically reported, accounting for ~0.02-0.08% cases. PRESENTATION OF CASE: We report the case of a 58-year-old woman with a segmental polyp protruding into the appendiceal orifice. The polyp was spotted during lower gastrointestinal endoscopy; however, treatment was postponed at the patient's request. During a confirmatory lower gastrointestinal endoscopy for treatment, the polyp was no longer found protruding from the appendiceal orifice and had disappeared. An appendicectomy was performed for diagnostic and therapeutic purposes. Pathological examination showed a low-degree atypical tubular adenoma with no malignant findings. DISCUSSION: Despite the risk of perforation, surgical resection remains the gold standard for treating appendiceal adenoma. Resection can be performed endoscopically if the stem and base of the adenoma can be identified. In the present case, laparoscopy was a good indication from the safety standpoint, and it was radically curative. Furthermore, upon performing an appendectomy, the patient was informed of the risks of cancer-related complications or the need for additional resection. CONCLUSION: This suggestive case proves that appendiceal tumors can disappear endoscopically depending on the timing of examination and treatment.

Machine Learning Algorithm Identifies the Importance of Environmental Factors for Hospital Discharge to Home of Stroke Patients using Wheelchair after Discharge.

BACKGROUND AND PURPOSE: Physical environmental factors are generally likely to become barriers for discharge to home of wheelchair users, compared with non-wheelchair users. However, the importance of environmental factors has not been investigated adequately. Application of machine learning technology might efficiently identify the most influential factors, although it is not easy to interpret and integrate various information including individual and environmental factors in clinical stroke rehabilitation. This study aimed to identify the influential factors affecting home discharge in the stroke patients who use a wheelchair after discharge by using machine learning technology. METHODS: This study used the rehabilitation database of our facility, which includes all stroke patients admitted into the convalescence rehabilitation ward. The chi-squared automatic interaction detection (CHAID) algorithm was used to develop a model to classify wheelchair-using stroke patients discharged to home or not-to-home. RESULTS: Among the variables, including basic information, motor functional factor, activities of daily living ability factor, and environmental factors, the CHAID model identified house renovation and the existence of sloping roads around the house as the first and second discriminators for home discharge. CONCLUSIONS: Our present results could scientifically clarify that the clinician need to focus on the physical environmental factors for achieving home discharge in the patients who use a wheelchair after discharge.

Hyperammonemia-induced impaired consciousness following mFOLFOX6 therapy in a patient with recurrent rectal cancer.

OBJECTIVES: FOLFOX is a standard chemotherapy regimen used to treat colorectal cancer. Adverse events associated with FOLFOX treatment include peripheral neuropathy and myelosuppression. This report discusses the case of a 64-year-old man with rectal cancer who developed hyperammonemia and impaired consciousness following initiation of mFOLFOX6 as a postoperative adjuvant therapy. METHODS: This case study reports on the clinical disease progression of the aforementioned patient. RESULTS: Following preoperative chemoradiotherapy, the patient underwent low anterior resection for rectal cancer. mFOLFOX6 was then initiated as postoperative adjuvant therapy. During the 5th cycle of mFOLFOX6 treatment, the patient presented with impaired consciousness and upper extremity convulsions. Blood testing revealed marked hyperammonemia (349 µg/dL (normal range: 12 - 66 µg/dL)). Imaging did not reveal any intracranial lesions that could cause impaired consciousness. The patient recovered within a day after rehydration and BCAA substitution. CONCLUSION: Although impaired consciousness is a rare adverse reaction of FOLFOX, it has a major psychological impact on the patient and his/her family. Hyperammonemia should therefore be considered a potential cause of impaired consciousness during FOLFOX therapy and should be appropriately diagnosed and treated.

A case of an elderly patient with high-grade colorectal cancer in poor general condition who showed near complete response to chemotherapy and achieved long-term survival.

INTRODUCTION: Chemotherapy is difficult to administer in patients with poor performance status (PS), advanced metastatic lesion, and unresectable colon cancer. We report herein our experience of a patient who showed complete response to chemotherapy and marked PS improvement. The patient presented with the following adverse factors poor PS, advanced progression of metastatic lesions, advanced unresectable colorectal cancer with severe stricture, and old age. PRESENTATION OF CASE: The patient was an 80-year-old male diagnosed with occlusive cancer of the descending colon with multiple metastases in the liver, Stage Ⅳb (National Comprehensive Cancer Network guidelines version 2. 2018). A 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) + panitumumab (Pmab) regimen was successfully administered and led to decreased tumor marker levels; oral intake also became possible. Additional examinations showed that the primary lesion and distant metastatic lesions had almost disappeared; the patient had achieved a near complete response (CR). Currently, 35 cycles of mFOLFOX6＋Pmab have been administered, and his near CR has been maintained for 32 months. DISCUSSION: Best supportive care (BSC) is the recommended option for elderly patients with advanced unresectable colon cancer. This is the first case in which an elderly patient with poor PS and advanced unresectable colorectal cancer was treated with combination chemotherapy of mFOLFOX6 + Pmab. CONCLUSION: Although the use of chemotherapy for elderly with advanced unresectable colorectal cancer or those with poor PS is limited, this case shows that systemic chemotherapy is now an option for such cases previously managed with BSC.

Abdominal CT-aided diagnosis of acute appendicitis in the presence of mobile cecum: A case report.

INTRODUCTION: A mobile cecum is a frequently encountered congenital anomaly. It is important to recognize this atypical position of the cecum as it may interfere with an accurate diagnosis of acute appendicitis. PRESENTATION OF CASE: A 48-year-old man presented with abdominal pain, anorexia, and fever. He had mild lower abdominal discomfort, and rebound tenderness in the suprapubic region, but no guarding or right lower quadrant findings. Laboratory tests identified an elevated white blood cell count (12350 cells/mL) and C-reactive protein level (4.56 mg/dL). In view of the clinical picture suggestive of localized peritonitis, an abdominal computed tomography (CT) was performed, which revealed a caudally located cecum, lying in the pelvis, along with evidence of an acutely inflamed appendix. An urgent surgical procedure was performed, which confirmed the diagnosis of acute appendicitis accompanying a mobile cecum. DISCUSSION: In the presence of a mobile cecum, the clinical findings of acute appendicitis may be atypical owing to the abnormal position of the appendix. In such cases, there is the possibility of a missed diagnosis. In our case, a CT examination that was performed in view of the clinical diagnosis of mild peritonitis aided in establishing the diagnosis of acute appendicitis and a mobile cecum. CONCLUSION: Anatomical variations of the cecum and the appendix may result in atypical presentation of acute appendicitis. A high index of suspicion, and a CT examination may be helpful in establishing the diagnosis in such cases.

Enzyme-like catalysis via ternary complex mechanism: alkoxy-bridged dinuclear cobalt complex mediates chemoselective O-esterification over N-amidation.

Hydroxy group-selective acylation in the presence of more nucleophilic amines was achieved using acetates of first-row late transition metals, such as Mn, Fe, Co, Cu, and Zn. Among them, cobalt(II) acetate was the best catalyst in terms of reactivity and selectivity. The combination of an octanuclear cobalt carboxylate cluster [Co4(OCOR)6O]2 (2a: R = CF3, 2b: R = CH3, 2c: R = (t)Bu) with nitrogen-containing ligands, such as 2,2'-bipyridine, provided an efficient catalytic system for transesterification, in which an alkoxide-bridged dinuclear complex, Co2(OCO(t)Bu)2(bpy)2(µ2-OCH2-C6H4-4-CH3)2 (10), was successfully isolated as a key intermediate. Kinetic studies and density functional theory calculations revealed Michaelis-Menten behavior of the complex 10 through an ordered ternary complex mechanism similar to dinuclear metallo-enzymes, suggesting the formation of alkoxides followed by coordination of the ester.