实验性自身免疫性脑脊髓炎小鼠中枢神经组织中CD_4 mRNA的变化及益肾达络饮对其的影响

目的观察中药复方益肾达络饮干预实验性自身免疫性脑脊髓炎(EAE)的疗效和作用机制。方法采用荧光定量PCR测定免疫后不同时间点EAE小鼠中枢神经组织中CD4mRNA表达的变化。结果中药复方益肾达络饮可以显著改善EAE模型小鼠神经功能评分。与模型组相比,激素组、中药组在免疫后14、24、40 d CD4mRNA在EAE小鼠大脑中表达水平明显降低,而在脊髓中仅在免疫后第14日显著降低。结论免疫炎性细胞CD4+T细胞是实验性自身免疫性脑脊髓炎的潜在调节细胞;中药复方益肾达络饮能有效改善EAE小鼠神经功能损伤,其干预EAE的作用机制与中枢神经系统免疫炎性细胞的调节密切相关。

实验性自身免疫性脑脊髓炎小鼠中枢神经组织中ZO-1 mRNA的变化及益肾达络饮对其的影响

目的研究血脑屏障紧密连接蛋白在EAE发病中的作用,观察中药复方益肾达络饮干预实验性自身免疫性脑脊髓炎(EAE)的疗效和作用机制。方法采用荧光定量PCR测定免疫后不同时间点EAE小鼠中枢神经组织中ZO-1 mRNA表达的变化。结果中药复方益肾达络饮可以显著改善EAE模型小鼠神经功能评分。与正常组相比,激素组、中药组在免疫后14、24、40 d ZO-1 mRNA在EAE小鼠大脑中表达均未见显著改变,而脊髓中在免疫后第14日显著降低;在免疫后14、24、40 d模型组小鼠脊髓中ZO-1 mRNA表达均显著降低。结论 ZO-1是实验性自身免疫性脑脊髓炎血脑屏障破坏的一个重要因素;中药复方益肾达络饮能有效改善EAE小鼠神经功能损伤,其干预EAE的作用机制与血脑屏障紧密连接蛋白调节密切相关。

临床常用炎性标志物与肺癌的研究进展分析

慢性炎症反应在肺癌的发生、浸润和转移过程中起重要作用,与肺部肿瘤的发生、发展具有相关性。炎症可以促进恶性细胞的增殖和存活,削弱机体的获得性免疫反应。免疫炎症细胞、降钙素原、C-反应蛋白、细胞因子等血液炎症指标影响机体免疫反应,有助于早期发现肿瘤,也可削弱机体抗肿瘤作用,可为肺癌诊断、治疗、预后提供一定的指导价值。

复方黄柏液熏洗配合括约肌间入路治疗肛周脓肿的疗效及安全性研究

目的探究复方黄柏液熏洗配合括约肌间入路治疗肛周脓肿的疗效及安全性。方法选取2019年6月至2022年6月河南科技大学第一附属医院收治的60例肛周脓肿患者纳入研究,按随机数表法分为对照组和观察组各30例。两组患者均给予括约肌间入路手术治疗,术后对照组予以康复新液熏洗,观察组予以复方黄柏液熏洗,直至创面愈合。4周后比较两组患者的临床疗效,术后7 d、14 d及21 d的肛门疼痛程度、肉芽生长情况、创面愈合率、创面组织形态和术前、术后7 d、14 d及21 d的免疫炎性因子水平[白介素(IL)-6、肿瘤坏死因子-α(TNF-α)、C-反应蛋白(CRP)]以及术后4周、6周及8周的肛门功能评分;同时比较两组患者术后并发症发生情况。结果观察组患者的治疗总有效率为96.67%,明显高于对照组的73.33%,差异有统计学意义(P<0.05);观察组患者术后7 d、14 d及21 d的创面肉芽生长情况评分分别为(1.22±0.57)分、(0.62±0.27)分、(0.25±0.04)分,明显低于对照组的(1.83±0.85)分、(1.32±0.48)分、(0.67±0.32)分,肛门疼痛程度分别为(2.15±0.53)分、(1.25±0.22)分、(1.07±0.13)分,明显低于对照组的(4.64±1.34)分、(3.57±1.08)分、(1.85±0.59)分,创面愈合率分别为(15.82±1.56)%、(72.37±3.85)%、(95.83±4.37)%,明显高于对照组的(10.37±1.31)%、(55.69±3.29)%、(77.52±3.57)%,差异均有统计学意义(P<0.05);观察组患者术后7 d、14 d及21 d的巨噬细胞比例、新生毛细血管数、成纤维细胞数明显高于对照组,血清IL-6、CRP、TNF-α水平明显低于对照组,差异均有统计学意义(P<0.05);观察组患者术后4周、6周及8周的肛门功能评分明显低于对照组,差异均有统计学意义(P<0.05);观察组患者的术后并发症发生率为6.67%,明显低于对照组的30.00%,差异有统计学意义(P<0.05)。结论复方黄柏液熏洗配合括约肌间入路治疗肛周脓肿能有效减轻患者的肛门疼痛程度,降低免疫炎性反应和术后并发症发生率,有助于术后创面愈合,临床治疗效果较好。

转移性肝癌边缘回声与其生长关系的研究

应用彩色多普血流显像和超声引导下穿刺活检，观察了转移性肝癌边缘回声与其生长关系（大小变化、形态改变、生长方式和快慢）。结果发现边缘回声与其病理改变有关，与原发部位无关。转移性癌生长快慢与肿瘤周边有无结维包膜及免疫炎性细胞多少、血供有关，周边纤维结缔组织包膜的存在对转移性肝癌的生长起限制作用，边界不清，呈浸润性生长，血供丰富，生长迅速，由园形变为不规则形。同时还发现部分低回声晕是由血管组成，边缘回声反映了肿瘤病理和生长的特性，为防止炜移性肝癌形成和生长提供依据，对指导转移癌的治疗、判断疗效、估计预后具有重要意义。

Alterations of red blood cell immunoadherence function in hepatitis B patients

AIMS To investigate the alterations of RBC immunoadherence function in patients with various hepatitis B. METHODS RBCC3bRR,RBCICRR and serum CIC levels were measured in 42 patients with acute and chronic hepatitis B at ac- tive and convalescence stages. RESULTS RBCC3bRRs at the active/acute stage of various hepatitis were decreased.They were 13,54%±5,23% in AH, 7.61%±4.12% in AFH,and 16.18%±6.10% in CH, respectively,all of which were lower than those in normal persons (18.12%±3.91% ).At the quiescent/recovery stage of various hepatitis,the RBCC3bRRs were increased significantly.The changes of RBCICRR and serum CIC level were contrary to those of RBCC3bRR. CONCLUSIONS RBC immunoadherence function is decreased in acute and chronic hepatitis.The decrease is in direct proportion to the severity of the diseases.

Aetiopathogenesis of autoimmune hepatitis

The histological hallmark of autoimmune hepatitis（AIH） is a dense portal mononuclear cell infiltrate that invades the surrounding parenchyma and comprises T and B lymphocytes,macrophages,and plasma cells.An unknown but powerful stimulus must be promoting the formation of this massive inflammatory cellular reaction that is likely to initiate and perpetuate liver damage.An autoimmune attack can follow different pathways to inflict damage on hepatocytes.Liver damage is likely to be orchestrated by CD4^＋ T lymphocytes recognizing an autoantigenic liver peptide.To trigger an autoimmune response,the peptide must be embraced by an HLA class Ⅱ molecule and presented to naive CD4^＋ T helper（Th0） cells by professional antigen presenting cells,with the co-stimulation of ligand-ligand fostering interaction between the two cells.Th0 cells become activated,differentiate into functional phenotypes according to the cytokines prevailing in the microenvironment and the nature of the antigen,and initiate a cascade of immune reactions determined by the cytokines produced by the activated T cells.Th1 cells,arising in the presence of the macrophage-derived interleukin（IL） -12,secrete mainly IL-2 and interferon-gamma（IFN-γ）,which activate macrophages,enhance expression of HLA classⅠ（increasing liver cell vulnerability to a CD8^＋ T cell cytotoxic attack）,and induce expression of HLA class Ⅱ molecules on hepatocytes.Th2 cells,which differentiate from Th0 if the microenvironment is rich in IL-4,produce mainly IL-4,IL-10,and IL-13 which favour autoantibody production by B lymphocytes.Physiologically,Th1 and Th2 antagonize each other.Th17 cells,a recently described population,arise in the presence of transforming growth factor beta（TGF-β） and IL-6 and appear to have an important effector role in inflammation and autoimmunity.Theprocess of autoantigen recognition is strictly controlled by regulatory mechanisms,such as those exerted by CD4^＋CD25^＋ regulatory T cells,which derive from Th0 in the presence of TGF-β,but in the absence of IL-6.If regulatory mechanisms fail,the autoimmune attack is perpetuated.Over the past three decades different aspects of the above pathogenic scenario have been investigated.In particular,a defect in immunoregulation affecting CD4^＋CD25^＋ regulatory T cells（T-regs） has been demonstrated in AIH,particularly at diagnosis or during relapse.Advances in the study of autoreactive T cells have occurred mostly in AIH type 2,since the knowledge that CYP2D6 is the main autoantigen has enabled the characterization of both CD4 and CD8 T cells targeting this cytochrome.CD4 T cells from patients with type 2 AIH positive for the predisposing HLA allele DRB10701 recognize seven regions of CYP2D6,five of which are also recognized by CD8 T cells.High numbers of IFN-γ producing CD4 T cells and CD8 T cells are associated with biochemical evidence of liver damage,suggesting a combined cellular immune attack.

Mesenchymal stem cells： a new strategy for immunosuppression and tissue repair

Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immunosuppressive in vitro and in vivo. Our recent studies have shown that un-stimulated MSCs are indeed incapable of immunosuppression; they become potently immunosuppressive upon stimulation with the supernatant of activated lymphocytes, or with combinations of IFN-γ, with TNF-α, IL-1α or IL-1β. This observation revealed that under certain circumstances, inflammatory cytokines can actually become immunosuppressive. We showed that there is a species variation in the mechanisms of MSC-mediated immunosuppression： immunosuppression by cytokine-primed mouse MSCs is mediated by nitric oxide （NO）, whereas immunosuppression by cytokine-primed human MSCs is executed through indoleamine 2, 3-dioxygenase （IDO）. Additionally, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into the proximity with MSCs, where NO or IDO is predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO produced by MSCs. Thus, our results provide novel information about the mechanisms of MSC-mediated immunosuppression and for better application of MSCs in treating tissue injuries induced by immune responses.

Adenosine:An immune modulator of inflammatory bowel diseases

Inflammatory bowel disease(IBD)is a common and lifelong disabling gastrointestinal disease.Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response.Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models.High extracellular adenosine suppresses and resolves chronic inflammation in IBD models.High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis.Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation. Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells,respectively. Increased extracellular adenosine levels activate the A2a receptor,which would reduce cytokines responsible for chronic inflammation.

Immunostaining of PD-1/PD-Ls in liver tissues of patients with hepatitis and hepatocellular carcinoma

AIM: To investigate the expression of programmed death (PD)-1,PD ligand 1 (PD-L1) and PD-L2 in liver tissues in the context of chronic hepatitis and hepatocellular carcinoma (HCC).METHODS: Liver biopsies and HCC specimens from patients were collected and histologically examined.The expression of PD-1,PD-L1,and PD-L2 in biopsy specimens of chronic hepatitis and HCC specimens was evaluated by immunohistochemical staining.The association between the expression level of PD-1,PD-L1,and PD-L2 and clinical and pathological variables was analyzed statistically.RESULTS: Expression of PD-1 was found in liverinfiltrating lymphocytes.In contrast,PD-L1 and PD-L2 were expressed in non-parenchyma liver cells and tumor cells.The expression of PD-L1 was significantly correlated with hepatitis B virus infection (1.42 ± 1.165 vs 0.50 ± 0.756,P = 0.047) and with the stage of HCC (7.50 ± 2.121 vs 1.75 ± 1.500 vs 3.00 ± 0.001,P = 0.018).PD-1 and PD-Ls were significantly up-regulated in HCC specimens (1.40 ± 1.536 vs 5.71 ± 4.051,P = 0.000;1.05 ± 1.099 vs 4.29 ± 3.885,P = 0.004;1.80 ± 1.473 vs 3.81 ± 3.400,P = 0.020).CONCLUSION: PD-L1 may contribute to negative regulation of the immune response in chronic hepatitis B.PD-1 and PD-Ls may play a role in immune evasion of tumors.

The roles of toll-like receptors in carcinogenesis and cancer immunotherapy

Toll-like receptors （TLRs） are probably the most important class of pattern-recognition receptors. Members of the TLR family play key roles in the both innate and adaptive immune responses. Recognition of pathogen-associated molecular patterns （PAMPs） by TLRs, either alone or in heterodimedzation with other TLR or non-TLR receptors, induces the production of signals that are responsible for the activation of genes important for an effective host defense, especially those of proinflammatory cytokines. Thus, TLRs are involved in the development of many pathological conditions including infectious diseases, tissue damage, and cancer especially. In this review, the contribution of TLRs to tumorgenesis is evaluated. We hope to provide new insight into the progression of cancer and more importantly into the potential for TLRs as targets of therapeutics.

Role of the endothelium in inflammatory bowel diseases

Inflammatory bowel diseases(IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease.At the core of these alterations are endothelial cells,whose continual adjustments in structure and function coordinate vascular supply,immune cell emigration,and regulation of the tissue environment.Expansion of the endothelium in IBD(angiogenesis),mediated by inflammatory growth factors,cytokines and chemokines,is a hallmark of active gut disease and is closely related to disease severity.The endothelium in newly formed or inflamed vessels differs from that in normal vessels in the production of and response to inflammatory cytokines,growth factors,and adhesion molecules,altering coagulant capacity,barrier function and blood cell recruitment in injury.This review examines the roles of the endothelium in the initiation and propagation of IBD pathology and distinctive features of the intestinal endothelium contributing to these conditions.

Cytomegalovirus hepatitis and myopericarditis

Cytomegalovirus (CMV) infection in inmunocompetent hosts generally is asymptomatic or may present as a mononucleosis syndrome but rarely can lead to severe organ complications. We report a case of simultaneous hepatic and pericardic CMV infection in a 36-year old immunocompetent man. He was admitted to coronary unit with fever, chest pain radiated to shoulders, changes on electrocardiogram with diffuse ST elevation and modest laboratory elevations in the MB fraction of creatine kinase (CK-MB) of 33.77 μg/L (0.1-6.73), serum cardiac troponin T of 0.904 ng/mL (0-0.4), creatine kinase of 454 U/L (20-195) and myoglobin of 480.4 μg/L (28-72). Routine laboratory test detected an elevation of aminotransferase level: alanine aminotransferase 1445 U/L, aspartate aminotransferase 601 U/L. We ruled out other causes of hepatitis with normal results except IgM CMV. The patient was diagnosed with myopericarditis and hepatitis caused by cytomegalovirus and started symptomatic treatment with salicylic acid. In few days the laboratory findings became normal and the patient was discharged.

Systemic immune-inflammation index for predicting prognosis of colorectal cancer

AIM To investigate the clinical significance of preoperative systemic immune-inflammation index(SII) in patients with colorectal cancer(CRC). METHODS A retrospective analysis of 1383 cases with CRC was performed following radical surgery. SII was calculated with the formula SII =(P × N)/L, where P, N, and L refer to peripheral platelet, neutrophil, and lymphocyte counts, respectively. The clinicopathological features and follow-up data were evaluated to compare SII with other systemic inflammation-based prognostic indices such as the neutrophil-lymphocyte ratio(NLR) and platelet-lymphocyte ratio(PLR) in patients with CRC.RESULTS The optimal cut-off point for SII was defined as 340. The overall survival(OS) and disease-free survival(DFS) were better in patients with low NLR, PLR, and SII(P < 0.05). The SII was an independent predictor of OS and DFS in multivariate analysis. The area under the receiver-operating characteristics(ROC) curve for SII(0.707) was larger than those for NLR(0.602) and PLR(0.566). In contrast to NLR and PLR, SII could effectively discriminate between the TNM subgroups. CONCLUSION SII is a more powerful tool for predicting survival outcome in patients with CRC. It might assist the identification of high-risk patients among patients with the same TNM stage.

Thl和Th2型细胞因子在椎间盘突出组织中的表达及意义

腰椎间盘突出症是骨科的常见病,近年来,随着研究的深入,对于腰椎间盘突出症的病因、病理、发病机制等方面存在着不同的学说和观点,并且一直存在争论。目前,突出椎间盘所诱发的自身免疫反应在其发病过程中起着重要作用。

胃癌组织中肿瘤相关巨噬细胞和自然杀伤细胞浸润的临床意义

肿瘤相关巨噬细胞（TAMs）和自然杀伤细胞（NK）是重要的免疫炎性细胞。本研究旨在探讨胃癌组织中TAMs和NK细胞浸润分布的临床意义，

N-乙酰半胱氨酸联合抗结核药治疗慢性阻塞性肺疾病合并肺结核患者的相关指标分析

目的:分析N-乙酰半胱氨酸(N-acetylcysteine, NAC)联合抗结核治疗对老年慢性阻塞性肺疾病(chronic obstructive pulmonary diseases, COPD)合并肺结核(tuberculosis, TB)患者肺功能、免疫炎性因子及其与预后的关系。方法:回顾性选取2018年1月至2019年6月某院收治的90例老年COPD合并TB患者作为研究对象,随机分为对照组(n=44)和观察组(n=46)。对照组患者给予常规四联抗结核治疗,观察组再联合NAC治疗。治疗6个月后,比较治疗前后2组患者肺功能、免疫炎性因子及生活质量。结果:治疗后,观察组患者结核病变程度、病灶吸收及空洞愈合状况均优于对照组。观察组患者肺功能FEV1、FVC及FEV1/FVC分别为(1.36±0.11) L、(1.77±0.18) L和(56.85±5.91)%;CD3^(+)、CD4^(+)、CD8^(+)T淋巴细胞和NK细胞比例较治疗前明显升高,而B淋巴细胞百分比有所下降(P<0.05);炎性因子TNF-α及IL-6水平和治疗前比较均有降低,IL-10含量明显升高;患者肺功能、免疫炎性相关指标改善情况均显著优于对照组(P<0.05)。观察组生活质量如症状、活动及日常生活影响评分显著低于对照组,差异有统计学意义(P<0.05)。结论:NAC联合抗结核治疗可有效提高结核病灶吸收率及空洞愈合率,其通过改善机体免疫功能、减轻炎症反应,进而改善患者肺功能和预后生活质量。

A corn straw-based diet increases release of inflammatory cytokines in peripheral blood mononuclear cells of dairy cows

Recent studies have shown that diet can affect the body＇s immunity. Roughage of dairy cows consists of a variety of plant materials which make different contributions to health. This study investigated the effect of different roughages on the immunity of dairy cows. Serum, peripheral blood mononuclear cells （PBMCs）, and milk samples were collected from 20 multiparous mid-lactation cows fed mixed forage （MF）- or corn straw （CS）-based diets. Ex- pression profile analysis was used to detect the differentially expressed genes （DEGs） from PBMCs. The results showed that milk protein in the MF group increased to 3.22 g/100 ml, while that of the CS group milk was 2.96 g/100 ml; by RNA sequencing, it was found that 1615 genes were differentially expressed between the CS group and the MF group among the 24027 analyzed probes. Gene ontology （GO） and pathway analysis of DEGs suggested that these genes （especially genes coding cytokines, chemokine and its receptors） are involved in the immune response. Results were confirmed at the protein level via detecting the levels of interleukin-2 （IL-2）, IL-6, IL-10, IL-12, leptin （LEP）, interferon-γ （IFN-γ）, transforming growth factor-βl （TGF-β1）, and tumor necrosis factor-α （TNF-α） in peripheral blood by enzyme-linked immunosorbent assay （ELISA） and radioimmunoassay analysis. Our data supported the conclusions that the protein content in milk of the MF group was higher than that of the CS group, the CS-based diets induced more release of cytokines than the MF-based diets in dairy cows＇ PBMCs, and milk protein content may be affected by cytokines.

Effect of Liuweibuqi capsule, a Chinese patent medicine, on the JAK1/STAT3 pathway and MMP9/TIMP1 in a chronic obstructive pulmonary disease rat model

OBJECTIVE： To observe effect of Liuweibuqi Capsule, a Traditional Chinese Medicine （TCM）, on the janus kinase （JAK）/signal transducer and activator of transcription （STAT） pathway and matrix metalloproteinases （MMPs） in a chronic obstructive pulmonary disease （COPD） rat model with lung deficiency in terms of TCM＇s pattern differentiation. METHODS： Rats were randomly divided into a normal group, model group, Liuweibuqi group, Jinshuibao group, and spleen aminopeptidase group （n= 10）. Aside from the normal group, all rats were ex-posed to smoke plus lipopolysaccharide tracheal instillation to establish the COPD model with lung deficiency. Models were established after 28 days and then the normal and model groups were given normal saline （0.09 g/kg）, Liuweibuqi group was given Liuweibuqi capsule （0.35 g/kg）, Jinshuibao group was given Jinshuibao capsules （0.495 g/kg）, and the spleen group was given spleen aminopeptidase （0.33 mg/kg）, once a day for 30 days. Changes in symptoms, signs, and lung histology were observed. Lung function was measured with a spirometer. Serum cytokines were detected using enzyme-linked immunosorbent assay, and changes in the JAK/STAT pathway, MMP-9, and MMPs inhibitor 1 （TIMP1） were detected by immunohistochemistry, RT-PCR, and western blotting, respectively.RESULTS： Compared with the normal group, lung tissue was damaged, and lung function was reduced in the model control group. Additionally, the levels of interleukin （IL）-1β, y interferon （IFN-γ）, and IL-6 were higher, while IL-4 and IL-10 were lower in the model control group than those in the normal group. The expressions of JAK1, STAT3, ρ-STAT3, and MMP-9 mRNA and protein in lung tissue were higher, and TIMP1 mRNA and protein was lower in the model group compared with the normal group. After treatment, compared with the model group, the expression of inflammatory cytokines was lower in each treatment group, and expressions of JAK/ STAT pathway, MMPs were lower. Compared with the positive control groups, the Jinshuibao and spleen aminopeptidase groups, lung function was better, and JAK1, STAT3, and p-STAT3 protein were lower and TIMP1 was higher in the Liuweibuqi group.CONCLUSION： Liuweibuqi capsules can improve the symptoms of COPD possibly by regulating the expression of the JAK1/STAT3 pathway and MMP9/ TIMP1.

Autoimmune pancreatitis:current concepts

Autoimmune pancreatitis （AIP） is a distinct type of chronic pancreatitis with unique clinical, pathological, serological, and imaging features. AIP usually presents with obstructive jaundice. Imaging studies often reveal enlargement of the pancreas with a pancreatic mass and strictures of the main pancreatic duct. Two subtypes of AIP have recently been identified. Type 1 AIP is more prevalent in elderly Asian males and is characterized by lymphoplasmacytic sclerosing pancreatitis, obliterative phlebitis, and infiltration of large numbers of IgG4-positive plasma cells. Type II AIP is more prevalent in Caucasians and is characterized by granulocyte epithelial lesions. Most patients with type I AIP have a significantly elevated serum IgG4 con- centration, which is an important feature for diagnosis and for differentiating between AIP and other conditions such as pan- creatic cancer. Extrapancreatic complications are common, such as sclerosing cholangitis, sclerosing sialadenitis, retroperito- neal fibrosis in type I AIP, and ulcerative colitis in type II AIP. A rapid response to glucocorticoids treatment is suggestive of AlP, but the relapse rate is high, warranting the use of immunosuppressant treatment. B-cell depletion with rituximab may be a promising therapy. The prognosis of AIP is generally benign if treated promptly, and spontaneous remission occurs in a pro- portion of patients.