Volume 89  ·   Issue 19  ·  2009

Glioma is the most common primary tumor of the nervous system in the cranium, and its incidence rate accounts for about 45% of all intracranial tumors, among which malignant glioma accounts for 70%. In 2008 alone, 21 810 newly diagnosed primary brain tumors in the United States led to 13 070 deaths. In the past 30 years, the incidence of malignant brain tumors has increased year by year, with an increasing rate of 1.2% in the elderly population. No major breakthrough has been made in the treatment of glioma so far, and the median survival time of glioblastoma and anaplastic astrocytoma is only 12~15 months and 2~5 years, respectively, making it one of the most difficult to cure among intracranial tumors [1].

Objective To detect the expressions of Rev1, Pol ζ, Pol η, Pol ι and Pol κ mRNA in human primary glioma tissues, and to analyze the relationship between the expression and the pathological grade.Methods We applied SYBR Green real-time PCR to investigate the mRNA expressions of the 6 genes in 85 primary glioma tissues and 14 normal brain tissues.Results The expressions of 4 genes including Rev3, Rev7, Pol η and Pol ι were significantly(P＜0.05)higher in glioma tissues in grade Ⅱ, Ⅲ and Ⅳ as compared to normal brain tissues. The expressions of Rev1 and Pol κ were significantly(P＜0.05)higher in grade Ⅳ glioma compared to the normal brain tissue. The positive correlation existed (P＜0.01) between the expression of all genes mRNA and the pathologic grade of the human glioma, except for Rev7.Conclusion The up-regulation of DNA translesion synthesis genes, including Rev1, Rev3, Rev7, Pol η, Pol ι and Pol κ, may be associated with pathogenesis of glioma.

Objective To evaluate the application of intra-operative ultrasound (IOUS) in detecting the boundaries of intracranial gliomas.Methods One hundred and five consecutive patients with supra-tentorial glioma were included, male: 42 cases, female: 46 cases, age ranged from 15-67years (mean 41 yrs), intra-operative ultrasound B was used to detect tumour boundaries before and after resection in 88 cases, tissues with suspicious echo was taken for verification by histological examination. And repeated MRI scan was received within 3 day after operation to judge the resection extent. The result was judged by Ultrasound doctor, neurosurgeon and pathologist, respectively.Results Eighty-eight patients were operated assisted by IOUS B.Tumour was nearly total removed in 83 cases and subtotal removed in 5 cases.Histological examination showed WHO Grade Ⅱ 30 cases, Grade Ⅲ 31 cases and Grade Ⅳ 27 cases.One hundred and twenty samples were taken and 101 were verified as tumours.And residuary tumours were found in 17 cases and brain contusion and laceration was found in 1 case.The sensitivity of IOUS was 80.1% and the specificity was 69.8%.Conclusions IOUS could produce a marked effect in judging boundaries of glioma, especially in low grade gliomas. IOUS could be a routine technique in intracranial glioma operation.

Objective To investigate the clinical usefulness of diffusion tensor imaging(DTI) in demonstrating between gliomas and surrounding fibers.Methods 24 patients of glioma (WHO grade: grade Ⅰ-Ⅱ 16 cases; grade Ⅲ-Ⅳ 8 cases) were examined using DTI and conventional contrast-enhanced MRI of 3.0T MRI scanner(GE company, America). After the initial data acquisition introduced into workstation, image analysis was performed with the use of functool software. Mean diffusivity (MD) and fractional anisotropy (FA) values were measured in regions of solid tumor, surrounding edema and normal white matter of the high grade cerebral gliomas.Differences in these values among the tissues were assessed on the high grade cerebral gliomas. Anatomic relationship between intracranial tumors and surrounding fibers was analysed on fractional anisotropic (FA) map, color-coded directional map, three-dimensional white matter tractography. All patients′ symptoms were evaluated preoperative and postoperative respectively.Results The DTI patterns altered by the tumor were categorized as follows: displacement, infiltration and destruction. The tractography showed that the main influence in 16 cases of grade Ⅰ-Ⅱ glioma on adjacent white matter tracts was displacement, but infiltration and destruction were also revealed. The patients have definite improvement in symptoms. The destruction and infiltration of fiber tracts could be seen in all edema regions around grade Ⅲ-Ⅳ gliomas in 8 cases. The patients have not definite improvement in symptoms. Apparently significant differences of MD were found in solid tumor, surrounding edema, compared with normal white matter regions (P<0.05). But there was no significant difference among solid tumor and surrounding edema region (P＞0.05). There were significant differences of FA between solid tumor, surrounding edema and normal white matter region (P<0.05).Conclusions The DTI offered the optimal visualization of white matter tracts. DTI plays an important role in demonstrating relationship between gliomas and neighboring fibers. MD and FA values could be used to distinguish normal white matter from solid tumor and surrounding edema region of high grade glioma. The application of DTI in preoperation plays an guidance role in making microsurgery plans and the evaluation of brain functional recovery in postoperation. DTI should be of great value in the microsurgical planning as well as estimation and reduction of potential postoperative neurological deficits for the cerebral gliomas resection.

Objective To investigate the clinical and imaging features of hemorrhagic stroke during pregnancy and puerperium (HSPP).Methods A retrospective analysis was conducted about timing, precipitating factors, clinical manifestations, imaging characteristics, treatment and outcome of 7 HSPP patients.Results None of 7 HSPP occurred in the first trimester, 3 in the second trimester, 2 in the third trimester and 2 in the puerperium. Three of 4 patients whose etiology was due to ruptured arteriovenous malformations (AVM) occurred in the second trimester, including one case in the puerperium. Two patients had been diagnosed as cerebral vascular AVM before pregnancy. One patient had eclampsia during pregnancy. The initial symptoms and signs of 7 patients: 4 cases with headache, nausea and vomiting, 4 cases with extremity paralysis, 3 cases with disorders of consciousness, 4 cases with aphasia, 2 cases with central face and tongue paralysis and 1 case with extremity numbness. Cerebral imaging investigations showed 2 cases with basilar ganglia hemorrhage, 4 cases with lobar hemorrhage and 1 case with subarachnoid hemorrhage (SAH). There were 4 cases whose etiology was because of ruptured AVM. Two of 7 patients were treated with operation, 2 with endovascular intervention and 3 with conservative treatment. The prognosis included full recovery (1/7), marked improvement (4/7), slight improvement (1/7) and death (1/7).Conclusion The onset time of HSPP concentrated in the second, third trimester and the puerperium;Onset time of the patients because of ruptured AVM concentrated in the second trimester. Cerebral imaging examination could elucidate the nature of lesion and the etiology of disease.

Objective To determine whether mode of delivery is associated with the level of catecholamines in umbilical cord blood of neonates.Methods A study was carried out on 150 neonates. Among them 90 were healthy while 60 were diagnosed fetal distress. Then the subjects were first divided into 5 groups according to different modes of delivery: 30 were delivered by spontaneous labor for vaginal delivery without any pain relief;30 by vaginal delivery with epidural anaesthesia;30 by caesarean section without labor;30 by vaginal delivery with low forceps because of fetal distress and 30 by caesarean section of emergency because of fetal distress. After delivery, umbilical cord blood of both artery and vein was collected for determination of norepinephrine (NE), epinephrine(E), and dopamine (DA).Results (1) The concentration of NE and E of umbilical artery were different in each group (P＜0.01), the group with the highest concentrations of NE and E was the ones delivered by vaginal delivery with low forceps[(73±6) ng/L,(37.8±1.8)ng/L] while caesarean section[(35±5) ng/L,(27.2±1.2) ng/L] was associated with significantly lower concentrations of NE and E of umbilical artery. The ones delivered by vaginal delivery with low forceps[(33.7±4.5) ng/L] and caesarean section of emergency [(32.9±4.5) ng/L] had higher concentrations of DA compared with any other group (P＜0.01) . (2) The concentration of NE and E of umbilical vein were different in each group (P＜0.01) just like that of umbilical artery. The ones delivered by vaginal delivery with low forceps and caesarean section of emergency had higher concentrations of DA compared with any other group (P＜0.01) . (3) The neonates with fetal distress had higher levels of catecholamine both in umbilical artery and umbilical vein than the healthy ones(P＜0.01) ;at the same time, the ones with fetal distress got lower Apgar scores 1, 5, 10 min after born contrasted to the healthy ones.Conclusions If no indication for caesarean section exists, delivery by vaginal naturally can give higher level of catecholamines in cord blood, thus the neonate can get ready to adapt to the new environment better.

Objective To access the value of balloon atrial septostomy (BAS) in hybrid procedure for patients with complex congenital heart disease.Methods From September 2000 to February 2008, ten patients with complex congenital heart disease underwent BAS before surgical radical therapy with the guidance of X-ray or transthoracic echocardiography. Eight patients(ages from 2 daysto 50 days) were complete transposition of great arteries(TGA), and two patients (age was 60 days, 39 years respectively) were total anomalous of pulmonary venous connexion (TAPVC) with restrictive atrial septal defect.Results All procedure achieved successfully, no severe complications occurred. The average oxygen saturation of femoral arteries of patients increased from 68.3% (pre-procedure) to 81.8%(post-procedure) significantly. the status in short of oxygen of all patients improved immediately. All patients survived until a surgical radical therapy. After successful operations, nine patients discharged, only one patient died of disorder of electrolyte.Conclusion BAS was a ideal palliate therapy for some cynotic complex congenital heart disease ,and can play a important role in hybrid procedure for patients with complex congenital heart disease.

Objective To summarize the clinical features, treatment and prognosis of giant lymph node hyperplasia(Castleman′s disease, CD).Methods The clinical data of 43 CD patients with the tumor located in neck (n=10), chest (n=20), abdomen (n=9) and multi-centers (n=4) were analyzed.Results All the patients underwent surgical resection of tumor or lymph and the patients of multicentric disease underwent adjuvant chemotherapy or radiotherapy. All the diagnoses of CD were confirmed by pathological examination. Among all the cases, 26 patients were hyaline vascular subtype (HV), 16 patients plasma cell subtype (PC) and 1 patient mixed subtype. All 39 patients of unicentric disease survived without disease evidence.2 patients of multicentric disease died at 18 months and 54 months after surgery;1 patient survived with disease;1 patient survived with no evidence of disease.Conclusion Giant lymph node hyperplasia is a rare disease. The diagnosis depends mainly on the pathological examination. Surgery is the best choice for unicentric disease with an excellent prognosis. Patients with multicentric disease may benefit from surgery, adjuvant chemotherapy or radiotherapy, but the prognosis remains grim.

Objective To retrospectively evaluate the effects of pulmonary thromboendarterectomy (PTE) on chronic thromboembolic pulmonary hypertension (CTEPH).Methods Sixty-two cases of CTEPH operated with PTE from October 2002 to September 2008 at Anzhen Hospital were retrospectively reviewed and were assigned into either proximal CTEPH group (n=46)or distal CTEPH group(n=16).Result No early death was reported. 15 had residual pulmonary hypertension and 23 had pulmonary reperfusion injury postoperatively. And reperfusion injury was recovered with the support of ventilation or ECMO. Between pre and post-procedure, the pulmonary artery systolic pressure changed from 91 ±38 mm Hg to 53 ±21 mm Hg, the pulmonary vascular resistance from 916±548 dyn·s·cm-5 to 368 ±302 dyn·s·cm-5 (t=6.896,P=0.0001), and the arterial partial pressure of oxygen (PaO2) from 51±7 mm Hg to 90±7 mm Hg and the arterial oxygen saturation (SaO2) from 87.0%±3.9% to 96.1%±3.3%,P＜0.05.With the follow-up of (24.8±14.6) months (cumulative follow-up was 121.6 patient-years), there was no late death and 38 were in NYHA functional class Ⅰ, 20 class Ⅱ, 2 class Ⅲ and 2 class Ⅳ. According to Kaplan-Meier actuarial curve, the freedom from reembolism at 3 years was 96.7%±2.8%.The linear bleeding rate related to anticoagulation was 2.47% patient-years, and the linear thromboembolic rate related to anticoagulation is 1.64% patient-years.Conclusion The early and mid-long term survival rate of PTE procedure on CTEPH is acceptable and the complication rate related to anticoagulation with warfarin is relatively low.

Objective To develop an ovarian cancer-specific protein profiles in serum.On the basis, to analyze the protein profiles of multidrug resistance P-glucoprotein (MDR1)and multidrug resistance-associated protein (MRP) positive and negative expression sets for a rapid and sensitive serum protein pattern.Method Serum protein profiles from 36 epithelial ovarian cancer cases were compared with 30 healthy controls using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (DELDI-TOF-MS). Blinded test was done subsequently for identification of the protein pattern. Expression of MDR and MRP were detected in set of training cases by immunohistochemistry. The spectra were analyzed statistically between positive and negative groups.Results 29 peaks were significantly different between ovarian cancer and healthy controls (P<0.01, 15 peaks were up-regulated and 14 down-regulated). We selected a set of three peaks, at 5486, 6463 and 8575 m/z, from 29 sense peaks as ovarian cancer biomarker. It has a sensitivity of 100% and specificity of 93.33%. Identification by blinded validation indicated a positive predict value of 90%. MDR1 expression in ovarian cancer was 69.4 %. There 20 peaks were significantly different between positive and negative set (P<0.01). MRP expression in ovarian cancer was 63.8%. But there was just 1 peak detected (P<0.01).Conclusion It was an idealized pattern for applying SELDI mass spectrum approach to diagnosis of ovarian cancer. The multidrug resistance cases in ovarian cancer can be selected by it. Serum biomarker for detecting drug resistance in ovarian cancer could be established according to MDR1 immunohistochemistry.

Objectives To explore the effect of CAD and CAE related technique in separation of Pygopagus Conjoined Twins.Methods CT images of Pygopagus conjoined twins were obtained and reconstructed in three-dimensional by Mimics software. 3D entity model of skin and spine of conjoined twins were made by fast plastic technique and equipment according to 3D data model. The circumference and area of fused and independent dural sac were measured by software of AutoCAD.Results The entity model is real reflection of skin and spine of Pygopagus. It was used in the procedures of discussion, sham operation, skin flap design and informed consent. In the measure of MRI, the circumference and area of fused dural sac was more than of independent dural sac, that is to say, the defect of dural sac can be repaired by direct suture. The intraoperative finding match with imaging measure results.Conclusions The application of CAD and CAE in the procedure of preoperative plan have gave big help to successful separation of Pygopagus Conjoined Twins.

Objective To explore the surgical measures and principles in the retreatment of thoracic and thoracolumbar spinal tuberculosis.Methods Thirty retreatment cases of thoracic and thoracolumbar spinal tuberculosis in recent 3 years were retrospectively analyzed. The patients were hospitalized by inadequate decompression of spinal canal, tubercular toxic symptoms or sinuses.The disease course was an average of 6 months from the last operation.The patients were given anti-tuberculosis therapy according to the adjusted regimens for 2-8 weeks before reoperations.Ten cases were performed by anterior approach with debridement, 6 cases anterior approach (debridement, fusion & plate-screw fixation) and 4 cases dislodgment of transpedicular screw system and routine surgical treatment by anterior approach in one primary term. Debridement, Ti-mesh implantation and bone grafting, without taking out of the transpedicular screw systems was performed in 1 case of elder patient older than 70 years old with transpedicular screw system fixation. Nine cases underwent sinuses excision, debridement and dislodgment of transpedicular screw system in first attempt. After 2-3 weeks since incision healing, anterior approach was routinely performed. The tissues and liquor puris debrided from focus were sent for pathological examination, Bacillus tuberculosis detection and culture and drug sensitivity test. The patients were given anti-tuberculosis therapy according to the results of drug sensitivity test for 1-1.5 years. Follow-ups included relapse rate, fusion of bone graft and status of neurological recovery, etc.Results All 30 cases recovered from perioperation. The follow-up period ranged from 3 to 32 months (mean: 18 months). Fourteen of 21 cases with neurological deficits recovered partially or totally. All incisions had primary healing. No relapse occurred within follow-up period. All cases were confirmed with Bacillus tuberculosis infection by pathology. Bacillus tuberculosis was detected and cultured successfully in 16 cases(53.3%). Nine strains(56.3%)were drug resistant and in which 4 strains(25.0%)were multi-drug resistant.Conclusion For the retreatment of thoracic and thoracolumbar spinal tuberculosis, targeted chemotherapy, thorough debridement and reasonable operative options are key to therapeutic success.

Objective To investigate the characteristics of cognitive development in elementary school children using rest-fMRI methods.Methods Twenty-nine normal school children were divided into three groups according to their ages(8 ,10 & 12 years old)and received the resting-state fMRI scans. A regional homogeneity (ReHo) approach was used to analyze blood oxygen level-dependent fMRI (BOLD-fMRI)data in resting state.The fMRI data were processed with software SPM2 and REST 1.2.Results Compared with younger groups (10 vs 8, 12 vs 10, 12 vs 8), the elder groups showed more increases in superior temporal gyrus(Z=2.83, Z=3.21), middle temporal gyrus(Z=3.74, Z=3.19, Z=4.26), inferior temporal gyrus(Z=3.01)and lentiform nucleus(Z=3.31). In addition, the ReHo differences were demonstrated in superior frontal gyrus(Z=3.21), middle frontal gyrus(Z=3.19, Z=3.22), medial frontal gyrus(Z=3.15), lingual gyrus(Z=3.43)and cerebellum (Z=3.11, Z=2.97) increased more in 12 years old group (12 vs 10, 12 vs 8). And the precuneus(Z=2.95)and posterior cingutate(Z=2.64)had increasing ReHo values with the age growth (12 vs 8).Conclusion The function of execution control, accommodation of attention, visual spatial integration and default mode network became gradually developed with increasing age.

Objective To analyze miRNA expression profile of endometrioid adenocarcinoma.Methods Collect Endometrium was collected from cancer and paracancer tissue.And the total RNA was extracted. The microarray detection system was employed to analyze whether there was difference in microRNA expression between cancer tissue and paracancer tissue.Results A total of 111 differentially expressed miRNA were found, including 68 over-expression miRNA and 43 low-expression.Conclusion MiRNA may play important roles in tumorigenesis of endometrioid adenocarcinoma.The study of miRNA contributes to elucidate the molecular mechanism of endometrial cancer.

Objective To study the interfering effect of neuregulin-1β(NRG-1β)on the cerebral ischemic reperfusion injury in monkeys.Methods The models with middle cerebral artery occlusion reperfusion (MCAO/R) were established by inserting a micro-balloon catheter intra-arterially into MCA from femoral artery in 12 adult healthy monkeys. The NRG-1β was injected into MCA from micro-balloon catheter in the animals of treatment group at 2 h post-ischemia while the normal saline was simultaneously injected in the animals of control group. Then the micro-balloon catheter was withdrawn from the MCA to perfuse for 22 h. The nervous behavioral function was evaluated by task-oriented score and the infarct volume measured by TTC and MRI.Results The animals of control group had an onset of nervous functional disorders at 2 h post-ischemia and had no significant difference at reperfusion 22 h (59.8±15.7); the nervous function of monkeys had no improvement after NFG-1β treatment (61.3±16.2) (P＞0.05). The diffuse weight imaging (DWI) showed a high signal area but T1 and T2 imaging had no significant changes at 2 h post-ischemia in control group animals; while the T1 and T2 imaging showed a typical high signal areas, DWI high signal area expanded and TTC staining ischemic area appeared at reperfusion 22 h. The T1, T2 and DWI abnormal signal areas and TTC cerebral infarct volume did not shrink significantly in NFG-1β treatment group (P＞0.05).Conclusion The neuroprotective effects of NRG-1β upon cerebral ischemic reperfusion injury needs to be further studied.

Objective To investigate the effect of fentanyl upon the expression of mu-receptor and β-arrestin 2 in peri-aqueductal gray of morphine-tolerant rats.Methods Forty male SD rats weighing (230±20) g were randomly divided into 5 groups of eight animals each: group NS, group M, group MF1, group MF2 and group MF3.Rats in group NS received only subcutaneous normal saline 1ml/kg twice a day for 9 consecutive days;group M received subcutaneous morphine 10 mg/kg followed by NS 1 ml/kg twice a day for 9 consecutive days;In groups MF1, MF2 and MF3, morphine 10 mg·kg-1 was injected subcutaneously followed by fentanyl 3, 6, 12μg/kg respectively. All animals were sacrificed at Day 9 after measurement of pain threshold. Periaqueductal gray was removed for determination of the expression of mRNA (RT-PCR) and protein (Western-blot) of mu-receptor and β-arrestin 2.Results Compared with group NS, TFL of group M was significantly elevated after the first morphine injection (P<0.01). But TFL of group M returned to the baseline value after chronic morphine treatment. Compared with group M, TFL increased in groups MF2 and MF3 at Days 7 and 9 (P<0.05 or 0.01).However, TFL of group MF1 was negative (P＞0.05). The expression of mu-receptor mRNA and protein was significantly lower in group M than in group NS (P<0.01). Compared with group M, the expressions of mu-receptor mRNA and protein were significantly elevated in group MF2 and MF3 (P<0.05 or 0.01) but there was no significant change in group MF1 (P＞0.05). The expression of β-arrestin 2 mRNA and protein significantly decreased in group M as compared with group NS (P<0.01). Compared with group M, the expressions of β- arrestin 2 mRNA and protein were significantly elevated in group MF2 and MF3 (P<0.05 or 0.01), but there was no significant change in group MF1 (P>0.05).Conclusion Fentayl at 6 and 12μg/kg can partly inhibit morphine tolerance through an increased expression of mu-receptor and β-arrestin 2 in periaqueductal gray of morphine-tolerant rats.

Objective To determine which of the two,recombinant adeno- associated viral vector 2(rAAV2) and recombinant adenovirus vector 5(rAd5),is more suitable for gene transfer in rodent cochlea.Methods The rAAV2-EGFP and rAd5-EGFP particls were injected into the perilymph through round window membrane.The target tissue accessibility, time course of expression, tissue toxicity of gene transfer and effects on hearing were evaluated.Results The expression of EGFP was detected in spiral ligament,strial vascukarises, Reissner membrane,basilar membrane, spiral ganglion,and contralateral cochlea.EGFP expression in the rAAV2 lasted over 60 days, with peak expression between days 14 and 60. EGFP in the rAd5 was detected within 24 h of transfection, and peak expression was observed between days 1 to 21. EGFP activity decreased sharply on day 30 after transfection with rAd5, while high EGFP expression was observed 60 days after transfection with rAAV2.Conclusion AAV has significant advantages for long-term transgene expression and no ototoxicity in the cochlea compared to adenovirus vectors.

Objective To explore the protective effect of doxycycline (DC) upon dopaminergic neuron in lipopolysaccharide (LPS)-induce rat model of Parkinson′s disease (PD).Methods Sixty SD rats were randomly divided into three groups: control, LPS and doxycycline treatment. LPS was stereostatically injected into unilateral substantia nigra (SNc) of rats to establish the PD models. The damage to the substantia nigra DA neurons was observed by using tyrosine-hydroxylase (TH) immunohistochemical staining. Specific antibody OX6 (MHCⅡ marker) was used to detect the changes in morphology and the numbers of microglia. The contents of dopamine and DOPAC in striatum were measured by high performance liquid chromatography (HPLC). Western blot were used to detect the expression of MHCⅡ (Major histocompatibility complex classⅡ) protein.Results After doxycycline treatment,the number of TH-positive cells remaining in the SNc increased from 38%±5% to 79%±4%(P<0.01). The contents of dopamine and DOPAC in striatum increased from 4.89±0.27 and 0.70±0.07 to 7.00±0.34 and 1.10±0.10 respectively(P<0.01);there was a significant decrease in rotational asymmetry in the doxycycline treatment group[ (80±12) turns/30 min] when compared to the LPS group [(208±14) turns/30 min] (P<0.01).However, the number of MHCⅡ-positive microglia decreased significantly (LPS group: 835±82 vs doxycycline treatment group: 354±59, P<0.01) after doxycycline treatment. Western blot were used to detect the expression of MHCⅡprotein. The results showed that the expression of MHCⅡ protein on microglia of LPS group increased significantly compared to the control group,but the expression of MHCⅡ protein were inhibited significantly after doxycycline treatment in the doxycycline treatment group, as compared to the LPS group.Conclusions Doxycycline might inhibit dopaminergic neuron degeneration by down-regulating the MHCⅡexpression on microglia.

A 65-year-old male was admitted to hospital due to "repeated attacks of left limb weakness for 2 months". Two months before the onset of the disease, he suddenly developed left limb weakness, could not hold objects, and needed support to stand. The symptoms lasted for 10 minutes and then completely relieved. After that, the same symptoms occurred three times in 3 days, without leaving sequelae. The patient had a history of hypertension, hyperlipidemia and smoking.

A 17-year-old male was admitted to the Department of Rheumatology and Immunology of the Third Hospital of Peking University on February 28, 2008 due to fusiform swelling of the proximal interphalangeal joints of both hands for more than 2 years.