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.

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.

Molecular chaperone-mediated tau protein metabolism counteracts the formation of granular tau oligomers in human brain.

Intracellular accumulation of filamentous tau proteins is a defining feature of neurodegenerative diseases termed tauopathies. The pathogenesis of tauopathies remains largely unknown. Molecular chaperones such as heat shock proteins (HSPs), however, have been implicated in tauopathies as well as in other neurodegenerative diseases characterized by the accumulation of insoluble protein aggregates. To search for in vivo evidence of chaperone-related tau protein metabolism, we analyzed human brains with varying degrees of neurofibrillary tangle (NFT) pathology, as defined by Braak NFT staging. Quantitative analysis of soluble protein levels revealed significant positive correlations between tau and Hsp90, Hsp40, Hsp27, alpha-crystallin, and CHIP. An inverse correlation was observed between the levels of HSPs in each specimen and the levels of granular tau oligomers, the latter of which were isolated from brain as intermediates of tau filaments. We speculate that HSPs function as regulators of soluble tau protein levels, and, once the capacity of this chaperone system is saturated, granular tau oligomers form virtually unabated. This is expressed pathologically as an early sign of NFT formation. The molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapeutics for tauopathies. (c) 2007 Wiley-Liss, Inc.

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.

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.

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.

Cellular events at the onset of physiological root resorption in rabbit deciduous teeth.

For elucidation of how physiological root resorption of deciduous teeth is initiated, the cellular events that occur surrounding the root of rabbit deciduous teeth before and at the onset of physiological root resorption were observed by means of light and electron microscopy. In addition, the cytodifferentiation of odontoclasts during the initial phase of this root resorption was evaluated by histochemical staining of tartrate-resistant acid phosphatase (TRAP) activity as a marker odontoclasts and their precursors. The present investigation was focused on the physiological root resorption of the deciduous lower second molar of rabbits from Day 0-5 postnatally. At birth, the deciduous molar had not erupted yet, and no TRAP-positive cell could be found surrounding the tissue adjacent to the root of the deciduous tooth. TRAP-positive mononuclear cells were initially detected in the coronal portion of the dental follicle of the permanent tooth at Day 1 postnatally. Ultrastructurally, these mononuclear cells had moderate numbers of mitochondria and short-strand rough endoplasmic reticulum, as well as scattered free ribosomes throughout their cytoplasm. TRAP-positive mononuclear cells then appeared in the cementoblast layer immediately adjacent to the surface of the deciduous roots. These mononuclear cells projected cytoplasmic extensions between the cementoblasts and made contact with the cementum. At that time, cell-cell contact was frequently observed between these mononuclear cells and cementoblasts. During 3-5 days postnatally, the number of TRAP-positive multinucleate odontoclasts on the root surface gradually increased. They had well-developed ruffled borders and made typical resorption lacunae on the root surface of the deciduous tooth. During this early postnatal period, neither inflammatory cells nor necrotic tissue could be observed surrounding the deciduous root. This study demonstrates that the dental follicle of the permanent tooth as well as the connective tissue adjacent to the deciduous root might play important role in site- and time-specific recruitment, development, and activation of odontoclasts before and at the onset of physiological root resorption.

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.

Temporal changes in the distribution and number of macrophage-lineage cells in the periodontal membrane of the rat molar in response to experimental tooth movement.

In order to evaluate the possible role of macrophages in the remodelling of periodontal tissue in response to tooth movement, temporal changes in the number and distribution of macrophage-lineage cells in the periodontal membrane of the rat molar tooth after experimental tooth movement were examined immunohistochemically using four anti-rat monoclonal antibodies: ED1 (anti-monocyte/macrophage-lineage cells and dendritic cells), ED2 (anti-resident macrophages), KI-M2R (anti-tissue macrophages), and OX6 (anti-class II molecules). The right maxillary first molar tooth of Wistar rats was moved mesially by a closed-coil spring for 1, 3, 5, or 7 days. Sham-treated rats wearing an inactivated appliance for each experimental period and entirely untreated rats were used as controls. Alternate horizontal serial cryostat sections were cut and incubated with antibodies to ED1, ED2, KI-M2R, and OX6. In addition, cells immunopositive for each monoclonal antibody in the periodontal membrane during tooth movement were analysed on the tension and pressure sides. In the control rats, large numbers of cells positively stained with each monoclonal antibody were distributed throughout the periodontal membrane surrounding the distobuccal root. At 1 day after experimental tooth movement, the number of immunopositive cells obtained with all four monoclonal antibodies decreased as compared with those of the control on the mesial/pressure side. During the later experimental time periods, ED1- and OX6-positive cells in the periodontal membrane of this side were significantly increased in number compared with controls, whereas the density and distribution pattern of cells positive with ED2 or KI-M2R remained unchanged. On the mesial/pressure side, which underwent hyalinization, a marked accumulation of OX6- and ED1-reactive cells, but not of ED2- or KI-M2R-reactive cells, was frequently observed in the area of the hyalinized tissue at 5-7 days after the start of tooth movement. On the distal/tension side, no particular change in the distribution of immunopositive cells obtained with any antibody was detected throughout the experimental periods, with the exception that there was a significant increase in the number of ED1-positive cells and in of OX6-positive cells at 1 and 7 days, respectively, after the start of tooth movement. These results suggest that after the start of tooth movement OX6- and ED1-positive cells, which are mostly exudative macrophages, but not ED2- and KI-M2R-positive cells, i.e., resident macrophages, may be actively engaged in bone resorption and the remodelling of tissues on the pressure side of the periodontal membrane.

Multiple myeloma expressing CD19(+)CD56(-) phenotype.

A 70-year-old woman presented with monoclonal gammopathy, pancytopenia, and renal insufficiency, which were initially refractory to combination chemotherapy by VMMD (vincristine, ranimustine, melphalan, and dexamethasone) and MP (melphalan and prednisolone) regimens. The myeloma cells, which consisted of 73% of bone marrow nucleated cells, expressed CD38(+), CD19(+), CD56(-), CD45(-), CD49e(-), and MPC-1(+) phenotypes by flow cytometric analysis and showed the rearranged immunoglobulin heavy chain (IgH) gene by Southern blotting. By immunostaining, the myeloma cells were positive for cytoplasmic immunoglobulin light chain kappa. These results suggest that myeloma cells can express CD19(+)CD56(-), the phenotype considered to be expressed on only normal plasma cells.

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.

Missense point mutations of tau to segregate with FTDP-17 exhibit site-specific effects on microtubule structure in COS cells: a novel action of R406W mutation.

Missense and splicing point mutations have been found in the tau gene in families with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Of these mutations, we examined four exonic missense point mutations (G272V, P301L, V337M and R406W) in 3-repeat or 4-repeat tau isoform on the transfection experiment. The effects of two mutations (G272V or P301L) on microtubules were subtle whereas those of two other mutations (V337M or R406W) were dramatically significant when these two mutations were constructed into 3-repeat tau but not into 4-repeat tau. The R406W mutation induced an alternation of microtubules to form dotted or fragmented forms retaining colocalization of tau with tubulin whereas the V337M mutation predominantly disrupted microtubule networks and diminished colocalization of tau and tubulin. The effect of the mutations on microtubules were thus site-dependent and isoform-dependent. Tau with R406W mutation was found to be colocalized with tubulin without filamentous structures on confocal views, suggesting that the carboxyl region of tau played a different role from tubulin-binding domain on microtubule assemble. Another abnormal property was identified in tau with R406W mutation that failed to suffer phosphorylation. Thus, diverse effects of tau mutations on microtubules may explain the various clinicopathologies of FTDP-17 and related tauopathies.

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.

A high incidence of apolipoprotein E epsilon4 allele in middle-aged non-demented subjects with cerebral amyloid beta protein deposits.

We examined the apolipoprotein E (ApoE) genotypes of 19 middle-aged non-demented subjects with cerebral amyloid beta protein (Abeta) deposits, and compared the results with those of 16 patients with sporadic Alzheimer's disease (AD) and those of 34 age-matched controls. The frequency of the ApoE epsilon4 allele was higher (P = 0.0256) in these 19 subjects (0.211) than in controls (0.059), and was close to that in AD patients (0.281). This result suggests that middle-aged non-demented subjects with cerebral Abeta deposits are at high risk of developing AD, and that the diffuse Abeta deposits in these cases represent an early stage of AD pathology. We speculate that in the majority of late-onset sporadic AD patients, cerebral Abeta deposition commences when these patients are in their forties or fifties, and that the pathological process progresses gradually, taking 20 to 30 years for clinical manifestation of dementia.