Carbonic anhydrase 8 (CAR8) negatively regulates GLP-1 secretion from enteroendocrine cells in response to long-chain fatty acids.

Glucagon-like peptide-1 (GLP-1) is an incretin secreted from enteroendocrine preproglucagon (PPG)-expressing cells (traditionally known as L cells) in response to luminal nutrients that potentiates insulin secretion. Augmentation of endogenous GLP-1 secretion might well represent a novel therapeutic target for diabetes treatment in addition to the incretin-associated drugs currently in use. In this study, we found that PPG cells substantially express carbonic anhydrase 8 (CAR8), which has been reported to inhibit inositol 1,4,5-trisphosphate (IP3) binding to the IP3 receptor and subsequent Ca2+ efflux from the endoplasmic reticulum in neuronal cells. In vitro experiments using STC-1 cells demonstrated that Car8 knockdown increases long-chain fatty acid (LCFA)-stimulated GLP-1 secretion. This effect was reduced in the presence of phospholipase C (PLC) inhibitor; in addition, Car8 knockdown increased the intracellular Ca2+ elevation caused by α-linolenic acid, indicating that CAR8 exerts its effect on GLP-1 secretion via the PLC/IP3/Ca2+ pathway. Car8wdl null mutant mice showed significant increase in GLP-1 response to oral corn oil administration compared with that in wild-type littermates, with no significant change in intestinal GLP-1 content. These results demonstrate that CAR8 negatively regulates GLP-1 secretion from PPG cells in response to LCFAs, suggesting the possibility of augmentation of postprandial GLP-1 secretion by CAR8 inhibition.NEW & NOTEWORTHY This study focused on the physiological significance of carbonic anhydrase 8 (CAR8) in GLP-1 secretion from enteroendocrine preproglucagon (PPG)-expressing cells. We found an inhibitory role of CAR8 in LCFA-induced GLP-1 secretion in vitro and in vivo, suggesting a novel therapeutic approach to diabetes and obesity through augmentation of postprandial GLP-1 secretion by CAR8 inhibition.

Multiacquisition Variable-Resonance Image Combination Selective Can Improve Image Quality and Reproducibility for Metallic Implants in the Lumbar Spine.

The aim of this study is to evaluate how metallic artifacts in the lumbar spine can affect images obtained from magnetic resonance (MR) sequences. We performed a phantom experiment by scanning an agar containing an orthopedic metallic implant using 64-channel multidetector row computed tomography (CT) and a 3-tesla MR unit. We compared the reproducibility in each measurement, enlargement or reduction ratio of the CT and MR measurements, and signal deviation in each voxel from the control. The reproducibility on CT and multiacquisition variable-resonance image combination selective (MAVRIC SL) was good, but that on the other MR sequences showed either fixed bias or proportional bias. The reduction ratios of the distance between the nails were significantly smaller in MAVRIC SL than in the other MR sequences after CT measurements (p<0.001, respectively). MAVRIC SL was able to reduce the metallic artifact, permitting observation of the tissue surrounding the metal with good reproducibility.

Use of esophageal stent for the treatment of postoperative gastrointestinal-airway fistula after esophagectomy.

A gastrointestinal-airway fistula (GAF) after esophagectomy is a very serious postoperative complication that can cause severe respiratory complications due to digestive juice inflow. Generally, GAF is managed by invasive surgical treatment; less-invasive treatment has yet to be established. We performed esophageal stent placement (ESP) in three cases of GAF after esophagectomy. We assessed the usefulness of ESP through our clinical experience. All GAFs were successfully managed by ESP procedures. After the procedure, the stent positioning and expansion were appropriately evaluated by radiological assessments over time. The stent was removed after endoscopic confirmation of fistula closure on days 8, 23, and 71. Only one patient with a long-term indwelling stent developed a manageable secondary gastrobronchial fistula as a procedure-related complication. In conclusion, ESP was shown to be a less-invasive and effective therapeutic modality for the treatment of GAF.

Practical and innate carbon-hydrogen functionalization of heterocycles.

Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C-H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications--such as aqueous solubility and their ability to act as ligands--render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 °C or less), direct and operationally simple formation of medicinally relevant C-C bonds while reacting in a complementary fashion to other innate C-H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C-H insertion and C-H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.

A novel hook-shaped enhancement on contrast-enhanced sagittal magnetic resonance image in acute Sheehan's syndrome: a case report.

We report characteristic magnetic resonance (MR) image findings in a case of Sheehan's syndrome. A 37-year-old woman experienced complications of retained placenta and massive bleeding (3600 g) during delivery of a full-term baby. A pituitary function test demonstrated panhypopituitarism. MR image of the pituitary gland on postpartum day 10 revealed swelling of the anterior lobe. A hook-shaped enhancement was demonstrated on a sagittal image. The pituitary stalk, majority of the marginal zone of the anterior lobe, the anterior lobe just in front of the posterior lobe, and posterior lobe were well enhanced. In contrast, the central portion and the superior margin, just in front of the stalk insertion of the anterior lobe, were not enhanced. Anatomically, blood supply to these unenhanced portions of the anterior lobe was via the hypophyseal long portal vein and trabecular artery, which are tributaries of the superior hypophyseal artery that originate far from the internal carotid artery. Based on clinical history and MR image findings, the patient was diagnosed with Sheehan's syndrome and treated with hydrocortisone and levothyroxine. Follow-up MR image revealed marked atrophy of the anterior lobe. The characteristic hook-shaped enhancement in Sheehan's syndrome well reflected the vulnerability to massive bleeding based on the complex pituitary vasculature, which has not been reported previously. MR image with contrast enhancement is useful in the diagnosis of the acute phase of Sheehan's syndrome and in evaluating infarction of the anterior lobe.

Innate C-H trifluoromethylation of heterocycles.

Direct methods for the trifluoromethylation of heteroaromatic systems are in extremely high demand in nearly every sector of chemical industry. Here we report the discovery of a general procedure using a benchtop stable trifluoromethyl radical source that functions broadly on a variety of electron deficient and rich heteroaromatic systems and demonstrates high functional group tolerance. This C-H trifluoromethylation protocol is operationally simple (avoids gaseous CF(3)I), scalable, proceeds at ambient temperature, can be used directly on unprotected molecules, and is demonstrated to proceed at the innately reactive positions of the substrate. The unique and orthogonal reactivity of the trifluoromethyl radical relative to aryl radicals has also been investigated on both a complex natural product and a pharmaceutical agent. Finally, preliminary data suggest that the regioselectivity of C-H trifluoromethylation can be fine-tuned simply by judicious solvent choice.

A Case of Long-Term Survival with Recurrent Liver Metastases from Gastric Cancer Treated with Nivolumab.

Introduction: Improvements in overall survival from advanced gastric cancer have recently been reported with nivolumab. However, few reports have described long-term survival after discontinuing treatment. Case Presentation: A 67-year-old man diagnosed with advanced gastric cancer and abdominal aortic aneurysm initially underwent distal gastrectomy with D2 dissection. Histological examination revealed tub2 and T2N1M0 stage IIA. One month later, endovascular aneurysm repair was performed. Six weeks after gastrectomy, adjuvant chemotherapy with S-1 was started. Six months later, liver metastases were identified and liver segments S1 and S7 were resected. S-1 and oxaliplatin were added postoperatively, but multiple liver metastases recurred. Paclitaxel and ramucirumab, irinotecan, and docetaxel were administered. Liver metastases showed a temporary reduction in size, then enlarged again. Nivolumab was therefore administered and the liver metastases showed a significant reduction in size. The interval between doses gradually increased due to persistent general fatigue. At 28 months after starting nivolumab therapy, bronchitis and adrenal insufficiency appeared, so treatment was discontinued. As of 3.5 years after cessation of nivolumab immunotherapy, tumor regression continued to be maintained. The patient remains alive as of 8 years after recurrence of liver metastases. Conclusion: We encountered a case in which the patient received nivolumab therapy for recurrent liver metastases from gastric cancer and survived long term after discontinuing treatment.

Evaluation of overexposure risk when there is a space between the subject and the couch in computed tomography: a phantom study.

The purpose of this study was to investigate the risk of overexposure associated with automatic tube current modulation (ATCM) and automatic couch height positioning compensation mechanism (AHC) in computed tomography (CT) systems, particularly in scenarios involving a gap between the subject and the couch. Results revealed that when AHC was enabled, CT dose index volume (CTDIvol) increased by approximately 10% at 2.5 cm, 20% at 5.0 cm, and 40% at 10.0 cm gaps compared to close contact conditions. While the AHC function ensures consistent exposure doses and image quality regardless of subject positioning relative to the CT gantry isocenter, the study highlights a potential risk of overexposure when a gap exists between the subject and the couch. These findings offer valuable insights for optimizing CT imaging protocols and underscore the importance of carefully considering subject positioning in clinical practice.

Estimating the differences between inter-operator contrast enhancement in cerebral CT angiography.

BACKGROUND: Computed tomography (CT) angiography (CTA) is a non-invasive imaging method used to detect arteries and examine various brain diseases. When CTA is performed for follow-up or postoperative evaluation, reproducibility of vessel delineation is required. A reproducible and stable contrast enhancement can be achieved by manipulating the factors affecting it. Previous studies have investigated several factors that alter the contrast enhancement of arteries. However, no reports establishing the effect of different operators on contrast enhancement exist. PURPOSE: To assess the differences between inter-operator arterial contrast enhancement in cerebral CTA using Bayesian statistical modeling. METHODS: Image data were obtained using a multistage sampling method from the cerebral CTA scans of patients who underwent the process between January 2015 and December 2018. Several Bayesian statistical models were developed, and the objective variable was the mean CT number of the bilateral internal carotid arteries after contrast enhancement. The explanatory variables were sex, age, fractional dose (FD), and the operator's information. The posterior distributions of the parameters were computed via Bayesian inference using the Markov chain Monte Carlo (MCMC) method, with the Hamiltonian Monte Carlo method employed as the algorithm. The posterior predictive distributions were computed using the posterior distributions of the parameters. Finally, the differences between inter-operator arterial contrast enhancement on the CT number in cerebral CTA were estimated. RESULTS: The posterior distributions showed that all parameters representing the difference between operators included zero at the 95% credible intervals (CIs). The maximum mean difference between inter-operator CT number in the posterior predictive distribution was only 12.59 Hounsfield units (HUs). CONCLUSIONS: The Bayesian statistical modeling results suggest that contrast enhancement of cerebral CTA examination between operator-to-operator differences in postcontrast CT number was small compared to those within-operator differences resulting from factors not considered in the model.

Cerebral tumor embolism from thyroid cancer treated by mechanical thrombectomy: illustrative case.

BACKGROUND: Development in mechanical thrombectomy is progressing dramatically. Tumor embolism has been rarely reported on the basis of pathological study of the retrieved thrombus. Herein, the authors report a case of cerebral tumor embolism from advanced thyroid cancer, which was successfully treated with mechanical thrombectomy. OBSERVATIONS: A 57-year-old man was diagnosed with thyroid cancer with multiple lung metastases and chemotherapy was planned. He experienced left hemiparesis and was bought to the emergency section of the authors' hospital. Magnetic resonance angiography revealed right internal carotid artery occlusion and endovascular treatment was performed. Using a combination of aspiration catheter and stent retriever, white jelly-like embolus was retrieved. The pathological study demonstrated thyroid cancer embolism. Pulmonary vein invasion following lung metastasis of thyroid cancer was most presumably the cause of the tumor embolism. LESSONS: Lung metastasis invading the pulmonary vein may be a cause of tumor embolism. Mechanical thrombectomy using a combination of stent retriever and aspiration catheter is effective in removing the tumor embolus and the pathological examination of the embolus is essential.

Quantitative evaluation of the reduction of distortion and metallic artifacts in magnetic resonance images using the multiacquisition variable­resonance image combination selective sequence.

Magnetic resonance imaging (MRI) is superior to computed tomography (CT) in determining changes in tissue structure, such as those observed following inflammation and infection. However, when metal implants or other metal objects are present, MRI exhibits more distortion and artifacts compared with CT, which hinders the accurate measurement of the implants. A limited number of reports have examined whether the novel MRI sequence, multiacquisition variable-resonance image combination selective (MAVRIC SL), can accurately measure metal implants without distortion. Therefore, the present study aimed to demonstrate whether MAVRIC SL could accurately measure metal implants without distortion and whether the area around the metal implants could be well delineated without artifacts. An agar phantom containing a titanium alloy lumbar implant was used for the present study and was imaged using a 3.0 T MRI machine. A total of three imaging sequences, namely MAVRIC SL, CUBE and magnetic image compilation (MAGiC), were applied and the results were compared. Distortion was evaluated by measuring the screw diameter and distance between the screws multiple times in the phase and frequency directions by two different investigators. The artifact region around the implant was examined using a quantitative method following standardization of the phantom signal values. It was revealed that MAVRIC SL was a superior sequence compared with CUBE and MAGiC, as there was significantly less distortion, a lack of bias between the two different investigators and significantly reduced artifact regions. These results suggested the possibility of utilizing MAVRIC SL for follow-up to observe metal implant insertions.

A new reagent for direct difluoromethylation.

Molecular scaffolds containing alkylfluorine substituents are desired in many areas of chemical research from materials to pharmaceuticals. Herein, we report the invention of a new reagent (Zn(SO(2)CF(2)H)(2), DFMS) for the innate difluoromethylation of organic substrates via a radical process. This mild, operationally simple, chemoselective, and scalable difluoromethylation method is compatible with a range of nitrogen-containing heteroarene substrates of varying complexity as well as select classes of conjugated π-systems and thiols. Regiochemical comparisons suggest that the CF(2)H radical generated from the new reagent possesses nucleophilic character.

Stereo- and regioselective direct multi-deuterium-labeling methods for sugars.

Deuterium-labeled sugars can be utilized as powerful tools for the architectural analyses of high-sugar-containing molecules represented by the nucleic acids and glycoproteins, and chiral building blocks for the syntheses of new drug candidates (heavy drugs) due to their potential characteristics, such as simplifying the (1)H NMR spectra and the stability of C-D bonds compared with C-H bonds. We have established a direct and efficient synthetic method of deuterated sugars from non-labeled sugars by using the heterogeneous Ru/C-catalyzed H-D exchange reaction in D(2)O under a hydrogen atmosphere with perfect chemo- and stereoselectivities. The direct H-D exchange reaction can selectively proceed on carbons adjacent to the free hydroxyl groups, and the deuterium labeling of various pyranosides (such as glucose and disaccharides), as well as furanosides, represented by ribose and deoxyribose was realized. Furthermore, the desired number of deuterium atoms can be freely incorporated into selected positions by the site-selective protection of the hydroxyl groups using acetal-type protective groups because the deuterium exchange reaction never proceeds on positions adjacent to the protected hydroxyl groups.

Practical C-H functionalization of quinones with boronic acids.

A direct functionalization of a variety of quinones with several boronic acids has been developed. This scalable reaction proceeds readily at room temperature in an open flask using inexpensive reagents: catalytic silver(I) nitrate in the presence of a persulfate co-oxidant. The scope with respect to quinones is broad, with a variety of alkyl- and arylboronic acids undergoing efficient cross-coupling. The mechanism is presumed to proceed through a nucleophilic radical addition to the quinone with in situ reoxidation of the resulting dihydroquinone. This method has been applied to complex substrates, including a steroid derivative and a farnesyl natural product.

Frameless Free-Hand Navigation-Guided Biopsy for Brain Tumors: A Simpler Method with an Endoscope Holder.

CONTEXT/AIMS: Given the limitations of current navigation-guided brain biopsy methods, we aimed to introduce a novel method and validate its safety and accuracy. SETTING AND DESIGN: This was a retrospective study of twenty consecutive patients who underwent brain biopsy at Shimane University Hospital, Japan. SUBJECTS AND METHODS: Clinical records of 13 and 7 patients who underwent brain biopsy with the novel frameless free-hand navigation-guided biopsy (FFNB) method or a framed computed tomography-guided stereotactic biopsy (CTGB) method, respectively, were retrospectively reviewed. We compared age, sex, tumor location, histological diagnosis, maximum size of the tumor (target), depth from target to cortical surface on the same slice of CT or magnetic resonance imaging, operative position, anesthesia method, setup time for biopsy, incision-to-closure time, trial times for puncture, success rate, and complications in the two groups. STATISTICAL ANALYSIS: Fisher's exact test and the Wilcoxon rank-sum test were performed. RESULTS: Clinical characteristics and lesion size did not differ significantly between the FFNB and CTGB groups. The depth of the target lesion was significantly greater in the CTGB group (P < 0.05). All FFNB and CTGB procedures reached and obtained the target tissue. The number of punctures and the average incision-to-closure time did not differ between the FFNB and CTGB groups. However, the preoperative setup time was significantly shorter using FFNB (P = 0.0003). No complications were observed in either group. CONCLUSIONS: FFNB was comparable with CTGB in terms of safety, accuracy, and operative duration. The preoperative setup time was shorter using FFNB. Therefore, FFNB is a feasible method for brain tumor biopsy.

Extraperitoneal colostomy in robotic surgery for rectal cancer using a tip-up fenestrated grasper.

INTRODUCTION: Although extraperitoneal colostomy could reduce the risk for parastomal hernia formation, it is often technically demanding to dissect the extraperitoneal route laparoscopically. Here, we demonstrate our original surgical technique for extraperitoneal tunneling using a robotic instrument. MATERIALS AND SURGICAL TECHNIQUE: After total mesorectal excision (TME) and before specimen retrieval, the edge of the outer leaf of the parietal peritoneum was elevated by the grasper in the left hand and the tip-up fenestrated grasper (Tip-Up) in the right hand. The extraperitoneal tissue was opened using the scissor forceps (right hand). Then, extraperitoneal tunneling (inner tunnel) was performed using a Tip-Up with a width of approximately 4 cm that could reach adjacent to the lateral border of the abdominal rectus muscle. A round incision was made at a preoperatively marked site on the skin. The anterior rectal sheath was cut in a cruciate fashion. The abdominal rectus muscle was split, and then the posterior rectus sheath was cut longitudinally not just below the stoma marking site but also at a slant on the lateral side. The peritoneum was dissected with care to avoid opening the peritoneum. The outer side of the tunnel was broken through to the inner tunnel using an easy blunt dissection with two fingers. Kelly forceps were introduced through the extraperitoneal tunnel along with the fingers, and the stump of the sigmoid colon was grasped and exteriorized through this tunnel. DISCUSSION: Robotic retroperitoneal tunneling using a Tip-Up is easy and useful for preventing parastomal hernia.

Aggressive Intraoperative Cisternal Clot Removal After Clipping Aneurismal Subarachnoid Hemorrhage in Elderly Patients.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) in the elderly often has a poor prognosis even after surgical treatment in the acute phase. Additionally, subarachnoid clots are the strongest predictors of cerebral vasospasm and tend to be thicker and heavier due to cerebral atrophy. We aimed to compare the conventional surgical treatment in such patients and identify the independent predictors of a favorable outcome after aggressive surgical clot removal. METHODS: We included 40 patients with aSAH aged 70 or older. Each patient underwent aneurysmal clipping. We used the modified Rankin Scale to assess the primary outcome of neurologic status at discharge. We performed univariate analysis using the following factors: sex, age, neurologic, and general medical condition, radiographic data, aneurysm location, treatment approach, and timing of the aneurysm surgery. We divided the patients into irrigation and nonirrigation groups. We focused mainly on subarachnoid clots and analyzed them semiquantitatively using computed tomography. RESULTS: Clot removal was significantly greater in the irrigation group (n = 21) than in the nonirrigation group (n = 19). The period of intrathecal drainage was significantly shorter in the irrigation group (P = 0.002). The rate of occurrence of new low-density areas on CT scans was higher in the nonirrigation group. Outcomes were better in the irrigation group (P = 0.010). CONCLUSIONS: In elderly patients with aSAH in the acute phase, aggressive surgical clot removal after clipping showed favorable outcomes by facilitating early out-of-bed mobilization.

Takotsubo cardiomyopathy following mechanical thrombectomy for acute ischemic stroke: illustrative case.

BACKGROUND: Excess neurological stress by hemorrhagic stoke induces cardiomyopathy, namely takotsubo cardiomyopathy. Here, the authors report a case of takotsubo myopathy following mechanical thrombectomy for acute large vessel occlusion. OBSERVATIONS: A 73-year-old man was emergently brought to the authors' hospital because of left hemiparesis and consciousness disturbance. An ischemic lesion of the right cerebral hemisphere and the right internal carotid artery occlusion was revealed. Emergently, endovascular treatment was performed, and occlusion of the artery was reanalyzed. However, he suffered from hypotension with electrocardiogram abnormality. Subsequently, coronary angiography was performed, but the arteries were patent. The authors made a diagnosis of takotsubo cardiomyopathy. LESSONS: Endovascular recanalization for large cerebral artery occlusion is so effective that it is becoming widely used. Even in the successful recanalization, we need to care for the takotsubo cardiomyopathy.

Comparison of three fistula risk scores after pancreatoduodenectomy: A single-institution retrospective study.

BACKGROUND: Postoperative pancreatic fistula (POPF) after pancreatoduodenectomy greatly influences patients' postoperative course. Several evaluation methods have been used to assess the risk of clinically relevant POPF (CR-POPF) after pancreatoduodenectomy namely, the original, alternative, and updated alternative fistula risk scores (o-FRS, a-FRS, and ua-FRS, respectively). METHODS: We enrolled 106/179 patients who underwent pancreatoduodenectomy in our institution between April 2013 and Mar 2018. CR-POPF was defined as grade B and C POPF according to the 2016 definitions of the International Study Group on Pancreatic Surgery. RESULTS: Pancreatic gland texture was the only significant risk factor for CR-POPF (p = 0.007). The CR-POPF incidence increased significantly according to the risk groups defined by both o-FRS (p = 0.004) and a-FRS (p = 0.004). The area under the curve for o-FRS, a-FRS, and ua-FRS was 0.693, 0.693, and 0.671, respectively. CONCLUSION: o-FRS, a-FRS, and ua-FRS were almost equally useful for risk evaluation for CR-POPF after pancreatoduodenectomy. Further studies, especially for preoperative objective evaluation of pancreatic gland texture, are needed for more useful and accurate risk evaluation.