Great expectations for the World Health Organization: a Framework Convention on Global Health to achieve universal health coverage.

Establishing a reform agenda for the World Health Organization (WHO) requires understanding its role within the wider global health system and the purposes of that wider global health system. In this paper, the focus is on one particular purpose: achieving universal health coverage (UHC). The intention is to describe why achieving UHC requires something like a Framework Convention on Global Health (FCGH) that have been proposed elsewhere,(1) why WHO is in a unique position to usher in an FCGH, and what specific reforms would help enable WHO to assume this role.

Unilateral nephrectomy: effect on survival in NZB/NZW mice.

Male F1 New Zealand Black X New Zealand White mice, which spontaneously develop immune complex renal disease, underwent unilateral nephrectomy at 3 months of age and were compared with sham-operated controls. At 12 months of age only 24% of mice with a single kidney were alive, while 85% of sham-operated controls survived to the same age. Unilaterally nephrectomized mice had more severe renal histologic changes, as shown by light and immunofluorescence microscopy.

The effects of tadalafil on cold-induced vasoconstriction in patients with Raynaud's phenomenon.

Raynaud's phenomenon (RP) is a disorder characterized by episodic periods of vasoconstriction typically provoked by exposure to cold. Phosphodiesterase 5 (PDE5) inhibitors may improve digital blood flow and clinical symptoms in patients with RP, but the mechanisms are unknown. We examined the hypothesis that a PDE5 inhibitor, tadalafil, attenuates cold-induced vasoconstriction. Additionally, we examined whether tadalafil reduced vascular dysfunction following ischemia, thus altering the response to repeated cooling. We conducted a double-blind, placebo-controlled crossover study in 20 subjects with RP on two separate study days, when subjects received either placebo or tadalafil (10 mg). Digital blood flow (flux) was measured by laser Doppler flowmetry at rest and during two graduated local heat and cold exposure cycles. Temperature-response curves were evaluated by E(max) (maximal flux during heating), E(min) (minimal flux during cooling), and ET(50) and ET(90) (the local temperature at which flux decreased by 50% and 90% of E(max)-E(min), respectively). Tadalafil did not increase baseline flux (81.0+/-73.0 vs 91.3+/-114.0 arbitrary unit (AU), P=0.57), E(max) (280.0+/-107.6 vs 279.5+/-119.8 AU, P=0.94), ET(50) (25.4+/-4.4 vs 26.6+/-5.7 degrees C, P=0.62), or ET(90) (21.2+/-3.9 vs 21.8+/-5.0 degrees C, P=0.78), (cycle 1 values presented). There were no differences between cycles on either study day. In conclusion, in patients with RP, single-dose tadalafil does not increase digital blood flow at baseline or in response to heating, nor does it attenuate cold-induced vasoconstriction. Furthermore, it does not precondition the endothelium to resist a second cooling challenge. The clinical benefit in patients with RP treated with PDE5 inhibitors probably involves mechanisms other than acute inhibition of cold-induced vasoconstriction.

End-stage renal disease in diabetic persons: is the pandemic subsiding?

Analysis of data compiled by the United States Renal Data System and the National Health Interview Survey as reported in the Centers for Disease Control and Prevention's Weekly Morbidity and Mortality Report indicates that between 1990 and 2002, there has been a sharp decline in incidence rate of the number of persons with diabetes who develop end-stage renal disease. Although it is comforting to practitioners to attribute this improvement to a widely advocated regimen of renoprotection, consisting of careful regulation of hypertensive blood pressure, improved glycemic control, and lifestyle modification, evidence for this causal relationship is appearing only now. There is need to clarify the source of this epidemiologic change that will lessen the projected burden on medical and socioeconomic resources in the immediate future.

Differential response of premalignant epithelial cell classes to phorbol ester tumor promoters and to deoxycholic acid.

The effects of two agents, 12-O-tetradecanoylphorbol-13-acetate (TPA) and deoxycholic acid (DOC), which act as tumor promoters in the gastrointestinal epithelium of experimental animals, were compared using primary cultures of human premalignant colonic epithelial cells at different stages in tumor progression. Both DOC and TPA enhanced the size of the proliferative fraction in colonies of early-stage premalignant cells, with DOC providing more stimulation. TPA-treated intermediate- and late-stage premalignant cells elongated and then disrupted the monolayer by forming rills several cells in thickness and then multicellular clusters. This multilayering was reminiscent of the areas of carcinoma found within adenomas. DOC had no such effects on morphology. Cell clustering was concomitant with secretion of a protease with characteristics of a plasminogen activator. Premalignant cells secreted severalfold higher levels of protease in response to TPA than did either TPA-treated primary cultures of colonic adenocarcinomas or established colon carcinoma cell lines. These results suggest that (a) DOC and TPA act sequentially during tumor promotion and (b) cell clustering and protease release may be associated with the transition of premalignant epithelial cells to colonic carcinoma.

Disrupted communication between late-stage premalignant human colon epithelial cells by 12-O tetradecanoylphorbol-13-acetate.

Premalignant epithelial cells derived from benign tumors of the human colon fall into three classes based on the properties of the cultured cells and the pathology and clinical prognosis of the tumors themselves. Cellular communication was compared by injection of fluorescein into single cells in primary cultures of late- and early-stage premalignant cells, in primary cultures of colon adenocarcinomas, and in cultures of a tumorigenic established human colon carcinoma cell line. Many cells in both types of premalignant cultures appeared highly coupled inasmuch as the dye was often detected in several cells adjacent to the injection site. Thus, most premalignant cells within a colony were in communication with the surrounding cells. In contrast, many malignant cells were uncoupled and passed dye to few, if any, neighboring cells. The tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate caused extensive uncoupling of cells in late-stage premalignant cultures, while not eliminating the extensively coupled areas found in early-stage premalignant cultures. 12-O-Tetradecanoyl-phorbol-13-acetate had no effect on coupling between tumorigenic cells from an established carcinoma cell line which were already extensively uncoupled. Tumor promoters may play an important role in the transition of late-stage premalignant cells to malignancy by decreasing intercellular communication, between premalignant cells at this specific stage in tumor development.

Heterogeneous responses of human colon carcinomas to hexamethylene bisacetamide.

Primary cultures of resected human colon carcinoma were used to study differentiation agents directly on the biologically relevant cancer cells rather than on highly selected established cell lines. To achieve primary cultures which remained viable and replicating for several days, carcinomas were partly digested to epithelial organoids, which were selectively plated with high efficiency on collagen I-bovine serum albumin films in specially formulated serum-free medium. A monoclonal antibody, 29-15, was identified which binds to a cell surface epitope expressed on 16 of 21 invasive colon carcinomas of the Dukes' B2, C, or D histopathology classes, but not expressed on any of 11 noninvasive benign tumors (adenomas) at identical antibody titer. Noncytotoxic concentrations of the differentiation agent, hexamethylene bisacetamide (HMBA), induced the loss of the 29-15 epitope from HT29 colon carcinoma cells. HMBA also induced HT29 cells to lose the capacity for anchorage-independent growth with a similar dose-response curve and time course to the loss of 29-15 epitope. Twelve primary cultured human colon carcinomas exhibited differential responses when exposed to 1 to 7 mM HMBA for 7 days. Four moderately to well-differentiated carcinomas lost expression of the 29-15 epitope at each HMBA concentration. The tumor growth fraction was decreased in each tumor, with a mean decrease of 76% at 5 mM HMBA. A dose-dependent induction of nonproliferating tumor colonies, lacking [3H]thymidine labeling, occurred in three of the four carcinomas. In six other tumors, including those at less differentiated stages, HMBA induced the opposite effect: a two- to threefold increase in the tumor growth fraction at the optimal value of 5 mM HMBA, an increase in mean colony size, and no loss of the 29-15 malignancy epitope. No effects were observed in the two other carcinomas tested. Thus HMBA was able to induce growth arrest and loss of the malignancy epitope 29-15 in those carcinomas already at an advanced stage of differentiation, and to exert a growth stimulating effect on those carcinomas apparently at more immature stages.

New chemotherapeutic drug sensitivity assay for colon carcinomas in monolayer culture.

Ten previously untreated colon carcinomas were tested for chemotherapeutic drug sensitivity in primary monolayer culture. Colon carcinomas were partly digested to groups of epithelial cells which plated with a mean efficiency of 42 +/- 9% (SE) on a collagen I-bovine serum albumin substrate in serum-free medium, producing patches of tightly adherent epithelial cells. The cultured cells were judged epithelial by the presence of cytokeratins, an epithelial cell surface epitope, junctional complexes, and brush borders. Each carcinoma was plated in 40 to 60 Petri dishes (35 mm), yielding a mean of 28 +/- 8 (SE) colonies per dish (6832 +/- 1952 cells). Drugs tested in duplicate plates were mitomycin C, cisplatin, streptozotocin, and 5-fluorouracil at 0.1, 1, 10, and 100 micrograms/ml, and at 0.1, 1, and 2x the peak tolerated drug concentration in serum. Twenty-four h after plating, any nonadherent cells were removed, and the adherent tumor cells were continuously exposed to the drugs for 3 days. Each drug induced colony lysis in a dose-dependent manner in responsive tumors. Drug-resistant, cycling cells were identified by [3H]thymidine incorporation in colonies which were not lysed by drug treatment. Each of the ten carcinomas exhibited inherent resistance to one or more chemotherapy drugs within the concentration ranges clinically achievable.

Correction of erythrocyte deformability defect in ALX-induced diabetic rabbits after treatment with aminoguanidine.

To test whether treatment with aminoguanidine, a drug known to prevent cross-linking between glycated proteins, is effective in improving reduced erythrocyte deformability in diabetes, we studied a group (n = 6) of ALX-induced long-term (12.7 +/- 2.2 mo of hyperglycemia) diabetic New Zealand white rabbits before and after 20 wk of treatment with aminoguanidine (100 mg.kg-1 x day-1). The key findings were as follows: 1) at 12 wk of treatment with aminoguanidine, mean erythrocyte deformability normalized and remained within the normal reference range throughout the period of aminoguanidine administration; 2) 10 wk after discontinuing aminoguanidine in a subset of diabetic rabbits, mean erythrocyte deformability deteriorated by approximately 50%; 3) blood glucose and total GHb did not vary significantly during treatment with aminoguanidine nor after its discontinuation.

Improved survival in HIV-infected African-Americans with ESRD.

AIMS: To determine if there has been improvement in survival of HIV-infected patients with end-stage renal failure subsequent to widespread use of highly active antiretroviral therapy. METHODS: The United States Renal Data System is a national data system funded by the National Institute of Diabetes and Digestive and Kidney Disease with the Centers for Medicare and Medicaid. Using the United States Renal Data System Standard Analysis Files, we analyzed all African-American end-stage renal failure patients in the United States from 1990-2001. We compared survival rates for patients with HIV disease, sickle cell anemia, diabetes, and all other diagnoses for the time periods 1990-1994 and 1995-2001. The main outcome measure was one- and five-year survival in each cohort. RESULTS: One-year survival of African-American patients with end-stage renal disease and HIV increased from 46.6% during 1990-1994 to 65.1% during 1995-2001 (odds ratio 2.139). One-year survival decreased in the sickle cell group (odds ratio 0.595) and decreased slightly in the diabetic group (odds ratio 0.927) and all others (odds ratio 0.941). Five-year survival in the HIV group increased from 13.3% in 1990-1995 to 30.4% in 1995-2001 (odds ratio 2.847). There was no corresponding increase in survival for the sickle cell group (odds ratio 0.987), the diabetic group (odds ratio 1.06), or all others (odds ratio 1.137). CONCLUSIONS: We conclude that survival in African-American end-stage renal disease patients and HIV infection has substantially improved subsequent to introduction of highly active antiretroviral therapy. Our data support aggressive multi-drug treatment of end-stage renal failure patients with HIV infection.

Response to inhaled beta-agonist in a patient receiving beta-adrenergic blockers.

A 52-year-old man receiving long-term hemodialysis and a beta-adrenergic blocker for hypertension had symptoms of acute bronchospasm when exposed to a new hemodialyzer. Resistant to two doses of subcutaneous epinephrine (1 mL of 1:1000 dilution) and one intravenous dose of aminophylline (250 mg), the bronchospasm was rapidly relieved by metaproterenol sulfate given by inhalation one hour later.

Relationship of renal transplantation to hypertension in end-stage renal failure.

The relationship of renal transplantation to new onset or persistence of previously established hypertension was analyzed in 164 transplant recipients in whom the renal allograft functioned for six months or longer. Of the 164, thirty-seven (23%) had normal blood pressure and 127 (77%) were hypertensive prior to transplantation. Following transplantation 83 patients (51%) were normotensive; high blood pressure was found in 81 (49%). Posttransplant hypertension could not be correlated with the recipient's original renal disease, age, sex, renal donor source, donor age, or maintenance dose of prednisone. More normotensive paients had undergone prior binephrectomy when compared with the hypertensive group (P less than .05). Mean serum creatinine levels was higher (2.0 mg/dl) in hypertensives than in normotensives (1.54 mg/dl) (P greater than .05). Selective renal veins' renin measurements in patients with severe hypertension were not helpful in predicting the beneficial effects of either bilateral nephrectomy or surgical correction of transplant renal artery stenosis.

Water immersion in nephrotic syndrome.

Five adults suffering from nephrotic syndrome were immersed up to the neck in 1.3 m of warm water for four hours. There was a mean weight loss of 2 kg; 1 kg was lost through sweat and 1 kg was lost through urine. Thirty-five millimoles of sodium was excreted in the urine in four hours, 15 times more than on control days. The urine became hypotonic to plasma in the first two hours of immersion. Aldosterone levels did not change on immersion in three patients, but fell from elevated levels in two others. It is concluded that water immersion up to the neck in nephrotic patients warrants further investigation as a therapeutic agent in those cases that are not responding to conventional diuretic therapy.

Toward a hybrid artificial pancreas.

Management of insulinopenic diabetic individuals centers on administration of insulin by means of multiple injections, a wearable or implantable insulin-infusion pump, or a whole-organ or segmental-pancreas transplant. Preliminary trials indicate that surgical implantation of a hybrid device containing living insulin-secreting tissue may function as a combined glucose sensor and insulin-infusion pump. By means of a chamber composed of a semipermeable membrane shaped into hollow fibers or a box surrounding endocrine tissue, pilot studies have shown that isolated islets of Langerhans, fragments of insulinoma, or a fetal pancreas retains function for days to weeks, as judged by the ability to sustain euglycemic conditions in chemically induced diabetic rats. Lacking clear proof that normalizing blood glucose levels will prevent vascular complications of diabetes in humans, the case for further development of a hybrid (tissue plus fabricated components) device rests mainly on optimistic extrapolation of results attained in the chemically induced diabetic rat and dog. For the minority of diabetic patients who have insulin-dependent diabetes, the benefit afforded by a bionic device establishing internal insulin release regulated by silently sensed blood glucose level is more than enough payoff for the discomfort and surgery involved in its implantation. Further trials of a hybrid artificial pancreas in the dog appear warranted as a logical extension of preliminary studies with this species.

Advanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications.

Protein alteration resulting from a nonenzymatic reaction between ambient glucose and primary amino groups on proteins to form glycated residues called Amadori products is termed the Maillard reaction. By dehydration and fragmentation reactions, Amadori products are transformed to stable covalent adducts called advanced glycosylation end products (AGEs). In diabetes, accelerated synthesis and tissue deposition of AGEs is proposed as a contributing mechanism in the pathogenesis of clinical complications. Uremia in diabetes is associated with both a high serum level of AGEs and accelerated macro- and microvasculopathy. Diabetic uremic patients accumulate advanced glycosylated end products in "toxic" amounts that are not decreased to normal by hemodialysis or peritoneal dialysis but fall sharply to within the normal range within 8 h of restoration of half-normal glomerular filtration by renal transplantation. It follows that the higher mortality of hemodialysis-treated diabetic patients compared with those given a renal transplant may relate, in part, to persistent AGE toxicity. Pharmacologic prevention of AGE formation is an attractive means of preempting diabetic microvascular complications because it bypasses the necessity of having to attain euglycemia, an often unattainable goal. Pimagidine (aminoguanidine) interferes with nonenzymatic glycosylation and reduces measured AGE levels leading to its investigation as a potential treatment. The mechanism by which pimagidine prevents renal, eye, nerve, and other microvascular complications in animal models of diabetes is under investigation. Separate multicenter clinical trials of pimagidine in type 1 and type 2 diabetes, where proteinuria is attributable to diabetic nephropathy, are in progress. The effect of treatment on the amount of proteinuria, progression of renal insufficiency, and the course of retinopathy will be monitored.

Diabetic nephropathy. Management of the end-stage patient.

Diabetic nephropathy is currently the leading cause of new patients requiring dialysis in the United States. Management of the diabetic patient with ESRD is complicated by the frequent coexistence of complications affecting other organ systems, including retinopathy, cardiovascular disease, peripheral neuropathy, or autonomic neuropathy, manifested as gastroparesis, diarrhea or obstipation, cystopathy, or orthostatic hypotension. Associated clinical syndromes must be followed and treated, if possible, while preparing the patient to receive renal replacement therapy. Both the clinical condition and the psychosocial environment are key factors in choice of ESRD therapy for an individual patient. Rehabilitation data are best for patients who undergo kidney transplantation, but these data are confounded by the fact that the healthiest patients are referred for this treatment modality. Living, related kidney transplant is the preferred initial choice for the diabetic patient with kidney disease. At most centers, both in the United States and abroad, the cadaveric transplant is the second choice for uremia therapy. At the appropriate institution, the patient with type I diabetes may also be considered for a simultaneous cadaveric pancreas transplant. While awaiting cadaveric transplantation, or if contraindication to transplantation is present (chronic infection, recent malignancy, or severe cardiac disease), diabetic patients with severe impairment of the glomerular filtration rate (less than 10-15 ml/min) are referred for vascular access placement and/or insertion of a peritoneal catheter. The decision regarding the choice of CAPD vs. hemodialysis must be made on an individual basis. Rehabilitation and survival data for these therapies are similar, although technique survival rates for CAPD decline dramatically as time progresses because of infectious complications. In-center hemodialysis has the worst survival and rehabilitation profile, but the sickest, most debilitated patients with the highest number of comorbid conditions tend to be referred for that therapeutic modality. Most studies of rehabilitation were performed before use of recombinant human erythropoietin, and comparison between ESRD treatment modalities will have to be reevaluated now that the drug is routinely used.

Retrospective analysis of posttransplantation diabetes mellitus in black renal allograft recipients.

OBJECTIVE: To study the incidence, outcome, and possible etiopathogenic factors involved in posttransplantation diabetes mellitus in cyclosporine-treated black renal allograft recipients. RESEARCH DESIGN AND METHODS: One hundred thirty-eight nondiabetic black renal transplant recipients whose grafts survived greater than 1 yr were studied retrospectively. RESULTS: Twenty-eight (20.3%) patients developed posttransplantation diabetes mellitus, 46 and 75% were diagnosed by 6- and 12-mo posttransplantation, respectively, and 46% were insulin dependent. Diabetes was more frequently encountered in older recipients and recipients of cadaveric kidneys but was independent of sex, number of transplants, incidence of acute rejection, percentage of body weight gain, steroid or cyclosporine dose, and use of beta-blockers and/or diuretics. Renal function was similar in the diabetic group compared with the control group. Actuarial 5-yr graft survival was 82% in the diabetic cohort compared with 78% in the control group, with chronic rejection accounting for all graft losses within the diabetic group. CONCLUSIONS: Twenty percent of black cyclosporine-treated renal allograft recipients developed diabetes mellitus in the posttransplantation period. However, its presence did not appear to influence intermediate-term graft or patient survival.

Adverse impact of hypertension on diabetic recipients of transplanted kidneys.

The effect of hypertension on patient and allograft survival in 60 diabetic recipients of transplanted kidneys was assessed by retrospective chart analysis. Hypertension was present in 81% of recipients. Of eight of these patients who became normotensive after transplantation, all had functioning allografts and one died. By contrast, persistent hypertension after transplantation was associated with a higher mortality rate (25 of 54, 48%) and loss of kidney graft function (19 of 54, 35%). At a mean of 21 months after transplantation, living hypertensive diabetic recipients had worse renal function (mean serum creatinine of 3.1 mg/dl) than did nonhypertensive recipients (mean serum creatinine of 1.6 mg/dl). It is concluded that hypertension is a significant risk factor for diabetic patients and kidneys after transplantation.

Charcoal sorbent-induced hypolipidemia in uremia and diabetes.

Rats with hyperlipidemia associated with streptozotocin-induced diabetes or azotemia after subtotal nephrectomy were administered a diet containing 5% activated charcoal. Significant lowering of nonfasting serum cholesterol and triglyceride levels resulted. Charcoal-feeding also altered the abnormal high density lipoprotein electrophoresis pattern of diabetic rats toward normal.

Reduction in hyperlipidemia in hemodialysis patients treated with charcoal and oxidized starch (oxystarch).

A combination of two oral sorbents, oxystarch 35 g/day plus activated charcoal 35 g/day, was administered to four patients undergoing maintenance hemodialysis during thrice weekly and once weekly treatments. Patients tolerated oxystarch and charcoal without complaint during the 4-week period of thrice weekly hemodialyses. All four patients became clinically uremic when hemodialyses were reduced to once weekly and only two patients were able to continue through the end of this 4-week period. Mean serum cholesterol concentration diminished significantly from 200 mg/dl during control periods to 140 mg/dl after each 4-week trial of sorbents (P less than 0.02). Hypertriglyceridemia (range 181 to 543 mg/dl) was corrected in three of four patients with triglyceride values falling to less than 150 mg/dl during ingestion of sorbents (P less than 0.05). Activated charcoal, which is inert as an intestinal nitrogen binding sorbent, may lower serum lipids by direct intragut binding of lipids and bile acids. The potential use of oral charcoal in long-term therapy to reduce hyperlipidemia and prevent vascular accidents due to atherosclerosis requires additional study.