Outcomes of Pleural Space Infections in Patients With Indwelling Pleural Catheters for Active Malignancies.

BACKGROUND: Pleural infections related to indwelling pleural catheters (IPCs) are an uncommon clinical problem. However, management decisions can be complex for patients with active malignancies due to their comorbidities and limited life expectancies. There are limited studies on the management of IPC-related infections, including whether to remove the IPC or use intrapleural fibrinolytics. METHODS: We conducted a retrospective cohort study of patients with active malignancies and IPC-related empyemas at our institution between January 1, 2005 and May 31, 2021. The primary outcome was to evaluate clinical outcomes in patients with malignant pleural effusions and IPC-related empyemas treated with intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) compared with those treated with tPA alone or no intrapleural fibrinolytic therapy. The secondary outcome evaluated was the incidence of bleeding complications. RESULTS: We identified 69 patients with a malignant pleural effusion and an IPC-related empyema. Twenty patients received tPA/DNase, 9 received tPA alone, and 40 were managed without fibrinolytics. Those treated with fibrinolytics were more likely to have their IPCs removed as part of the initial management strategy ( P =0.004). The rate of surgical intervention and mortality attributable to the empyema were not significantly different between treatment groups. There were no bleeding events in any group. CONCLUSION: In patients with IPC-related empyemas, we did not find significant differences in the rates of surgical intervention, empyema-related mortality, or bleeding complications in those treated with intrapleural tPA/DNase, tPA alone, or no fibrinolytics. More patients who received intrapleural fibrinolytics had their IPCs removed, which may have been due to selection bias.

Development of a fast response neutron detector for the supersonic FRC collision process.

The collisional merging experiments of the field-reversing configuration (FRC) at supersonic/Alfvénic velocities have been performed in the FRC Amplification via Translation-Collisional Merging device only in Japan. This experiment may excite shockwaves and cause particle acceleration. To obtain supporting evidence of particle acceleration by shockwaves, we have proposed to observe neutrons originating from the D-D fusion reaction of accelerated non-thermal particles. A plastic scintillation detector has been developed for the supersonic/Alfvénic collision/merging FRC experiment. The developed neutron detector has sufficient performance of neutron sensitivity and nanosecond response time. In the collisional merging process, we obtained a signal that could be considered a neutron, which is not predicted by the adiabatic compression process in the two-dimensional magnetohydrodynamics simulation.

Risk Factors for and Time to Recurrence of Symptomatic Malignant Pleural Effusion in Patients With Metastatic Non-Small Cell Lung Cancer with EGFR or ALK Mutations.

BACKGROUND: The main goal of management in patients with non-small cell lung cancer (NSCLC) and malignant pleural effusion (MPE) is palliation. Patients with MPE and actionable mutations, because their disease is expected to respond quickly and markedly to targeted therapy, are less likely than those without actionable mutations to receive definitive MPE management. Whether such management is indicated in these patients is unclear. RESEARCH QUESTIONS: What is the time to ipsilateral MPE recurrence requiring intervention in patients with metastatic NSCLC by mutation status? What are the risk factors for MPE recurrence? STUDY DESIGN AND METHODS: Retrospective cohort study of consecutive patients who underwent initial thoracentesis for MPE. We used a Fine-Gray subdistribution hazard model to calculate the time to ipsilateral MPE recurrence requiring intervention within 100 days of initial thoracentesis and to identify variables associated with time to pleural fluid recurrence. RESULTS: A total of 396 patients, comprising 295 (74.5%) without and 101 (25.5%) with actionable mutations, were included. Most patients with actionable mutations (90%) were receiving targeted treatment within 30 days of initial thoracentesis. On univariate analysis, patients with actionable mutations showed a significantly higher hazard of MPE recurrence. On multivariate analysis, this difference was not significant. Larger pleural effusion size on chest radiography (P < .001), higher pleural fluid lactate dehydrogenase (P < .001), and positive cytologic examination results (P = .008) were associated with an increased hazard of recurrence. INTERPRETATION: Our findings indicate that patients with actionable mutations have a similar risk of MPE recurrence when compared with patients without mutations and would benefit from a similar definitive management approach to MPE.

Leptomeningeal Enhancement due to Neurosarcoidosis Mimicking Malignancy.

The present report describes the case of a 56-year-old African American man experiencing progressive disequilibrium, lower extremity weakness, difficulty walking, and hearing loss. Brain magnetic resonance imaging showed leptomeningeal enhancement. Initial differential diagnosis was broad, including malignant, infectious, and inflammatory etiologies. The cerebrospinal fluid analyses demonstrated lymphocytic pleocytosis, hypoglycorrhachia, and hyperproteinorrachia but no other abnormalities. An extensive infectious disease workup was negative. Positron emission tomography revealed hypermetabolic lymph nodes in the right mediastinum and right hilum, correlating with findings on endobronchial ultrasonography. Subsequently, image-guided fine-needle aspiration of the right upper paratracheal lymph node was performed, and biopsy studies showed noncaseating granulomatous inflammation. Based on the clinical picture, the diagnosis of neurosarcoidosis was made, and high-dose steroids were started and resulted in significant improvement.

Binding of monoclonal antibody AA4 to gangliosides on rat basophilic leukemia cells produces changes similar to those seen with Fc epsilon receptor activation.

The mAb AA4 binds to novel derivatives of the ganglioside Gd1b on rat basophilic leukemia (RBL-2H3) cells. Some of the gangliosides are located close to the high affinity IgE receptor (Fc epsilon RI), and binding of mAb AA4 inhibits Fc epsilon RI-mediated histamine release. In the present study, mAb AA4 was found to bind exclusively to mast cells in all rat tissues examined. In vitro, within 1 min of mAb AA4 binding, the cells underwent striking morphologic changes. They lost their normal spindle shaped appearance, increased their ruffling, and spread over the surface of the culture dish. These changes were accompanied by a redistribution of the cytoskeletal elements, actin, tubulin, and vimentin, but only the actin was associated with the membrane ruffles. Binding of mAb AA4 also induces a rise in intracellular calcium, stimulates phosphatidyl inositol breakdown, and activates PKC. However, the extent of these changes was less than that observed when the cells were stimulated with antigen or antibody directed against the Fc epsilon RI. None of these changes associated with mAb AA4 binding were seen when the cells were exposed to nonspecific IgG, IgE, or four other anti-cell surface antibodies, nor were the changes induced by binding mAb AA4 at 4 degrees C or in the absence of extracellular calcium. Although mAb AA4 does not stimulate histamine release, it enhances the effect of the calcium ionophore A23187 mediated release. The morphological and biochemical effects produced by mAb AA4 are similar to those seen following activation of the cell through the IgE receptor. Therefore, the surface gangliosides which bind mAb AA4 may function in modulating secretory events.

Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.

JNPL3 transgenic mice expressing a mutant tau protein, which develop neurofibrillary tangles and progressive motor disturbance, were crossed with Tg2576 transgenic mice expressing mutant beta-amyloid precursor protein (APP), thus modulating the APP-Abeta (beta-amyloid peptide) environment. The resulting double mutant (tau/APP) progeny and the Tg2576 parental strain developed Abeta deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. These results indicate that either APP or Abeta influences the formation of neurofibrillary tangles. The interaction between Abeta and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer's disease.

Tau oligomerization: a role for tau aggregation intermediates linked to neurodegeneration.

Intracellular accumulation of filamentous tau proteins is a defining feature of neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and frontotemporal dementia with Parkinsonism linked to chromosome 17, all known collectively as tauopathies. Tau protein is a member of microtubule (MT)-associated proteins. Tau is a highly soluble and natively unfolded protein dominated by a random coil structure in solution. It is believed that aberrant modifications of tau, including phosphorylation, truncation, and conformational changes, induce filamentous aggregation. However, the mechanism underlying the conversion of tau protein from a soluble state to one of insoluble aggregates still remains elusive. The importance of tau aggregation intermediates (e.g. tau dimer, tau multimer, and granular tau oligomer) in disease pathogenesis was suggested by recent studies. Here, we review the latest developments in tracking the structural changes of tau protein and discuss the utility improving our understanding of tau aggregation pathway leading to human tauopathies.

Hard tissue formation in subcutaneously transplanted rat dental pulp.

While dental pulp appears to be able to form mineralized matrices that do not always resemble dentin, the precise characteristics of the hard tissue and the mechanism of its induction remain unknown. Therefore, we evaluated hard tissue induced by transplantation of pulp into subcutaneous tissue. Seven days after transplantation, initial hard tissue was formed at the inner periphery of the pulp. After 14 days, this hard tissue expanded inwardly. Mineralized matrix was immunopositive for osteocalcin, osteopontin, and bone sialoprotein, but negative for dentin sialoprotein. Transplantation of GFP-labeled pulp into wild-type rats showed these formative cells to have been derived from the transplant. TEM observation revealed apatite crystals within necrotic cells and matrix vesicles at the initial stage of calcification. These results indicate that pulp cells possess the ability to form a bone- or cementum-like matrix. Calcification of the matrix may occur in necrotic cells and matrix vesicles, followed by collagenous calcification.

Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells.

Acute promyelocytic leukemia (APL) cells express a considerable level of CD33, which is a target of gemtuzumab ozogamicin (GO), and a significantly lower level of P-glycoprotein (P-gp). In this study, we examined whether GO was effective on all-trans retinoic acid (ATRA)- or arsenic trioxide (ATO)-resistant APL cells. Cells used were an APL cell line in which P-gp was undetectable (NB4), ATRA-resistant NB4 (NB4/RA), NB4 and NB4/RA that had been transfected with MDR-1 cDNA (NB4/MDR and NB4/RA/MDR, respectively), ATO-resistant NB4 (NB4/As) and blast cells from eight patients with clinically ATRA-resistant APL including two patients with ATRA- and ATO-resistant APL. The efficacy of GO was analyzed by (3)H-thymidine incorporation, the dye exclusion test and cell cycle distribution. GO suppressed the growth of NB4, NB4/RA and NB4/As cells in a dose-dependent manner. GO increased the percentage of hypodiploid cells significantly in NB4, NB4/RA and NB4/As cells, and by a limited degree in NB4/MDR and NB4/RA/MDR cells. Similar results were obtained using blast cells from the patients with APL. GO is effective against ATRA- or ATO-resistant APL cells that do not express P-gp, and the mechanism of resistance to GO is not related to the mechanism of resistance to ATRA or ATO in APL cells. Leukemia (2005) 19, 1306-1311. doi:10.1038/sj.leu.2403807; published online 26 May 2005.

Arsenic trioxide therapy for relapsed or refractory Japanese patients with acute promyelocytic leukemia: need for careful electrocardiogram monitoring.

Recent studies have shown that arsenic trioxide (As(2)O(3)) can induce complete remission in patients with acute promyelocytic leukemia (APL). We tested the efficacy and safety of As(2)O(3) for the treatment of patients with APL who had relapsed from or become refractory to all-trans retinoic acid (ATRA) and conventional chemotherapy in a prospective study. As(2)O(3) at a dose of 0.15 mg/kg was administered until the date of bone marrow remission to a maximum of 60 days. In patients who achieved complete remission (CR), one additional course of As(2)O(3) was administered using the same dose for 25 days. Of 14 patients, 11 (78%) achieved CR. Six of 10 patients who achieved CR showed disappearance of PML-RARalpha transcript by RT-PCR assay. The duration of As(2)O(3)-induced CR ranged from 4 to 22 months (median, 8 months) at a median follow-up of 17 months. Adverse events included 13 electrocardiogram abnormalities (13 QTc prolongation, eight ventricular premature contraction, four nonsustained ventricular tachycardia and two paroxysmal supraventricular tachycardia), seven nausea and vomiting, four pruritus, three peripheral neuropathy, three fluid retention and one APL differentiation syndrome. Four patients received antiarrhythmic agents. Hyperleukocytosis developed in five patients and in three cytotoxic drugs were necessary. Other adverse events were relatively mild. As(2)O(3) treatment is effective and relatively safe in relapsed or refectory patients with APL. Cardiac toxicities in patients with QTc prolongation should be carefully monitored.

Presenilin 1 cleavage is a universal event in human organs.

A panel of antibodies raised against various regions of human presenilin 1(PS1)--the amino-terminal domain, the domain between the transmembrane domains 1 and 2, the cleavage-site, loop domains, or carboxyl-terminal domain--was prepared to analyze PS1 in human tissues. We observed the predominance of two fragments (28-kDa NH2 and 18-kDa COOH fragments) in various tissues, including cerebral cortices. In addition to these two fragments, we found a previously unidentified amino-terminal fragment of PS1 with Mr 14 kDa in the lungs, spleen, pancreas, and testes. Using a sensitive ELISA for PS1, we measured the amount of PS1 species in tissues and found high contents of PS1 fragment in the testes. Our data show that common and unique processing pathways of PS1 occur in a tissue-dependent manner. It is likely that cleavage at the loop structure of PS1 to produce a functional form is a common event in human organs.

Identification and characterization of presenilin I-467, I-463 and I-374.

We cloned a novel isoform of presenilin I (presenilin I-374) besides previously published presenilin I-467 and I-463 in human lymphocytes. Presenilin I-463 was identical to presenilin I-467 except a 12 bp nucleotides deletion in its amino terminal region. Another isoform, presenilin I-374 was produced by an alternative splicing with an additional exon consisting of 92 bp nucleotides (exon 11), which resulted in the frame shift with a stop codon to generate a truncated presenilin consisting of 374 amino acids. The transcripts for presenilin I-467/463 was ubiquitously detected while that for presenilin I-374 was selectively detected in liver, spleen, kidney. Abnormal behavior of presenilin I on gel electrophoresis was found with affinity-purified antibodies against presenilin I.

Proteolytic processing of presenilin-1 (PS-1) is not associated with Alzheimer's disease with or without PS-1 mutations.

Cerebral presenilin-1 protein (PS-1) is normally composed of the amino-terminal fragment (NTF) with Mr 28 kDa and the carboxy-terminal fragment (CTF) with 18 kDa. We analyzed human PS-1 in brains with early-onset familial Alzheimer's disease (FAD) with and without PS-1 mutations to study whether mutated PS-1 was abnormally metabolized. Cerebral PS-1 were found to be cleaved into two fragments of NTF and CTF independently of the occurrence of PS-1 mutation in human brains. A small portion of PS-1 was recently found to suffer another processing by caspase-3, an apoptosis-related cysteine protease. In contrast to the recent finding that the Volga-German mutation on presenilin-2 (PS-2) affects the increasing caspase-3 PS-2 fragment, the PS-1 mutation did not cause a significant change in PS-1 fragmentation. We conclude that PS-1 fragmentation and other (probably caspase-3-mediated) digestion following apoptosis occur independently of PS-1 mutations.

Apolipoprotein E allele-dependent antioxidant activity in brains with Alzheimer's disease.

Thiobarbituric acid-reactive substances (TBARS), an index of lipid peroxidation, were assayed in postmortem brain. Basal TBARS levels were increased and oxidative stimulation produced more TBARS in AD relative to control brains. In addition, apolipoprotein E isoforms showed differing antioxidant activities, with E2 > E3 > E4, suggesting that the lowest antioxidant activity of E4 could contribute to its association with AD.

Fibrinogens Kosai and Ogasa: Bbeta15Gly-->Cys (GGT-->TGT) substitution associated with impairment of fibrinopeptide B release and lateral aggregation.

We found two heterozygous dysfibrinogenemias, designated fibrinogen Kosai and fibrinogen Ogasa. Kosai was associated with arteriosclerosis obliterans but Ogasa showed no bleeding or thrombotic tendencies. The plasma fibrinogen concentrations from the two propositi (Ogasa and Kosai) were much lower when determined by the thrombin-time method (0.94 and 1.06 g L(-1), respectively) than when determined by the immunological method (2.87 and 2.72 g L(-1), respectively). We performed DNA sequencing and functional analyses to clarify the relationship between the structural and functional abnormalities. Genetic analysis of PCR-amplified DNA from the propositi identified the heterozygous substitution Bbeta15Gly-->Cys (GGT-->TGT). Western blotting analysis of purified fibrinogen revealed the existence of albumin-fibrinogen complexes. Functional analyses indicated that compared with the normal control, the propositi's fibrinogen released only half the normal amount of fibrinopeptide B and showed markedly impaired polymerization. In addition, the observation of thinner fibers in fibrin clots (by scanning electron microscopy) indicated markedly defective lateral aggregation in the variant fibrinogens. The impaired functions may be due to the substitution of Cys for Bbetao15Gly plus the existence of some additional disulfide-bonded forms.

Morphological changes induced by the calcium ionophore A23187 in rat basophilic leukemia (2H3) cells.

RBL-2H3 cells have been widely used to study histamine release in vitro. It was previously shown that these cells undergo striking morphological changes after IgE-mediated secretion. The present study was undertaken to examine if the morphological changes were dependent on activation of the Fc epsilon receptor. Therefore, the cells were stimulated to release histamine by two different mechanisms: activation of the Fc epsilon receptor by antigen and treatment with the calcium ionophore A23187. Cell surface and cytoskeletal changes were examined by fluorescence microscopy and scanning electron microscopy after either IgE- or ionophore-mediated histamine release. After exposure of the cells to either secretagogue, the cells spread over the surface of the culture dish and underwent rearrangement of the cytoskeleton. In addition, scanning electron microscopy revealed that deep ruffles developed on the surface of the cells undergoing IgE-mediated release. The surface changes were not as pronounced with the ionophore. The distribution of the cytoskeletal elements was examined by immunofluorescence using FITC-phalloidin and antibodies against vimentin and tubulin. In unstimulated cells actin was localized at the cell periphery, just under the plasma membrane. In the stimulated cells it was associated with the cell periphery and concentrated in the surface ruffles. As the stimulated cells spread, intermediate filaments and microtubules became distributed throughout the cell body, but there was no obvious association with the membrane ruffles. These morphological changes were dependent on the presence of extracellular calcium and on the concentration of ionophore or antigen, and were also correlated with the amount of histamine released. Additionally, IgE-mediated stimulation led to increased uptake of the soluble-phase tracer Lucifer yellow, whereas stimulation with the ionophore A23187 showed no increase in Lucifer yellow internalization. Ionophore A23187 produced changes similar but not identical to those seen in the RBL-2H3 cells after IgE-mediated histamine release. The differences may be owing to the involvement of the Fc epsilon receptor in IgE-mediated secretion.

Immunohistochemical localization of dipeptidyl aminopeptidase IV in rat kidney, liver, and salivary glands.

Specific antibodies directed against dipeptidyl aminopeptidase (DAP) IV prepared from rat and pig kidneys were produced in rabbits. Using a peroxidase-labeled or fluorescein isothiocyanate-labeled antibody method, localization of DAP IV was investigated in various tissues of the rat (kidney, liver and salivary glands). DAP IV was mainly localized in the brush border of the proximal tubules (kidney), in the cell membrane around bile canaliculi of hepatic cells (liver), and in the cell membrane of serous acinar cells (parotid and submaxillary glands). These results substantiate that DAP IV is a membrane-bound peptidase.

Amyloid-beta-protein isoforms in brain of subjects with PS1-linked, beta APP-linked and sporadic Alzheimer disease.

To determine whether similar abnormalities of various soluble full-length and N-terminal truncated Abeta peptides occur in postmortem cerebral cortex of affected PS1 mutation carriers, we examined the amounts of two amyloid species ending at residue 40 or at residues 42(43) using sandwich ELISA systems. Our results indicate that PS1 mutations effect a dramatic accumulation in brain of the highly insoluble potentially neurotoxic long-tailed isoforms of the Abeta peptide such as Abeta1-42(43) and Abetax-42(43). This enhancing effect of PS1 mutation on Abetax-42(43) deposition was highly similar to that of a betaAPP mutation (Val717Ile) but the effects on Abetax-40 production were significantly different between these two causal genes. In contrast to previous studies of soluble Abeta in plasma and in supernatants from cultured fibroblasts of subjects with PS1 mutations, our studies also show that there is an increase in insoluble Abetax-40 peptides in brain of subjects with PS1 mutations.

The tau mutation (val337met) disrupts cytoskeletal networks of microtubules.

The missense point mutation found in the tau gene, which was segregated in a family with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), has proved to be the causal molecule for widely spread dementia diseases. Here we examined the effects of the tau mutation using confocal analysis. When wild-type tau cDNA was introduced into cells, extensive cell processes and well-developed thick bundles of microtubules were induced. On the other hand, when altered tau cDNA with the mutation (valine337-methionine) was introduced, cell lost processes and microtubule networks resulted in more round cell shape but showed intact mitochondria or endoplasmic reticulum. We conclude that the tau mutation primarily affects the microtubules and resultantly causes the loss of cellular organization and function due to microtubule disruption.