The long-term effect of comprehensive geriatric care on gait after hip fracture: the Trondheim Hip Fracture Trial--a randomised controlled trial.

SUMMARY: At present, most hip fracture patients are treated in orthopaedic wards. This study showed that a relatively short hospital intervention based on principles of comprehensive geriatric assessment resulted in safer and more efficient gait as long as 1 year following the fracture as compared to conventional orthopaedic treatment. INTRODUCTION: Hip fracture patients are frail, and the fracture is usually followed by substantial decline in gait function. Few studies have assessed gait characteristics other than gait speed and knowledge about the effect of early intervention on long-term gait outcome is sparse. The purpose of this study was to evaluate the long-term effect of pre- and post-surgery Comprehensive Geriatric Care (CGC) on ability to walk, self-reported mobility and gait characteristics in hip fracture patients. METHODS: Two armed, parallel group randomised controlled trial comparing CGC to conventional Orthopaedic Care (OC) in pre- and early post-surgery phase. Hip fracture patients (n = 397), community-dwelling, age >70 years and able to walk at time of the fracture were included. Spatial and temporal gait characteristics were collected using an instrumented walkway (GAITRite® system) 4 and 12 months post-surgery. RESULTS: Participants who received CGC had significantly higher gait speed, less asymmetry, better gait control and more efficient gait patterns, more participants were able to walk and participants reported better mobility 4 and 12 months following the fracture as compared to participants receiving OC. CONCLUSIONS: Pre- and post-surgery CGC showed an effect on gait as long as 1 year after hip fracture. These findings underscore the importance of targeting the vulnerability of these patients at an early stage to prevent gait decline in the long run. As presently, most hip fracture patients are treated in orthopaedic wards with larger focus on the fracture than on frailty, these results are important to inform new models for hip fracture care.

Effects of thiopental on transport and metabolism of glutamate in cultured cerebellar granule neurons.

This study was performed to analyze the effects of the barbiturate thiopental on neuronal glutamate uptake, release and metabolism. Since barbiturates are known to bind to the GABA(A) receptor, some experiments were carried out in the presence of GABA. Cerebellar granule neurons were incubated for 2 h in medium containing 0.25 mM [U-(13)C]glutamate, 3 mM glucose, 50 microM GABA and 0.1 or 1 mM thiopental when indicated. When analyzing cell extracts, it was surprisingly found that in addition to glutamate, aspartate and glutathione, GABA was also labeled. In the medium, label was observed in glutamate, aspartate and lactate. Glutamate exhibited different labeling patterns, indicating metabolism in the tricarboxylic acid cycle, and subsequent release. A net uptake of [U-(13)C]glutamate and unlabeled glucose was seen under all conditions. The amounts of most metabolites synthesized from [U-(13)C]glutamate were unchanged in the presence of GABA with or without 0.1 mM thiopental. In the presence of 1 mM thiopental, regardless of the presence of GABA, decreased amounts of [1,2, 3-(13)C]glutamate and [U-(13)C]aspartate were found in the medium. In the cell extracts increased [U-(13)C]glutamate, [1,2, 3-(13)C]glutamate, labeled glutathione and [U-(13)C]aspartate were observed in the 1 mM thiopental groups. Glutamate efflux and uptake were studied using [(3)H]D-aspartate. While efflux was substantially reduced in the presence of 1 mM thiopental, this barbiturate only marginally inhibited uptake even at 3 mM. These results may suggest that the previously demonstrated neuroprotective action of thiopental could be related to its ability to reduce excessive glutamate outflow. Additionally, thiopental decreased the oxidative metabolism of [U-(13)C]glutamate but at the same time increased the detectable metabolites derived from the TCA cycle. These latter effects were also exerted by GABA.

[Geriatric assessment in Norway. Scandinavian guidelines for geriatric medicine]. / Geriatrisk utredning i Norden. Nordiske retningslinjer for spesialisthelsetjenesten i geriatri.

The Nordic countries have collaborated on reviewing and updating the guidelines of comprehensive case assessment in geriatric medicine. The Norwegian version of the document produced has recently been published as the official guidelines for the Norwegian Geriatrics Association. The document describes the status of geriatric medicine in the Nordic countries and summarizes the available documentation on its effectiveness and management. It also presents a detailed plan for carrying out geriatric case assessment. Scales for clinical use are evaluated and specific recommendations made with regard to their use in clinical practice. In this article the document is briefly described and commented on.

Geriatric work-up in the Nordic countries. The Nordic approach to comprehensive geriatric assessment.

A group established by the Nordic professors of geriatrics has developed a position document presenting a shared and updated review of geriatric work-up as a way of comprehensive geriatric assessment in the Nordic countries. The main intention is that the document will serve as support and help for the clinician concerned with hospital based geriatric medicine. It may also be useful for quality control and teaching. Not least, it may be useful for health professionals other than geriatricians. To some extent, the position of geriatric medicine in the Nordic countries varies between the countries. However, the background for developing a Nordic version of geriatric work-up is shared attitudes and principally the same organization of the health care system, and collaboration within geriatrics for many years. Several trials on comprehensive geriatric assessment and management performed in different settings have shown favourable outcomes. Results from controlled Nordic trials are compiled and summaries of meta-analyses are presented. The concept of Nordic geriatric work-up is based on a model defining health and disease in old age as dimensions of pathology, impairments, functional limitations, and disability, all being modified by extra- and intraindividual factors. Handicap is defined as the disability gap. Different health professionals have varying responsibilities in the geriatric team-work, but all should be dedicated to establish common goals. The geriatric work-up is presented with success factors and barriers, stating important differences between multidisciplinary and interdisciplinary processes. Checklists and assessment scales may be very useful when performing a geriatric work-up, but they should be used with caution. Specific scales covering different functional areas of the geriatric patient are recommended for clinical practice. Such scales must be valid, reliable, acceptable to the patient, responsive to change, and should be in an appropriate format, as well as easy to administer. Prior to the use among geriatric teams in the Nordic countries the scales should be translated into all the Nordic languages, and the translated versions should ideally have been subjected to validity and reliability testing. However, so far no scale meets these demands regarding all the five Nordic languages.

[Diagnosis and treatment of high blood pressure. How to invest?]. / Diagnostikk og behandling av høyt blodtrykk. Hvordan investere?

High blood pressure is a major risk factor for development of cardiovascular diseases. During 1992 and 1993, several national consensus reports about treatment of arterial hypertension have been published. There are discrepancies between the recommendations contained in the reports, which has caused uncertainty among physicians. We discuss the basic problems connected to evaluation and recommendation, and the demand for standardization and organization of the health service programme for patients with high blood pressure. It is possible to learn from, and thereby achieve better quality of medical practice, through a continuous registration of our routines and results. The Trondheim model is designed to depict specific information from the primary health services in a follow-up programme. This information is sampled in a data base from which primary physicians can obtain feedback on statistical evaluations twice a year. This is defined as a quality assurance programme to secure and improve the quality of the medical service to patients with high blood pressure.

Flow cytometric assessment of peripheral blood contamination and proliferative activity of human bone marrow cell populations.

Bone marrow aspiration is superior to bone marrow biopsies due to less discomfort to the volunteer or patient, but it is inferior concerning the reproducibility of cytokinetic information. Therefore, a method that could select aspirates of quality and reproducibility equal to those of biopsies was sought. Low-density (mononucleated) bone marrow cells were labelled with T200 common leukocyte antigen, CD45, which differentiate cells into erythroid, myeloid, and lymphocyte + monocyte subpopulations based on their immunofluorescence intensity. A hypotonic propidium iodide solution was added, and DNA cell cycle characteristics of the total cells and the subpopulations were obtained. Twenty-two aspirations were performed on three healthy men. There was a strong negative correlation between the amount of CD45-gated lymphocytes + monocytes, indicative of peripheral blood cell contamination in the aspirate, and the percentage of total cells and subpopulations in DNA S phase. A marked reduction in the percentage of cells in S phase was observed when the lymphocyte + monocyte counts were higher than 30%; this level was used to exclude aspirates with an unacceptable degree of peripheral blood cell admixture. Twelve of the aspirates were found to be of acceptable quality due to their low lymphocyte + monocyte count. These aspirates were compared with 11 bone marrow biopsy expellates from hematologically normal patients undergoing open cardiac surgery. The 12 aspirates were found to have almost identical mean percent S-phase cells as the biopsy expellates, both for the total cell population (14% +/- 3.45% vs. 15% +/- 1.5%) and for the erythroid (24% +/- 6% vs. 24.4% +/- 3.3%) and myeloid (10% +/- 2.4% vs. 10.7% +/- 2.5%) subpopulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Colony-forming unit-granulocyte-macrophage and DNA synthesis of human bone marrow are circadian stage-dependent and show covariation.

Bone marrow samples from sternum and iliac crests were harvested every 4 hours during 19 24-hour periods from 16 healthy male volunteers, and myeloid progenitor cells were cultured by the colony-forming unit-granulocyte-macrophage (CFU-GM) assay. A large interindividual variation was observed in the mean number of colonies during each 24-hour period, with the highest 24-hour mean colony number being about 600% greater than the lowest (range: 16 +/- 2.3 to 100.3 +/- 4.5). For each individual the difference between the lowest and highest colony number throughout the day ranged from 47.4% to 256.3% of the mean colony number of each series. A circadian stage-dependent variation in the number of colony-forming units of myeloid progenitor cells (CFU-GM) of human bone marrow was demonstrated, with values 150% higher, on the average, during the day as compared with the night. The overall data (891 CFU-GM replicates) exhibited a significant 24-hour rhythm (P less than .001) with an acrophase at midday (12.09 hours with 95% confidence limits from 10.32 to 13.49 hours) and a trough at midnight. This 24-hour variation was found to covary with DNA synthesis in the total proliferating bone marrow cell population. A seasonal effect on CFU-GM numbers was detected by ANOVA (P = .014) and by the least squares fit of a 1-year cosine (P = .015), with the highest number found in summer. The potential relevance of these findings should be examined in relation to cytotoxic cancer therapy, use of hematopoietic growth factors, and bone marrow transplantation.

DNA synthesis in human bone marrow is circadian stage dependent.

Fraction of human bone marrow (BM) cells in DNA synthesis has been studied by sampling BM from the sternum or the iliac crests every 4 hours during one 24-hour period in 16 healthy male volunteers. Three of the subjects underwent the sampling procedure twice, resulting in 19 24-hour profiles. The percentage of cells in DNA synthesis measured by flow cytometry demonstrated a large variation along the circadian time scale for each 24-hour profile, with a range of variation from 29% to 339% from lowest to highest value. Seventeen profiles (89.5%) had the highest DNA synthesis during waking hours between 08:00 hours and 20:00 hours, and the lowest percentage of cells in DNA synthesis between 00:00 hours and 04:00 hours. The mean value of the lowest DNA synthesis for each 19 24-hour period was 8.7% +/- 0.6%, while the mean value of the highest DNA synthesis was 17.6% +/- 0.6%, ie, a twofold difference. There was no difference in DNA synthesis between winter and summer. A significantly higher DNA synthesis was demonstrated for samples obtained from sternum as compared with the iliac crests, but the same circadian pattern was demonstrated for both localizations. By taking circadian stage-dependent variations in DNA synthesis into account it may be possible to reduce BM sensitivity to cytotoxic chemotherapy, to increase the effect of hematopoietic growth factors as well as increase the fraction of proliferating cells with careful selection of time of day for harvesting BM cells for auto- or allografting.

Cytometry and time-dependent variations in peripheral blood and bone marrow cells: a literature review and relevance to the chronotherapy of cancer.

By flow cytometry of individual cells, multiple cell properties can be analyzed. Such parameters may be important in relation to cytotoxic treatment of cancer. For example, DNA measurements will answer questions regarding cell kinetics. Myelosuppression is the major dose-limiting toxicity during cancer treatment. Therefore, the study of cell cycle parameters in bone marrow cells is highly relevant. However, inattention to the existence and potential importance of biological rhythms may introduce artifacts and misleading results. The literature of rhythms in hematology is reviewed. Time-dependent variations in hematological variables have been extensively studied and rhythms have been described for all kinds of blood cells. Also the numbers of hemopoietic stem cells in the bone marrow undergo circadian variations. Our group has shown how such variations change with aging in mice. The relevance of time sequence studies in aging research of hemopoiesis was clearly demonstrated. In animal studies using cytometry, our group has demonstrated extensive circadian variations in cell cycle distribution of bone marrow cells, especially the DNA synthesis (S-phase). In humans a few and rather small time sequence studies of the bone marrow have been performed, so far. In this overview the clinical implications of circadian rhythms of S-phase variations measured by flow cytometry of human bone marrow cells are discussed. Male volunteers were examined every 4 h around-the-clock. The data indicated a lower proliferative activity during night, suggesting the possibility of reducing the bone marrow toxicity to cancer treatment when taking these time-dependent variations into consideration.

Multipotent stem cell (CFU-S) numbers and circadian variations in aging mice.

The multipotent stem cell (CFU-S) numbers were studied in aging female C3H mice (16, 21 and 26 months old, respectively) versus young controls (3 months old). Using the spleen colony technique, the d-8 CFU-S numbers were measured every 3 h during the 24-h period at three different times of the year. Prominent circadian variations were found in young mice. The peak and trough values were significantly different also in aging mice, although the peak-trough differences were declining. When comparing young and old mice at different times of the 24-h period, the CFU-S numbers were sometimes significantly different, but often not. The 24-h mean values were consistently declining during aging. Young mice had different circadian variation patterns and 24-h mean values when examined at different times of the year. It is concluded that the d-8 CFU-S numbers decline in aging mice. Conflicting reports may partly be due to neglect of physiological variations.

The dimer of hemoregulatory peptide (HP5B) stimulates mouse and human myelopoiesis in vitro.

A synthetic analogue of a pentapeptide associated with mature granulocytes has been described earlier and shown to suppress myelopoietic colony formation in vitro in concentrations from 10(-13) to 10(-6) M. By oxidation of the peptide, a dimer will rapidly occur by formation of disulfide bridges between cysteine residues. We here demonstrate that this dimer has the opposite effects of the monomer. For both mouse and human granulocyte-macrophage colony-forming units (CFU-GM), a dose-dependent enhancement of colony formation was observed in the dose range 10(-16) to 10(-5) M, where a saturation level was reached above 10(-8) M. At low doses of colony-stimulating activity (CSA) and in the linear stimulating phase, an up to ten times increase of colony formation was seen, whereas at higher doses the effect was less pronounced. Also at the plateau level of CSA stimulation an increased colony yield was seen. All types of colonies were stimulated. The dimer itself had no colony-stimulating factor activity and was not toxic to bone marrow cells in suspension cultures up to 24 h. Upon reduction of the dimer by use of sulfhydryl compounds, inhibitory effects on CFU-GM were restored. The peptide had no effect on the phagocytic process in human granulocytes, including attachment and internalization of bacteria or Zymosan particles. The monomerdimer equilibrium of hemoregulatory peptide may constitute a new mechanism for proliferative regulation of myelopoietic cells.

Alterations of cell cycle distribution in the bone marrow of aging mice measured by flow cytometry.

The effect of aging on the cell cycle distribution in bone marrow cells was measured by flow cytometry with special reference to the lability in bone marrow physiology. Female C3H mice were examined every 3 h during a 24-h period at the age of 16, 21 and 26 months, vs 3-month-old control mice. Considerable circadian fluctuations were found in the different cell cycle phases in young mice. The rhythmicity patterns were different when comparing different months. In aging mice the variations were dampened, while consistent age-related phase shifts were not seen. The maximal 24-h mean numbers of cells in all three cell phases, but especially the S and G2 phases were reached at 21 months. The relative number of S and G2 phases were significantly reduced in 26-month-old mice, indicating an age-related shift of the proliferative capacity. The present findings are discussed in relation to age-related changes in granulopoiesis and the increase of myelotoxic effects during cancer chemotherapy in aging individuals.

Circadian and circannual variations of cell cycle distribution in the mouse bone marrow.

The cell cycle distribution of bone marrow cells from the femurs of female C3H mice has been investigated by flow cytometry according to the time of the day and month of the year. Both circadian and seasonal variations were found for the different cell cycle phases as well as the total cell numbers per femur. Both the mesor, the acrophase and the amplitude of the S, G2 and (G1 + G0) phases varied significantly in some months, while in other months only insignificant rhythms were found. The relative cell cycle distribution only partly reflected variations in the total numbers of proliferating cells, since the total cell number per femur was also variable. The total numbers of cells in DNA synthesis seem to be higher in the first part of the year, indicating increased cell proliferation during winter and spring. In this period the acrophases of DNA synthesis and G2 were in the morning, while the second half of the year showed the peak later in the day. In general, hemopoietic cell proliferation seems to constitute a labile equilibrium with rapidly changing activities.

Age-related differences and circadian and seasonal variations of myelopoietic progenitor cell (CFU-GM) numbers in mice.

The effect of aging on the myelopoietic progenitor cell (CFU-GM) numbers in mice was studied with special emphasis on biological rhythms in hemopoiesis. Female C3H mice, 16-, 21- and 26-month-old, were investigated versus 3-month-old controls every 3 hours during the 24-h period at three different times of the year. Strong circadian rhythms were observed in both CFU-GM concentration and content in the femur of all age-groups. The amplitudes and the 24-h mean values were declining in mice aged 21 and 26 months. From 16 months of age, a significant advance of circadian peak phases was observed. The overlapping was variable during the 24-h period. The present results may explain previous inconsistencies regarding myelopoietic progenitor cell numbers in aging mice. Some seasonal differences in rhythmicity patterns were also observed. Fitting of original data to single sinus functions was highly significant, although important details sometimes were obscured.

Rhythmic variations of different hemopoietic cell lines and maturation stages in aging mice.

Non-proliferative and proliferative myeloid, and lymphoid and erythroid bone marrow cells were studied in aging female C3H mice. A chronobiological approach was used and mice aged 16, 21 and 26 months were examined vs. 3 month-old mice every 3 h during the 24-h period in three different experiments. Significant circadian fluctuations were observed in most of the cell populations, even in the oldest mice. The rhythmicity patterns might be different at different times of the year, and in young mice seasonal fluctuations in the 24-h mean values were observed. The absolute numbers of the 24-h means seemed to be highest at 21 months of age in all cell lines and maturation stages. Sinus function fitting indicated a decline of the amplitudes in aging mice. Minor age-related phase-differences were indicated in some populations. However, the fitting of original data to single sinus functions was variable and often obscured important features in the cell number variations. The present investigation illustrates the importance of performing time-sequence studies in hematology.

Circadian rhythms of peripheral blood leukocytes in aging mice.

The effect of aging on white blood cell numbers was studied with special reference to the lability in blood cell physiology. Thus, the total numbers of leukocytes, polymorphonuclear granulocytes (PMNs) and lymphocytes were investigated in C3H mice, 3-month-old mice vs. mice aged 16, 21 and 26 months. Strong circadian rhythms were observed in the different cell classes, while there were insignificant seasonal changes. Even the oldest mice had significant variations, especially in the total leukocyte numbers and the PMNs. Subtle age-related shifts in the rhythmicity patterns were indicated. When comparing the 24-h means, there was a shift between the different white blood cell classes. A permanent reduction of the lymphocyte number was observed from the age of 16 months, while the number of PMNs steadily increased in the aging mice. The present results may explain inconsistencies among previous studies, demonstrating the significance of a chronobiological approach.

Effects of a hemoregulatory peptide (HP5b) on erythroid and myelopoietic colony formation in vitro.

A hemoregulatory peptide (HP5b) associated with mature human granulocytes has been investigated for inhibitory effects on murine hemopoietic stem cells in vitro. Both highly purified peptide from natural sources and a synthetic analog peptide have been investigated in parallel. Strong inhibitory effects were found on myelopoietic colony formation in the dose range 10(-13)-10(-5) mol/l. On exceeding this dose, the inhibitory effect disappeared. Moderate to slight inhibitory effects on erythroid colony formation (BFU-E and CFU-E) from adult animals were only seen in 1,000 X the optimal doses for myelopoiesis. No effect was found on CFU-E from fetal liver. The peptide thus has a selective effect on myelopoiesis in a certain dose range. A regulatory mechanism for the peptide on hemopoiesis is proposed.