Risk of conversion to mild cognitive impairment or dementia among subjects with amyloid and tau pathology: a systematic review and meta-analysis.

BACKGROUND: Measurement of beta-amyloid (Aß) and phosphorylated tau (p-tau) levels offers the potential for early detection of neurocognitive impairment. Still, the probability of developing a clinical syndrome in the presence of these protein changes (A+ and T+) remains unclear. By performing a systematic review and meta-analysis, we investigated the risk of mild cognitive impairment (MCI) or dementia in the non-demented population with A+ and A- alone and in combination with T+ and T- as confirmed by PET or cerebrospinal fluid examination. METHODS: A systematic search of prospective and retrospective studies investigating the association of Aß and p-tau with cognitive decline was performed in three databases (MEDLINE via PubMed, EMBASE, and CENTRAL) on January 9, 2024. The risk of bias was assessed using the Cochrane QUIPS tool. Odds ratios (OR) and Hazard Ratios (HR) were pooled using a random-effects model. The effect of neurodegeneration was not studied due to its non-specific nature. RESULTS: A total of 18,162 records were found, and at the end of the selection process, data from 36 cohorts were pooled (n= 7,793). Compared to the unexposed group, the odds ratio (OR) for conversion to dementia in A+ MCI patients was 5.18 [95% CI 3.93; 6.81]. In A+ CU subjects, the OR for conversion to MCI or dementia was 5.79 [95% CI 2.88; 11.64]. Cerebrospinal fluid Aß42 or Aß42/40 analysis and amyloid PET imaging showed consistent results. The OR for conversion in A+T+ MCI subjects (11.60 [95% CI 7.96; 16.91]) was significantly higher than in A+T- subjects (2.73 [95% CI 1.65; 4.52]). The OR for A-T+ MCI subjects was non-significant (1.47 [95% CI 0.55; 3.92]). CU subjects with A+T+ status had a significantly higher OR for conversion (13.46 [95% CI 3.69; 49.11]) than A+T- subjects (2.04 [95% CI 0.70; 5.97]). Meta-regression showed that the ORs for Aß exposure decreased with age in MCI. (beta = -0.04 [95% CI -0.03 to -0.083]). CONCLUSIONS: Identifying Aß-positive individuals, irrespective of the measurement technique employed (CSF or PET), enables the detection of the most at-risk population before disease onset, or at least at a mild stage. The inclusion of tau status in addition to Aß, especially in A+T+ cases, further refines the risk assessment. Notably, the higher odds ratio associated with Aß decreases with age. TRIAL REGISTRATION: The study was registered in PROSPERO (ID: CRD42021288100).

Evidence for gait improvement with robotic-assisted gait training of children with cerebral palsy remains uncertain.

BACKGROUND: Cerebral palsy (CP) is a group of neuromotor diseases that develops as a result of damage to the developing central nervous system during the perinatal period. The condition is usually accompanied by musculoskeletal problems resulting in movement disorders. Gait improvement therefore, is an important part of its treatment. Roboticassisted gait training (RAGT) is a new potential rehabilitation tool for CP patients, however there is no clear evidence for the effectiveness of this method. RESEARCH QUESTION: Can robotic-assisted gait training improve walking function in children with CP? METHODS: A systematic search was performed in five databases: MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Scopus, and Web of Science. Eligible studies were randomized controlled trials (RCT) with CP patients under the age of 18. Gross motor function and kinematic gait parameters of patients were the main outcomes. Two authors determined the risk of bias of the RCTs independently using the revised Risk of Bias 2 (ROB 2) tool. Mean Differences (MDs) along with their 95% Confidence Interval (CI) were calculated when at least three studies were present for an outcome, subgroup analysis was performed based on the treatment of the control group. RESULTS: Of the 7363 screened articles, 13 papers met our inclusion criteria and among them, 7 studies could be used in our meta-analyses. The results related to RAGT suggest nonsignificant improvement in standing and walking function (Gross Motor Function Measure D, E), moreover changes in gait speed, step length, and in cadence were also only comparable to controls. SIGNIFICANCE: The results indicate that there is a trend in some gait parameters where the improvement was higher in the intervention group than in control group. The therapeutic effect of RAGT was probably not superior to physiotherapy combined with treadmill training.

Plasma Exchange versus Intravenous Immunoglobulin in Worsening Myasthenia Gravis: A Systematic Review and Meta-Analysis with Special Attention to Faster Relapse Control.

Currently used rescue interventions to prevent rapid myasthenic deterioration are plasma exchange (PLEX) and intravenous immunoglobulin (IVIG). We investigated the evidence to determine whether the two methods were interchangeable or whether one was superior to the other. This review was registered on PROSPERO (CRD42021285985). Only randomized controlled trials (RCTs) comparing the efficacy and safety of PLEX and IVIG in patients with moderate-to-severe myasthenia gravis (MG) were included. Five major databases were systematically searched (PubMed, CENTRAL, Embase, Scopus, and Web of Science). Odds ratios (OR) with 95% confidence intervals (CI) were calculated for adverse events and mean differences (MD) for changes in quantitative myasthenia gravis scores (QMG). Three RCTs met the inclusion criteria. Two investigating 114 patients in total were eligible for meta-analysis to analyze efficacy and safety. For the change in QMG score, the MD was -2.8 (95% CI: -5.614-0.113), with PLEX performing better. For adverse events, an OR of 1.04 was found (95% CI: 0.25-4.27). This study demonstrated a low risk of bias in evaluating treatment efficacy but indicated a high risk of bias in assessing procedural safety outcomes. Although the results did not show any significant difference, there was a tendency indicating faster efficacy of PLEX in the first two weeks of treatment. In such a critical clinical condition, this tendency may be clinically meaningful, but further studies should clarify this benefit.

[Scapula dyskinesis in medium size full-thickness supraspinatus muscle tears]. / Scapuladyskinesis közepes méretu, teljes vastagságú supraspinatusizom-szakadások esetén.

INTRODUCTION: Scapular motion abnormality in rotator cuff tears is a well-known symptom, but its significance is not clear. Some authors consider it as a cause of rotator cuff tear, others as a consequence of the disease. OBJECTIVE: The aim of our study was to assess the changes in scapular motion in medium size full-thickness rotator cuff tear of degenerative origin compared to a healthy control group. MATERIAL AND METHOD: 10 healthy (control group) and 9 subjects with a medium size (1-3 cm), complaining rotator cuff tear (study group) were included in our study, in whom we analyzed the movements of the shoulder girdle, including the scapula, during sagittal and scapular plane flexion using a VICON 3D motion capture system and U.L.E.M.A. motion analysis software. A two-sample t-test was used to test whether significant differences in scapular posterior tilting, upward rotation and protraction values were observed between the two groups for each humeral flexion angular position. RESULTS: In the study group, a significant increase in scapular protraction was demonstrated in sagittal arm elevations at 40 and 50 degrees of arm elevation compared to the control group (p<0.05), whereas no significant difference in scapular upward rotation and posterior tilting was demonstrated. During scapular plane flexion, no significant difference in scapular movements was demonstrated compared to the control group. CONCLUSION: Scapular dyskinesis is already present in cases of medium size rotator cuff tears. In scapular dyskinesis, a significant difference in protraction is first observed, which may affect scapular upward rotation and tilting as the tear continues to grow. Orv Hetil. 2023; 164(31): 1213-1221.

[Hungarian adaptation of the Caregiver Priorities and Child Health Index of Life with Disabilities questionnaire]. / Cerebralis paresisben szenvedo gyermekek egészségindexe.

INTRODUCTION: Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire is a measurement tool for assessing health status and wellbeing of disabled children, which evaluates children's quality of life from the caregiver point of view. OBJECTIVE: The aim of our work was the Hungarian translation and cultural adaptation of the questionnaire and also validation of the CPCHILD on Hungarian cerebral palsy patients. Further aim was to test the eligibility of the questionnaire for superficial assessment of caregiver's psychological attitudes. METHOD: Translation of the questionnaire was carried out according to the Beaton's guidelines. Test-retest, interrater reliability (ICC) and also internal consistency (Cronbach-alpha) were calculated for reliability. The importance of the questions was assessed for face validity and known group validity test was done to measure construct validity. For examining parental attitudes, the patients were divided into ambulatory and non-ambulatory groups and the 36 quality of life questions of the 7th domain were used to find relations. RESULTS: During test-retest reliability measurements, the ICC was 0.96 (95% CI: 0.88-0.98), and Cronbach-alpha exceeded the minimal expected value of 0.7 (0.74-0.97) except in the 5th domain (0.67), while measuring interrater reliability the ICC was 0.87 (95% CI 0.70-0.94). Face validity was above the 2.0 threshold in every question (2.6-4.5; mean: 3.4 ± 1.34) and the known group validity calculations showed significant differences between the CPCHILD scores of ambulatory and non-ambulatory groups. Examining parental attitudes, a significant difference was also shown among the parents of ambulatory and non-ambulatory children in assessing the importance of sitting in the quality of life of their children (2.89 ± 1.28 vs. 3.51 ± 0.82; p<0.01). CONCLUSION: The final outcome of our study is that CPCHILD questionnaire has become widely accessible in Hungarian language. Our result, that the answers referring to the sitting abilities and the activities should be carried out in sitting position, was significantly different among the caregivers of the ambulatory and non-ambulatory children, showing that the parents of the GMFCS IV and V category children evaluate the importance of sitting ability higher compared to those parents who care for GMFCS I, II and III category children. Furthermore, the results draw attention to the wellbeing and health of the children measurable with CPCHILD as well as that parental caregiver attitudes can be recognized which may give further help in finding the balance between expectations and possibilities during the rehabilitation of cerebral palsy children. Orv Hetil. 2023; 164(16): 610-617.

Hemoadsorption Therapy for Critically Ill Patients with Acute Liver Dysfunction: A Meta-Analysis and Systematic Review.

Critically ill patients are at risk of developing acute liver dysfunction as part of multiorgan failure sequelae. Clearing the blood from toxic liver-related metabolites and cytokines could prevent further organ damage. Despite the increasing use of hemoadsorption for this purpose, evidence of its efficacy is lacking. Therefore, we conducted this systematic review and meta-analysis to assess the evidence on clinical outcomes following hemoadsorption therapy. A systematic search conducted in six electronic databases (PROSPERO registration: CRD42022286213) yielded 30 eligible publications between 2011 and 2023, reporting the use of hemoadsorption for a total of 335 patients presenting with liver dysfunction related to acute critical illness. Of those, 26 are case presentations (n = 84), 3 are observational studies (n = 142), and 1 is a registry analysis (n = 109). Analysis of data from individual cases showed a significant reduction in levels of aspartate transaminase (p = 0.03) and vasopressor need (p = 0.03) and a tendency to lower levels of total bilirubin, alanine transaminase, C-reactive protein, and creatinine. Pooled data showed a significant reduction in total bilirubin (mean difference of -4.79 mg/dL (95% CI: -6.25; -3.33), p = 0.002). The use of hemoadsorption for critically ill patients with acute liver dysfunction or failure seems to be safe and yields a trend towards improved liver function after therapy, but more high-quality evidence is crucially needed.

A Novel Three-Dimensional Computational Method to Assess Rod Contour Deformation and to Map Bony Fusion in a Lumbopelvic Reconstruction After En-Bloc Sacrectomy.

Introduction: En-bloc resection of a primary malignant sacral tumor with wide oncological margins impacts the biomechanics of the spinopelvic complex, deteriorating postoperative function. The closed-loop technique (CLT) for spinopelvic fixation (SPF) uses a single U-shaped rod to restore the spinopelvic biomechanical integrity. The CLT method was designed to provide a non-rigid fixation, however this hypothesis has not been previously tested. Here, we establish a computational method to measure the deformation of the implant and characterize the bony fusion process based on the 6-year follow-up (FU) data. Materials and Methods: Post-operative CT scans were collected of a male patient who underwent total sacrectomy at the age of 42 due to a chordoma. CLT was used to reconstruct the spinopelvic junction. We defined the 3D geometry of the implant construct. Using rigid registration algorithms, a common coordinate system was created for the CLT to measure and visualize the deformation of the construct during the FU. In order to demonstrate the cyclical loading of the construct, the patient underwent gait analysis at the 6th year FU. First, a region of interest (ROI) was selected at the proximal level of the construct, then the deformation was determined during the follow-up period. In order to investigate the fusion process, a single axial slice-based voxel finite element (FE) mesh was created. The Hounsfield values (HU) were determined, then using an empirical linear equation, bone mineral density (BMD) values were assigned for every mesh element, out of 10 color-coded categories (1st category = 0 g/cm3, 10th category 1.12 g/cm3). Results: Significant correlation was found between the number of days postoperatively and deformation in the sagittal plane, resulting in a forward bending tendency of the construct. Volume distributions were determined and visualized over time for the different BMD categories and it was found that the total volume of the elements in the highest BMD category in the first postoperative CT was 0.04 cm3, at the 2nd year, FU was 0.98 cm3, and after 6 years, it was 2.30 cm3. Conclusion: The CLT provides a non-rigid fixation. The quantification of implant deformation and bony fusion may help understate the complex lumbopelvic biomechanics after sacrectomy.

Prevalence of cerebral palsy and data quality assessment of patient documentation at the Clinics of Semmelweis University / A cerebralis paresis elofordulása és a betegdokumentáció minoségi vizsgálata a Semmelweis Egyetem klinikáin

Introduction, aim: Quality control of patient documentation for cerebral palsy (CP) at Semmelweis University. METHOD: In our retrospective audit, we revised patient records for all children born between 2005 and 2015, with suspected CP, registering 673 cases with confirmed CP. Based on the available patient data, we assessed clinical and etiological classification of CP and data availability. RESULTS: Patient records of 86% of children were suitable for clinical classification. Among them, 90.5% were spastic, 7.8% hypotonic, 1.2% dyskinetic and 0.5% ataxic. Among the classifiable spastic cases (98% of all spastic cases), 51% presented with tetraparetic/tetraplegic, 26% diparetic/diplegic and 23% hemiparetic/hemiplegic localization; in the remaining 2%, sufficient data for topological classification was unavailable. Severity assessed on Gross Motor Function Classification System was definable in 82% of cases, 43% showing grade I-II, 28% grade III and 29% grade IV-V impairment. Patient history was specified in 91% of cases. Prematurity was documented in 55%, perinatal asphyxia/hypoxic-ischemic encephalopathy in 31%, intraventricular/intracranial haemorrhage in 27%, multiple births in 19%, intrauterine growth restriction in 18%, intrauterine/perinatal/infancy infection in 15%, congenital malformation in 12%, in vitro fertilisation in 5%, stroke in 3% and CP-associated genetic mutation in 3% of cases. Negative patient history was determined in 16% of children. CONCLUSIONS: Our audit established that clinical documentation of CP is performed based on uniform criteria, detecting missing data primarily in clinical classification and patient history. We propose a patient documentation standard in the clinical care of affected children, which is a prerequisite for unified data recording and a future national CP registry. Orv Hetil. 2020; 161(21): 873-880.

[Prevalence of blood transfusion after primary total hip arthroplasty]. / A vértranszfúzió gyakorisága primer csípoprotézis-beültetés után.

Introduction: Total hip arthroplasty is one of the most common surgical procedures that requires blood transfusion, with the possible risk of significant complications. Aim: A retrospective study was performed to analyze the predictors of blood transfusion after primary total hip arthroplasty. Method: We collected the data of 210 consecutive patients undergoing total hip arthroplasty. Patient's data, preoperative hemoglobin and hematocrit level, the type of the prosthesis, the use of a suction drain, tranexamic acid or anticoagulants and the type and amount of blood transfusion were recorded. Results: A total of 41% of our patients required transfusion, 8.6% receiving allogenic blood. Significant predictors of allogenic blood transfusion were preoperative hemoglobin and hematocrit levels, the type of prosthesis, the use of suction drainage and the use of tranexamic acid. Patients with pre-donated autologous blood did not require allogenic blood transfusion. Conclusion: Based on our study, total hip arthroplasty necessitates allogenic blood transfusion in 8.6%. Major predictors associated with the need for transfusion are preoperative hemoglobin and hematocrit levels, the type of prosthesis, the use of suction drainage and the use of tranexamic acid. Pre-donated autologous blood helps to reduce allogenic transfusion rate. Orv Hetil. 2020; 161(8): 290-294.

[Biomechanical and functional comparison of kayaking by abled-disabled athletes]. / Ép és mozgásukban korlátozott kajakos sportolók biomechanikai mozgáselemzése és összehasonlító vizsgálata.

Introduction: During kayaking, the whole body works in a perfect harmony. While the trunk is doing a rotation, flexion-extension helps to the upper limb to create a special cyclic paddle. The purpose of this study was to gain a better understanding of the physical disabled (later disabled) person's kayaking motions and to probe whether there were any significant differences between disabled and non-disabled kayakers with special focus on the use of footrest. We hypothesised significantly different ranges of motion and muscle activity in lower limbs but no significant differences in those of the upper limbs. Aim: Our goal was to know more about the abled and disbled kayaking and compare the athlete's kayaking movements. Method: Thirteen (n = 13) elite disabled athletes (age range: 18-40 years, height range: 164-194 cm, body mass range:74-93 kg), eleven (n = 11) elite non-disabled athletes (age range: 18-40 years, height range:172-197 cm, body mass range: 72-96 kg) and nine (n = 9) athletes whose movements were artificially limited to imitate disabled conditions("imitation disabled" group) (age range: 18-40 years, height range: 172-197 cm, body mass range: 72-96 kg) were measured. Weba sport kayak ergometer, surface electromyography (EMG), and a 3-dimensional Vicon (MX T40) camera system were used to record the data, and a combined Matlab and MS Excel system was used to analyse the results. Results: In line with our basic assumption, range of motion of the upper limbs was not significantly different between disabled athletes and non-disabled athletes (p ≥ 0.05). However, muscle activities were significantly different in the disabled group compared to the non-disabled group (p ≤ 0.05). In the disabled group the knee joint and trunk motions and muscle activities were also significantly different compared to those in the non-disabled group (p ≤ 0.05). The differences in performance force applied to both footrests and force were significant (p ≤ 0.05). Discussion: The assumption that shoulder and elbow ranges of motion were not significantly different in disabled athletes compared to non-disabled athletes was proven. However, muscle activities were significantly different in the disabled group. In the disabled group, knee and trunk motions and muscle activities were also significantly different compared to the non-disabled group. Significant differences were found in performance, force and footrest use. Our results proved our assumption that motions and muscle activities of disabled and non-disabled athletes were significantly different. Orv Hetil. 2019; 160(52): 2061-2066.

[Botulinum toxin treatment in children with cerebral palsy]. / Botulinumtoxin-kezelés infantilis cerebralis paresisben.

Introduction: Botulinum toxin is used for decreasing spasticity, improving gait pattern and preventing secondary deformities and orthopedic surgeries in children with cerebral palsy. Despite its wide use, there is no evidence for the long-term beneficial effect of the toxin. Aim: The authors focused on the short-term effects of the toxin and on the subjective evaluation done by the parents about the botox treatment. Method: First, the calf muscle of 18 children was treated and casting was also performed. In our second patient group, multilevel lower limb injection was done in 12 cases. Joints' range of motion, muscle tone and spasticity were assessed before and 4-6 weeks after treatment. In ambulatory children, gait analysis was done. Side effects were recorded and parental opinion about the treatment was requested. Results: Increased ankle range of motion and decreased muscle tone and spasticity were seen in our first patient group. In the second group, hip flexion contracture became milder and hip abduction and the popliteal angle improved. However, gait analysis results only slightly changed after botox treatment. Occasional mild and transient adverse effects were observed during the pharmacologically active period of the toxin. Associate beneficial effects were also reported such as better comfort, easier movements, improving function of the non-injected upper limb, decreasing dysarthria and dysphagia. Conclusion: Our study strengthens the observation that botox treatment of the spastic calf muscle together with plaster casting can result in improved ankle dorsiflexion. Multilevel botox treatment can improve lower limb joints range of motion, however, gait pattern remains unchanged. The administration of botulinum toxin with respect to the guidelines has no major adverse effects. Further studies are needed to clarify the observed beneficial associate effects of the toxin. Orv Hetil. 2019; 160(28): 1105-1111.

Epiphysis preserving resection of malignant proximal tibial tumours.

PURPOSE: The purpose of the study was to evaluate the treatment of five patients with proximal tibial epiphysis preserving resection for malignant tumours of the tibia. METHOD: Three patients suffered from Ewing sarcoma, two had osteosarcoma. The proximal level of the resection was in the line of the growth plate in four patients, and 2 cm below of the growth plate in one patient. The distal resection level was in the diaphysis, depending on the tumour border. The resected part of the tibia was substituted by both the ipsilateral and contralateral fibulas. The two fibulas were proximally built into the epiphysis, the contralateral, freely transplanted fibula was placed distally into the tibial diaphysis. The leg was fixed in an Ilizarov frame. RESULTS: The follow-up period was 4.9 years on average (range, 3.5-8 years). Neither local recurrence nor metastasis was noticed in patients with tibia tumour resection during the observation time. Proper fixation of the transplanted fibula with all of the patients, both proximal to the tibia epiphysis and distal to diaphysis, was experienced. The range of motion of the knee was 122° on the average. Two patients can walk without support and three can walk with an orthosis fully weight bearing. The limb shortening of the affected side was 2.6 cm on average (range,1.5-4.5 cm). In three patients the transplanted opposite side fibula has broken. In one patient, chronic osteomyelitis developed at the distal part of the transplanted fibula. CONCLUSIONS: The difficulties of intercalary segment supplementation were present to a greater extent because of the small size of proximal epiphysis, but the preserved knee joint can produce better function for the patient in this limb-saving surgery.

The humerus is the best place for bone lengthening.

The aim of this study was to examine the effectiveness of lengthening the humerus in children and young adults. Between 1984 and 2005, the Orthopaedic Department of Semmelweis University elongated 11 humeri (ten patients) for reasons of congenital hypoplasia (four cases), osteomyelitis (three cases), epiphyseolysis, growth plate closure after irradiation and obstetrical paralysis (one case each). The study cohort consisted of five females and five males, with an average age at the time of surgery of 17.8 years (range: 12-31 years). In every case, the lengthening was performed with a unilateral Wagner fixator. The lengthening protocol was 1 mm distraction daily (callotasis) after a 7-day latency period. The fixator was removed after total bone healing. Plate fixation or bone transplantation was not used. The average rate of lengthening was 6.2 cm (4.5-10.5 cm), and the achieved lengthening was 27% (range: 16-44%). The average healing index was 32 day/cm. One patient who suffered from temporary radial paresis, and temporary flexion contracture of the elbow was regarded as a complication following placement of the fixator. Based on our results, humeral shortening can effectively be treated with the unilateral Wagner fixator. The main difference between the original Wagner method and our approach is that we were able to leave the fixator in the humerus until total bony reconstruction so there was no need for plate fixation or bone transplantation.

Dysplasia epiphysealis hemimelica (Trevor's disease): 7 of our own cases and a review of the literature.

BACKGROUND AND PURPOSE: Dysplasia epiphysealis hemimelica is characterized by irregular overgrowth of cartilage in the epiphysis, usually affecting the knee and ankle. We treated 7 children by surgery between 1980 and 2005. After reporting one child case, we summarize our cases and the cases described in the literature. METHOD: We discuss the diagnosis of this dysplasia, especially the role of radiography. We describe the suggested treatment, which could be surgical or non-surgical depending on the location and the symptoms. RESULTS: After reviewing 57 cases, we found that this dysplasia occurs twice as often in males as in females. The medial side of the epiphysis is affected twice as often as the lateral side. In two-thirds of the cases, more than one epiphysis was affected. If the location of the exostosis suggests that it might lead to joint deformity, early surgical excision is recommended. INTERPRETATION: Since there is often involvement of more than one epiphysis, we emphasize the importance of a skeletal survey once this dysplasia is diagnosed.

Angiotensin II activates the human renin promoter in an in vitro model: the role of c-Jun-N-terminal kinase.

BACKGROUND: Angiotensin II (Ang II) down-regulates renin expression in juxtaglomerular cells, however, recent experimental evidence obtained in transgenic mice suggested that Ang II may "paradoxically" increase transcriptional activity of the proximal renin promoter. METHODS: To dissect signalling mechanisms contributing to the up-regulation of the proximal renin promoter by Ang II, porcine proximal tubular cells stably expressing the rabbit AT(1) receptor (LLC-PK/AT(1)) were transiently transfected with a luciferase reporter construct containing the 582 bp long piece of the human renin promoter. Activation of mitogen-activated protein kinases (MAPK) was detected by western blotting using phospho-MAPK-specific antibodies. RESULTS: Ang II dose-dependently stimulated the transcriptional activity of the human renin promoter (10(-7) M Ang II: 3.50+/-1.25-fold stimulation). In these cells Ang II activated both extracellular signal-regulated kinase (ERK) and the c-Jun-N-terminal kinase (JNK). Inhibition of the ERK cascade did not reduce the stimulation of the renin promoter by Ang II, however, two expression vectors designed to inhibit the JNK pathway, the dominant negative JNK and the Jun-kinase interacting peptide inhibited the fold stimulation induced by Ang II (2.75+/-0.69 vs 1.6+/-0.23 and 1.8+/-0.34, respectively; P<0.01). Furthermore, genistein, a tyrosine kinase inhibitor, blocked the effect of Ang II both on the JNK and the promoter activation. CONCLUSION: Ang II may have a stimulatory effect on the proximal renin promoter in proximal tubular cells and this effect is mediated by tyrosine kinases and the JNK cascade.