Developmental changes in red blood cell counts and indices of infants after exclusion of iron deficiency by laboratory criteria and continuous iron supplementation

The developmental changes in red blood cell counts and indices were determined in infants after mild iron deficiency was excluded. The normal values were obtained from a selected group of healthy, term infants who were receiving continuous iron supplementation during a period of one year while normal values for transferrin saturation and serum ferritin were being maintained. The data indicated marked developmental changes in red blood cell counts and indices during the first year of life that are independent of iron intake. Serial analysis of individual infant's values indicated that the red cell measurement at 4 months of age are, to some extent, predictive of the level of subsequent values within the normal range.     

Reduced nuclear expression of transcription factor AP-2 associates with aggressive breast cancer.

PURPOSE: We proposed to investigate the expression and prognostic significance of activator protein 2 (AP-2) in breast cancer. EXPERIMENTAL DESIGN: AP-2 was immunohistochemically analyzed in a prospective, consecutive series of 420 breast cancer patients diagnosed and treated between 1990 and 1995 at Kuopio University Hospital, Kuopio, Finland. AP-2 expression was further compared with clinicopathological parameters and patients' survival. RESULTS: Nuclear AP-2 expression was lower in carcinomas compared with normal ductal breast epithelium (P < 0.001). Nuclear expression was more often seen in lobular than in ductal or other carcinomas (P = 0.048). Cytoplasmic staining was present in 47% of the carcinomas. Low nuclear AP-2 expression level in carcinomas was associated with advanced stage (P = 0.002), axillary lymph node positivity (P = 0.012), poor differentiation (P = 0.001), and recurrences (P = 0.003). In univariate survival analyses, low nuclear AP-2 expression (P = 0.0028), advanced stage (P < 0.0001), lymph node metastases (P < 0.0001), and poor differentiation (P = 0.0498) predicted shorter recurrence-free survival (RFS). Low nuclear AP-2 staining and/or shift to cytoplasmic expression predicted shorter RFS (P = 0.0050) and breast cancer-related survival (BCRS; P = 0.0314) in univariate analyses. Cytoplasmic expression alone did not have prognostic value. In multivariate analysis, low nuclear AP-2 expression (P = 0.0292) and advanced stage (P = 0.0001) were independent predictors of shorter RFS; and stage (P < 0.0001) and ER-status (P = 0.0321) independently predicted BCRS. In the lymph-node positive patients, RFS was independently predicted by stage (P = 0.0110) and nuclear AP-2 status (P = 0.0151). CONCLUSIONS: AP-2 seems to have a protective role in breast cancer. Low nuclear AP-2 expression was associated with disease progression and increased metastatic capability of the tumor. In addition, reduced nuclear AP-2 expression independently predicted elevated risk of recurrent disease in breast cancer.     

Antiviral (RNA) activity of selected Amaryllidaceae isoquinoline constituents and synthesis of related substances.

A series of 23 Amaryllidaceae isoquinoline alkaloids and related synthetic analogues were isolated or synthesized and subsequently evaluated in cell culture against the RNA-containing flaviviruses (Japanese encephalitis, yellow fever, and dengue viruses), bunyaviruses (Punta Toro, sandfly fever, and Rift Valley fever viruses), alphavirus (Venezuelan equine encephalomyelitis virus), lentivirus (human immunodeficiency virus-type 1) and the DNA-containing vaccinia virus. Narciclasine [1], lycoricidine [2], pancratistatin [4], 7-deoxypancratistatin [5], and acetates 6-8, isonarciclasine [13a], cis-dihydronarciclasine [14a], trans-dihydronarciclasine [15a], their 7-deoxy analogues 13b-15b, lycorines 16 and 17, and pretazettine [18] exhibited consistent in vitro activity against all three flaviviruses and against the bunyaviruses, Punta Toro and Rift Valley fever virus. Activity against sandfly fever virus was only observed with 7-deoxy analogues. In most cases, however, selectivity of the active compounds was low, with toxicity in uninfected cells (TC50) occurring at concentrations within 10-fold that of the viral inhibitory concentrations (IC50). No activity was observed against human immunodeficiency virus-type 1, Venezuelan equine encephalomyelitis virus, or vaccinia viruses. Pancratistatin [4] and its 7-deoxy analogue 5 were evaluated in two murine Japanese encephalitis mouse models (differing in viral dose challenge, among other factors). In two experiments (low LD50 viral challenge, variant I), prophylactic administration of 4 at 4 and 6 mg/kg/day (2% EtOH/saline, sc, once daily for 7 days, day -1 to +5) increased survival of Japanese-encephalitis-virus-infected mice to 100% and 90%, respectively. In the same model, prophylactic administration of 5 at 40 mg/kg/day in hydroxypropylcellulose (sc, once daily for 7 days, day -1 to +5) increased survival of Japanese-encephalitis-virus-infected mice to 80%. In a second variant (high LD50 viral challenge), administration of 4 at 6 mg/kg/day (ip, twice daily for 9 days, day -1 to +7) resulted in a 50% survival rate. In all cases, there was no survival in the diluent-treated control mice. Thus, 4 and 5 demonstrated activity in mice infected with Japanese encephalitis virus but only at near toxic concentrations. To our knowledge, however, this represents a rare demonstration of chemotherapeutic efficacy (by a substance other than an interferon inducer) in a Japanese-encephalitis-virus-infected mouse model.     

Cardiac arrhythmias during occupational exposure to fluorinated hydrocarbons

The effects of occupational exposure to chlorodifluoromethane (FC 22) and dichlorodifluoromethane (FC 12) on cardiac rhythm were examined. The subjects were six men who repaired refrigerators (age 31-56, mean 46 years) and a control group of six plumbers (age 29-54, mean 45 years). Ambulatory electrocardiograms (ECG) were recorded for 24 hours on the day of exposure and on a control day. The ECG tapes were automatically analysed with a Reynolds pathfinder 3 apparatus and all aberrant complexes recorded by the machine were checked. One person read all the tapes without knowing whether or not they were recorded during exposure. The number of ventricular ectopic beats were compared between the day of exposure and the control day and with the tape of the control. In addition, the number of ventricular ectopic beats during exposure was compared with the number occurring during the rest of the day. The concentrations of fluorocarbons were measured in four instances. High peak concentrations of fluorocarbons (1300-10,000 cm3/m3) were measured during refrigerator repair work. No clear connection between fluorocarbons and cardiac arrhythmia was found, although one subject had several ventricular ectopic beats which may have been connected with exposure.     

Involvement of P450 1A1 in Benzo(a)Pyrene but Not in Benzo(a)Pyrene-7,8-Dihydrodiol Activation by 3-Methylcholanthrene-Induced Mouse Liver Microsomes

Abstract: Synchronous fluorescence spetrophotometry for benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE)-DNA adducts was used to study the activation pathway of benzo(a)pyrene in C57BL/6 mice. Benzo(a)pyrene but not benzo(a)pyrene-7,8-diol activation by 3-methylcholanthrene-induced mouse liver microsomes was inhibited by a monoclonal antibody (Mab 1–7–1) against CYP1A1/2 suggesting that 1A1 probably takes part in the first P450 reaction. However, aryl hydrocarbon hydroxylase activity, a classical measure of benzo(a)pyrene metabolism, was not inhibited by the same concentration of Mab 1–7–1. None of the other antibodies used, detecting 2A, 2B, 2C or 2E subfamilies, inhibited the adduct formation. Troleandomycin and gestodene, chemical inhibitors of human 3A4, inhibited benzo(a)pyrene-7,8-diol activation by 3-methylcholanthrene-induced microsomes to some extent only in high concentrations. Although liver microsomes from 3-methylcholanthrene-induced mice catalyzed the formation of BPDE-DNA in vitro clearly more than uninduced microsomes, 3-methylcholanthrene pretreatment in vivo decreased the adduct formation in benzo(a)pyrene-treated mice. These results emphasize the significance of detoxicating and DNA-repairing pathways in vivo. Finally, synchronous fluorescence spectrophotometry for BPDE-DNA measures the end-point of the three-step activation pathway while aryl hydrocarbon hydroxylase measures a one-step hydroxylation. Thus, these methods should be used rather as corroborative than mutually exclusive assays.     

Community pharmacists' involvement in smoking cessation: familiarity and implementation of the National smoking cessation guideline in Finland

Background  

Guidelines on smoking cessation (SC) emphasize healthcare cooperation and community pharmacists' involvement. This study explored the familiarity and implementation of the National SC Guideline in Finnish community pharmacies, factors relating to Guideline familiarity, implementation and provision of SC services.     

The moral dangers of home birth: parents' perceptions of risks in home birth in Finland

This study explored Finnish home-birth parents' perceptions of risks in home birth through interviews. It was found that the parents considered three types of risks in their decision-making: medical risks of pregnancy and birth, iatrogenic risks of medical practice and moral risks of going against medical authoritative knowledge. While the parents' choice was guided by their image of the hospital as an iatrogenic environment for birth, they did not refuse prenatal examinations but, rather, negotiated the extent of their use to ensure the medical safety of their home-birth plan. Yet, they often concealed the plan from prenatal care staff in order not to be confronted with being labelled as a 'risk parent'. It is argued that the authoritative medical definition of childbirth as risky and as requiring hospitalisation contains a moral subtext which defines home birth as risky behaviour, for which the parents can be blamed and stigmatised.     

Serotonin‐transporter‐linked promoter region polymorphism and serotonin transporter binding in drug‐naïve patients with major depression

Aims: Both the serotonin transporter and its genetic regulation by the serotonin‐transporter‐linked polymorphic region have a role in the pathophysiology of depression. Most of the previous studies have found no influence of serotonin‐transporter‐linked polymorphic region allelic variation on serotonin transporter binding in healthy controls or patients with major depression. Due to the inconsistency of the previous findings, we compared single photon emission computed tomography imaging with the serotonin‐transporter‐linked polymorphic region genotype in patients with major depressive disorder. Methods: A total of 23 drug‐naïve patients with major depressive disorder were genotyped and brain imaged with ^[123I]nor‐β‐CIT single photon emission computed tomography. The severity of depression was evaluated with the 17‐item Hamilton depression rating scale. Results: Depressed patients homozygous for the short allele had lower ^[123I]nor‐β‐CIT binding in the medial prefrontal cortex, but not in the midbrain, compared with the other genotypes. Conclusion: The decreased medial prefrontal cortical serotonin transporter binding in the patients homozygous for the short allele may be linked to altered function of the serotonin‐transporter‐linked polymorphic region gene expressed in these patients, especially in the medial prefrontal cortex.     

Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer

Biallelic mutations in the ataxia-telangiectasia mutated (ATM)gene result in ataxia-telangiectasia (A-T). Studies on A-T familieshave shown that obligate female carriers have increased riskof developing breast cancer. Here we have evaluated the roleof known Finnish ATM germ line mutations as possible breastcancer predisposing alleles outside A-T families by analyzingtheir prevalence in large cohorts of familial and unselectedbreast cancer cases. Of seven different alterations, two wereobserved in the studied breast cancer material. ATM 6903insA(causing protein truncation) was seen in 3/541 familial and5/1124 unselected cases, but not among healthy population controls(0/1107). 7570G>C (Ala2524Pro) occurred in 1/541 familialand 2/1124 unselected cases compared with 1/1107 in controls.Additionally, 8734A>G (Arg2912Gly) associated previouslywith breast cancer susceptibility and suggested to be causativealso for A-T was detected in 2/541 of familial cases, but notin unselected cases (0/1124) or controls (0/1107). In total,heterozygous ATM mutation carriers were observed in 6/541 familial[P = 0.006, odds ratio (OR) 12.4, 95% confidence interval (CI)1.5–103.3) and 7/1124 unselected cases (P = 0.07, OR 6.9,95% CI 0.9–56.4), compared with 1/1107 in controls, suggestingan apparent yet overall limited contribution to predispositionto cancer. The current results also provided evidence for foundereffects in the geographical distribution of these mutations.Interestingly, results from functional analysis of the breastcancer-associated ATM mutations indicated that cancer susceptibilityis not restricted to mutations with dominant-negative effecton kinase activity, displayed only by 7570G>C, whereas 8734A>Gshowed only a partial defect in the phosphorylation of ATM substrates,and 6903insA seemed to be a null allele. Abbreviations: AI, allelic imbalance; A-T, ataxia-telangiectasia; ATM, ataxia-telangiectasia mutated; CI, confidence interval; IR, ionizing radiation; LCL, lymphoblast cell line; OR, odds ratio