Mitosin and pHH3 predict poorer survival in astrocytomas WHO grades II and III.

AIMS: The limitations of the current WHO classification of astrocytomas call for a sustained effort to improve diagnostic and prognostic accuracy. The relationship between tumour growth and clinical outcome suggests that proliferative activity should be examined. The objective of this study was to evaluate the diagnostic and prognostic value of the proliferation markers mitosin and phosphohistone H3 (pHH3) in infiltrative astrocytomas WHO grades II and III and compare the findings with mitotic count and Ki-67/MiB-1 immunostaining. METHODS: Fifty-nine and thirty-three infiltrative astrocytomas WHO grades II and III, respectively, were immunostained with the proliferation markers mitosin and pHH3 using standard immunohistochemical procedures. The expression was quantified as a proliferative index (PI) and statistically evaluated with Spearman's rank correlation test, Wilcoxon-Mann-Whitney U test, and univariable and multivariable COX regression survival analyses. RESULTS: Significant positive correlations were found between these proliferation markers. The number of mitoses, pHH3 mitotic figures (MFs), the Ki-67/MiB-1 PI and the mitosin PI were greater in WHOgrade III anaplastic astrocytomas compared to WHO grade II diffuse astrocytomas, while pHH3 PI only showed a trend. All proliferation markers were associated with poorer prognosis, but mitotic count was not. Ki-67/MiB-1, mitosin and pHH3 MF achieved statistical significance in the univariable analyses of both time to relapse (TTR) and overall survival (OS). Only mitosin remained significant in both multivariable analyses. pHH3 was significant in the multivariable analysis of OS but not of TTR. Clinical factors including age, extent of surgical resection and WHO performance status were also significantly correlated with survival. CONCLUSIONS: In conclusion, mitosin and pHH3 immunostaining have prognostic and diagnostic value in the clinical assessment of patients with infiltrative astrocytomas. The inclusion of proliferation markers in a layered diagnosis should be considered in the upcoming revision of the WHO classification system.

Endothelin-1 synthesis and endothelin B receptor expression in human coronary artery smooth muscle cells and monocyte-derived macrophages is up-regulated by low density lipoproteins.

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide exerting its effects predominantly by paracrine and autocrine mechanisms. ET-1 acts as a mitogen and co-mitogen on vascular smooth muscle cells, and accumulating evidence suggests that ET-1 is involved in the pathogenesis of atherosclerosis. Deposition of low density lipoproteins (LDL) in the vessel wall is known to play a crucial role in the development of atherosclerotic lesions. In the present study, we have investigated the effect of native LDL (nLDL) and oxidatively modified LDL (oxLDL) on ET-1 synthesis and endothelin receptor expression in cultured human coronary artery smooth muscle cells and human monocyte-derived macrophages. Native LDL and oxLDL induced a significant stimulation of ET-1 release and ET-1 mRNA expression in human coronary artery smooth muscle cells and monocyte-derived macrophages. Antibodies against the scavenger receptor CD36 significantly reduced the oxLDL-induced stimulation of ET-1 synthesis. The antioxidants trolox and probucol did not significantly inhibit the LDL-induced rise of ET-1 release. Endothelin B receptor expression was up-regulated in both cell types after incubation with nLDL and oxLDL. In coronary smooth muscle cells, endothelin A receptor expression was slightly increased by LDL, whereas endothelin A receptor was not detectable in monocyte-derived macrophages. Coronary artery smooth muscle cells secreted a more than 150-fold higher amount of immunoreactive ET-1 into the cell culture medium than monocyte-derived macrophages. In summary, the present data, demonstrating a LDL-induced up-regulation of the endothelin system in coronary smooth muscle cells and in monocyte-derived macrophages, provide further support for a pathophysiological role of endothelin in coronary atherosclerosis and suggest that ET-1 might be involved in mediating the atherogenic effects of LDL.

Characterization of modified low density lipoprotein subfractions by capillary isotachophoresis.

Oxidative modification of low density lipoproteins (LDLs) is an important pathogenetic factor in atherosclerosis. The various steps in oxidative modifications of LDL can be monitored using different methodologies with varying degrees of complexity. In this study, we propose capillary isotachophoresis (CITP) as a suitable tool to detect and measure the degree of oxidation of LDL. LDL was isolated from pooled plasma of healthy volunteers by sequential ultracentrifugation, and oxidation was performed in vitro as well as in cell culture experiments. Native LDL and oxidatively modified LDL were characterized by apo B-100 fluorescence and conjugated diene formation. Samples were separated by CITP combined with sudan black B staining. To underline the inherent advantages of this approach, CITP was compared with classical lipoprotein electrophoresis using agarose gel. We demonstrate the CITP method to be highly sensitive, as changes in peak area of the separated LDL subfractions were detected after only 2 h of oxidation. The leading LDL peaks increased, while the terminating LDL peaks decreased in parallel throughout the duration of oxidation. The LDL samples, oxidized for 4-24 h, also exhibited an increased migration velocity of the fractions. In summary, we present the first study investigating LDL-subfractions separated by CITP and the alterations of these LDL-subfractions after gradual in vitro oxidation and after oxidative modification by monocyte-derived macrophages and vascular smooth muscle cells.

Hepatocyte growth factor is upregulated by low-density lipoproteins and inhibits endothelin-1 release.

Low-density lipoproteins (LDL) are known to cause endothelial injury and to promote the development of atherosclerotic lesions. This study demonstrates a significant concentration-dependent stimulatory effect of LDL on hepatocyte growth factor (HGF) synthesis (maximum release: 423 +/- 16% of control) and HGF receptor mRNA expression in cultured human coronary artery endothelial cells (HCAEC). HGF is a potent mitogen for endothelial cells but does not affect smooth muscle cell proliferation. In contrast, endothelin-1 (ET-1) acts as a mitogen on vascular smooth muscle cells and seems to be upregulated in coronary atherosclerosis. In this study, the basal ET-1 synthesis in HCAEC was concentration-dependently reduced by HGF (minimum: 54 +/- 3% of control). This inhibitory effect seems to be mediated via the tyrosine kinase activity of the HGF receptor c-met, since it was antagonized by the tyrosine kinase inhibitor lavendustin A. In addition, HGF also significantly reduced the LDL-stimulated ET-1 release. The LDL-induced upregulation of HGF synthesis in HCAEC and the inhibitory effect of HGF on ET-1 synthesis suggest a protective role of HGF in coronary atherosclerosis.

Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy.

As cytokines and 1,25-dihydroxyvitamin D [1,25-(OH)2D] appear to have an important role in bone homeostasis, we examined the possibility that human immunodeficiency virus (HIV)-infected patients, characterized by enhanced levels of proinflammatory cytokines and 1,25-(OH)2D deficiency, have disturbed bone metabolism by analyzing serum markers of bone formation (osteocalcin) and bone resorption (C-telopeptide) in 73 HIV-infected patients. HIV-infected patients with advanced clinical and immunological disease and high viral load were characterized by increased C-telopeptide and particularly by markedly depressed osteocalcin levels. HIV-infected patients had enhanced activation of the TNF system. Serum concentrations of p55 and p75-TNF receptors were negatively correlated with osteocalcin, and p75-TNF receptor was positively correlated with C-telopeptide. HIV-infected patients with advanced disease also had decreased serum concentrations of 1,25-(OH)2D, but this parameter was not correlated with osteocalcin or C-telopeptide. During 24 months with highly active antiretroviral therapy there was a marked rise in serum osteolcalcin levels together with a profound fall in viral load and TNF components and a marked rise in CD4+ T cell counts. Also, there was a shift from no correlation to a significant correlation between osteocalcin and C-telopeptide levels during such therapy. The present study suggests disturbed bone formation and resorption during HIV infection. Our findings indicating synchronization of bone remodeling during highly active antiretroviral therapy may represent a previously unrecognized beneficial effect of such therapy and expand our knowledge of the interactions between cytokines and bone in the bone-remodeling process.

Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis.

The serum level of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D], the biologically most potent metabolite of vitamin D, is tightly regulated within narrow limits in human healthy adults. 1,25-(OH)2D deficiency is rare and is associated with disturbances in calcium and bone metabolism. We have previously reported a marked decrease in serum levels of 1,25-(OH)2D in human immunodeficiency virus (HIV)-infected patients. The present study was designed to further examine the causes and consequences of severe 1,25-(OH)2D deficiency in these patients. The design was a prospective cohort study. Fifty-four HIV-infected patients clinically classified according to the revised criteria from Centers for Disease Control and Prevention and healthy controls were studied. Parameters related to vitamin D and calcium metabolism as well as immunological and nutritional status were determined. Twenty-nine of the patients (54%) had serum levels of 1,25-(OH)2D below the lower reference limit, and 18 of these had undetectable levels. In contrast, HIV-infected patients had normal serum levels of 25-hydroxyvitamin D and vitamin D-binding protein. HIV-infected patients as a group had modestly depressed serum calcium and PTH levels. There were, however, no correlations between these parameters and serum levels of 1,25-(OH)2D. There were no differences in serum calcium or PTH levels or nutritional status when patients with severe 1,25-(OH)2D deficiency were compared to other patients, but patients with undetectable 1,25-(OH)2D had significantly elevated serum phosphate levels. Furthermore, patients with undetectable 1,25-(OH)2D levels were characterized by advanced clinical HIV infection, low CD4+ lymphocyte counts, and high serum levels of tumor necrosis factor-alpha (TNFalpha). We conclude that inadequate 1alpha-hydroxylation of 25-hydroxyvitamin D seems to be the most likely cause of 1,25-(OH)2D deficiency in HIV-infected patients, possibly induced by an inhibitory effect of TNFalpha. The low 1,25-(OH)2D and high TNFalpha levels observed may impair the immune response in HIV-infected patients both independently and in combination and may represent an important feature of the pathogenesis of HIV-related immunodeficiency. Markedly depressed 1,25-(OH)2D serum levels are also present in certain other disorders characterized by immunological hyperactivity. Thus, the findings in the present study may not only represent a previously unrecognized immune-mediated mechanism for induction of 1,25-(OH)2D deficiency in human disease, but may also reflect the importance of adequate serum levels of 1,25-(OH)2D for satisfactory performance of the immune system in man.

Different effect of 1,25-dihydroxyvitamin D3 on replication of Mycobacterium avium in monocyte-derived macrophages from human immunodeficiency virus-infected subjects and healthy controls.

Mycobacterium avium complex (MAC) is the most common cause of disseminated bacterial infection in patients with acquired immune deficiency syndrome (AIDS) and macrophage dysfunction is important both in the pathogenesis of AIDS- and MAC-infection. 1,25-Dihydroxyvitamin D3 (1,25D), the active metabolite of vitamin D, has a number of effects on cell types of the immune system including monocytes/macrophages. The present study was designed to investigate whether 1,25D supplementation in vitro could modulate MAC replication in macrophages from HIV-infected patients. It was therefore of particular interest to examine whether the effect of 1,25D differs between cells from HIV-infected patients and healthy control subjects. After 3 and 7 days of infection, 1,25D supplementation increased numbers of bacteria in cells from control subjects. In contrast, there was no change or even a decrease in numbers of bacteria in cells from HIV-infected patients. These findings suggest that HIV infection may significantly modulate the macrophage response to 1,25D stimulation, and that 1,25D may have inhibitory effects on MAC replication in macrophages from HIV-infected patients.

Enhanced interleukin-10 production in response to Mycobacterium avium products in mononuclear cells from patients with human immunodeficiency virus infection.

Patients with advanced human immunodeficiency virus (HIV) infection are susceptible to infections with Mycobacterium avium complex (MAC). Interleukin (IL)-10 may impair immunity to MAC; therefore, the effect of different MAC preparations on IL-10 production was examined in mononuclear cell cultures from HIV-infected patients. IL-10 levels in cultures for 26 patients were higher than those in 20 control cultures. The highest IL-10 levels were found in cultures from patients with the most advanced HIV disease. Monocytes were the major IL-10 producers, while little IL-10 could be attributed to Th2 lymphocytes. Cultures for patients produced reduced levels of tumor necrosis factor-alpha and normal levels of IL-12; the production of these cytokines increased after neutralization of IL-10. Circulating IL-10 was higher in HIV-infected patients than in controls, with the highest levels in the AIDS group. Elevated monocyte/macrophage-derived IL-10 production may contribute to the high susceptibility to MAC infection seen in patients with advanced HIV disease.

Persistent activation of the tumor necrosis factor system in a subgroup of patients with common variable immunodeficiency--possible immunologic and clinical consequences.

In patients with common variable immunodeficiency (CVI), we have previously defined a subgroup of patients (CVIHyper) characterized by decreased numbers of CD4+ lymphocytes in peripheral blood, splenomegaly, and persistent immune activation in vivo, particularly of monocytes/macrophages. To further characterize this hyperactivity, parameters of activation of the tumor necrosis factor (TNF) system (TNF alpha and soluble TNF receptors [sTNFRs]) were measured in 24 patients with CVI and 20 healthy controls. Patients with CVI had significantly higher serum levels of TNF alpha and both types of sTNFRs, with the highest levels in the CVIHyper subgroup. In vitro, peripheral blood mononuclear cells (PBMC) and purified monocytes from CVIHyper patients spontaneously released significantly higher levels, and, after lipopolysaccharide (LPS) stimulation, significantly lower levels of TNF alpha and soluble p75-TNFR than cells from both other CVI patients and healthy controls. CVIHyper patients also had significantly higher TNF alpha:sTNFRs ratios in both serum and in unstimulated PMBC supernatants. The present study demonstrates persistent in vivo activation of the TNF system in CVI, particularly in the CVIHyper subgroup. This activation may contribute to the pathogenesis of both clinical and immunologic manifestations in CVI.

Disseminated Mycobacterium avium complex infection in AIDS: immunopathogenic significance of an activated tumor necrosis factor system and depressed serum levels of 1,25 dihydroxyvitamin D.

Disseminated Mycobacterium avium complex (MAC) infection is associated with considerable morbidity and mortality in patients with AIDS. Because both tumor necrosis factor-alpha (TNF-alpha) and 1,25-dihydroxyvitamin D3 (1,25D) may be involved in the normal control of MAC infection, these parameters were studied in AIDS patients with disseminated MAC infection. Of 53 AIDS patients studied, 24 had no clinical events, 11 had disseminated MAC infection, and 18 had other clinical events. Patients with disseminated MAC infection had significantly higher serum levels of both TNF-alpha and soluble TNF receptors compared with other AIDS patients; almost half of the MAC-infected patients had TNF bioactivity in serum. MAC-infected patients also had severely decreased serum 1,25D levels compared with all other AIDS patients. The activation of the TNF system was significantly correlated with the degree of 1,25D deficiency. These findings may reflect interaction between vitamin D and the TNF system in the pathophysiology of disseminated MAC infection in AIDS.

Real-time monitoring of renal function during ischemic injury in the rhesus monkey.

The presence of delayed graft function (DGF) following cadaver donor renal transplantation is associated with inferior graft survival as well as decreased patient survival. Delay in onset of function eliminates a valuable indicator of allograft viability, which is not easily replaced by standard diagnostic procedures. The purpose of this study was to demonstrate that a new clearance technique could be used to measure renal function minute to minute and under conditions similar to those observed in humans in the immediate posttransplantation period. A monkey model was used to provide controlled conditions. Increasing levels of ischemic injury were produced in 12 Rhesus monkeys by renal hilum cross-clamping. Real-time measurements of glomerular filtration rate (GFR) were obtained from the rate of clearance of the extracellular fluid of the GFR agent 99mTc-DTPA, as measured with a specially designed external radioactivity counting device called the ambulatory renal monitor, or ARM. GRF was measured every 2-5 min as the slope (k) of the log of activity measured minute to minute versus time. GFR measurements were correlated with blood urea nitrogen (BUN), plasma creatinine (Cr), routine light microscopy, and measurement of proliferating cell nuclear antigen (PCNA), a marker of cell proliferation. Large changes in renal function due to ischemia or ureteral obstruction were observed within minutes. In addition, the rate constant on Day 1 was predictive of peak serum Cr(R =--0.86, R2=.74, p = .0001). Acute tubular necrosis (ATN) resolution was reflected more quickly when using the rate constant (Day 1) than when using either BUN or plasma Cr (Day 3-4). Because of renal functional reserve, BUN and plasma Cr were relatively insensitive indicators of mild to moderate reductions in GFR as compared with the rate constant. We conclude that ARM is a simple method which provide an accurate, near real-time GFR readout with potential applications not only for the clinical management of patients with DGF, but also as a research tool in acute renal failure (ARF).

Elevated plasma endothelin concentrations in cyclosporine-treated patients after bone marrow transplantation.

Administration of cyclosporine is often associated with the development of renal dysfunction and hypertension. Since recent data from animal experiments provide evidence that endothelin, a potent vasoconstrictive peptide, might play a role in mediating cyclosporine-related renal and cardiovascular side-effects, the present study was designed to investigate whether plasma endothelin concentrations are elevated in cyclosporine-treated patients. Plasma endothelin concentrations, determined by radioimmunoassay after Sep Pak C18 extraction, were significantly elevated in cyclosporine-treated patients after bone marrow transplantation (8.3 +/- 1.4 ng/l, n = 28) compared to patients not treated with cyclosporine after bone marrow transplantation (3.9 +/- 0.2* ng/l, n - 11), patients with haematological disorders (3.9 +/- 0.3** ng/l, n = 11) not treated with bone marrow transplantation and to normal control subjects (3.1 +/- 0.2*** ng/l, n = 33) (*P < 0.05, **P < 0.01, ***P < 0.001). Furthermore, plasma endothelin levels exhibited a significant correlation with cyclosporine concentrations (r = 0.57, P < 0.01). The present data, demonstrating elevated plasma endothelin concentrations in cyclosporine-treated patients, suggest that the cyclosporine-associated renal and cardiovascular side-effects might in part be mediated by cyclosporine-induced stimulation of endothelin release.

Release of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist after intravenous immunoglobulin administration in vivo.

We investigated the in vivo effects of one bolus injection (400 mg/kg) of intravenous immunoglobulin (IVIG) on a number of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist (IL-1Ra) in plasma in 12 patients with primary hypogammaglobulinemia. A significant and rapid increase in plasma levels of IL-6, IL-8, and tumor necrosis factor alpha (TNF alpha) was seen within 1 hour after IVIG infusion. This increase was accompanied by a more prolonged elevation in levels of both types of soluble TNF receptors (sTNFRs), which remained elevated throughout the study period (44 hours) although they reached peak levels within 1 hour. After an initial increase in the ratio between TNF alpha and sTNFRs, this ratio decreased to values significantly lower than baseline values 20 and 44 hours postinfusion with approximately 600-fold molar excess of sTNFRs to TNF alpha (trimer). Although only a modest but statistically significant increase in plasma levels of IL-1 beta was seen, IVIG infusion was followed by a marked increase in plasma levels of IL-1Ra with 1,000-fold molar excess of IL-1Ra to IL-1 beta in some patients. The demonstrated effects of IVIG infusion on the cytokine network, particularly the induction of IL-1Ra and sTNFRs release, might be important for the therapeutic effects of IVIG in several immune-mediated disorders.

Liver transplantation for primary hepatic cancer.

Although early survival following transplantation for primary hepatic cancer is excellent, previously reported high recurrence rates have generally discouraged liver replacement for this indication. Since the inception of the Boston Center for Liver Transplantation (BCLT) in 1983, 33 of 383 (8.6%) liver allograft recipients have undergone orthotopic transplantation as definitive treatment for otherwise unresectable cancer. Diagnoses included hepatocellular carcinoma (HCCA) in 24 patients (73%), and cholangiocarcinoma (CHCA) in 9 patients (27%). Actuarial survival rates for patients with hepatocellular carcinoma were 71%, 56%, and 42% at 1, 2, and 3 years, respectively. The actuarial survival rates for patients with cholangiocarcinoma were 89% at 6 months, and 56% at 1, 2, and 3 years. Of the nine patients with cholangiocarcinoma, 56% (5/9) developed recurrent disease. Although this recurrence rate is disheartening, because of the lack of other morbidity, long-term survival in these patients is comparable to patients with HCCA. In contrast, recurrent hepatocellular carcinoma developed in 25% of recipients (5/20) who survived longer than 3 months posttransplantation. Other causes of death in patients with hepatocellular carcinoma included perioperative complications, 16.6% (4/24); sepsis, 8.3% (2/24); coronary artery disease, 4.2% (1/24); and lymphoma, 4.2% (1/24). Favorable prognostic factors included: primary tumor less than 3 cm in size and absence of associated cirrhosis. These results emphasize that orthotopic liver transplantation can provide a long-term cure for approximately 50% of patients whose primary hepatic malignancy is unresectable by conventional procedures.

Review of arterial thoracic outlet syndrome with a report of five new instances.

Arterial damage, causing ischemia of the limb, occurs in less than 5 per cent of all instances of thoracic outlet syndrome. Arterial complications are usually associated with cervical ribs or rudimentary first ribs, but 12 per cent have occurred in patients with no osseous abnormality. The physiopathologic factors begin with compression of the subclavian artery which, in most patients, produces stenosis, poststenotic dilatation, formation of aneurysms and mural thrombosis. In other patients, aneurysms do not form, but the compression still causes stenosis, intimal injury and mural thrombosis. With either scenario, distal embolization can occur and produce signs and symptoms of ischemia that can limb-threatening. In this study, more than 200 patients reported previously and five additional sides in four patients were reviewed. Treatment depends upon the condition of the patient at presentation. Those with osseous abnormalities and no aneurysm or symptoms are not treated, while those with poststenotic dilatation or small aneurysms undergo rib resection only. Aneurysms more than twice the arterial diameter, intimal injury or mural thrombus are indications to resect, replace or bypass the subclavian artery. Patients who have had distal embolization and severe ischemic symptoms require, in addition to the aforementioned, distal thromboembolectomy, dorsal sympathectomy or both. Good results from treatment have been reported in 84 per cent of the 137 patients reported since 1970; 3 per cent required amputation and 3 per cent had cerebral emboli. Because the severe arterial complications were primarily the result of delayed therapy, they can best be avoided by early recognition, diagnosis and treatment.

Recurrent thoracic outlet syndrome.

Recurrent symptoms develop in 15% to 20% of patients undergoing either first rib resection or scalenectomy for thoracic outlet syndrome. Over the past 22 years 134 operations for recurrence were performed in 97 patients. Four operations were used: transaxillary first rib resection (26); supraclavicular first rib resection with neurolysis (15); scalenectomy with neurolysis (58); and brachial plexus neurolysis (35). Complications included temporary plexus injury (0.7%), temporary phrenic palsy (3.7%), and permanent phrenic palsy (1.4%). The combined primary success rate of all four operations for recurrence was 84% in the first 3 months. This fell to 59% at 1 to 2 years; 50% at 3 to 5 years; and 41% at 10 to 15 years. No significant difference was found in results between the four operations used for recurrence. When recurrence was caused by trauma the results of reoperations were better than when recurrence was spontaneous. The primary success rates of three initial operations for thoracic outlet syndrome were compared to their secondary success rates (improved after reoperation). By use of life-table methods, reoperation improved the 5- to 10-year success rate of transaxillary first rib resection from 69% to 86% and for scalenectomy from 69% to 84%. Reoperation is successful in most cases of recurrent thoracic outlet syndrome and better when recurrence is the result of a neck injury.

Subclavian vein obstruction and thoracic outlet syndrome: a review of etiology and management.

This is a comprehensive review of acute and chronic venous obstruction, both thrombotic and nonthrombotic. It covers the anatomy, etiology, clinical features, management, and results of treatment of this uncommon condition. The typical clinical symptoms are pain and swelling in the arm, aggravated by exercise. Venography is the essential diagnostic test. The treatment options for acute thrombosis and their results include: anticoagulants, 49% improvement in 185 cases; fibrinolysis, 74% improvement in 62 cases, 36 of whom later had first rib resection and three of whom had angioplasty; and thrombectomy, 94% improvement in 33 cases. For chronic obstruction, treatment alternatives are first rib resection, 77% improvement in 97 patients; claviculectomy, 83% improvement in six patients; scalenectomy and soft tissue division, 83% improvement in 23 cases; endovenectomy, 90% improvement in 10 cases; and venous bypass, 67% improvement in 15 cases. The definitions of "improvement" are variable and sometimes ambiguous. The data do not provide a rigid guideline for specific management of each condition; rather, the options are presented with their supporting data to permit an individualized approach.