Assisted reproductive technology treatment and risk of breast cancer: a population-based cohort study.

STUDY QUESTION: Is there an increased risk of breast cancer among women after ART treatment including ovarian hormone stimulation? SUMMARY ANSWER: The risk of breast cancer was slightly increased among women after ART treatment compared to age-matched, untreated women in the background population, and the risk was further increased among women initiating ART treatment when aged 40+ years. WHAT IS KNOWN ALREADY: The majority of breast cancer cases are sensitive to oestrogen, and ovarian hormone stimulation has been suggested to increase the risk of breast cancer by influencing endogenous oestrogen levels. Previous studies on ART treatment and breast cancer have varied in their findings, but several studies have small sample sizes or lack follow-up time and/or confounder adjustment. Recent childbirth, nulliparity and higher socio-economic status are breast cancer risk factors and the latter two are also associated with initiating ART treatment. STUDY DESIGN, SIZE, DURATION: The Danish National ART-Couple II (DANAC II) cohort includes women treated with ART at public and private fertility clinics in 1994-2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with no cancer prior to ART treatment were included (n = 61 579). Women from the background population with similar age and no prior history of ART treatment were randomly selected as comparisons (n = 579 760). The baseline mean age was 33.1 years (range 18-46 years). Results are presented as hazard ratios (HRs) with corresponding CIs. MAIN RESULTS AND THE ROLE OF CHANCE: During follow-up (median 9.69 years among ART-treated and 9.28 years among untreated), 5861 women were diagnosed with breast cancer, 695 among ART-treated and 5166 among untreated women (1.1% versus 0.9%, P < 0.0001). Using Cox regression analyses adjusted for nulliparity, educational level, partnership status, year, maternal breast cancer and age, the risk of breast cancer was slightly increased among women treated with ART (HR 1.14, 95% CI 1.12-1.16). All causes of infertility were slightly associated with breast cancer risk after ART treatment. The risk of breast cancer increased with higher age at ART treatment initiation and was highest among women initiating treatment at age 40+ years (HR 1.37, 95% CI 1.29-1.45). When comparing women with a first birth at age 40+ years with or without ART treatment, the increased risk among women treated with ART persisted (HR 1.51, 95% CI 1.09-2.08). LIMITATIONS, REASONS FOR CAUTION: Although this study is based on a large, national cohort of women, more research with sufficient power and confounder adjustment is needed, particularly in cohorts with a broad age representation. WIDER IMPLICATIONS OF THE FINDINGS: An increased risk of breast cancer associated with a higher age at ART treatment initiation has been shown. Ovarian stimulation may increase the risk of breast cancer among women initiating ART treatment when aged 40+ years. Age-related vulnerability to hormone exposure or higher hormone doses during ART treatment may explain the increased risk. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a PhD grant to D.V. from the Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Funding for establishing the DANAC II cohort was received from the Ebba Rosa Hansen Foundation. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Assisted reproductive technology treatment and risk of ovarian cancer-a nationwide population-based cohort study.

STUDY QUESTION: Does hormone stimulation during assisted reproductive technology (ART) treatment increase the risk of ovarian cancer? SUMMARY ANSWER: No increased risk of ovarian cancer was found among ART-treated women, with the exception of ART-treated women with endometriosis. WHAT IS KNOWN ALREADY: Previous studies on the association between ovarian stimulation during ART and ovarian cancer have shown conflicting results. The risk of ovarian cancer varies according to the cause of infertility, and only a few studies on ART treatment and risk of ovarian cancer have had sufficient data to address this issue. Endometriosis has been linked to an increased risk of ovarian cancer. STUDY DESIGN, SIZE, DURATION: Women undergoing ART treatment during 1994-2015 were registered in the Danish IVF register. Data were linked with data from the Danish Cancer Register and socio-demographic population registers using an individual person identification number assigned to people residing in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women undergoing ART treatment were age-matched with a random sample of the female background population and followed for up to 22 years. After relevant exclusions, the population consisted of 58 472 ART-treated women and 625 330 untreated women, all with no previous malignancies. Ovarian cancer risk was assessed using multivariable cox regression analyses with adjustment for educational level, marital status, parity and treatment year. Results are shown as hazard ratios (HRs) with corresponding CIs. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 393 (0.06%) women were diagnosed with ovarian cancer during follow-up (mean 9.7 years). Women treated with ART had an increased risk of ovarian cancer (HR 1.20, 95% CI 1.10-1.31), which diminished over time. The increased risk was apparent among women with female factor infertility (HR 1.36, 95% CI 1.25-1.48), whereas no female factor infertility was associated with a lower risk (HR 0.87, 95% CI 0.76-1.00). The risk was increased among women with endometriosis (HR 3.78, 95% CI 2.45-5.84), whereas no increased risk was found among ART-treated women with polycystic ovary syndrome, other female causes of infertility and unexplained infertility. LIMITATIONS, REASONS FOR CAUTION: The association between ART treatment and ovarian cancer is likely influenced by increased detection due to multiple ultrasound scans during ART treatment. WIDER IMPLICATIONS OF THE FINDINGS: Undergoing ART treatment without the presence of endometriosis was not associated with an increased risk of ovarian cancer, which is reassuring. Whether ART treatment increases the risk of ovarian cancer among women with endometriosis needs further investigation. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a PhD grant to D.V. from the Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Funding for establishing the Danish National ART-couple II cohort was achieved from Ebba Rosa Hansen Foundation. The funders had no influence on data collection, analyses or results presented. The authors have no conflicts of interest to declare.

Recurrent pregnancy loss: couples' perspectives on their need for treatment, support and follow up.

STUDY QUESTION: What do couples referred to or attending a recurrent pregnancy loss (RPL) clinic believe they need in terms of treatment, support and follow up? SUMMARY ANSWER: Men and women wish for more information, earlier access to treatment, support and follow up that is sensitive to their history of pregnancy loss (PL), includes both members of the couple, and acknowledges the psychological impact of RPL. WHAT IS KNOWN ALREADY: Previous research has highlighted women's dissatisfaction with medical care provided post-PL and their desire for medical professionals to have increased awareness about PL and recognition of the psychological impact of PL. Less is known about the needs of the male partner, the needs of those experiencing RPL and whether the needs differ during different reproductive stages. STUDY DESIGN, SIZE, DURATION: Over a 2-month period in 2017-2018, 13 couples who were referred to the national RPL program in Copenhagen, Denmark were qualitatively interviewed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were heterosexual couples with at least three consecutive PLs before 12 weeks' gestation with no children or one child prior to the PLs, not currently pregnant, and willing to be interviewed in English. Couples were interviewed together in a semi-structured format. Data were analyzed using thematic analysis. Invitations (n = 30) were sent to couples recently referred to the RPL program who indicated an interest in participating and 17 couples contacted the interviewer to schedule an interview. Due to cancellations, 15 interviews were held. Data from 13 interviews that met the study criteria were used for the current analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The participants had experienced a median of three PLs (range 3-6). Both men and women described the cumulative effect of RPL with an increase in pressure and exhaustion by the third and subsequent losses. Inclusion of the male partner in consultations and treatment was seen as important. Men felt pressured to remain positive and support their partners despite their own feelings of loss. The findings showed that couples desired reliable and accurate information about RPL. They wished for recognition from the medical community that RPL has a significant psychological impact, and stressed that effective treatment should include both members of the couple, with attention to both physical and psychological aspects of the RPL and should be tailored to their current reproductive stage, in order to help them cope with the negative impact of RPL and the anxiety associated with conception and another pregnancy. LIMITATIONS, REASONS FOR CAUTION: Participants were self-selected thus findings cannot be generalized to all couples with RPL. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study addressing the needs of the female and male partners in couples suffering from RPL. The findings highlight a disconnect between couples' perceived needs and their experience of medical care after RPL. This may be partly due to a discrepancy in couples' and medical professionals' perceptions of the PLs. The findings highlight that medical professionals need to take a holistic and couple-focused approach in their treatment of RPL and include attention to the psychological impact and cumulative effect of the multiple PLs on the couple. The results underscore the need for informational resources and psychological support for couples experiencing RPL, tailored to their reproductive stage. STUDY FUNDING/COMPETING INTEREST(S): EK was funded by a Travel/Training Fellowship from ReproUnion, co-financed by the European Union, Interreg V ÖKS. No other competing interests were declared. TRIAL REGISTRATION NUMBER: N/A.

Hypothalamus enlargement in mood disorders.

OBJECTIVE: The purpose of this study was to determine, in vivo, whether the hypothalamus volume is reduced in patients with mood disorders. METHODS: The cross-sectional study included 20 unmedicated (MDDu) and 20 medicated patients with major depressive disorder, 21 patients with bipolar disorder, and 23 controls. Twenty of the controls were matched to the MDDu. Seven Tesla, T1-weighted magnetic resonance images were acquired and processed using methods specifically developed for high-precision volumetry of the hypothalamus. RESULTS: An overall group difference was observed for the left hypothalamus volume corrected for intracranial volume. Planned contrasts identified that the left hypothalamus was approximately 5% larger in each patient group compared with the control group. A paired t-test with the 20 matched pairs of MDDu and controls and without correction for covariates confirmed the larger left hypothalamus volume in MDDu. CONCLUSIONS: Contrary to our expectations, the hypothalamus volume was increased in patients with uni- and bipolar affective disorders. The effect was left-sided and independent of medication status or statistical correction for covariates. Supported by emerging evidence that the stress response may be related to structural and functional asymmetry in the brain, our finding suggests a crucial role of the hypothalamus in mood disorders.

Putting patients at the center of kidney care transitions: PREPARE NOW, a cluster randomized controlled trial.

Care for patients transitioning from chronic kidney disease to kidney failure often falls short of meeting patients' needs. The PREPARE NOW study is a cluster randomized controlled trial studying the effectiveness of a pragmatic health system intervention, 'Patient Centered Kidney Transition Care,' a multi-component health system intervention designed to improve patients' preparation for kidney failure treatment. Patient-Centered Kidney Transition Care provides a suite of new electronic health information tools (including a disease registry and risk prediction tools) to help providers recognize patients in need of Kidney Transitions Care and focus their attention on patients' values and treatment preferences. Patient-Centered Kidney Transition Care also adds a 'Kidney Transitions Specialist' to the nephrology health care team to facilitate patients' self-management empowerment, shared-decision making, psychosocial support, care navigation, and health care team communication. The PREPARE NOW study is conducted among eight [8] outpatient nephrology clinics at Geisinger, a large integrated health system in rural Pennsylvania. Four randomly selected nephrology clinics employ the Patient Centered Kidney Transitions Care intervention while four clinics employ usual nephrology care. To assess intervention effectiveness, patient reported, biomedical, and health system outcomes are collected annually over a period of 36 months via telephone questionnaires and electronic health records. The PREPARE NOW Study may provide needed evidence on the effectiveness of patient-centered health system interventions to improve nephrology patients' experiences, capabilities, and clinical outcomes, and it will guide the implementation of similar interventions elsewhere. TRIAL REGISTRATION: NCT02722382.

Meeting report: Spontaneous lesions and diseases in wild, captive-bred, and zoo-housed nonhuman primates and in nonhuman primate species used in drug safety studies.

The combination of loss of habitat, human population encroachment, and increased demand of select nonhuman primates for biomedical research has significantly affected populations. There remains a need for knowledge and expertise in understanding background findings as related to the age, source, strain, and disease status of nonhuman primates. In particular, for safety/biomedical studies, a broader understanding and documentation of lesions would help clarify background from drug-related findings. A workshop and a minisymposium on spontaneous lesions and diseases in nonhuman primates were sponsored by the concurrent Annual Meetings of the American College of Veterinary Pathologists and the American Society for Veterinary Clinical Pathology held December 3-4, 2011, in Nashville, Tennessee. The first session had presentations from Drs Lowenstine and Montali, pathologists with extensive experience in wild and zoo populations of nonhuman primates, which was followed by presentations of 20 unique case reports of rare or newly observed spontaneous lesions in nonhuman primates (see online files for access to digital whole-slide images corresponding to each case report at http://www.scanscope.com/ACVP%20Slide%20Seminars/2011/Primate%20Pathology/view.apml). The minisymposium was composed of 5 nonhuman-primate researchers (Drs Bradley, Cline, Sasseville, Miller, Hutto) who concentrated on background and spontaneous lesions in nonhuman primates used in drug safety studies. Cynomolgus and rhesus macaques were emphasized, with some material presented on common marmosets. Congenital, acquired, inflammatory, and neoplastic changes were highlighed with a focus on clinical, macroscopic, and histopathologic findings that could confound the interpretation of drug safety studies.

Use of complementary and alternative medicines associated with a 30% lower ongoing pregnancy/live birth rate during 12 months of fertility treatment.

BACKGROUND: There seems to be little discussion between patient and physician about the use of complementary and alternative medicines (CAMs), perhaps because they are not perceived to have adverse effects on fertility. We therefore compared ongoing pregnancy and live birth rate in spontaneous users and non-users of CAM during a 12-month period of assisted reproduction technique (ART) treatment. Consent was by questionnaire return. METHOD: This was a prospective observational cohort study with a 12-month follow-up period, sampling consecutive patients attending five ART clinics in Denmark. N = 728 women about to have ART for the first time completed self-report assessments prior to treatment (Time 1, T1) and at 12-month follow-up (Time 2, T2). Data from treatment records were also available for n = 590. RESULTS: About 30.6% (n = 223) of women used CAMs during the observation period. At T2 the ongoing pregnancy and live birth rate was 31.3% lower in CAM users (42.2%) compared with non-users (61.4%). Adjusted odds of pregnancy/live birth remained lower in CAM users versus non-users, odds ratio = 0.467 (95% confidence interval 0.306-0.711) after controlling for prognostic indicators (age, parity, years infertile). CONCLUSIONS: Concurrent use of CAM during treatment with ART was associated with a 30% lower pregnancy rate that could not be explained by poor prognosis or life style factors. The mechanisms that could account for this association were discussed. Concurrent CAM use should be monitored during ART. A main limitation was that we could not ascertain which type of CAM was most associated with lower pregnancy rates.

Polycyclic aromatic hydrocarbons, aliphatic hydrocarbons, trace elements, and monooxygenase activity in birds nesting on the North Platte River, Casper, Wyoming, USA.

Tree swallow (Tachycineta bicolor) and house wren (Troglodytes aedon) eggs and chicks were collected near a refinery site on the North Platte River, Casper. Wyoming, USA and at a reference site 10 km upstream. Total polycyclic aromatic hydrocarbon (PAH) concentrations in swallow and wren chicks were higher at the refinery site than at the reference site. Polycyclic aromatic hydrocarbon concentrations in sediment and chick dietary samples were consistent with these findings. The general lack of methylated PAHs in sediment, diet, and bird carcasses suggested that the PAHs were derived from combustion and not from petroleum. The predominance of odd-numbered aliphatic hydrocarbons and the low ratios (< or =0.25) of pristane:n-C17 and phytane:n-C18 in chick and diet samples also suggested that swallow and wren chicks were not being chronically exposed to petroleum. Mean ethoxyresorufin-O-dealkylase and benzyloxyresorufin-O-dealkylase activities in tree swallow livers averaged nine times higher at the refinery site than at the reference site and were probably induced by exposure to PAHs. Trace element concentrations in eggs and livers of swallows and wrens were similar or greater at the reference site than at the refinery site. Selenium, strontium, and boron concentrations were elevated in eggs and livers of swallows and wrens at both the refinery and reference sites.

Continuity and discontinuity of behavioral inhibition and exuberance: psychophysiological and behavioral influences across the first four years of life.

Four-month-old infants were screened (N = 433) for temperamental patterns thought to predict behavioral inhibition, including motor reactivity and the expression of negative affect. Those selected (N = 153) were assessed at multiple age points across the first 4 years of life for behavioral signs of inhibition as well as psychophysiological markers of frontal electroencephalogram (EEG) asymmetry. Four-month temperament was modestly predictive of behavioral inhibition over the first 2 years of life and of behavioral reticence at age 4. Those infants who remained continuously inhibited displayed right frontal EEG asymmetry as early as 9 months of age while those who changed from inhibited to noninhibited did not. Change in behavioral inhibition was related to experience of nonparental care. A second group of infants, selected at 4 months of age for patterns of behavior thought to predict temperamental exuberance, displayed a high degree of continuity over time in these behaviors.

Acoustic startle electromyographic (EMG) activity indexed from an electroculographic (EOG) electrode placement: a methodological note.

Acoustic startle EMG responses were indexed from a traditional EOG electrode placement in 11 young adults while they viewed slides which varied in affective valence. We found, replicating earlier work that subjects' startle responses became more augmented as the content of the slides became more negative. The advantages of using an EOG electrode placement for measuring acoustic startle responses are discussed.

Loss of heterozygosity of the human cytosolic glutathione peroxidase I gene in lung cancer.

The consistent deletion of 3p21 in lung cancer has led to intensive efforts to identify a lung tumor suppressor gene at this locus. We recently mapped the gene for the selenium-dependent drug-detoxifying enzyme glutathione peroxidase 1 (GPX1) to this location by in situ hybridization. We developed a polymerase chain reaction-based assay which demonstrated the existence of three GPX1 alleles characterized by the number of alanines in a polyalanine coding sequence in exon 1. These three alleles produced a heterozygote frequency of 70% in two separate populations: normal tissue DNA taken from Centre d'Etude du Polmorphisme Humain (CEPH) parents and normal tissue taken from cancer patients. In contrast, 10 heterozygote tumors were detected out of 64 lung cancer specimens. Linkage analysis of GPX1 to Genethon 3p markers in CEPH pedigrees demonstrated that GPX1 was located between the two microsatellite markers believed to flank the lung cancer deletion site. Nucleotide sequence analysis of GPX1 alleles did not reveal any mutations of this gene in lung tumors. However, sequence analysis did reveal that the three GPX1 alleles were characterized by three nucleotide substitutions in addition to the polyalanine polymorphism, including a substitution at codon 198 which results in either a proline or leucine at that position. Therefore, the different GPX1 alleles encode structurally different hGPx1 subunits. In addition, analysis of allele frequency suggests that the GPX1*ALA7 allele may occur less frequently in tumors with 3p21 deletions.

von Hippel-Lindau syndrome: cloning and identification of the plasma membrane Ca(++)-transporting ATPase isoform 2 gene that resides in the von Hippel-Lindau gene region.

We have isolated and analyzed full-length complementary DNA clones encoded by a 200-kilobase gene encompassing the D3S601 locus that resides in the von Hippel-Lindau (VHL) gene region. The deduced amino acid sequence shows 99% identity with the published sequence of the rat plasma membrane Ca(++)-transporting ATPase isoform 2 complementary DNA, implying that we have cloned and positioned the human plasma membrane Ca(++)-transporting ATPase isoform 2 gene within the VHL critical region. The gene is expressed in VHL target tissues and should be considered a potential candidate gene for the VHL disease.

Chronic nightly tidal peritoneal dialysis.

Nightly tidal peritoneal dialysis (NTPD) is a technique in which, after an initial fill of the peritoneal cavity, only a portion of dialysate is rapidly cycled. Five anuric, stable, PD patients entered a 4 month study to determine the NTPD session length necessary for clinically adequate dialysis and creatinine clearance similar to those on four daily 2 L CAPD exchanges. NTPD was performed using a modified PAC-X-2 cycler, with the drain phase regulated by a target volume. One patient completed 3.5 months of study, one 4 months, three 6 months, and one patient each continued on NTPD for 13, 14, and 32 months. The mean NTPD session time was 9 hr 24 min (range 8 hr 35 min to 9 hr 55 min) at the end of 4 months. All patients had clinically adequate dialysis. Three patients preferred NTPD over CAPD, particularly because of an empty abdomen during the daytime. One patient required an increase in NTPD time, and an addition of one daytime exchange, because of low creatinine clearance. In conclusion, NTPD provides weekly creatinine clearances comparable to CAPD, with an acceptable duration of nightly dialysis sessions in most anuric patients. A new PD machine providing inexpensive dialysis solution in large quantities, as well as safe and false alarm free dialysis sessions, is needed for practical NTPD implementation.

Ex vivo lipopolysaccharide-induced interleukin-1 secretion from murine peritoneal macrophages inhibited by probucol, a hypocholesterolemic agent with antioxidant properties.

Probucol, 4,4'-(isopropylidenedithio)bis(2,6-di-tert-butyl-phenol), has been shown to inhibit atherogenesis in genetically hypercholesterolemic (Watanabe) rabbits. Since atherosclerotic lesions contain macrophages capable of screting interleukin 1 (IL 1) and other cytokines that could contribute to the pathogenesis of the disease, we have investigated whether probucol affects IL 1 secretion. Resident peritoneal macrophages from mice dosed with probucol secreted 40-80% less IL 1 than macrophages from control animals when stimulated in vitro with lipopolysaccharide (LPS). The inhibitory effect of probucol was observed when IL 1 was assayed by the standard bioassay, the thymocyte proliferation assay, or a competitive IL 1 receptor binding assay. Probucol treatment had no effect on LPS-induced membrane IL 1 expression; secretion of tumor necrosis factor (TNF); Con A-induced splenic interleukin 2 (IL 2) and interleukin 3 (IL 3) release; and prostaglandin- or zymosan-induced secretion of prostacyclin, leukotriene C4, acid phosphatase, or superoxide anion. In contrast to the effect of oral administration, direct addition of probucol to macrophage cultures did not inhibit IL 1 release. Probucol administration did, however, inhibit the fall in serum zinc level induced by intravenous injection of LPS in zymosan-primed mice but had no effect on the LPS-induced increase in serum triglyceride levels, which indirectly confirms that probucol administration inhibits IL 1 but not TNF secretion. Paw granuloma induced in mice by heat-killed mycobacteria was inhibited by oral administration of probucol, an effect that may be attributable to inhibition of IL 1 secretion. Probucol neither reduced zymosan-induced liver granulomata in mice nor inhibited adjuvant-induced arthritis in rats. We suggest that inhibition of IL 1 secretion from macrophages by probucol contributes to its therapeutic effects in atherosclerosis and may also result in beneficial activity in some chronic inflammatory diseases.

[Iron resorption and the effects of iron supplementation in blood donors]. / Untersuchungen zur Eisen-Resorption und des Effektes der Eisen-Supplementierung bei Blutspendern.

Topical values for some haematological factors such as Hb and Ery as well as transferrin and ferritin were determined in 7 female blood donors and 8 male blood donors during the years of their work as blood donors. Subsequently, an iron resorption test was carried out which unexpectedly resulted in low rates of resorption ranging from 5.6% in men to 3.7% in women. After supplementing with vitaferro for 3 months the ferritin values which initially lay around the lower limiting value of 20 or 10 mg/l in men or women had doubled.

Oral calcium chloride in hypoparathyroidism refractory to massive doses of calcium carbonate and vitamin D.

Surgically induced hypoparathyroidism often responds satisfactorily to intravenous Ca administration, oral CaCO3 and vitamin D2. A 17-year-old girl developed hypoparathyroidism following partial thyroidectomy for thyrotoxicosis. Hypocalcemia was refractory to treatment with massive doses of vitamin D2, up to 150,000 U, 3-6 gm of oral Ca as CaCO3 and 2 micrograms of 1,25-dihydroxycholecalciferol per day. Intravenous Ca gluconate (360 mg of elemental Ca/d, in divided doses) was needed to correct tetany. After 25 days of unsuccessful therapy, oral administration of 30 ml of a 10% solution of CaCl2 (1.09 gm of elemental Ca) was followed by normalization of serum Ca (8.9 mg/dl) within 7 hours. This dose was repeated every 8 hours for 6 days and oral CaCO3 and IV Ca gluconate were discontinued. Serum Ca remained within normal range but hyperchloremic acidosis developed. This was corrected by providing, in addition to vitamin D, 2 g/d of Ca supplementation, 1 gm in the form of 10% CaCl2 solution and 1 gm as CaCO3 in two doses given simultaneously. During 12 months of observation, serum Ca, P and Cl have been consistently within normal limits. This patient was found to have achlorhydria, unresponsive to normalization of thyroid function and serum Ca. These findings indicate that refractoriness to oral CaCO3 and vitamin D may be caused by achlorhydria. Oral administration of CaCl2 solution can promptly correct this defect. Monitoring of serum Cl and CO2 is needed to avoid hyperchloremic acidosis.

Effectiveness of a phosphorous educational program for dialysis patients.

Fifty-four percent of all dialysis patients followed by a single center had elevated serum phosphorus levels on more than 25% of all measurements. A phosphorus patient education program was developed and implemented and knowledge was measured with a pretest and posttest. The continuous ambulatory peritoneal dialysis group had a significant increase in knowledge and a minor, but statistically significant, decrease in serum phosphorus after participating in the education program. In contrast, center hemodialysis patients did not demonstrate a significant increase in knowledge or decrease in serum phosphorus. These different outcomes could not be attributed to specific differences between the two groups. Serum phosphorus control is a complex process, and this education program did not result in a clinically significant improvement in serum phosphorus levels.

Appraisals of compounds of diverse chemical classes for capacities to cure infections with sporozoites of Plasmodium cynomolgi.

Compounds (265) of widely diverse structures were appraised for radical curative activity in rhesus monkeys infected with sporozoites of the B strain of Plasmodium cynomolgi, using an evaluation system that provided a preliminary assessment with from 0.1-1.0 g of compound and tests against one to five active infections. None of 32 compounds in a miscellaneous structure category, none of seven agents of antibiotic origin, none of 12 1,5-naphthyridines, and none of seven 7-aminoquinolines exhibited curative activity at the largest test doses. There was a suggestion that one of 12 newly synthesized pyrocatechols was curative. Two of 20 6-aminoquinolines effected cure at or near maximum tolerated doses. In contrast, 90 of 174 newly synthesized 8-aminoquinolines effected cure; 18 of the 90 being as active as primaquine, eight twice as active, and six four times as active. There were major disagreements between the above results and those recorded by others in mice inoculated with sporozoites of P. berghei yoelii or P. yoelii nigeriensis. These discrepancies were of serious dimensions in evaluations of the 8-aminoquinolines. This, plus previous near flawless performances of P. cynomolgi in identifying agents that would cure naturally acquired P. vivax infections, led to the suggestion that the abbreviated simian model employed in these studies be used hereafter in primary screening of new agents for radical curative activity.

(+)-4-Dimethylamino-2,alpha-dimethylphenethylamine (FLA 336(+)), a selective inhibitor of the A form of monoamine oxidase in the rat brain.

(+)-4-Dimethylamino-2,alpha-dimethylphenethylamine (FLA 336(+)) and its N-demethylated secondary amino derivative FLA 788(+) were examined for their monoamine oxidase (MAO) inhibitory effects in the rat brain. They were found to be reversible and very selective inhibitors of the A form of monoamine oxidase in vitro and in vivo after oral administration. FLA 788(+) was 2-6 times more active than FLA 336(+) in vitro depending on the assay technique employed but the two compounds had similar potency after oral administration. Both compounds inhibited competitively the deamination of 5-hydroxytryptamine by hypothalamic mitochondria. Although the irreversible inhibitor clorgyline was 60 times more potent than FLA 336(+) in vitro, it was equipotent with FLA 336(+) and FLA 788(+) in the rat brain after oral administration. There was a high correlation between the log plasma concentration of FLA 788(+) and the MAO inhibition in hypothalamic slices. The plasma concentration of the metabolite FLA 788(+) exceeded that of FLA 336(+) after oral administration of the latter compound. Thus, the MAO inhibition produced by FLA 336(+) in vivo, appears in part to be due to the metabolite FLA 788(+).