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Background Naldemedine, a novel peripherally-acting mu-opioid receptor antagonist, has improved opioid-induced constipation in randomized controlled trials. The most frequent adverse event of naldemedine is diarrhea, which can cause abdominal pain and often leads to treatment discontinuation. We aimed to identify risk factors and appropriate management strategies for key adverse events including diarrhea associated with naldemedine, since those have not been extensively studied. Methods We conducted a multi-center retrospective cohort study. Eligible patients had cancer, had undergone palliative care at participating centers, had been prescribed regular opioids, and had taken at least one dose of naldemedine between June 2017 and March 2018. The primary endpoint was the incidence of diarrhea according to baseline characteristics. Secondary endpoints included the duration of naldemedine administration, daily defecation counts before and after starting naldemedine, duration and severity of diarrhea as an adverse event of naldemedine, other adverse events, and the incidence of constipation within 7 days after recovery from diarrhea. We defined patients who started naldemedine within three days of starting a regularly prescribed opioid as the early group, and the remainder as the late group. Results Among 103 patients who received naldemedine, 98 fulfilled the eligibility criteria. The median age was 68 years and 48% of the patients were female. Median performance status was 3, and the median oral intake was 50%. The median duration of naldemedine administration and overall survival were 25 and 64 days, respectively. The incidence of diarrhea in the early group (n = 26) was significantly lower than in the late group (n = 72) (3.9% vs. 22.2%, p = 0.02). Daily defecation counts increased after late (median 0.43 to 0.88, p p = 0.34). Constipation after the diarrhea was resolved was common (53%), especially among patients who stopped naldemedine (78%). The diarrhea was improved within three days in 92% of patients who stopped other laxatives. Conclusions The early administration of naldemedine is beneficial because it reduces adverse events including diarrhea. Diarrhea caused by naldemedine can be effectively managed by stopping other laxatives while continuing naldemedine.

Background Hyponatremia and syndrome of inappropriate antidiuretic hormone (SIADH) is a potentially fatal adverse effect of antidepressants (ADs) and antipsychotics (APs), although its frequency and onset time have not been well documented. Objective To analyze the frequency and onset time of AD- or AP-induced hyponatremia/SIADH. Methods We used plural data-mining techniques to search the US Food and Drug Administration Adverse Event Reporting System (FAERS) database for reports on hyponatremia/SIADH induced by psychotropic drugs from January 2004 to June 2020. For each item, we assessed the reporting odds ratio, 95% CI, median onset time, and Weibull distribution parameters. Results We identified 36 422 reports related to hyponatremia/SIADH. Signals were detected for all psychotropic drugs that we analyzed, except for clozapine. The median onset time of total AD-induced hyponatremia/SIADH was shorter than that of AP. For all ADs and APs except clozapine, hazards were considered to be the early failure type. In contrast, the hazard of clozapine was considered to be the random failure type. The limitations of this study included several reporting biases and the presence of confounding variables, particularly age. Conclusion and Relevance Most ADs and APs were found to be associated with a risk for hyponatremia/SIADH. In addition, sufficient attention should be paid to signs of hyponatremia/SIADH in the early phase when most ADs and APs are administered. These data are potentially useful for determining AD- or AP-induced hyponatremia/SIADH in the early stage and for preventing its further aggravation into a serious condition.

To clarify the volume of water required to paste pediatric powders, we herein established a standard for the powder paste state by measuring yield values when water was added to powders. The powders used in the present study were selected from 8 types including original and generic drugs. Tipepidine hibenzate is prescribed in the pediatric field in combination with ambroxol hydrochloride and l-carbocysteine. The volumes of water needed to achieve the paste state of ambroxol hydrochloride between the original and generic drugs were similar. However, the volumes of water needed for l-carbocysteine markedly differed between the original and generic drugs due to differences in their additives. The spreadability of the mixture when water was added to the powders was evaluated using a spread meter. Among the powders tested in the present study, the yield value to achieve a paste state with the addition of water was approximately 1000 dyne/cm2. The optimum volume of water estimated from this yield value using the linear proportional relationship for the amount of powder may be applied to the mixture of each pediatric power for dosage/body weight.

Key Clinical Message Myeloid/natural killer cell precursor acute leukemia (MNKPL) is a rare leukemia subtype characterized by a high incidence of extramedullary infiltration. No appropriate treatment strategy has so far been developed. Acute myelogenous leukemia‐type chemotherapy combined with L‐Asparaginase is an effective treatment for MNKPL. Hematopoietic cell transplantation is a second option in refractory cases.

SummaryThe aim of the present study was to determine the effects of increased dietary intake and high fat diet (HFD) in mice on artificial oocyte activation by using puromycin or roscovitine. Six-week-old mice were fed as either a control diet group, an increased dietary intake group or an HFD group for 4 weeks. Oocytes were obtained following superovulation and were divided into three treatment groups (no activation treatment, calcium ionophore and puromycin treatment, and calcium ionophore and roscovitine treatment) and were incubated for 4 h. Retrieved oocytes and numbers of oocytes activated as assessed by morphological changes were compared among the three treatment groups. The proportion of degenerated oocytes in HFD mice was significantly higher than that in control diet mice. The rates of activation in oocytes treated with roscovitine were 90.3% in control diet mice, 89.8% in increased dietary intake mice and 67.9% in HFD mice. The rate of activation in oocytes treated with roscovitine in HFD mice was significantly lower than the rates in control diet mice and increased dietary intake mice. The rates of activation in oocytes treated with puromycin were 90.6% in control diet mice, 94.0% in increased dietary intake mice and 71.4% in HFD mice, and the rate of activation in oocytes treated with puromycin in HFD mice was significantly lower than the rates in control diet mice and increased dietary intake mice. HFD-induced obesity deteriorated induction of oocyte activation by roscovitine or puromycin in mice.

Incorporation of the heme into globin induces a prominent circular dichroism (CD) band in the Soret region. The appearance of heme optical activity is widely believed to arise from the interaction between the heme and aromatic residues of the globin. However, hemoglobin (Hb) containing the reversed heme exhibits a CD spectrum obviously different from that of native Hb, indicating that the interactions of heme side chains with globin contribute to the appearance of heme optical activity. We examined this possibility by comparing CD spectra of native myoglobin (Mb) and those of Mb reconstituted with synthetic hemes lacking vinyl and/or propionate. Replacement of 2,4-vinyl groups with methyl induced moderate changes. In contrast, replacement of 6,7-propionate groups with carboxylate resulted in complete disappearance of the positive Soret CD band. To get theoretical basis for the contributions of 6,7-side chains on the band, we investigated the CD spectra at a time-dependent density functional theory level. In the antiparallel conformation of the 6,7-side chains, the rotational strengths were calculated to be positive, on the other hand in the parallel conformation to be negative. We also found that the weak Soret CD band in 2,4-dimethyl-6,7-dicarboxyheme can be explained by canceling between different carboxyl conformers.

Helical [5]thiaheterohelicene 5HM, which rapidly interconverts between P and M enantiomers in solution, was connected to helical l -phenylalanine oligomers with an ester linkage to give peptidehelicenes (5Fn, where n: number of bonded phenylalanines). The characteristics of 5F4 and 5F5 with two types of helixes in a molecule were investigated, particularly in comparison with those of 5F1–5F3 with an incomplete coil of a peptide moiety. l -Phenylalanine peptide chains induced a shift in the equilibrium between the P and M helixes of 5HM toward the P side for all the 5Fns examined. The enantiomeric excess (ee) of the P form increased with a decrease in temperature, together with an elongation of the peptide chains. 5F4 and 5F5 in hot solutions of some solvents formed a gel at room temperature, whereas 5F1–5F3 showed no such behavior. In this gel, the stable helical form of the 5HM moiety in 5F4 and 5F5 was observed to be the M form in contrast to that in their solutions.

A variety of protic 2-(tertiary phosphino)-1-amines (R2PCH2CHR′NHR′′, P−NH) have been prepared from 2-oxazolidinones and secondary phosphines using a newly developed acid-promoted decarboxylative C−P bond formation reaction. Treatment of the resulting chiral P−NH compounds with Cp*RuCl(isoprene) in CH2Cl2 smoothly furnished chiral Cp*RuCl(P−NH) complexes with a typical three-legged piano-stool structure, which prove to be excellent catalyst precursors for asymmetric reactions, including the isomerization of allylic alcohols and hydrogenation of imides.

To our knowledge the influence of sex hormones on urinary stone formation remains undetermined. We investigated the effect of castration on urinary lithogenic factors and renal osteopontin expression in rats previously treated with ethylene glycol.Sprague-Dawley rats were divided normal males, castrated males, males with 2 weeks of 0.75% ethylene glycol treatment, castrated males with 2 weeks of 0.75% ethylene glycol treatment, normal females, castrated females, females with 2 weeks of 0.75% ethylene glycol treatment and castrated females with 2 weeks of 0.75% ethylene glycol treatment. We analyzed 24-hour urine samples for urinary constituents, such as calcium, oxalate, citrate, uric acid, phosphate, magnesium, sodium, potassium and creatinine. The kidneys were examined for osteopontin expression by Northern blot analysis and for crystal deposition by histological examination.In intact male rats calcium and citrate excretion decreased and oxalate excretion increased significantly after ethylene glycol treatment. Castrated male rats with ethylene glycol had greater calcium and less oxalate excretion than male intact rats with ethylene glycol. In intact female rats uric acid excretion decreased and only calcium excretion increased significantly after ethylene glycol treatment. Castrated female rats with ethylene glycol excreted significantly more oxalate and less calcium than intact female rats with ethylene glycol. Renal osteopontin expression was the same in male intact and castrated rats, and in female intact and castrated rats. In males with ethylene glycol expression was stronger in castrated than in intact rats. In females with ethylene glycol expression was weaker in castrated than in intact rats. No crystal deposits were found in the kidneys in any group.Testosterone appears to promote stone formation by suppressing osteopontin expression in the kidneys and increasing urinary oxalate excretion. Estrogen appears to inhibit stone formation by increasing osteopontin expression in the kidneys and decreasing urinary oxalate excretion.

Whether specific metabolic abnormalities are related to nephrolithiasis in patients with medullary sponge kidney (MSK) remains a debated issue. The purpose of this study is to determine metabolic disorders in patients with MSK and nephrolithiasis compared with idiopathic calcium-stone[ndash ]forming patients. One hundred eighty-four patients with recurrent calcium-stone formations were investigated with regard to metabolic abnormalities. Of these, 22 patients (11.9[percnt]; 13 men, 9 women) showed MSK by radiological examination. MSK was defined as a kidney that presented at least three linear or round papillary opacities in the affected papilla on urography. Multiple stones (more than five) existed in both kidneys in all patients with MSK. The remaining 162 patients (109 men, 53 women) were idiopathic calcium-stone formers. Frequencies of low urine volume (urine [lt ] 1,500 mL[sol ]24 h) and hyperoxaluria (oxalate [gt ] 40 mg[sol ]24 h) were similar between the groups. Hypercalciuria (men, calcium [gt ] 300 mg[sol ]24 h; women, calcium of 250 mg[sol ]24 h) was found less frequently in the MSK group. The frequency of hypocitraturia (citrate [lt ] 300 mg[sol ]24 h) was significantly greater in the MSK group than the idiopathic group (77.3[percnt] versus 33.9[percnt], respectively). Mean 24-hour urinary excretions of calcium, citrate, uric acid, and magnesium were significantly less in the MSK group. No differences were found in serum calcium, phosphate, and parathyroid hormone levels between the groups. Low urinary excretions of citrate and magnesium are the most typical metabolic disorders that distinguish MSK stone patients from idiopathic calcium-stone[ndash ]forming patients. In addition to such anatomic abnormalities as ectatic collecting ducts, low levels of urinary inhibitors of stones seem to contribute to the pathogenesis of nephrolithiasis in patients with MSK.

[Background] Mixed lineage leukemia (MLL also called KMT2A) rearrangement-positive leukemia is one of the most aggressive types of leukemia. It is diagnosed predominantly in infants and typically shows a multi-lineage phenotype. Since current chemotherapy fails in more than 50% of infantile acute lymphoblastic leukemia (ALL) with MLL-rearrangement, a better understanding of biological features of the disease is important in order to develop more specific and successful treatment strategies. Despite the evident biological and clinical significance of MLL-rearrangement, it has also been shown in vitro and in vivo that MLL-rearrangement is not sufficient to induce full leukemic transformation, indicating additional hits are required for complete leukemogenesis. Recently, sequencing-based genome-wide studies have suggested collaborative involvement of RAS-PI3K pathway in infant leukemogenesis through identification of recurrent mutations affecting RAS-PI3K pathway genes, in infant ALL with or without MLL-rearrangement. However, genetic basis of infant ALL with MLL-rearrangement are not fully elucidated. [Materials and Methods] Here, we performed whole exome sequencing in leukemia samples with matched peripheral blood T lymphocyte from 46 cases of infant ALL including 3 cases with germline MLL. Our cohort included samples from the Infant Leukemia Sub-committee, Japan Children's Cancer Group. For mapping and mutation calling, we used publicly available "Genomon Pipeline". [Results] In total, 198 somatic non-silent mutations (4.3 mutations per case) were identified, including 125 missense, 4 nonsense, 8 splice site mutations, 49 frameshift indels, and 12 in-frame indels. Thirteen genes were recurrently affected, among which RAS-PI3K pathway mutations were the most frequent: KRAS (10/46 cases, 21.7%), NRAS (4/46 cases, 8.7%) and PTPN11 (3/46 cases, 6.5%). In addition, novel recurrent mutations were detected in HSP90AB1 (5/46 cases, 10.9%), MAPRE3 (2/46 cases, 4.3%) and SRCAP (2/46 cases, 4.3%), as well as known candidate driver mutations in FLT3 (7/46 cases, 15.2%), TP53 (3/46 cases, 6.5%), CHD4 (2/46 cases, 4.3%) and PAX5 (2/46 cases, 4.3%). HSP90AB1 is a member of Heat shock protein90 (Hsp90) family that encodes a group of molecular chaperones involved in stabilization and activation of multiple oncogenic proteins and pathways. Overexpression of Hsp90 is observed in ALL, chronic myeloid/lymphocytic leukemia and several non-hematological malignancies. Another recurrently mutated gene, SRCAP, encodes the core component of chromatin-remodeling Snf2-related CREBBP activator protein complex. Recurrent mutations in this gene have recently been reported in FLT3-ITD positive acute myeloid leukemia with significantly high co-occurrence of MLL3 mutations. Overall, RAS-PI3K pathway mutations were detected in 19/46 cases of infant ALL (41.3%). In our cohort, none of 3 germline MLL cases contained RAS-PI3K pathway mutations; one case had a PAX5 mutation, another had a SRCAP mutation, and the other had no candidate driver mutations. In the germline MLL case without candidate drivers, G-banding had identified a structural abnormality, t(5;15)(p15;q11.2), that is rare but reported to be predominant in infant ALL rather than other hematological/non-hematological malignancies. [Conclusion] Our results demonstrated that aberrations of cell proliferation signaling, transcription factors, as well as cell cycle/epigenetic regulators are co-operative oncogenic events in MLL-rearrangement cases. The mutation spectrum is similar to myeloid malignancies rather than lymphoid cancers. Intriguingly, we identified novel recurrent mutations in the oncogenic proteins, such as HSP90AB1, MAPRE3, and SRCAP,suggesting that these are potentially targetable by small-molecule therapy. In addition, we also illustrated the genetic differences between MLL-rearrangement and germline MLL. Thus, our mutational landscape provides a novel insight into the molecular mechanisms of infant ALL and may contribute to improving the clinical outcome of infant patients suffering from the intractable ALL. Disclosures Ogawa: Kan research institute: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding.

Little is known regarding the metabolic features associated with aging and gender in urolithiais patients. We compared the metabolic characteristics among 3 generations (young, middle-aged and old) with recurrent calcium-containing urinary stones.One hundred and eighty-one patients with recurrent calcium-containing stones, including 71 patients aged/=45 years (group 1), 71 patients aged 46-60 years (group 2) and 39 patients aged/=61 years (group 3), were investigated by metabolic evaluation. The frequencies of metabolic abnormalities, the value of each urinary constituent and the supersaturation index (AP(CaOx) index) were compared among subgroups of the 3 generations, containing both males and females.The number of metabolic abnormalities was the greatest in group 1, followed by group 2 and group 3. Hyperoxaluria was the most common abnormality in each group. Group 1 females showed a lower frequency of hypocitraturia than group 3 females. This was the only characteristic that showed a significant difference between the groups. Urinary calcium excretion was significantly greater in group 1 than in group 3. Urinary citrate excretion and the AP(CaOx) index were significantly higher in group 1 than in group 3 in females. Male patients had a significantly higher number of metabolic abnormalities than female patients, especially in group 1.Multiple metabolic abnormalities, particularly a high calcium excretion appear to be crucial factors in the development and recurrence of urolithiasis in young patients. Low urinary citrate excretion could play an important role in the occurrence of urolithiasis in elderly females.

Background Since a report on the first successful pregnancy of a woman on long-term haemodialysis in Japan in 1977, there has been a growing number of case reports on successful pregnancy in patients on dialysis. We undertook a nationwide survey on pregnancy in women on renal replacement therapy in 1996. Methods A preliminary questionaire was sent to 2504 dialysis units and 143 renal transplant units in Japan. For each reported pregnancy, a more detailed questionaire was sent to collect nephrological, obstetric and neonatal information. Results There were 172 pregnancies (0.44%) reported in 38889 women on dialysis, with 90 successful pregnancies (0.23%), and 194 pregnancies reported in 852 female renal transplant recipients. Detailed pregnancy information was collected from 74 women on dialysis and 194 renal transplant recipients. Of the 74 pregnancies in the women on dialysis, 36 (48.6%) resulted in surviving infants, nine (12.2%) in neonatal death, nine (12.2%) spontaneous abortions and 14 (18.9% elective abortions were reported. The outcome of six pregnancies (8.1%) was unknown. Of 194 pregnancies in renal transplant recipients, 159 (82.0%) resulted in surviving infants, two (1.4%) in neonatal death and 28 (14.4%) in spontaneous or elective abortion. In five cases the pregnancy outcome was not reported. No congenital anomalies were reported, except two infants with mental retardation and one with epilepsy. Conclusion The current survey revealed that the rate of successful pregnancy in women on dialysis has improved. More than half of the pregnancies resulted in infant survival. But, premature birth is a major problem for the children of women on dialysis and there is a higher rate of neonatal death. There are significant differences in gestational age, birth weight, frequency and severity of prematurity and rates of neonatal death between pregnancies of women undergoing dialysis and those who are renal transplant recipients.

Highly enantioselective hydrogenative desymmetrization of bicyclic imides has been developed with chiral Cp*Ru(PN) catalysts. The present hydrogenation directly provides stereochemically well-defined cyclic compounds with excellent enantiomeric exessses, which might otherwise require a detour to reach.

This work represents the first catalytic hydrogenation of imides into amides and primary alcohols, in which the unique chemoselectivity is originated from the bifunctional nature of ruthenium-NH moiety in the catalyst.

We assessed the medium-term (3-year) efficacy of transurethral ethanol injection therapy of the prostate (EIP) for benign prostatic hyperplasia.A total of 34 patients were followed for a median of 4.3 years after EIP. Mean age was 68.1 years and mean baseline prostate volume was 49.3 ml. With the patient under combined sacral and urethral anesthesia, dehydrated ethanol was injected into the prostate with endoscopic guidance. A urethral catheter was inserted postoperatively.Mean total ethanol dose was 6.4 ml and a catheter was required for a mean of 7.6 days postoperatively. Mean International Prostate Symptom Score was 21.8 points before EIP (in 34 patients), and decreased to 13.1 points after 3 years (in 17, p0.01). Mean quality of life index decreased from 5.0 points before EIP to 2.8 points after 3 years (p0.001). Mean peak urine flow rate was 8.3 ml per second before EIP and increased to 12.7 ml per second after 3 years (p0.01). Mean residual urine volume decreased from 93 ml before EIP to 28 ml after 3 years (p0.01). Mean prostate volume decreased from 49.3 ml before EIP to 45.7 ml after 1 year (p0.001), but increased to 51.4 ml after 3 years. No major complications were experienced. By 3 years after surgery 59.0% of patients had not required further treatment.Transurethral EIP caused minimal complications while maintaining improvement of the prostate symptom score and an increased peak urine flow after 3 years.

Background : In the present series of 170 patients who underwent extracorporeal shock-wave lithotripsy (SWL) treatment for ureteral stones, the authors determine which patients with ureteral stones had an unsuccessful outcome. Methods: The records of 170 patients with ureteral stones who were treated with SWL using the Dornier lithotriptor U/50 (EMSE 140) between January 1998 and December 1999 were retrospectively investigated. One hundred and thirty-one patients were treated with SWL alone (single session, n = 98; multiple session, n = 33) and 39 patients required auxiliary treatment due to failure of SWL (33 with transurethral ureterolithotripsy (TUL), one with open lithotomy, and five with residual fragments who were followed up). These two groups were compared using multivariate logistic regression analysis. Results : Lower ureteral stones and stones more than 12 mm in diameter were associated with a poor outcome of SWL. There were no significant differences in age, gender, number of stones, JJ stent placement, and degree of ureteral obstruction due to the stone between the two groups. The odds ratios of lower ureteral stones and stones ≥ 12 mm were 4.18 and 2.57, respectively. Conclusion : Patients with distal ureteral stones and/or stones more than 12 mm in diameter were difficult to treat successfully with SWL. Alternatives such as TUL should possibly be considered as a first-line therapy for these stones.

Although new forms of lithotripsy, such as new-generation shockwave and laser lithotripsies, have recently been developed, the optimal treatment for impacted ureteral stones (IUS) remains controversial. We investigated, retrospectively, the outcome of IUS treated with ureteroscopic pneumatic lithotripsy.Twenty-two IUS cases were treated using ureteroscopic pneumatic lithotripsy. Of 22 stones, 8 (36%) were treated by ureteroscopic pneumatic lithotripsy as initial treatment and 14 (64%) with pneumatic lithotripsy as an auxiliary treatment after SWL. The stone sizes ranged from 7 to 16 mm with 14 located in the proximal, 3 in the middle, and 5 in the distal ureter.Twenty stones (91%) were effectively fragmented by ureteroscopic pneumatic lithotripsy and eliminated within 1 month after treatment. One stone could not be observed with the ureteroscope secondary to the kinking and stricture of the ureter under the stone, and the stone moved into the kidney during the procedure. The stone was subsequently treated successfully with SWL. One other stone was first fragmented into two pieces; and one big piece, which migrated into the kidney, was treated successfully with SWL. Complications such as bleeding, ureteral injury, and perforation did not occur. Although a few small fragments migrated into the kidney during the procedure in three cases, the overall stone-free rate at 1 month after a one-session treatment with pneumatic lithotripsy was 91%.Impacted ureteral stones can be treated effectively with ureteroscopic pneumatic lithotripsy in both the short and the long term.

Retroperitoneal laparoscopic pyelolithotomy via a posterior approach was successful in a patient with a large impacted renal pelvic stone. This procedure is beneficial as an alternative to open surgery for stones that cannot be treated by SWL or intracorporeal lithotripsy. This procedure may also be the initial treatment in selected cases.