Teduglutide-induced acute gastric mucosal necrosis in short bowel syndrome with hepatorenal failure: Case report.

INTRODUCTION: Short bowel syndrome (SBS) resulting from acute aortic dissection (AAD)-induced visceral malperfusions leads to chronic intestinal failure (CIF), necessitating patients to adopt home parenteral nutrition to prevent malabsorption. Teduglutide (TED), a glucagon-like peptide-2 analog, is a promising pharmacotherapy for intestinal rehabilitation that reduces parenteral support and improves the quality of life. Gastric mucosal necrosis, a rare gastrointestinal disorder, had never been observed as an adverse event relevant to this drug. We report a case of mucosal necrosis in the stomach after TED treatment for SBS-CIF with hepatorenal failure. PRESENTATION OF CASE: A 68-year-old Japanese man who underwent massive intestinal resection for AAD experienced malnutrition and diarrhea caused by SBS-CIF. The patient received TED to improve intestinal absorption and entero-hepatic circulation besides controlling infectious diseases. Endoscopy showed mucosal hyperplasia in the stomach and duodenum 1.5 months after TED administration. The patient consented to enteral nutrition via a nasogastric tube because of anorexia. The nutritional status gradually improved after initiating enteral feeding. However, the patient experienced hematemesis 13 days after enteral feeding, and endoscopy revealed acute gastric mucosal necrosis, followed by fatal septic shock. DISCUSSION: For patients with SBS, TED is expected to increase intestinal absorption through epithelial proliferation. When SBS is accompanied by multiple ischemic organ failure, TED therapeutic effects remain unclear as malnutrition-associated infectious diseases are refractory, and many underlying mechanisms can be involved. CONCLUSION: TED administration should be deliberately considered for patients with SBS-CIF and multiple organ failure experiencing uncontrolled systemic infection.

Measuring body temperature of freely moving mice under an optogenetics-induced long-term hypothermic state.

We present a protocol for inducing a hibernation-like state in free-moving mice using optogenetics. We have recently developed an optogenetic technique utilizing modified Opsin4, which is activated by weak blue light, resulting in prolonged neuronal excitation. We describe a protocol that includes detailed instructions for virus injection, implantation of optic fibers and temperature transmitters, photostimulation, and real-time recording of body temperature in mice. This method is valuable for investigating the mechanisms underlying torpor and thermoregulation in mice. For complete details on the use and execution of this protocol, please refer to Takahashi et al.1.

Harmonically mode-locked laser pulse accumulation in a self-resonating optical cavity.

Optical enhancement cavities enabling laser pulses to be coherently stacked in free space are used in several applications to enhance accessible optical power. In this study, we develop an optical cavity that accumulates harmonically mode-locked laser pulses with a self-resonating mechanism for X-ray sources based on laser-Compton scattering. In particular, a Fabry-Perot cavity composed of 99% reflectance mirrors maintained the optical resonance in a feedback-free fashion for more than half an hour and automatically resumed the accumulation even if the laser oscillation was suspended. In contrast to conventional optical enhancement cavity systems with a dedicated feedback controller, this characteristic is highly beneficial in practical applications, such as for laser-Compton scattering X-ray sources. Lastly, upscaling and adoption of the proposed system might improve the operability and equipment use of laser Compton-scattering X-ray sources.

Optogenetic induction of hibernation-like state with modified human Opsin4 in mice.

We recently determined that the excitatory manipulation of Qrfp-expressing neurons in the preoptic area of the hypothalamus (quiescence-inducing neurons [Q neurons]) induced a hibernation-like hypothermic/hypometabolic state (QIH) in mice. To control the QIH with a higher time resolution, we develop an optogenetic method using modified human opsin4 (OPN4; also known as melanopsin), a G protein-coupled-receptor-type blue-light photoreceptor. C-terminally truncated OPN4 (OPN4dC) stably and reproducibly induces QIH for at least 24 h by illumination with low-power light (3 µW, 473 nm laser) with high temporal resolution. The high sensitivity of OPN4dC allows us to transcranially stimulate Q neurons with blue-light-emitting diodes and non-invasively induce the QIH. OPN4dC-mediated QIH recapitulates the kinetics of the physiological changes observed in natural hibernation, revealing that Q neurons concurrently contribute to thermoregulation and cardiovascular function. This optogenetic method may facilitate identification of the neural mechanisms underlying long-term dormancy states such as sleep, daily torpor, and hibernation.

Combined Environment Simulator for Low-Dose-Rate Radiation and Partial Gravity of Moon and Mars.

Deep space exploration by humans has become more realistic, with planned returns to the Moon, travel to Mars, and beyond. Space radiation with a low dose rate would be a constant risk for space travelers. The combined effects of space radiation and partial gravity such as on the Moon and Mars are unknown. The difficulty for such research is that there are no good simulating systems on the ground to investigate these combined effects. To address this knowledge gap, we developed the Simulator of the environments on the Moon and Mars with Neutron irradiation and Gravity change (SwiNG) for in vitro experiments using disposable closed cell culture chambers. The device simulates partial gravity using a centrifuge in a three-dimensional clinostat. Six samples are exposed at once to neutrons at a low dose rate (1 mGy/day) using Californium-252 in the center of the centrifuge. The system is compact including two SwiNG devices in the incubator, one with and one without radiation source, with a cooling function. This simulator is highly convenient for ground-based biological experiments because of limited access to spaceflight experiments. SwiNG can contribute significantly to research on the combined effects of space radiation and partial gravity.

Aggressive variant of splenic marginal zone lymphoma characterized using a cancer panel test and treated with rituximab-containing chemotherapy: A case report.

RATIONALE: Aggressive variant of splenic marginal zone lymphoma (AV-SMZL) is a very rare disease that is often associated with TP53 mutations and has a poor prognosis. On the other hand, recent advances in genome sequencing techniques enable us to understand the molecular characteristics of rare cancers such as AV-SMZL. Here we present a case of AV-SMZL analyzed using a genetic test. PATIENT CONCERNS: A 66-year-old woman was admitted with splenomegaly and lymphocytosis. Computed tomography revealed marked splenomegaly without lymphadenopathy in any other areas. The serum soluble interleukin-2 receptor (sIL-2R) level was significantly elevated. Peripheral and bone marrow blood tests showed an increase in abnormal lymphocytes. DIAGNOSIS: A splenectomy revealed an SMZL pattern with increased numbers of large cells and mitotic cells and a high Ki-67 positivity rate, which led to a diagnosis of AV-SMZL. Although TP53 mutation was not detected, mutations in NOTCH2, NCOA4, PTEN, EPHA3, and KMT2D were identified. Among these, the mutations in NCOA4, PTEN, and EPHA3 were novel pathogenic mutations in SMZL, which suggests they may be related to the aggressiveness and persistence of the disease. INTERVENTIONS: The patient was administered a rituximab-containing regimen and rituximab-maintenance therapy. OUTCOMES: The patient continues to exhibit a complete response. LESSONS: This is a case of AV-SMZL in which a cancer panel test successfully detected genetic alterations that are potentially associated with its pathogenesis. These findings suggest that genetic analysis is useful for making diagnoses as well as for determining treatment strategies in AV-SMZL.

A discrete neuronal circuit induces a hibernation-like state in rodents.

Hibernating mammals actively lower their body temperature to reduce energy expenditure when facing food scarcity1. This ability to induce a hypometabolic state has evoked great interest owing to its potential medical benefits2,3. Here we show that a hypothalamic neuronal circuit in rodents induces a long-lasting hypothermic and hypometabolic state similar to hibernation. In this state, although body temperature and levels of oxygen consumption are kept very low, the ability to regulate metabolism still remains functional, as in hibernation4. There was no obvious damage to tissues and organs or abnormalities in behaviour after recovery from this state. Our findings could enable the development of a method to induce a hibernation-like state, which would have potential applications in non-hibernating mammalian species including humans.

Estimation of production and sedimentation of cyanobacterial toxins (microcystin) based on nutrient budgets in the reservoir of Isahaya Bay, Japan.

The increasing eutrophication of freshwater and brackish habitats globally has led to a corresponding increase in the occurrence of harmful cyanobacterial blooms. Cyanobacteria can produce highly toxic substances such as microcystins (MCs) that affect the health of livestock, wildlife, and humans. The present study broaden the understanding of cyanobacteria ecology and MC dynamics in the field, focusing on the estimation of the production and sedimentation rates of MCs in a natural habitat. The nutrient concentrations of the reservoir water and sediment pore water were monitored at 3-h intervals for 24 h during the summer cyanobacterial bloom. The DIN uptake rate of Microcystis in the Isahaya reservoir was estimated and the large-scale blooms in the reservoir were largely controlled by the interactions between rainfall and nutrient levels in the warm season. By using calculations based on the nitrogen budgets and tracking changes of the MC concentrations in the water column, the total MC production and sedimentation rates were estimated to be 52.2 kg MCs d-1 and 21.5 kg MCs d-1, respectively. Although MCs could be degraded in the environment, the MC sedimentation still comprised 41% of the in-water production.

Efficiency of fluorescent cholangiography during laparoscopic cholecystectomy for subvesical bile ducts: A case report.

INTRODUCTION: The subvesical bile ducts are located in the peri-hepatic connective tissue of the gallbladder fossa. Injury of the subvesical bile ducts provokes the severe complication of bile leak. Until now, fluorescent cholangiography has been employed during hepatobiliary surgery. Herein, we report the detection of subvesical bile ducts by fluorescent cholangiography during laparoscopic cholecystectomy. PRESENTATION OF CASE: A 63-year-old female was admitted to our department for surgery for symptomatic cholelithiasis. The subvesical bile ducts were not observed on drip-infusion cholangiography with computed tomography. Immediately following induction of anesthesia, 2.5 mg of indocyanine green was intravenously injected. Fluorescent cholangiography demonstrated two thin aberrant bile ducts during dissection of Calot's triangle. We considered them to be subvesical bile ducts. We ligated them with clips, divided them, and then performed laparoscopic cholecystectomy using a standard procedure. The patient had a good post-operative recovery without bile leakage. Postoperative laboratory test results were all within normal limits. Computed tomography revealed no dilatation of the intrahepatic bile duct after laparoscopic cholecystectomy. The patient was discharged on postoperative day 4. DISCUSSION: Injury to the subvesical bile ducts is one of the most common causes of bile leakage associated with cholecystectomy. Fluorescent cholangiography enabled real-time identification of the thin subvesical bile ducts, which were undetectable by drip-infusion cholangiography with computed tomography. CONCLUSION: Fluorescent cholangiography during laparoscopic cholecystectomy may be useful for preventing postoperative bile leakage.

Impact of decreased insulin resistance by ezetimibe on postprandial lipid profiles and endothelial functions in obese, non-diabetic-metabolic syndrome patients with coronary artery disease.

The association between insulin resistance and lipid dysmetabolism after consuming a meal is unclear. We aimed at assessing the effects of ezetimibe on postprandial hyperlipidemia and hyperinsulinemia and to find out whether the medication improves endothelial function in obese metabolic syndrome (MetS) patients with coronary artery disease (CAD). We obtained oral fat loading test results (4 and 6 h after load) and brachial flow-mediated vasodilation (FMD) measurements before and 24 weeks after ezetimibe treatment initiation from 27 MetS patients with CAD and from 68 control patients with CAD alone. Serum triglyceride (TG) and insulin levels (2 h after the loading dose) were significantly higher in MetS patients than in control patients. The incremental areas under the curve (iAUCs) for these levels decreased significantly after ezetimibe treatment in MetS patients but not in control patients. Treatment with ezetimibe resulted in significant FMD changes in MetS patients (from 3.4 to 4.9%, P = 0.002), but not in control patients (from 5.1 to 5.4%, P = 0.216). When MetS patients were divided into two groups based on the median insulin iAUC reduction rate (higher group ≥ 34%, n = 14; lower group < 34%, n = 13), those in the higher group showed a significantly higher rate of change in the iAUCs of TG and FMD than those in the lower group (TG, 31.0% vs. 10.8%; P = 0.033; FMD, 39.2% vs. 9.8%; P = 0.037). These results suggest that ezetimibe may reverse insulin resistance, reducing lipid dysmetabolism after a meal and endothelial dysfunction in MetS patients with CAD.

Severe adverse events by tyrosine kinase inhibitors decrease survival rates in patients with newly diagnosed chronic-phase chronic myeloid leukemia.

OBJECTIVE: This multicenter cooperative study aimed to analyze the adverse events (AEs) associated with tyrosine kinase inhibitors (TKIs) used as initial treatment for chronic-phase chronic myeloid leukemia (CML-CP) and their impact on outcome. METHODS: We retrospectively evaluated 450 patients with CML-CP who received TKIs between 2004 and 2014. RESULTS: The 5-year overall survival (OS) and event-free survival (EFS) rates were 95.1% and 89.0%, respectively. Patients with comorbidities (46.4%) and aged ≥60 years (50.4%) at diagnosis had significantly inferior OS to those without comorbidities and aged <60. Patients achieved higher rates of major molecular response (MMR) at 6 and 12 months after initial treatment with dasatinib or nilotinib compared to imatinib, but final MMR rates were almost the same. Sixty-six percent of patients required treatment modifications from first-line TKI therapy; the main reasons were AEs (48.4%) and failure (18%). Grade III-IV AEs in first-line TKI therapy were significantly correlated to inferior OS/EFS compared to grade 0-II AEs. CONCLUSION: Although long-term outcomes were similar in CML-CP patients treated with each TKI regardless of first-line TKI selection, severe AEs in first-line TKI therapy decreased their survival rates. Early change in TKIs is recommended, when faced with severe AEs of specific TKIs.

Percutaneous transradial artery approach for femoro- popliteal artery intervention in the current era in Japan.

The percutaneous transradial artery approach for coronary angiography and intervention has been recognized as a safe and effective method, however, it is limited for endovascular therapy (EVT) for femoro-popliteal artery because of lack of devices with longer shaft. Herein, we report two EVT cases for superficial femoral artery disease treated with a long shaft balloon through the radial artery. Although femoro-popliteal artery intervention with this approach has several limits for available devices and technical issues, it is effective for particular patients who are impossible in EVT with femoral artery approach.

Generation and Characterization of a Novel Small Biologic Alternative to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Antibodies, DS-9001a, Albumin Binding Domain-Fused Anticalin Protein.

Since it was recently reported that an antibody for proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces the risk of cardiovascular events in a clinical context, PCSK9 inhibition is thought to be an attractive therapy for dyslipidemia. In the present study, we created a novel small biologic alternative to PCSK9 antibodies called DS-9001a, comprising an albumin binding domain fused to an artificial lipocalin mutein (ABD-fused Anticalin protein), which can be produced by a microbial production system. DS-9001a strongly interfered with PCSK9 binding to low-density-lipoprotein receptor (LDL-R) and PCSK9-mediated degradation of LDL-R. In cynomolgus monkeys, single DS-9001a administration significantly reduced the serum LDL-C level up to 21 days (62.4% reduction at the maximum). Moreover, DS-9001a reduced plasma non-high-density-lipoprotein cholesterol and oxidized LDL levels, and their further reductions were observed when atorvastatin and DS-9001a were administered in combination in human cholesteryl ester transfer protein/ApoB double transgenic mice. Additionally, their reductions on the combination of atorvastatin and DS-9001a were more pronounced than those on the combination of atorvastatin and anacetrapib. Besides its favorable pharmacologic profile, DS-9001a has a lower molecular weight (about 22 kDa), yielding a high stoichiometric drug concentration that might result in a smaller administration volume than that in existing antibody therapy. Since bacterial production systems are viewed as more suited to mass production at low cost, DS-9001a may provide a new therapeutic option to treat patients with dyslipidemia. In addition, considering the growing demand for antibody-like drugs, ABD-fused Anticalin proteins could represent a promising new class of small biologic molecules.

Orexin modulates behavioral fear expression through the locus coeruleus.

Emotionally salient information activates orexin neurons in the lateral hypothalamus, leading to increase in sympathetic outflow and vigilance level. How this circuit alters animals' behavior remains unknown. Here we report that noradrenergic neurons in the locus coeruleus (NALC neurons) projecting to the lateral amygdala (LA) receive synaptic input from orexin neurons. Pharmacogenetic/optogenetic silencing of this circuit as well as acute blockade of the orexin receptor-1 (OX1R) decreases conditioned fear responses. In contrast, optogenetic stimulation of this circuit potentiates freezing behavior against a similar but distinct context or cue. Increase of orexinergic tone by fasting also potentiates freezing behavior and LA activity, which are blocked by pharmacological blockade of OX1R in the LC. These findings demonstrate the circuit involving orexin, NALC and LA neurons mediates fear-related behavior and suggests inappropriate excitation of this pathway may cause fear generalization sometimes seen in psychiatric disorders, such as PTSD.

Near Tetraploidy Acute Myeloid Leukemia in Long-term Remission with Persistent Clonal Hematopoiesis with del(20)(q12q13).

Patients with near tetraploidy/tetraploidy (NT/T)-acute myeloid leukemia (AML) are rare and generally show poor survival. A 62-year-old man was referred to our hospital with pancytopenia. A bone marrow examination revealed the proliferation of extremely large blasts, and led to the diagnosis of AML M0. A cytogenetic analysis showed an NT-karyotype of 91, XXYY, -5, add(18)(p21),del(20)(q12q13) ×2. Complete remission was achieved with single remission induction chemotherapy. Although consolidation chemotherapies were not available because of his critical condition, he remained in remission and survived for more than 40 months without cytopenia. However, repeated bone marrow examinations showed persistent clonal hematopoiesis with del(20)(q12q13) without apparent myelodysplasia.

[A Case of Biopsy Confirmed Unresectable Retroperitoneal Seminoma Successfully Treated with Chemotherapy].

We herein report a case of a retroperitoneal tumor of unknown origin that was diagnosed as a seminoma after tumor biopsy and was successfully treated with chemotherapy containing bleomycin, etoposide, and cisplatin(BEP). A 47-year old man visited our hospital with left abdominal pain. An endoscopic examination revealed an ulcer lesion on the third part of the duodenum. Abdominal CT scan revealed a retroperitoneal tumor invading the abdominal aorta with the tumor thrombus in the inferior vena cava(IVC). An endoscopic biopsy could not identify the tumor's origin because of the negative staining of various surface markers on immunohistochemistry. Surgical biopsy of the unresectable retroperitoneal tumor that was finally diagnosed as a seminoma was performed. The patient was treated with BEP according to the International Germ Cell Consensus Classification(IGCCC)for risks, and orchiectomy was performed. He has been alive for 7 months with progressive shrinkage of the retroperitoneal tumor, in which 18F-fluorodeoxyglucose(FDG)positron emission tomography(PET)has shown a dramatic reduction of the maximum standardized uptake value(SUV)during chemotherapy.

Sudden failure of ventricular pacing and recovery in a patient with cardiac sarcoidosis.

A 76-year-old woman with sarcoidosis who had an implantable pacemaker for complete atrioventricular block was admitted with syncope. Electrocardiogram revealed ventricular pacing failure, and a marked rise in the ventricular pacing threshold. 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) indicated increased uptake of FDG in the ventricular septum. Three days after steroid therapy, the ventricular pacing threshold reverted to normal, and FDG-PET showed decreased FDG uptake in the ventricular septum. In this case report, we demonstrate that a sudden deterioration in the ventricular pacing threshold due to worsening cardiac sarcoidosis can be reversed with early steroid therapy.