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We herein report a 56-year-old woman who developed allergic bronchopulmonary aspergillosis (ABPA) possibly due to fungal exposure after disastrous heavy rainfall in Western Japan in 2018. She was diagnosed with ABPA complicated with asthma, increased peripheral blood eosinophil count, elevation of specific immunoglobulin E for Aspergillus fumigatus, positive Aspergillus fumigatus precipitation antibody reaction test results, and notable chest computed tomography findings. After treatment with benralizumab, her symptoms, peripheral blood eosinophil count, radiological findings, and respiratory function dramatically improved. The administration of benralizumab appears to be an effective treatment strategy for ABPA.

Gitelman syndrome is an autosomal recessive genetic disease caused by pathogenic variants in SLC12A3 resulting in the loss of function of the Na–Cl co-transporter (NCC) in the distal tubules. Hypokalemia and diuretic effects can cause secondary type 2 diabetes and renal function decline. Here, we present the case of a 49-year-old male patient with chronic persistent treatment-resistant hypokalemia for the past 13 years who had been receiving treatment for type 2 diabetes mellitus for 6 years. He was referred to our department due to the presence of urinary protein, impaired renal function, high renin activity, and hyperaldosteronism. Laboratory test results showed hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Using next-generation and Sanger sequencing, we identified a novel stop-gain variant (NM_000339.3:c.137del [p.His47fs]) and a missense variant (NM_000339.3:c.2927C > T [p.Ser976Phe]) in the SLC12A3 gene. This novel pathogenic variant was located at the intracellular N-terminus of the NCC. Based on these findings, the patient was diagnosed with Gitelman syndrome. The use of next-generation sequencing facilitated the exclusion of diseases with similar clinical symptoms.

Foxp3 is the master transcriptional regulator of regulatory T cells (Tregs), and the stabilization of Foxp3 expression is regulated by the demethylation of conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Recent studies have shown that TCR stimulation is required for the demethylation of Foxp3 CNS2 during Treg development. However, the relationship between the strength of TCR stimulation and the demethylation of Foxp3 CNS2 remains unclear. To address this issue, we compared the frequency of demethylation of the Foxp3 CNS2 among in vitro-induced Tregs (iTreg) that had received a range of TCR stimulation during their development. We found that the frequency of demethylation of the Foxp3 CNS2 was increased with increased TCR stimulation strength, whereas CD28 stimulation had only a limited effect. Mechanistically, the binding of Tet2, a member of the TET family of enzymes involved in DNA demethylation, on the Foxp3 CNS2 was increased by strong TCR stimulation. Furthermore, compared with iTreg induced by weak TCR stimulation, iTreg induced by strong TCR stimulation maintained Foxp3 expression both in vitro and in vivo. These data indicate that the strength of TCR stimulation is a key factor for induction of the demethylation of Foxp3 CNS2 and the generation of stable Tregs.

Infiltration by IgG-positive plasma cells is a common finding in tubulointerstitial nephritis. Indeed, it has been thought that CD138-positive mature plasma cells secrete mainly IgG, and the occurrence of tubulointerstitial nephritis with CD138-positive plasma cells secreting IgM has rarely been reported. Routine immunofluorescence of fresh frozen sections is considered the gold standard for detection of immune deposits. However, the immunoenzyme method with formalin-fixed, paraffin-embedded sections is superior for detecting IgM- or IgG-positive cells within the renal interstitium, thus histologic variants may often go undetected. We recently discovered a case of tubulointerstitial nephritis showing IgM-positive plasma cell accumulation within the interstitium. To further explore the morphologic and clinical features of such cases, we performed a nationwide search for patients with biopsy-proven tubulointerstitial nephritis and high serum IgM levels. We identified 13 patients with tubulointerstitial nephritis and IgM-positive plasma cell infiltration confirmed with the immunoenzyme method. The clinical findings for these patients included a high prevalence of distal renal tubular acidosis (100%), Fanconi syndrome (92%), and anti-mitochondrial antibodies (82%). The pathologic findings were interstitial nephritis with diffusely distributed CD3-positive T lymphocytes and colocalized IgM-positive plasma cells, as well as tubulitis with CD3-positive T lymphocytes in the proximal tubules and collecting ducts. Additionally, levels of H+-ATPase, H+, K+-ATPase, and the HCO3−-Cl− anion exchanger were markedly decreased in the collecting ducts. We propose to designate this group of cases, which have a common histologic and clinical form, as IgM-positive plasma cell–tubulointerstitial nephritis.

Two approaches to the synthesis of compounds corresponding to the C17-C27 fragment of the 20-deoxybryostatins are described. The first approach is based on the palladium(0) catalysed coupling of tin enolates, generated in situ from enol acetates using tributyltin methoxide, with vinylic bromides. The vinylic bromides were prepared using the Sharpless asymmetric dihydroxylation to introduce the hydroxyl groups corresponding to those at C25 and C26 in the bryostatins. Following several steps to introduce alkynyl ester functionality, the stereoselective addition of a tributyltin cuprate followed by tributyltin-bromine exchange gave the required vinylic bromides. The palladium(0) catalysed couplings worked very well for enol esters containing thioether substituents and gave products with retention of the position and geometry of the trisubstituted double bond derived from the vinylic bromide. These were taken through to compounds corresponding to fully developed C17-C27 fragments ready for assembly of the 16,17-double-bond of bryostatins by Julia reactions. This chemistry was also applied to prepare intermediates suitable for incorporation into bryostatins by ring-closing metathesis but, in this case, the coupling reaction gave mixtures of products including both the required βγ-unsaturated ketone and a conjugated diene formed by a competing Heck reaction. To avoid this problem, a second approach to compounds suitable for incorporation into a metathesis-based assembly of 20-deoxybryostatins was developed. In this organotin-free synthesis, the key step was the conjugate addition of an organic cuprate generated from allylmagnesium bromide to an alkynoate that gave the required (Z)-trisubstituted alkene with excellent stereoselectivity. This was converted into metathesis precursors in a few steps.

It is thought that CD28 plays a crucial role in the maintenance of regulatory T cell (Treg) pool size through promoting the development and proliferation of these cells. However, recently we found that the dependency on CD28 co-stimulation for their development is different between Treg subsets, thymus-derived Tregs (tTregs, CD28-dependent) and peripherally-derived Tregs (pTregs, CD28-independent), suggesting that CD28 may also have differential influences on the homeostasis of each Treg subset. Here, we demonstrated that both Treg subsets were reduced in secondary lymphoid organs of CD28 deficient mice, and that this reduction was due to impaired proliferation in both Treg subsets by the intrinsic CD28 defect. However, we found that the massive proliferation of both Treg subsets under lymphopenic condition was regulated by CD28, whereas the proliferative activity of tTregs but not pTregs in the steady state was dependent on CD28. Also, experiments using mutant CD28 knock-in mice revealed that proliferation of pTregs under lymphopenic condition required only the Lck-NFκB pathway of CD28, whereas tTregs required an additional unknown pathway. These findings indicate that the dependency on CD28 for proliferation in each Treg subset differs depending on the environment.

It is well-established that CD28 co-stimulation is required for the development and the proliferation of thymus-derived regulatory T cells (tTregs). Meanwhile, the role of CD28 co-stimulation in the homeostasis of peripherally derived Tregs (pTregs) remains unclear. To clarify this issue, we analyzed Tregs in small and large intestines (SI and LI), the principle sites of pTreg development. Interestingly, and different from in the thymus, Tregs were abundant in the intestines of CD28−/− mice, and most of them were phenotypically pTregs. We showed that CD28−/− naive T cells differentiated into pTregs in the LI after oral exposure to antigens and that CD28−/− pTregs in the LI had the same highly proliferative activity as CD28+/− cells. CD28−/− pTregs acquired these Treg-specific features at transcriptional and epigenetics levels. On the other hand, some immune suppressive molecules were down-regulated in CD28−/− pTregs. Correspondingly, the suppressive activity of CD28−/− pTregs was weaker than CD28+/+ cells. These results indicate that the homeostasis of pTregs in the intestines is maintained even in the absence of CD28, whereas CD28 is required for the maximal suppressive activity of intestinal pTregs.

Preliminary studies into the use of ring-closing metathesis (RCM) in a convergent approach for the total synthesis of bryostatins are described. An ester that would have provided an advanced intermediate for a synthesis of a 20-deoxybryostatin by a RCM was prepared from an unsaturated acid and alcohol corresponding to the C1–C16 and C17–C27 fragments. However, studies of the formation of the C16–C17 double-bond by RCM were not successful and complex mixtures of products were obtained. To provide an insight into factors that may be involved in hindering RCM in this system, a slightly simplified C1–C16 acid and modified C17–C25 alcohols were prepared and their use for the synthesis of analogues of bryostatins was investigated. Although only low yields were obtained, it appeared that macrolides analogous to the bryostatins can be prepared by RCM, using the Grubbs II catalyst, if the precursors lack the two methyl groups at C18. RCM was not observed, however, for substrates in which these methyl groups were present.

The multi-scale structures of turbulent wakes generated by three kinds of bluff body, i.e. circular cylinder, square cylinder and compound of cylinder and square (CS) cylinders, have been experimentally investigated in this paper. Firstly, the instantaneous velocity fields and vorticity were measured by the high-speed PIV technique in a circulating water channel. The instantaneous streamlines and corresponding normalized vorticity contours are obtained at a Reynolds number of 5600. Then one- and two-dimensional wavelet multi-resolution technique was used to analyze the instantaneous velocities and vorticity measured by the high-speed PIV. The turbulence structures were separated into a number of subsets based on their central frequencies, which are linked with the turbulence scales. The instantaneous vorticity and Reynolds shear stresses of various scales were examined and compared between the three generators. It is found that the large-scale turbulent structure makes the largest contribution to the vorticity and Reynolds shear stresses for the three wake generators and exhibits a strong dependence upon the initial conditions or the wake generators. The large-scale vorticity and the sizes of vortex in the circular and square cylinders are larger than those in the CS cylinder wake. The contributions to the Reynolds shear stresses from the large-scale turbulent structures account for 90–96% to the measured maximum Reynolds shear stresses for the three wakes. However, the small-scale structures make less contribution to the vorticity and Reynolds shear stresses.

Methotrexate (MTX) has been documented to accumulate in "third spaces'' such as pleural effusions or ascitic fluids, resulting in delayed clearance and severe toxicity. We present a case of Burkitt lymphoma possessing large liver cysts, up to the size of 7 x 7 cm, wherein clearance of high-dose MTX was severely delayed, despite normal renal and liver functions. The serum MTX concentration was higher than 0.1 microM on day 12 and remained at toxic levels, higher than 0.01 microM, even on day 25, resulting in severe neutropenia, anorexia, and diarrhea. It was presumed that MTX accumulated in the liver cysts over time and was slowly released back into the serum, resulting into prolonged high serum MTX concentrations. High dose of MTX in patients with large liver cysts induces severe toxicity by virtue of MTX accumulation in the cysts and its subsequent delayed clearance.

Preliminary investigations into the synthesis of bryostatins using ring-closing metathesis to form the C(16)–C(17) double bond led to a synthesis of the bryostatin analogue 51 ; precursors 26 and 52 , which possess the geminal dimethyl group at C-18, did not undergo the required ring-closing metathesis.

Total syntheses of epothilone B and pamamycin 607, which feature reactions between functionalized allylstannanes and aldehydes to introduce a (Z)-trisubstituted double-bond and remote stereocenters stereoselectively, are discussed. Recent work concerned with carrying out this chemistry without the use of allylstannanes as starting materials and progress toward a total synthesis of bryostatins are also presented.

A synthesis of the C(1)–C(16) fragment of the brysostatins has been developed. Key steps are the stereoselective copper(I) catalysed addition of allylmagnesium bromide to an alkynyl ester, a condensation of a βγ-unsaturated aldehyde with a ketophosphonate, and the formation of the B-ring under mild conditions by stereoselective intramolecular conjugate addition.

S-1 and cisplatin are used as one of the first-line chemotherapies for gastric cancer in Japan. The plasma concentration of 5-fluorouracil (5-FU) is increased in patients with renal dysfunction because gimeracil in S-1 inhibits the degradation of 5-FU and about 50% of gimeracil is excreted in the urine. We describe a 35-year-old man with acute kidney injury while taking S-1 and cisplatin for advanced gastric cancer and who presented severe adverse effects of 5-FU. This case report describes the evolution of the plasma concentrations of 5-FU with haemodialysis along with a decrease in the adverse drug effects.

Renal interstitial fibrosis is the common pathway in progressive renal diseases, where oxidative stress promotes inflammation and macrophage infiltration. Febuxostat is a novel nonpurine xanthine oxidase (XO)-specific inhibitor for treating hyperuricemia. While some reports suggest a relationship between hyperuricemia and chronic kidney disease (CKD), the renoprotective mechanism of an XO inhibitor in CKD remains unknown. Recent reports have focused on XO as a source of oxidative stress.Here, we investigate the potential of febuxostat to reduce fibrogenic and inflammatory responses in an established interstitial fibrosis model-unilateral ureteric obstruction (UUO). Male Sprague-Dawley rats were divided into three groups: sham-operated group, vehicle-treated UUO group, and febuxostat-treated UUO group.Treatment with febuxostat diminished XO activity in obstructed kidneys, and suppressed nitrotyrosine, a marker of oxidative stress. Consequently, febuxostat inhibited early proinflammatory cytokine expression, followed by a reduction of interstitial macrophage infiltration. In addition, febuxostat suppressed transforming growth factor-β messenger RNA expression, thereby ameliorating smooth muscle alpha actin and type I collagen expression.Our results provide evidence for the renoprotective action of febuxostat against the formation of interstitial fibrosis. A decrease in macrophage infiltration and interstitial fibrosis, along with a decrease of the oxidative stress marker, strongly suggests the existence of a causal relationship between them. Febuxostat may have therapeutic value in slowing or preventing interstitial fibrosis in patients with CKD.

Sir—A number of chronic kidney disease patients with diabetes receive intensive insulin therapy nowadays, and many of them are also treated for several comorbidities. The combination of insulin therapy and other comorbidities could result in an unexpected complication.