Comparison of the outcomes of Pneumocystis jirovecii pneumonia in rheumatoid arthritis patients treated with and without biologics.

BACKGROUND: To investigate the outcomes of Pneumocystis jirovecii pneumonia (PCP) between patients with rheumatoid arthritis (RA) treated with and without biologics before PCP onset. PATIENTS AND METHODS: We retrospectively included rheumatoid arthritis (RA) patients with PCP treated with and without biologics before PCP onset. The primary endpoints were 30-day and 180-day survival rates, and the secondary endpoint was severe PCP, including in-hospital death, intensive care unit admission, and requirement of respiratory support during hospitalization. RESULTS: Eighty-two patients were enrolled in this study, including the Biologics group (n = 39) and Non-Biologics group (n = 43). There were no significantly differences in the 30-day and 180-day survival rates and severe PCP rate in the Biologics group and the Non-Biologics group before and after adjusting the patient characteristics. Kaplan-Meier survival curves for death showed no significantly differences between the Biologics and Non-Biologics groups. Cox regression hazard analysis revealed that the average daily prednisolone dose within 90 days before PCP onset was weakly associated with mortality after PCP. CONCLUSIONS: Biologic use before PCP onset did not increase the severity and mortality of PCP compared to non-biologics use in patients with RA.

Low-Dose vs Conventional-Dose Trimethoprim-Sulfamethoxazole Treatment for Pneumocystis Pneumonia in Patients Not Infected With HIV: A Multicenter, Retrospective Observational Cohort Study.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) is an effective treatment for Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients with and without HIV infection; however, a high incidence of adverse events has been observed. Low-dose TMP-SMX is a potentially effective treatment with fewer adverse events; however, evidence is limited. RESEARCH QUESTION: What is the efficacy and safety of low-dose TMP-SMX for non-HIV PCP compared with conventional-dose TMP-SMX after adjusting for patient background characteristics? STUDY DESIGN AND METHODS: In this multicenter retrospective cohort study, we included patients diagnosed with non-HIV PCP and treated with TMP-SMX between June 2006 and March 2021 at three institutions. The patients were classified into low-dose (TMP < 12.5 mg/kg/d) and conventional-dose (TMP 12.5-20 mg/kg/d) groups. The primary end point was 30-day mortality, and the secondary end points were 180-day mortality, adverse events grade 3 or higher per the Common Terminology Criteria for Adverse Events v5.0, and initial treatment completion rates. Background characteristics were adjusted using the overlap weighting method with propensity scores. RESULTS: Fifty-five patients in the low-dose group and 81 in the conventional-dose group were evaluated. In the overall cohort, the average age was 70.7 years, and the proportion of women was 55.1%. The average dose of TMP-SMX was 8.71 mg/kg/d in the low-dose group and 17.78 mg/kg/d in the conventional-dose group. There was no significant difference in 30-day mortality (6.7% vs 18.4%, respectively; P = .080) or 180-day mortality (14.6% vs 26.1%, respectively; P = .141) after adjusting for patient background characteristics. The incidence of adverse events, especially nausea and hyponatremia, was significantly lower in the low-dose group (29.8% vs 59.0%, respectively; P = .005). The initial treatment completion rates were 43.3% and 29.6% in the low-dose and conventional-dose groups (P = .158), respectively. INTERPRETATION: Survival was similar between the low-dose and conventional-dose TMP-SMX groups, and low-dose TMP-SMX was associated with reduced adverse events in patients with non-HIV PCP.

Effectiveness and safety of lower dose sulfamethoxazole/trimethoprim therapy for Pneumocystis jirovecii pneumonia in patients with systemic rheumatic diseases: A retrospective multicenter study.

OBJECTIVES: To evaluate the effectiveness and safety of lower-dose sulfamethoxazole/trimethoprim therapy (SMX/TMP) for Pneumocystis jirovecii pneumonia (PCP) in patients with systemic rheumatic diseases. METHODS: In this multicenter retrospective study, we compared effectiveness and safety of SMX/TMP for the treatment of PCP among patients divided into three groups according to the initial dosage of SMX/TMP: the low, ≤10 mg/kg/day; the intermediate, 10-15 mg/kg/day; and the high and conventional, 15-20 mg/kg/day for TMP dose. RESULTS: Eighty-one patients, including 22, 30, and 29 patients in the low-, the intermediate- and the high-dose group could be analyzed and the 30-day survival rate were 100%, 93.3%, and 96.7%, respectively (P = 0.28). There were significant dose-dependent increasing trends of severe adverse drug reactions (ADRs) for SMX/TMP that were graded as ≥3 according to the Common Terminology Criteria for Adverse Events. When stratified by presence of severe hypoxemia defined by alveolar-arterial O2 gradient ≥45 mmHg, the 30-day survival and treatment modification rate were similar among the three groups, but frequency of severe ADRs were significantly decreased in the low-dose group. The low-dose group was independently and negatively associated with treatment modification within 14 days and severe ADRs. CONCLUSIONS: Lower dose SMX/TMP therapy with ≤10 mg/kg/day for TMP was as effective as higher dose therapy for the treatment of PCP and associated with lower rates of treatment modification and severe ADRs in patients with systemic rheumatic diseases.

Pneumococcal vertebral osteomyelitis at three teaching hospitals in Japan, 2003-2011: analysis of 14 cases and a review of the literature.

BACKGROUND: Pneumococcal vertebral osteomyelitis (PVO) is a rare disease whose clinical characteristics have not been clarified. This study aimed to investigate the clinical features and outcomes of patients with PVO. METHODS: We retrospectively evaluated all adult patients diagnosed with PVO at three teaching hospitals in Japan from January 2003 to December 2011. All cases were identified through a review of the medical records of patients with invasive pneumococcal disease (IPD). RESULTS: Among 208 patients with IPD, we identified 14 with PVO (6.4%; 95% CI, 3.5-10%). All 14 patients (nine male, five female; median age 69 years) had acquired PVO outside the hospital and had no recent history of an invasive procedure or back injury. Five patients (36%) had diabetes mellitus, and four (29%) had heavy alcohol intake. Fever (n = 13; 93%) or back pain/neck pain (n = 12; 86%) were present in most patients. The lumbar spine was affected in nine patients (64%) but the cervical spine was the site of infection in four patients (29%). All patients except one had a positive blood culture for Streptococcus pneumoniae, and there were no distant infected sites in most patients (n = 10; 71%). Intravenous beta-lactam therapy was initiated within 1 week after the onset of symptoms in 11 patients (79%). No patients died within 30 days, but one patient died from aspiration pneumonia on day 37 after admission. CONCLUSIONS: PVO was relatively common among adult patients with IPD, and mortality was low in this study. S. pneumoniae may be the causative pathogen of vertebral osteomyelitis, especially among community-onset cases without a history of invasive procedures or back injury.

Morbidity and mortality among newly hospitalized patients with community-acquired pneumococcal bacteremia: a retrospective cohort study in three teaching hospitals in Japan.

AIM: Although the mortality rate of pneumococcal bacteremia has been intensively studied, few studies have examined how it influences patient morbidity. This study aimed to fill this research gap by clarifying the impact of pneumococcal bacteremia on mortality and morbidity. METHODS: We carried out a retrospective cohort study of adult patients hospitalized with community-acquired pneumococcal bacteremia in three teaching hospitals in Japan from January 2003 to December 2010. Morbidity was defined as a worsening Katz Index score compared with that before infection onset, new impairment of oral intake or new requirement for oxygen assistance at discharge. RESULTS: Of 135 patients identified (mean age 70 years; 38% female), 116 (86%) were able to carry out activities of daily living independently before the onset of the infection. Pneumonia was found to be the most common infective source (69%), followed by meningitis (10%) and septic arthritis or vertebral osteomyelitis (8.1%). The 14-day, 30-day, and inpatient mortality rates were found to be 15%, 20% and 25%, respectively. The morbidity at discharge was 26 out of 101 (26%) among all survivors and 18 out of 42 (43%) among survivors who were aged ≥ 75 years. Multivariate analysis showed that an age of ≥ 75 years is an independent predictor of morbidity (adjusted odds ratio 16.3, 95% CI 2.0-135.9). CONCLUSIONS: Our study showed that a high proportion of inpatient morbidity and mortality occurs in adult patients with pneumococcal bacteremia, especially among those aged ≥ 75 years.

A retrospective cohort study of panipenem/betamipron for adult pneumococcal bacteremia at three teaching hospitals in Japan.

Panipenem/betamipron (PAPM/BP) may be highly effective for life-threatening Streptococcus pneumoniae infection. However, the efficacy of PAPM/BP for S. pneumoniae infections has not been compared with that of other antimicrobial agents. We retrospectively compared PAPM/BP with other carbapenems for treatment of life-threatening infections in newly hospitalized adults with pneumococcal bacteremia. Clinical information for cases of pneumococcal bacteremia was collected from three teaching hospitals in Japan from January 2003 to December 2010. In total, 17 patients who received PAPM/BP therapy and 34 treated with other carbapenems (27 with meropenem, 4 with imipenem/cilastatin, and 3 with biapenem) were identified. The mean age (71 vs. 70 years old), sex distribution (women, 29 vs. 21 %), Charlson comorbidity index (CCI) (1.5 vs. 1.6), and rates of septic shock (29 vs. 38 %), and meningitis (5.9 vs. 8.8 %) did not differ significantly between the two groups. The inpatient mortality rates were lower in the PAPM/BP group (12 vs. 44 %, p = 0.03). Multiple logistic regression analysis adjusted for age, sex, CCI, and severe sepsis/septic shock showed that use of other carbapenems was associated with higher in-hospital mortality, with an odds ratio of 6.922 (95 % CI, 1.171-40.92) compared to PAPM/BP therapy. Initial PAPM/BP therapy might have a therapeutic advantage over other carbapenems in treatment of severe Streptococcus pneumoniae infections.

Heart-specific small subunit of myosin light chain phosphatase activates rho-associated kinase and regulates phosphorylation of myosin phosphatase target subunit 1.

Phosphorylation of myosin regulatory light chain (MLC) plays a regulatory role in muscle contraction, and the level of MLC phosphorylation is balanced by MLC kinase and MLC phosphatase (MLCP). MLCP consists of a catalytic subunit, a large subunit (MYPT1 or MYPT2), and a small subunit. MLCP activity is regulated by phosphorylation of MYPTs, whereas the role of small subunit in the regulation remains unknown. We previously characterized a human heart-specific small subunit (hHS-M(21)) that increased the sensitivity to Ca(2+) in muscle contraction. In this study, we investigated the role of hHS-M(21) in the regulation of MLCP phosphorylation. Two isoforms of hHS-M(21), hHS-M(21)A and hHS-M(21)B, preferentially bound the C-terminal one-third region of MYPT1 and MYPT2, respectively. Amino acid substitutions at a phosphorylation site of MYPT1, Ser-852, impaired the binding of MYPT1 and hHS-M(21). The hHS-M(21) increased the phosphorylation level of MYPT1 at Thr-696, which was attenuated by Rho-associated kinase (ROCK) inhibitors and small interfering RNAs for ROCK. In addition, hHS-M(21) bound ROCK and enhanced the ROCK activity. These findings suggest that hHS-M(21) is a heart-specific effector of ROCK and plays a regulatory role in the MYPT1 phosphorylation at Thr-696 by ROCK.

Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy.

AIMS: Z-band alternatively spliced PDZ-motif protein (ZASP)/Cypher is a Z-disc component of which several dilated cardiomyopathy (DCM)-associated mutations have been reported. Most of the mutations were found in exons 4 and 10 of ZASP/Cypher gene LDB3 and both exons were expressed preferentially in the heart. The aim of this study was to investigate the functional alteration of ZASP/Cypher caused by the DCM-associated mutations. METHODS AND RESULTS: The yeast-two-hybrid method was used to identify the protein bound to a domain encoded by exon 4 of LDB3. Interaction of ZASP/Cypher with the binding protein was investigated in relation to the functional alterations caused by LDB3 mutations. Localization of the ZASP/Cypher-binding protein was examined at the cellular level in rat cardiomyocytes. Phosphoglucomutase 1 (PGM1), a metabolic enzyme involved in glycolysis and gluconeogenesis, was identified as a protein interacting with ZASP/Cypher. PGM1 bound to ZASP/Cypher at the domains encoded by exons 4 and 10. Two LDB3 mutations in exon 4 (Ser189Leu and Thr206Ile) and another mutation in exon 10 (Ile345Met) reduced the binding to PGM1. PGM1 showed diffuse localization in the cytoplasm of rat cardiomyocytes under standard culture conditions, and distribution at the Z-discs was observed under stressed culture conditions. Binding of endogenous PGM1 and ZASP/Cypher was found to be enhanced by stress in rat cardiomyocytes. CONCLUSION: ZASP/Cypher anchors PGM1 to Z-disc under conditions of stress. The impaired binding of PGM1 to ZASP/Cypher might be involved in the pathogenesis of DCM.

Complex divergence at a microsatellite marker C1_2_5 in the lineage of HLA-Cw/-B haplotype.

The human leukocyte antigen (HLA) complex locus has shaped a framework for evolutionary processes because of the dense clustering and strong linkage disequilibrium (LD) of polymorphic genes. Although the landscape of LD among conventional single-nucleotide polymorphisms (SNPs) has been described, the data on the lineage of major histocompatibility complex (MHC) haplotype are limited to pairwise comparisons of several haplotypes in Caucasoid populations. Multi-allelic markers, including microsatellite markers, may provide us with a larger power to analyze the MHC haplotype lineage because the mutation rate of microsatellite exceeds that of SNPs by several orders of magnitude. In this study, we investigated the complex structure of repeat motifs in a microsatellite to figure out the structural lineage of HLA-Cw/-B segments in Japanese. It was found that the genetic differences of HLA-Cw/-B haplotype lineage were reflected by repeat motif patterns at C1_2_5 locus, suggesting that unique mutational dynamics of microsatellites may be a useful marker to chase the haplotype lineage.

[Tsutsugamushi disease during the last seven years in the past in Hamamatsu City, Shizuoka Prefecture--including evaluation of hyponatremia in scrub typhus].

Six cases of scrub typhus (tsutsugamushi disease) were reported to the Shizuoka Prefecture Hamamatsu City public health center during the seven years from 2001 to 2007. The content of the clinical record of the five cases were investigated. High serum titers of antibody to Gilliam-type Orientia tsutsugamushi were detected by immunofluorescense assay in most of these patients. Fever, rash, headache and relative bradycardia seen at a high frequency. On peripheral blood smear examination, atypical lymphocytes were detected in 3 cases. Serum electrolyte examination revealed hyponatremia in 4 (80%) patients; SIADH was suspected in one of these cases. All the patients improved promptly following start of therapy with intravenous or oral minocycline.

[Case of tsutsugamushi disease (scrub typhus) presenting with fever and pain indistinguishable from trigeminal neuralgia].

A 64-year-old man visited our clinic with a 9-day history of headache and fever. He had frequent, severe, electric shock-like pain in his left eye, forehead, and scalp. The body temperature was 37.1 degrees. Cranial nerve functions were intact. Limb weakness and stiff neck were absent. There were injection of the conjunctiva, a red rash on the trunk, and an eschar in the axilla. Abnormal laboratory findings included AST 40 IU, ALT 44 IU, CRP 16.0 mg/dl, WBC 11,090/microl, and proteinuria. CT scan was unremarkable. The cerebrospinal fluid (CSF) showed 2 polymorphs/microl, 6 lymphocytes/microl, 65 mg/dl of glucose, and 42 mg/dl of protein. A diagnosis of scrub typhus was made. Treatment with minocycline brought about prompt disappearance of the fever and dramatic clinical improvement. Increased antibody titers confirmed the diagnosis. Although almost all patients present with high fever and severe headache, only a small number of patients have CSF pleocytosis. The present case illustrates that pain in scrub typhus is, on rare occasions, indistinguishable from trigeminal neuralgia. Neurologists should have a high index of suspicion in patients with fever and headache during the epidemic season and should be familiar with the systemic symptoms and signs.