Role of raloxifene as a potent inhibitor of experimental postmenopausal polyarthritis and osteoporosis

OBJECTIVE: In postmenopausal rheumatoid arthritis (RA), both estrogen deficiency and the inflammatory disease contribute to the development of generalized osteoporosis. Hormone replacement therapy (HRT) with estradiol preserves bone mineral density (BMD) and ameliorates arthritis, but long-term therapy is no longer an option due to significant side effects. We therefore used a mouse model of human RA to test the hypothesis that a selective estrogen receptor modulator (SERM), the raloxifene analog LY117018, could be beneficial in the treatment of both arthritis and osteoporosis. METHODS: Female DBA/1 mice were ovariectomized and arthritis was induced with collagen immunization. Mice received an injection of raloxifene, estradiol, or vehicle control, administered prophylactically or therapeutically, and thereafter the clinical arthritis score was evaluated continuously. At termination, BMD was analyzed with peripheral quantitative computed tomography. Paws were collected for histology, and sera were analyzed for cytokines and markers of bone and cartilage turnover. Levels of cytokine messenger RNA (mRNA) were investigated with real-time polymerase chain reaction. RESULTS: Treatment with raloxifene dramatically decreased the frequency and severity of arthritis. Effective preservation of bone and cartilage was seen in raloxifene-exposed mice, as demonstrated by increased BMD and decreased serum levels of cartilage oligomeric matrix protein in the raloxifene-treated mice compared with controls. Decreased levels of mRNA for both tumor necrosis factor alpha and RANKL in spleen cells from raloxifene-treated arthritic mice indicated an immunosuppressive action of this SERM. CONCLUSION: In a well-established model of postmenopausal RA, the raloxifene analog LY117018 potently inhibits the progression of arthritis and the associated development of osteoporosis, both in a prophylactic and in a therapeutic regimen. Since long-term HRT has been associated with significant side effects, raloxifene may be a useful adjuvant treatment for postmenopausal RA.     

Mechanical bowel preparation does not affect the intramucosal bacterial colony count

Purpose  

The aim of this study was to determine if mechanical bowel preparation (MBP) influences the intramucosal bacterial colony count in the colon.     

Self-care ability among home-dwelling older people in rural areas in southern Norway

Scand J Caring Sci; 2012; 26; 113–122
Self‐care ability among home‐dwelling older people in rural areas in southern Norway Introduction: The growing number of older people is assumed to represent many challenges in the future. Self‐care ability is a crucial health resource in older people and may be a decisive factor for older people managing daily life in their own homes. Studies have shown that self‐care ability is closely related to perceived health, sense of coherence and nutritional risk. Aim: The aim of this study was to describe self‐care ability among home‐dwelling older individuals living in rural areas in southern Norway and to relate the results to general living conditions, sense of coherence, screened nutritional state, perceived health, mental health and perceived life situation. Methods: A cross‐sectional survey was carried out in rural areas in five counties in 2010. A mailed questionnaire, containing background variables, health‐related questions and five instruments, was sent to a randomly selected sample of 3017 older people (65+ years), and 1050 respondents were included in the study. Data were analysed with statistical methods. Results: A total of 780 persons were found to have higher self‐care ability and 240 to have lower self‐care ability using the Self‐care Ability Scale for the Elderly. Self‐care ability was found to be closely related to health‐related issues, self‐care agency, sense of coherence, nutritional state and mental health, former profession, and type of dwelling. Predictors for high self‐care ability were to have higher self‐care agency, not receiving family help, having low risk for undernutrition, not perceiving helplessness, being able to prepare food, being active and having lower age. Conclusions: When self‐care ability is reduced in older people, caregivers have to be aware about how this can be expressed and also be aware of their responsibility for identifying and mapping needs for appropriate support and help, and preventing unnecessary and unwanted dependency.     

Inflammatory response in patients with malignant obstructive jaundice

Objective. Surgery in patients with malignant obstructive jaundice is associated with increased risks for postoperative septic complications. The aim of this study was to investigate the inflammatory and the local cellular immune response in patients accepted for surgery because of tumours in the hepatic-pancreatic-biliary (HPB) tract. Material and methods. Patients with obstructive jaundice (group HPB⁺) were compared with those without (HPB^?). Patients undergoing surgery for benign abdominal disorders served as controls. Obstructive jaundice was present in 18 out of 33 HPB patients. Preoperatively, blood was analysed for bacteria, endotoxins and cytokines (TNF-α, IL-6 and IL-10). At operation, mesenteric lymph nodes (MLNs) were excised for bacterial cultures using standard microbiological techniques, and immunohistochemistry, using antibodies CD4 and CD8 (mainly staining T lymphocytes), CD68 (macrophages), and anti-caspase-3 (to determine the rate of apoptosis). Results. Bacterial translocation was not demonstrated in any of the patients. Increased preoperative concentrations of endotoxins were found in group HPB⁺. The number of macrophages and the rate of apoptosis in MLNs were increased in jaundiced patients, while the number of T lymphocytes was decreased. Conclusions. Malignant obstructive jaundice causes increased blood concentrations of endotoxins and cytokines, an increased number of macrophages in MLNs, a higher rate of apoptosis in MLNs, but a decreased number of T lymphocytes in MLNs. The lymphocyte depletion is probably due to the increased rate of apoptosis, and might reduce the ability of jaundiced patients to eradicate infection.     

Muscle performance and fatigue in compensated chronic liver disease

Abstract

Background: A common and debilitating symptom in patients with chronic liver disease is fatigue (CLD). Muscle dysfunction has been suggested to be a key mechanism of fatigue in CLD.

Objective: We aimed to evaluate fatigue and the potential association with muscle performance and physical activity in outpatients with CLD.

Methods: Two-hundred seventy outpatients with CLD were included, (52?±?15 years, mean?±?SD; 151 females) with autoimmune hepatitis (n?=?49), primary biliary cholangitis (n?=?45), primary sclerosing cholangitis (n?=?46), chronic hepatitis B (n?=?57) or C (n?=?73). Patients with a Child-Pugh >6 were excluded. The questionnaire Fatigue Impact Scale (FIS) was used to evaluate fatigue, and physical activity was evaluated through a self-reported level of physical activity. Muscle function was assessed with four muscle tests, walking speed, handgrip strength, standing heel-rise test (SHT) and ‘Timed Up and Go’ test (TUG).

Results: The median total FIS score was 30 (40% had FIS > 40, considered high-fatigue). Diminished muscle performance was observed in the SHT (% of predicted value: 53?±?26%) and with maximum grip strength (85?±?20%). The FIS score was significantly different between groups of CLDs (p?=?.004). In multivariate analysis the TUG (p?=?.001), SHT (p?=?.005), antidepressants (p?p?=?.001) were associated with fatigue (R²?=?29%). Subjects with higher levels of physical activity had lower FIS (p?Conclusions: In patients with CLD, fatigue was associated with low muscle performance and reduced level of physical activity, which could be a potential therapeutic target.     

Acoustic radiation force impulse elastography and serum fibrosis markers in chronic hepatitis C

Objective. In published studies there is a lack of data about the risks, management and how women with autoimmune hepatitis (AIH) decide on and are advised about pregnancy. The aim of this study was to investigate how women with AIH consider pregnancies, are advised and pharmacologically treated, as well as the outcome. Material and methods. A questionnaire was mailed to 128 women with AIH diagnosed during their fertile period and data from the Swedish National Birth Register was also used for matched controls. Results. There was an 83% response rate to the questionnaires. Sixty-three pregnancies were reported by 35 women. 48% did not consult their doctors before getting pregnant. More than half of the women reduced or stopped the immune suppression during pregnancy or breastfeeding. Some women were advised to abstain from pregnancy or even to have an abortion. Caesarean sections were performed more frequently in the AIH group (16% compared with 6.5% in the control group p<0.01).There were no significant differences in the number of stillborn infants or infants with malformations. However, 30% of the patients experienced flare-up after delivery. Conclusions. In general, the outcome of pregnancy in women with AIH seems to be good. Current pharmacological treatment appears to be safe, including azathioprine during pregnancy and lactation. After delivery an active preparedness to increase pharmacotherapy should be considered.     

Voice characteristics in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Objective  Congenital adrenal hyperplasia (CAH) is an autosomal recessive inherited disorder resulting in lack of cortisol and often aldosterone and overproduction of androgens. Raised levels of androgens can lead to increased mass in the laryngeal tissues, which may lower the fundamental frequency (F0) of the voice.
Design/patients  A follow-up study of voice characteristics in 38 women with CAH and 24 age-matched controls between 18 and 63 years of age using subjective self-ratings of voice symptoms and acoustic and perceptual analyses. The results were correlated to mutation and treatment.
Measurements  The subjects rated degree of hoarseness, dark voice, voice problems and vocal fatigue on visual analogue scales. Audio recordings were made of a standard reading passage in a sound treated booth. Acoustic analyses were made of the subjects' mean, minimum and maximum F0 in the habitual speech range. Three voice clinicians made perceptual evaluations of dark voice in terms of timbre.
Results  Women with CAH rated higher values than controls with regard to the statement 'my voice is a problem in my daily life'. They spoke with significantly lower mean, lower minimum and lower maximum F0, as well as darker voice quality as compared with the controls. Affected voice symptoms were associated with a late diagnosis or problems with medication.
Conclusion  The voices in women with CAH can be virilized because of late diagnosis or suboptimal treatment with glucocorticoids. These voice problems may need referral for voice assessment and should be considered when treating CAH.     

Smad5 is dispensable for adult murine hematopoiesis

Smad5 is known to transduce intracellular signals from bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-beta (TGF-beta) superfamily and are involved in the regulation of hematopoiesis. Recent findings suggest that BMP4 stimulates proliferation of human primitive hematopoietic progenitors in vitro, while early progenitors from mice deficient in Smad5 display increased self-renewal capacity in murine embryonic hematopoiesis. Here, we evaluate the role of Smad5 in the regulation of hematopoietic stem cell (HSC) fate decisions in adult mice by using an inducible MxCre-mediated conditional knockout model. Surprisingly, analysis of induced animals revealed unperturbed cell numbers and lineage distribution in peripheral blood (PB), bone marrow (BM), and the spleen. Furthermore, phenotypic characterization of the stem cell compartment revealed normal numbers of primitive lin(-)Sca-1(+)c-Kit(+) (LSK) cells in Smad5(-)(/)(-) BM. When transplanted in a competitive fashion into lethally irradiated primary and secondary recipients, Smad5-deficient BM cells competed normally with wild-type (wt) cells, were able to provide long-term reconstitution for the hosts, and displayed normal lineage distribution. Taken together, Smad5-deficient HSCs from adult mice show unaltered differentiation, proliferation, and repopulating capacity. Therefore, in contrast to its role in embryonic hematopoiesis, Smad5 is dispensable for hematopoiesis in the adult mouse.