Magnesium intake and vascular structure and function: the Hoorn Study.

PURPOSE: Circulating and dietary magnesium have been shown to be inversely associated with the prevalence of cardiovascular disease (CVD) and mortality in both high and low-risk populations. We aimed to examine the association between dietary magnesium intake and several measures of vascular structure and function in a prospective cohort. METHODS: We included 789 participants who participated in the vascular screening sub-cohort of the Hoorn Study, a population-based, prospective cohort study. Baseline dietary magnesium intake was estimated with a validated food frequency questionnaire and categorised in energy-adjusted magnesium intake tertiles. Several measurements of vascular structure and function were performed at baseline and most measurements were repeated after 8 years of follow-up (n = 432). Multivariable linear and logistic regression was performed to study the cross-sectional and longitudinal associations of magnesium intake and intima-media thickness (IMT), augmentation index (Aix), pulse wave velocity (PWV), flow-mediated dilatation (FMD), and peripheral arterial disease (PAD). RESULTS: Mean absolute magnesium intake was 328 ± 83 mg/day and prior CVD and DM2 was present in 55 and 41% of the participants, respectively. Multivariable regression analyses did not demonstrate associations between magnesium intake and any of the vascular outcomes. Participants in the highest compared to the lowest magnesium intake tertile demonstrated in fully adjusted cross-sectional analyses a PWV of -0.21 m/s (95% confidence interval -1.95, 1.52), a FMD of -0.03% (-0.89, 0.83) and in longitudinal analyses an IMT of 0.01 mm (-0.03, 0.06), an Aix of 0.70% (-1.69, 3.07) and an odds ratio of 0.84 (0.23, 3.11) for PAD CONCLUSION: We did not find associations between dietary magnesium intake and multiple markers of vascular structure and function, in either cross-sectional or longitudinal analyses.

Binding Domain Characterization of Growth Hormone Secretagogue Receptor.

Background and Objectives: Activation of ghrelin receptor growth hormone secretagogue receptor (GHS-R) by endogenous or synthetic ligands amplifies pulsatile release of growth hormone (GH) and enhances food intake, very relevant to development and growth. GHS-R is a G-protein coupled receptor that has great druggable potential. Understanding the precise ligand and receptor interactions is crucial to advance the application of GHS-R. Materials and Methods: We used radiolabeled ligand-binding assay and growth hormone release assay to assess the binding and functional characteristics of GHS-R to synthetic agonists MK-0677 and GHS-25, as well as to endogenous peptide ligand ghrelin. We analyzed the ligand-dependent activity of GHS-R by measuring aequorin-based [Ca++]i responses. To define a ligand-binding pocket of GHS-R, we generated a series of human/puffer fish GHS-R chimeras by domain swapping, as well as a series of mutants by site-directed mutagenesis. Results: We found that the synthetic ligands have high binding affinity to GHS-R in the in vitro competitive binding assay. Remarkably, the in vivo GH secretagogue activity is higher with the synthetic agonists MK-0677 and GHS-25 than that of ghrelin. Importantly, the activity was completely abolished in GHS-R knockout mice. In GHS-R chimera analysis, we identified the C-terminal region, particularly the transmembrane domain 6 (TM6), to be critical for the ligand-dependent activity. Our site-directed mutagenesis study further revealed that amino acid residues D99 and W276 in GHS-R are essential for ligand binding. Interestingly, critical residues distinctively interact with different ligands, MK-0677 activation depends on E124, while ghrelin and GHS-25 preferentially interact with F279. Conclusion: The ligand-binding pocket of human GHS-R is mainly defined by interactive residues in TM6 and the adjacent region of the receptor. This novel finding in GHS-R binding domains advances the structural/ functional understanding of GHS-R, which will help to select/design better GHS-R agonists/ antagonists for future therapeutic applications.

Mechanism of bone loss after liver transplantation: A histomorphometric analysis.

Organ transplantation is associated with increased bone loss and high fracture risk, but the pathophysiological mechanisms responsible have not been established. We have performed a histomorphometric analysis of bone remodeling before and 3 months after liver transplantation in 21 patients (14 male, 7 female) aged 38-68 years with chronic liver disease. Eight-micrometer undecalcified sections of trans-iliac biopsies were assessed using image analysis. Preoperatively, bone turnover was low with a tendency toward reduced wall width and erosion depth. The bone formation rate increased from 0.021 +/- 0.016 (mean +/- SD) to 0.067 +/- 0.055 microm2/microm/day after transplantation (p < 0.0002) and activation frequency from 0.24 +/- 0.21/year-1 to 0.81 +/- 0. 67/year-1 (p < 0.0001). No significant change was observed in wall width, but there was a trend toward an increase in indices of resorption cavity size. There was a small increase in osteoid seam width postoperatively (p< 0.02) and decrease in mineralization lag time (p < 0.001). No significant changes in indices of cancellous bone structure were observed in the postoperative biopsies. These results demonstrate a highly significant and quantitatively large increase in bone turnover in the first 3 months after liver transplantation. Although no significant disruption of cancellous bone structure was demonstrated during the time course of the study, the observed changes in bone remodeling predispose to trabecular penetration and may thus result in long-term adverse effects on bone strength.

Modification of human tumor pH by elevation of blood glucose.

Nine patients with metastatic or recurrent superficial tumors of varying size and histology were administered 100 g oral glucose to investigate whether hyperglycemia can selectively lower tumor pH. pH was measured by a 21 ga modified glass needle electrode inserted through an 18 ga open-ended Angiocath. Serum glucose was monitored every 7.5 min by finger stick and a blood glucose analyzer. Tumor pH was measured over 50-80 min concomitantly with determination of blood glucose. In five nondiabetic patients (eight measurement points) tumor pH decreased 0.05-0.5 units from a pre-glucose range of 6.8-7.4 (7.14 +/- 0.08) to 6.4-7.3 (6.90 +/- 0.10) as blood glucose increased from a baseline of 80-120 mg/dl to 165-215 mg/dl. There was considerable heterogeneity from patient to patient regardless whether blood glucose increased to a peak at 40-60 min post-ingestion and then decreased, or whether it remained elevated up to the end of the 80 min observation period. In general, tumor pH decreased as blood glucose increased and then continued to fall throughout the period of observation. In one patient, tumor pH did not change although blood glucose increased to 175 mg/dl. Normal tissue pH was 7.36 +/- 0.02 when determined on four occasions in three patients (subcutaneous and intramuscular sites), and was unaffected by glucose administration. As a further control for tumor tissue and pH probe stability, pH probes in two patients were left in place for 30 min before glucose ingestion. The tumor pH was stable for the entire interval. Interestingly, three patients had an abnormal glucose response: two of those patients (one patient on two separate occasions) had an increase in blood glucose to 230-260 mg/dl in 40-60 min and pH actually increased 0.1-0.3 units. The third patient had a transient increase in blood glucose to 290 mg/dl along with a corresponding increase and subsequent decrease in tumor pH. In summary, whether glucose was given pre- or post-hyperthermia, independently of position in the tumor, and independently of whether pH increased or decreased, the slope of the curve of pH = f(time) was similar in a given patient tumor on all measurement occasions. These preliminary results suggest that hyperglycemia may be useful in non-diabetic patients, and perhaps in diabetic patients given insulin, to selectively reduce tumor pH and sensitize tumors to hyperthermia.

Gentisic acid: a new stabilizer for low tin skeletal imaging agents: concise communication.

In vitro stabilization of low-tin bone-imaging agents has previously been achieved with ascorbic acid. In this study gentisic acid is shown to be an equally effective antioxidant for the (1-hydroxyethylidene) diphosphonate (HEDP) and hydroxymethylenediphosphonate (HMDP) skeletal agents. In vitro studies show less than 2% free sodium [99mTc] pertechnetate at 24 hr with the gentisic acid stabilizer. Studies in guinea pigs at 3 and 24 hr--whether with C-14 or H-3-labeled gentisic acid as stabilizer--show no alteration in the biodistribution of either skeletal imaging agent by the addition of the gentisic acid. Gentisic acid is a safe and effective stabilizer, and clinical studies have shown bioequivalency with ascorbic acid.

United States National Cancer Institute Radiotherapy Development Program.

The United States National Cancer Institute (NCI) has long supported research in radiotherapy since its establishment by an act of Congress in 1937. One of the first grants for research awarded in 1938 was to support work in developing a cyclotron for conducting clinical research on therapeutic uses of neutrons and radioactive isotopes. Support for training cancer specialists was given high priority in the early days of NCI. In 1961, the Cancer Centers Program was instituted which included a radiation research program that became the primary source of grant support for radiotherapy clinical research centers in the US. There is a need for radiotherapy research because approximately 50-60% of people with newly diagnosed cancers will receive radiotherapy at some time during their disease. In 1979, the Radiotherapy Development Branch (RDP) assumed responsibility for all radiation program grants including radiation physics, radiobiology, and radiotherapy. The RDB manages a portfolio of grants and contracts with an annual budget of over $45 million. In fiscal year (FY) 1984, research support for individual investigator grants, program project grants, and contracts amounted to $22, 15, and 6 million, respectively. The accomplishments of NCI research grantees and contractors in radiotherapy-related areas have been considerable over the past 45 years. It is essential that NCI continue its commitment to radiotherapy research and development.

Representation of Asian Americans in clinical cancer trials.

PURPOSE: The objectives of this study are to analyze the accrual of Asian Americans to National Cancer Institute (NCI)-supported prevention, screening/diagnosis, and treatment trials and to determine if there is proportional ethnic representation. METHODS: Data were obtained on all participants accrued to ongoing prevention and screening/ diagnosis trials and on all patients accrued to treatment trials from 1994 to mid-1998. In the analysis, the percentage of Asian Americans to the total number of trial participants is calculated. For treatment trials, participants were stratified into five age groups: 0-20 years, 21-44 years, 45-54 years, 55-64 years, and 65 or more years. RESULTS: Asian Americans represented 4.8% of subjects accrued in screening/diagnosis trials, 1.8 to 2.2% of subjects in treatment trials, and 0.9% of subjects in prevention trials. Comparison of treatment trial age groups revealed that younger Asian Americans participate significantly more in treatment trials than older Asian Americans. CONCLUSIONS: Asian American accrual in NCI-supported trials is representative of the cancer burden of Asian Americans in the United States. However, Asian Americans 65+ years are underrepresented. Their full participation in cancer trials is justified.

Cancer research studies in Native Hawaiians and Pacific Islanders.

PURPOSE: To review and assess published findings from relevant cancer research studies in Native Hawaiians and other Pacific Islanders and to develop strategies for designing and implementing successful cancer research studies in the future. METHODS: Data were collected primarily from MEDLINE and BIOSIS Preview searches of the English literature during a 30-year period for published reports of cancer surveillance studies and epidemiological and clinical cancer studies in the Native Hawaiian and Pacific Islander populations. The cancer burden was critically assessed in the retrieved citations for each of the indigenous groups from Hawai'i, American Samoa, Guam, Commonwealth of the Northern Mariana Islands, Federated States of Micronesia, Republic of Palau, and the Republic of the Marshall Islands. RESULTS: A review of the published literature revealed a lack of systematic data collection on cancer incidence and mortality in Pacific Islanders. Wide variations were found regarding the status of cancer research among ethnic groups. It is estimated that Native Hawaiians represent 0.1% of subjects accrued to cancer prevention trials, and that Pacific Islanders represent 0.5% of subjects in a large cancer screening trial. CONCLUSION: The paucity of cancer data and clinical cancer research supports the need for increased attention to these indigenous populations to improve the quality of cancer care in Native Hawaiian and Pacific Island communities.

Rapid bioassay for chloramphenicol in the presence of other antibiotics.

A simple, rapid bioassay for the measurement of chloramphenicol in serum or cerebrospinal fluid was developed using a multiply antibiotic-resistant strain of Escherichia coli. The agar diffusion system involved the addition of patients' specimens and three standard concentrations of chloramphenicol to 7.5 mm diameter wells cut in agar seeded with the test organism. Assays of chloramphenicol using this system could be read routinely in three to four hours and allowed determinations of levels of 5-60 micrograms/ml. Chloramphenicol could be measured accurately in the presence of a variety of beta-lactam, aminoglycoside, sulfonamide, and tetracycline antimicrobial agents, but not cefoxitin or trimethoprim-sulfamethoxazole. Repetitive assays of sera containing known concentrations of chloramphenicol indicated a coefficient of variation of 8%. Seeded assay plates could be stored at 2-8 degrees C for up to five days prior to use.

Comparison of automated and rapid manual methods for the same-day identification of Enterobacteriaceae.

The Vitek AMS automated instrument method for identification of Enterobacteriaceae was compared with two rapid manual methods intended for the same purpose, the Micro ID System and the API 20E Same-Day procedure, on a series of 400 consecutive fresh clinical isolates. Results were compared with identifications obtained using the API 20E System with overnight incubation and supplemental tube biochemicals (when needed). Both the final (8-hour) and a manually requested, presumptive 5-hour result from the AMS were compared with the 4-hour results provided by the Micro ID and the 5-hour results provided by the API. The Micro ID system proved to be the most rapid and accurate of the three test systems by correctly identifying 96.8% (387/400) of isolates. The API 20E using 5-hour readings identified 90.7% (363/400) of isolates, although 96.8% (387/400) could be identified if supplemental overnight tests were employed to separate profile codes with "good likelihood, but low selectivity." The AMS correctly identified 88.8% (355/400) isolates after 5 hours, and 95.0% (380/400) following 8 hours incubation.

A survey of traditional medical practices used for the treatment of malignant tumors in an East African population.

A group of 119 Tanzanians with cancer were interviewed regarding previous traditional medical experiences prior to evaluation for radiation treatment. Forty-nine (49.1%) percent of the females and 40.6% of the males had been treated with traditional medicines. Seventy-four percent of the traditionally-treated patients had consulted a traditional doctor prior to being seen by a Western-trained doctor. The most common given treatment was a combination of several traditional methods. More than half of all traditionally-treated patients reported progression of their diseases after treatment. Only one patient had any subjective improvement. These patients tended to have less formal education and a lower standard of living than untreated patients. Problems associated with the diagnosis of cancer are addressed.

Radiotherapy in Tanzania.

The treatment of malignancies with radiotherapy and intracavitary techniques at the Tanzanian Tumor Center in Dar es Salaam, Tanzania, during an eight-month period in 1979 is reported. Cancer of the uterine cervix was the tumor most frequently treated by radiation, as well as breast, esophagus, skin, and bladder cancers.

Geographical aspects of cancer in Tanzania.

Cancer is an important cause of morbidity and mortality in Tanzania. According to the Tanzanian Cancer Registry, which records all histologically confirmed malignant tumors, the number of reported cancer cases has increased significantly over the past three decades. The most commonly diagnosed tumors are cervix cancer, skin cancer, primary liver cancer, Kaposi's sarcoma, and Burkitt's lymphoma. Geographical and tribal variations exist in disease frequency. Environmental factors appear to have a major role in the distribution. Through elimination of these factors, cancer in Tanzania could be reduced if not totally prevented.

Vitiligo associated with Kaposi's sarcoma.

A patient who had Kaposi's sarcoma and an associated vitiligo is reported. This is the first known case of Kaposi's sarcoma associated with vitiligo.

Advanced skin cancer in Tanzanian albinos: preliminary observations.

Ten cases of advanced squamous cell carcinoma of the skin in albinos, treated by radiotherapy from 1973 to 1979 at the Muhimbili Medical Center of Dar-es-Salaam, have been reviewed. Age, sex, duration of symptoms, anatomic distribution, stage of disease, and treatment are reviewed. The relationship between albinism, sunlight, and skin cancer is discussed and a practical program of prevention is suggested. Advanced carcinoma of skin in albinos may be managed successfully with judicious radiation therapy. Excellent objective responses have been noted. No assessment of long-term control is made due to poor follow-up of patients.

High dose remote afterloading radiotherapy for cervix carcinoma in Tanzania: early results.

From February 1977 through January 1979, 206 patients with histologically confirmed cervix carcinoma were treated with high dose rate afterloading irradiation at the Muhimbili Medical Center of the University of Dar es Salaam, Tanzania. Tribal and regional patterns of disease conform to geographical distributions of referring hospitals. The age at presentation, namely, at over 40 years, is similar to that reported elsewhere from East Africa. Parity among patients ranged from 0 to 14 pregnancies. Vaginal bleeding was the most common symptom in 69 percent of patients. Squamous cell carcinoma was noted in 96 percent of cases. Seventy-six percent of patients had early stage disease. Good initial responses to treatment were recorded in 57 percent of patients. Follow-up of cervical cancer patients is poor. Fifty-six (27 percent) patients were followed 1 to 17 months after treatment. Due to poor follow-up, no definite conclusions are reached regarding late radiation reactions and patient survival. The role or radiotherapy in reducing morbidity, however, is of importance.

Particle radiation therapy: requiem or reveille.

The 1960s and 1970s witnessed a surge of many institutions devoted to electron therapy. Currently, many facilities are adding or have added particle types of radiation to their armamentarium against cancer. The authors review the concepts, problems, and potentials of this form of therapy.

Twice-a-day treatment in the radiotherapeutic management of malignant mixed tumor of the parotid gland: A case report.

A patient with a 2,300 gm malignant mixed tumor of the parotid gland had recurrence 19 days post surgery. The recurrent mass failed to respond to daily fractions of 200 rad conventional irradiation four times per week and actually increased in size. A superfractionation scheme was substituted, employing twice-a-day 200 rad at 4-5½ hours intervals three times a week for 2½ weeks. At the completion of treatment, there was a 50 percent regression of the recurrent tumor mass and a 100 percent regression two weeks post irradiation. A protocol using a twice-a-day treatment is discussed.

Remote afterloading for intracavitary irradiation of cervix carcinoma.

The technique of remote afterloading for intracavitary radiotherapy was developed by Henschke et al 15 years ago, and since then the technique has received wide acceptance, both abroad and in the United States. Here at Howard University, it plays an integral part in the intracavitary portion of the treatment of cervix carcinoma. Most applications are done on an outpatient basis without anesthesia or sedation. This has become possible by dilating the cervical canal painlessly with thin laminaria rods. Spread of the lateral colpostats is accomplished by inflating a Foley balloon secured to the applicator with contrast medias, instead of using the customary gauze packing for increased rectal distance.A single cobalt-60 source of 1 mm diameter and 3 to 7 Curies is used, which can be moved during the treatment to simulate linear sources of different lengths and loading. Our present treatment policy calls for 4,000 rad given to the whole pelvis in 20 fractions of 200 rad three times per week plus eight fractions of 400 rad by the remote afterloading technique given one fraction per week concomtant with the external irradiation. Only 18 patients have been treated to date with minimal adverse tissue reactions. There is only an 18-month maximum follow-up, so survival figures are still pending but all patients so treated are currently living without recurrence.

Ecoterrorism and nontraditional military threats.

The menace facing U.S. service personnel from ecoterrorism and other nontraditional threats may increase as military deployments in war and peace increase, the availability of devastating biological, chemical, and radioactive agents increases, and adversaries or terrorist groups become more inclined to use them. A vital concern for field medical commanders is the requirement to understand the environmental issues associated with military deployment. More important is the need to recognize potential ecological threats to deployed military troops. The Gulf War was replete with numerous documented acts of ecoterrorism. The current world crisis from terrorism dictates that we be knowledgeable of the medical consequences of weapons of mass destruction and skilled in the management of casualties. The processes of human health risk assessment of deployed soldiers and ecological risk assessment are discussed as strategies to effectively prevent or reduce the health and medical consequences of ecoterrorism.