[Non-primary solid malignancies of breast in needle core biopsy: a clinicopathological analysis of 23 cases].

Objective: To investigate the accurate diagnosis and differential diagnosis of non-primary solid malignant tumors in breast needle core biopsy. Methods: Twenty-three cases of breast, axilla or neck lymph nodes pathologically diagnosed as non-primary solid malignant tumors were collected at the First Affiliated Hospital of Nanjing Medical University, Nanjing, China from January 2013 to March 2023. The differential diagnoses and diagnostic features were analyzed, based on combining clinical data, histology, and expression characteristics of biomarkers. Results: All patients were female, with age ranging from 29 to 75 years (average 56 years). The average time from the diagnosis of primary tumor to the current diagnosis was 21 months (0 to 204 months).The primary sites included the ovary (9 cases), the lung (5 cases), the gastrointestinal tract (4 cases), the pancreas, intrahepatic bile duct, thyroid gland, nasal cavity and forearm skin (1 case each). No carcinoma in situ was found in any of the cases. The morphological differences were significant among the tumors, but similar to the primary tumors. The tumors of neuroendocrine and female reproductive tract had great morphological and immunophenotypic overlaps with breast cancer. Metastatic lung cancer cells showed obvious atypia and tumor giant cells. The morphology and immunophenotype of metastatic serous carcinoma of female reproductive system might resemble invasive micropapillary carcinoma of the breast. Metastatic adenocarcinoma of the gastrointestinal tract often had features of mucous secretion. Metastatic neuroendocrine tumors were bland in appearance and morphologically similar to solid papillary carcinoma of breast, but negative for ER. TRPS1 was mostly negative (18/23) and variably positive in ovarian (4/9) and intrahepatic bile duct (1/1) tumors. Conclusions: The diagnosis of breast needle core biopsy specimen should be combined with clinical history, imaging study, and careful examination of histological features, such as presence of in situ component, morphological similarity between the primary and metastatic tumors, and using appropriate markers to differentiate the primary from metastatic tumors.

[TRPS1 expression in salivary gland-type breast carcinoma and its clinical application].

Objective: To investigate the expression of TRPS1 in salivary gland-type breast carcinoma and its clinical application. Methods: A total of 30 cases of salivary gland-type breast carcinoma diagnosed from May 2015 to November 2022 at the Department of Pathology of the First Affiliated Hospital of Nanjing Medical University were collected. The expression of TRPS1 was detected by immunohistochemistry and compared with that of GATA3. TRPS1 and GATA3 expression in 24 cases of primary salivary gland carcinoma. Results: There were 10 cases of breast secretory carcinoma, aged 21-61 years (median 53.5 years), with the size ranging from 0.9-2.2 cm (median 1.6 cm), 2 of which were accompanied by axillary nodal macrometastasis. All patients were alive after 2-55 months of follow-up (median 29.5 months, mean 29.7 months). There were 20 cases of breast adenoid cystic carcinoma, aged 36-77 years (median 53.5 years), with the size ranging from 1.2-5.5 cm (median 2.5 cm), 3 of which were accompanied by axillary nodal macrometastasis. All patients were alive after 3-92 months of follow-up (median 22.5 months, mean 31.7 months), and 1 patient had lung metastasis 15 months after surgery. The medium/high expression ratio of TRPS1 in breast secretory carcinoma was 10/10, which was higher than that of GATA3 (7/10). TRPS1 was also positive in the 2 cases with lymph node metastases. The medium/high expression rate of TRPS1 in breast adenoid cystic carcinoma was 20/20, which was significantly higher than that of GATA3 (2/20). TRPS1 was highly expressed in both classic and solid subtypes, while GATA3 was only expressed in a few cases of the classic subtype. TRPS1 was also positive in 3 cases with lymph node metastases and 1 case of the pulmonary metastases. The expression level of TRPS1 was the same in 1 case before and after neoadjuvant chemotherapy. In addition, TRPS1 was positive in parotid secretory carcinoma and adenoid cystic carcinoma. The medium/high expression rate of TRPS1 in parotid secretory carcinoma (6/6) was higher than that of GATA3 (2/6), and the medium/high expression rate of TRPS1 in parotid adenoid cystic carcinoma (17/18) was higher than that of GATA3 (2/18). Conclusions: The expression of TRPS1 is highly sensitive to salivary gland-type breast carcinoma, especially in GATA3-negative solid subtype of adenoid cystic carcinoma, which plays an important role in clinical practice.

[Efficacy comparison between a new generation of artificial ligaments and bone-patellar tendon-bone autograft for anterior cruciate ligament revision].

Objective: To compare the clinical efficacy of a new generation of ligaments (LARS artificial ligament) and bone-patellar tendon-bone (BPTB) autograft as grafts in anterior cruciate ligament (ACL) revision. Methods: A retrospective cohort study. The clinical data of 54 patients who underwent ACL revision from January 2018 to June 2020 in the First Hospital Affiliated to Army Medical University were retrospectively analyzed. There were 44 males and 10 females with a mean age of (28.5±7.7) years (15-45 years). Among them, 24 cases underwent ACL revision with LARS artificial ligament (LARS group), the other 30 cases underwent ACL revision with BPTB (BPTB group). The subjective and objective knee joint evaluation indexes were compared between the two groups to evaluate the clinical efficacy. The subjective evaluation indexes included Tegner score, Lysholm score and the International Knee Documentation Committee (IKDC) score. The objective evaluation indexes included the Lachman test, pivot-shift test, the anterior tibial translation (ATT) measurement at the weight-bearing position and the rate of patients returned to pre-injury sports. Results: The follow-up period was (32.8±5.3) months (24-42 months). At the last follow-up, the IKDC score, Tegner score and Lysholm score in the two groups significantly increased when compared with those before surgery (all P<0.05), and there was no significant difference in those indexes between the two groups (all P>0.05). The ATT measurement in the weight-bearing position was (3.1±0.7) mm in the LARS group and it was (4.1±0.9) mm in the BPTB group, which were significantly improved when compared with those before surgery (both P<0.05), and it was better in the LARS group than in the BPTB group (P<0.05). Postoperative Lachman test and pivot-shift test results in the LARS group were better than those in the BPTB group with statistically significant difference (both P<0.05). The rate of patients returned to pre-injury sports one year after surgery was 79.2%(19/24) in the LARS group and it was 50.0%(15/30) in the BPTB group, and the difference was statistically significant (P=0.029). Conclusions: Both LARS artificial ligament and BPTB autograft can achieve good short-term clinical efficacy in ACL revision, but LARS artificial ligament group has more advantages than BPTB autograft group in knee stability and early return to sports.

Synergistic effects ofα-Fe2O3nanoparticles and Fe-doping on gas-sensing performance of NiO nanowires and interface mechanism.

High surface area nickel oxide nanowires (NiO NWs), Fe-doped NiO NWs andα-Fe2O3/Fe-doped NiO NWs were synthesized with nanocasting pathway, and then the morphology, microstructure and components of all samples were characterized with XRD, TEM, EDS, UV-vis spectra and nitrogen adsorption-desorption isotherms. Owing to the uniform mesoporous template, all samples with the same diameter exhibit the similar mesoporous-structures. The loadedα-Fe2O3nanoparticles should exist in mesoporous channels between Fe-doped NiO NWs to form heterogeneous contact at the interface of n-typeα-Fe2O3nanoparticles and p-type NiO NWs. The gas-sensing results indicate that Fe-dopant andα-Fe2O3-loading both improve the gas-sensing performance of NiO NWs sensors.α-Fe2O3/Fe-doped NiO NWs sensors presented the highest response to 100 ppm ethanol gas (55.264) compared with Fe-doped NiO NWs (24.617) and NiO NWs sensors (3.189). The donor Fe-dopant increases the ground state resistance and the absorbed oxygen content in air.α-Fe2O3nanoparticles in electron depletion region result in the increasing resistance in ethanol gas and decreasing resistance in air. In this way,α-Fe2O3/Fe-doped NiO NWs sensor presents the excellent gas-sensing performance due to the formation of heterogeneous contact at the interface.

Rubber seed oil and flaxseed oil supplementation alter digestion, ruminal fermentation and rumen fatty acid profile of dairy cows.

Rubber seed oil (RO) that is rich in polyunsaturated fatty acids (FA) can improve milk production and milk FA profiles of dairy cows; however, the responses of digestion and ruminal fermentation to RO supplementation in vivo are still unknown. This experiment was conducted to investigate the effect of RO and flaxseed oil (FO) supplementation on nutrients digestibility, rumen fermentation parameters and rumen FA profile of dairy cows. Forty-eight mid-lactation Holstein dairy cows were randomly assigned to one of four treatments for 8 weeks, including basal diet (CON) or the basal dietary supplemented with 4% RO, 4% FO or 2% RO plus 2% FO on a DM basis. Compared with CON, dietary oil supplementation improved the total tract apparent digestibility of DM, neutral detergent fibre and ether extracts ( P < 0.05). Oil treatment groups had no effects on ruminal digesta pH value, ammonia N and microbial crude protein ( P > 0.05), whereas oil groups significantly changed the volatile fatty acid (VFA) profile by increasing the proportion of propionate whilst decreasing total VFA concentration, the proportion of acetate and the ratio of acetate to propionate ( P < 0.05). However, there were no differences in VFA proportions between the three oil groups (P > 0.05). In addition, dietary oil supplementation increased the total unsaturated FA proportion in the rumen by enhancing the proportion of trans-11 C18:1 vaccenic acid (VA), cis-9, trans-11 conjugated linoleic acid (CLA) and α-linolenic acid (ALA) ( P < 0.05). These results indicate that dietary supplementation with RO and FO could improve nutrients digestibility, ruminal fermentation and ruminal FA profile by enhancing the VA, cis-9, trans-11 CLA and ALA composition of lactating dairy cows. These findings provide a theoretical basis for the application of RO in livestock production.

[Ramsey-Hunt syndrome with initial syndrome of hoarseness: a case report].

Summary Ramsey-Hunt syndrome is caused by the varicella zoster virus, which mainly affects the facial nerve. The typical clinical features of Ramsey-Hunt syndrome are peripheral facial paralysis and ear herpes. In this case, initial symptoms were hoarseness and coughing, afterwards typical symptom occurred 5 days later which were earache, late-onset herpes, and facial paralysis. Ramsey-Hunt syndrome are difficult to diagnose because of its seemingly unrelated initial symptoms.

Effects of source on bioavailability of selenium, antioxidant status, and performance in lactating dairy cows during oxidative stress-inducing conditions.

In the current study, we used heat stress (HS) as an oxidative stress model to examine the effects of hydroxy-selenomethionine (HMSeBA), an organic selenium source, on selenium's bioavailability, antioxidant status, and performance when fed to dairy cows. Eight mid-lactation Holstein dairy cows (141 ± 27 d in milk, 35.3 ± 2.8 kg of milk/d, parity 2 or 3) were individually housed in environmental chambers and randomly assigned to 1 of 2 treatments: inorganic Se supplementation (sodium selenite; SS; 0.3 mg of Se/kg of dry matter; n = 4) or HMSeBA supplementation (0.3 mg of Se/kg of dry matter; n = 4). The trial was divided into 3 continuous periods: a covariate period (9 d), a thermal neutral (TN) period (28 d), and a HS period (9 d). During the covariate and TN periods, all cows were housed in TN conditions (20°C, 55% humidity). During HS, all cows were exposed to cyclical HS conditions (32-36°C, 40% humidity). All cows were fed SS during the covariate period, and dietary treatments were implemented during the TN and HS periods. During HS, cows fed HMSeBA had increased Se concentrations in serum and milk, and total Se milk-to-serum concentration ratio compared with SS controls. Superoxide dismutase activity did not differ between Se sources, but we noted a treatment by day interaction in glutathione peroxidase activity as HS progressively reduced it in SS controls, whereas it was maintained in HMSeBA cows. Supplementation with HMSeBA increased total antioxidant capacity and decreased malondialdehyde, hydrogen peroxide, and nitric oxide serum concentrations compared with SS-fed controls. We found no treatment effects on rectal temperature, respiratory rate, or dry matter intake. Supplementing HMSeBA tended to increase milk yield and decrease milk fat percentage. No other milk composition parameters differed between treatments. We observed no treatment effects detected on blood biochemistry, except for a lower alanine aminotransferase activity in HMSeBA-fed cows. These results demonstrate that HMSeBA supplementation decreases some parameters of HS-induced oxidative stress.

Effects of dietary neutral detergent fiber and starch ratio on rumen epithelial cell morphological structure and gene expression in dairy cows.

This study was designed to investigate the effect of dietary neutral detergent fiber to starch ratio on rumen epithelial morphological structure and gene expression. Eight primiparous dairy cows including 4 ruminally fistulated cows were assigned to 4 total mixed rations with neutral detergent fiber to starch ratios of 0.86, 1.18, 1.63, and 2.34 in a replicated 4 × 4 Latin square design. The duration of each period was 21 d including 14 d for adaptation and 7 d for sampling. Rumen epithelial papillae were collected from the ruminally fistulated cows for morphological structure examination and mRNA expression analysis using quantitative real-time PCR of several genes related to volatile fatty acid absorption and metabolism, and cellular growth. Increasing dietary neutral detergent fiber to starch ratio resulted in a linear increase in the thickness of the stratum spinosum and basale. In contrast, expression of HMGCS2 (encoding the rate-limiting enzyme in the synthesis of ketone bodies) decreased linearly, whereas the expression of MCT2 (encoding a transporter of volatile fatty acid) increased linearly with increasing dietary neutral detergent fiber to starch ratio. As dietary neutral detergent fiber to starch ratio increased, expression of IGFBP5 (a gene related to the growth of rumen epithelial papillae) decreased, whereas IGFBP6 expression increased. Both of these IGFBP genes are regulated by short-chain fatty acids. Overall, the data indicate that dietary neutral detergent fiber to starch ratio can alter the thickness of the rumen epithelial papillae partly through changes in expression of genes associated with regulating volatile fatty acid absorption, metabolism, and cell growth.

Locally linear embedding and neighborhood rough set-based gene selection for gene expression data classification.

Cancer subtype recognition and feature selection are important problems in the diagnosis and treatment of tumors. Here, we propose a novel gene selection approach applied to gene expression data classification. First, two classical feature reduction methods including locally linear embedding (LLE) and rough set (RS) are summarized. The advantages and disadvantages of these algorithms were analyzed and an optimized model for tumor gene selection was developed based on LLE and neighborhood RS (NRS). Bhattacharyya distance was introduced to delete irrelevant genes, pair-wise redundant analysis was performed to remove strongly correlated genes, and the wavelet soft threshold was determined to eliminate noise in the gene datasets. Next, prior optimized search processing was carried out. A new approach combining dimension reduction of LLE and feature reduction of NRS (LLE-NRS) was developed for selecting gene subsets, and then an open source software Weka was applied to distinguish different tumor types and verify the cross-validation classification accuracy of our proposed method. The experimental results demonstrated that the classification performance of the proposed LLE-NRS for selecting gene subset outperforms those of other related models in terms of accuracy, and our proposed approach is feasible and effective in the field of high-dimensional tumor classification.

Leptin improves osteoblast differentiation of human bone marrow stroma stem cells.

OBJECTIVE: To study the effects of leptin (LEP) on the osteogenic differentiation of human bone marrow stromal cells (hBMSCs) and to explore the mechanism controlling the process. MATERIALS AND METHODS: Respectively cultivated the third-generation hBMSCs with 100 ng/ml bone morphogenetic protein (BMP) culture media containing 320, 160, 80 and 40 ng/mL LEP, and regular medium. We administered alkaline phosphatase (ALP) dye (on the 7th day) and mineralized nodules alizarin red (on the 21st day) and tested the ALP activity as well as osteocalcin (OCN) level on 7th, 14th, 21st day in each group to establish the best inducing concentration of LEP. 7 days later, we tested bone differentiation related genes expression in the control, 160 ng/mL LEP and 100 ng/mL BMP groups using RT-PCR. RESULTS: The activity of ALP and OCN in the 160 ng/mL LEP group after 7, 14 and 21 days was lower than that of the BMP group but higher than that of other groups. However, LEP significantly promoted the expression of bone differentiation related genes, namely, Cbfal, ALP, COL-I and OCN. CONCLUSIONS: LEP promoted the bone differentiation in hBMSCs by promoting the expression of genes related to bone differentiation.

Effectiveness of rubber seed oil and flaxseed oil to enhance the α-linolenic acid content in milk from dairy cows.

This experiment was conducted to investigate effect of rubber seed oil compared with flaxseed oil when fed alone or in combination on milk yield, milk composition, and α-linolenic acid (ALA) concentration in milk of dairy cows. Forty-eight mid-lactation Holstein dairy cows were randomly assigned to 1 of 4 treatments according to a completely randomized design. Cows were fed a basal diet (control; CON) or a basal diet supplemented with 4% rubber seed oil (RO), 4% flaxseed oil (FO), or 2% rubber seed oil plus 2% flaxseed oil (RFO) on a dry matter basis for 9 wk. Feed intake, milk protein percentage, and milk fat levels did not differ between the treatments. Cows fed the RO, FO, or RFO treatments had a higher milk yield than the CON group (up to 10.5% more), whereas milk fat percentages decreased. Compared with the CON, milk concentration of ALA was substantially higher in cows receiving RO or RFO, and was doubled in cows receiving FO. The ALA yield (g/d) increased by 31.0, 70.3, and 33.4% in milk from cows fed RO, FO, or RFO, respectively, compared with the CON. Both C18:1 trans-11 (vaccenic acid) and C18:2 cis-9,trans-11 (conjugated linoleic acid; CLA) levels were higher in cows fed added flaxseed or rubber seed oil. The CLA yield (g/d) increased by 336, 492, and 484% in cows fed RO, FO, or RFO, respectively, compared with the CON. The increase in vaccenic acid, ALA, and CLA was greater in cows fed RFO than in cows fed RO alone. Compared with the CON, the milk fat from cows fed any of the dietary supplements had a higher concentration of unsaturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids; conversely, the saturated fatty acids levels in milk fat were 30.5% lower. Insulin and growth hormones were not affected by dietary treatments; however, we noted an increase in both cholesterol and nonesterified fatty acids levels in the RO, FO, or RFO treatments. These results indicate that rubber seed oil and flaxseed oil will increase milk production and the concentration of functional fatty acids (ALA, vaccenic acid, and CLA) in milk fat while decreasing the content of saturated fatty acids.

Co-expression network analysis prioritizes signaling pathways regulating liver regeneration after partial hepatectomy in rats.

The liver has extraordinary powers of regeneration following partial hepatectomy (PH). Changes in gene expression levels play a key role in cell proliferation and differentiation during liver regeneration (LR). To understand the molecular mechanisms underlying LR, this study was designed to assess the time-dependent changes in rat hepatic gene expression. We obtained a gene expression profile of rat LR with high temporal resolution. We then constructed gene co-expression networks of regenerating liver tissue and identified 13 LR-specific modules from 1772 differentially expressed genes, and prioritized signaling pathways that regulated LR after PH. The results indicated that adipocytokine signaling, histone acetylation, and IL-6-related pathways play an important role in LR. Co-expression network analysis provides novel insight into understanding the molecular mechanisms behind LR.

Role of death receptors in the regulation of hepatocyte proliferation and apoptosis during rat liver regeneration.

The balance between hepatocyte proliferation and apoptosis is critical for liver homeostasis during liver regeneration. We created a rat liver regeneration model by partial hepatectomy (PH) to investigate the overall mechanism that regulates the proliferation and apoptosis of hepatocytes. The Rat Genome 230 2.0 Array was used to investigate changes in the expression levels of genes associated with the known proliferation or apoptosis signaling pathways. Ingenuity Pathway Analysis 9.0 was used to determine interactions among these signaling pathways. The results revealed that the expression levels of multiple key genes in three death receptor (DR) pathways, Fas/FasL, TNFR/TNFα, and DR6, were significantly altered in hepatocytes after PH. The expression level of the gene encoding DR6 increased by over 100-fold, whereas the levels of the genes encoding Fas, FasL, and TNFα were increased by 2-4-fold 12 h after PH. Fas/FasL, TNFR/TNFα, and DR6 are known to participate in numerous cellular events including cell proliferation and apoptosis. Our results suggest that the DR6 pathway plays a major role in the regulation of hepatocyte apoptosis, whereas Fas/FasL and TNFR/TNFα pathways may have roles in coordinating signaling activities between proliferation and apoptosis.

Alpha-methylacyl-CoA racemase: a multi-institutional study of a new prostate cancer marker.

AIM: To test whether alpha-methylacyl-CoA racemase (AMACR) is a sensitive and specific marker of prostate cancer. METHODS AND RESULTS: The expression levels of AMACR mRNA were measured by real-time polymerase chain reaction. A total of 807 prostatic specimens were further examined by immunohistochemistry specific for AMACR. Quantitative immunostaining analyses were carried out by using the ChromaVision Automated Cellular Imaging System and the Ariol SL-50 Imaging System, respectively. AMACR mRNA levels measured in prostatic adenocarcinoma were 55 times higher than those in benign prostate tissue. Of 454 cases of prostatic adenocarcinoma, 441 were positive for AMACR, while 254 of 277 cases of benign prostate were negative for AMACR. The sensitivity and specificity of AMACR immunodetection of prostatic adenocarcinomas were 97% and 92%, respectively. Both positive and negative predictive values were 95%. By automatic imaging analyses, the AMACR immunostaining intensity and percentage in prostatic adenocarcinomas were also significantly higher than those in benign prostatic tissue (105.9 versus 16.1 for intensity, 45.7% versus 0.02% and 35.03% versus 4.64% for percentage, respectively). CONCLUSIONS: We have demonstrated the promising features of AMACR as a biomarker for prostate cancer in this large series and the potential to develop automated quantitative diagnostic tests.

The development of highly efficient onium-type peptide coupling reagents based upon rational molecular design.

Novel and highly efficient immonium-, pyridinium- and thiazolium-type peptide coupling reagents, such as BOMI, BDMP, BPMP, BEP, FEP, BEPH, FEPH and BEMT, were developed by rational modifying of the molecular structures of commonly used uronium-type reagents. The high efficiency of these onium salts has been evaluated and proven by model reaction tests and the successful synthesis of various oligopeptides and biologically active peptides, both in solution and in the solid-phase, for example Leu-enkephalin, the pentapeptide moiety of Dolastatin 15 and the immunosuppressive undecapeptide cyclosporin O. Based upon these results, the relationship between the molecular structure and the capability of onium-type peptide coupling reagents was studied. A preliminary guideline for the molecular design of onium-type coupling reagents was developed.

Cytotoxicity of 2-chlorodeoxadenosine (cladribine, 2-cdA) in combination with other chemotherapy drugs against two lymphoma cell lines.

Cladribine is a purine analog with impressive activity in patients with low-grade lymphoproliferative disorders. We studied the combination of cladribine with other antineoplastic drugs against two human-derived B-cell lymphoma cell lines in vitro. Cladribine was combined with cisplatin, daunorubicin, chlorambucil, paclitaxel or etoposide. Under the experimental conditions studied, only the combination of cladribine and cisplatin showed significantly increased cytotoxicity compared to the effect of either drug alone.

A pharmacodynamic study of morphine and its glucuronide metabolites after single morphine dosing in cancer patients with pain.

Eleven morphine naïve patients with cancer-related pain were given a single dose of either intravenous morphine (n = 5) or oral morphine (n = 6). Blood sampling was performed over a 24-hr period and serial pain assessments were made using a categorical scale. Plasma samples were analyzed for morphine, morphine-6-glucuronide (M-6-G), morphine-3-glucuronide (M-3-G), and normorphine using high-performance liquid chromatography. In neither the intravenous nor oral group was there a correlation between analgesia duration and the half-lives of morphine and M-6-G. There was no correlation between the time to peak analgesia and time to peak concentration for morphine or M-6-G. There was no significant difference in absolute concentrations of M-6-G or M-3-6 nor in the ratio of M-3-G to M-6-G at peak analgesia versus relapse.

Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor.

Signals from CD4+ T cells induce two opposite fates in B cells: clonal proliferation of B cells that bind specifically to foreign antigens and clonal deletion of equivalent B cells that bind self-antigens. This B cell fate decision is determined by the concerted action of two surface proteins on activated T cells, CD40-and Fas-ligands (CD40L and FasL), whose effects are switched by signals from the B cell antigen receptor (BCR). Foreign antigens that stimulate the BCR acutely cause CD40L and FasL to promote clonal proliferation. CD40L and FasL trigger deletion, however, when the BCRs become desensitized by chronic stimulation with self-antigens or when BCRs have not bound an antigen. The need for both Fas and CD40L to correctly regulate self-reactive B cell fate may explain the severe autoantibody disorders in Fas- or CD40L-deficient children.

Disruption of CD40-CD40 ligand interactions results in an enhanced susceptibility to Leishmania amazonensis infection.

To study the role of CD40 ligand (CD40L) in the host immune responses against intracellular pathogens, we infected CD40L knockout (CD40L-/-) mice with Leishmania amazonensis. Although wild-type mice were susceptible to infection and developed progressive ulcerative lesions, tissue parasite burdens in CD40L-/- mice were significantly higher. This heightened susceptibility to infection was associated with an impaired T cell and macrophage activation and altered inflammatory response, as reflected by low levels of IFN gamma, lymphotoxin-tumor necrosis factor (LT-TNF), and nitric oxide (NO) production. Furthermore, CD40L-/- mice failed to generate a protective immune response after immunization. These results indicate an essential role of cognate CD40-CD40L interactions in the generation of cellular immune responses against an intracellular parasite.