The CMS19 disease model specifies a pivotal role for collagen XIII in bone homeostasis.

Mutations in the COL13A1 gene result in congenital myasthenic syndrome type 19 (CMS19), a disease of neuromuscular synapses and including various skeletal manifestations, particularly facial dysmorphisms. The phenotypic consequences in Col13a1 null mice (Col13a1-/-) recapitulate the muscle findings of the CMS19 patients. Collagen XIII (ColXIII) is exists as two forms, a transmembrane protein and a soluble molecule. While the Col13a1-/- mice have poorly formed neuromuscular junctions, the prevention of shedding of the ColXIII ectodomain in the Col13a1tm/tm mice results in acetylcholine receptor clusters of increased size and complexity. In view of the bone abnormalities in CMS19, we here studied the tubular and calvarial bone morphology of the Col13a1-/- mice. We discovered several craniofacial malformations, albeit less pronounced ones than in the human disease, and a reduction of cortical bone mass in aged mice. In the Col13a1tm/tm mice, where ColXIII is synthesized but the ectodomain shedding is prevented due to a mutation in a protease recognition sequence, the cortical bone mass decreased as well with age and the cephalometric analyses revealed significant craniofacial abnormalities but no clear phenotypical pattern. To conclude, our data indicates an intrinsic role for ColXIII, particularly the soluble form, in the upkeep of bone with aging and suggests the possibility of previously undiscovered bone pathologies in patients with CMS19.

Regulation of Salivary Peptidoglycan Recognition Protein 1 in Adolescents.

INTRODUCTION: Peptidoglycan recognition protein 1 (PGLYRP1), a member of peptidoglycan recognition proteins, is known to be involved in the proinflammatory response toward bacterial infections. Recently, PGLYRP1 was identified as a ligand for triggering receptor expressed on myeloid cells 1 (TREM-1). Although PGLYRP1 is involved in immune and inflammatory responses, its levels in initial stages of periodontal disease in adolescents are currently unknown. OBJECTIVES: We aimed to investigate salivary levels of PGLYRP1 and its correlation with TREM-1, polymorphonuclear leukocyte elastase (PMN elastase), and an active matrix metalloproteinase 8 (aMMP-8) in adolescents. METHODS: Whole saliva samples (n = 537) were collected from 15- to 16-y-old adolescents at Kotka Health Center, Finland, prior to periodontal examination, including measurement of periodontal pocket depth (PPD), visible plaque index (VPI), and bleeding on probing (BOP). Adolescents, clustered as periodontally healthy, gingivitis, or subclinical periodontitis, were tested for salivary levels of TREM-1, PGLYRP1, and PMN elastase by enzyme-linked immunosorbent assay and aMMP-8 by a time-resolved immunofluorometric assay (IFMA). RESULTS: Salivary levels of PGLYRP1 and aMMP-8 were significantly higher in adolescents with subclinical periodontitis and gingivitis compared to individuals with healthy periodontium. TREM-1 and PMN elastase levels were higher in adolescents with subclinical periodontitis compared to healthy individuals but did not reach significance. PGLYRP1 correlated positively with BOP, PPD, VPI, aMMP-8, and TREM-1. CONCLUSIONS: Elevated PGLYRP1 levels in adolescents with gingivitis and subclinical periodontitis and its positive correlation with TREM-1 and aMMP-8 may indicate an association of PGLYRP1 with initial stages of periodontal disease. Sex and poor oral hygiene but not smoking are also associated with higher levels of PGLYRP1. However, PGLYRP1 has a lower discriminating capacity and is therefore a less reliable marker alone in the diagnosis of initial stages of periodontal disease in adolescents. KNOWLEDGE TRANSFER STATEMENT: PGLYRP1, a member of peptidoglycan recognition proteins, is a ligand for TREM-1. Elevated PGLYRP1 levels in adolescents with gingivitis and subclinical periodontitis and its positive correlation with TREM-1 and aMMP-8 may indicate an association of PGLYRP1 with initial stages of periodontal disease. However, it has a lower discriminating capacity and is therefore a less reliable marker alone in the diagnosis of periodontal disease in adolescents.

Finnish Dentists Find Smoking Cessation Important but Seldom Offer Practical Support for Their Patients.

OBJECTIVES: To investigate Finnish dentists' smoking cessation related attitudes, consultation practices and familiarity with the local treatment guideline on smoking cessation. BASIC RESEARCH DESIGN: An online questionnaire was sent to 1740 dentists, which corresponds to 39% of dentists in Finland. A total of 456 dentists responded (response rate 26%), of whom 435 (95%) were clinicians. The dentists' smoking cessation practices were also compared to ones reported in a previous study in Finnish physicians. RESULTS: Dentists found smoking cessation important and often discussed and recommended quitting to the patients, but concrete withdrawal actions were seldom provided. The local treatment guideline on smoking cessation was actively utilized by 36% of the dentists. Adherence to the guideline was associated with higher rates of smoking cessation activities and success in them. Smoking cessation activity among dentists was significantly lower than in Finnish physicians. In accordance with the literature, among dentists, the most common barriers for smoking cessation were lack of time (44%) and education (42%). CONCLUSION: Although smoking cessation is discussed with patients, dentists are less active in taking concrete actions to support the patient on withdrawal. Adherence to the local treatment guideline was associated with better capabilities in dealing with tobacco withdrawal and a more active role in smoking cessation. The results suggest that more education on the local smoking cessation treatment guideline and cessation intervention is needed in order to overcome the remaining barriers to promoting effective smoking cessation in dental practice.

Dissolution properties of co-amorphous drug-amino acid formulations in buffer and biorelevant media.

Co-amorphous formulations, particularly binary drug-amino acid mixtures, have been shown to provide enhanced dissolution for poorly-soluble drugs and improved physical stability of the amorphous state. However, to date the dissolution properties (mainly intrinsic dissolution rate) of the co-amorphous formulations have been tested only in buffers and their supersaturation ability remain unexplored. Consequently, dissolution studies in simulated intestinal fluids need to be conducted in order to better evaluate the potential of these systems in increasing the oral bioavailability of biopharmaceutics classification system class II drugs. In this study, solubility and dissolution properties of the co-amorphous simvastatin-lysine, gibenclamide-serine, glibenclamide-threonine and glibenclamide-serine-threonine were studied in phosphate buffer pH 7.2 and biorelevant media (fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, respectively)). The co-amorphous formulations were found to provide a long-lasting supersaturation and improve the dissolution of the drugs compared to the crystalline and amorphous drugs alone in buffer. Similar improvement, but in lesser extent, was observed in biorelevant media suggesting that a dissolution advantage observed in aqueous buffers may overestimate the advantage in vivo. However, the results show that, in addition to stability advantage shown earlier, co-amorphous drug-amino acid formulations provide dissolution advantage over crystalline drugs in both aqueous and biorelevant conditions.

Antibiotic prophylaxis for hysterectomy, a prospective cohort study: cefuroxime, metronidazole, or both?

OBJECTIVE: To evaluate cefuroxime and metronidazole antibiotic prophylaxis. DESIGN: Observational nonrandomised 1-year prospective cohort study. SETTING: Fifty-three hospitals in Finland. POPULATION: A total of 5279 women undergoing hysterectomy for benign indications, with cefuroxime given to 4301 and metronidazole given to 2855. Excluding other antibiotics, cefuroxime alone was given to 2019, metronidazole alone was given to 518, and they were administered in combination to 2252 women. METHODS: Data on 1115 abdominal hysterectomies (AHs), 1541 laparoscopic hysterectomies (LHs), and 2133 vaginal hysterectomies (VHs) were analysed using logistic regression adjusted for confounding factors. MAIN OUTCOME MEASURES: Postoperative infections. RESULTS: Cefuroxime had a risk-reductive effect for total infections (adjusted odds ratio, OR, 0.29; 95% confidence interval, 95% CI, 0.22-0.39), but the independent effect of metronidazole and the interaction effect of cefuroxime and metronidazole were nonsignificant. In subgroup analyses of AHs, LHs, and VHs involving those receiving the two main antibiotics only, the effect of cefuroxime alone nonsignificantly differed from that of cefuroxime and metronidazole in combination for all types of infection. The absence of cefuroxime, assessed by comparing metronidazole alone with cefuroxime and metronidazole in combination, led to an increased risk for total infections in AHs (adjusted OR 3.63; 95% CI 1.99-6.65), in LHs (OR 3.53; 95% CI 1.74-7.18), and in VHs (OR 4.05; 95% CI 2.30-7.13), and also increased risks for febrile events in all categories (AHs, OR 2.86; 95% CI 1.09-7.46; LHs, OR 13.19; 95% CI 3.66-47.49; VHs, OR 12.74; 95% CI 3.01-53.95), wound infections in AHs (OR 6.88; 95% CI 1.09-7.49), and pelvic infections in VHs (OR 4.26; 95% CI 1.76-10.31). CONCLUSIONS: In this study, cefuroxime appeared to be effective in prophylaxis against infections. Metronidazole appeared to be ineffective, with no additional risk-reductive effect when combined with cefuroxime.

Circadian rhythmicity of inflammatory serum parameters: a neglected issue in the search of biomarkers in multiple sclerosis.

Inflammatory serum parameters are intensely investigated in the search of biomarkers for disease activity and treatment response in multiple sclerosis (MS). A reason for contradictory results might be the timing of blood collection for analyzing serum concentrations of inflammatory parameters which are subject to diurnal changes. We included 34 untreated patients with relapsing-remitting MS and 34 age- and sex-matched healthy controls. 12 MS patients showed acute disease activity in corresponding MRI scans. Blood samples were obtained at 7.00, 11.00 am, 2.30, 6.00 and 9.30 pm within 1 day. We determined serum levels of cortisol and inflammatory markers including soluble tumor necrosis factor-beta (sTNF-ß), soluble TNF-Receptor-1 (sTNF-R1) and -2 (sTNF-2), soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) by ELISA. We observed significantly higher serum levels of sTNF-R1 (p < 0.001) and sTNF-R2 (p < 0.001) in the morning and a significant decline of sICAM-1 (p < 0.005) and sVCAM-1 (p < 0.001) in the afternoon in both, MS patients and healthy controls. Comparison of diurnal serum levels between MS patients with active versus with non-active disease revealed significantly higher serum levels of sVCAM-1 (p < 0.05) around noon and in the early afternoon in MS patients with active disease. A significant decline of sICAM-1 (p < 0.05) in the afternoon was seen in MS patients with active and non-active disease. Our data indicate that increased awareness of potential diurnal serum concentration changes of biomarkers can eliminate one major cause of biased data as they occur in most of the investigated immunological parameters.

Pharmaceutical thrombosis prophylaxis, bleeding complications and thromboembolism in a national cohort of hysterectomy for benign disease.

BACKGROUND: Pharmaceutical thrombosis prophylaxis (PTP) with low-molecular-weight heparin (LMWH) is highly effective in preventing venous thromboembolic events (VTEs) and fatal pulmonary embolism. Important risk factors for VTEs are surgery and immobilization, along with malignancy. Many studies involving gynaecological malignancies show no increased risk for bleeding complications with PTP. Little is known about the PTP-associated risk for bleeding complications with hysterectomy for benign disease, or about current VTE incidence in the less-invasive hysterectomy methods. METHODS: Our observational prospective national 1-year cohort from 1 January to 31 December 2006 in 53 hospitals represented 79.4% (5297 of 6645) of hysterectomies performed for benign cause in Finland in 2006. We evaluated PTP use and VTE incidence. Operative and post-operative bleeding complications were analysed with logistic regression adjusted for confounders: age, BMI, experience of the gynaecological surgeon, hospital type, indication for hysterectomy, uterine weight, operative haemorrhage, concomitant surgery, adhesiolysis and antibiotic prophylaxis. RESULTS: Hysterectomies were performed by three main approaches: 2345 vaginal hysterectomies (VHs, 44%), of which 1433 were for uterine prolapse and 912 for other indications, 1679 laparoscopic hysterectomies (LHs, 32%) and 1255 abdominal hysterectomies (AHs, 24%). PTP was given to 64.8% of patients (3420 of 5279) and was identified as LMWH in 3313 patients (97%); 107 left unidentified. By type of hysterectomy, PTP was given in VH for uterine prolapse to 73.2% of patients, VH for other indication to 51.6%, in LH to 59.4% and in AH to 71.9%. For all hysterectomies analysed together, PTP doubled the odds for post-operative haemorrhage or haematoma. By type of hysterectomy, PTP associated with post-operative haemorrhage or haematoma in VH for prolapse [2.7% of PTP given, versus 0.8% of no PTP; odds ratio (OR): 4.82, 95% confidence interval (CI): 1.38-16.83]; and in AH (3.1% versus 1.4%; OR: 2.87, 95% CI: 1.03-7.98), and in AH also with post-operative transfusion (3.1% versus 1.4%; OR: 3.34, 95% CI: 1.41-7.88). For LH and VH for indications other than prolapse, the effect of PTP on post-operative haemorrhage was non-significant. For VH, the risk for post-operative haemorrhage fell with age. Operative mean haemorrhage with all hysterectomy types, and operative bleeding complications in AH and VH also fell with age. Obesity increased haemorrhage and operative bleeding complications for LH and VH, whereas post-operative bleeding complications were less for the obese in AH. VTEs were 6 of 5279 (0.1%): two PEs each occurred after AH and VH, and two deep venous thromboses after LH. CONCLUSIONS: With a relatively wide PTP coverage (64.8%), VTEs were rare (0.1%). All affected had received PTP. Analysis of efficacy, meaning interpretation of how many VTEs or deaths were prevented, cannot be done from our observational study but related to safety in hysterectomy for benign disease, PTP associated with post-operative bleeding complications with AH and with VH for prolapse. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov protocol (NCT00744172).

Transplacental transfer of nitrosodimethylamine in perfused human placenta.

Nitrosodimethylamine (NDMA) is a carcinogenic compound present in tobacco smoke and food such as cured meat, smoked fish and beer. The O(6)-methylguanine formed in human cord blood in mothers highly exposed to such products implicates NDMA exposure of the fetus. Dual recirculating human placental perfusion was used to get direct evidence of the transplacental transfer of NDMA and DNA adduct formation in perfused human placenta. Eleven placentas from normal full-term pregnancies were collected immediately after delivery and an isolated lobule was perfused with 1 or 5 microM of (14)C-NDMA with a reference substance, antipyrine (0.1mg/ml) added to the maternal circulation. Perfusate samples were collected from both maternal and fetal circulations every half an hour for the first two hours and once per hour from thereon. NDMA was analyzed by scintillation counting and antipyrine by high performance liquid chromatography. The transfer of NDMA was comparable to that of antipyrine and probably occurred through passive diffusion, with the concentrations in maternal and fetal sides equilibrating in 2-3h. No indication of any effect by efflux transporters on NDMA kinetics was noticed in the experiments utilizing Caco-2 or MDCK- MDCKII-MDR1 cell culture monolayer in a transwell system, either. Furthermore, no NDMA-DNA-adducts were found after the perfusions and no DNA-binding of NDMA was seen in in vitro incubations with human placental microsomes from 8 additional placentas. Thus, our study demonstrates that the human fetus can be exposed to NDMA from the maternal circulation. According to this study and the literature, NDMA is not metabolized in full-term human placenta from healthy non-smoking, non-drinking mothers. It remains to be studied whether NDMA concentrations high enough to evoke fetal toxicity can be obtained from dietary sources.

Privacy and occupational health services.

Privacy is a key ethical principle in occupational health services. Its importance is emphasised in several laws, in ethical codes of conduct as well as in the literature, yet there is only very limited empirical research on privacy in the occupational health context. Conceptual questions on privacy in the occupational health context are discussed. The baseline assumption is that, in this context, privacy cannot be approached and examined only from the employee's (an individual) vantage point but the employer's (a group) point of view must also be taken into account, and that the concept has several dimensions (physical, social, informational and psychological). Even though privacy is a basic human need, there is no universally accepted definition of the concept and no consensus on whether an organisation can have privacy in the same way as people do. Many of the challenges surrounding privacy in the context of occupational health seem to be associated with the dual loyalties of occupational health professionals towards the employee and employer and with their simultaneous duties of disseminating and protecting information (informational privacy). Privacy is thus not an absolute value, but more research is needed to understand its multidimensional nature in the context of occupational health.

Child psychiatric skills in primary healthcare--self-evaluation of Finnish health centre doctors.

OBJECTIVE: To study Finnish general practitioners' (GP's) perceptions of their child psychiatric skills. METHODS: The study sample consisted of physicians (n=755) working in health centres situated in the special response area of the Tampere University Hospital, Finland. They were requested to assess their competence in 16 areas on a four-step Likert scale. The response rate was 66.1% (n=499). RESULTS: Physicians evaluated their child psychiatric skills as inadequate on many issues. The ability to identify depression was poorer the younger the child in question. Only a minority (14%) felt they were well able to identify a depressed infant. Many physicians considered themselves poorly skilled in assessing the relationship between infant and parents (39.8%), in assessing a child's need for psychiatric treatment (42.7%) and in identifying a child with attention-deficit disorder (40.7%). A majority (75.9%) rated their skills poor in co-operating with daycare personnel or school staff in matters concerning a child with conduct disturbance. Only 26.8% could assess the necessity of taking a child into custody. Women gave higher ratings of their skills in identifying depressed infants and in assessing the infant-parent relationship than men, whereas men assessed their skills as better in cases in which there were problems in co-operation with parents. CONCLUSIONS: In order to provide good psychiatric services for children, attention should be paid to the GPs' child psychiatric skills.

Morbidity of 10 110 hysterectomies by type of approach.

BACKGROUND: Since the late 1980s, the option of laparoscopic hysterectomy has raised questions about the most suitable approach to hysterectomy. METHODS: To evaluate the influence of the type of approach, in causing or avoiding certain complaints in hysterectomies a prospective nationwide study was conducted comprising all hysterectomies for benign disease performed in Finland during 1996. The primary outcomes of interest were the operation-related morbidity, common surgical details and post-operative complications. RESULTS: A total of 10 110 hysterectomies, including 5875 abdominal, 1801 vaginal and 2434 laparoscopic operations showed a low rate of overall complications, 17.2, 23.3 and 19.0% respectively. Infections were the most common complications with incidences of 10.5, 13.0 and 9.0% in the abdominal, vaginal and laparoscopic group respectively. The most severe type of haemorrhagic events occurred in 2.1, 3.1 and 2.7% in the abdominal, vaginal and laparoscopic group respectively. Ureter injuries were predominant in laparoscopic group [relative risk (RR) 7.2 compared with abdominal] whereas bowel injuries were most common in vaginal group (RR 2.5 compared with abdominal). Surgeons who had performed >30 laparoscopic hysterectomies had a significantly lower incidence of ureter and bladder injuries (0.5 and 0.8% respectively) than those who had performed < or =30 operations (2.2 and 2.0% respectively). A decreasing trend of bowel complications was also seen with increasing experience in vaginal hysterectomies. CONCLUSIONS: This large-scale observational study on hysterectomies provides novel information on operation-related morbidity of abdominal, vaginal or laparoscopic approach. The results support the importance of the experience of the surgeon in reducing severe complications, especially in laparoscopic and vaginal hysterectomies.

The protective effect of hormone-replacement therapy on fracture risk is modulated by estrogen receptor alpha genotype in early postmenopausal women.

Genetic factors regulate bone mineral density (BMD) and possibly development of osteoporosis. It has been suggested that estrogen receptor alpha (ERalpha) genotype is associated with BMD, but the association between ERalpha genotype, fracture risk, and postmenopausal hormone replacement therapy (HRT) has not been studied. Therefore, we evaluated whether ERalpha polymorphism is associated with fracture risk in a 5-year trial with HRT in a population-based, randomized group of 331 early postmenopausal women. The participants consisted of two treatment groups: the HRT group (n = 151) received a sequential combination of 2 mg of estradiol valerate (E2Val) and 1 mg of cyproterone acetate with or without vitamin D3, 100-300 IU + 93 mg calcium as lactate per day; and the non-HRT group (n = 180) received 93 mg of calcium alone or in combination with vitamin D3, 100-300 IU/day. All new symptomatic, radiographically defined fractures were recorded. Pvu II restriction fragment length polymorphism of the ERalpha was determined using polymerase chain reaction (PCR). In all, 28 women sustained 33 fractures during the approximately 5.1-year follow-up. In the HRT group, the ERalpha genotype (PP, Pp, and pp) was not significantly associated with fracture risk (p = 0.138; Cox proportional hazards model). When the genotype was dichotomized (PP + Pp vs. pp), the incidence of new fractures in the HRT group was significantly reduced in women with the P allele (p = 0.046) with the relative risk (HR) of 0.25 (95% CI, 0.07-0.98), in comparison with the non-P allele group. After adjustment for time since menopause and previous fracture, the association between the dichotomous genotype and fracture risk persisted with HR of 0.24 (95% CI, 0.06-0.95;p = 0.042). In the non-HRT group, the ERalpha genotype was not significantly associated with fracture risk. During HRT, women with the pp genotype have a greater fracture risk than those with the P allele. The results suggest that the pp genotype is a relatively hormone-insensitive genotype, and it appears that women with the P allele may benefit more from the protective effect of HRT on fracture risk than women with the pp genotype.

Identification of early postmenopausal women with no bone response to HRT: results of a five-year clinical trial.

Hormone replacement therapy (HRT) prevents postmenopausal bone loss and fractures. However, the occurrence of women with no bone response to HRT has not been widely examined. We identified the densitometric nonresponders to long-term HRT and investigated some characteristics and biochemical variables as possible predictors of densitometric nonresponse in postmenopausal women. The study population was a subsample of the Kuopio Osteoporosis Study (n = 14,220). A total of 464 early postmenopausal women were randomized into four treatment groups: (1) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate); (2) vitamin D3; (3) HRT + Vitamin D3 combined; and (4) placebo. In this study, the data from HRT and placebo groups were analyzed. Lumbar (L2-4) and femoral neck bone mineral density (BMD) were determined by dual-energy X-ray absorptiometry (DXA) at baseline and after 5 years of treatment. A densitometric nonresponder was defined as a woman whose 5-year BMD change was similar to the mean BMD change (+95% CI) of the placebo group or worse. Altogether, 74 women in the HRT group and 104 women in the placebo group complied with the treatment. According to spinal BMD analysis, 11% of the women were classified as densitometric nonresponders; the corresponding proportion for femoral BMD analysis was 26%. Both smoking (p = 0.003) and low body weight (p = 0.028) were significant risk factors for densitometric nonresponse to HRT. After 6 months of treatment the densitometric nonresponders (hip) had a significantly higher mean serum follicle stimulating hormone (FSH) level (p = 0.038) and lower increases in serum estradiol levels (p = 0.006) than the densitometric responders. The mean changes in serum FSH and alkaline phosphatase levels were significantly lower among the densitometric nonresponders (spine) than responders (p = 0.043 and 0.017, respectively). In conclusion, this prospective study shows that especially current smokers and women with low body weight are at increased risk of poor bone response to HRT. Repeated serum FSH, estradiol and alkaline phosphatase measurements during the first months of long-term HRT may be helpful in identifying the women with no bone response to HRT.

Early postmenopausal bone loss is associated with PvuII estrogen receptor gene polymorphism in Finnish women: effect of hormone replacement therapy.

Genetic factors regulate bone mineral density (BMD) and possibly the development of osteoporosis. An association between estrogen receptor (ER) polymorphism, BMD, and postmenopausal hormone replacement therapy (HRT) has not been established. Therefore, we studied the influence of the ER genotype on BMD before and after a 5-year HRT in a placebo-controlled, population-based, randomized group of 322 early postmenopausal women. The participants were randomized into two treatment groups: the HRT group (n = 145) received a sequential combination of 2 mg estradiol valerate and 1 mg CPA with or without vitamin D3, 100-300 IU + 500 mg calcium lactate/day (equal to 93 mg Ca2+), and the non-HRT group (n = 177) received calcium lactate, 500 mg alone or in combination with vitamin D3, 100-300 IU/day. PvuII restriction fragment length polymorphism (RFLP) of the ERalpha was determined using polymerase chain reaction (PCR). BMDs of the lumbar spine (L2-4) and proximal femur were measured by using dual-energy X-ray absorptiometry (DXA). At the baseline, there were no significant differences in the lumbar or femoral neck BMDs between the three ER PvuII genotype groups (PP, Pp, pp). After 5 years, the BMD of the femoral neck remained unaltered and that of the lumbar spine increased by 1.7% in the HRT group, whereas both BMDs were decreased by 4-5% in the non-HRT group. The ER genotype did not modulate the femoral neck BMD change during the follow-up. In contrast, in the non-HRT-group the lumbar spine BMD decreased more in subjects with the ER genotypes PP (6.4%) and Pp (5.2%) than in subjects with the pp genotype (2.9%) (p = 0.002). In the HRT group, the relative changes of the lumbar spine BMD were similar in all three ER genotype groups. Thus without HRT, the pp genotype was associated with a smaller decrease in the lumbar spine BMD than the Pp and PP genotypes. Long-term HRT seemed to eliminate the ER genotype-related differences in the BMD. We conclude that subjects with the ER PvuII genotypes PP and Pp may have a greater risk of relatively fast bone loss after menopause than those with the pp genotype and that they may preferentially derive benefit from HRT.

Does apolipoprotein E genotype relate to BMD and bone markers in postmenopausal women?

OBJECTIVES: Bone mineral density (BMD) and development of osteoporosis are partly determined by genetic factors. The associations between one of suggested candidate, apolipoprotein E (apo E) genotype to bone mineral density (BMD) and bone biochemical markers was studied in 464 subjects recruited from a population-based group of early postmenopausal women (n = 13100). Additionally, the influence of apo E genotype on BMD changes during a 5-year follow-up with or without hormone replacement therapy (HRT) was investigated. METHODS: Participants were randomized into two treatment groups: HRT group: Sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3, 100-300 IU/day + calcium lactate, 500 mg/day (n = 232), and the non-HRT group: Calcium lactate, 500 mg/day alone or in combination with vitamin D3, 100-300 IU/day (n = 232). BMD was measured from the lumbar spine and proximal femur at baseline and after 5 years of treatment (n = 352). In a subgroup (n = 59), the serum concentrations of bone biochemical markers (intact osteocalcin (OC), bone-specific alkaline phosphatase (BAP) and type I collagen carboxy-terminal telopeptide (ICTP)) were measured at baseline and after 1 year of follow-up. RESULTS: At baseline, the BMDs were similar between the five apo E genotype groups (2/3, 2/4, 3/3, 3/4, 4/4). No significant differences in lumbar or femoral neck BMDs of women with the apo E4 allele were found compared with those without it. There was a statistically significant difference in 5-year BMD changes between the HRT and non-HRT groups. After 5 years, the BMD of the femoral neck had remained constant and the mean lumbar spine BMD had increased by 1.5% in the HRT group, whereas both BMDs had decreased by 4-5% in the non-HRT group. However, the apo E genotype did not modify the changes in BMD in either group. Additionally, the baseline concentrations of bone metabolic markers and their 1-year changes showed no genotype-related associations. CONCLUSIONS: The results of our population-based study indicate that apo E genotype does not modify lumbar or femoral neck BMDs or serum bone biochemical markers or their response to HRT in early postmenopausal Caucasian women.

Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women: a population-based 5-year randomized trial.

The long term effects of hormone replacement therapy (HRT) and vitamin D3 (Vit D) on bone mineral density (BMD) were studied. A total of 464 nonosteoporotic early postmenopausal women from the Kuopio Osteoporosis Study (n = 13100) were randomized to four groups: 1) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate, 2) Vit D3 (300 and 100 IU/day during the fifth year), 3) HRT and Vit D combined, and 4) placebo. Lumbar (L2-L4) and femoral neck BMD were determined by dual x-ray absorptiometry (DXA) at baseline and after 2.5 and 5 yr of treatment. Intention to treat analysis (n = 464) showed that after 5 yr, lumbar BMD remained unchanged in the HRT and HRT plus Vit D groups [+0.2% (P = 0.658) and +0.9% (P = 0.117), respectively], whereas lumbar BMD decreased by 4.6% in the Vit D group and by 4.5% in the placebo group (P < 0.001 in both). The loss of femoral neck BMD was less in the HRT (-1.4%; P = 0.005) and HRT plus Vit D (-1.3%; P = 0.003) groups than in the Vit D and placebo groups (-4.3%; P < 0.001 in both). Among those 370 women who complied with the 5-yr treatment, the effect was more pronounced: lumbar BMD had increased by 1.5% in the HRT (P = 0.009) and by 1.8% in the HRT plus Vit D group (P = 0.005), with a plateau after 2.5 yr, whereas lumbar BMD had decreased in both the Vit D and placebo groups (4.6% and 4.7%; P < 0.001, respectively). Femoral neck BMD decreased again less in the HRT (-0.4%) and HRT plus Vit D (-0.6%) groups than in the Vit D and placebo groups (-4.4% in both). This study confirms the positive long term effect of HRT on BMD also seen in intention to treat analysis. The data suggest that low dose vitamin D3 supplementation does not prevent bone loss in healthy, nonosteoporotic, early postmenopausal women, and it confers no benefit additional to that of HRT alone.

Is the response of serum lipids and lipoproteins to postmenopausal hormone replacement therapy modified by ApoE genotype?

Postmenopausal hormone replacement therapy (HRT) has favorable effects on the serum lipid profile, and it also decreases the risk of cardiovascular diseases. The apolipoprotein E genotype has influence on serum levels of lipids and lipoproteins; apoE allele epsilon4 (apoE4) is associated with high total and LDL cholesterol levels. Genotype also influences the lipid responses to treatment with diet and statins, but the effect of HRT in different apoE genotypes is unknown. We studied the effects of HRT on the concentrations of serum lipids in apoE4-positive early postmenopausal women (genotypes 3/4 and 4/4) compared with apoE4-negative women (genotypes 2/3 and 3/3) in a population-based, prospective 5-year study. In all, 232 early postmenopausal women were randomized into 2 treatment groups: an HRT group (n=116), which received a sequential combination of 2 mg estradiol valerate (E2Val) from day 1 to 21 and 1 mg cyproterone acetate (CPA) from day 12 to 21 (Climen), and a placebo group (n=116), which received 500 mg/d calcium lactate. Serum concentrations of total, LDL, and HDL cholesterol and triglycerides were measured at baseline and after 2 and 5 years of treatment. A total of 154 women completed the final analysis. During the follow-up period, serum total cholesterol and LDL cholesterol concentrations decreased in the HRT group in apoE4-negative women (8.1% and 17.1%, respectively; P<0.001) but did not change in the HRT group in apoE4-positive women or in the placebo group. Serum HDL cholesterol concentrations decreased in the placebo group (apoE4-negative, 3.9%, P=0.015; apoE4-positive, 8.1%, P=0.004) but did not change significantly in the HRT group. Serum triglyceride levels tended to increase in both study groups and genotypes (15.1% to 36.2%, P<0.038 to 0.001), but no differences were observed between the study groups or genotypes, respectively. Our finding was that in postmenopausal Finnish women LDL cholesterol levels in apoE4-negative subjects respond more favorably to HRT than those in apoE4-positive subjects. This finding has potential importance in postmenopausal women with hypercholesterolemia, if confirmed in other studies.

Does vitamin D strengthen the increase in femoral neck BMD in osteoporotic women treated with estrogen?

The long-term effects on bone of estrogen therapy (HRT) combined with vitamin D3 supplementation were evaluated and compared with the effects of HRT without vitamin D3 supplementation in a 4-year prospective, partly randomized study among 60 osteoporotic women (mean age 55.4 years; range 49.7-59.4 years). The women studied were a subgroup of the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) (n = 13,100). The bone mineral densities (BMD) of the lumbar spine and femoral neck were determined by dual-energy X-ray absorptiometry (DXA) in 3236 perimenopausal women. Those 106 women with baseline BMD more than 2 SDs less than the mean value in this population, either at the lumbar spine (BMD < 0.826 g/cm2) and/or femoral neck (BMD < 0.684 g/cm2), were offered treatment for osteoporosis. After exclusions, 60 women were included in the analyses. Group allocation was: HRT (estradiol valerate (2 mg) plus cyproterone acetage, 1 mg, sequentially: ClimenR) (n = 21); HRT + Vit D: Climen + vitamin D3 (cholecalciferol, 300 IU/day, no intake during June-August) (n = 23); controls: 16 women who refused all treatment served as a non-randomized control group. In the HRT group, the highly significant increase in lumbar BMD was 5.4%, 5.3%, 4.7% and 4.0% after 1, 2, 3 and 4 years of treatment, respectively, all compared with the baseline values and with the control group. The increase in femoral neck BMD was statistically insignificant (1.4%, 2.2%, 1.9% and 2.1%, respectively; p > 0.05). In the HRT + Vit D group, the lumbar BMD increased by 3.7%, 4.9%, 4.9% and 4.9% (p < 0.001), whereas the 5.8% increase in femoral neck BMD reached significance at 4 years (p < 0.01) when compared with the control group as well as with the baseline values. However, there were no statistically significant differences in lumbar or femoral BMD changes between the two HRT groups. In conclusion, estrogen can substantially increase lumbar bone mass in patients with postmenopausal osteoporosis. In addition, the combination of HRT and vitamin D3 may increase femoral neck BMD in osteoporotic women more than estrogen alone.

Postmenopausal hormone replacement therapy and autoantibodies against oxidized LDL.

OBJECTIVES: Oxidative modification of low-density lipoprotein (oxLDL) has been suggested to play an important role in the pathogenesis of atherosclerosis, and autoantibodies against oxLDL have recently found to reflect this process. The antioxidant effect and inhibition of LDL oxidation may be one of the cardioprotective mechanisms of postmenopausal estrogen therapy. METHODS: The effects of postmenopausal hormone replacement therapy (HRT) on the concentrations of serum lipids and oxLDL autoantibodies were studied in a population-based prospective 1-year study with 64 early postmenopausal women (mean age 52.2 +/- 0.4 (S.E.M.) years). The participants were randomized into two treatment groups: HRT-group: Sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate alone or in combination with vitamin D3, 300 IU/day + calcium lactate, 500 mg/day (n = 31) and the non-HRT-group: Calcium lactate, 500 mg/day alone or in combination with vitamin D3, 300 IU/day (n = 33). The groups were well matched regarding age, body mass index and baseline serum lipid concentrations. RESULTS: The serum concentrations of total cholesterol and LDL-cholesterol decreased in the HRT-group (4.1%, P = 0.05 and 6.4%, P = 0.03, respectively, paired t-test) but did not change in the non-HRT-group. No changes in the serum concentrations of HDL-cholesterol or triglycerides were observed. Additionally, no changes in oxLDL autoantibody concentrations were observed in either group. CONCLUSIONS: Although 1-year HRT lowered serum total- and LDL-cholesterol levels, it did not influence oxLDL antibody titers. On the basis of the present results we cannot question the possibility of there being beneficial effects of HRT on the oxidative modification of LDL. However, this effect is not reflected in the levels of oxLDL autoantibodies.