A Case of Pneumocystis Pneumonia Developed During Rheumatoid Arthritis Treatment With Methotrexate and Golimumab.

Here, we report a case of an 87-year-old female patient with rheumatoid arthritis (RA) treated with methotrexate (MTX) and golimumab who developed severe pneumocystis pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia. The patient presented with chief complaints of dyspnea on exertion, dry cough, and fatigue. A high-resolution chest CT scan revealed diffuse, unevenly distributed ground-glass opacities throughout both lungs. The patient was clinically diagnosed with PCP based on the clinical settings, imaging, and a high level of serum ß-D-glucan. While the patient required high-flow oxygen therapy, low-dose trimethoprim/sulfamethoxazole and corticosteroid therapy improved her condition, and the patient was discharged on day 25. Although to our knowledge no case report has been published regarding PCP in patients with RA treated with golimumab, this case emphasizes the importance of attention to opportunistic infections in elderly patients receiving immunosuppressive therapy. MTX use alongside tumor necrosis factor inhibitors like golimumab may increase the risk of serious infections such as PCP. The case underscores the necessity of prophylactic measures and early intervention for PCP, highlighting the delicate balance between immunosuppression benefits and infection risks in RA management.

Discovery of TP0628103: A Highly Potent and Selective MMP-7 Inhibitor with Reduced OATP-Mediated Clearance Designed by Shifting Isoelectric Points.

Matrix metalloproteinase-7 (MMP-7) has been shown to play an important role in pathophysiological processes such as cancer and fibrosis. We previously discovered selective MMP-7 inhibitors by molecular hybridization and structure-based drug design. However, the systemic clearance (CLtot) of the biologically active lead compound was very high. Because our studies revealed that hepatic uptake by organic anion transporting polypeptide (OATP) was responsible for the high CLtot, we found a novel approach to reducing their uptake based on isoelectric point (IP) values as an indicator for substrate recognition by OATP1B1/1B3. Our "IP shift strategy" to adjust the IP values culminated in the discovery of TP0628103 (18), which is characterized by reduced in vitro OATP-mediated hepatic uptake and in vivo CLtot. Our in vitro-in vivo extrapolation of OATP-mediated clearance and the "IP shift strategy" provide crucial insights for a new medicinal chemistry approach to reducing the systemic clearance of OATP1B1/1B3 substrates.

Structure-Based Optimization and Biological Evaluation of Potent and Selective MMP-7 Inhibitors for Kidney Fibrosis.

Matrix metalloproteinase-7 (MMP-7) has been shown to play important roles in pathophysiological processes involved in the development/progression of diseases such as cancer and fibrosis. We discovered selective MMP-7 inhibitors composed of arylsulfonamide, carboxylate, and short peptides by a molecular hybridization approach. These compounds interacted with MMP-7 via multiple hydrogen bonds in the cocrystal structures. To obtain compounds for in vivo evaluation, we attempted structural optimization, particularly targeting Tyr167 at the S3 subsite through structure-based drug design, and identified compound 15 as showing improved MMP-7 potency and MMP subtype selectivity. A novel π-π stacking interaction with Tyr167 was achieved when 4-pyridylalanine was introduced as the P3 residue. Compound 15 suppressed the progression of kidney fibrosis in a dose-dependent manner in a mouse model of unilateral ureteral obstruction. Thus, we demonstrated, for the first time, that potent and selective MMP-7 inhibitors could prevent the progression of kidney fibrosis.

On-site Gram staining that increases a post-test probability of an ominous infection: a case of necrotizing fasciitis caused by Vibrio vulnificus: a case report.

BACKGROUND: Gram staining is a classic but standard and essential procedure for the prompt selection of appropriate antibiotics in an emergency setting. Even in the era of sophisticated medicine with technically developed machinery, it is not uncommon that a classic procedure such as Gram staining is the most efficient for assisting physicians in making therapeutic decisions in a timely fashion. CASE PRESENTATION: A 65-year-old Asian man with alcoholic cirrhosis complicated by esophageal varices was brought to the emergency division of Saga Medical School Hospital in early August, complaining of severe pain, redness, swelling, and purpura of the lower extremities. On physical examination he appeared in a critically ill condition suggestive of deep-seated soft tissue infection, raising a pre-test probability of streptococci, staphylococci, Vibrio sp., or Aeromonas sp. as a causative pathogen. A characteristic of his residency in an estuarine area is that raw seafood ingestion, as documented in this patient prior to the current admission, predisposes those who have a chronic liver disease to a life-threatening Vibrio vulnificus infection. Given the pathognomonic clinical features suggestive of necrotizing fasciitis, our immediate attempt was to narrow down the differential list of candidate pathogens by obtaining clinical specimens for microbiological investigation, thus inquiring about the post-test probability of the causative pathogen. The Gram stain of the small amount of discharge from the test incision of the affected lesion detected Gram-negative rods morphologically compatible with V. vulnificus. After two sets of blood culture, intravenous meropenem and minocycline were immediately administered before the patient underwent emergency surgical debridement. The next day, both blood culture and wound culture retrieved Gram-negative rods, which were subsequently identified as V. vulnificus by mass spectrometry, matrix-assisted laser desorption/ionization. The antibiotics were switched to intravenous ceftriaxone and minocycline. CONCLUSION: The pre-test probability of V. vulnificus infection was further validated by on-site Gram staining in the emergency division. This case report highlights the significance of a classic procedure.

Discovery of Highly Potent and Selective Matrix Metalloproteinase-7 Inhibitors by Hybridizing the S1' Subsite Binder with Short Peptides.

Matrix metalloproteinase-7 (MMP-7) has emerged as a protein playing important roles in both physiological and pathophysiological processes. Despite the growing interest in MMP-7 as a potential therapeutic target for diseases including cancer and fibrosis, potent and selective MMP-7 inhibitors have yet to be identified. Compound 1, previously reported by Edman and co-workers, binds to the S1' subsite of MMP-7, exhibiting moderate inhibitory activity and selectivity. To achieve both higher inhibitory activity and selectivity, we conceived hybridizing 1 with short peptides. The initially designed compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over other MMP subtypes.

Is trimethoprim/sulfamethoxazole-associated increase in serum creatinine a pseudo-elevation or true nephrotoxicity?

INTRODUCTION: The aim of this study was to determine the rates of trimethoprim/sulfamethoxazole (TMP/SMX)-associated pseudo-elevation and true nephrotoxicity by comparison of creatinine-estimated and cystatin C-estimated GFRs (glomerular filtration rates) before and after TMP/SMX administrations. METHODS: Patients in whom serum creatinine and cystatin C were simultaneously measured are the cohort of this study. A decreasing of creatinine-estimated GFR posterior to TMP/SMX by ≥ 20% and a decreasing of cystatine C-estimated GFR posterior to TMP/SMX by ≥ 20% were defined as true nephrotoxicity. A decreasing of creatinine-estimated GFR posterior to TMP/SMX by ≥ 20% and a decreasing of cystatine C-estimated GFR posterior to TMP/SMX by < 20% were defined as pseudo-elevation. RESULTS: A total of 66 patients were enrolled. Within the 19 patients in whom serum creatinine and cystatin C were measured simultaneously both before and after TMP/SMX administrations, 10 patients (52.6%) had nephrotoxicity. Fewer random error and systematic bias between creatinine- and cystatine C-estimated GFR were observed after TMP/SMX than before TMP/SMX by Bland-Altman analysis. CONCLUSIONS: Using cystatin C, we reveled TMP/SMX-associated nephrotoxicity is not uncommon. We should equally pay attention to TMP/SMX-associated nephrotoxicity and pseudo-elevation. In spite of pseudo-elevation, creatinine-estimated GFR after receiving TMP/SMX is ironically reliable as surrogate maker for renal clearance.

Clinical pharmacokinetic and pharmacodynamic analysis of daptomycin and the necessity of high-dose regimen in Japanese adult patients.

The objective of this study was to explore the optimal dosage regimen of daptomycin and to determine the necessity and validity of a high-dose regimen from the perspectives of PK/PD parameters using Monte Carlo Simulation (MCS) and therapeutic drug monitoring (TDM) in a Japanese clinical setting. The volume of distribution (0.13 ± 0.012 L/kg) in this study was greater than that in healthy volunteers reported in Japan. The range of half-lives was between 8.9 and 34.9 h, which were gradually prolonged as creatinine clearance decreased. In MCS, the cumulative fractions of response (CFR) of the peak/MIC â‰§ 60 and the AUC/MIC â‰§ 666 at the 6 mg/kg q 24 h were 72.0% and 78.8% but at the 10 mg/kg q 24 h, the CFRs improved to both 99%. In TDM with 6 mg/kg q 24 h regimen, the patients who reached the peak and AUC target were 40% (2 out of 5 patients), respectively. The intraindividual variability in daptomycin PK may indicate the necessity of TDM and high-dose regimen, such as over 8 mg/kg, may be needed to ensure the effectiveness especially on Japanese patients with normal renal function.

Reliability of radiographic measurement of lateral capitellohumeral angle in healthy children.

This retrospective cohort study was designed to validate the reliability of measurement of the lateral capitellohumeral angle (LCHA), an index of sagittal angulation of the elbow, in healthy children. The results were compared to the Baumann angle (BA), which is a similar concept to LCHA.Sixty-two radiographs of the elbow in healthy children (range, 2-11 years) were reviewed by 6 examiners at 2 sessions. The mean value and reliability of the measurement of LCHA and BA were assessed. Intraobserver reliability and interobserver reliability were calculated using intraclass correlation coefficients (ICCs).The mean LCHA value was 45° (range, 22° to 70°) and the mean BA was 71° (range, 56° to 86°). The ICCs for intraobserver reliability of the LCHA measurements were almost perfect for 2 examiners, substantial for 3 examiners, and moderate for 1 examiner with a mean value of 0.77 (range, 0.57-0.95). For BA measurements, the ICCs were almost perfect for 1 examiner and substantial for 5 examiners with a mean value of 0.74 (range, 0.66-0.83). The ICCs for interobserver reliability between the first and second measurements were both moderate for LCHA (0.56 and 0.51) and for BA (0.52 and 0.50).LCHA showed almost the same reliability in measurement as BA, which is the gold standard assessment for coronal alignment of the elbow. LCHA showed moderate-to-good reliability in the evaluation of sagittal plane elbow alignment.

Vincristine-induced peripheral neuropathic pain and expression of transient receptor potential vanilloid 1 in rat.

The clinical anti-cancer efficacy of vincristine is limited by the development of dose-dependent peripheral neuropathy. Up-regulation of transient receptor potential vanilloid 1 (TRPV1) is correlated with peripheral neuropathy following anti-cancer drug treatment. To analyze the contribution of TRPV1 to the development of vincristine-induced mechanical allodynia/hyperalgesia, TRPV1 expression in the rat dorsal root ganglion (DRG) was analyzed after vincristine treatment. Mechanical allodynia/hyperalgesia was tested with von Frey filaments 14 days after intraperitoneal administration of 0.1 mg/kg vincristine in rats. TRPV1 expression in DRGs following vincristine treatment was assessed with western blot analysis and in situ hybridization histochemistry. Vincristine-induced mechanical allodynia/hyperalgesia after day 14 was significantly inhibited by the TRP antagonist ruthenium red (3 mg/kg, s.c.) and the TRPV1 antagonist capsazepine (30 mg/kg, s.c.). Vincristine treatment increased the expression of TRPV1 protein in DRG neurons. In situ hybridization histochemistry revealed that most of the TRPV1 mRNA-labeled neurons in the DRG were small in size. Immunohistochemistry showed that isolectin B4-positive small DRG neurons co-expressed TRPV1 protein 14 days after treatment. These results suggest that vincristine treatment increases TRPV1 expression in small DRG neurons. TRPV1 expression may contribute to the development of vincristine-induced painful peripheral neuropathy.

Reliability and Validity of Radiographic Measurement of the Humerus-Elbow-Wrist Angle in Healthy Children.

This article was updated on May 4, 2017, because of a previous error. The proximal line drawn in Figure 1 was different from the line described in the Materials and Methods section, which reads "The proximal line was drawn at the level of the radial tuberosity, and the distal line was made at the level of the top of the radial bowing (Fig. 1)." The correct figure is presented in this version of the article. An erratum has been published: JBJS Open Access. 2017 May 26;2(2):e0012ER. BACKGROUND: We conducted a retrospective cohort study to evaluate the normal value, range, reliability, and validity of measurement of the humerus-elbow-wrist angle, an index of valgus-varus angulation of the elbow, in healthy children. This measurement has been used to assess postoperative radiographic results. METHODS: Radiographs of the elbow in 62 healthy children ranging from 2 to 11 years of age were reviewed by 6 examiners at 2 sessions. The mean value and the reliability of measurement of the humerus-elbow-wrist angle, the carrying angle, and the Baumann angle were assessed. Intraobserver and interobserver reliability were calculated with use of intraclass correlation coefficients (ICCs). To determine concurrent validity, the association between the humerus-elbow-wrist angle and carrying angle measurements was examined with use of Pearson correlation coefficients. RESULTS: The mean humerus-elbow-wrist angle value was 12.0° (range, 1° to 24°), and the mean carrying angle was 14.6° (range, 4° to 28°). The ICCs for intraobserver measurements of the humerus-elbow-wrist angle were almost perfect for 4 examiners and were substantial for 2 examiners, with a mean value of 0.85 (range, 0.73 to 0.94). The ICCs for interobserver reliability with regard to the first and second measurements of the humerus-elbow-wrist angle were both substantial (0.76 and 0.78). A significant association between the humerus-elbow-wrist angle and the carrying angle was observed, with the Pearson correlation coefficients ranging from 0.74 to 0.90 (p < 0.001). CONCLUSIONS: Measurement of the humerus-elbow-wrist angle demonstrated good reliability and validity. The humerus-elbow-wrist angle is a reliable radiographic measure of coronal alignment of the humerus and forearm.

Paclitaxel-induced peripheral neuropathy increases substance P release in rat spinal cord.

Peripheral neuropathy is a common adverse effect of paclitaxel treatment. The major dose-limiting side effect of paclitaxel is peripheral sensory neuropathy, which is characterized by painful paresthesia of the hands and feet. To analyze the contribution of substance P to the development of paclitaxel-induced mechanical hyperalgesia, substance P expression in the superficial layers of the rat spinal dorsal horn was analyzed after paclitaxel treatment. Behavioral assessment using the von Frey test and the paw thermal test showed that intraperitoneal administration of 2 and 4mg/kg paclitaxel induced mechanical allodynia/hyperalgesia and thermal hyperalgesia 7 and 14 days after treatment. Immunohistochemistry showed that paclitaxel (4mg/kg) treatment significantly increased substance P expression (37.6±3.7% on day 7, 43.6±4.6% on day 14) in the superficial layers of the spinal dorsal horn, whereas calcitonin gene-related peptide (CGRP) expression was unchanged. Moreover, paclitaxel (2 and 4mg/kg) treatment significantly increased substance P release in the spinal cord on day 14. These results suggest that paclitaxel treatment increases release of substance P, but not CGRP in the superficial layers of the spinal dorsal horn and may contribute to paclitaxel-induced painful peripheral neuropathy.

Discovery of N-{5-[3-(3-hydroxypiperidin-1-yl)-1,2,4-oxadiazol-5-yl]-4-methyl-1,3-thiazol-2-yl}acetamide (TASP0415914) as an orally potent phosphoinositide 3-kinase γ inhibitor for the treatment of inflammatory diseases.

Class I phosphoinositide 3-kinases (PI3Ks), particularly PI3Kγ, have become attractive drug targets for inflammatory and autoimmune disorders such as rheumatoid arthritis. Herein, we describe the synthesis and the structure-activity relationships (SAR) of a series of 2-amino-5-oxadiazolyl thiazoles, culminating in the identification of 8j (TASP0415914), an orally potent inhibitor of phosphoinositide 3-kinase γ (PI3Kγ). TASP0415914 demonstrated good potency in a cell-based assay and, furthermore, exhibited in vivo efficacy in a collagen induced arthritis (CIA) model in mice after oral administration.

Discovery and optimization of a series of 2-aminothiazole-oxazoles as potent phosphoinositide 3-kinase γ inhibitors.

A novel series of 2-aminothiazole-oxazoles was designed and synthesized as part of efforts to develop potent phosphoinositide 3-kinase γ (PI3Kγ) inhibitors. The modification of a high-throughput screening hit, compound 1, resulted in the identification of compounds 10 and 15, which displayed potent inhibitory activities in enzyme-based and cell-based assays.

Furan fatty acid as an anti-inflammatory component from the green-lipped mussel Perna canaliculus.

A lipid extract of Perna canaliculus (New Zealand green-lipped mussel) has reportedly displayed anti-inflammatory effects in animal models and in human controlled studies. However, the anti-inflammatory lipid components have not been investigated in detail due to the instability of the lipid extract, which has made the identification of the distinct active components a formidable task. Considering the instability of the active component, we carefully fractionated a lipid extract of Perna canaliculus (Lyprinol) and detected furan fatty acids (F-acids). These naturally but rarely detected fatty acids show potent radical-scavenging ability and are essential constituents of plants and algae. Based on these data, it has been proposed that F-acids could be potential antioxidants, which may contribute to the protective properties of fish and fish oil diets against chronic inflammatory diseases. However, to date, in vivo data to support the hypothesis have not been obtained, presumably due to the limited availability of F-acids. To confirm the in vivo anti-inflammatory effect of F-acids in comparison with that of eicosapentaenoic acid (EPA), we developed a semisynthetic preparation and examined its anti-inflammatory activity in a rat model of adjuvant-induced arthritis. Indeed, the F-acid ethyl ester exhibited more potent anti-inflammatory activity than that of the EPA ethyl ester. We report on the in vivo activity of F-acids, confirming that the lipid extract of the green-lipped mussel includes an unstable fatty acid that is more effective than EPA.

Reprogramming of adult human testicular cells by four transcription factors (OCT4, SOX2, KLF4, and C-MYC).

PURPOSE: Induced pluripotent stem (iPS) cells have been generated from mouse and human fibroblasts by several groups; however, transplanted mouse iPS cells can cause teratomas, depending on their tissue of origin. Therefore, human iPS cells are preferable, and various tissues are being evaluated for their potential to generate human iPS cells. METHODS: We examined whether adult human testicular tissue had undergone reprogramming by introducing four transcription factors, OCT4, SOX2, KLF4, and C-MYC, using lentiviral vectors. RESULTS: We obtained embryonic stem (ES)-like cells derived from human testicular tissue by introducing four cDNAs, encoding the transcription factors OCT4, SOX2, KLF4, and C-MYC, using lentiviral vectors. We showed that DAZL and VASA were expressed in testicular cells but down-regulated in ES-like cells, indicating that the cells had undergone reprogramming. ES-like cells could develop tumors, which is a hallmark of pluripotency, when SCID mice were injected with these cells. CONCLUSIONS: We induced iPS cells from adult human testicular tissue by introducing four transcription factors, OCT4, SOX2, KLF4, and C-MYC, using lentiviral vectors. Future studies on these cells may elucidate the causes of male infertility, and eventually lead to treatments with autologous testicular tissue-derived iPS cells.

Ring-fused pyrazole derivatives as potent inhibitors of lymphocyte-specific kinase (Lck): Structure, synthesis, and SAR.

We have identified a novel series of ring-fused pyrazole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <1nM) as well as excellent cellular activity against mixed lymphocyte reaction (MLR) (IC(50)s <1nM).

Palladium-catalyzed reaction of acylzirconocene chloride and stereoselective formation of bicyclo[3.3.0] compounds.

The acylzirconocene chloride complex as an acyl group donor reacts with omega-unsaturated alpha,beta-enones and -ynones under Pd-Me(2)Zn(Me(2)AlCl)-catalyzed conditions to give stereoselectively bicyclo[3.3.0] compounds through (i) formation of a Pd(II) intermediate by an oxidative addition of the Pd(0) catalyst to an enone function, (ii) cyclization of the Pd intermediate to an omega-unsaturated group, (iii) an acyl group transfer from zirconium to Pd metal, (iv) reductive elimination of the Pd metal, and (v) intramolecular cis-selective aldol reaction. [reaction: see text]