Does cryptogenic organizing pneumonia change seasonal?

BACKGROUND AND AIM: Meteorological factors affect the respiratory system, and the most important factor is the change in ambient temperature and humidity. We aimed to investigate the seasonal characteristics of patients diagnosed with cryptogenic organizing pneumonia. METHODS: The study included 84 cryptogenic organizing pneumonia, 55 chronic obstructive pulmonary disease, and 42 asthma patients. To determine the characteristics of the disease according to the seasons, the number of attacks and admissions was grouped according to the seasonal characteristics and analyzed for three groups. RESULTS: Among cryptogenic organizing pneumonia and chronic obstructive pulmonary disease patients, males significantly predominated (p<0.001). The hospitalization rate was highest in chronic obstructive pulmonary disease patients but similar to cryptogenic organizing pneumonia and asthma patients (p<0.001). The highest admission rate in cryptogenic organizing pneumonia patients was observed in spring (39.3% in spring, 26.2% in fall, 22.6% in winter, and 11.9% in summer). In winter, cryptogenic organizing pneumonia patients were admitted less frequently than chronic obstructive pulmonary disease and asthma patients. The neutrophil-to-lymphocyte ratio was higher in cryptogenic organizing pneumonia patients than in asthma patients and similar to chronic obstructive pulmonary disease patients. CONCLUSION: As a result of our study, the high rate of diagnosis and admission in the spring in cryptogenic organizing pneumonia suggested that the effect of allergens on the formation of cryptogenic organizing pneumonia should be investigated. In contrast, it should be kept in mind that cryptogenic organizing pneumonia may develop as a prolonged finding of involvement that may occur in the lung parenchyma due to lung infections and/or cold weather triggering during the winter months. In this regard, further studies can be conducted in which allergens and/or the history of infection in patients and meteorological variables are also evaluated.

Does cryptogenic organizing pneumonia change seasonal?

SUMMARY BACKGROUND AND AIM: Meteorological factors affect the respiratory system, and the most important factor is the change in ambient temperature and humidity. We aimed to investigate the seasonal characteristics of patients diagnosed with cryptogenic organizing pneumonia. METHODS: The study included 84 cryptogenic organizing pneumonia, 55 chronic obstructive pulmonary disease, and 42 asthma patients. To determine the characteristics of the disease according to the seasons, the number of attacks and admissions was grouped according to the seasonal characteristics and analyzed for three groups. RESULTS: Among cryptogenic organizing pneumonia and chronic obstructive pulmonary disease patients, males significantly predominated (p<0.001). The hospitalization rate was highest in chronic obstructive pulmonary disease patients but similar to cryptogenic organizing pneumonia and asthma patients (p<0.001). The highest admission rate in cryptogenic organizing pneumonia patients was observed in spring (39.3% in spring, 26.2% in fall, 22.6% in winter, and 11.9% in summer). In winter, cryptogenic organizing pneumonia patients were admitted less frequently than chronic obstructive pulmonary disease and asthma patients. The neutrophil-to-lymphocyte ratio was higher in cryptogenic organizing pneumonia patients than in asthma patients and similar to chronic obstructive pulmonary disease patients. CONCLUSION: As a result of our study, the high rate of diagnosis and admission in the spring in cryptogenic organizing pneumonia suggested that the effect of allergens on the formation of cryptogenic organizing pneumonia should be investigated. In contrast, it should be kept in mind that cryptogenic organizing pneumonia may develop as a prolonged finding of involvement that may occur in the lung parenchyma due to lung infections and/or cold weather triggering during the winter months. In this regard, further studies can be conducted in which allergens and/or the history of infection in patients and meteorological variables are also evaluated.

Limited field adaptive radiotherapy for glioblastoma: changes in target volume and organ at risk doses.

OBJECTIVE: This study aimed to investigate the tumor volume changes occurring during limited-field radiotherapy (RT) for glioblastoma patients and whether a volume-adapted boost planning approach provided any benefit on tumor coverage and normal tissue sparing. MATERIALS AND METHODS: Twenty-four patients underwent simulation with magnetic resonance (MR) and computed tomography (CT) scans prior to RT (MR_initial, CT_initial) and boost treatment (MR_adapt, CT_adapt). For the boost phase, MR_initial and MR_adapt images were used to delineate GTV2 and GTV2_adapt, respectively. An initial boost plan (Plan_initial) created on CT_initial for PTV2 was then reoptimized on CT_adapt by keeping the same optimization and normalization values. Plan_adapt was generated on CT_adapt for PTV2_adapt volume. Dose volume histogram parameters for target volumes and organs-at-risk were compared using these boost plans generated on CT_adapt. Plan_initial and Plan_adaptive boost plans were summed with the first phase plan and the effect on the total dose was investigated. RESULTS: Target volume expansion was noted in 21% of patients while 79% had shrinkage. The average difference for the initial and adaptive gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV) volumes were statistically significant. Maximum dose differences for brainstem and optic chiasm were significant. Healthy brain tissue V10 and ipsilateral optic nerve maximum doses were found to decrease significantly in Plan_adaptive. CONCLUSION: Results of this study confirm occurrence of target volume changes during RT for glioblastoma patients. An adaptive plan can provide better normal tissue sparing for patients with lesion shrinkage and avoid undercoverage of treatment volumes in case of target volume expansion especially when limited-fields are used.

Urethra-Sparing Stereotactic Body Radiation Therapy for Prostate Cancer: Quality Assurance of a Randomized Phase 2 Trial.

PURPOSE: To present the radiation therapy quality assurance results from a prospective multicenter phase 2 randomized trial of short versus protracted urethra-sparing stereotactic body radiation therapy (SBRT) for localized prostate cancer. METHODS AND MATERIALS: Between 2012 and 2015, 165 patients with prostate cancer from 9 centers were randomized and treated with SBRT delivered either every other day (arm A, n = 82) or once a week (arm B, n = 83); 36.25 Gy in 5 fractions were prescribed to the prostate with (n = 92) or without (n = 73) inclusion of the seminal vesicles (SV), and the urethra planning-risk volume received 32.5 Gy. Patients were treated either with volumetric modulated arc therapy (VMAT; n = 112) or with intensity modulated radiation therapy (IMRT; n = 53). Deviations from protocol dose constraints, planning target volume (PTV) homogeneity index, PTV Dice similarity coefficient, and number of monitor units for each treatment plan were retrospectively analyzed. Dosimetric results of VMAT versus IMRT and treatment plans with versus without inclusion of SV were compared. RESULTS: At least 1 major protocol deviation occurred in 51 patients (31%), whereas none was observed in 41. Protocol violations were more frequent in the IMRT group (P < .001). Furthermore, the use of VMAT yielded better dosimetric results than IMRT for urethra planning-risk volume D98% (31.1 vs 30.8 Gy, P < .0001), PTV D2% (37.9 vs 38.7 Gy, P < .0001), homogeneity index (0.09 vs 0.10, P < .0001), Dice similarity coefficient (0.83 vs 0.80, P < .0001), and bladder wall V50% (24.5% vs 33.5%, P = .0001). To achieve its goals volumetric modulated arc therapy required fewer monitor units than IMRT (2275 vs 3378, P <.0001). The inclusion of SV in the PTV negatively affected the rectal wall V90% (9.1% vs 10.4%, P = .0003) and V80% (13.2% vs 15.7%, P = .0003). CONCLUSIONS: Protocol deviations with potential impact on tumor control or toxicity occurred in 31% of patients in this prospective clinical trial. Protocol deviations were more frequent with IMRT. Prospective radiation therapy quality assurance protocols should be strongly recommended for SBRT trials to minimize potential protocol deviations.

Long-term neuromusculoskeletal side effects and quality of life in nasopharyngeal cancer patients receiving radiochemotherapy.

AIM: In this study, we aimed to evaluate the neuromusculoskeletal late side effects and their impact on the quality of life of patients with nasopharyngeal carcinoma treated with radiochemotherapy. PATIENTS AND METHODS: Twenty-seven patients were included. The mean follow-up was 61 months (range, 18-111 months). The median external radiotherapy dose applied to the nasopharynx and primary tumor was 70 Gy (range, 61-73 Gy). The mean dose received by the temporomandibular joint in the dose-volume histograms of these patients was 60.7 Gy. The maximal doses of the muscles responsible for cervical motion in different ranges were greater than 60 Gy, and the mean doses were greater than 40 Gy in the muscle groups, except for the extensor muscles. RESULTS: Two patients had brachial plexus involvement, while 89% of the patients had restriction in flexion and extension movements. Of the patients, 52% had trismus. There was a significant correlation between extension restriction and general heath score and the physical subscale of the quality-of-life questionnaire (p = 0.01). There was also a correlation between trismus and pain killer usage (p = 0.004). CONCLUSION: This is the first study to analyze long-term muscle and nerve toxicity and their correlation between doses in nasopharyngeal cancer patients following radiochemotherapy. Despite the advances in radiotherapy techniques, it is necessary to pay attention to the doses of the nerves and muscles for late effects.

Urethra-sparing stereotactic body radiotherapy for prostate cancer: how much can the rectal wall dose be reduced with or without an endorectal balloon?

BACKGROUND: This is a dosimetric comparative study intended to establish appropriate low-to-intermediate dose-constraints for the rectal wall (Rwall) in the context of a randomized phase-II trial on urethra-sparing stereotactic body radiotherapy (SBRT) for prostate cancer. The effect of plan optimization on low-to-intermediate Rwall dose and the potential benefit of an endorectal balloon (ERB) are investigated. METHODS: Ten prostate cancer patients, simulated with and without an ERB, were planned to receive 36.25Gy (7.25Gyx5) to the planning treatment volume (PTV) and 32.5Gy to the urethral planning risk volume (uPRV). Reference plans with and without the ERB, optimized with respect to PTV and uPRV coverage objectives and the organs at risk dose constraints, were further optimized using a standardized stepwise approach to push down dose constraints to the Rwall in the low to intermediate range in five sequential steps to obtain paired plans with and without ERB (Vm1 to Vm5). Homogeneity index for the PTV and the uPRV, and the Dice similarity coefficient (DSC) for the PTV were analyzed. Dosimetric parameters for Rwall including the median dose and the dose received by 10 to 60% of the Rwall, bladder wall (Bwall) and femoral heads (FHeads) were compared. The monitor units (MU) per plan were recorded. RESULTS: Vm4 reduced by half D30%, D40%, D50%, and Dmed for Rwall and decreased by a third D60% while HIPTV, HIuPRV and DSC remained stable with and without ERB compared to Vmref. HIPTV worsened at Vm5 both with and without ERB. No statistical differences were observed between paired plans on Rwall, Bwall except a higher D2% for Fheads with and without an ERB. CONCLUSIONS: Further optimization to the Rwall in the context of urethra sparing prostate SBRT is feasible without compromising the dose homogeneity to the target. Independent of the use or not of an ERB, low-to-intermediate doses to the Rwall can be significantly reduced using a four-step sequential optimization approach.

Critical appraisal of RapidArc radiosurgery with flattening filter free photon beams for benign brain lesions in comparison to GammaKnife: a treatment planning study.

BACKGROUND: To evaluate the role of RapidArc (RA) for stereotactic radiosurgery (SRS) of benign brain lesions in comparison to GammaKnife (GK) based technique. METHODS: Twelve patients with vestibular schwannoma (VS, n = 6) or cavernous sinus meningioma (CSM, n = 6) were planned for both SRS using volumetric modulated arc therapy (VMAT) by RA. 104 MV flattening filter free photon beams with a maximum dose rate of 2400 MU/min were selected. Data were compared against plans optimised for GK. A single dose of 12.5 Gy was prescribed. The primary objective was to assess treatment plan quality. Secondary aim was to appraise treatment efficiency. RESULTS: For VS, comparing best GK vs. RA plans, homogeneity was 51.7 ± 3.5 vs. 6.4 ± 1.5%; Paddick conformity Index (PCI) resulted 0.81 ± 0.03 vs. 0.84 ± 0.04. Gradient index (PGI) was 2.7 ± 0.2 vs. 3.8 ± 0.6. Mean target dose was 17.1 ± 0.9 vs. 12.9 ± 0.1 Gy. For the brain stem, D(1cm3) was 5.1 ± 2.0 Gy vs 4.8 ± 1.6 Gy. For the ipsilateral cochlea, D(0.1cm3) was 1.7 ± 1.0 Gy vs. 1.8 ± 0.5 Gy. For CSM, homogeneity was 52.3 ± 2.4 vs. 12.4 ± 0.6; PCI: 0.86 ± 0.05 vs. 0.88 ± 0.05; PGI: 2.6 ± 0.1 vs. 3.8 ± 0.5; D(1cm3) to brain stem was 5.4 ± 2.8 Gy vs. 5.2 ± 2.8 Gy; D(0.1cm3) to ipsi-lateral optic nerve was 4.2 ± 2.1 vs. 2.1 ± 1.5 Gy; D(0.1cm3) to optic chiasm was 5.9 ± 3.1 vs. 4.5 ± 2.1 Gy. Treatment time was 53.7 ± 5.8 (64.9 ± 24.3) minutes for GK and 4.8 ± 1.3 (5.0 ± 0.7) minutes for RA for schwannomas (meningiomas). CONCLUSIONS: SRS with RA and FFF beams revealed to be adequate and comparable to GK in terms of target coverage, homogeneity, organs at risk sparing with some gain in terms of treatment efficiency.

V30 as a predictor for radiation-induced hypothyroidism: a dosimetric analysis in patients who received radiotherapy to the neck.

INTRODUCTION: The purpose of this study is to evaluate the possible predictors of thyroid disorders after neck radiotherapy, with a focus on radiation dose-volume factors. METHODS: Thyroid function was measured in 100 patients who had received radiotherapy to the neck, including the thyroid. All radiation-induced thyroid dysfunctions were determined with an endpoint of abnormal thyroid stimulating hormone (TSH), free triiodothyronine (fT3) and thyroxine (fT4) and thyroid peroxidase antibodies and (TPA). The total volume of the thyroid, mean radiation dose to the thyroid (Dmean) and thyroid volume percentage that received radiation doses of 10-50 Gy (V10-V50) were calculated in all patients. The evaluated risk factors for thyroid dysfunction included dose-volume parameters, sex, age, previous surgery, chemotherapy and comorbidity. RESULTS: There were 52 patients with hypothyroidism and V30 (p = 0.03), thyroid volume (p = 0.01) and Dmean (p = 0.03) appeared to be correlated with hypothyroidism in univariate analysis. However, there was not association found in multivariate analysis for these factors. CONCLUSIONS: Thyroid disorders after radiation therapy to the neck still represent a clinically underestimated problem. V30 may be a useful tool for evaluating the risk of hypothyroidism when determining an individual patient's treatment.

Effect of thyroid function on COPD exacerbation frequency: a preliminary study.

BACKGROUND: Frequent exacerbations of chronic obstructive pulmonary disease (COPD) have negative effects on quality of life and survival. Thus, factors related to exacerbations should be determined. We aimed to evaluate the effects of thyroid function on quality of life and exacerbation frequency in COPD patients. METHODS: The study population (n = 128) was divided into 3 groups (Group 1: COPD patients with hypothyroidism (n = 44); Group 2: COPD patients with normal thyroid function tests (n = 44); Group 3: Healthy subjects (n = 40)). Pulmonary function tests, maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) measurements were performed. Quality of life questionnaire (Short Form 36, SF-36) was carried out. Patients were followed up for one year and number of exacerbations was recorded. RESULTS: FVC, FEV1/FVC, and FEF 25-75% measurements were statistically different between group 1 and 2 (p = 0.041, p = 0.001, p = 0.009 respectively). Although MEP values were significantly different between group 1 and 2 (p = 0.006), there was no significant difference in MIP values between groups (p = 0.77). Quality of life scores in group 1 and 2 were significantly lower than control group. Exacerbation frequency was significantly higher in group 1 than in group 2 (p = 0.017). TSH values and exacerbation frequency had positive correlation (p < 0.0001; r = 0.82). CONCLUSIONS: The results of the present study suggest that thyroid function has an effect in exacerbation frequency of COPD. Decrease in exacerbation numbers with early detection of impairment in thyroid function will have positive contribution on quality of life in COPD patients.

The effect of magnesium and vitamin E pre-treatments on irradiation-induced oxidative injury of cardiac and pulmonary tissues in rats: a randomized experimental study.

OBJECTIVE: The aim of this study was to investigate the effect of pre-treatment with the free radical scavenging molecules, magnesium and vitamin E, on lipid peroxidation to limit radiation-induced heart and lung injury. METHODS: Female Sprague-Dawley rats were divided into 4 groups by a simple randomization method as saline-treated control (n=4), saline-treated irradiated (IR; n=6), magnesium sulphate-treated irradiation (IR) (Mg+IR; n=6) and vitamin E-treated IR (vit E+IR; n=6), respectively. The animals were given either saline, Mg (600 mg/kg/day) or vit E (100 mg/kg/day) intraperitoneally for five days prior to irradiation. Twelve hours after the fifth injection, animals in irradiation groups were irradiated to 20 Gy using 6 MV photons in linear accelerator. Twenty-four hours later cardiac and lung tissue samples were obtained for determination of myeloperoxidase activity (MPO), malondialdehyde (MDA) levels, and luminol and lucigenin levels measured by chemiluminescence (CL) methods. RESULTS: No significant changes were observed between cardiac and pulmonary MDA and CL results of the experimental groups. However, cardiac and pulmonary MPO activities in the saline-treated IR group were increased as compared to control group (p<0.05 for all), while in the Mg-pretreated and vit E pretreated groups neutrophil infiltration was reduced, reaching to statistical significance only in the Mg-pretreated group (p<0.05). CONCLUSION: Prophylactic use of magnesium sulfate has limited the infiltration of neutrophils to both the cardiac and pulmonary tissues at the early 24 h of irradiation. However, how limiting neutrophils as the sources of free radicals and inflammatory mediators would alter oxidative stress of heart and lung tissues in the long-term is not clear yet.

Prophylactic feeding with immune-enhanced diet ameliorates chemoradiation-induced gastrointestinal injury in rats.

PURPOSE: To investigate the protective effect of immune-enhanced diet (IED) on chemoradiation-induced injury of the gastrointestinal mucosa. MATERIALS AND METHODS: Forty-eight Sprague-Dawley rats were divided into control (C, n=6), irradiation (IR, n=14), fluoropyrimidine (5-FU, n=14)-treated, IR + 5-FU (n=14)-treated groups. Half of each irradiated and/or 5-FU-treated groups were previously fed with IED containing arginine, omega-3-fatty acids and RNA fragments, while the other half were fed a standard rat diet (SD) for eight days before the induction of IR or injection of 5-FU. In IR groups, whole abdominal irradiation (11 Gy) was performed with 6 MV photons. In the 5-FU groups, fluoropyrimidine (100 mg/kg) was administered intraperitoneally 30 min prior to irradiation. All animals were sacrificed on the 4th day of IR or 5-FU injection. RESULTS: Bacterial colony counts in the ceca and mesenteric lymph nodes of IED-fed rats, which have received either 5-FU and/or irradiation were significantly lower than the corresponding SD-fed groups. Morphometric results revealed that gastric, ileal and colonic injuries were less in IED-treated IR or IR + 5-FU + IED groups, as compared to SD-fed groups. However, IED did not alter DNA fragmentation ratios. CONCLUSION: Prophylactic feeding of IED has a protective effect on chemoradiation-induced gastrointestinal injury, which appears to involve the eradication of bacterial overgrowth.

Gamma Knife 3-D dose distribution near the area of tissue inhomogeneities by normoxic gel dosimetry.

The accuracy of the Leksell GammaPlan, the dose planning system of the Gamma Knife Model-B, was evaluated near tissue inhomogeneities, using the gel dosimetry method. The lack of electronic equilibrium around the small-diameter gamma beams can cause dose calculation errors in the neighborhood of an air-tissue interface. An experiment was designed to investigate the effects of inhomogeneity near the paranosal sinuses cavities. The homogeneous phantom was a spherical glass balloon of 16 cm diameter, filled with MAGIC gel; i.e., the normoxic polymer gel. Two hollow PVC balls of 2 cm radius, filled with N2 gas, represented the air cavities inside the inhomogeneous phantom. For dose calibration purposes, 100 ml gel-containing vials were irradiated at predefined doses, and then scanned in a MR unit. Linearity was observed between the delivered dose and the reciprocal of the T2 relaxation time constant of the gel. Dose distributions are the results of a single shot of irradiation, obtained by collimating all 201 cobalt sources to a known target in the phantom. Both phantoms were irradiated at the same dose level at the same coordinates. Stereotactic frames and fiducial markers were attached to the phantoms prior to MR scanning. The dose distribution predicted by the Gamma Knife planning system was compared with that of the gel dosimetry. As expected, for the homogeneous phantom the isodose diameters measured by the gel dosimetry and the GammaPlan differed by 5% at most. However, with the inhomogeneous phantom, the dose maps in the axial, coronal and sagittal planes were spatially different. The diameters of the 50% isodose curves differed 43% in the X axis and 32% in the Y axis for the Z =90 mm axial plane; by 44% in the X axis and 24% in the Z axis for the Y=90 mm coronal plane; and by 32% in the Z axis and 42% in the Y axis for the X=92 mm sagittal plane. The lack of ability of the GammaPlan to predict the rapid dose fall off, due to the air cavities behind or near the lesion led to an overestimation of the dose that was actually delivered. Clinically, this can result in underdosing of lesions near tissue inhomogeneities in patients under treatment.

Blockade of lymphotoxin pathway exacerbates autoimmune arthritis by enhancing the Th1 response.

OBJECTIVE: To study the role of the lymphotoxin (LT) signaling pathway in the development and pathogenesis of collagen-induced arthritis (CIA), and to understand the mechanisms by which blockade of the LT pathway influences the arthritogenic response to type II collagen (CII). METHODS: LTalpha-deficient and wild-type C57BL/6 mice were immunized with CII. Male DBA/1 mice were immunized with CII and treated with LTbeta receptor immunoglobulin fusion protein (LTbetaR-Ig) or control Ig. Mice were monitored for the development and severity of arthritis. The effects of LT blockade on immune responses were evaluated by cytokine production and antigen-specific proliferation in vitro, the delayed-type hypersensitivity (DTH) response, and serum levels of CII-specific antibodies. RESULTS: CIA that developed in LTalpha-deficient mice was more severe and prolonged than that which developed in wild-type mice. Blocking LT signaling with LTbetaR-Ig significantly exacerbated the disease. Exacerbation of CIA was associated with an enhanced Th1-type response, including increased type 1 cytokine production, an enhanced DTH response, and elevated production of CII-specific IgG2a antibodies. CONCLUSION: Blockade of the LT signaling pathway exacerbates the development and progression of CIA, probably by skewing the Th1/Th2 balance that determines the outcome of autoimmune responses.

Potentiation of a dendritic cell vaccine for murine renal cell carcinoma by CpG oligonucleotides.

PURPOSE: An ideal vaccine therapy for tumors should activate both effector and memory immune responses against tumor-specific antigens. Here we investigated the effect of CpG oligodeoxynucleotides (CpG-ODN) for their ability to potentiate the activity of tumor antigen-pulsed bone marrow-derived dendritic cells (DC) in a vaccine model for the treatment of murine renal cell carcinoma (RENCA). EXPERIMENTAL DESIGN: First we evaluated the effects of a murine renal cell carcinoma (RENCA) on immune cell activity in a mouse model using in vitro assays for T-cell proliferation and natural killer cell activation. To overcome the immune suppression of the tumor, we s.c. injected groups of 10 mice with dendritic cells and tumor cells. We compared the effect of different conditioning regimens of the DCs with RENCA antigen and/or CpG-ODNs before injection by measuring tumor size twice a week. RESULTS: Tumor growth was shown to negatively affect spleen cell and T-cell proliferation, IFN-gamma production, natural killer cell activity, and NF-kappaB activation in T cells. In this model, we have shown that RENCA-pulsed CpG-ODN-treated DCs were able not only to significantly reduce tumor growth but also to prevent tumor implantation in 60% of mice. Tumor-free mice were resistant to tumor challenge and the immunity conferred by the vaccine was transferable and tumor specific. CONCLUSIONS: This data show that RENCA down-modulates the immune response, and DC vaccine therapy, in conjunction with CpG-ODN, can restore tumor-specific immunity.

CXCL13 neutralization reduces the severity of collagen-induced arthritis.

OBJECTIVE: To investigate the role of CXCL13 in the development and pathogenesis of collagen-induced arthritis (CIA), and to determine the mechanisms involved in the modulation of arthritogenic response by CXCL13 neutralization. METHODS: Mice were immunized with type II collagen (CII) and treated with anti-CXCL13 or control antibodies during boosting. Mice were monitored for the development and severity of arthritis. The effects of CXCL13 neutralization on immune response to CII were evaluated by cytokine production by CII-specific T cells and CII-specific antibody production. Follicular response in the spleen and in synovial tissue was determined by in situ immunohistology. RESULTS: Mice receiving neutralizing antibodies to CXCL13 developed significantly less severe arthritis compared with mice injected with phosphate buffered saline or control antibodies. Follicular response both in the spleen and in synovial tissue was inhibited by anti-CXCL13 treatment. Injection with anti-CXCL13 antibodies did not significantly affect antigen-specific recall lymphocyte proliferation or type 1 cytokine production in vitro. Antibody response specific to CII was not inhibited by anti-CXCL13 treatment. However, anti-CXCL13 treatment induced significantly higher levels of interleukin-10 production after in vitro CII stimulation. CONCLUSION: Neutralization of CXCL13 inhibits the development of CIA and reduces follicular response in both lymphoid and nonlymphoid tissues. These findings may have important implications regarding the pathogenesis and treatment of autoimmune arthritis.

Relative dose distribution in gamma knife treatment near tissue inhomogeneties.

The primary goal in this study was to investigate 3-D dose distribution, near the areas of tissue inhomogeneities, in Gamma Knife Radiosurgery with the gel dosimetry. The spherical glass balloon of a diameter of 16 cm filled with the gel forms the homogeneous phantom; and an identical balloon with two corks placed on each side to represent the air cavities forms the inhomogeneous phantom. Dose calibration is performed by irradiating vials at known doses and then utilizing the R2- dose calibration curve. Stereotactic frames and fudicial markers were attached to the phantoms for MR scanning and image processing. Dose distributions from a single shot, using all 201 Cobalt sources, delivered to a known point with identical coordinates, are calculated both in homogeneous and inhomogeneous gel phantoms. In the aspect of dosimetrical quality control, the Gamma Knife planning system predicted dose distribution is compared with the experimental results. In the homogeneous phantom, the gel dosimetry calculated dose distribution is in good agreement with the GammaPlan predicted dose distribution. However, with the inhomogeneous phantom, the dose distribution is spatially different and significant differences in dose levels are observed.

Enhanced differentiation of splenic plasma cells but diminished long-lived high-affinity bone marrow plasma cells in aged mice.

In the present work, we have dissected the mechanisms responsible for the impaired humoral responses in aging. We found that there was a substantially higher level of Ab-forming cells in the spleens of aged mice than that of young controls. However, the number of high-affinity, class-switched Ab-forming cells was severely decreased in the spleen of aged mice. The accumulation of low-affinity IgM Ab-forming cells in the spleens of aged animals was not due to a deficiency in isotype switching because the number of total IgG1 splenic plasma cells was not significantly reduced. Remarkably, plasma cells of both low and high affinity were significantly diminished in the bone marrow of aged mice compared with that of young mice. The results from reconstitution experiments showed that aged bone marrow was less supportive for plasma cells derived from young splenic B cells. These findings suggest that humoral immune deficiency in aging results from at least two mechanisms: the inability to generate sufficient numbers of high-affinity Ab-forming cells, which is a result of diminished germinal center reaction, and the defective bone marrow environment that has diminished ability to support the selection and survival of long-term Ab-forming cells.

CD4-deficient T helper cells are capable of supporting somatic hypermutation and affinity maturation of germinal center B cells.

Collaborative interactions between B lymphocytes and CD4+ helper T cells are necessary for the induction of Ab responses to most protein Ag and for the generation of memory B cells in germinal centers. To study the role of the CD4 molecule in the germinal center response and in the development of B cell memory, we have investigated T helper function in the initiation and maturation of humoral immunity in CD4-deficient mice. In the absence of CD4+ T cells, immunization with thymus-dependent Ag was able to induce germinal center formation and Ig somatic hypermutation. In addition, Ag-driven affinity maturation and development of B cell memory were largely intact in CD4-deficient mice. Thus, CD4-deficient T helper cells are able to collaborate with Ag-activated B cells to elicit the germinal center reaction, switch on the mutational machinery, and deliver signals necessary for B cell memory development.