Longitudinal Measurements of FGF23, Sarcopenia, Frailty and Fracture in Older Community Dwelling Women.

BACKGROUND: FGF23 has been associated with frailty and functional performance in older individuals, but the association to sarcopenia is unknown. OBJECTIVES: To investigate the association between FGF23, frailty, sarcopenia and fractures in older community dwelling women. DESIGN: Prospective longitudinal cohort study. SETTING: Malmö, Sweden. PARTICIPANTS: 995 75-year-old women, followed prospectively for ten years, with re-investigations after five (n=667) and ten (n=324) years. MEASUREMENTS: C-terminal levels of FGF23 were measured and a frailty index of 'deficits in health' created. Sarcopenia was defined by low muscle mass and strength and "probable sarcopenia" by low muscle mass only. Incident fractures were continuously registered for 10-years. Based on tertiles of FGF23, odds ratio for frailty, sarcopenia and probable sarcopenia was investigated using logistic regression models adjusted for: eGFR, PTH, calcium, vitamin D and phosphate. Fracture-free survival during 10-year follow-up was depicted using Kaplan Meier curves. RESULTS: While fracture-free survival did not differ between tertiles, women in the highest tertile of FGF23 had lower muscle strength and gait speed, and higher proportion with impaired mobility at baseline. At age 75, these women had higher odds of also being frail (ORadj 1.6 (95% CI 1.1-2.4)) and suffering from probable sarcopenia (ORadj 1.8 (95% CI 1.1-3.1)), but not sarcopenia. At follow-up the association between FGF23 and probable sarcopenia was not evident. While the association with frailty was attenuated at age 80 after adjustment (ORadj 1.6 (95% CI 1.0-2.5)), women in the highest tertile had higher odds of being frail at age 85 (ORadj 3.4 (95% CI 1.7-6.6)). CONCLUSIONS: FGF23 may be a promising clinical marker for muscle strength, functional performance, and frailty in older women, but not for future fragility fractures. Whether FGF23 is also associated with sarcopenia requires further investigation.

Traceable methods for vertical scale characterization of dynamic stroboscopic scanning white-light interferometer measurements.

Stroboscopic scanning white-light interferometry (SSWLI) can be used for 3D imaging of oscillating samples. It allows measurement of micrometer to millimeter size samples with nanometer vertical precision. Unlike coherent light source systems the SSWLI can measure unambiguously samples with vertical steps. Traceability of the vertical displacement measurement is important with SSWLI since the height measurement is not related to any specific monochromatic light wavelength. For static measurements SSWLI can be calibrated using, e.g., step height standards, but to characterize dynamic measurements traceable samples with accurate motion are needed due to error sources related to the frequency response of the SSWLI. In the presented method, SSWLI measurements are performed on dynamic transfer standards, which are characterized using a laser interferometer traceable to the SI meter. In this work dynamic SSWLI measurements at subkilohertz to 10.7 kHz frequencies with micrometer range displacement are characterized. The expanded uncertainty (k=2) was 9.6 nm for a measured displacement of 766 nm at 10.7 kHz. The methodology can be used up to the frequency limits of the SSWLI using suitable samples.

Food groups and the risk of colorectal carcinoma in an Asian population.

BACKGROUND: Singapore Chinese have experienced a rapid transition toward a pattern of disease in which lifestyle-related, chronic, degenerative diseases are major public health concerns. The rates of colorectal carcinoma have increased 2-fold over the last 3 decades. It has long been known that dietary factors play a role in the risk of this disease, although studies in Asian populations, with their unique dietary intake, have been few. METHODS: The authors conducted a population-based case-control study that included 121 Chinese patients with colorectal carcinoma and 222 healthy control participants who provided information on usual intake of major food groups in the preceding 3 years, physical activity, family history of colorectal carcinoma, and demographic variables through an in-person questionnaire. RESULTS: High intake of red meat, but not other meats, indicated a predisposition to risk of colorectal carcinoma (adjusted odds ratio [OR] for the highest tertile vs. the lowest tertile, 2.2; 95% confidence interval [95%CI], 1.1-4.2). A low vegetable intake also was associated with a higher risk, and the combined effect appeared to be additive. Those in the highest tertile of meat intake and the lowest quartile of vegetable intake had an OR of 2.6 (95%CI, 1.0-6.7). The authors observed a slight, albeit nonsignificant, positive association with foods high in refined sugars. There was no association observed with fruit or soy-legume intake in this study. Among nondietary variables, a family history of colorectal carcinoma conferred a significant increase in risk (OR, 6.7; 95% CI 2.4-18.7). CONCLUSIONS: Meat intake and vegetable intake were associated significantly with risk of colorectal carcinoma in this Asian population, and further studies on the effects of changes in these specific types of food may shed light on how best to reduce the rapid increase in rates in similar populations.

Blood transfusion in marrow graft recipients.

Of 182 consecutive patients undergoing allogeneic bone marrow transplantation (BMT), the relative numbers of those who received red blood cells (RBC), platelets (PLT), and granulocytes were 82%, 96%, and 26%, respectively. The transfused patients received an average of 1.26 (SD +/- 2.0) RBC units, 9.41 (SD +/- 13.2) PLT transfusions, and 0.33 (SD +/- 1.1) granulocyte concentrates per week per 50 kg body wt. in the period starting on the day of bone marrow transplantation (BMT) up to 60 days post BMT. The total number of units per transfused patient was 7.7 (range 1-63) RBC, 55.2 (range 2-394) PLT and 6.2 (range 1-36) granulocytes in the same period. Patients with grades II-IV acute graft-versus-host disease (GVHD) needed more RBC and PLT (p less than 0.001) than patients with grades 0-I acute GVHD. Patients with late engraftment required more granulocyte and PLT transfusion than those with early engraftment (p less than 0.05). Patients with high-risk malignancy had greater need for RBC and PLT than "low-risk patients" (p less than 0.02 and p less than 0.01), respectively). Patients with major ABO-incompatible donors showed a greater need for RBC than patients with minor ABO incompatibility (p = 0.02) or ABO identical donors (p = 0.01). Patients with relatively poor estimated survival required the most RBC and PLT.

Importance of bone marrow cell dose in bone marrow transplantation.

The importance of the size of the infused marrow cell dose (MCD) was investigated in 274 patients undergoing allogeneic BMT between 1975 and 1990. Among those, 65 had acute myelogenous leukemia (AML), 79 acute lymphoblastic leukemia (ALL), 58 chronic myelogenous leukemia (CML) and 25 severe aplastic anemia (SAA). MCD was analyzed in bivariate and multivariate analysis together with 6 other clinical factors. In multivariate analysis a low MCD was significantly associated with increased incidence of acute graft-versus-host disease (GvHD) in all patients (p = 0.005) and in ALL patients (p = 0.02) whereas in CML a high dose was instead correlated to acute GvHD. A low MCD was also correlated to an increased incidence of symptomatic cytomegalovirus (CMV) infection (p = 0.001). A low MCD was also correlated to death in acute GvHD in all patients (p = 0.01) and to a poor survival in all patients (p = 0.04) (AML, p = 0.07).

Response to tetanus toxoid immunization after allogeneic bone marrow transplantation.

An ELISA was used to study long-term immunity and immunization responses to tetanus toxoid in 48 bone marrow transplant recipients. Among patients who were seropositive to tetanus before transplant, 51% had lost their seropositivity 1 year later. All patients who were not reimmunized with tetanus toxoid were seronegative 2 years after transplant. All patients who were seronegative before transplant remained seronegative 1 year later regardless of the donor's serologic status. There was no difference in the ability to remain seropositive to tetanus toxoid between patients with and without chronic graft-versus-host disease. Of 21 patients immunized with one dose of tetanus toxoid 1 year after transplant, 14 were seronegative at the time of immunization (response rate, 64%). At 1 year after immunization, 7 remained seropositive. Ten patients were reimmunized with two doses of tetanus toxoid. All responded and 90% remained seropositive 1 year later. When 21 patients were primarily immunized with three doses of tetanus toxoid, all patients seronegative at immunization responded and all tested patients remained seropositive 2 years later. The immunization responses were significantly superior in patients receiving three doses compared with those who received one. Reimmunization with tetanus toxoid of long-term survivors after marrow transplant seems necessary. A three-dose immunization schedule is recommended to obtain an adequate immune response.

[Application of the Weibull function to the study of in vivo/in vitro correlation]. / Application de la fonction de Weibull à l'étude des corrélations in vivo/in vitro.

After transformation of concentration-time curves by integration, the Weibull function is calculated, producing an equation for a derived function representing the plasma (or salivary) kinetics. This model can be employed in the analysis of in vivo/in vitro correlations, since cumulated dissolution percentages can be directly expressed as Weibull functions. A method was developed for prediction of salivary kinetics from in vitro dissolution data and the in vivo kinetics of a solution of the drug. This method was applied to results obtained for slow release formulations of acetaminophen and theophylline administered by the oral route.

Allogeneic bone marrow transplantations at Huddinge Hospital and strategies to improve survival.

At Huddinge Hospital 275 patients underwent allogeneic bone marrow transplantation. Among children in first remission of acute leukemia or chronic phase CML (early leukemia), with HLA-identical marrow the 8-year leukemia-free survival was 77%. This was better than 38% in children undergoing transplantation in second to fourth remission (p less than 0.0009). In adults with early leukemia, the 8-year leukemia-free survival was 47% compared to 21% for intermediate-risk adults (p = 0.007). Among 25 patients with severe aplastic anemia receiving marrow from HLA-identical siblings, the actuarial 10-year survival was 78%. In 14 patients with various metabolic disorders, of whom half received marrow from HLA-mismatched donors, the actuarial 7-year survival was 71%. Forty-three patients were given marrow from HLA-mismatched donors and had an increased incidence of acute graft-versus-host disease (GvHD) and death due to GvHD compared to recipients of HLA-identical bone marrow. The major causes of death among our patients were relapse of leukemia, death due to GvHD, cytomegalovirus (CMV) pneumonitis, bacterial infection and invasive fungal infections. By preventing GvHD with T-cell depletion or methotrexate (MTX) combined with cyclosporine (CsA) acute GvHD decreased, but the incidence of relapse increased compared to patients treated with MTX or CsA alone. This resulted in improved survival in patients older than 30 years, but a nonsignificant decrease in leukemia-free survival in younger patients. There was an association between herpes virus immunity in the recipient and GvHD. CMV pneumonitis increased following GvHD and decreased in patients treated with MTX combined with CsA. Invasive fungal infections may be treated or prevented using amphotericin B encapsulated in liposomes with few side effects.

Cytomegalovirus-infected adherent cells interact synergistically and antagonistically with Staphylococcus aureus protein A in vitro.

Cytomegalovirus (CMV) has been shown to exert suppressive effects on the immune response but also to have mitogenic properties. A bacterial product, protein A from Staphylococcus aureus (SpA) was chosen to study possible interactions in vitro between bacterial products and adherent cells incubated with infectious CMV and ultraviolet light (UV)-inactivated CMV. Small amounts of infectious CMV potentiated SpA-induced DNA synthesis and Ig secretion measured by induction of plaque-forming cells (PFC). The reason for this may be that CMV in small amounts may act in synergism with the non-specific mitogen SpA. UV-inactivated CMV did not influence these responses except for a markedly enhanced PFC induction with SpA in lymphocytes from seronegative individuals. This remarkable synergism with SpA was also seen in enriched B cells. No synergism was seen in lymphocytes from seropositive donors. Large amounts of infectious CMV markedly reduced SpA-induced immune responses. Preliminary data suggest that the immunosuppressive effects are mediated by an interleukin 1 inhibitory factor. CMV was not shown to be a polyclonal B-cell activator but may, possibly in small amounts, act as such together with bacterial products, which would explain certain autoimmune phenomena. To conclude, CMV could in interaction with a bacterial product generate both synergistic and suppressive effects on immune response.

Variables predicting bacterial and fungal infections after allogeneic marrow engraftment.

Sixty-seven consecutive patients with aplastic anemia or leukemia who had been treated by allogeneic marrow transplantation and had survived for more than 1 month were surveyed in order to determine the incidence of nonviral infections occurring from 1 month to 3 years after transplantation. Twenty-eight of the 67 patients had one or more infections during this period. Around 20% suffered from pulmonary infections and 20% were classified as having a systemic infection. Ten patients died of bacterial or fungal infection, of whom 6 had graft-versus-host disease. In multivariate analyses acute graft-versus-host disease (P less than 0.0009), splenectomy (P less than 0.02), cytomegalovirus infection (P less than 0.05), and a low marrow cell dose (P less than 0.07) were correlated with nonviral infections.

Immunological recovery after bone marrow transplantation: role of age, graft-versus-host disease, prednisolone treatment and infections.

Cellular immune recovery was studied in 67 patients who had survived for one month to more than 6 years after bone marrow transplantation (BMT). From a number of immunological parameters the mitogens phytohemagglutinin, concanavalin A and rabbit antibodies to beta 2 microglobulin (A-beta 2m) were chosen because of relevant increases in lymphocyte responses with time after BMT for analysis with exponential functions (covariance analysis). Patients with younger donors had a markedly higher lymphocyte response level and a faster rate of increase with time than patients with older donors. High recipient age was also significantly associated with a depressed level of immunological response but to a lesser degree than donor age. Patients with chronic graft-versus-host disease (GVHD) had a more severely impaired response compared to patients without chronic GVHD. Furthermore, patients with GVHD showed a negative development over time with the A-beta 2m test. Lymphocytes from patients receiving a low donor marrow cell dose showed impaired response levels and rate of recovery compared to the high-dose group although the differences were not significant. Patients treated with prednisolone for grade I GVHD had depressed lymphocyte stimulations for up to 1 1/2 years post BMT compared to patients without GVHD and not receiving prednisolone. Patients with non-viral infections seemed to have more depressed lymphocyte responses than non-infected patients. Patients undergoing cytomegalovirus infections had lower response levels for all three mitogens.

Induction of immunoglobulin secretion and DNA synthesis in human lymphocytes in vitro by cytomegalovirus preparations.

Immunoglobulin secretion as evidenced by plaque-forming cells (PFC) in an indirect haemolysis-in-gel assay, and DNA synthesis were induced in human blood lymphocytes by the following preparations of cytomegalovirus (CMV): Nucleocapside Nc-CMV antigen, membrane M-CMV antigen, crude C-CMV preparations and CMV-incubated adherent cells. Peak stimulations occurred around day 6 in culture. Nc-CMV and M-CMV only stimulated PFC and DNA synthesis in lymphocytes from CMV seropositive individuals. C-CMV also stimulated lymphocytes from CMV seronegative individuals but gave better responses in lymphocytes from CMV seropositive individuals. CMV-incubated adherent cells occasionally stimulated lymphocytes from CMV seronegative individuals but always in CMV seropositive blood donors. Nc-, M-, and C-CMV gave high numbers of PFC in B cells enriched by sheep erythrocyte sedimentation and in co-cultures of enriched T and B cells. Almost no PFC were induced in enriched T cells. DNA synthesis induced by all the three antigenic CMV preparations increased after removal of adherent cells. Strong DNA synthesis was induced in enriched T cells compared to almost none in enriched B cells. It is concluded that some pure CMV preparations act as antigens and more crude preparations induce polyclonal activation. Different CMV preparations may be used to diagnose CMV, to study immune reactivity against CMV and as a model for CMV infections in vitro.

Enhancive and suppressive effects of cytomegalovirus on human lymphocyte responses in vitro.

Virus-specific lymphocyte proliferation in the presence of cytomegalovirus (CMV) without and with monocytes was studied in healthy persons. Three categories of lymphocyte response could be distinguished: seropositive low responders, naturally high responders, and lymphocyte populations responding well to CMV antigen in the presence of added CMV-incubated autologous monocytes. This latter category could be identified by preincubating autologous monocytes with CMV. CMV-seronegative persons were nonresponders. Early CMV antigens were produced in monocytes but not in lymphocytes by all CMV isolates. Infection of monocytes as detected by antibody to early viral protein did not appear to abort the antigen-presenting ability. The virus-specific responding lymphocytes were mainly of the T4+ phenotype. In contrast, addition of CMV to polyclonal mitogens significantly suppressed total lymphocyte DNA synthesis. CMV thus may have an enhanced virus-specific stimulatory effect on lymphocytes together with monocytes but a suppressive effect on the total lymphocyte population.

Pharmacokinetics, safety and preliminary clinical experiences using foscarnet in the treatment of cytomegalovirus infections in bone marrow and renal transplant recipients.

Fifty seven episodes of severe cytomegalovirus (CMV) infection were treated with iv foscarnet in 13 bone marrow and 33 renal graft recipients. The ranges of the daily dose, duration, average steady state level and total dose were 23-268 mg/kg, 2-46 days, 42-400 mg/l and 2-399 g, respectively. Adverse effects, such as decreased haemoglobin, decreased renal function and increased serum calcium, were observed in a few patients only. Increased liver enzymes, hallucinations and tremor were seen in one uraemic patient and coincided with foscarnet plasma concentrations above 400 mg/l. Among 25 patients evaluated for clinical efficacy, 12 died. Improvements, such as eradication of CMV (8/14 assessable patients), resolution of fever (11/22), and improved laboratory values (13/23) were noted in 17/24 (70%). Controlled trials are warranted on the basis of this study.

The importance of pre bone marrow transplantation serology in determining subsequent cytomegalovirus infection. An analysis of risk factors.

The yearly incidence of cytomegalovirus (CMV) infection among 73 consecutive bone marrow transplant (BMT) recipients was 68%. Recipients with negative CMV serology prior to transplantation had a yearly incidence of CMV infection of 35% compared to 87% in CMV seropositive patients (p = 0.0001). When the ages of donors and recipients were analysed as continuous variables, both recipients with a younger donor and young recipients had a lower incidence of CMV infection (p = 0.04; p = 0.05). White cell transfusions were significantly associated with an increased incidence of CMV infection (p = 0.03). If white cell transfusions were controlled for, lower marrow cell doses were significantly associated with an increased risk of CMV infection, compared to higher cell doses (p = 0.035). In multivariate analyses, the impact of negative recipient serology was so strong that the other analysed factors did not affect the prognosis for CMV infection, when taken together or separately. 14 patients had symptomatic CMV infection and 13 of those were seropositive prior to BMT. The one-year incidence of symptomatic CMV infection was 33%. None of 12 clinical factors analysed were significantly associated with symptomatic CMV infection. The CMV antibody titer level prior to BMT was not correlated to the risk for symptomatic CMV infection and/or death. The ability to respond with a significant titer rise after BMT was lowered for patients with interstitial pneumonitis compared to patients with other clinical symptoms of CMV infection.

An analysis of factors predisposing to chronic graft-versus-host disease.

Among 75 consecutive allogeneic bone marrow transplant recipients, 24 developed chronic graft-versus-host disease (GVHD), which was diagnosed from day 31 to day 368 after transplantation. Eight (33%) patients had more extensive chronic GVHD, and five patients died. The actuarial incidence of chronic GVHD was 48% at 400 days. A number of factors were analyzed for their association with chronic GVHD. Recipients of marrow from donors over 17 years of age had an actuarial incidence of chronic GVHD at 400 days of 74%, compared with 27% if the donors were under 17 years of age (log-rank test on survival curves, p less than 0.001). Other factors that appeared to predispose for chronic GVHD in bivariate analysis were recipient age above 17 years (p less than 0.02), treatment with donor unirradiated buffy-coat cells (p less than 0.01), grade-II-IV acute GVHD (p less than 0.01), and a preceding cytomegalovirus (CMV) infection (p less than 0.01). In multi-variate analysis, however, only donor age above 17 years, treatment with donor buffy-coat cells, and grade-II-IV acute GVHD were significantly associated with chronic GVHD. The possible role of CMV infection in the development of chronic GVHD is discussed.

Faster immunological recovery after bone marrow transplantation in patients without cytomegalovirus infection.

The following findings were noted among 45 bone marrow transplant recipients. The patients without cytomegalovirus (CMV) infection or chronic graft-versus-host disease (GVHD) showed normal lymphocyte stimulation in vitro by concanavalin A (Con A) more than 3 months after transplantation, and normal stimulation by phytohemagglutinin (PHA), anti-beta 2-microglobulin (A-beta 2m) and protein A (SpA) after 6 months. In contrast, the patients who had CMV infection without chronic GVHD had Con A and SpA responses within the normal range after 12 months and reduced lymphocyte responses to PHA and A-beta 2m more than 12 months after transplantation. The patients with chronic GVHD had reduced responses to all of these four mitogens after more than 12 months. In comparison with other patients those who later developed chronic GVHD showed an increased mixed lymphocyte culture stimulation during the first 3 months that decreased between 6-12 months. Patients with chronic GVHD still had reduced IgA levels at 12 months after transplantation. Patients with CMV infection, but without chronic GVHD, had higher percentages of lymphocytes with surface membrane Ig than healthy controls during the first 3 months after transplantation. The data suggest that CMV infection, regardless of chronic GVHD, delays immunologic recovery after marrow transplantation.