Clinicopathologic Study of Sickle Cell-associated Kidney Disease: A Nigerian Experience.

BACKGROUND: Improvements in sickle cell disease (SCD) care have resulted in the survival of many patients into adulthood, although this is accompanied by the increased incidence of end-organ damage, including chronic kidney disease (CKD). OBJECTIVES: This study assessed the prevalence, pattern and predictors of renal dysfunction in SCD patients and investigated the associated renal histopathologic changes. METHODS: We evaluated 105 patients with SCD, for proteinuria, estimated glomerular filtration rate (eGFR), and tubular dysfunction. Renal biopsy was conducted on 22 patients who qualified. Data were analysed using SPSS package version 23. RESULTS: Thirty-seven (35.2%) of the 105 patients had CKD, as defined by an eGFR of 60 ml/min/1.73 m2 and/or proteinuria. The fractional excretion of potassium (FEK) was elevated in all patients, whereas the fractional excretion of sodium (FENa) was elevated in 98.1%. Glomerular filtration rate was negatively correlated with irreversible percentage sickle cell count (r = -0.616, P = 0.0001), FEK (r = -0.448, P = 0.0001) and FENa (r = -0.336, P = 0.004). Age, irreversible percentage sickle cell count, haemoglobin levels and FENa were the major predictors of CKD. The histological pattern in the 22 patients who had biopsies was consistent with mesangioproliferative glomerulonephritis 11 (50%), minimal change disease 6 (27.3%), focal segmental glomerulosclerosis 3 (13.6%) and interstitial nephritis 2 (9.1%). CONCLUSIONS: CKD was prevalent in SCD patients, and it was characterised by tubular dysfunction and mesangioproliferative glomerulonephritis. The main predictors of CKD were increased age, severity of vaso-occlusive crisis, worsening anaemia and tubular dysfunction.

Histopathological pattern of primary bone tumours and tumour-like lesions in Ile-Ife, Nigeria.

INTRODUCTION: Bone tumours are relatively rare in comparison with neoplasms in other parts of the body. Previous studies have noted higher frequencies of these tumours in young adults with potentially devastating consequences. METHODS: This study aimed to demonstrate the histopathological pattern of primary bone tumours and tumour-like lesions in Ile-Ife, Nigeria with emphasis on relative frequencies and distribution according to age, sex and anatomical location. A 13 year (1991-2003) retrospective study was carried out on 100 cases of primary bone tumours and tumour-like lesions. Records were retrieved from the surgical registers of the Histopathology Department, Qbafemi Awolowo University Teaching Hospitals Complex, Ile-Ife. Original histopathological slides were retrieved for examination and when they were unavailable, the paraffin blocks were searched out and new slides were made. RESULTS: A total of 100 cases met the inclusion criteria for this study accounting for 1.55% of the 6,464 cases of all neoplasms seen within this period. Of the 100 cases, 50 were malignant (50%), 28 were benign (28%) and 22 had tumour-like lesions (22%). The male to female ratio was 1.3:1 and the most common benign and malignant tumours were osteochondroma and osteosarcoma respectively. The femur was the most frequently involved bone in primary malignant lesions (24%) followed by the pelvis and the maxilla (14% each). CONCLUSION: The age, sex and morphological distribution of benign and malignant bone tumours is similar to earlier reports in other African and international journals. Tumour-like lesions occur more frequently in females than in males. The femur is the most favourable site for malignant primary bone tumours and the jaw bones for tumour-like lesions.

Bellini duct carcinoma of the kidney masquerading as an iliac bone tumour in an adult Nigerian.

Bellini Duct Carcinoma (BDC) of the Kidney is a rare type of Renal Cell Carcinoma. It usually presents with features of local advancement or metastasis and rarely diagnosed incidentally. We present a case report of a young man who was found to have BDC of the Right Kidney following presentation with an iliac bone tumour. A 40 year old man presented to the Orthopaedic outpatient clinic on account of right sided pelvic pain and limping following a trivial fall at home. There was no antecedent history of loin pain, loin mass or haematuria. On evaluation, he was found to have a huge right iliac bone tumour invading the contiguous muscles. An incidental hypodense central ipsilateral renal mass with enlarged peri-hilar lymph nodes were found. He subsequently had right radical nephrectomy via a right sub-coastal approach and wide local excision of the Iliac bone tumour in two separate procedures. The resection margins were negative for tumour cells. Histology of the resected specimens were consistent with a metastatic right BDC of the kidney. He had a smooth post-operative recovery. One third of BDC of the kidney presents with metastasis. A high index of suspicion is required in order to diagnose BDC following such unusual presentations.

Signet ring lymphoma: The import of immunohistochemistry in resolving diagnostic dilemmas.

Signet ring cell lymphomas are a rare subtype of non Hodgkin lymphoma characterised by malignant lymphoid cells with cytoplasmic inclusions that displace the nucleus and imparts a "signet ring" appearance. This poses a diagnostic challenge as it can be mistaken for an adenocarcinoma or any other epithelial malignancy. A 54yr old male presented with a 6month history of generalised lymphadenopathy. Examination of excision biopsy of the lymph nodes show effacement of architecture by sheets neoplastic cells with abundant cytoplasm distended by eosinophilic amorphous substances. Immunohistochemistry with a panel of three monoclonal antibodies [LCA, CD20, and CD3] confirmed these cells to be of lymphoid origin.

Lymphomas in Ile-Ife, Nigeria: Immunohistochemical Characterization and Detection of Epstein-Barr virus Encoded RNA.

BACKGROUND: The proper histopathological characterization of malignant lymphomas requires the use of immunohistochemistry along with other molecular pathology techniques. MATERIALS AND METHODS: Malignant lymphomas histologically diagnosed in our hospital were reclassified according to the WHO scheme using immunohistochemistry while in-situ hybridization was performed for the detection of Epstein-Barr virus encoded RNA. RESULTS: There were 83 cases of lymphoma. The male to female ratio was 1.9:1 while the overall mean age was 41.7 years. Non-Hodgkin lymphomas (NHL) constituted about 79.5% of cases. The majority of cases (98.8%) were B-cell lymphomas. Nine subtypes of lymphomas were identified with diffuse large B-cell lymphomas (56.4% of which were of the germinal centre type) constituting the largest group (47.0%). Intermediate and high grade subtypes were more common. The majority of cases (72.3%) were nodal lymphomas with cervical lymph node being the commonest site (48.2%). Only classical Hodgkin lymphoma (HL) (20.5%) was seen of which the mixed cellularity subtype was the most common. Epstein Barr virus (EBV) encoded ribonucleic acid was detected in 7 cases (8.4%) including 4 cases of HL, 2 cases of Burkitt lymphoma and the only case of plasmablastic lymphoma. About five cases were reclassified as non-lymphoid malignant lesions. CONCLUSION: Immunohistochemistry is vital to the proper classification of lymphomas even in a resource poor environment. Although nine subtypes of lymphomas were identified, diffuse large B-cell lymphomas formed the largest single group. Epstein-Barr virus probably plays an important role in lymphomatogenesis in this environment. A larger multicentre study is required to prove this.

Neo-adjuvant capecitabine chemotherapy in women with newly diagnosed locally advanced breast cancer in a resource-poor setting (Nigeria): efficacy and safety in a phase II feasibility study.

The majority of clinical trials of neo-adjuvant therapy for breast cancer have been conducted in resource-rich countries. We chose Nigeria, a resource-poor country, as the major site for a phase II feasibility open-label multicenter clinical trial designed to evaluate the efficacy, safety, and tolerability of neo-adjuvant capecitabine in locally advanced breast cancer (LABC). Planned treatment consisted of 24 weeks of capecitabine at a dose of 1,000 mg/m(2) twice daily (2,000 mg/m(2) total per day). The primary endpoints were overall, partial, complete clinical response rate (OCR, PCR, CCR) and complete pathologic response (cPR). A total of 16 patients were recruited from August 2007 to April 2010. The study was terminated early as a result of slow accrual. After the first three cycles of therapy, PCR were seen in five of 16 patients (31%; 95% CI 11-59%). Of the remaining 11 patients, eight had no response (NR) or stable disease (SD), and three had progressive disease (PD). Seven patients proceeded with further therapy of which had SD. OCR at the end of eight cycles was 44% (95% CI 20-70%). Clinical response and radiologic response by ultrasonomammography were highly concordant (spearman correlation 0.70). The most common adverse effect was Grade 1 hand-foot syndrome, which was seen in 75% of patients. Despite several limitations, we successfully carried out this phase II feasibility study of neo-adjuvant capecitabine for LABC in Nigeria. Capecitabine monotherapy showed good overall response rates with minimal toxicity and further studies are warranted.

Childhood idiopathic steroid resistant nephrotic syndrome in Southwestern Nigeria.

Clinical charts of 23 Nigerian children diagnosed with idiopathic steroid resistant nephrotic syndrome (iSRNS) between January 2001 and December 2007 were retrospectively reviewed to determine their clinicopathologic characteristics and outcome. iSRNS (54.8%) was primary in 19 patients (83%) and secondary in four (17%). The mean age at diagnosis was 8.3 ± 3.5 years (2.1-13 years). Histopathology revealed membranoproliferative glomerulonephritis (MPGN) in 43.5%, focal and segmental glomerulosclerosis (FSGS) in 39.1% and mesangial proliferative glomerulonephritis in 8.7% of the patients while minimal change disease (MCD) and membranous nephropathy accounted for 4.35% each. Routine treatment protocol comprised pulse intravenous (i.v.) cylophosphamide infusion and i.v. dexamethasone lisinopril or spironolactone. Cumulative Complete Remission (CR) rate was 57.12%. The overall median time to CR from start of steroid sparing agents in 12/21 treated patients was 4.5 weeks. CR was better achieved in MPGN than FSGS (P = 0.0186). Five patients had eight relapses with the overall median relapse-free duration being four months. Cumulative renal survival at 36 months was 41.8%. The median follow-up duration was eight months. Our study revealed that there was a high prevalence of iSRNS and preponderance of non-MCD lesions, with MPGN and FSGS being the major morphologic lesions. The outcome with steroid and cyclophosphamide-based treatment for iSRNS was further enhanced with addition of either lisinopril or spironolactone.

Quartan malaria-associated childhood nephrotic syndrome: now a rare clinical entity in malaria endemic Nigeria.

BACKGROUND: The study determined (i) whether or not quartan malaria nephropathy (QMN) is still a major cause of childhood nephrotic syndrome (CNS) in Nigeria, (ii) secondary causes other than QMN and their associated glomerular pathology and (iii) renal and patient outcome. METHODS: The study was a prospective non-randomized study of consecutive cases of secondary CNS. Patients with idiopathic CNS were excluded. RESULTS: Twenty-four of 78 (30.8%) CNS cases were of secondary aetiology. Overall mean ages at onset of secondary CNS aetiology and CNS onset were 8.97 +/- 3.59 (1-15.3) and 9.95 +/- 3.15 (5-15.3) years, respectively. Male (14)/female (10) ratio was 1.4. Secondary causes comprised systemic lupus erythematosus (SLE, 37.5%), sickle cell anaemia (SCA, 16.7%), hepatitis B virus (HBV, 16.7%) infection, Churg-Strauss syndrome (12.6%), SLE/human immunodeficiency virus infection (4.2%), rhabdomyosarcoma (4.2%), bee stings (4.2%) and Addison's disease (4.2%). The overall cumulative complete remission (CR) rate was 88.0%. Remission was sustained in 11 of 16 (68.8%) CR patients, while one patient (6.25%) relapsed; the remaining four patients (24.95%) were yet to attain sustained remission. Median relapse-free period was 10.5 (0.75-25) months. Cumulative renal survival was 75.2% at 3 years. Three patients were lost to follow-up, while two died. Overall cumulative patient survival probability at 36 months was 90.8%. All patients were followed for a median period of 12.5 (0.11-36.0) months. CONCLUSION: Overall outcome of CNS has improved significantly compared to the 1960s and 1970s when the poor outcome of QMN was the predominant glomerular lesion in Nigeria. While quartan malaria-associated nephrotic syndrome has become a rare clinical entity, SLE, SCA and HBV infection have become the major secondary aetiologies of CNS in Nigeria.

Incidental carcinoma of the prostate gland presenting with initial manifestation of disseminated intravascular coagulopathy (dic) in a middle aged man: a case report.

BACKGROUND: Incidental carcinoma of the prostate gland is a common clinical problem among elderly males but this malignancy presenting initially with features of Disseminated Intravascular Coagulopathy (DIC) in the African blacks is rare. Disseminateded intravascular coagulathy is the most frequent coagulation disorder in patients with prostate cancer, However DIC as a first manifestation of prostate cancer is unusual. CASE REPORT: This paper reports a case of a 56 year old Nigerian civil servant who presented initially with clinical features of DIC characterised by bleeding from multilple orifices but was subsequently diagnosed at autopsy to be infiltrating adenocarcinoma of the prostate. CONCLUSION: This rare case of DIC should be considered especially in elderly men when no other cause can be found for coagulopathy.

Focal segmental glomerulosclerosis and nephrotic syndrome in a child with embryonal rhabdomyosarcoma.

A case of nephrotic syndrome (NS) and acute renal failure (ARF) associated with embryonal rhabdomyosarcoma (RMS) in a 10-year-old boy is reported. Ultrasound revealed irregular, echogenic, circumferential urinary bladder base mass, bilateral hydroureter and hydronephrosis. Histopathology of percutaneous renal and urethrocystoscopic biopsy specimens, respectively, revealed focal segmental glomerulosclerosis (FSGS) and embryonal RMS. Tumour remission was induced with pulse doses of intravenous vincristine, cyclophosphamide, methotrexate and actinomycin D over a 15-month period. He has been followed-up for 28 months and has maintained a drug-free tumour and proteinuria remission for 1 year. While some malignancies have been reported in association with NS, its occurrence in association with RMS is quite exceptional. We conclude that RMS may be associated with FSGS and NS. Effective treatment of the RMS was associated with sustained remission of the nephrotic proteinuria.

Renal disease in HIV-seropositive patients in Nigeria: an assessment of prevalence, clinical features and risk factors.

In order to determine the pattern of renal disease and risk factors for renal disease in HIV-infected Nigerians, we studied 400 consecutive HIV/AIDS patients (210 males, 190 females) aged between 18 and 65 years (mean +/- SD; 34.6 +/- 9.4 years), and examined renal disease factors attributable to the infection. Diagnosis of renal disease was based on the consistent presence of at least 1+ albuminuria and/or elevated serum creatinine (>132 micromol/l) as well as the absence of other identifiable causes of chronic kidney disease (CKD). We determined socio-demography and clinical findings, as well as full laboratory work-ups including haemogram, CD4+ cell count, serum electrolytes, urea, creatinine, protein, cholesterol and urine analysis. Renal biopsies were taken in 10 patients who had moderate to massive proteinuria and had consented to the procedure. Finally, we compared HIV/AIDS cases with and without renal disease to determine the risk factors for nephropathy. We observed a high prevalence of renal disease (proteinuria and/or elevated serum creatinine), which was present in 152 (38%) of the patients. This subgroup included 74 males and 78 females with a M:F ratio of 1:1. The mean age (+/-SD) was 35.8 (+/-10.01) years. Systolic and/or diastolic hypertension was seen in 13.2% of these patients while the mean (+/- SD) body mass index (BMI) and packed cell volume (PCV) were 18.5 (+/-3.1) kg/m(2) and 25.26 (+/-6.81)%, respectively. The mean (+/-SD) CD4+ count was 246.49 (+/-192.8) cells/microl, while the mean (+/-SD) serum creatinine and 24-h urine protein excretion rates were 210.11 (+/-337.8) micromol/l and 2.57 (+/- 2.42) g/day, respectively. In subjects with and without nephropathy, there were significant differences in age, BMI, serum cholesterol, serum albumin and CD4+ counts, suggesting that these parameters may be risk factors for nephropathy. Histology revealed mainly focal glomerulosclerosis (FGS) with glomerular collapse. We conclude that the prevalence of proteinuria in HIV-seropositive patients is high in Nigeria. Such subjects show an equal male:female distribution, and glomerular histology revealed that a majority of biopsied patients had the collapsing FSGS variant. The risk factors for renal disease included severity of the HIV infection (inferred from the generally low CD4+ count), anaemia, malnutrition and increasing age.

Lymphoreticular diseases in Nigerians.

BACKGROUND: The lymphoreticular system plays a major role in both the innate and adaptive immune responses. This study reviews retrospectively cases of lymphoreticular diseases seen at a tertiary institution in Nigeria. MATERIALS AND METHODS: This is a retrospective study in which biopsies from the bone marrow, spleen, lymph nodes and extranodal lymphoid tissues reported within a period of 16 years were reviewed with respect to age, sex and pathological diagnosis. Statistical analysis was performed for differences in proportion using Chi square by SPSS version 12. RESULTS: Nine hundred and forty four cases comprising 559 biopsies from lymph nodes and extranodal lymphoid tissues, 272 bone marrow biopsies and 113 spleen biopsies were studied. Non Hodgkin's lymphoma (NHL) and tuberculosis were the most common lesions in lymph nodes and extranodal lymphoid tissues. The axillary and cervical nodes accounted for most cases of metastasis. Breast cancer accounted for the majority of metastasis to lymph nodes. The most common pathological changes in bone marrow were NHL and reactive hyperplasia. Patients with chronic lymphocytic leukaemia (CLL) had the highest mean age, which was significantly higher than in those with NHL (p=.001, 95% confidence interval -27.91 to -7.76). The most common finding in the spleen was splenic rupture and haemoperitoneum from road traffic accident. CONCLUSION: NHL and tuberculosis should be high on the list of differential diagnosis of lymphadenopathy in Nigerians. Whereas trauma from RTA was the major reason for splenectomy in Nigerians, in the elderly splenic biopsy would likely show CLL.

Clinicopathology of childhood-onset renal systemic lupus erythematosus.

AIMS: To determine the clinicolaboratory renal manifestations; glomerular, extra-glomerular histopathologic lesions; renal tubular dysfunction (RTD) frequency and outcome of a short-term renal follow up in Nigerian children with systemic lupus erythematosus (SLE). METHODS: A non-randomized prospective study of consecutive cases of childhood-onset SLE with nephropathy was conducted. Baseline/follow-up clinicolaboratory data were collected. Each patient was followed up for 12 months. RESULTS: Seven of the 11 children studied were girls. The median age at diagnosis was 11.0 years. Median diagnosis time interval (1.9 years) and median time of renal disease onset (1.0 year) were similar. Hypertension, nephrotic syndrome and acute renal failure (ARF) occurred in 45.5%, 54.5% and 63.7% of the patients, respectively. The glomerular lesions were non-proliferative lupus nephritis (LN) in 9.0% (class II LN); focal (class III LN) and diffuse (class IV LN) proliferative LN (PLN) in 27.0% and 64.0%, respectively. Tubulointerstitial nephritis (TIN, 91.0%) and RTD (64.0%) were common. ARF (P = 0.033) and RTD (P = 0.015) were significantly associated with severe TIN. Complete renal remission rate at end-point was 71.4%. Relapse and renal survival rates were 14.3% and 86.0%, respectively. RTD was persistent in 43.0%. CONCLUSION: Renal function disorders, diffuse PLN and extra-glomerular lesions were frequent. Significant association of ARF and RTD with severe TIN in this series suggests the need for early renal tubular function (RTF) assessment in our SLE patients. Deranged RTF may be marker of severe TIN in SLE warranting early confirmatory renal biopsy and aggressive interventional treatment.

Hypertension, erythrocyturia and proteinuria in childhood non-Hodgkin's lymphoma.

AIM: The objectives were to determine the prevalence and outcome of hypertension, significant microerythrocyturia and proteinuria among children with acute renal failure (ARF) due to Burkitt-type non-Hodgkin's lymphoma (BNHL). METHODS: A retrospective analysis of clinical and laboratory data of children with BNHL/ARF was undertaken. RESULTS: Nine of 23 (39.13%) BHNL/ARF children aged 5-14 years were found to have significant microerythrocyturia and proteinuria as urinary markers of glomerulonephritis (GN). Eight of nine were hypertensive with hypertensive encephalopathy (HTE) in three, and congestive heart failure (CCF)/pulmonary oedema in six. Three of nine patients (33.3%) died from these complications; two from CCF and one from a combination of CCF and HTE. A fourth death was due to uraemia. Treatments with cytotoxic drugs and anti-tumour lysis syndrome therapy resulted in normotension, improved clinical outcome and normalisation of laboratory features of ARF and GN in all five (55.6%) survivors. CONCLUSION: We conclude that all the children with BNHL/ARF had enlarged kidneys and evidence of glomerular disease. The mechanism of the glomerular disease is unclear. It is associated with a high mortality rate.

Autopsy diagnosis of endemic burkitt lymphoma as the primary etiology of acute renal failure in children.

Two cases of Burkitt lymphoma are reported who presented atypically with acute renal failure and significant proteinuria as initial features of the lymphoma. The cases underscore the need for high index of suspicion for Burkitt lymphoma in any child with rapidly enlarging kidneys and acute renal failure of obscured origin in parts of the world where Burkitt lymphoma is endemic.

Orofacial non-Hodgkins lymphoma in Nigerians.

PURPOSE: In this study, we sought to determine the occurrence of primary non-Hodgkins lymphoma (NHL) in the oral and maxillofacial region among Nigerians. PATIENTS AND METHODS: We retrospectively studied hospital records that included radiographs of all patients with a histopathologically confirmed diagnosis of NHL in the Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria, between January 1992 and December 1997. Data were expressed as mean +/- SD or number (%). RESULTS: During the study period, 66 cases of NHL were recorded. Seventeen patients had concomitant extranodal lymphomas involving the gastrointestinal tract, nasopharynx, skin, lungs, kidney, and thyroid, in descending order. Three patients (4.5%) presented primarily with extranodal oral and maxillofacial disease. The ages of these patients ranged from 18 to 50 years (mean +/- SD, 32.3 +/- 16.3 years; median, 29 years). Within the same period, there were 121 cases of Burkitts lymphoma. The onset of lesions varied from 6 to 20 weeks. Two patients had intermediate-grade lesions; the remainder had low-grade lesions. Two presented with stage II disease, and the remainder were stage I. All of the patients had chemotherapy with remission of their lesions but were followed up to 6 months. Most of them did not complete the treatment cycles due to financial and social constraints. CONCLUSIONS: The rarity of primary NHL of oral and maxillofacial region has been aptly shown in this study. The need for the establishment of an effective oncology policy with the active collaboration of voluntary agencies is emphasized. This would ensure ready availability of the required chemotherapeutic agents and hospital care at affordable costs.

Pediatric acute renal failure in southwestern Nigeria.

BACKGROUND: Acute renal failure (ARF) was investigated to determine the prevalence of ARF clinical types, etiology, comorbidities, and outcome in Nigerian children. METHODS: Consecutive cases of ARF admitted from March, 1994 through February, 2003 were prospectively studied. Information were obtained concerning the following: age, gender, body surface area, early (within 48 hours of onset of ARF) or late (>48 hours of onset of ARF) presentation, admission duration, etiology, comorbidities, urine volume/day, dialysis need, reasons for considering dialysis, laboratory investigations, and outcome in each patient. Histopathologic reports of percutaneous renal and surgical biopsies, as well as autopsy specimens, were reviewed. RESULTS: There were 78 boys and 45 girls (M:F, 1.73:1); mean age was 6.28 +/- 4.0 years. A portion of patients presented early (46.3%), while 53.7% presented late. Oliguric (63.41%), anuric (20.33%), and nonoliguric (16.26%) ARF were the clinical types seen. Dialysis requirement was significantly higher in oliguric (P < 0.005) and anuric (P < 0.005) than nonoliguric ARF. Primary and secondary etiologies accounted for 29% and 71% of ARF cases, respectively. Renal Burkitt's lymphoma (47.2%), glomerulonephritis (27.8%), nephrotic syndrome (16.7%), hemolytic uremic syndrome (5.5%), and acute tubulointerstitial nephritis (2.8%) were primary etiologies. Plasmodium falciparum malaria (42.53%), septicemia (28.73%), hypovolemia (11.49%), and obstructive uropathy (8.05%) were major secondary etiologies. Financial constraints on the part of parents of patients, as well as inadequate and/or lack of dialysis equipment, were major inhibitions to effective management of the patients; in fact, 6 patients took voluntary discharge due to inability to afford the cost of treatment. Mortality risk factors were late presentation [odds ratio (OR) 3.5, P < 0.001], dialysis eligibility (OR 3.8, P < 0.001), nondialysis (OR 23.1, P= 0.00004), primary etiology (OR 2.6, P < 0.025), and presence of > or =2 comorbidities (OR 2.9, P < 0.025); overall mortality rate was 46.2%. CONCLUSION: These results show that many of the causes of ARF in our patients are preventable; it should be possible to reduce morbidity due to ARF through purposive preventive measures.