Therapeutic and prophylactic thalidomide in TNBS-induced colitis： Synergistic effects on TNF-α, IL-12 and VEGF production

AIM： To evaluated the therapeutic and prophylactic effect of thalidomide on 2, 4, 6-trinitrobenzene sulfonic acid （TNBS）-induced colitis. Thalidomide has been reported to downregulate the expression of tumor necrosis factor α （TNF-α）, IL-12, and vascular endothelial growth factor （VEGF）, hallmarks of intestinal inflammation in Crohn＇s disease （CD）.
METHODS： Male Wistar rats were divided in five groups of ten animals each. Four groups received a rectal infusion of TNBS in ethanol. The first group was sacrificed 7 d after colitis induction. The second and third groups received either thalidomide or placebo by gavage and were sacrificed at 14 d. The fourth group received thalidomide 6 h before TNBS administration, and was sacrificed 7 d after induction. The fifth group acted as the control group and colitis was not induced. Histological inflammatory scores of the colon were performed and lamina propria CD4＋ T cells, macrophages, and VEGF＋ cells were detected by immunohistochemistry. TNF-α and IL-12 were quantified in the supernatant of organ cultures by ELISA.
RESULTS： Significant reduction in the inflammatory score and in the percentage of VEGF＋ cells was observed in the group treated with thalidomide compared with animals not treated with thalidomide. Both TNF-α and IL-12 levels were significantly reduced among TNBS induced colitis animals treated with thalidomide compared with animals that did not receive thalidomide. TNF-α levels were also significantly reduced among the animals receiving thalidomide prophylaxis compared with untreated animals with TNBS-induced colitis. Intestinal levels of TNF-α and IL-12 were significantly correlated with the inflammatory score and the number of VEGF＋ cells.
CONCLUSION： Thalidomide significantly attenuates TNBS-induced colitis by inhibiting the intestinal production of TNF-α, IL-12, and VEGF. This effect may support the use of thalidomide as an alternate approach in selected patients with CD.     

Differential effects of stromal derived factor‐1α (SDF‐1α) on early and late stages of human megakaryocytic development

Stromal derived factor‐1α (SDF‐1α), the high‐affinity ligand of CXC‐chemokine receptor 4 (CXCR4), was added to human CD34⁺ hematopoietic progenitor cells that can be induced to differentiate along the monocytic or megakaryocytic lineages. In control liquid cell cultures supplemented with two different cytokine cocktails: stem cell factor (SCF), interleukin‐3 (IL‐3), macrophage‐colony stimulating factor (M‐CSF), and 10% fetal calf serum (FCS), or, SCF and thrombopoietin (TPO), the expression of surface CXCR4 progressively increased in both the CD14⁺ monocytic and CD41⁺ megakaryocytic lineages. While SDF‐1α caused only modest effects on cells of the monocytic lineage, it induced profound down‐regulation of CXCR4 in megakaryocytic cells at all stages of differentiation. Moreover, while SDF‐1α initially up‐regulated the early megakaryocytic antigen CD41, at later time points (days 12–16) it induced down‐regulation of the late megakaryocytic antigen CD42b. Consistently, at day 16, the number of mature megakaryocytes was significantly decreased in cultures supplemented with SDF‐1α. These findings indicate that, besides its primary role in regulating the retention of precursor cells in hematopoietic tissues, the SDF‐1α/CXCR4 system participates in the regulation of megakaryocytic development by stimulating the formation of immature megakaryoblasts and inhibiting the formation of mature megakaryocytes. Anat Rec 260:141–147, 2000. © 2000 Wiley‐Liss, Inc.     

Oronasal masks require higher levels of positive airway pressure than nasal masks to treat obstructive sleep apnea

Purpose

The purpose of this study was to compare the therapeutic pressure determined by an automated CPAP device (AutoCPAP) during the titration period, between nasal and oronasal mask and the residual apnea-hypopnea index (AHI) on a subsequent poligraphy performed with the established therapeutic CPAP.

Methods

As a retrospective study, 109 subjects with moderate and severe obstructive sleep apnea-hypopnea (apnea-hypopnea index?≥?15 events/h) were studied. CPAP titration was performed using an auto-titrating device.

Results

There was significant difference in the mean pressure delivered with autoCPAP between the group of patients using the nasal mask (mean 10.0 cmH₂O?±?2.0 SD) and the group which used the oronasal mask (mean 11.2 cmH₂O?±?2.1) (p?p?r?=?0.245, p 0.008).

Conclusions

Therapeutic CPAP level for OSAH is higher when administered via oronasal mask, leaving more residual events. These findings suggest that nasal mask should be the first choice for OSAH treatment.     

Concealed renal insufficiency and adverse drug reactions in elderly hospitalized patients

BACKGROUND: Adverse drug reactions (ADRs) are common causes of in-hospital complications for elderly people. The purpose of the present study is to verify whether concealed renal insufficiency, that is, reduction of the estimated glomerular filtration rate (GFR) in people with normal serum creatinine levels, is a risk factor for ADRs in elderly hospitalized patients. METHODS: We used data on 11,687 hospitalized patients enrolled in the Gruppo Italiano di Farmacovigilanza nell'Anziano study. The outcomes of the study were any ADR, ADR to hydrosoluble drugs, and ADR to any other drug during the hospital stay. We compared 3 groups: normal renal function (normal serum creatinine levels and normal estimated GFRs), concealed (normal serum creatinine levels and reduced estimated GFRs), or overt (increased creatinine levels and reduced estimated GFRs) renal insufficiency. The relationship between renal function and ADR was evaluated using contingency tables and multiple regression analysis including potential confounders. RESULTS: Concealed renal insufficiency was detected in 1631 (13.9%) patients and was frequently associated with male sex and poor nutritional status. Hydrosoluble drugs were responsible for 301 of the 941 recorded ADRs. After adjusting for potential confounders, both concealed (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.15-1.25) and overt (OR, 2.02; 95% CI, 1.54-2.65) renal failure were associated with ADR to hydrosoluble drugs, but not with ADR to other drugs (OR, 0.83 [95% CI, 0.65-1.08], and OR, 1.01 [95%CI, 0.83-1.23], respectively). CONCLUSION: Older hospitalized patients frequently have impaired renal function despite normal serum creatinine levels and are exposed to an increased risk of ADRs to hydrosoluble drugs.     

Pharmacological profile of NOP receptors coupled with calcium signaling via the chimeric protein Gαqi5

In this study, the Gα_qi5 protein was used to force the human nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor to signal through the Ca²⁺ pathway in CHO cells. [Ca²⁺]_i levels were monitored using the fluorometer FlexStation II and the Ca²⁺ dye Fluo 4 AM. Concentration response curves were generated with a panel of full and partial agonists, while NOP antagonists were assessed in inhibition-response curves. The following rank order of potency of antagonists was measured: naloxone, which is superimposable to literature findings. The rank order of potency of full and partial agonists is also similar to that obtained in previous studies with the exception of a panel of ligands (UFP-112, Ro 64-6198, ZP120, UFP-113) whose potency was relatively low in the Gα_qi5–NOP receptor calcium assay. Interestingly, these NOP ligands are characterized by slow kinetic of interaction with the NOP receptor, as demonstrated by bioassay experiments. These results demonstrated that the FlexStation II–Gα_qi5–NOP receptor calcium assay represents an adequate and useful screening for NOP receptor ligands, particularly for antagonists.     

Plasma levels of polychlorinated biphenyls (PCB) and the risk of soft tissue sarcoma

Background::Soft tissue sarcoma (STS) is a heterogeneous group of rare neoplasms whose aetiology is largely unknown. Dioxin and dioxin-like compounds, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and polychlorinated biphenyls (PCBs), are potential risk factors for STS.Objectives:To investigate the relation of 17 PCBs congeners, assessed in human plasma, with STS risk.Methods:We conducted a case-control study in Italy, including 52 STS cases and 99 hospital-based controls. Selected PCB were extracted by high-performance liquid chromatography (HPLC) and measured with gas chromatography-mass spectrometry (GC-MS). Odds ratios (OR), and the corresponding 95% confidence intervals (CI), were estimated through multivariate logistic regression models.Results:The most frequently detected PCB congeners were 138, 170, 180 and 149 (detected in 40-77% of controls). The OR for the sum of all 17 PCB congeners was 1.20 (95% CI 0.50-2.92). In categorical analysis no consistent association was found for individual congeners and for groups based on Wolff’s classification or the degree of chlorination. For continuous estimates, borderline positive associations emerged for Wolff’s groups 2A (OR 1.23, 95% CI 0.97-1.55), 2B (OR 1.34, 95% CI 1.00-1.77, and 3 (OR 1.19, 95% CI 0.96-1.49), for moderately (OR 1.20, 95% CI 0.96-1.51) and highly (OR 1.18, 95% CI 0.99-1.41) chlorinated PCBs, and for congeners 170 (OR 1.26, 95% CI 0.98-1.63), 180 (OR 1.26, 95% CI 0.97-1.64) and 138 (OR 1.45, 95% CI 1.02-2.04).Discussion:Most associations between PCBs and STS risk were not significant, but, given the limited sample size, we cannot exclude moderate associations.Key words: Soft tissue sarcoma, polychlorinated biphenyls, epidemiology, environmental risk factors, chemical contaminants, case-control study     

Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation

Background

The contraceptive efficacy of emergency contraceptive pills containing levonorgestrel (LNG-EC) has been estimated in most previous studies by judging the day of ovulation from presumptive menstrual cycle data, thus providing poorly reliable estimates.

Methods

In the present study, the efficacy of LNG-EC was determined in 393 cycles by dating ovulation on the basis of reliable hormonal and ovarian parameters validated by a database constructed in a separate study. In addition, the efficacy was determined separately for cycles in which LNG-EC was given before or after ovulation.

Results

For the 148 women who had sexual intercourse during the fertile days, the overall accumulated probability of pregnancy was 24.7, while altogether 8 pregnancies were observed. Thus, the overall contraceptive efficacy of LNG-EC was 68%. Among the 103 women who took LNG-EC before ovulation (days −5 to −1), 16 pregnancies were expected and no pregnancy occurred (p<.0001). Among the 45 women who took LNG-EC on the day of ovulation (day 0) or thereafter, 8 pregnancies occurred and 8.7 were expected (p=1.00). These findings are incompatible with the inhibition of implantation by LNG-EC in women. The same cases were also analyzed using the presumptive menstrual cycle data, and important discrepancies were detected between the two methods.

Conclusion

The efficacy of LNG-EC has been overestimated in studies using presumptive menstrual cycle data. Our results confirm previous similar studies and demonstrate that LNG-EC does not prevent embryo implantation and therefore cannot be labeled as abortifacient.     

Rectal dose-volume constraints in high-dose radiotherapy of localized prostate cancer

PURPOSE: To investigate the relationship between rectal bleeding and dosimetric-clinical parameters in patients receiving three-dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer. METHODS: In a retrospective national study (AIROPROS01-01, AIRO: Associazione Italiana Radioterapia Oncologica), planning/clinical data for 245 consecutive patients with stage T1-4N0-x prostate carcinoma who underwent 3D-CRT to 70-78 Gy (ICRU point) were pooled from four Italian institutions. The correlation between late rectal bleeding and rectal dose-volume data (the percentage of rectum receiving more than 50, 55, 60, 65, 70, and 75 Gy [V(50-70)]) and other dosimetric and clinical parameters were investigated in univariate (log-rank) and multivariate (Cox regression model) analyses. Median follow-up was 2 years. RESULTS: Twenty-three patients were scored as late bleeders according to a modified RTOG definition (Grade 2: 16; Grade 3: 7); the actuarial 2-year rate was 9.2%. Excepting V75, all median and third quartile V(50-70) values were found to be significantly correlated with late bleeding at univariate analysis. The smallest p value was seen for V(50) below/above the third quartile value (66%). The V70 (cut-off value: 30%) was found to be also predictive for late bleeding. In the high-dose subgroup (74-78 Gy), Grade 3 bleeding was highly correlated with this constraint. The predictive value of both V(50) and V(70) was confirmed by multivariate analyses. CONCLUSIONS: The present article provides evidence for correlation between rectal DVH parameters and late rectal bleeding in patients treated with curative intent with 3D-CRT. To keep the rate of moderate/severe rectal bleeding below 5-10%, it seems advisable to limit V(50) to 60-65%, V(60) to 45-50%, and V70 to 25-30%.     

Immunocytoehemical localization of substance P in the spinal trigeminal nucleus of the rat: A light and electron microscopic study

The neuropeptide substance P is a transmitter candidate for certain primary afferent fibers which terminate in the substantia gelatinosa. In this study the light and electron microscopic localization of substance P in the substantia gelatinosa of the spinal trigeminal nucleus of the rat has been studied using immunocytochemical procedures. Substance P immunoreactive fibers were observed mainly in lamina I and outer lamina II. Ultrastructural analysis revealed immunoreactivity in unmyelinated fibers and in axon terminals which contained agranular spherical vesicles and large dense-cored vesicles and which made predominantly simple asymmetric axodendritic synaptic contacts. Immunoreactive terminals only rarely formed the central terminal of synaptic glomeruli and in only one example was a stained terminal possibly postsynaptic to an unstained terminal. The majority of synapses were onto small dendrites in outer lamina II and in some cases these dendrites were themselves presynaptic to other dendrites. Immunoreactive terminals also synapsed with the soma and proximal dendrites of large neurons on the border of laminae I and II. The results show that there are at least two distinct targets for substance P immunoreactive terminals in the substantia gelatinosa, namely the large lamina I neurons and lamina II probable intemeurons. Some of the former may be projection neurons while some of the latter may correspond to the inhibitory islet cells described by Gobel and colleagues in the cat. In addition the results indicate that few substance P immunoreactive terminals receive axoaxonic synapses and emphasize instead the role of postsynaptic interactions. In particular the results suggest several sites at which substance P might interact postsynaptically with the neuropeptide enkephalin.