A single mechanism for the timing of spontaneous and evoked saccades.

The study of saccadic latency-the reaction time between presenting a visual stimulus and initiating an eye movement to look at it--has led to a better understanding of decision mechanisms in general, through the development of quantitative models such as LATER. But outside the laboratory, evoked saccades of this kind are rare. Most saccades are made spontaneously while viewing static scenes. Can their initiation be explained by the same decision mechanism? We suggest that in a series of spontaneous saccades, each can be considered to be evoked by the new retinal image generated by its predecessor, so that the intersaccadic interval (ISI) can be regarded as equivalent to latency. We measured ISIs in subjects spontaneously viewing static scenes, and found their distributions to be qualitatively similar to those of evoked saccades, differing quantitatively in just two respects: (1) the main part of the distribution is slower; and (2) there is an increased number of very early responses. By using novel saccadic tasks we show that (1) can be accounted for by lateral inhibition between multiple, suddenly presented image elements, and (2) by the fact that the stimulus is necessarily extremely predictable. Adding these two factors to an evoked saccadic task produced latency distributions indistinguishable from those of spontaneous ones. This suggests that the mechanisms generating evoked and spontaneous movements may be less functionally distinct than is commonly assumed. Both clinically and scientifically, a common, unified framework for explaining both spontaneous and evoked movements is an exciting prospect.

[Abdominal ultrasound: a task for the internist]. / Abdominale echografie: zaak van de internist.

For the internist, ultrasound echography is the ideal bedside imaging technique to increase his diagnostic capabilities. It is not harmful, easy to apply, and cheap. It obviates the need to send a patient to the radiologist, which saves time and thus shortens the course of the illness. Echography should be integrated into the training of internists.

[The formation of infliximab and anti-infliximab immune complexes as an explanation for non-responding to infliximab treatment of rheumatoid arthritis: observational study in 4 patients]. / Het ontstaan van immuuncomplexen van infliximab en anti-infliximab als een verklaring voor het falen van infliximabtherapie bij reumatoïde artritis: observationeel onderzoek bij 4 patiënten.

OBJECTIVE: To investigate the in vivo mechanism of non-responding to infliximab treatment of patients with rheumatoid arthritis (RA) and the role of anti-infliximab antibodies by using radiolabeled infliximab. DESIGN: Descriptive and comparative study. METHOD: Two responding and two non-responding RA patients were infused with radiolabeled infliximab. Subsequently imaging investigations and serum analysis were performed at set times. RESULTS: The scintigrams showed that the labelled infliximab was mainly present in the blood until 24 h after infusion. There was a trend of faster blood clearance and higher liver and spleen uptake of 99mTc-infliximab in one non-responding patient. Labelled infliximab was taken up by inflamed joints. The anti-infliximab level was high (1008 and 1641 U/ml) in the non-responders and low or not detectable in the responders. Sucrose gradients of serum revealed antibody complexes in both non-responders. Various sizes of antibody complexes, including very large ones, were observed in one non-responder who developed a serious infusion reaction. CONCLUSION: Infliximab-anti-infliximab immune complexes were found to form in RA non-responders due to the presence of significant quantities of anti-infliximab. This finding may partly explain the failure of the infliximab treatment.

Hospital standardised mortality ratio: A reliable indicator of quality of care?

BACKGROUND: This study investigates (1) whether the hospital standardised mortality ratio (HSMR) model underestimates or overestimates disease severity and (2) the completeness of the data collected by administrators to calculate HSMR in a cohort of deceased patients with the diagnosis of pneumonia. METHODS: In this retrospective cohort study Pneumonia Severity Index (PSI) and Abbreviated Mortality in Emergency Department Sepsis (abbMEDS) scores and associated mortality probabilities were obtained from 32 deceased pneumonia patients over the year 2014 in the VU University Medical Centre. These were compared with mortality probabilities of the Central Bureau for Statistics (CBS) calculated for every patient using the HSMR model. Clinical charts were examined to extract relevant comorbidities to determine the reliability of data sent to the national registration of hospital care. RESULTS: Risk categories determined by using the PSI and the abbMEDS were significantly higher compared with the risk categories according to HSMR (p = 0.001, respectively p = 0.000). The mean difference between the number of comorbidities in our registration and the coders' registration was 1.97 (p = 0.00). The mean difference was 0.97 (p = 0.000) for the number of comorbidities of influence on the Charlson Comorbidity Index (CCI) and 1.25 (p = 0.001) for the calculated CCI. CONCLUSION: The results of this study suggest that the mortality probabilities as calculated by the CBS are an underestimation of the risk of dying for each patient. Our study also showed that the registration of data sent to the CBS underestimated the actual comorbidities of the patient, and could possibly influence the HSMR.

Human IgM monoclonal antibody 16.88: pharmacokinetics and immunogenicity in colorectal cancer patients.

Twenty colorectal cancer patients were given an intravenous injection of human IgM monoclonal antibody (MAb) 16.88 (8 mg) conjugated to 131I for tumor localization. After a 2-week interval, a second injection with 200, 500, or 1000 mg of unlabeled antibody added was given to groups of five patients each. at the end of the 2-hour infusion, 66% of the radioactivity remained in the circulation. Blood clearance of the 131I-labeled MAb 16.88 was biphasic with a mean half-life (T1/2 alpha) of 12 hours and T1/2 beta of 45 hours. Clearance rate was 0.09 L/hour. More than 90% of the 131I in serum was protein bound, with an immunoreactive fraction of 80% in the first 48 hours. Size exclusion chromatography indicated no degradation products other than 131I in serum and urine. The urinary excretion rate of 131I increased to 1.5% of the dose per hour at 24 hours, with 50% of the dose excreted in 34 hours. The pharmacokinetic profile of 131I-labeled MAb 16.88 was neither influenced by the total protein dose of antibody administered nor affected by specific uptake in tumor tissue in individual patients, as determined on early immunoscintigrams. The larger antibody doses showed a slightly slower excretion of 131I. The assays applied to determine immunogenicity were enzyme-linked immunosorbent assay, radioimmunoassay, and the dot-blot assay. They had sensitivities ranging from 5 ng/mL to 0.5 micrograms/mL for goat or rabbit antihuman IgM. The assays did not reveal antihuman antibody responses.

Kinetics and tissue distribution of the radiolabeled chimeric monoclonal antibody MOv18 IgG and F(ab')2 fragments in ovarian carcinoma patients.

Twenty-four patients suspected of having ovarian carcinoma received i.v. injection with a combination of radiolabeled intact IgG (1 mg) and F(ab')2 fragments (1 mg) of the chimeric monoclonal antibody MOv18, each form labeled with 1.85 MBq 131I or 125I. Laparotomy was performed either 2 or 6 days after injection, and the uptake of radioactivity was determined in a total of 329 biopsies of normal and malignant tissues. The mean elimination half life in plasma of cMOv18 IgG and F(ab')2 was 70 +/- 8 (SD) and 20 +/- 5 h, respectively. The mean uptake of IgG in tumor biopsies was 3.6-fold higher two days after injection and 6.9-fold higher than the uptake of F(ab')2 6 days after injection. Uptake in normal tissues was 3.3 and 5.5 times higher for IgG at 2 and 6 days, respectively. Two days after injection, the mean ratio of the uptake in tumor:normal tissue/patient was 3.8 +/- 1.5 and 4.0 +/- 1.8 for radiolabeled cMOv18 IgG and F(ab')2, respectively. Six days after injection, this was 6.7 +/- 4.7 for Ig G and 5.7 +/- 4.1 for F(ab')2. cMOv18 IgG has a longer circulation time in blood, a higher uptake in tumor and normal tissues, and a longer retention time compared to the F(ab')2 fragments. However, the tumor:normal tissue ratios are similar. The results do not warrant a definite conclusion as to which antibody form is most suitable for therapeutic application of antibodies but provide a more firm basis for rational design of therapeutic targeting studies using immunoconjugates.

Radioimmunoscintigraphy of head and neck cancer using 99mTc-labeled monoclonal antibody E48 F(ab')2.

The diagnostic value of 99mTc-labeled monoclonal antibody E48 F(ab')2 (750 MBq, 1 mg) was evaluated in 10 patients with a histologically proven squamous cell carcinoma of the head and neck and with clinical evidence of cervical lymph node involvement. Preoperative findings on lymph node status obtained by radioimmunoscintigraphy (RIS), computerized tomography, magnetic resonance imaging, and palpation were defined per side (left and/or right side of the neck) as well as per lymph node level (I through V) and compared with the histopathological outcome of the neck dissection specimen. In 10 patients, all 8 known tumors at the primary site were detected by RIS. Furthermore, RIS was correct in 13 of 13 tumor involved neck sides and in 17 of 20 tumor involved lymph node levels. False-negative observations comprised 3 levels containing tumor deposits smaller than 1 cm in diameter, 2 of which were not detected by any other diagnostic modality. Palpation, computerized tomography, and magnetic resonance imaging were correct in, respectively, 13, 15, and 15 of the 20 tumor involved levels. There were 2 false-positive observations with monoclonal antibody E48 and 3 with palpation. No false-positive detections occurred with computerized tomography or magnetic resonance imaging. In two of the patients, RIS provided clinically important information which was not provided by any other diagnostic method. In one patient, recurrence of laryngeal carcinoma was established at the primary site after previous radiotherapy. In another patient, bilateral instead of unilateral lymph node involvement became apparent. These preliminary data indicate that radioimmunoscintigraphy with monoclonal antibody E48 may be helpful in the diagnosis of metastatic and recurrent head and neck cancer.

Biodistribution of (111)indium-labeled engineered human antibody CTMO1 in ovarian cancer patients: influence of protein dose.

Thirty-one patients suspected of having ovarian cancer received a single i.v. injection of radiolabeled (100 MBq (111)In) engineered human CTMO1 (hCTMO1) to investigate its potential as an internalizing drug carrier. hCTMO1 is a complementary-determining region-grafted human IgG4 monoclonal antibody recognizing an ovarian carcinoma-associated antigen, the MUC-1-gene product. The amount of radioactivity was determined in tumor tissue, various normal tissues, including liver biopsies, and blood samples obtained at laparotomy, 6 days after injection of either 0.1 or 1.0 mg hCTMO1/kg of body weight. Circulating antigen-15-3 was measurable in all patients before injection, and immune complex formation was already present at the end of infusion. In the 0.1 mg/kg group, most of the radioactivity was bound to immune complexes, whereas in the 1.0 mg/kg group, most was bound to IgG monomers. Increasing the hCTMO1 dose 10-fold did not influence the overall disappearance of (111)In from the blood, but the elimination half-life of (111)indium bound to immune complexes was increased 2-fold. Uptake in tumor tissue 6 days postinjection at the 0.1 mg/kg dose was 7.6 times higher (P = 0.0009) than in normal tissue and 2.5 times higher (P = 0.03) than in blood. At the 1.0 mg/kg dose, the uptake in tumor tissue was 14.0 times higher (P = 0.0003) than in normal tissue and 8.1 times higher (P = 0.0007) than in blood. Liver activity was substantial (23.7 +/- 10.5 and 18.3 +/- 6.7% of the injected dose/kg for the 0.1 and 1.0 mg/kg dose group, respectively). These results are superior to those found with other clinically tested anti-MUC-1 gene product antibodies. hCTMO1 seems to be a suitable carrier for cytotoxic agents in ovarian carcinoma patients; the better uptake results and tumor-to-blood ratios are obtained at the higher dose of 1.0 mg hCTMO1/kg body weight.

Biodistribution of radiolabeled monoclonal antibody E48 IgG and F(ab')2 in patients with head and neck cancer.

Biodistribution and pharmacokinetics of radiolabeled mAb E48 IgG and E48 F(ab')2 were analyzed and compared in 39 patients with histologically proven squamous cell carcinoma of the head and neck who were included in a radioimmunoscintigraphy study and underwent surgery 44 h after injection. Three groups of patients were distinguished: group 1 (n = 19) received technetium-99m (99mTc)-labeled E48 F(ab')2, group 2 (n = 9) received 99mTc-labeled E48 IgG, and group 3 (n = 11) received 99mTc- and 131I-labeled E48 IgG as well as 125I-labeled F(ab')2. Two patients in group 1 and four patients in group 3 received a high mAb dose (10-50 mg), while all other patients received a low mAb dose (1-4 mg). From all patients in groups 2 and 3 biopsies from the surgical specimen were obtained 44 h postinjection. Tumor uptake of 99mTc-labeled E48 IgG was high, ranging from 0.007 to 0.082% of the injected dose/g, with a mean of 0.031 +/- 0.020% of the injected dose/g. The mean tumor:nontumor ratio of this conjugate was 2.8 for mucosa, 4.6 for bone marrow aspirate, 4.1 for blood, 20.3 for fat, and 21.0 for muscle. Activity uptake in tumor positive lymph nodes was 4.7 times higher as compared to negative lymph nodes. Sixteen h postinjection radioimmunoscintigraphy revealed activity uptake in the primary tumor, lymph node metastases, oral cavity, and adrenal glands. Using regions of interest, the uptake in the adrenal glands was estimated to be 0.050% of the injected dose/g. If a high mAb dose was used, no adrenal glands were visualized and the uptake in the oral cavity was clearly diminished, while the tumor uptake and tumor:nontumor ratios were increased. The mean elimination half-lifes t1/2 alpha and t1/2 in plasma were: for E48 IgG (n = 20) 6.6 +/- 2.6 and 54.1 +/- 24.3 h and for E48 F(ab')2 (n = 19) 2.3 +/- 0.4 and 19.9 +/- 4.6 h, respectively. Tumor uptake of 131I-labeled E48 IgG was 49% higher than of 125I-labeled F(ab')2. For most tissues except normal oral mucosa, tumor:nontumor ratios were slightly higher for F(ab')2 than for IgG. The present study shows that mAb E48 accumulates selectively and to a high level in head and neck squamous cell carcinoma. Although no definite conclusions can be drawn as to which mAb form is more suitable, IgG or F(ab')2, mAb E48 seems to have potential for radioimmunotherapy in head and neck squamous cell carcinoma patients.

Radioimmunoscintigraphy and biodistribution of technetium-99m-labeled monoclonal antibody U36 in patients with head and neck cancer.

So far, mAb E48 is the most promising antibody described for specific targeting of head and neck squamous cell carcinoma (HNSCC) in patients. On the basis of its more homogeneous reactivity pattern on HNSCC, the novel mAb U36 may be even better suited for targeting. In this study the biodistribution of mAb U36 was evaluated by radioimmunoscintigraphy (RIS) and biopsy measurements in 10 patients who were suspected of having neck lymph node metastases from a histologically proven HNSCC and who had been scheduled to undergo resection of the primary tumor and neck dissection. Patients received 1.8-53.0 mg mAb U36 IgG labeled with 756 +/- 95 MBq technetium-99m i.v. Preoperatively, palpation, computerized tomography, magnetic resonance imaging, and RIS were performed. RIS images included planar and single-photon emission computerized tomography images of the head and neck and planar images of the whole body. The diagnostic findings were recorded per side as well as per lymph node level of the neck and compared to the histopathological outcome. Radioactivity in blood samples and biopsies from the surgical specimens were measured. All 10 primary tumors were visualized by RIS. All diagnostic modalities were correct in 7 of 14 tumor-involved lymph node levels. The missed lymph node metastases comprised micrometastases, small tumor-involved nodes (<9 mm), and tumor-involved nodes with much necrosis, keratin, or fibrin. There were no false-positive observations with mAb U36. Besides activity uptake in tumor tissue, only a slight accumulation of activity was observed in the mouth, lungs, liver, spleen, kidneys, and scrotal area. Biopsies from the surgical specimen showed a high tumor uptake of 20.4 +/- 12.4% of the injected dose/kg (range, 8.0-43.0% of injected dose/kg), 44 h postinjection. An increase in the mAb dose did not influence uptake of activity in tumor tissue. The mean tumor:nontumor ratio at this time point was 2.3 for mucosa, 2.8 for blood, 3.0 for bone marrow aspirate, 12.9 for fat, and 13.0 for muscle tissue. The present clinical study shows that technetium-99m-labeled U36 IgG accumulates selectively and to a high level in HNSCC. The tumor-targeting results for U36 IgG are comparable to those previously described for E48 IgG. On the basis of the results of ongoing biodistribution studies in which both mAbs E48 and U36, labeled with different iodine isotopes, are simultaneously evaluated for tumor uptake and retention in HNSCC patients, one of these mAbs will be selected for future adjuvant radioimmunotherapy trials.

Safety and biodistribution of 99mTechnetium-labeled anti-CD44v6 monoclonal antibody BIWA 1 in head and neck cancer patients.

The CD44 protein family consists of isoforms, encoded by standard exons and up to nine alternatively spliced variant exons (v2-v10), which are expressed in a tissue-specific way. Expression of v6-containing variants (CD44v6) has been related to aggressive behavior of various tumor types and was shown to be particularly high in squamous cell carcinoma (SCC). Therefore, CD44v6 might be a suitable target for radioimmunoscintigraphy (RIS) and therapy. The present study evaluates the novel high-affinity murine anti-CD44v6 monoclonal antibody (MAb) BIWA 1 for its safety and targeting potential in patients with SCC of the head and neck (HNSCC). Twelve HNSCC patients, who had planned to undergo resection of the primary tumor and neck dissection, were included. Preoperatively, 2, 12, or 52 mg of 99nTc-labeled MAb BIWA 1 was administered. RIS results obtained 21 h after injection were compared with palpation, computed tomography, and magnetic resonance imaging, with histopathology as the gold standard. Moreover, biodistribution of BIWA 1 was evaluated by radioactivity measurement in blood and bone marrow and in biopsies from the surgical specimen obtained 40 h after injection. The distribution of BIWA 1 in tumor biopsies was analyzed by immunohistochemistry. BIWA 1 integrity in the blood was assessed by high-performance liquid chromatography and related to soluble CD44v6 levels in serum samples. No drug-related adverse events were observed. Human antimouse antibody responses were observed in 11 patients. The diagnostic efficacy of RIS appeared to be comparable for the three BIWA 1 dose levels and for the four diagnostic methods. Besides activity uptake in tumor tissue, minimal accumulation of activity was observed in mouth, lungs, spleen, kidney, bone marrow, and scrotal area. Analysis of tissue biopsies revealed high uptake in tumors, with a mean value of 14.2+/-8.4% of the injected dose/kg tumor tissue and a mean tumor:blood ratio of 2.0+/-1.4 at 40 h after injection. Differences among the three dose groups were not statistically significant, although a trend toward lower uptake in the highest dose group was noted. Distribution of BIWA 1 throughout the tumor was heterogeneous for all dose groups, which might be related to the high affinity of the MAb. The mean biological half-life in blood (34.5+/-6.1 h) was not dose dependent. Extensive complex formation of BIWA 1 was observed in the 2-mg group, most probably with soluble CD44v6 present in the blood, and complex formation relatively diminished upon increase of the MAb dose. BIWA 1 is a promising MAb for targeting HNSCC because it can be safely administered to HNSCC patients, while it shows high and selective tumor uptake. However, BIWA 1 is immunogenic, and therefore a chimerized or humanized derivative of BIWA 1 with intermediate affinity will be used in future clinical trials.

Orphan drugs: expensive yet necessary.

Whether the prices of certain orphan treatments are justified is highly controversial. One argument is that such therapies should not be funded through the public purse or private health plans because a patient with a rare disease requires more than their 'fair share' of a limited health care budget. Orphan medications can also be denied because they fare poorly in the cost-effectiveness assessments of drugs. This paper takes the unusual line that life-saving treatments should be provided regardless of their cost. This contention is based on the Harvard philosopher John Rawls' theory of justice. We offer three rules to limit the use of cost-effectiveness approaches: efficiency assessments should not be deployed (i) when the choice is between an only treatment and no treatment, or to (ii) prioritise between different patients and patient groups. However a well considered cost efficiency calculation may have its place (iii) where a patient has a choice between two or more equally safe and effective treatments. We rebut potential objections to this analysis, and conclude that there has been a tendency to classify appeals for orphan treatments as a minority interest and in conflict with the aims of public health and society at large. Rawls' concept of societal justice shows that a distinction between the individual and society in this context is bogus. The funding of orphan therapies is as much a matter for public health as the funding of treatments for other conditions. Treatment must not be withheld on economic grounds.

Determinants of bone mineral density in older men and women: body composition as mediator.

This study aimed to assess the relative importance of several determinants of bone mineral density (BMD) and to examine to what extent these potential determinants influence total hip BMD through body composition. The study population consisted of 522 participants (264 women and 258 men) of the Longitudinal Aging Study Amsterdam (LASA), aged 65 years and over, and living in Amsterdam and its vicinity. BMD of the total hip was measured using dual-energy X-ray absorptiometry (DXA). Potential determinants of BMD were age, weight change since age 25 years, lifestyle factors, chronic diseases, medication use, and hormonal factors. Potential mediators between the possible determinants and BMD were two measures of body composition: fat mass (FM) and appendicular muscle mass (AMM). Multiple regression analyses including all potential determinants in one model without body composition identified age, weight change, walking activity, and sex hormone-binding globulin (SHBG) as independent determinants for total hip BMD in women. In men, current smoking, participation in sports, and parathyroid hormone (PTH) concentration were independently associated with total hip BMD. When total hip BMD was regressed on the potential determinants and each measure of body composition, it appeared that FM, and to a lesser extent, muscle mass (MM), were independently related to BMD. In women, adjustment for FM reduced the strength of the associations of weight change, walking activity, and SHBG with total hip BMD. Adjustments for MM did not influence the associations between the determinants and BMD. In men, neither FM nor MM appeared to play a mediating role between the determinants and BMD. It can be concluded that (1) FM and MM are strong independent determinants of total hip BMD and that (2) FM possibly plays a mediating role in the association of weight change, walking activity, and SHBG with total hip BMD in women.

Alendronate in the prevention of bone loss after a fracture of the lower leg.

Fracture of a leg and the consequent absence from weight-bearing lead to local bone loss. A 1-year, single-center, prospective, randomized, double-blind study was conducted, to determine whether bone loss would occur in the proximal femur and the calcaneus after a fracture of the lower leg and whether this loss could be prevented by the antiresorptive drug bisphosphonate alendronate. Twenty-three men and 18 women with a recent unstable fracture of the lower leg were randomized to receive either 10 mg of alendronate daily or placebo. Bone mineral density (BMD) of both hips and the lumbar spine was measured at baseline and 6 weeks and 3, 6, and 12 months after start of the treatment. Quantitative ultrasound (QUS) measurements of the calcaneus were performed at baseline on the noninjured side and at 6 weeks and 3, 6, and 12 months after start of treatment on both sides. After 1 year, in the placebo group, there was a significant decrease from baseline in BMD of the hip on the side of the fracture. In the alendronate group, there was no significant change from baseline. The differences in BMD between the two treatment groups on the side of the fracture were significant in all sites of the hip: 4.4% (p = 0.016) in the trochanter, 4.6% (p = 0.016) in the femoral neck, and 3.9% (p = 0.009) in the total hip. In the hip on the contralateral side, there were no significant changes from baseline in either treatment group and there was no difference between the two treatment groups. BMD in the lumbar spine increased in the alendronate group, and after 1 year there was a significant difference between the active treatment and placebo group of 3.4% (p = 0.04). One year after fracture, ultrasound parameters of the calcaneus in the placebo group were significantly lower on the fractured side compared with the contralateral side (p < 0.01). In the alendronate group, no significant difference between the two sides was observed. In conclusion, BMD of the proximal femur was still decreased 1 year after a fracture of the lower leg. Alendronate prevented this bone loss.

Pubertal maturation characteristics and the rate of bone mass development longitudinally toward menarche.

To assess risks for osteoporosis and to compare bone mass in different groups of healthy children or children with diseases, it is important to have knowledge of their sexual maturation status during puberty. The aim of our study was to evaluate bone mass formation longitudinally in relation to pubertal maturation characteristics in healthy white girls. We investigated the bone mineral content (BMC) and the bone mineral density (BMD) at different skeletal sites in 151 girls with increasing pubertal stages in relation with their chronological age and with an early or late onset of puberty or menarche and with a slow or fast maturation. Bone mass was measured at the onset of puberty, during puberty, and at menarche. We conclude the following: (1) from midpuberty to menarche, the increase in bone mass formation is highest at all skeletal sites in white girls; (2) early mature girls at the onset of puberty have slightly but definitely lower bone masses at all skeletal sites and at all pubertal stages than late mature girls, whereas the average bone mass formation from the onset of puberty to menarche is similar in both groups; (3) girls with a slow rate of pubertal maturation have lower bone mass values 2 years after the onset of puberty, but at menarche bone mass is similar compared with fast maturers; and (4) it cannot be confirmed that there is an effect of menarcheal age on bone mass values at menarche.

Vitamin D status and sex hormone binding globulin: determinants of bone turnover and bone mineral density in elderly women.

To examine the relation of the vitamin D status and the remaining estrogen activity with bone turnover and bone mineral density (BMD) in elderly women, BMD was measured at both hips using dual-energy X-ray absorptiometry and at the distal radius using single photon absorptiometry, in 330 healthy women aged 70 and over. Vitamin D metabolites, sex hormone binding globulin (SHBG), PTH(1-84), osteocalcin, alkaline phosphatase, and hydroxyproline and calcium excretion in 2 h fasting urine were measured. Multiple linear regression was used to adjust for potential confounders. In 65% of the women, serum 25(OH)D was below 30 nmol/l. Only values below a threshold for 25(OH)D were negatively related to serum PTH(1-84) (p = 0.02, threshold at 25 nmol/l) and to osteocalcin levels (p = 0.04, threshold at 30 nmol/l). BMD of the femoral neck and trochanter was positively related to serum 25(OH)D (left neck p = 0.001) with thresholds at 30 nmol/l whereas the distal radius was not (p = 0.32). Serum PTH was negatively related to BMD at all measurement sites (all p < 0.001). Serum SHBG, an inverse measure of estrogen activity, was positively related to osteocalcin levels (p = 0.004) and the urinary hydroxyproline/creatinine ratio (p = 0.002) and negatively related to the BMD of the trochanter (left trochanter p = 0.02) and the distal radius (p = 0.001). We conclude that in elderly women, serum 25(OH)D levels below 30 nmol/l are associated with secondary hyperparathyroidism and increased bone turnover. SHBG is positively related to bone turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effect of salt loading on sodium and lithium excretion in Dahl salt-resistant and -sensitive rats.

Fractional excretion of lithium, as a marker for proximal sodium reabsorption, was determined in normotensive Dahl S rats (susceptible to NaCl hypertension) and Dahl R rats (resistant to NaCl hypertension) before and following an acute sodium load. Baseline mean arterial pressures, inulin clearances, sodium excretion rates, and fractional lithium clearances were not different between the R and S rats. Following the salt loading and despite similar mean arterial pressures and degree of volume expansion, the glomerular filtration rate, urinary flow rates, and absolute sodium excretion rates were greater in R than S rats. The fractional excretion of lithium was also greater in R than S rats. These data demonstrate that, at equal mean arterial pressures, Dahl S rats have a reduced capacity for sodium excretion, and that this defect is present prior to the development of hypertension. Furthermore, the observation that these animals also have a lower fractional lithium excretion during volume expansion suggests that salt loading reduces proximal tubule reabsorption to a lesser extent in Dahl S than R rats. These data suggest that the subnormal sodium and water excretion observed after sodium loading in S rats may be partially due to an abnormality in proximal tubule sodium handling.

Sodium balance in renal failure. A comparison of patients with normal subjects under extremes of sodium intake.

To gain insight into the factors involved in the maintenance of sodium balance in patients with chronic renal failure, we studied 10 patients with a creatinine clearance of 11.5 +/- 4.0 ml/min after equilibrium on 20 and 120 mEq of sodium per day. The measurements included blood pressure, plasma volume, blood volume, extracellular fluid volume, plasma renin activity, plasma aldosterone, and plasma norepinephrine. For comparison, eight normal volunteers were studied after equilibration on 20, 200, and 1128 mEq of sodium per day. The latter intake was chosen to match the high sodium intake per residual renal function in the patients. In the patients, equilibrium after raised sodium intake was accompanied by a marked increase in blood pressure and blood volume, a moderate fall in plasma renin activity and levels of aldosterone and norepinephrine, and only little expansion of the interstitial space. The 24-hour creatinine clearance rose by 21.2 +/- 7.2%. Fractional sodium excretion (X 100%) was 5.3 +/- 0.8% during the 120 mEq sodium diet. In the normal volunteers, increasing the sodium intake from 20 to 1128 mEq/day evoked no consistent change in blood pressure but caused a comparable rise in blood volume, considerable suppression of plasma renin activity, aldosterone, and norepinephrine, and a much larger increase in interstitial volume. Their creatinine clearance had risen by 22.4 +/- 6.5%, and their fractional sodium excretion during the 1128 mEq sodium intake was 3.9 +/- 0.2%.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of growth hormone (GH) on histomorphometric indices of bone structure and bone turnover in GH-deficient men.

We investigated the effects of GH on bone structure and turnover by histomorphometry in GH-deficient adults. Therefore, transiliac bone biopsies were obtained before and after 1 yr of treatment in 36 GH-deficient men (mean age, 28 +/- 4 yr). Thirteen patients had isolated GH deficiency and 23 patients had multiple pituitary hormone deficiencies. Patients were randomly assigned to four treatment groups. Groups 1, 2, and 3 received 1, 2, and 3 IU/m2/day (0.35, 0.69, and 1.3 mg/m2/day) [corrected] GH, respectively, and the fourth group received placebo for the first 6 months and 2 IU/m2/day (5.8 mg/m2/day) GH for the subsequent 6 months. GH treatment resulted in an increase of cortical thickness from 0.98 +/- 0.27 to 1.20 +/- 0.35 mm (P = 0.005), but trabecular bone volume did not change. Bone formation variables increased significantly: osteoid surface increased from 8.5 +/- 5.3 to 15.5 +/- 6.1% (P = 0.0002), mineralizing surface increased from 6.7 +/- 2.5 to 10.8 +/- 4.4% (P = 0.0002), and bone formation rate increased from 0.04 +/- 0.02 to 0.08 +/- 0.04 mm3/mm2/day (P = 0.0001). Eroded surface did not change, but osteoclast number increased from 0.6 +/- 0.5 to 1.25 +/- 0.5 Oc/mm2 (P = 0.0001). The relative formation period increased significantly (P = 0.001), whereas the resorption period, including reversal phase, decreased from 65 to 40 days (P = 0.02). Activation frequency increased from 0.39 +/- 0.17 to 0.74 +/- 0.34 y(-1) (P = 0.0001). These data indicate a stimulated bone turnover as a result of GH treatment and a shorter resorption and reversal time. The increased turnover did not result in an increased trabecular bone volume, but the cortical thickness increased significantly.

Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial.

The purpose of the study was to determine the effect of vitamin D supplementation on bone turnover and bone loss in elderly women. Three hundred forty-eight women, ages 70 yr and older, were randomized to receive 400 IU vitamin D3 per day (n = 177) or placebo (n = 171), double-blind, for a period of 2 yr. Main outcome measures were bone mineral density of both hips (femoral neck and trochanter) and the distal radius, as well as biochemical markers of bone turnover. The effect of vitamin D supplementation was expressed as the difference in mean (percentage) change between the placebo group and the vitamin D group. The measurements were repeated in 283 women after 1 yr and in 248 women after 2 yr. Vitamin D supplementation significantly increased serum 25-hydroxyvitamin D (250HD) (+35 nmol/L) and 1,25-dehydroxyvitamin D [1,25-(OH)2D] (+7.0 pmol/L) levels and urinary calcium/creatinine ratios (+0.5%) and significantly decreased PTH(1-84) secretion (-0.74 pmol/L) after 1 yr. No effect was found for the parameters of bone turnover. The effect on the bone mineral density of the left femoral neck was +1.8% in the first yr, +0.2% in the second yr, and +1.9% during the whole period (95% confidence interval 0.4, 3.4%). At the right femoral neck the effects were +1.5%, +1.1%, and +2.6% (confidence interval 1.1, 4.0%), respectively. No effect was found at the femoral trochanter and the distal radius. Supplementation with 400 IU vitamin D3 daily in elderly women slightly decreases PTH secretion and increases bone mineral density at the femoral neck.