Pyopneumothorax with bronchopleural fistula due to pulmonary infection caused by Porphyromonas gingivalis in a patient with periodontitis

Pyopneumothorax with bronchopleural fistula is a rare complication of lung infection. We herein report a case of pyopneumothorax with bronchopleural fistula caused by Porphyromonas gingivalis infection, a common pathogenic pathogen of periodontitis, in a 49-year-old man with periodontitis. The patient was admitted with respiratory failure. Pleural puncture yielded a lot of gas continually and foul-smelling light brown pus, which was found to be caused due to infection with P. gingivalis by the metagenomic next generation sequencing (mNGS) and anaerobic culture.     

Morbidly obese patient with non‐alcoholic steatohepatitis‐related cirrhosis who died from sepsis caused by dental infection of Porphyromonas gingivalis: A case report

Non‐alcoholic steatohepatitis (NASH) is associated with increased risks of developing lifestyle‐related diseases including type 2 diabetes, cardiovascular disease and cerebral vessel disease. While the two‐hit hypothesis and, recently, multiple parallel hits hypothesis of NASH pathogenesis were proposed, further details have not emerged. Recently, dental infection of Porphyromonas gingivalis (P. gingivalis) has been reported as a critical risk factor for NASH progression, which acts as multiple parallel hits to induce inflammation and fibrogenic responses in steatosis. We describe here a 54‐year‐old woman who died from sepsis and was diagnosed with NASH. Briefly, her body mass index (BMI) at the age of 35 years old had been 25.6 kg/m², but she became obese after withdrawing into her home at the age of 45 years. Severe obesity continued over 19 years without diabetes mellitus. She was admitted to our hospital due to a sudden disturbance of consciousness. On admission, her BMI was 48.5 kg/m². Computed tomography revealed cirrhotic liver with massive ascites, and laboratory data indicated increased inflammatory responses, renal failure and C grade Child–Pugh classification, suggesting the diagnosis of sepsis. Also, severe periodontal disease was present, because the patient's front teeth fell out easily during intubation. Although the focus of infection was not specified, the oral flora Parvimonas micra, a periodontal pathogen, was detected in venous blood. In spite of intensive care including artificial respiration management and continuous hemodiafiltration, she died on the 43rd day after admission. Surprisingly, P. gingivalis was detected in her hepatocytes. This case may represent the significance of P. gingivalis in the progress to cirrhosis in NASH patients.     

A theoretical framework for the immunoepidemiology of helminth infection

Field studies of parasitic helminths in endemically infected human communities have provided quantitative information on the relationships between parasite burdens, immune responses and age. There are considerable difficulties in the interpretation of these immunoepidemiological data due to the complexities of the biological processes generating the observed patterns. In this paper simple mathematical models are used to explore the expected patterns of variation with host age in parasite burdens, the aggregation of parasites among hosts, levels of immune response, and the correlation between parasite burdens and immune responses. These relationships reflect rates of infection, rates of parasite mortality, the strength of the immune response, and the duration of immunological memory. The models generate some complex and counterintuitive patterns. The analysis suggests that some of these patterns might serve to (i) distinguish effects due to acquired immunity from effects due to age-dependent exposure, (ii) identify potentially protective immune responses, and (iii) identify the parasite stages important in the development of acquired immunity. The results imply that previous analyses of immunoepidemiological data may have been overly simplistic and, especially, that patterns believed to be inconsistent with protective immunity may have been incorrectly interpreted.     

A highly variable segment of human subterminal 16p reveals a history of population growth for modern humans outstide Africa

We have sequenced a highly polymorphic subterminal noncoding region from human chromosome 16p13.3 flanking the 5' end of the hypervariable minisatellite MS205, in 100 chromosomes sampled from different African and Euroasiatic populations. Coalescence analysis indicates that the time to the most recent common ancestor (approximately 1 million years) predates the appearance of anatomically modern human forms. The root of the network describing this variability lies in Africa. African populations show a greater level of diversity and deeper branches. Most Euroasiatic variability seems to have been generated after a recent out-of-Africa range expansion. A history of population growth is the most likely scenario for the Euroasiatic populations. This pattern of nuclear variability can be reconciled with inferences based on mitochondrial DNA.     

High-throughput sequencing reveals a simple model of nucleosome energetics

We use genome-wide nucleosome maps to study sequence specificity of intrinsic histone-DNA interactions. In contrast with previous approaches, we employ an analogy between a classical one-dimensional fluid of finite-size particles in an arbitrary external potential and arrays of DNA-bound histone octamers. We derive an analytical solution to infer free energies of nucleosome formation directly from nucleosome occupancies measured in high-throughput experiments. The sequence-specific part of free energies is then captured by fitting them to a sum of energies assigned to individual nucleotide motifs. We have developed hierarchical models of increasing complexity and spatial resolution, establishing that nucleosome occupancies can be explained by systematic differences in mono- and dinucleotide content between nucleosomal and linker DNA sequences, with periodic dinucleotide distributions and longer sequence motifs playing a minor role. Furthermore, similar sequence signatures are exhibited by control experiments in which nucleosome-free genomic DNA is either sonicated or digested with micrococcal nuclease, making it possible that current predictions based on high-throughput nucleosome-positioning maps are biased by experimental artifacts.     

A theoretical framework for the immunoepidemiology of blocking antibodies to helminth infection

Epidemiological evidence is widely cited in support of the hypothesis that certain antibody responses to human helminth, especially schistosome, infection exhibit blocking activity. This evidence includes positive correlations between antibody levels and the rate of re-establishment of infection following chemotherapy, antibody levels which peak in younger and more susceptible age classes, lower ratios of blocking antibodies to others in older and less susceptible age classes. In this paper simple mathematical models are used to explore expected age-specific relationships between antibody levels, parasite burdens and re-establishment rates for different combinations of protective, neutral and blocking immune responses. In general, all the above cited patterns may be generated without invoking blocking activity, especially if the abilities to produce different antibody responses have different immunological memories, i.e. persist for different lengths of time in the absence of continued exposure to antigen. None of these patterns, including a positive correlation between antibody levels and rates of re-establishment following chemotherapy, offers unambiguous evidence for blocking activity. Blocking activity is also predicted to affect the shape of the age-intensity curve and the relationship between susceptibility to infection and age in ways which are not necessarily consistent with the epidemiological evidence. The importance of the blocking activity, which has been convincingly demonstrated in vitro, to population level immunoepidemiological patterns in the field therefore remains uncertain.     

A model system of oral HIV exposure, using human palatine tonsil, reveals extensive binding of HIV infectivity, with limited progression to primary infection

Oral exposure to human immunodeficiency virus (HIV) type 1 results in systemic infection, but many details surrounding virus transmission remain unresolved. We developed a mucosal model, using human palatine tonsil with intact external epithelium, to study events after oral exposure to HIV. When applied to the external epithelium, semen from an HIV-seropositive patient and cell-free virus both established HIV infection in individual tonsillar cells. However, clusters of infected tonsillar cells were detected where the epithelial surface was damaged. Investigation of the initial events in HIV transmission revealed extensive and stable binding of HIV virions and seminal cells to tonsil epithelium. In experiments modeling physiologically relevant events, the addition of seminal plasma resulted in enhanced virion binding to epithelial cells. These results indicate that, although extensive binding of HIV virions and seminal cells can be demonstrated at an exposed mucosal surface, there is only limited progression from binding to primary infection.     

Clinical and laboratory practices in investigation of suspected transfusion-transmitted bacterial infection: a survey of Canadian hospitals

Transfusion of a bacterially contaminated blood product can have serious consequences. We undertook an electronic survey of representative Canadian hospitals to determine current clinical and laboratory practices for investigating such reactions, prior to the development of national guidelines. There was considerable variability in symptoms and signs that would trigger investigation of possible contamination. The most frequent laboratory investigations performed were aerobic blood cultures of recipients and the residual component. If there is no residual product in the component bag, 36% of respondents would use a segment to perform testing. Guidelines could be helpful in improving and standardizing these practices.     

Impact of enhanced tuberculosis diagnosis in South Africa: a mathematical model of expanded culture and drug susceptibility testing

South Africa has high rates of tuberculosis (TB), including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Expanding access to culture and drug susceptibility testing (DST) for TB diagnosis may help control this epidemic, but the potential impact of existing and novel TB diagnostics is uncertain. By fitting to World Health Organization epidemiological estimates, we developed a compartmental difference-equation model of the TB/HIV epidemic among South African adults. Performing culture and DST in 37% of new cases and 85% of previously treated cases was projected to save 47,955 lives (17.2% reduction in TB mortality, 95% simulation interval (S.I.) 8.9-24.4%), avert 7,721 MDR-TB cases (14.1% reduction, 95% S.I. 5.3-23.8%), and prevent 46.6% of MDR-TB deaths (95% S.I. 32.6-56.0%) in South Africa over 10 years. Used alone, expanded culture and DST did not reduce XDR-TB incidence, but they enhanced the impact of transmission-reduction strategies, such as respiratory isolation. In South Africa, expanding TB culture and DST could substantially reduce TB, and particularly MDR-TB, mortality. Control of XDR-TB will require additional interventions, the impact of which may be enhanced by improved TB diagnosis.     

A pilus-deficient mutant of Haemophilus ducreyi is virulent in the human model of experimental infection

Haemophilus ducreyi expresses fine tangled pili, which are composed predominantly of a major subunit (FtpA). Confocal microscopy showed that an FtpA-specific monoclonal antibody bound to bacteria in biopsy samples obtained from infected human volunteers. To test the role of pili in pathogenesis, an isogenic mutant (35000HP-SMS1) was constructed by insertionally inactivating ftpA. 35000HP-SMS1 did not express FtpA and was nonpiliated but was otherwise identical to its parent, 35000HP. Seven healthy adults were challenged on the upper arm with the isogenic isolates in a double-blinded, escalating dose-response study. Sites inoculated with the mutant produced papules and pustules at rates similar to the rates observed at sites inoculated with the parent. The recovery rate of H. ducreyi from cultures and the histopathology of biopsy samples obtained from pustules inoculated with 35000HP or 35000HP-SMS1 were similar. Although pili are expressed in vivo, FtpA is not required for pustule formation in the human challenge model.     

A quantitative framework for a multi-group model of Schistosomiasis japonicum transmission dynamics and control in Sichuan,China

A quantitative framework is presented for the site-specific characterization of schistosomiasis transmission with the object of developing local control strategies. Central to the framework is a worm-burden model using ordinary differential equations of disease transmission in risk groups defined by residence and occupation. The model incorporates temperature- and precipitation-dependent seasonality of infectious stages, snail population dynamics, and seasonal patterns of human water contact specific to the local agricultural setting. The model's parameters are separated into two main subsets, those associated with the general biology of the parasite and its life cycle in the human and the snail and those associated with directly measurable features of disease status in the local population or relevant aspects of the local environment. In this regard, the model is structured and parameterized to take maximum advantage of data that can be collected in rural China by conventional methods. For example, it includes a statistical model for egg excretion to the environment by each risk group which is based on local population surveys of the prevalence and intensity of infection. The second element of the framework of analysis relates to the strategy for parameter estimation and calibration to local conditions. We propose a Bayesian approach in which parameter estimates are refined over time by methods employing extensive computer simulations. An early analysis of data collected between 1987 and 1989 in endemic villages near Xichang City in southwestern Sichuan provides encouragement that parametric uncertainty can be reduced to levels adequate to explore effective control strategies.     

A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation

The gene causative for the human nonsyndromic recessive form of deafness DFNB22 encodes otoancorin, a 120-kDa inner ear-specific protein that is expressed on the surface of the spiral limbus in the cochlea. Gene targeting in ES cells was used to create an EGFP knock-in, otoancorin KO (Otoa^EGFP/EGFP) mouse. In the Otoa^EGFP/EGFP mouse, the tectorial membrane (TM), a ribbon-like strip of ECM that is normally anchored by one edge to the spiral limbus and lies over the organ of Corti, retains its general form, and remains in close proximity to the organ of Corti, but is detached from the limbal surface. Measurements of cochlear microphonic potentials, distortion product otoacoustic emissions, and basilar membrane motion indicate that the TM remains functionally attached to the electromotile, sensorimotor outer hair cells of the organ of Corti, and that the amplification and frequency tuning of the basilar membrane responses to sounds are almost normal. The compound action potential masker tuning curves, a measure of the tuning of the sensory inner hair cells, are also sharply tuned, but the thresholds of the compound action potentials, a measure of inner hair cell sensitivity, are significantly elevated. These results indicate that the hearing loss in patients with Otoa mutations is caused by a defect in inner hair cell stimulation, and reveal the limbal attachment of the TM plays a critical role in this process.The sensory epithelium of the cochlea, the organ of Corti (Fig. 1), contains two types of hair cell, the purely sensory inner hair cells (IHCs) and the electromotile, sensorimotor outer hair cells (OHCs). These cells are critically positioned between two strips of ECM, the basilar membrane (BM) and the tectorial membrane (TM). Signal processing in the cochlea is initiated when sound-induced changes in fluid pressure displace the BM in the transverse direction, causing radial shearing displacements between the surface of the organ of Corti (the reticular lamina) and the overlying TM (1). The radial shear is detected by the hair bundles of the IHCs and the OHCs (2), with the stereocilia of the OHC hair bundles forming an elastic link between the organ of Corti and the overlying TM (3). Deflection of the stereocilia gates the hair cell’s mechanoelectrical transducer (MET) channels, thereby initiating a MET current (4) that promotes active mechanical force production by the OHCs, which, in turn, influences mechanical interactions between the TM and the BM (5, 6). This nonlinear frequency-dependent enhancement process, which boosts the sensitivity of cochlear responses to low-level sounds and compresses them at high levels, is known as the cochlear amplifier (7).Open in a separate windowFig. 1.Schematic cross-section of WT cochlea. Spiral lamina (SLAM), spiral ligament (SLIG), inner pillar cells (IPC), outer pillar cells (OPC), Deiters'' cells (DC), phalangeal process of DC (PhP), Claudius cells (CC), OHC, IHC, reticular laminar (RL), spiral limbus (SL), and major noncellular elements (BM and TM).Whereas the hair bundles of the OHCs are imbedded into the TM and therefore directly excited by relative displacement of the undersurface of the TM and the reticular lamina, those of the IHCs are not in direct contact with the TM, and the way in which they are driven by motion of the BM remains unclear. Intracellular recordings of the receptor potentials in IHCs indicate that the bundles are velocity-coupled (to fluid flow) at low frequencies and displacement-coupled at higher frequencies of stimulation (2, 8, 9). Direct measurements of the motion of the reticular lamina and the lower surface of the TM in an ex vivo preparation of the guinea pig cochlea provide evidence that, at frequencies below 3 kHz, counterphase transverse movements of the two surfaces generate pulsatile fluid movements in the subtectorial space that could drive the hair bundles of the IHCs (10). At higher frequencies, the two surfaces move in phase, and radial shear alone is thought to dominate. Theoretical studies (11) reveal that the boundary layers will be vanishingly thin at high frequencies, that the fluid in the gap between the TM and the reticular lamina will be inviscid, and that the hydrodynamic forces on the hair bundle will be inertial. Although an overlying TM that is not directly attached to a hair bundle does not apply torque to the hair bundle (11), the inertial force of the fluid driving the hair bundle depends on its mass and therefore the size of the gap between the reticular lamina and the TM (11, 12).The TM is composed of radially arrayed collagen fibrils that are imbedded in a noncollagenous matrix composed of a number of different glycoproteins, including Tecta, Tectb, otogelin, otolin, and Ceacam16 (13–16). Mutations in Tecta cause recessive (DFNB21) and dominant (DFNA8/12) forms of human hereditary deafness (17–19), and a dominant missense mutation in Ceacam16 (DFNA4) has been identified recently as a cause of late-onset progressive hearing loss in an American family (15). Mutations in Tecta are one of the most common causes of autosomal-dominant, nonsyndromic hereditary hearing loss (20), and mouse models for the recessive (21) and dominant (22) forms of deafness arising from mutations in Tecta have been created. Together with data from a Tectb-null mutant mouse (23), these studies have provided evidence that the TM plays multiple roles in hearing (24). Although much is known about the structure of the TM, an ECM that is unique to the cochlea, relatively little is known about how it attaches to the apical surface of the cochlear epithelium. Otoancorin, a product of the DFNB22 locus, is expressed on the apical surface of the spiral limbus and has been suggested to mediate TM attachment to this region of the cochlear epithelium (25). In this study, we use gene targeting to inactivate otoancorin. This provides a mouse model for DFNB22, reveals a loss of IHC sensitivity as the primary cause of deafness, and isolates a specific role for the limbal attachment of the TM in driving the hair bundles of the IHCs.     

Analysis of preanalytical errors in a clinical chemistry laboratory: A 2-year study

Patient safety and medical diagnosis of patients are mainly influenced by laboratory results. The present study aimed to evaluate the errors in the preanalytical phase of testing in a Clinical Chemistry diagnostic laboratory.A review was conducted at the Clinical Chemistry Laboratory of a hospital in Saudi Arabia from January 2019 to December 2020. Using the laboratory information system, the data of all canceled tests and requests were retrieved and evaluated for preanalytical errors.A total of 55,345 laboratory test requests and samples from different departments were evaluated for preanalytical errors. An overall rate of 12.1% (6705) was determined as preanalytical errors. The occurrence of these errors was found to be highest in the emergency department (21%). The leading preanalytical errors were nonreceived samples (3.7%) and hemolysis (3.5%). The annual preanalytical errors revealed an increasing rate in outpatient and inpatient departments, while a decreasing rate was observed in the emergency department. An increased rate of errors was also noted for the 2-year study period from 11.3% to 12.9%.The preanalytical phase has a significant impact on the quality of laboratory results. The rate of error in the study was high and the leading causes were nonreceived samples and hemolysis. An increased occurrence of hemolyzed samples in the outpatient department was noted. Enhanced educational efforts emphasizing specimen quality issues and training in sample collection among hospital staff must be carried out.     

结核分枝杆菌低剂量感染小鼠模型的建立与分析

目的 建立结核分枝杆菌低剂量感染的小鼠模型,分析感染小鼠组织荷菌量、组织病理随感染时间的动态变化。 方法 以100 菌落形成单位(CFU)的结核分枝杆菌标准株H37Rv经尾静脉途径感染雌性C57BL/6J小鼠40只,于感染后1、3、5、8、12、16、20、24周取材,每个时间点5只小鼠,脾、肺组织匀浆培养检测脾脏组织的荷菌量,脾脏、肺脏及肝脏组织经HE染色分析病理变化。 结果 小鼠感染后3周脾脏荷菌量达到（4.97±0.19）lg CFU,在感染后5周下降至（3.64±0.22）lg CFU,至感染后8周降到最低的（2.75±0.23）lg CFU;感染后3周肝、脾、肺等脏器出现病理改变,感染5周时病变加重,感染8周时病变自然减轻。 结论 成功建立了结核分枝杆菌低剂量感染小鼠模型,为结核分枝杆菌慢性持续感染或潜伏感染的研究可提供有用的工具。     

An anti-CD20-IL-2 immunocytokine is highly efficacious in a SCID mouse model of established human B lymphoma

We have engineered an anti-CD20-interleukin 2 (IL-2) immunocytokine (ICK) based on the Leu16 anti-CD20 antibody and have deimmunized both the variable (V) regions as well as the junction between the heavy (H) chain constant region and IL-2. Mutations were made to remove potential T-cell epitopes identified by in silico binding to major histocompatibility complex (MHC) class II molecules. The resulting immunocytokine, DI-Leu16-IL-2, retained full anti-CD20 activity as assessed by fluorescence-activated cell-sorting (FACS) analysis, and had enhanced antibody-dependent cellular cytotoxicity (ADCC) effector function relative to the DI-Leu16 antibody or control anti-CD20 antibody (rituximab). In a severe combined immunodeficient (SCID) mouse model of disseminated, residual lymphoma, anti-CD20-IL-2 immunocytokines based on Leu16 were far more effective at a dose of 0.25 mg/kg than anti-CD20 antibody given at 25/mg/kg, despite a shorter half-life of the ICK. Anti-CD20-IL-2 was also far more effective than a control ICK targeted to an antigen with greatly reduced expression on Daudi tumor cells, or various combinations of anti-CD20 antibodies and IL-2. Antitumor activity of DI-Leu16-IL-2 was shown to partially but not entirely depend on Fc receptor (R) binding, suggesting that ADCC and targeting of IL-2 both play roles in the mechanism of tumor clearance. Based on these animal models, DI-Leu16-IL-2 could offer therapeutic potential for patients with CD20 positive lymphoma. Clinical trials are currently under development.