Biomedical subjects

D Cantarovich

Publications and source records attributed to D Cantarovich.

At least 19 recordsLinked to original sources

PubMed2005

[Dialysis-associated spondyloarthropathy. Case report and literature review].

Hemodialysis has considerably prolonged the life of patients suffering from terminal renal failure. However, long-term hemodialysis leads to new bone complications and spinal disorders such as destructive spondyloarthropathy (DSA). At the present time DSA is reported in 8% to 18% of the dialysed patients. Diagnosis is based on severe narrowing of the intervertebral disk, erosions and geodes of the adjacent vertebral plates simulating infectious spondylitis. Lesions progressively involve posterior joints and may lead to severe destruction of the spine. The pathogenesis of this syndrome is still unknown. Several factors have been implicated, including microcrystal deposition, amyloidosis, inflammatory and foreign body reactions and suggest that the pathogenesis of erosive spondyloarthropathies of hemodialysed patients is multifactorial. Spinal instability inducing myelopathy and radiculopathy were observed in 8% of the cases. Treatment must be accorded to the natural disease course and to the quality of the bone. We report the case of a chronic dialysed patient with destructive spondyloarthropathy involving the cervical and thoracic spine. Pathogenesis, radiological datas and therapeutic approach are discussed.

Adult↗

PubMed2000

Low incidence of kidney rejection after simultaneous kidney-pancreas transplantation after antithymocyte globulin induction and in the absence of corticosteroids: results of a prospective pilot study in 28 consecutive cases.

BACKGROUND: Recipients of simultaneous kidney-pancreas transplantation receive a combination of polyclonal antithymocyte globulin (ATG), cyclosporin or tacrolimus, mycophenolate mofetil (MMF) and corticosteroids (Cs). To avoid the side effects and adverse events associated with Cs, we investigated a new immunosuppressive regimen without Cs after simultaneous kidney-pancreas transplantation. METHODS: A total of 28 consecutive patients who underwent simultaneous kidney-pancreas transplantation were included in this study. All patients received ATG, cyclosporin, and MMF. RESULTS: All patients but one tolerated the ATG course well. MMF was definitively discontinued in three patients because of leukopenia. Cytomegalovirus infection was diagnosed in eight patients (28.5%). Only two patients (7%) required an antirejection treatment. Patient, kidney, and pancreas survival is currently 96.4, 96.4, and 75%, respectively. CONCLUSIONS: The combination of ATG, cyclosporin, and MMF, without Cs, was well tolerated. The unexpectedly low (7%) incidence of acute kidney rejection observed suggests that Cs may partially interfere with the immunosuppressive effect of ATG.

Adolescent↗

PubMed2000

Prevention of acute rejection with antithymocyte globulin, avoiding corticosteroids, and delaying cyclosporin after renal transplantation.

BACKGROUND: Despite their well-known side-effects, corticosteroids (Cs) are currently used after kidney transplantation. Avoidance of Cs may improve patient quality of life and eventual long-term survival. We report on a regimen using antithymocyte globulin (ATG) and mycophenolate mofetil (MMF) for induction, and cyclosporin (CsA) plus MMF for maintenance treatment of recipients of primary kidney transplantation. METHODS: We studied 11 consecutive, non-sensitized renal transplant patients (nine cadaver and two living donors). Initial immunosuppression consisted of ATG (1.5 mg/kg/day, i.v.) given for 10 days and MMF (1.0 g/b.i.d.). CsA (8 mg/kg, in two divided doses) was started on post-operative day 11. Cs were only allowed in the case of MMF discontinuation, for the treatment of acute rejection, and in the event of recurrence of the primary glomerulonephritis. RESULTS: All patients completed the entire 10-day ATG course. Main side-effects included fever (>38 degrees C) and serum sickness, observed in 73 and 27% of the patients respectively. The incidence of acute rejection was 27% (three of 11 patients). In two patients with acute rejection, serum sickness was concomitantly diagnosed and renal histology was partially compatible with immune-complex disease. The remaining patient had two episodes of low-grade rejection. All rejection episodes were rapidly reversed. Two patients (18%) were treated with ganciclovir for cytomegalovirus (CMV) infection. Two patients (18%) are currently receiving Cs for recurrence of the native glomerulonephritis and two rejection episodes respectively. All patients are currently alive with functioning kidneys (average follow-up of 8.4 months; average creatinine level of 128 micromol/l). CONCLUSION: This pilot study suggests that ATG induction in combination with MMF and delayed introduction of CsA, in the absence of Cs, is not well tolerated in recipients of kidney transplants. An earlier introduction of calcineurin inhibitors and/or a shorter course of ATG may reduce the incidence of fever and serum sickness secondary to ATG.

Acute Disease↗

PubMed2000

Evaluation of clinical guidelines for the management of end-stage renal disease in europe: the EU BIOMED 1 study.

BACKGROUND: There are wide national and international variations in the management of patients with end-stage renal disease (ESRD). The aim of this study was to develop, harmonize, implement, and evaluate consensus-based clinical guidelines for the management of renal anaemia and renal bone disease in patients with ESRD, and for the prevention and management of cytomegalovirus disease in renal transplant recipients across six renal centres in Europe. METHODS: The trial was a prospective, multicentre, randomized balanced incomplete block design. Nephrologists from the six European renal units were randomized to develop and implement guidelines for two out of the three conditions and to act as a control for the third condition. Data were collected pre- (1 year) and post- (9 months) intervention on aspects of patient monitoring, management, and outcome. RESULTS: Eight hundred and twenty-nine dialysis patients from the six European dialysis centres were included in the study. Multivariate analysis (adjusting for case-mix and secular trends) showed a significant increase in the number of monitoring events in the guideline group compared with control group (6%, 95% CI, 1-11%). There was no concomitant increase in either appropriate management or the number of favourable patient outcomes. CONCLUSIONS: In the first European collaboration on renal guidelines, the introduction of the guidelines improved the monitoring of the patients, but did not improve patient management or outcome. This study suggests the potential for creating clinical guidelines with the aim of standardizing treatment protocols across international boundaries, and improving the quality of the medical care provided.

Adolescent↗

PubMed2000

Clinical relevance of direct quantification of pp65 antigenemia using flow cytometry in solid organ and stem cell transplant recipients.

A total of 1,305 blood samples from 85 solid organ transplant (SOT) recipients and 25 stem cell transplant (SCT) recipients at risk for cytomegalovirus (CMV) infection were prospectively collected and tested using the shell vial assay (SVA) and a leukocytic qualitative PCR (q-PCR). Of these, 462 specimens were further tested by direct quantification of CMV antigenemia by flow cytometry (FC-Ag), 125 were tested with a quantitative competitive PCR, and 200 were tested for pp65 antigenemia using the slide method (S-Ag). Laboratory data were statistically analyzed according to the presence of CMV-related symptoms. In SOT and SCT recipients, active CMV infection occurred in 63.5 and 36%, respectively, and CMV disease occurred in 53 and 24%, respectively. FC-Ag results correlated better with q-PCR and S-Ag than with SVA. The first test found to be positive during follow-up was FC-Ag in 73% of cases. In SOT recipients, FC-Ag showed the highest sensitivity and negative predictive value for the diagnosis of any grade of CMV disease. For FC-Ag, the threshold beyond which CMV disease was highly probable seemed to lie at 0.20% positive polymorphonuclear leukocytes. FC-Ag appears to be a useful test for the early detection of CMV infection and the prediction of CMV disease.

Adolescent↗

PubMed1999

Use of reverse transcription polymerase chain reaction with colorimetric plate hybridization to detect a cytomegalovirus late spliced mRNA in polymorphonuclear leukocytes from renal transplant patients.

Human cytomegalovirus replication was evaluated in polymorphonuclear leukocytes from ten renal transplant recipients. Three new reverse transcription polymerase chain reactions with plate hybridization suitable for automation were developed for the detection of immediate-early spliced UL123 mRNA, early-late pp65 mRNA, and late spliced UL22 mRNA. The presence of UL22mRNA was found to be significantly associated with the occurrence of cytomegalovirus (CMV) disease.

Colorimetry↗

PubMed1998

Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens.

BACKGROUND: Long-term administration of cyclosporin carries a risk of renal toxicity, and immunosuppressants are associated with an increased rate of malignant disorders. We undertook an open randomised study of the risks and benefits of two long-term maintenance regimens of cyclosporin in kidney-allograft recipients. The primary endpoint was graft function; secondary endpoints were survival and occurrence of cancer and rejection. METHODS: 231 recipients of a first allograft with at most one previous rejection episode were randomised 1 year after transplantation. Most were receiving cyclosporin and azathioprine. One group received cyclosporin doses adjusted to yield trough blood concentrations of 75-125 ng/mL (low-dose group); the second received doses that yielded trough concentrations of 150-250 ng/mL (normal-dose group). Analysis was by intention to treat. FINDINGS: At 66 months' follow-up, the low-dose and normal-dose groups were similar in mean serum creatinine (182 [SD 160] vs 184 [157] micromol/L; p=0.9) and mean creatinine clearance (47.5 [25.1] vs 45.3 (22.5] mL/min; p=0.6). Nine of 116 patients in the low-dose group and one of 115 in the normal-dose group had symptoms of rejection (p<0.02). There was no difference between the low-dose and normal-dose groups in survival (95 vs 92%; p=0.7) or graft survival (89 vs 82%; p=0.17) at 6 years. 60 patients developed cancers, 37 in the normal-dose group and 23 in the low-dose group (p<0.034); 66% were skin cancers (26 vs 17; p<0.05). INTERPRETATION: We found no evidence that halving of trough blood cyclosporin concentrations significantly changes graft function or graft survival. The low-dose regimen was associated with fewer malignant disorders but more frequent rejection. The design of long-term maintenance protocols for transplant recipients based on powerful immunosuppressant combinations should take these potential risks into account.

Adolescent↗

PubMed1998

Delayed graft function of more than six days strongly decreases long-term survival of transplanted kidneys.

BACKGROUND: We reviewed 843 first cadaver kidney transplants carried out consecutively at our center to examine the effect on long-term graft survival of the duration of delayed graft function (DGF), defined as the time taken for the kidney to attain the threshold of a Cockcroft calculated creatinine clearance (cCCr) > or = 10 ml/min. METHODS: Using a multivariate Cox survival analysis we evaluated the consequences of DGF on allograft survival, and then by regression analysis identified the factors contributing to the occurrence of DGF. Finally, using a Kaplan Meier analysis we compared the profiles of graft failure according to the duration of DGF. RESULTS: Defining DGF in terms of cCCr rather than necessity for dialysis after transplantation allowed better prediction of long-term graft loss. Indeed, patients with a Cockcroft-based DGF > six days who did not require dialysis (12%) had a significantly poorer long-term graft outcome than those with a DGF < or = six days. Furthermore, we showed that a DGF of six days could be taken as a cut-off point that marked a significant difference in the long-term graft survival rate (P < 0.0001). Surprisingly, further extension of the duration of DGF > six days was not associated with further worsening of graft survival (except in DGF > 30 days). CONCLUSION: Our results suggest a threshold effect in the lesions that ultimately results in long-term functional deficiency. In addition, we show that the need for dialysis is not an adequate criterium for DGF in terms of long-term outcome prediction.

Adolescent↗

PubMed1998

Randomized comparison of triple therapy and antithymocyte globulin induction treatment after simultaneous pancreas-kidney transplantation.

BACKGROUND: The incidence of acute rejection is considered to be higher after simultaneous pancreas-kidney (SPK) transplantation as compared to renal transplant alone. Therefore, the majority of SPK transplant recipients commonly receive a combination of cyclosporine (CsA) or tracolimus, and azathioprine or mycophenolic mofetyl, corticosteroids and/or antilymphocyte preparations. This study was designed to compare two immunosuppressive protocols for the prevention of acute rejection in patients undergoing SPK transplantation. The primary end-point was the incidence of acute rejection during the first 12 months after transplantation METHODS: Fifty patients with type-I insulin-dependent diabetes and chronic renal failure were randomized to receive a triple drug immunosuppressive regimen including CsA, azathioprine and corticosteroids (N = 25), or the quadruple sequential combination of rabbit antithymocyte globulin (ATG) given for 10 days, azathioprine, corticosteroids and delayed CsA (N = 25). Maintenance immunosuppression (CsA and azathioprine, without corticosteroids) was similar in both arms. RESULTS: The average follow-up was 36 months in both groups (range 9 to 60 months). No patient was excluded from the study. Although the percentage of patients with adverse events was higher in the ATG group (80 vs. 40%, P < 0.01), none of them resulted in premature discontinuation of the drug. Patients receiving ATG experienced a lower incidence (36% vs. 76%, P < 0.01) and number (13 vs. 29, P < 0.05) of acute renal rejection episodes. However, no difference was observed in patient, pancreas and kidney survival rates between groups. No case of isolated pancreas rejection was observed. CONCLUSIONS: The quadruple sequential combination ATG, azathioprine, corticosteroid and CsA significantly reduced the one year incidence of acute renal rejection after SPK transplantation, compared to a triple immunosuppressive regimen.

Adrenal Cortex Hormones↗

PubMed1998

Comparing outcomes in renal replacement therapy: how should we correct for case mix?

The need to evaluate the effectiveness of clinical practice to justify expensive therapy in the face of financial constraints in all areas of health care delivery makes it necessary to identify groups of patients who are likely to benefit most from treatment. Various risk stratification methods have been used for analyzing survival probabilities for patients receiving renal replacement therapy. Complicated risk stratification methods produce large numbers of risk groups of small sizes, which makes comparison between individual centers difficult. We compared three simple methods of risk stratification, that divided patients into low-, medium-, and high-risk groups, in a cohort of 1,407 patients who commenced renal replacement therapy in five European countries during a 7-year period. Method 1 considered age (>55 years) and diabetes alone; method 2 used a higher age limit (>70 years) and comorbid illnesses, including those other than diabetes; and method 3 used only the number of comorbidities (none, 1, or > or =2) for stratification. Kaplan-Meier survival curves were constructed for comparison between risk groups and Cox's regression model used to assess strength of relationship with mortality. Although patient survival was significantly different between the low-, medium-, and high-risk groups using all three methods, Cox's regression analysis showed that method 2 provided the greatest discrimination between risk groups. In predicting mortality, method 2 (based on comorbidities and age) showed the highest sensitivity and specificity (84% and 80%, respectively) compared with method 1 (80% and 74%) and method 3 (64% and 82%). Validation of this approach in other populations in a prospective study is required before this method, which takes into account the influences of both age and comorbidity for risk stratification, can be used for comparing survival data and for presenting results of renal replacement therapy.

Adolescent↗

PubMed1998

Efficacy Endpoints Conference on Acute Rejection in Kidney Transplantation: review of the conference questionnaire.

Basic differences in the diagnosis and management of acute rejection in renal transplant can be found between centers. A questionnaire was developed to ascertain the profile of these variables. Sixteen fundamental questions were presented to the program directors of 17 transplant groups from around the world. The questions were brief and designed to identify clinical practice and behaviors related to the definition of acute and steroid-resistant rejection, successful response to therapy, use of histological diagnosis, estimated frequency of rejection, and frequency of mild, moderate, or severe acute rejections. Clinicians were presented with case studies and asked to respond to specific questions regarding the rejection management described in these cases to determine similarities in management practices. Results indicated that clinicians relied on clinical symptoms only rarely. Biopsy findings were used by 53% of clinicians, and 94% of clinicians indicated that rejection was suspected if creatinine increased. Successful response was defined as a return to prerejection creatinine level by 77% of clinicians and that steroid-resistant rejection is evident by 5 days. Biopsy was used by 80% of centers to diagnose first acute rejection episode, and only 18% of rejection episodes are expected to be severe. This report was then used to develop a more detailed questionnaire to be used in profiling acute rejection in consecutive transplant recipients.

Acute Disease↗

PubMed1997

Disposition of basiliximab, an interleukin-2 receptor monoclonal antibody, in recipients of mismatched cadaver renal allografts.

BACKGROUND: Basiliximab is an interleukin-2 receptor (IL-2R; CD25) chimeric monoclonal antibody for immunoprophylaxis against acute rejection in renal transplantation. Its pharmacokinetics were characterized in a multicenter open-label, prospective dose-escalation study to identify a single-dose regimen providing IL-2R-saturating serum concentrations in the critical first posttransplant month. METHODS: Thirty-two recipients of primary, mismatched cadaver kidneys were enrolled: 20 men and 12 women, who were 47+/-11 years old and weighed 65+/-12 kg. The immunosuppression regimen consisted of steroids and azathioprine from day 0 and cyclosporine from day 10. Basiliximab was infused over 30 min as a single dose preoperatively. RESULTS: Thirty patients were evaluable for basiliximab pharmacokinetics: 24 received 40 mg and 6 received 60 mg. Basiliximab was well tolerated without evidence of cytokine-release syndrome, hypersensitivity reactions, or anti-idiotype antibody response. Peak concentration and area under the concentration curve increased proportionally with dose. Postinfusion concentrations declined in a biphasic manner with a terminal half-life of 6.5+/-2.1 days. Weak, widely dispersed correlations were noted between body weight versus distribution volume (r=0.29) and versus clearance (r=0.45), suggesting no clinical relevance for weight-adjusted dosing. There were no apparent gender-related differences in basiliximab disposition. Previous phase II data indicated that serum concentrations in excess of 0.2 microg/ml are sufficient to saturate IL-2R epitopes on circulating T lymphocytes. Concentrations were above this threshold for 26+/-8 days (range 16 to 46) at the 40-mg dose level and for 32+/-11 days (range 22 to 51) at the 60-mg dose level. CONCLUSIONS: Total basiliximab doses of 40-60 mg were well tolerated, nonimmunogenic, and estimated to provide immunoprophylaxis to cover the first posttransplant month.

Adult↗

PubMed1997

Usefulness of DNA viral load quantification for cytomegalovirus disease monitoring in renal and pancreas/renal transplant recipients.

BACKGROUND: The purpose of this prospective study was to evaluate the usefulness of quantifying DNA-cytomegalovirus (CMV) load for the diagnosis and monitoring of CMV disease among renal and pancreas transplant patients under immunosuppressive drugs. METHODS: A longitudinal study was conducted among 34 consecutive, unselected renal and pancreas/renal transplanted patients in our unit. During the first 3 posttransplant months, weekly monitoring of CMV infection and CMV disease was done, involving the determination of viremia by the shell vial assay, qualitative DNAemia by semi-nested polymerase chain reaction (PCR) and quantitative DNAemia by the hybrid capture system (HCS), a new and original hybridization method (337 samples were collected for each test). Qualitative and quantitative DNAemia results were blinded to physicians and three grades of disease were defined according to CMV related symptom occurrence. RESULTS: PCR was the most sensitive (100%) but the least specific (78%) method for the diagnosis of CMV disease. HCS was specific for CMV genome detection, sensitive and reproducible. Blood DNA levels above 60 pg/ml were predictive of severe or moderate CMV disease (sensitivity, 92%; specificity, 100%). A significant decrease in viral load was observed after ganciclovir administration, and a positive PCR or HCS result at the end of the antiviral treatment was associated with relapse of CMV infection or disease. CONCLUSIONS: It is concluded that quantitative DNAemia detection, with this new commercially available method, can predict disease and may be useful for a rational evaluation of ganciclovir preemptive therapy in such patients.

Adolescent↗

PubMed1997

Successful quantification of cytomegalovirus DNA by competitive PCR and detection with capillary electrophoresis.

Human cytomegalovirus (HCMV) is responsible for severe infections in immunocompromised patients. Viral load has recently been identified as one of the major risk factors for subsequent development of HCMV disease. In this context, we developed a protocol allowing rapid, sensitive and precise quantification of HCMV DNA using competitive PCR run to saturation. Long primers were used for amplification, and internal DNA standard was constructed by PCR, with a primer inducing formation of a loop on the target sequence. The obtained fragment differed from the wild one (142 bp) by 6 bp. Quantitative analysis of PCR-amplified HCMV DNA was carried out using an original system combining capillary gel electrophoresis and u.v. detection. This procedure was evaluated on renal transplant recipients, and the results of quantitative PCR were compared with those of viraemia, qualitative DNAemia and HCMV-related symptoms. High levels of HCMV DNA were associated with HCMV-related symptoms, and in all cases a significant decrease of viral load was observed following DHPG treatment. Competitive PCR with capillary electrophoresis detection appears to provide a sensitive quantification method for HCMV DNA in leukocytes and is easily adaptable to routine laboratory use.

Cytomegalovirus↗

PubMed1997

Development of a method for direct quantification of cytomegalovirus antigenemia by flow cytometry.

Cytomegalovirus (CMV) antigenemia was directly detected in polymorphonuclear leukocytes (PMNLs) from transplant recipients by using flow cytometry (FC). Two fixation and permeabilization methods and seven anti-CMV monoclonal antibodies (MAbs) were evaluated. 1C3, SL20, and NEA-9221 MAbs were more efficacious. The antigenemia detection threshold of FC was 0.05% positive PMNLs, and percentages correlated well with DNA viral load and the appearance of clinical symptoms.

Antibodies, Monoclonal↗

PubMed1996

Anti-CD4 MoAb therapy in kidney transplantation--a pilot study in early prophylaxis of rejection.

B-F5, a mouse IgG1 anti-CD4 MoAb, was used in recipients of a first cadaveric kidney allograft. Eighteen patients received 30 mg/day MoAb with a quadruple sequential therapy. All but one kidney were functioning at 6 months, with a mean serum creatinine of 153 micromol/L. However, 50% of the patients had an acute rejection episode within the first three months, and most of the early episodes (i.e., < 1 month) occurred in patients with low levels of circulating MoAb. The biological analysis showed a strong depleting effect on the CD4+ cell counts, a saturation by the MoAb of the remaining circulating CD4+ cells, and no detectable immunization against B-F5. Although the biological parameters indicate an action of B-F5 in vivo, the clinical data associated with poor MoAb bioavailability suggest the need for an improved pharmacokinetic behavior of the MoAb to determine its use for prophylaxis of early rejection.

Adult↗

PubMed1996

[Economic contribution of mofetil mycofenolate as preventive immunosuppressive treatment after renal transplantation from cadaver].

OBJECTIVES: The economic impact resulting from the clinical consequences of immunosuppressive strategy using mycophenolate mofetil in new renal transplant recipients was conducted considering the viewpoint of the health insurance system. METHODS: The analysis was based on the results of three controlled randomized double-blind clinical trials comparing mycophenolate mofetil with placebo or azathioprine in 1003 out of 1493 included patients respectively. Health care costs associated with each event were determined by 7 French experts in renal transplantation working in six different hospitals. Direct cumulative costs for each strategy were compared. RESULTS: The studies demonstrated a difference in the incidence of acute rejection and treatment failures whatever the cause. The three trials showed that, compared with current strategies, use of mycophynolate mofetil in the immunosuppression protocol generated a 19 to 38% cost reduction during the 6 months after transplantation. Cost reduction resulted from lower incidence of acute rejection and the subsequent nephrectomics and dialysis sessions. The sensitivity analysis on the most important cost factors-cost of hospitalization per day and number of hospitalization days-confirmed strength of the results. CONCLUSION: Use of mycophenolate mofetil in the immunosuppressive prophylaxis protocol after renal transplantation allows a reduction in the direct costs during the 6 months following transplantation.

Adult↗

PubMed1996

Survival on renal replacement therapy in Europe: is there a 'centre effect'?

OBJECTIVE: Survival is the ultimate outcome measure in renal replacement therapy (RRT) and may be used to compare performance among centres. Such comparison, however, is meaningless if the influences of comorbidity, age and early deaths are not considered. We therefore studied survival rates on RRT in seven centres in Europe after taking into account the influence of age, early deaths, primary renal diagnoses, and comorbidity. DESIGN: A retrospective survival analysis was carried out on 1407 patients who commenced RRT in seven centres across five European countries during a 7-year period. Patients were stratified into low-, medium- and high-risk groups based mainly on comorbidity and to a lesser extent on age at commencement of RRT. Kaplan-Meier survival and Cox's proportional hazards model were used to compare survival. RESULTS: Before risk stratification overall 2-year survival across the seven centres ranged from 60.2 to 85.3% (69.3-89.9%) after excluding early deaths) masking a range of survivals of 27.4% for the high-risk group with the worst survival to 100% in the low-risk group with the best survival. After excluding early deaths 2-year survival in the low risk groups (n=622) was greater than 90% in all centres. Multivariate analysis showed that the mortality risk increased four fold from low- to medium- and a further 1.6-fold from medium- to high-risk group. However, despite this adjustment for comorbidity and age there still remained a significant difference in survival among some centres, i.e. a 'centre effect' which ranked the centres. CONCLUSION: Risk stratification diminishes the variance in survival between centres but a centre effect remains despite adjusting for age and comorbidity. Multicentre prospective studies are urgently required to identify the reasons for this apparent centre effect.

Adult↗