A case of myocardial muscular bridging causing severe hypotension during exercise-electrocardiography test.

Outlining the severity of the myocardial bridge (MB) is a critical step for selecting the appropriate option among medical, surgical, or angioplasty-based treatments. Invasive treatments are usually preferred if treatment-resistant symptoms are observed or ischemia is proven by tests such as fractional flow reserve or myocardial perfusion scintigraphy (MPS). In this report, we present a patient who developed severe hypotension during treadmill exercise test, even though there were no perfusion defects during adenosine-induced MPS. This case suggests MPS with adenosine is not a good choice for evaluating ischemia in MB patients, as it may cause false negative results.

The role of positron emission tomography with 18F-fluorodeoxyglucose in nodal staging of clinical and radiological N0 head and neck cancers.

The objective of the study was to evaluate the impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) imaging on nodal staging for head and neck cancers. This was a retrospectively analyzed single institution study. The study population consisted of 36 patients with head and neck cancers who were evaluated with PET/CT and went on to neck dissection. All of them had clinically and radiographically negative neck (N0) and each patient underwent PET/CT imaging before undergoing selective neck dissection for N0 disease. Tissues were submitted for histopathologic examination and were oriented for the pathologist to permit correlation between the histopathologic findings and the imaging results. The sizes of the lymph nodes and the maximum standardized uptake values (SUVmax) measured from PET/CT images were compared with the histopathologic findings. All primary tumors were visualized with PET/CT. On histopathological examination, 19 patients had positive and 17 patients had negative lymph nodes. Receiver operating characteristic analyses were used to predict the optimal corrected SUVmax cutoffs; the optimal value was 2.95 for respective outcomes of lymph node involvement. This cutoff value yielded 84.2% sensitivity and 76.5% specificity for nodal-level staging. PET/CT proved to be accurate in 27 (75%) patients and inaccurate in 9 (25%) patients. PET/CT was a valuable tool to assess nodal stage of head and neck cancers, and should be considered before surgical treatment.

Hepatopulmonary syndrome in children with cirrhotic and non-cirrhotic portal hypertension: a single-center experience.

BACKGROUND: Hepatopulmonary syndrome (HPS) is defined as an arterial oxygenation defect induced by intrapulmonary vascular dilatation (IPVD) associated with hepatic disease. The prevalence and clinical characteristics of HPS in portal hypertensive children is not well characterized. AIMS: The aim of this study was to investigate the prevalence and clinical characteristics of HPS in 40 portal hypertensive children. METHODS: We studied 40 children (11 girls and 29 boys; mean age, 111 months ± 52 months; range, 24-216 months) with portal hypertension (24 cirrhotic, 16 non-cirrhotic) for the presence of HPS using blood gas analysis, contrast-enhanced echocardiography (CEE), and Tc99m-macroaggregated albumin scintigraphy. Clinical and laboratory characteristics of patients were recorded. HPS was considered to be present in a patient with hypoxemia and/or an elevated alveolar-arterial oxygen gradient (PAaO(2)) ≥ 15 mmHg) and positive CEE and/or scintigraphy. RESULTS: Elevated PAaO(2) was detected in 7 of 24 patients with cirrhosis. Four of them also had IPVD with CEE. An intrapulmonary shunt in Tc99m-MAA with CEE was shown in one patient. A diagnosis of HPS was made in 16.7% of the patients with cirrhosis. Cirrhotic patients without IPVD had significantly better hepatic function and lower pediatric end-stage liver disease scores. Although, 2 of the 16 patients with non-cirrhotic portal hypertension had elevated PAaO(2,) none of them showed IPVD. One normoxemic patient in the non-cirrhotic portal hypertension group showed IPVD with CEE. None of the non-cirrhotic patients fulfilled the diagnostic criteria of HPS. CONCLUSION: Hepatopulmonary syndrome particularly occurs in cirrhotic portal hypertensive patients with severe hepatic dysfunction.

Preoperative detection of parathyroid adenomas with Tc-99m MIBI and Tc-99m pertechnetate scintigraphy: histopathological and biochemical correlation with Tc-99m MIBI uptake.

AIM: The objective of this study was to compare the dual phase MIBI scinitgraphy with MIBI and Tc-99m pertechnetate (MIBI + Tc-99m) study in defining the parathyroid adenomas, and to evaluate the effect of histologic and biochemical characteristics on the imaging of parathyroid adenomas with Tc-99m methoxyisobutylisonitrile (MIBI) scintigraphy. METHODS: Thirty-six patients with parathyroid adenomas were studied prospectively. All patients were evaluated with both MIBI and (MIBI + Tc-99m) study. MIBI uptake of adenomas correlated with oxyphill, chief cell and tumour weight of the surgically excised glands. MIBI uptake was also compared with serum calcium (Ca), phosphorus (P) and intact parathormone (iPTH) levels. RESULTS: A total of 38 parathyroid adenomas were surgically excised from 36 patients. MIBI + Tc-99m identified 35 of the parathyroid lesions (92%). Whereas, MIBI study detected 30 of the 38 parathyroid adenomas (79% sensitivity) (p=0.0001). There were no false positives. Adenoma weight showed significiant correlation with MIBI uptake (p=0.001). Oxyphyill cell content also showed high correlation with MIBI uptake. Delayed images showed better correlation than the early views (Early MIBI p=0.033; Delayed MIBI; p=0.001). CONCLUSION: MIBI + Tc-99m pertechnetate interpretation is more sensitive than only dual MIBI imaging for the detection of parathyroid adenoma. Oxyphill cell content and weight of the lesions proved to be important determinants of 99mTc-MIBI accumulation in parathyroid adenoma. We found no significant correlation between MIBI accumulation, Ca, P and iPTH serum levels (Tab. 2, Fig. 2, Ref. 15). Full Text (Free, PDF) www.bmj.sk.

Intense fluoro-2-deoxyglucose uptake in high-grade prostatic adenocarcinoma with negligible prostate-specific membrane antigen expression.

While 68Gallium prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA) has demonstrated increasing utility in the evaluation of prostatic carcinoma, it is essential to be aware of false-negative findings. Further subtype analyses of prostate cancer will be helpful in the understanding of the underlying reasons. We herein present a high-grade prostate adenocarcinoma, with metastatic lesions showing high 18F-labeled fluoro-2-deoxyglucose uptake instead of 68Ga-PSMA.

Effects of vascular bundle implantation on autograft, fresh-frozen allograft, and xenograft incorporation in a rabbit model.

This study examined the effects of vascular bundle implantation into a bone graft. Vascularized and nonvascularized autografts, allografts, and xenografts were placed inside defects in the proximal tibia in rabbits. Evaluation using radiographs, magnetic resonance imaging, bone scintigraphy, and microscopy showed autografts fused more rapidly than allografts and xenografts, and the majority of the vascularized grafts were incorporated completely. Autografts emerged as the gold standard. These findings indicate vessel implantation enhances and accelerates vascularization, new bone formation, and incorporation in autografts, allografts, and xenografts.

Evaluation of renal function in Turkish children receiving BFM-95 therapy for acute lymphoblastic leukemia.

This study examined renal function in 42 children with acute lymphoblastic leukemia (ALL) treated according to BFM-95 protocol. Fifteen (group 1) were investigated longitudinally at 3 time points: before (T1), 4 weeks after (T2), and 2-6 months after (T3) consolidation therapy with high-dose methotrexate (HDMTX). The frequency of abnormalities in glomerular and tubular tests were nil at T1 and ranged from 13 to 40% at T2 and 7 to 33% at T3 in group 1. Twenty percent of the patients (n = 10) in group 2, who were examined at a single time point 7-36 months after consolidation, had glomerular and tubular abnormalities. There was only mild tubular abnormality in 5.8% of patients (n = 17) in group 3, who were examined at a single time point a mean of 56.1 +/- 12.5 months after completion chemotherapy. These data show that consolidation therapy with HDMTX is frequently associated with acute renal toxicity in children with ALL but does not leave clinically significant late sequelae.

Fate of bulk autografts in uncemented total hip arthroplasty. Evaluation by bone scintigraphy.

OBJECTIVE: To review short term results of uncemented cup implantation and the fate of bulk femoral head autografts in patients with acetabular bone deficiency due to dysplasia of the hip. We used bone scintigraphy to assess the viability of the grafts. METHODS: We treated 19 hip joints of 17 patients with osteoarthritis due to developmental dysplasia of the hip with uncemented total hip arthroplasty between 1997-2003 in the Department of Orthopedics and Traumatology, Gazi University, Ankara, Turkey. The average age was 49.1 (31-72 years), and the average follow up period was 36 months. We used femoral head autografts to reconstruct superolateral segmental deficiencies of the acetabuli. We evaluated the patients clinically and radiologically to assess acetabular loosening, and we used three-phase bone scintigraphy to evaluate the viability of the autograft. RESULTS: There was no acetabular component revision throughout the follow up period. There was no radiological evidence of graft resorption or graft displacement in any of the patients. In bone scintigraphy, we observed hyperemia in the blood pool phase, and the osteoblastic activity of the bone graft was at the level of the neighboring iliac bone. CONCLUSION: The application of a non-cemented acetabular component with femoral autograft in superolateral acetabulum deficiency increases the stability of the implant and increases the bone stock. It is not easy to evaluate the viability of the graft by the use of radiological methods. Bone scintigraphy gives sufficient information about the viability of the graft as a non-invasive method.

The Therapeutic Role of Lamotrigine And Topiramate In A Depressive Patient With Anxiety Symptoms And Cognitive Decline: Neurometabolic Correlates.

We describe here 67 years old women presented with symptoms of anxiety and cognitive impairment that responded well to the combined treatment of lamotrigine and topiramate. In contrast to recent data, we have shown that lamotrigine and topiramate treatment additively increased the cerebral glucose metabolism that was associated with complete resolution of the neuropsychiatric symptoms. Our findings indicate that the therapeutic effect of both agents involve a cortico-subcortical network and suggest the functional role of a bi-directional hippocampal-cingulate connectivity. The main limitation of this report is that this a single case study and that these findings need to be replicated in a larger sample e.g., as part of a controlled trial.

Orbital gallium-67 scintigraphy in Graves' ophthalmopathy: a disease activity parameter that predicts the therapeutic response to immunosuppressive treatment.

In this study, orbital gallium-67 citrate ((67)Ga) scintigraphy was evaluated as a disease activity parameter that can predict the therapeutic response to immunosuppressive treatment in Graves' ophthalmopathy. Orbital scintigraphic analysis was performed on 32 patients demonstrating moderate to severe Graves' ophthalmopathy. Single-photon emission computed tomography (SPECT) images were obtained 48 hours after intravenous injection of 148 MBq of radioactive (67)Ga complex, and orbit/occipital (O/Occ) ratios were calculated to correct the background activity. Intravenous methylprednisolone was given as immunosuppressive treatment to 24 patients (group 1) and 8 patients were followed up without any treatment and evaluated as controls (group 2). Orbital (67)Ga scintigraphy was repeated in all patients after 6 months to analyze the changes in clinical findings and orbital (67)Ga accumulation. In Group 1, the mean +/- standard deviation (SD) (67)Ga O/Occ ratio of responders (2.23 +/- 0.2, 16 cases) was statistically different from nonresponders (1.49 +/- 0.1, 8 cases, p < 0.001). Additionally, the corticosteroid treatment provided a significant decrease in orbital (67)Ga accumulation in responders (p < 0.001), however, it did not change statistically in nonresponders (p:0.13). In group 2, the patients did not demonstrate clinical improvement and orbital (67)Ga uptake did not change after the follow-up period (p:0.81). The receiver-operator-characteristic curve showed that the best threshold for discriminating responder and nonresponder groups was 1.70 (sensitivity, 94%; specificity, 88%). This study demonstrated that orbital (67)Ga scintigraphy may be a useful imaging technique in predicting the therapeutic response to immunosuppressive treatment in Graves' ophthalmopathy.

Effects of radiation therapy on oesophageal transit in patients with inner quadrant breast tumour.

OBJECTIVES: The aim of this study was to evaluate quantitatively the effect of low doses of radiation therapy on the oesophageal transit in patients with inner quadrant breast carcinoma. METHODS: Eighteen female patients with locally advanced inner quadrant breast tumour were included in this study. A total dose of 5000 cGy in 25 fractions of 200 cGy was applied from four different treatment portals to all patients. Oesophageal motility was evaluated before and immediately after radiotherapy using oesophageal scintigraphy. The oesophageal transit times (ETTs) for the upper one-third, the lower two-thirds portion and the whole oesophagus were calculated. RESULTS: The upper one-third portion of the oesophagus received a mean dose of 600 cGy and the lower two-thirds portion received a mean dose of 1530 cGy as a result of 5000 cGy dose application. All of the patients developed grade 1 oesophageal toxicity. Post-radiation therapy ETT values were significantly higher compared to pre-radiation therapy ETT values (P<0.001). Before irradiation, ETT values for the upper one-third, distal two-thirds of the oesophagus and the whole oesophagus were 4.77+/-1.08, 11.22+/-2.85 and 11.61+/-2.97 s, respectively. After irradiation, ETT values for the upper one-third, distal two-thirds of the oesophagus and the whole oesophagus were 6.92+/-2.15, 23.30+/-5.65 and 23.74+/-5.70 s, respectively. CONCLUSIONS: Oesophageal transit seems to be affected by radiation even without a clinically significant oesophageal symptom and oesophageal scintigraphy allows sensitive, non-invasive and quantifiable assessment of the oesophageal transit time.

Orbital gallium-67 scintigraphy in Graves' ophthalmopathy.

Assessment of orbital disease activity in patients with Graves' ophthalmopathy is important in planning the therapeutic approach. In this study, orbital uptake of gallium-67 citrate ((67)Ga) was evaluated in 46 consecutive patients demonstrating active or inactive Graves' ophthalmopathy. The disease activity with Graves' ophthalmopathy was evaluated by using clinical activity score (CAS). Orbital (67)Ga scintigraphies of 8 patients without any history of ophthalmic, thyroid, or autoimmune disease were studied as controls. (67)Ga scintigraphy was performed 48 hours after intravenous injection of 4 mCi (128 MBq) of radioactive complex. Single-photon emission computed tomography (SPECT) images were obtained with a gamma camera. Intravenous corticosteroid treatment was given to 8 selected patients demonstrating bilateral active orbital disease and (67)Ga scintigraphy was repeated 6 months after the treatment. Quantitative analysis of mean orbital (67)Ga uptake demonstrated significant difference between active, inactive, and control groups (p = 0.0001). The orbital uptake of (67)Ga was significantly elevated in the active group compared to the inactive and control groups. A threshold orbital (67)Ga uptake value was calculated to differentiate active and inactive groups based on receiver operating characteristic (ROC) analysis. A significant correlation was found between the CAS and the (67)Ga orbital uptake (r = 0.73, p = 0.0001). Clinical improvement and significant decrease in orbital (67)Ga uptake were achieved after immunosuppressive treatment (p = 0.0004). These preliminary results suggest that orbital (67)Ga scintigraphy may provide objective assessment of the disease activity in Graves' ophthalmopathy.

99mTc ethylene dicysteine scintigraphy for diagnosing cortical defects in acute pyelonephritis: a comparative study with 99mTc dimercaptosuccinic acid.

AIM: To evaluate the clinical usefulness of early cortical phase images in the diagnosis of acute pyelonephritis and to compare the measurements of differential renal function obtained by both 99mTc ethylene dicysteine (99mTc-EC) and 99mTc dimercaptosuccinic acid (99mTc-DMSA). METHODS: Forty-three children who had undergone both 99mTc-EC and 99mTc-DMSA studies within 5 days of acute infection were studied. Cortical images of 99mTc-EC were obtained by the sum of the renogram frames achieved between the first 60-120 s of the renogram study. DMSA and EC images were visually interpreted using four points of semiquantitative ratings: 0, normal; 1, mild hypoactivity; 2, moderate hypoactivity with partial loss of margins; 3, marked hypoactivity with loss of cortical margins. Values for the differential renal function were obtained for both studies. RESULTS: DMSA detected a total of 109 lesions in 36 patients and EC detected 90 lesions with a sensitivity of 82.5%. 99mTc-EC successfully detected moderate-to-severe cortical lesions but was less effective with mild lesions (sensitivity 60%). Bland-Altman analysis demonstrated good agreement among the results for differential renal function (95% CI -0.26 to 0.96). CONCLUSION: 99mTc-EC early phase images detected most of the cortical lesions. Its sensitivity depends on the severity of the lesions. EC provided reliable information in the estimation of differential renal function.

Value of bone scintigraphy in patients with carpal trauma.

OBJECTIVE: We planned this study to evaluate the role of bone scintigraphy in patients with suspected carpal fracture and normal or suspicious radiographs following carpal injury. METHODS: Three-phase bone scintigraphy using Tc-99m-MDP was performed on 32 patients with negative radiographs but clinically suspected fracture at two weeks after the trauma. Focally increased radiopharmaceutical uptake was interpreted as a fracture. The final diagnosis was established with clinical follow-up. RESULTS: Twelve (38%) patients had a normal scan excluding fracture. Twelve patients had a single fracture. Multifocal fracture was present in 8 (25%) patients. Eight patients showed scaphoid fractures; of these three showed single scaphoid fracture, and the other five patients revealed accompanying fractures. Distal radius fractures and carpal bone fractures other than scaphoid were both observed in 12 patients. These were eleven fractures of distal radius; three fractures of pisiform; two fractures of hamate; and single fractures of lunate, trapezium and triquetrum. In one patient there was fracture of a first metacarpal bone. CONCLUSION: In patients with suspected carpal bone fracture and normal or suspicious radiographs, bone scintigraphy can be used as a reliable method to confirm or exclude the presence of a scaphoid fracture and to detect clinically unsuspected fractures of distal radius and other carpal bones.

Evaluation of sentinel nodes in the assessment of cervical metastases from head and neck squamous cell carcinomas.

AIMS AND BACKGROUND: To delineate the lymphatic drainage in head and neck squamous cell carcinoma (SCC) patients by lymphoscintigraphy and to investigate whether the results of histopathological evaluation of sentinel nodes have any diagnostic relevance with regard to the metastatic involvement of all cervical lymph nodes. METHODS: Forty-one patients clinically pre-diagnosed as having primary head and neck SCC underwent Tc-99m nanocolloid lymphoscintigraphy and were evaluated according to the Memorial Sloan Kettering cervical lymph nodes level system. Treatment of 24 of these patients included neck dissection in addition to surgery for the primary tumor. RESULTS: Among the 24 operated patients nine were found to be pathologically N+. In two (22%) of these nine patients there were histopathological metastases in non-sentinel lymph nodes. In one patient with a metastatic lymph node, no sentinel nodes were identified. Altogether, lymphoscintigraphic sentinel node detection failed in three (33%) cases. CONCLUSION: The procedure of lymphoscintigraphic imaging of sentinel lymph nodes and its use in the determination of squamous cell carcinoma metastases is theoretically promising. However, in order to assess the true value of sentinel lymph node imaging and make treatment plans based on this technique, it's necessary to increase the number of cases included in the studies, and obtain results that are specific for the primary tumor and involved lymph nodes.

Comparison of three different diuretic renal scintigraphy protocols in patients with dilated upper urinary tracts.

PURPOSE: To compare 3 different diuretic renal scintigraphy protocols in patients with dilated upper urinary tract. MATERIALS AND METHODS: Three diuresis renography protocols were performed in 22 adult patients (28 kidneys) with upper urinary tract dilatation. The diuretic was given 20 minutes after (F+20), at the same time as (F+0), and 15 minutes before (F-15) radionuclide administration. The mean age was 29.8 years (range, 18-43 years). The 3 protocols were identical, except for the time of injection of furosemide. The F+0 protocol could not be performed in 1 and F-15 in 2 of the patients. Each of the 3 protocols was performed for the rest of the patients. The results were classified as nonobstructive, equivocal, and obstructive according to the renogram images and curves. RESULTS: None of the patients showed equivocal results in both F+0 and F-15 protocols. In the F+20 studies, 7 of the 28 kidneys were evaluated as equivocal. Of these, 5 kidneys showed nonobstructive and 2 kidneys revealed obstructive renogram patterns with the other 2 protocols (F+0 and F-15). Moreover, one kidney, which was evaluated as nonobstructive in the F+20 protocol, showed an obstructive pattern in both F+0 and F-15 protocols. All of the kidneys showing obstructive patterns in the F+20 study also revealed obstruction in the F+0 and F-15 investigations. We could not find any difference between the renogram patterns of F+0 and F-15 investigations. CONCLUSIONS: F+0 and F-15 protocols allow clarification in cases of equivocal F+20 studies. Because the F+0 study is more practical and shorter, we suggest the F+0 method when equivocal results are obtained by an F+20 study or as a single test when there is only one opportunity to confirm or exclude the presence of obstruction.

99mTechnetium-labeled methylene diphosphonate uptake in maxillary bone during and after rapid maxillary expansion.

The purpose of this study was to evaluate bone activity at the midpalatal suture that had been biomechanically stimulated by rapid maxillary expansion (RME). A rigid acrylic-bonded expansion device with a maxiskeleton screw was used for RME in three patients who were in three different growth periods. The screw was activated twice a day by 1/4 turns. After sufficient expansion, the screw was fixed with acrylic resin, and the same appliance was used as a removable retention plate for three months. Single photone emission computed tomography (SPECT) bone scintigraphy records were obtained before (T1) and at the end of RME (T2) and three months after the retention period (T3). According to the scintigraphic records, the increase in bone activity was highest in the anterior and medial sections on both the left and right sides of the maxilla in all cases. After three months of retention, the bone activity returned to its original level. Therefore, it may be stated that the retention period of three months was sufficient for bone reorganization.

The use of technetium-99m hexamethylpropylene amine oxime lung scintigraphy in the detection of subclinical lung injury in patients with noninsulin-dependent diabetes mellitus.

PURPOSE: The aims of this study were to evaluate subclinical pulmonary injury in patients with noninsulin-dependent diabetes mellitus (NIDDM) who showed normal chest radiograph and pulmonary function test results by using technetium-99 hexamethylpropylene amine oxime (Tc-99m-HMPAO) scintigraphy and to investigate the relationship between Tc-99m-HMPAO lung uptake and duration of diabetes, glycemic control, and the presence of diabetes-related microvascular complications. MATERIALS AND METHODS: A total of 40 patients with NIDDM (19 men, 21 women; age 56.5 ± 6.8 years; duration of diabetes: 13.1 ± 6.7 years) were included in this study. The pulmonary vascular damage was represented as lung/liver uptake ratios (L/L ratios) calculated by Tc-99m-HMPAO lung scintigraphy. Results were compared with those of age-matched controls. RESULTS: The L/L ratio was 0.36 ± 0.07 in normal controls and 0.51 ± 0.16 in patients with NIDDM. The L/L ratio was significantly higher in NIDDM patients than in the control group (P=0.002). No correlation was observed between L/L ratio and the presence of diabetic complications, glycemic control, and diabetes duration. CONCLUSION: Tc-99m-HMPAO lung scintigraphy is a sensitive and an objective method for the detection of subclinical lung injury in NIDDM patients. Tc-99m-HMPAO lung uptake serves as an indicator of pulmonary injury due to diabetes, regardless of diabetes age, glycemic control, and the presence of other diabetes-related microvascular complications.

FDG-PET after 1 cycle of therapy predicts outcome in diffuse large cell lymphoma and classic Hodgkin disease.

BACKGROUND: Early prediction of response to therapy may offer the potential to identify patients who will benefit from standard conventional therapy. The objective of this study was to determine the predictive value of FDG-PET as an early response indicator after 1 cycle of chemotherapy for progression-free survival (PFS) in diffuse large cell lymphoma (DLCL) and classic Hodgkin disease (HD). METHODS: FDG-PET was performed before, after 1 cycle, and after completion of chemotherapy in 47 patients. The patients were followed with a median follow-up of 21 months (range, 3-47 months). PFS was compared between PET-positive and PET-negative patients after 1 cycle and after completion of therapy. RESULTS: All PET-negative patients after 1 cycle (n = 31) had sustained complete remission with a median follow-up of 28 months. Fourteen of 16 PET-positive patients after 1 cycle had refractory disease or relapsed (median PFS, 5.5 months). There were 2 false-positive results, 1 with an active infection at the biopsy site and the other in a patient who had been in remission after radiation therapy. There was good agreement between the results obtained after 1 cycle and at completion of therapy (kappa, 0.80); however, the negative predictive value was higher for FDG-PET after 1 cycle than after completion of chemotherapy (100% vs 91.4%), although not statistically different (P = .40). CONCLUSIONS: FDG-PET had a high prognostic value after 1 cycle of chemotherapy, thus it can be a valid alternative for posttreatment evaluation of DLCL and HD and may offer the potential for change in treatment paradigms.