Natural Killer Cells from Patients with Chronic Rhinosinusitis Have Impaired Effector Functions

Natural killer (NK) cells are multicompetent lymphocytes of the innate immune system that play a central role in host defense and immune regulation. Although increasing evidence suggests that innate immunity plays a key role in the pathogenesis of chronic rhinosinusitis (CRS), the role of NK cells in CRS has been poorly studied. This study aimed to characterize the peripheral blood NK cells from patients with CRS, and to compare the functions of these cells with those from non-CRS controls. The correlation between NK cell functional activity and prognosis was also assessed. Eighteen CRS patients and 19 healthy non-CRS controls were included. The patients with CRS were classified into two subgroups, namely a treatment-responsive group and recalcitrant group. NK cell degranulation was determined by measuring the cell surface expression of CD107a against 721.221 and K562 cells. Intracytoplasmic cytokine production was determined by flow cytometry. Compared to the controls, the NK cells of CRS group had an impaired ability to degranulate and to produce cytokines such as IFN-γ and TNF-α. The recalcitrant subgroup showed the most severe defects in NK cell effector functions. Moreover, the decreased NK cell functions in patients with CRS were associated with poor prognostic factors such as concomitant asthma and peripheral blood eosinophilia. NK cells, which were originally named for their ability to mediate spontaneous cytotoxicity towards diseased cells including infected cells, may play an important role in regulating the inflammatory process in CRS pathogenesis.     

Chitin-supplemented foliar application of chitinolytic Bacillus cereus reduces severity of Botrytis gray mold disease in chickpea under controlled conditions

AIM: To identify and evaluate chitinolytic bacteria for control of Botrytis gray mold (BGM), a devastating disease in chickpea. METHODS AND REsults: Two antifungal bacterial isolates, chitinolytic Bacillus cereus CRS 7 and nonchitinolytic Pseudomonas fluorescens CRS 31, from the rhizosphere of chickpea, were applied as a prophylactic foliar spray and evaluated for control of BGM. In a controlled environment, the two isolates reduced the severity of BGM on the susceptible cv. JG 62 to 6.0 and 5.6, respectively, compared with 9.0 in the control, measured on a 1-9 rating scale. Supplementation of the foliar application of CRS 7 with 0.5% and 1.0% colloidal chitin reduced BGM severity to 4.4 and 4.1 respectively, while chitin-supplemented application of CRS 31 was similar to CRS 31 applied alone. Partially purified 47-kDa chitinase from the cell-free culture filtrate of CRS 7 at 20 and 40 mug protein ml(-1) (enzyme activity 3.1 units ml(-1)) inhibited the germination and lysed the conidia of Botrytis cinerea, and as a prophylactic foliar spray reduced BGM severity to 5.4 and 4.8, respectively. CONCLUSION: Chitin supplementation improved the biocontrol of the foliar disease BGM by chitinolytic bacterium. Disease control with partially purified chitinase of CRS 7 supported the major role of chitinolysis in improved control of BGM. SIGNIFICANCE AND IMPACT OF THE STUDY: Enhanced control of BGM by chitin-supplemented application of CRS 7 is of significant in view of the frequent inconsistency in biocontrol of foliar diseases. This study supports further attempts on chitinolysis-based biocontrol methods for foliar disease biocontrol.     

Associations of granulocyte colony-stimulating factor with toxicities and efficacy of chimeric antigen receptor T-cell therapy in relapsed or refractory multiple myeloma

Background aimsFew studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) multiple myeloma (MM). We present a retrospective study performed on 113 patients with R/R MM who received single anti-BCMA CAR T-cell, combined with anti-CD19 CAR T-cell or anti-CD138 CAR T-cell therapy.MethodsEight patients were given G-CSF after successful management of CRS, and no CRS re-occurred thereafter. Of the remaining 105 patients that were finally analyzed, 72 (68.6%) received G-CSF (G-CSF group), and 33 (31.4%) did not (non G-CSF group). We mainly analyzed the incidence and severity of CRS or NEs in two groups of patients, as well as the associations of G-CSF timing, cumulative dose and cumulative time with CRS, NEs and efficacy of CAR T-cell therapy.ResultsBoth groups of patients had similar duration of grade 3–4 neutropenia, and the incidence and severity of CRS or NEs.There were also no differences in the incidence and severity of CRS or NEs between patients with the timing of G-CSF administration ≤3 days and those >3 days after CAR T-cell infusion. The incidence of CRS was greater in patients receiving cumulative doses of G-CSF >1500 μg or cumulative time of G-CSF administration >5 days. Among patients with CRS, there was no difference in the severity of CRS between patients who used G-CSF and those who did not. The duration of CRS in anti-BCMA and anti-CD19 CAR T-cell–treated patients was prolonged after G-CSF administration. There were no significant differences in the overall response rate at 1 and 3 months between the G-CSF group and the non–G-CSF group.ConclusionsOur results showed that low-dose or short-time use of G-CSF was not associated with the incidence or severity of CRS or NEs, and G-CSF administration did not influence the antitumor activity of CAR T-cell therapy.     

Bacterial biofilms in patients with chronic rhinosinusitis

The possible presence of biofilms was examined in mucosal specimens of 15 patients, undergoing functional endoscopic sinus surgery or a modified Caldwell-Luc approach for chronic rhinosinusitis (CRS). Biofilms were found in 7 of the 15 patients, positive cultures being obtained in most samples, which supports the role of biofilms as an important factor in the pathogenesis of CRS.     

Recent advances on the complement system of teleost fish

The complement system plays an essential role in alerting the host of the presence of potential pathogens, as well as in their clearing. In addition, activation of the complement system contributes significantly in the orchestration and development of an acquired immune response. Although the complement system has been studied extensively in mammals, considerably less is known about complement in lower vertebrates, in particular teleost fish. Here we review our current understanding of the role of fish complement in phagocytosis, respiratory burst, chemotaxis and cell lysis. We also thoroughly review the specific complement components characterized thus far in various teleost fish species. In addition, we provide a comprehensive compilation on complement host-pathogen interactions, in which we analyze the role of fish complement in host defense against bacteria, viruses, fungi and parasites. From a more physiological perspective, we evaluate the knowledge accumulated on the influence of stress, nutrition and environmental factors on levels of complement activity and components, and how the use of this knowledge can benefit the aquaculture industry. Finally, we propose future directions that are likely to advance our understanding of the molecular evolution, structure and function of complement proteins in teleosts. Such studies will be pivotal in providing new insights into complement-related mechanisms of recognition and defense that are essential to maintaining fish homeostasis.     

Monitoring congenital rubella embryopathy

BACKGROUND: Currently, all developed countries include rubella vaccination in their immunization programs, targeting the complete elimination of congenital rubella syndrome (CRS). In the underdeveloped world, where this severely disabling condition still exists, only a few countries have implemented vaccination policies, and almost no data on their effectiveness or on prevalence rates are available. The aims of the present work were to search for the best phenotype to be used as a sentinel for CRS in a large series of malformed newborns and to propose a CRS surveillance system, based only on clinical data. METHODS: A total of 43 infants diagnosed as having CRS were obtained from 19,184 multimalformed infants, ascertained by the Latin-American Collaborative Study of Congenital Malformations, World Health Organization (WHO) Collaborating Centre for the Prevention of Birth Defects (ECLAMC), over 3,883,165 consecutive births, between 1982 and 2003. They were distributed by country and the most frequent birth defects were identified. From the 19,184 multimalformed infants, all cases presenting the birth defects identified were selected. The sensitivity, specificity, and likelihood ratio (LR) in detecting CRS were determined for these birth defects, alone and in combination. The sample size of multimalformed infants required to detect different levels of increase in the rate of CRS was determined for three sentinel phenotypes. RESULTS: The rate of CRS was highest in Brazil. Based on the best possible combination of sensitivity, specificity, and LR, the dyad comprising eye anomalies and congenital heart defects was shown to be the most appropriate sentinel, with the lowest sample size required, to detect CRS in neonates. CONCLUSIONS: A surveillance system for CRS, based on clinical data in newborns, is being proposed, in an attempt to monitor ongoing vaccination policies, aimed at eliminating CRS in developing countries.     

Identification of a Biomarker in Cerebrospinal Fluid for Neuronopathic Forms of Gaucher Disease

Gaucher disease, a recessive inherited metabolic disorder caused by defects in the gene encoding glucosylceramidase (GlcCerase), can be divided into three subtypes according to the appearance of symptoms associated with central nervous system involvement. We now identify a protein, glycoprotein non-metastatic B (GPNMB), that acts as an authentic marker of brain pathology in neurological forms of Gaucher disease. Using three independent techniques, including quantitative global proteomic analysis of cerebrospinal fluid (CSF) in samples from Gaucher disease patients that display neurological symptoms, we demonstrate a correlation between the severity of symptoms and GPNMB levels. Moreover, GPNMB levels in the CSF correlate with disease severity in a mouse model of Gaucher disease. GPNMB was also elevated in brain samples from patients with type 2 and 3 Gaucher disease. Our data suggest that GPNMB can be used as a marker to quantify neuropathology in Gaucher disease patients and as a marker of treatment efficacy once suitable treatments towards the neurological symptoms of Gaucher disease become available.     

Clinical severity of β-thalassaemia/Hb E disease is associated with differential activities of the calpain-calpastatin proteolytic system

Earlier observations in the literature suggest that proteolytic degradation of excess unmatched α-globin chains reduces their accumulation and precipitation in β-thalassaemia erythroid precursor cells and have linked this proteolytic degradation to the activity of calpain protease. The aim of this study was to correlate the activity of calpain and its inhibitor, calpastatin, with different degrees of disease severity in β-thalassaemia. CD34(+) cells were enriched from peripheral blood of healthy individuals (control group) and patients with mild and severe clinical presentations of β(0)-thalassaemia/Hb E disease. By ex vivo cultivation promoting erythroid cell differentiation for 7 days, proerythroblasts, were employed for the functional characterization of the calpain-calpastatin proteolytic system. In comparison to the control group, enzymatic activity and protein amounts of μ-calpain were found to be more than 3-fold increased in proerythroblasts from patients with mild clinical symptoms, whereas no significant difference was observed in patients with severe clinical symptoms. Furthermore, a 1.6-fold decrease of calpastatin activity and 3.2-fold accumulation of a 34 kDa calpain-mediated degradation product of calpastatin were observed in patients with mild clinical symptoms. The increased activity of calpain may be involved in the removal of excess α-globin chains contributing to a lower degree of disease severity in patients with mild clinical symptoms.     

Increased oxidative metabolism in phytohemagglutinin-stimulated lymphocytes from patients with systemic lupus erythematosus is associated with serum SSA antibody.

We have examined oxidative metabolism in phytohemagglutinin (PHA)-stimulated lymphocytes from patients with systemic lupus erythematosus (SLE) because increased oxygen free radicals would explain the DNA abnormality previously observed in these cells. Almost no oxidative activity was found in freshly isolated control or lupus lymphocytes or control lymphocytes stimulated with PHA. However, increased oxidative metabolism, measured by nitroblue tetrazolium (NBT) conversion to formazan, was found in PHA-stimulated lymphocytes from 14 of 21 lupus patients. A time course study showed that NBT activity appeared in positive lupus lymphocytes at 1-2 days of PHA stimulation, increased to a maximum at 2-4 days, and diminished thereafter. NBT activity was not related to specific disease symptoms, drug therapy, or serum dsDNA, Sm, RNP, or SSB (La) antibodies. The selected population of lupus patients studied precluded conclusions about NBT activity and disease severity. However, the intensity of NBT response in stimulated lupus lymphocytes was positively correlated with the presence of serum SSA (Ro) antibody. We suggest that increased oxidative activity of SLE lymphocytes generates a chemical change in endogenous DNA in vivo and may be a primary event in the pathogenesis of autoimmunity. Absence of detectable oxidative activity in stimulated lymphocytes in a subgroup of lupus patients suggests that at least two different mechanisms are associated with the altered DNA profiles observed in this disorder.     

Chronic Stress Causes Sex-Specific and Structure-Specific Alterations in Mitochondrial Respiratory Chain Activity in Rat Brain

Chronic restraint stress (CRS) induces a variety of changes in brain function, some of which are mediated by glucocorticoids. The response to stress occurs in a sex-specific way, and may include mitochondrial and synaptic alterations. The synapse is highly dependent on mitochondrial energy supply, and when mitochondria become dysfunctional, they orchestrate cell death. This study aimed to investigate the CRS effects on mitochondrial respiratory chain activity, as well as mitochondrial potential and mass in cell body and synapses using hippocampus, cortex and striatum of male and female rats. Rats were divided into non-stressed (control) and stressed group (CRS during 40 days). Results showed that CRS increased complex I–III activity in hippocampus. We also observed an interaction between CRS and sex in the striatal complex II activity, since CRS induced a reduction in complex II activity in males, while in females this activity was increased. Also an interaction was observed between stress and sex in cortical complex IV activity, since CRS induced increased activity in females, while it was reduced in males. Glucocorticoid receptor (GR) content in cortex and hippocampus was sexually dimorphic, with female rats presenting higher levels compared to males. No changes were observed in GR content, mitochondrial potential or mass of animals submitted to CRS. It was concluded that CRS induced changes in respiratory chain complex activities, and some of these changes are sex-dependent: these activities are increased in the striatal mitochondria by CRS protocol mainly in females, while in males it is decreased.

     

Bf and C3 polymorphisms in rheumatoid arthritis

Properdin factor B (Bf) and complement C3 polymorphisms were studied in 225 unrelated rheumatoid arthritis (RA) patients from North-East England. Patients were subdivided on the presence or absence of significant titres of rheumatoid factor and antinuclear factor. No association with the C3 system was detected. For the Bf system, a significant excess of Bf SS and deficiency of Bf FS phenotypes was observed in seropositive RA patients lacking antinuclear antibodies. This finding suggests that auto-antibody-defined subgroups of RA may be genetically heterogeneous with respect to Bf and confirms the status of Bf SS phenotype as a marker for RA susceptibility and/or severity.     

Evaluation of CD40, its ligand CD40L and Bcl-2 in psoriatic patients

Psoriasis is a chronic, recurrent, inflammatory disease. Recent investigations indicate an autoimmune pathogenesis of the disease. Apoptosis plays an important role in the regulation of immune mechanisms in many autoimmune diseases. Although CD40, CD40L, and Bcl-2 have already been studied in psoriatic skin lesions, little is known about their circulating forms. The aim of the present study was to evaluate the serum concentrations of Bcl-2, soluble CD40 and CD40L in psoriatic patients. The study was performed using ELISA kits in 39 psoriatic patients before treatment and after two weeks of topical ointment. Data was analyzed with respect to severity of psoriasis, duration of the disease, and coexisting psoriatic arthritis. Our results revealed that serum concentrations of soluble CD40 and CD40L before and after treatment were significantly higher (p < 0.01 and p < 0.001) in patients with psoriasis compared to the control group. Topical treatment of psoriatic lesions with dithranol ointment failed to decrease serum of CD40 and CD40L, which has not been described until now. There was no significant difference in serum Bcl-2 concentration between the compared groups. We did not find significant differences in serum concentrations of Bcl-2, CD40 or CD40L between patients with mild or severe psoriasis, nor any correlation between disease duration and the presence of psoriatic arthritis symptoms. Our data indicates upregulation of the CD40/CD40L system in psoriatic patients despite topical treatment and suggests their possible role in the pathogenesis of psoriasis.     

Mannose-binding lectin contributes to the severity of Guillain-Barré syndrome

In Guillain-Barré syndrome (GBS), complement activation plays a crucial role in the induction and extent of the postinfectious immune-mediated peripheral nerve damage. Mannose-binding lectin (MBL) activates the complement system via the lectin pathway after recognition of repetitive sugar groups on pathogens. We investigated whether the MBL2 genotype, serum MBL level, and MBL complex activity are associated with the development and severity of GBS. Single nucleotide polymorphisms in the promoter region (-550 H/L and -221 X/Y) and exon 1 (A/O) of the MBL2 gene were determined in 271 GBS patients and 212 healthy controls. The frequencies of the H allele, HY promoter haplotype, and HYA haplotype, which are related to high MBL activity, were all increased in GBS patients compared with healthy controls (p < or = 0.03), particularly in severely affected GBS patients (MRC-sum score < 40) (p < or = 0.02). Severe weakness was also associated with high MBL concentrations and MBL complex activity in sera from GBS patients (p < 0.01). The MBL2 B allele was associated with functional deficiency and relatively mild weakness. These results support the hypothesis that complement activation mediated by MBL contributes to the extent of nerve damage in GBS, which is codetermined by the MBL2 haplotype.     

Influence of Self-Reported Chronic Rhinosinusitis on Health-Related Quality of Life: A Population-Based Survey

Chronic rhinosinusitis (CRS) is a frequently occurring chronic respiratory disease. There is evidence that effective treatment of CRS can improve patients’ quality of life, but the data regarding the extent to which CRS impairs patients’ quality of life (QoL) is sparse. This study aimed to evaluate the effect of self-reported CRS on health-related QoL and to determine whether the influence was associated with gender, age and socio-economic status. A four-stage random sampling method was used to select the participants from the general population in Guangzhou, China. All participants were interviewed face-to-face at their homes using a standardized questionnaire. The health-related QoL of each participant was assessed using the SF-36 Health Survey. The scores of the SF-36 after adjusting for gender, age, socioeconomic conditions, smoking and some important comorbid conditions were compared between the CRS group and the non-CRS group using analysis of covariance. A multiple linear regression model with interaction terms was established to determine whether CRS affected QoL to the same degree across the different subpopulations. Among a total of 1,411 participants aged at least 15 years, 118 persons (8.4%) had self-reported CRS. Subjects with CRS had an increased prevalence of allergic rhinitis, chronic obstructive pulmonary disease and gout than subjects without CRS. The CRS group had lower scores in all eight domains and the physical and mental component summary than those without CRS (P<0.05), and the greatest differences were in role emotional function (RE), general health (GH) and role physical function (RP). The impairments of the CRS participants in RE and RP were greater among the females than the males. Moreover, physical domains were affected to greater degrees among the elderly and those with high-level education. In conclusion, CRS is a common chronic disorder. Persons with self-reported CRS perceived themselves as having impaired QoL in both the physical and mental domains. These findings shed new light on the health burden of CRS and should be taken into account by clinicians involved in the care of CRS patients.     

Control of Paratrichodorus allius and Corky Ringspot Disease in Potato with Shank-injected Metam Sodium

Corky ringspot disease (CRS) of potato produces necrotic areas in tubers that are considered quality defects that can lead to crop rejection. CRS is caused by tobacco rattle virus that is vectored by stubby-root nematodes (Paratrichodorus spp., Trichodorus spp.) at very low population densities, making disease management difficult and expensive. Fumigation with metam sodium (MS) is a common practice to control soil-borne fungi and increase potato yield. MS is generally applied in water via chemigation (water-run, WR) but is ineffective at controlling CRS when WR-applied, even at high rates. Therefore, WR MS is often used in combination with 1,3-dichloropropene (1,3-D), aldicarb or oxamyl to attain adequate CRS control. Between 1996 and 2000, fields with a history of CRS were treated with WR MS, shank-injected MS, and/or 1,3-D, and tubers were evaluated for symptoms of CRS. Shank injection of MS (SH MS) at depths of 41 cm, 15 and 30 cm, or 15, 30 and 45 cm controlled CRS over 3 years of testing. All rates of 280 liters/ha or greater were effective. Shank injection of metam potassium (MP) at rates of 448 liters/ha was also effective. 1,3-D controlled CRS alone or in combination with WR or SH MS. Proper shank application of MS or MP may adequately control CRS without the additional cost of other nematicides at low (<10 P. allius/250 g soil) to moderate (10 to 30 P. allius/250 g soil) populations of the nematode vector. Although SH MS was superior to WR MS, additional research is necessary to determine if this practice would be sufficient at higher CRS disease pressure or if addition of other nematicides would be necessary.     

Blood BDNF Level Is Gender Specific in Severe Depression

Though the role of brain derived neurotrophic factor (BDNF) as a marker for major depressive disorder (MDD) and antidepressant efficacy has been widely studied, the role of BDNF in distinct groups of patients remains unclear. We evaluated the diagnostic value of BDNF as a marker of disease severity measured by HAM-D scores and antidepressants efficacy among MDD patients. Fifty-one patients who met DSM-IV criteria for MDD and were prescribed antidepressants and 38 controls participated in this study. BDNF in serum was measured at baseline, 1st, 2nd and 8th treatment weeks. Depression severity was evaluated using the Hamilton Rating Scale for Depression (HAM-D). BDNF polymorphism rs6265 (val66met) was genotyped. We found a positive correlation between blood BDNF levels and severity of depression only among untreated women with severe MDD (HAM-D>24). Serum BDNF levels were lower in untreated MDD patients compared to control group. Antidepressants increased serum BDNF levels and reduced between-group differences after two weeks of treatment. No correlations were observed between BDNF polymorphism, depression severity, duration of illness, age and BDNF serum levels. Further supporting the role of BDNF in the pathology and treatment of MDD, we suggest that it should not be used as a universal biomarker for diagnosis of MDD in the general population. However, it has diagnostic value for the assessment of disease progression and treatment efficacy in individual patients.     

Using swallow sound and surface electromyography to determine the severity of dysphagia in patients with myasthenia gravis

One of the main symptoms of patients with myasthenia gravis is dysphagia, which will reduce the patients’ nutritional absorption and influences the quality of living. The activity of swallowing involves interaction and coordination between a variety of muscles and the nervous system. It is, therefore, difficult for clinicians to detect dysphagia. Furthermore, the symptoms of myasthenia gravis are unstable, making clinical judgment troublesome. How to accurately diagnose the severity of dysphagia in the clinic has become an important research topic. This paper proposes a dysphagia severity discrimination system for patients with myasthenia gravis. It uses a non-invasive Adam's apple microphone and surface electromyography to collect the swallow signal generated by sound and muscle activity when the patient swallows water. The system then extracts features to discriminate the severity of dysphagia during each swallow phase. The experimental results show that the system can provide concrete features for clinicians to diagnose dysphagia in myasthenia gravis patients.     

Effect of fish oil on offensive and defensive factors in gastric ulceration in rats

The effect of fish oil (FO) derived from Scomberoides commersonianus containing omega-3 polyunsaturated fatty acids was studied on gastric ulcers and as well as on offensive and defensive factors in gastric mucosal damage, following experimental gastric ulceration. FO significantly reduced the severity of ulceration in gastric ulcers induced by aspirin, cold-restraint stress (CRS), alcohol, and pylorus ligation. The results also indicated the potentiality of FO in maintaining the integrity of gastric mucosa by virtue of its effect on both offensive and defensive gastric mucosal factors. It decreased the offensive acid-pepsin secretion and augmented the defensive factors like mucin secretion, cellular mucus and life span of mucosal cells following pylorus ligation. FO significantly increased activity of anti-oxidant enzymes (catalase and glutathione peroxidase) and decreased lipid peroxidation in gastric mucosa of CRS rats. The study indicates the beneficial role of FO in gastric ulceration by inhibition of offensive mucosal factors and oxidative stress, and augmentation of defensive mucosal factors.