Mortality and Disability-Adjusted Life-Years (Dalys) for Common Neglected Tropical Diseases in Ethiopia, 1990-2015: Evidence from the Global Burden of Disease Study 2015.

INTRODUCTION: Neglected tropical diseases (NTDs) are important public health problems in Ethiopia. In 2013, the Federal Ministry of Health (FMOH) has launched a national NTD master plan to eliminate major NTDs of public health importance by 2020. Benchmarking the current status of NTDs in the country is important to monitor and evaluate the progress in the implementation of interventions and their impacts. Therefore, this study aims to assess the trends of mortality and Disability-adjusted Life-Years (DALY) for the priority NTDs over the last 25 years. METHODS: We used the Global Burden of Disease (GBD) 2015 estimates for this study. The GBD 2015 data source for cause of death and DALY estimation included verbal autopsy (VA), Demographic and Health Surveys (DHS), and other disease specific surveys, Ministry of Health reports submitted to United Nations (UN) agencies and published scientific articles. Cause of Death Ensemble modeling (CODEm) and/or natural history models were used to estimate NTDs mortality rates. DALY were estimated as the sum of Years of Life Lost (YLL) due to premature mortality and Years Lived with Disability (YLD). RESULTS: All NTDs caused an estimated of 6,293 deaths (95% uncertainty interval (UI): 3699-10,080) in 1990 and 3,593 deaths (95% UI: 2051 - 6178) in 2015, a 43% reduction over the 25 years. Age-standardized mortality rates due to schistosomiasis, STH and leshmaniasis have declined by 91.3%, 73.5% and 21.6% respectively between 1990 to 2015. The number of DALYs due to all NTDs has declined from 814.4 thousand (95% UI: 548 thousand-1.2million) in 1990 to 579.5 thousand (95%UI: 309.4 thousand-1.3 million) in 2015. Age-standardized DALY rates due to all NTDs declined by 30.7%, from 17.6 per 1000(95%UI: 12.5-26.5) in 1990 to 12.2 per 1000(95%UI: 6.5 - 27.4) in 2015. Age-standardized DALY rate for trachoma declined from 92.7 per 100,000(95% UI: 63.2 - 128.4) in 1990 to 41.2 per 100,000(95%UI: 27.4-59.2) in 2015, a 55.6% reduction between 1990 and 2015. Age-standardized DALY rates for onchocerciasis, schistosomiasis and lymphiaticfilariasis decreased by 66.2%, 29.4% and 12.5% respectively between 1990 and 2015. DALY rate for ascariasis fell by 56.8% over the past 25 years. CONCLUSIONS: Ethiopia has made a remarkable progress in reducing the DALY rates for most of the NTDs over the last 25 years. The rapid scale of interventions and broader system strengthening may have a lasting impact on achieving the 2020 goal of elimination of most of NTDs. Ethiopia should strengthen the coverage of integrated interventions of NTD through proper coordination with other health programs and sectors and community participation to eliminate NTDs by 2020.

Radioimmunotherapy for breast cancer using indium-111/yttrium-90 BrE-3: results of a phase I clinical trial.

UNLABELLED: BrE-3 is a murine IgG1 monoclonal antibody that binds to 97% of human ductal breast cancer specimens. A previous study documented the ability of 111In-labeled 1,4-methyl-benzyl isothiocyanate diethylenetriamine pentaacetic acid (111In-MX-DTPA) BrE-3 to specifically target breast cancer tissue in patients, and the dosimetry derived from the pharmacokinetics suggested that a useful therapeutic index could be obtained with 90Y-MX-DTPA BrE-3. A Phase I maximum tolerated dose study was, therefore, initiated. METHODS: Six patients received 111In/90Y-MX-DTPA BrE-3, three of them receiving 6.25 and the other three receiving 9.25 mCi/m2 of 90Y. Pharmacokinetics, dosimetry, human anti-mouse antibody (HAMA), toxicity and clinical responses were evaluated. RESULTS: Three of six patients demonstrated a minor and transient, but objective tumor response, and none of the patients had significant toxicity. Tumor dosimetry ranged from 39 to 167 rad/mCi of 90Y (442-1887 rad/ dose). HAMA response occurred in five of six patients. CONCLUSION: Minimal toxicity, dosimetric calculations and clinical assessment indicate that a useful therapeutic index can be achieved with this therapy. Indium-111/yttrium-90-MX-DTPA BrE-3 can be safely administered to patients with metastatic breast cancer, and therapy doses yielded pharmacokinetics similar to those of tracer doses. Clinical responses, albeit transient, were achieved with single-dose therapy. Rapid onset of the HAMA response will hinder multicycle therapy, unless it is prevented with immunosuppressive drugs or the use of a "humanized" antibody. Further studies are needed to determine the optimal use of BrE-3 for radioimmunotherapy.

Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma.

PURPOSE: The CD20 B-lymphocyte surface antigen expressed by B-cell lymphomas is an attractive target for radioimmunotherapy, treatment using radiolabeled antibodies. We conducted a phase I dose-escalation trial to assess the toxicity, tumor targeting, and efficacy of nonmyeloablative doses of an anti-CD20 monoclonal antibody (anti-B1) labeled with iodine-131 (131I) in 34 patients with B-cell lymphoma who had failed chemotherapy. PATIENTS AND METHODS: Patients were first given tracelabeled doses of 131I-labeled anti-B1 (15 to 20 mg, 5 mCi) to assess radiolabeled antibody biodistribution, and then a radioimmunotherapeutic dose (15 to 20 mg) labeled with a quantity of 131I that would deliver a specified centigray dose of whole-body radiation predicted by the tracer dose. Whole-body radiation doses were escalated from 25 to 85 cGy in sequential groups of patients in 10-cGy increments. To evaluate if radiolabeled antibody biodistribution could be optimized, initial patients were given one or two additional tracer doses on successive weeks, each dose preceded by an infusion of 135 mg of unlabeled anti-B1 one week and 685 mg the next. The unlabeled antibody dose resulting in the most optimal tracer biodistribution was also given before the radioimmunotherapeutic dose. Later patients were given a single tracer dose and radioimmunotherapeutic dose preceded by infusion of 685 mg of unlabeled anti-B1. RESULTS: Treatment was well tolerated. Hematologic toxicity was dose-limiting, and 75 cGy was established as the maximally tolerated whole-body radiation dose. Twenty-eight patients received radioimmunotherapeutic doses of 34 to 161 mCi, resulting in complete remission in 14 patients and a partial response in eight. All 13 patients with low-grade lymphoma responded, and 10 achieved a complete remission. Six of eight patients with transformed lymphoma responded. Thirteen of 19 patients whose disease was resistant to their last course of chemotherapy and all patients with chemotherapy-sensitive disease responded. The median duration of complete remission exceeds 16.5 months. Six patients remain in complete remission 16 to 31 months after treatment. CONCLUSION: Nonmyeloablative radioimmunotherapy with 131I-anti-B1 is associated with a high rate of durable remissions in patients with B-cell lymphoma refractory to chemotherapy.

High-dose 90Y Mx-diethylenetriaminepentaacetic acid (DTPA)-BrE-3 and autologous hematopoietic stem cell support (AHSCS) for the treatment of advanced breast cancer: a phase I trial.

This Phase I trial explores the use of high-dose 90Y conjugated to the antibreast cancer monoclonal antibody BrE-3 and autologous hematologic cell support in the treatment of women with stage four breast cancer. Nine women with heavily pretreated disease were enrolled. All of the patients had BrE-3-positive tumors by immunostaining and were treated with increasing doses of 90Y (15 mCi/m2, 3 patients), 20 mCi/M2 (six patients), and a fixed (50 mg) dose of BrE-3. 111In-labeled BrE-3 (5 mCi) was given simultaneously for scanning purposes. The only toxicity noted was hematological. Grade 4 platelet toxicity requiring transfusion support occurred in four patients. Grade 4 WBC toxicity was seen in two patients that resolved in 3-9 days. All hematological nadirs occurred approximately 25 days after treatment. Objective partial responses were noted in 4 of 8 (50%) patients with measurable tumors. Dose escalation is ongoing.

Radioimmunolocalization of metastatic breast carcinoma using indium-111-methyl benzyl DTPA BrE-3 monoclonal antibody: phase I study.

Pharmacokinetics of radiolabeled BrE3 monoclonal antibody (Mab), reactive against a breast mucin epitope, were assessed in 15 patients with advanced breast cancer. Patients received 5 mCi (185 MBq) of 111In-methyl benzyl isothiocyanate DTPA (MX-DTPA) conjugated BrE-3 Mab intravenously with total antibody doses of 10, 50 or 100 mg. Serial quantitative imaging, blood and urine clearance were obtained to measure pharmacokinetics, assess tumor localization and estimate radiation dose. Organ function was followed to determine toxicity. Mild allergic reactions occurred in four patients. Eighty-six percent of 70 known lesions and 5 unsuspected lesions were detected by antibody imaging. Biexponential modeling of radiolabeled antibody in serum showed a T1/2 alpha = 9.5 +/- 2.7 hr and T1/2 beta = 56 +/- 25.4 hr. Total urinary excretion averaged 35.5% +/- 19.3% injected dose (ID) by Day 8. Quantitative imaging showed that 0.02-2.56% ID localized in tumors. Extrapolating dosimetry from 111In-MX-DTPA-BrE-3 to 90Y-MX-DTPA-BrE-3, we estimate therapeutic radiation doses could be delivered to some tumors with tolerable toxicity.

Improved delivery of radiolabeled anti-B1 monoclonal antibody to Raji lymphoma xenografts by predosing with unlabeled anti-B1 monoclonal antibody.

A human B-cell lymphoma xenograft model was used to test whether the administration of unlabeled MoAb prior to injection of radiolabeled monoclonal antibody (MoAb) improves delivery of the radiolabeled MoAb to tumor prior to testing in clinical radioimmunotherapy trials. The anti-B1/CD20 pan-B-cell MoAb reactive with human B-cell lymphomas and leukemias but not reactive with mouse B-cells was used in this study. Athymic nude mice bearing human Raji Burkitt lymphoma xenografts were given injections of 2.5 muCi (0.3 microgram) 131I-labeled anti-B1 with or without a 2-h prior single injection of 100 micrograms of unlabeled anti-B1 antibody. Four days later the animals given injections of 131I-labeled anti-B1 and the unlabeled anti-B1 predose had a tumor uptake of 12.72 +/- 1.17% (SEM) of injected dose/g which was 44% greater than the animals receiving the 131I-labeled anti-B1 alone (P = 0.014). The uptake in most normal tissues was unchanged, although the blood level of 131I-labeled anti-B1 appeared to be greater following unlabeled anti-B1 predosing (P = 0.067). Predosing with isotype matched irrelevant MoAb did not result in a greater tumor uptake or blood concentration of 131I-labeled anti-B1 compared to the administration of 131I-labeled anti-B1 alone. In studies using 111In-labeled anti-B1, the effect of unlabeled antibody predosing was more pronounced. For animals given injections of 4.5 muCi (0.4 microgram) 111In-labeled anti-B1 and the unlabeled anti-B1 predose, the uptake in tumor was 12.37 +/- 2.07% of injected dose/g which was 162% greater than the animals receiving the 111In-labeled anti-B1 alone (P = 0.009). Predosing decreased 111In-labeled anti-B1 uptake in spleen, while the blood level was significantly greater. Predosing was more effective than simultaneous injection in improving tumor delivery. When tumor-bearing mice were either simultaneously given injections of 36 micrograms of unlabeled anti-B1 and 4 micrograms 111In-labeled anti-B1 or were given preinjections of 36 micrograms unlabeled anti-B1 3 h prior to injection of 4 micrograms 111In-labeled anti-B1, tumor uptake 3 days later was 1.3-fold higher in the animals which received the preinjection of unlabeled antibody (P = 0.011). As the quantity of unlabeled anti-B1 was increased (36, 96, 996 micrograms) in the predose, significantly greater uptake in tumor was observed, although this uptake appeared to plateau at the highest predoses.(ABSTRACT TRUNCATED AT 400 WORDS)

Imaging of non-small cell lung cancers with a monoclonal antibody, KC-4G3, which recognizes a human milk fat globule antigen.

To determine the role of lung cancer tumor imaging with monoclonal antibodies directed against high molecular weight human milk fat globule antigens, we administered i.v. 111In-KC-4G3 to 24 patients with advanced non-small cell lung cancer. One mg of 111In-KC-4G3 was mixed with 0, 9, 49, 99, or 499 mg of unlabeled KC-4G3 and infused i.v. over 1 to 5 h. The mean 111In-KC-4G3 radiochemical purity was greater than 97% and the resultant immunoreactivity averaged 62%. Successful imaging of cancer sites was accomplished in 92% of 24 patients, and 57% of 91 total lesions were visualized. Successful localization of tumor sites related to size (P less than 0.001), with 81% of lesions greater than 3.0 cm in diameter, 50% of lesions 1.5 to 3 cm, and 6% of lesions less than 1.5 cm successfully imaging, and to location (P less than 0.05), with 69% of pulmonary lesions, 80% of soft tissue lesions, and only 32% of bone metastases being visualized. Nonspecific reticulo-endothelial uptake of radioactivity was a major problem. Approximately 35% of 111In was chelated to serum transferrin by 24 and 48 h after infusion. The mean t 1/2 beta for plasma radioisotope and immunoreactive KC-4G3 was 29 and 27 h, respectively. There was no correlation between total infused antibody dose and imaging success or between total dose and effect on 111In and KC-4G3 kinetics. Circulating free KC-4 antigen was measurable in all but one patient before study. Tumor biopsy following infusion could demonstrate antibody presence but not saturable antigen binding. We conclude that (a) 111In-KC-4G3 demonstrates successful tumor localization in non-small cell lung cancers bearing generally high expression of its antigen and (b) further investigations to diminish nonspecific radioactivity for imaging and utilization of high dose radiolabeled antibody for therapeutic intent are warranted.

Characterization of cleavage products in selected human lutropin preparations. A protease-sensitive site in human lutropin beta subunit.

Low molecular weight fragments derived from the beta subunit of human lutropin have been frequently observed. These fragments are detected by polyacrylamide gel electrophoresis in sodium dodecyl sulfate following reduction of the disulfide bonds. A sample of human lutropin was identified that had a major portion of its beta subunit showing this proteolytic nick. Over 83% of the subunit was nicked based on reduction, carboxymethylation, and isolation of the low molecular weight fragments. This preparation had 53% of the activity of an intact human lutropin (radioligand assay). The proteolytic nick in the subunit was shown by N-terminal sequencing of the C-terminal fragments to be derived from three clips in a hexapeptide region (residues 44-49) characterized by hydrophobic alkyl side chains. Specific clips were on the amino side of Leu-45 (8%), Val-48 (45%) and Leu-49 (47%). Thus the proteolytic activity, presumably derived from the pituitary during processing, has a substrate specificity reminiscent of the bacterial protease, thermolysin.

Estrous behavior and circadian discharge of luteinizing hormone in the prepubertal gilt in response to exogenous estrogen.

The influence of varying doses of estradiol benzoate (EB) on the induction of estrus and luteinizing hormone (LH) discharge was studied in crossbred prepubertal gilts of 135 to 150 days of age. Five gilts were assigned randomly to each of 6 groups and treated with 0, 10, 20, 100 or 200 micrograms EB/kg body weight (BW) at 1200 h or with 10 micrograms/kg at 2400 h. The characteristics of the estrous and endocrine responses of the prepubertal gilts to EB were compared to the responses of 4 ovariectomized, adult gilts treated with EB. Dose of EB administered to prepubertal gilts had no influence on the interval from injection to estrus. Amount of EB administered, however, was correlated positively (r = 0.82, P less than 0.001) with the duration of estrus. Increasing the dose of EB tended to increase (0.05 less than P less than 0.10) the proportion of prepubertal gilts in estrus. Ovariectomized adult gilts treated with 10 micrograms EB/kg BW were in estrus for a duration similar to that of prepubertal gilts treated with that dose of EB. All doses of EB induced at least one surge of LH in each prepubertal gilt. As the dose of EB was increased, a greater proportion of prepubertal gilts showed 2 surges of LH at a 24-h interval. Dose had no influence either on the magnitude or the duration of LH surges. In all gilts, whether prepubertal or mature, surges of LH occurred at either 2400 or 0600 h. Thus, gilts treated with EB at either 2400 or 1200 h were asynchronous with respect to time after treatment until LH peak but were synchronous relative to the time during the day of LH surge. Ovariectomized adult gilts treated with EB had a single surge of LH that was similar in magnitude and duration to the first surge of LH observed in prepubertal gilts.(ABSTRACT TRUNCATED AT 400 WORDS)

Isolation and characterization of hamster luteinizing hormone.

Hamster pituitaries were collected over an 8-yr period to obtain 3.5 g of dried pituitaries that were submitted to fractionation by extraction with 40% ethanol-acetate buffer at pH 5.5. The 80% acetone precipitate contained all of the gonadotropin activity. This enriched fraction was further purified by Sephadex G-100 and CM-Sephadex chromatography to obtain 4 mg purified hamster LH (haLH). From 1.5 mg haLH, 0.6 mg of the alpha- and beta-subunits were isolated by countercurrent distribution. haLH assayed 0.53 times NIH-LH-S19 by radioligand assay or 0.16 times NIH-LH-S19 by rat Leydig cell steroidogenesis assay. The amino acid N-terminal sequence was: haLH alpha, L-P-D-G-D-F-T-M-Q-G-C-P-; and haLH beta, S-R-G-P-L-R-P-L-C-R-P-I-N*-A-, as represented by the single letter code. The asparagine residue marked by an asterisk was placed by analogy, as this is apparently a carbohydrate-bearing residue. The amino acid compositions of haLH and its subunits are presented. Both subunits are glycoproteins.