Lack of correlation between plaque burden and cognition in the aged monkey

The incidence rates of IDDM in Italy show remarkable variability. Sardinia, a region with the second highest incidence rate in the world, co-exists with other regions with lower rates. We review and compare epidemiologic data on the incidence of childhood-onset IDDM in Italy. papers published from 1980 to 1996 reporting incidence data in Italian areas were found by search of Medline and non-indexed Italian journals. The incidence data found cover only 57% of the Italian population. The analysis of our results shows how difficult it is to make a careful study of epidemiology of IDDM in Italy. The RIDI (the Registry for Insulin-dependent Diabetes mellitus in Italy) project started in 1996 according to international guidelines. The aims is to coordinate local IDDM registries, to promote the start of new registries in uncovered areas, and to standardize registration and data collection.     

Density dependence of expiratory flow and bronchodilator response in asthma

Change in the magnitude of density dependence of the maximal expiratory flow (D/MEF) following inhalation of isoproterenol was used as a test for predicting the long term response to isoproterenol vs atropine in 24 adult patients with longstanding asthma. Eleven subjects showed a decrease in D/MEF manifested by increase in volume of isoflow (VisoV) and/or decrease in Vmax50 Helox/air following isoproterenol inhalation (group 1). Thirteen subjects manifested an opposite response (group 2). Atropine sulphate (0.08 mg/kg) and isoproterenol hydrochloride (2.5 mg) were then administered by inhalation, each four times a day for seven days in a randomized double-blind cross over fashion to all subjects. One of group 1 but ten of group 2 subjects had a greater subjective and objective improvement with atropine than with isoproterenol (P less than .005). An increase in D/MEF following isoproterenol can be used as a test to predict a better response to atropine than to isoproterenol over a one week period. Such a response occurs in almost half of the adult chronic asthmatic patients. The results are consistent with a preferential dilatation of the large airways by atropine.     

Relationship between renal plasma flow response to angiotensin II and blood pressure in a population-based sample

OBJECTIVE: The positive short-term effects of postmenopausal hormone replacement therapy (HRT) on serum lipids are well known, but it has been suggested that they vanish with time. Cholecalciferol (vitamin D3) is widely used to prevent postmenopausal osteoporosis but the influence of vitamin D3 on serum lipids is poorly known. The long-term effects of HRT and vitamin D3 on the concentrations of serum lipids were studied in a population-based prospective 3-year study. DESIGN AND METHODS: 464 women were randomized into four treatment groups: (i) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate), (ii) Vit D3 (vitamin D3 300 IU/day), (iii) HRT+Vit D3 (both as above), (iv) placebo (calcium lactate 500 mg/day). RESULTS: 320 women completed the study. After three years of treatment, serum concentrations of low density lipoprotein (LDL) cholesterol decreased in the HRT group (10.1%, P<0.001) and the HRT+Vit D3 group (5.9%, P=0.005), increased in the Vit D3 group (4.1%, P=0.035) but remained unchanged in the placebo group. The concentrations of total cholesterol decreased by 5.8% in the HRT group (P<0.001) and by 3.3% in the HRT+Vit D3 group (P=0.023), but did not change in the other two groups. Serum concentrations of high density lipoprotein (HDL) cholesterol decreased in the Vit D3 group (5.2%, P=0.001), HRT+Vit D3 group (3.7%, P=0.046), and the placebo group (4.5%, P=0.006) but did not change significantly in the HRT group. The HDL/LDL ratio increased in the HRT group (10.5%, P=0.006) and decreased in the Vit D3 group (10.5%, P<0.001) whereas no changes occurred in the other two groups. In addition, serum triglycerides increased similarly in all groups (14.0-18.8%, P<0.05-0.001). CONCLUSIONS: Our results confirm the positive long-term effect of HRT with sequential estradiol valerate and cyproterone acetate on serum lipid concentrations. In addition, the results suggest that vitamin D3 supplementation may have unfavorable effects on lipids in postmenopausal women. Pure vitamin D3 treatment was associated with increased serum LDL cholesterol. Furthermore, the beneficial effects of HRT on serum LDL cholesterol content were reduced when estradiol valerate was combined with vitamin D3. However, the relevance of these associations to cardiovascular morbidity remains to be established.     

Lack of correlation between in vitro and in vivo replication of precisely defined benz-a-anthracene adducted DNAs

Like other polycyclic aromatic hydrocarbons, certain metabolites of benz[a]anthracene have been implicated as potent carcinogens. These effects are thought to be caused by the covalent binding of these species to nucleophilic groups on the bases of DNA. To address the molecular mechanisms by which these molecules induce mutations, this study employed oligonucleotides containing four site-specific N6 adenine-benz[a]anthracene diol epoxide adducts. Using a prokaryotic in vivo replication system, we have shown that both non-bay region anti-trans-benz[a]anthracene adducts are essentially nonmutagenic. In contrast, the bay region anti-trans-benz[a]anthracene lesions do induce point mutations at the adduct site. The mutagenic frequency of these bay region lesions is dependent on the stereochemistry about the adduct-forming bond, as well as the strain of Escherichia coli in which they are replicated. The ability of the bacterial replication machinery to bypass the lesions does not correlate with the differences observed in their mutagenesis. While both non-bay region adducts are readily bypassed in vivo, the bay region adducts are both blocking to approximately the same degree. In vitro studies of the interactions of E. coli DNA polymerase III with these adducts have also been undertaken to further dissect the relationship between adduct structure and biological activity.     

Lack of correlation between the detection of Chlamydia trachomatis DNA in synovial fluid from patients with a range of rheumatic diseases and the presence of an antichlamydial immune response

OBJECTIVE: To resolve how frequently Chlamydia trachomatis and Chlamydia pneumoniae DNA are present in the joints of unselected patients with reactive arthritis (ReA) and undifferentiated oligoarthritis, and to determine if there is an accompanying serologic or cellular antichlamydial immune response. METHODS: Two polymerase chain reaction (PCR) protocols to detect the plasmid of C. trachomatis and the outer membrane protein 1 gene of C. pneumoniae were developed for specific use with synovial fluid (SF). Subsequently, the assays were used to detect DNA from the 2 organisms in SF from 54 adult patients with rheumatic diseases, including 4 with sexually acquired ReA and 31 with undifferentiated oligoarthritis. The presence of chlamydial antibodies and SF lymphocyte proliferation responses were determined in parallel. RESULTS: The PCR protocols were species-specific and highly sensitive. SF samples from 15 patients (8 with undifferentiated oligoarthritis, 3 with ReA, 1 with rheumatoid arthritis, and 1 with psoriatic arthritis) were positive for C. trachomatis. There was no significant correlation between the presence of C. trachomatis DNA in the joint and a Chlamydia-specific synovial T cell response or a serologic response. C. pneumoniae was not detected in any of the 54 patients, although it was identified in the SF from a rheumatoid arthritis patient outside this study, demonstrating that the assay was capable of detecting the organism in the joint. CONCLUSION: C. trachomatis DNA was present in ReA patients and in nearly one-third of unselected patients with undifferentiated oligoarthritis, which further supports the hypothesis that it plays an important role in disease pathogenesis. However, its presence did not correlate with evidence of an antichlamydial immune response. Despite previous anecdotal reports, C. pneumoniae does not appear to be a major cause of undifferentiated oligoarthritis or ReA.     

Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners

BACKGROUND: Semen analysis is part of the routine assessment of infertile couples. WHO defines a sperm concentration above 20x10(6) per mL seminal fluid as normal. We studied the association between semen quality and the probability of conception in a single menstrual cycle in Danish couples with no previous reproductive experience. METHODS: In 1992-94, we invited 52,255 trades-union members aged 20-35 years, who lived with a partner and had no children to take part in the study; 430 couples agreed. The couples discontinued use of contraception, and were followed up for six menstrual cycles or until a pregnancy was verified within this period. Each man was asked to provide a semen sample at enrolment (which was analysed without freezing). Women kept a daily record of vaginal bleeding and sexual activity. The association between semen quality and likelihood of pregnancy was assessed by logistic regression, adjusted for sexual activity and female factors associated with low fertility. RESULTS: There were 256 (59.5%) pregnancies among the 430 couples: 165 (65.0%) among those with a sperm concentration of 40x10(6)/mL or more and 84 (51.2%) among those with lower sperm concentrations. The probability of conception increased with increasing sperm concentration up to 40x10(6)/mL, but any higher sperm density was not associated with additional likelihood of pregnancy. The proportion of sperm with normal morphology was strongly related to likelihood of pregnancy independently of sperm concentration. Semen volume and motility were of limited value in pregnancy prediction. INTERPRETATION: Our study suggests that the current WHO guidelines for normal semen quality should be used with caution. Some men with sperm counts above the lower limit of the normal range defined by WHO may in fact be subfertile.     

Lack of correlation between V3-loop peptide enzyme immunoassay serologic subtyping and genetic sequencing

OBJECTIVE: To compare the performance of V3-loop peptide enzyme immunoassay (PEIA) methodologies from four different laboratories for subtyping HIV-1, and to determine the causes for the lack of correlation between V3-loop PEIA serotyping and subtyping by sequencing. MATERIALS AND METHODS: Synthetic peptides derived from the amino-acid consensus sequences of the V3-loop of group M strains representing genetic subtypes A-F as well as reference strains were evaluated in PEIA by four different laboratories for their ability to accurately determine the subtype in a panel of 85 sera obtained from persons infected with known HIV-1 subtypes (28 subtype A, 34 subtype B, four subtype C, 10 subtype D, seven subtype F, one each of subtype H and G). Furthermore, the V3 loop of the corresponding virus was compared with the V3 loop of the peptides used in PEIA. RESULTS: The correlation between HIV-1 subtyping by sequencing and V3-loop PEIA from the different laboratories varied considerably for the different HIV-1 subtypes: subtype A (46-68%), B (38-85%), C (75-100%), D (29-50%), and F (17-57%). A 70% agreement between PEIA and sequencing subtypes was observed for samples with the concordant presence of the same octameric sequences in the V3 loop of the virus and the V3 loop of the peptide used in PEIA; however, only 42% of specimens with different V3-loop octameric viral and peptide sequences yielded concordant results in V3-loop serotyping and genetic subtyping. CONCLUSION: Our results indicate that V3-loop PEIA methodologies used in different laboratories correlate poorly with genetic subtyping, and that their accuracy to predict HIV-1 subtypes in sera of Belgian individuals infected with different HIV-1 subtypes (A, B, C, D, F, G and H) vary considerably. The poor correlation between serotyping and genetic subtyping was partly due to the simultaneous occurrence of subtype-specific octameric sequences at the tip of the V3 loop of viruses belonging to different genetic subtypes.     

Lack of correlation between myocardial nitric oxide and cyclic guanosine monophosphate content in both nitrate-tolerant and -nontolerant rats

We studied the effect of nitroglycerin (NTG) on cardiac nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) content in nitrate-tolerant/nontolerant rats in vivo. The effect of the pharmacological blockade of endogenous NO synthesis and the effect of exogenous NO on cardiac cGMP were also examined. Rats were treated with 100 mg/kg of NTG and corresponding vehicle s.c. three times a day for 2.5 days to induce NTG-tolerance/nontolerance. Rats were then administered a single dose of s.c. 100 mg/kg of NTG to test the effect of NTG in tolerant/nontolerant states, respectively. Nontolerant rats treated with vehicle were controls, and nontolerant rats treated with the NO synthesis inhibitor NG-nitro-L-arginine (LNNA, 20 mg/kg) were negative controls. Another group of nontolerant rats treated i.v. with the direct NO donor sodium nitroprusside (SNP, 3 mg/kg) were positive controls. Cardiac NO assessed by electron spin resonance after in vivo spin-trapping increased 100-fold (P < 0.05) in the positive control, 10-fold (P < 0.05) in the NTG-tolerant group, and 4-fold (P < 0.05) in the single NTG group, when compared to controls. In the negative control group, NO was reduced to near the detection limit (four-fold reduction, P < 0.05). Cardiac cGMP measured by radioimmunoassay was increased significantly (two-fold, P < 0.05) only in the positive control group, and there were no differences among the other groups. This shows that: 1) in vivo cardiac bioconversion of NTG to NO is not impaired in nitrate tolerance; and 2) changes in cardiac NO content are not reflected by changes in cGMP content in nitrate-tolerant and -nontolerant rats.     

Clinical correlation between the premortem study and autopsy

BACKGROUND: Lately, autopsies are performed less frequently in hospitals, despite their importance as a diagnostic tool. AIM: To study the concordance between clinical diagnosis and postmortem study in patients that died in a teaching hospital. MATERIAL AND METHODS: Autopsy findings in 57 patients (aged 16 to 85 years old, 28 female) that died at a University hospital were analyzed. Clinical diagnoses were compared with those of the postmortem examination and the degree of concordance between both diagnoses was calculated. RESULTS: Seven major omissions (12.3%), whose knowledge could have changed the clinical course of patients, were detected. These omissions occurred in patients with complex diseases or due to limitations of diagnostic procedures. Also, seven omissions, found in severely ill patients, whose knowledge would not change the patient's evolution, were also detected. CONCLUSIONS: Autopsy still is a valuable tool to assess the quality of care for patients that die during their hospitalization.     

Mantle-cell lymphoma: a population-based clinical study

PURPOSE: From a population-based non-Hodgkin's lymphoma (NHL) registry, 41 patients with mantle cell lymphoma (MCL) -- a recently defined distinct B-cell NHL -- were selected and compared with patients with low- or intermediate-grade NHL from the same registry. PATIENTS AND METHODS: The incidence and behavior of MCL in the area of the Comprehensive Cancer Center West (CCCW) from 1981 to 1989 were analyzed. Age, performance, tumor bulk, extranodal localization, stage, response to therapy, and survival were registered. Expression of cyclin D1 protein and Ki-67 were measured in 29 patients. RESULTS: MCL made up 3.7% of NHLs. The median age was 68 years, and the male-to-female ratio was 1.6:1. Seventy-eight percent presented with stage IV, with the majority having bone marrow involvement. The complete response (CR) rate was 32% (13 of 41), with a median duration of 25 months. The median overall survival time was 31.5 months. The International Prognostic Index identified five patients with a low-risk score and a median survival time of 93+ months. In 23 of 29 patients, cyclin D1 overexpression was present, without any relation to overall or disease-free survival. In contrast, a proliferative index less than 10% was significantly related to a better overall survival time (50 v 24 months). CONCLUSION: MCL is a disease of the elderly, who present with widespread disease and with a poor response to therapy. Although it harbors features of an indolent NHL, it behaves clinically as an aggressive NHL with a short overall survival time.     

Incidental pituitary macroadenoma: a population-based study

Epidemiologic analysis of incidental macroadenoma is limited to autopsy studies and case series. There are no published data about prevalence of incidental pituitary macroadenoma in living patients. The objective of this study was to determine the prevalence of incidental pituitary macroadenoma. It was designed as an observational study of cranial computed tomography reports. An urban department of veterans affairs medical center was used for the setting. The subject group consisted of 3,550 consecutive patients at the Cleveland Department of Veterans Affairs Medical Center from January 1993 to January 1996. Patients with known or suspected pituitary or parasellar disease were excluded. Cranial computed tomography reports were reviewed. Original films and medical charts of all patients with pituitary macroadenoma were reviewed. Seven patients with incidentally discovered pituitary macroadenoma that ranged from 1 cm to 2.5 cm were found; prevalence was 0.20% (95% confidence interval 0.05, 0.35%). Evidence of partial hypopituitarism was found in most patients. All patients had normal visual fields at initial examination despite the size of the tumor, but 1 of 4 had a field cut demonstrated by Goldmann perimetry. These data confirm that, although the prevalence of incidental pituitary macroadenoma is low, screening identified patients to detect deficiency of corticotropin, thyroid-stimulating hormone, and gonadotropins and to detect visual field defects is important.     

Lack of correlation between vacuolating cytotoxin activity, cagA gene in Helicobacter pylori, and peptic ulcer disease in children

To determine the prevalence of the cagA gene and vacuolating cytotoxin in Helicobacter pylori isolates obtained from children and to characterize the relationship between cagA, cytotoxin production, and ulcerogenesis, pediatric Helicobacter pylori isolates were tested for cagA by the polymerase chain reaction and for vacuolating cytotoxin by a cell culture assay. Helicobacter pylori isolates were obtained from 33 children referred for upper gastrointestinal endoscopy. Twenty-six of these isolates were tested for cagA by the polymerase chain reaction; all 26 (100%) were positive. Of the 26 children from whom these isolates were obtained, 26 (100%) had chronic gastritis and 12 (46%) had duodenal ulcers. Nine (30%) of 30 isolates tested showed expression of vacuolating cytotoxin, only three of which came from patients with duodenal ulceration (odds ratio 0.81, 95% confidence interval 0.1-5.3). Of the 23 cagA-positive isolates tested for cytotoxin, only nine (39%) were positive. There was no association between vacuolating cytotoxin and clinical symptoms, nor was cytotoxicity associated with ulcerogenesis. In summary, the findings suggest that cagA is not a marker of duodenal ulceration or of vacuolating cytotoxin production in children referred for endoscopy.     

Lack of correlation between repair of DNA interstrand cross-links and hypersensitivity of hamster cells towards mitomycin C and cisplatin

We have examined the integrity of J774 cell nitric oxide (NO) production and glutathione maintenance, whilst NADPH supply was compromised by inhibition of the pentose pathway with 6-aminonicotinamide. In resting cells 6-phosphogluconate accumulation began after 4 h and glutathione depletion after 24 h of 6-aminonicotinamide treatment. Cellular activation by lipopolysaccharide/interferon-lambda decreased glutathione by approximately 50% and synchronous 6-aminonicotinamide treatment exacerbated this to 31.2% of control (P < 0.05). In activated cells NO2- production was inhibited by 60% with 6-aminonicotinamide (P < 0.01), and superoxide production by 50% (P < 0.01) in zymosan-activated cells. NADPH production via the pentose pathway is therefore important to sustain macrophage NO production whilst maintaining protective levels of glutathione.     

Lack of correlation between EBV serology and presence of EBV in the Hodgkin and Reed-Sternberg cells of patients with Hodgkin's disease

Epstein-Barr virus (EBV) is detected in Hodgkin and Reed-Sternberg (HRS) cells in up to 50% of patients with Hodgkin's disease (HD). HD patients have been reported to express high serum titers against EBV antigens, even prior to the diagnosis of HD. Patients with high serum titers have a poorer prognosis. The aim of this study was to examine the relationship between the presence of EBV in HRS cells and the antibody titers reactive with different EBV antigens. Frozen serum and histopathological tissues were available from 107 untreated HD patients diagnosed between 1979 and 1991. The presence of EBV in the HRS cells was evaluated with immunohistochemistry directed against the LMP-1 antigen and/or with in situ hybridization of EBER-1. Analyses were performed of serum titers against early antigen (EA), diffuse (IgA and IgG) and restricted (IgG), virus-capsid antigen (VCA) (IgA and IgG), and EBV-encoded nuclear antigens (EBNA, EBNA 1, EBNA 2A, EBNA 2B, EBNA 6). EBV was detected in 27/107 (25%) tumor specimens, with a higher proportion in the MC group 8/13 (62%) (p < 0.01). IgG VCA and EBNA were detected in 99/107 (93%), evidence of a previous EBV infection. There were no significant relationships between antibody titers reactive with different EBV antigens and detectable EBV in HRS cells. Furthermore, there did not appear to be any relationship between EBV serology or the presence of EBV in HRS cells and clinical outcome. The role of EBV in the development of HD, especially its relationship to the immunological response, remains unclear.     

Lack of correlation between apoptosis and DNA single-strand breaks in X-irradiated human peripheral blood mononuclear cells in the course of ageing

Inositol(1,3,4,5)tetrakisphosphate (InsP4) and phosphatidylinositol(3,4,5)trisphosphate (PtdInsP3) are two potential second messengers with a still largely unknown mode of action. We recently cloned the 42 kDa protein p42IP4 previously purified from pig cerebellum, which binds InsP4 (Kd approximately 2 nM) and PtdInsP3 with comparable affinities (Stricker et al., FEBS Lett. 405 (1997) 229). The protein p42IP4 (pig) is highly homologous to centaurin-alpha, a larger protein of 46 kDa, derived from a rat brain cDNA library clone (Hammonds-Odie et al., J. Biol. Chem. 271 (1996) 18859). Here we investigated whether also p42IP4 is expressed in rat brain and how it might be related to centaurin-alpha. When we carried out RT-PCR using mRNA from brain of rats of different ages we obtained several clones corresponding to p42IP4, but not to centaurin-alpha. The existence of p42IP4 in rat brain is supported by the following findings: (1) biochemical analysis of the purified rat brain protein shows inositol phosphate ligand affinities identical to those of the protein from other species; (2) Western blot analysis of rat brain membrane fractions using a peptide-specific antiserum revealed only the 42 kDa protein (p42IP4), but did not give evidence for the occurrence of a larger 46 kDa centaurin-alpha-like protein in rat brain; and (3) the amino acid sequences deduced from p42IP4 cDNA are highly homologous in several species and are confirmed by protein fragment microsequences. Thus, p42IP4 from rat brain which has two pleckstrin homology domains is a protein largely conserved between different species and most likely has an important function in inositol phosphate or inositol lipid signal transduction.     

Lack of correlation between the effects of transient exposure to glutamate and those of hypoxia/reoxygenation in immature neurons in vitro

To assess the influence of brain immaturity on the effects of oxygen deprivation and the participation of excitotoxicity, the consequences of a 6-h exposure to either hypoxia (95% N2/5% CO2) or 100 microM glutamate were studied in cultured fetal rat forebrain neurons taken at two maturational stages, i.e., 6 and 13 days in vitro. Cells were examined for their morphology, viability, energy metabolism reflected by 2-D-[3H]deoxyglucose uptake, and protein synthesis assessed by [3H]leucine incorporation. Apoptosis and necrosis were scored using the fluorescent dye 4,6-diamidino-2-phenylindole. Whereas 6-day-old neurons responded to a 6-h hypoxia by transient hypermetabolism, biphasic increase in protein synthesis, and cycloheximide-sensitive apoptotic death within 72 h postexposure, glutamate did not affect cell characteristics by the same time. In 13-day-old neurons, hypoxia induced both apoptosis (8.2%) and necrosis (22.3%). At this age, glutamate definitely reduced energy metabolism (26%) and protein synthesis (17%) by the end of exposure. The percentage of necrotic neurons reached 40.7%, but the rate of apoptosis was unchanged compared with controls. Therefore, excitotoxicity cannot account for hypoxia-induced injury in immature neurons, but its participation is suggested in older cells by the suppression of the necrotic component of hypoxia by glutamate receptor antagonists at 13 days.     

Lack of correlation between the reduction of sevoflurane MAC and the cerebellar cyclic GMP concentrations in mice treated with 7-nitroindazole

The clinical spectrum of leishmaniasis and control of the infection are influenced by the parasite-host relationship. The role of cellular immune responses of the Th1 type in the protection against disease in experimental and human leishmaniasis is well established. In humans, production of IFN-gamma is associated with the control of infection in children infected by Leishmania chagasi. In visceral leishmaniasis, an impairment in IFN-gamma production and high IL-4 and IL-10 levels (Th2 cytokines) are observed in antigen-stimulated peripheral blood mononuclear cells (PBMC). Moreover, IL-12 restores IFN-gamma production and enhances the cytotoxic response. IL-10 is the cytokine involved in down-regulation of IFN-gamma production, since anti-IL-10 monoclonal antibody (mAb) restores in vitro IFN-gamma production and lymphoproliferative responses, and IL-10 abrogates the effect of IL-12. In cutaneous and mucosal leishmaniasis, high levels of IFN-gamma are found in L. amazonensis-stimulated PBMC. However, low or absent IFN-gamma levels were observed in antigen-stimulated PBMC from 50% of subjects with less than 60 days of disease (24 +/- 26 pg/ml). This response was restored by IL-12 (308 +/- 342 pg/ml) and anti-IL-10 mAb (380 +/- 245 pg/ml) (P < 0.05). Later during the disease, high levels of IFN-gamma and TNF-alpha are produced both in cutaneous and mucosal leishmaniasis. After treatment there is a decrease in TNF-alpha levels (366 +/- 224 pg/ml before treatment vs 142 +/- 107 pg/ml after treatment, P = 0.02). Although production of IFN-gamma and TNF-alpha might be involved in the control of parasite multiplication in the early phases of Leishmania infection, these cytokines might also be involved in the tissue damage seen in tegumentary leishmaniasis.     

Fractures after thyroidectomy in men: a population-based cohort study

Bone mass is purportedly reduced by an endogenous or exogenous excess of thyroid hormone or, perhaps, by calcitonin deficiency. Patients who have undergone thyroidectomy could be subject to all of these effects, yet their practical implications in terms of fracture risk are poorly defined. Interpretation is further hampered by the focus on women, where results may be influenced by involutional osteoporosis. Consequently, we assessed the potential for fractures among the 136 Rochester, Minnesota men who underwent thyroidectomy between 1935 and 1979, relative to a group of age-matched control men from the community. With 2194 person-years of follow-up in each group, survival free of any fracture of vertebra, proximal humerus, distal forearm, pelvis, or proximal femur was similar in the two groups (p = 0.23), and the relative risk of any of these fractures for thyroidectomized patients versus their controls was increased only 1.5-fold (95% CI, 0.7-3.2). The difference was entirely accounted for by a statistically significant excess of proximal femur fractures in the men with thyroidectomy. Risk factors for fractures among men with thyroidectomy included greater age at surgery, greater extent of surgery, and the presence of risk factors for secondary osteoporosis. Thus, thyroidectomy, performed mainly for adenoma or goiter, seems to have little overall influence on the risk of age-related fractures in men. However, the association with hip fractures requires further evaluation.     

Lack of interaction between tramadol and coumarins

The objective of this study was to investigate whether the central analgesic tramadol influences the effects of the coumarin anticoagulant phenprocoumon during multiple-dose administration. Nineteen patients receiving long-term anticoagulant therapy who had been in a stable hypothrombinemic state for at least 3 months completed a double-blind, placebo-controlled, crossover study. Tramadol was administered in the usual therapeutic dose of 50 mg three times daily. The average daily phenprocoumon dose was identical for individual patients in both treatment periods. The equivalence ratio (tramadol/placebo) of the international normalized ratio (INR) values was 0.99 (90% confidence interval 0.89-1.10), thus fulfilling predetermined bioequivalence criteria (0.70-1.43). Therefore, tramadol does not affect INR in patients being treated with phenprocoumon. These data suggest a lack of interaction between tramadol and coumarin anticoagulants.