Pregnancy outcomes following maternal venlafaxine use: A prospective observational comparative cohort study.

BACKGROUND: Venlafaxine is a serotonin noradrenaline reuptake inhibitor used to treat major depressive episodes and anxiety disorders. The primary aim of this study was to investigate spontaneous abortion risks following gestational exposure. METHODS: This prospective observational comparative cohort study utilised data collected by the UK Teratology Information Service (UKTIS) between 1995 and 2018. The study sample included 281 venlafaxine exposed pregnancies matched to antidepressant unexposed (n = 1405) and SSRI exposed (n = 843) comparator groups. RESULTS: After correction for variation in competing outcome rates and the stage of pregnancy at reporting, no statistically significant differences in the hazard of spontaneous abortion was observed following gestational venlafaxine use compared with either antidepressant unexposed (HR 1.28, 95% CI; 0.850-1.94) or SSRI exposed (HR 1.03, 95% CI; 0.681-1.57) pregnancies. CONCLUSIONS: No conclusive evidence is provided from this study that venlafaxine increases the risk of adverse pregnancy or fetal outcomes.

Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza A/H1N1 pandemic: a national prospective surveillance study.

OBJECTIVE: To conduct enhanced surveillance for signals of teratogenesis following use of the neuraminidase inhibitors zanamivir and oseltamivir in the treatment or post-exposure prophylaxis of 2009 A/H1N1 influenza during pregnancy. DESIGN: Prospective cohort study, using national surveillance data collected by the UK Teratology Information Service (UKTIS) during the 2009 A/H1N1 pandemic. SETTING: United Kingdom. POPULATION: Pregnant women who were reported to UKTIS by healthcare professionals seeking advice about exposure to zanamivir and oseltamivir or to other non-teratogenic drugs. METHODS: Pregnancy outcomes were collected for prospectively reported pregnancies exposed to zanamivir (n = 180) or oseltamivir (n = 27), and compared with a reference group of 575 prospectively reported pregnancies exposed to non-teratogenic drugs over the same period. MAIN OUTCOME MEASURES: Rates of major congenital malformation, preterm delivery and low birth weight. RESULTS: No significant differences in overall rates of major malformation in live-born infants [adjusted odds ratios (aOR): zanamivir 0.37 (95% confidence interval 0.02-2.70); oseltamivir aOR 0.81 (0.05, 14.15)], preterm delivery [aOR: zanamivir 0.95 (0.45, 1.89); oseltamivir aOR 1.68 (0.38, 5.38)] or low birth weight [aOR: zanamivir 0.94 (0.25, 2.90); oseltamivir aOR 4.12 (0.59, 17.99)] were observed following exposure at any gestation. No major malformations were reported in 37 zanamivir or eight oseltamivir first trimester exposures. CONCLUSION: These surveillance data do not provide a signal that use of zanamivir or oseltamivir in pregnancy is associated with an increased risk of the adverse pregnancy outcomes studied but the data are too limited to state conclusively that there is no increase in risk.

Quantification of in situ nutrient and heavy metal remediation by a small pearl oyster (Pinctada imbricata) farm at Port Stephens, Australia.

The use of pearl oysters has recently been proposed as an environmental remediation tool in coastal ecosystems. This study quantified the nitrogen, phosphorus and heavy metal content of the tissue and shell of pearl oysters harvested from a small pearl oyster farm at Port Stephens, Australia. Each tonne of pearl oyster material harvested resulted in approximately 703 g metals, 7452 g nitrogen, and 545 g phosphorus being removed from the waters of Port Stephens. Increasing current farm production of 9.8 tyr(-1) to 499 tyr(-1) would balance current nitrogen loads entering Port Stephens from a small Sewage Treatment Plant (STP) located on its southern shores. Furthermore, manipulation of harvest dates to coincide with oyster condition would likely remove substantially greater quantities of nutrients. This study demonstrates that pearl aquaculture may be used to assist in the removal of pollutants from coastal waters while producing a commercially profitable commodity.

Angiotensin-converting enzyme inhibition in adult hypertensive rats: a stereological study of renal filtration surface area.

1. Angiotensin-converting enzyme (ACE) inhibitor treatment leads to beneficial effects on kidney function. The aim of the present study was to determine whether ACE inhibition at high or low doses affects glomerular capillary surface area and length, glomerular number or total renal filtration surface area in rats with established hypertension and, if so, to determine whether these effects are mediated through bradykinin potentiation. 2. Spontaneously hypertensive rats (SHR) were treated with the ACE inhibitor perindopril at either 3 or 0.1 mg/kg per day (high and low doses, respectively) from 16 to 24 weeks of age. Some rats were concomitantly treated with the bradykinin B2 receptor antagonist S16118 (10 nmol/kg per day). Blood pressure was measured twice weekly during the treatment period. At 24 weeks of age, rats were perfusion fixed at 140 mmHg, the kidneys removed, embedded in resin and examined stereologically to estimate glomerular number and volume, length and surface area of glomerular capillaries and total renal filtration surface area. 3. High- and low-perindopril treatment significantly reduced systolic blood pressure compared with control SHR. However, the rats treated with low-dose perindopril were still considered hypertensive. Neither low-dose nor high-dose perindopril treatment had any observable effect on glomerular number (23 876 +/- 1201 vs 26 240 +/- 1465 glomeruli/kidney, respectively) or volume (2.25 +/- 0.21 and 1.96 +/- 0.06 x 10-3 mm3, respectively) compared with controls (glomerular number 25866 +/- 1210 glomeruli/kidney; glomerular volume 2.24 +/- 0.21 x 10-3 mm3). As a result, there was no significant difference in total renal filtration surface area between any of the experimental groups (8161.6 +/- 550.9, 8699.7 +/- 427.6, 9081.9 +/- 453.6, 8830.2 +/- 521.2 and 8559.4 +/- 341.4 mm2 for SHR, SHR low-dose perindopril, SHR low-dose perindopril + B2 antagonist, SHR high-dose perindopril and SHR high-dose perindopril + B2 antagonist, respectively). Coadministration of the bradykinin antagonist had no observable effect on any of the parameters studied. 4. In conclusion, because neither high-dose nor low-dose perindopril had any effect on total renal filtration surface area, the observed beneficial effects of ACE inhibition on kidney function are not the result of enhancement in glomerular capillary surface area.

Plasma cholesterol levels and Irlen syndrome: preliminary study of 10- to 17-yr.-old students.

The preliminary study investigated metabolic anomalies in children and teenagers with Irlen Syndrome, particularly in relation to the levels of n-3 and n-6 essential fatty acids, plasma cholesterol levels, and the relative abundance of plasma saturated fatty acids. The experimental group involved 13 subjects with Irlen Syndrome (M=13.3 yr., SD=2.5 yr.), with a comparison group of 16 age- and sex-matched controls (M=13.8 yr., SD=2.4 yr.). The Irlen Syndrome group were selected from people referred for help with reading and writing problems. The control group were primarily recruited from the general public. All subjects were screened for symptoms of the syndrome using the Scotopic Sensitivity Syndrome Screening Manual. Samples of whole blood were collected and plasma extracted. Metabolites were compared using the Student t test. There were no differences in n-3 and n-6 essential fatty acids between Irlen Syndrome and control groups, although the former group had lower mean levels in most of these essential fatty acids. Total plasma cholesterol level was significantly decreased for the Irlen Syndrome group, and there was a significant increase in the relative abundance of the odd-chain fatty acid, heptadecanoic acid. The differences in heptadecanoic acid may have implications for altered membrane function and neurotransmission. The differences in plasma cholesterol levels, as well as heptadecanoic acid, may also point to the presence of viral or bacterial infection.

Effect of angiotensin-converting enzyme inhibition on renal filtration surface area in hypertensive rats.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitor treatment leads to protective effects on the cellular structure of the glomerulus and the kidney. The aim of this study was to determine whether ACE inhibition increases renal filtration surface area in the spontaneously hypertensive rat (SHR). METHODS: SHR were treated with the ACE inhibitor perindopril at a high dose (3 mg/kg/day) or a low dose (0.1 mg/kg/day) during the period of hypertension development, from 7 to 14 weeks of age. Some animals were treated concomitantly with the bradykinin B2 receptor antagonist, S16118. Tail-cuff systolic blood pressure and body weights were measured twice weekly. At termination of treatment, glomerular number and volume, length, and surface area of glomerular capillaries and renal filtration surface area were estimated using unbiased stereological techniques. RESULTS: There were significant dose-related reductions in blood pressure with high- and low-dose perindopril treatment. Neither low- nor high-dose perindopril treatment had any effect on glomerular number or size or glomerular capillary length and surface area. Hence, there was no significant difference in total renal filtration surface area between any of the experimental groups (8721 +/- 610 mm2 in untreated SHR and 7879 +/- 338 mm2 and 8767 +/- 437 mm2 in the low and high dose perindopril-treated groups, respectively). Coadministration of the bradykinin antagonist did not affect any of the glomerular parameters. CONCLUSIONS: ACE inhibition during the period of hypertension development does not lead to an enhanced glomerular capillary growth or increases in total renal filtration surface area in this model.

The anti-malarial artesunate is also active against cancer.

Artesunate (ART) is a semi-synthetic derivative of artemisinin, the active principle of the Chinese herb Artemisia annua. ART reveals remarkable activity against otherwise multidrug-resistant Plasmodium falciparum and P. vivax malaria. ART has now been analyzed for its anti-cancer activity against 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute, USA. ART was most active against leukemia and colon cancer cell lines (mean GI50 values: 1.11+/-0.56 microM and 2.13+/-0.74 microM , respectively). Non-small cell lung cancer cell lines showed the highest mean GI50 value (25.62+/-14.95 microM) indicating the lowest sensitivity towards ART in this test panel. Intermediate GI50 values were obtained for melanomas, breast, ovarian, prostate, CNS, and renal cancer cell lines. Importantly, a comparison of ART's cytotoxicity with those of other standard cytostatic drugs showed that ART was active in molar ranges comparable to those of established anti-tumor drugs. Furthermore, we tested CEM leukemia sub-lines resistant to either doxorubicin, vincristine, methotrexate, or hydroxyurea which do not belong to the N.C.I. screening panel. None of these drug-resistant cell lines showed cross resistance to ART. To gain insight into the molecular mechanisms of ART's cytotoxicity, we used a panel of isogenic Saccaromyces cerevisiae strains with defined genetic mutations in DNA repair, DNA checkpoint and cell proliferation genes. A yeast strain with a defective mitosis regulating BUB3 gene showed increased ART sensitivity and another strain with a defective proliferation-regulating CLN2 gene showed increased ART resistance over the wild-type strain, wt644. None of the other DNA repair or DNA check-point deficient isogenic strains were different from the wild-type. These results and the known low toxicity of ART are clues that ART may be a promising novel candidate for cancer chemotherapy.

Pet111p, an inner membrane-bound translational activator that limits expression of the Saccharomyces cerevisiae mitochondrial gene COX2.

The protein specified by the Saccharomyces cerevisiae nuclear gene PET111 specifically activates translation of the mitochondrially coded mRNA for cytochrome c oxidase subunit II (Cox2p). We found Pet111p specifically in mitochondria of both wild-type cells and cells expressing a chromosomal gene for a functional epitope-tagged form of Pet111p. Pet111p was associated with mitochondrial membranes and was highly resistant to extraction with alkaline carbonate. Pet111p was protected from proteolytic digestion by the mitochondrial inner membrane. Thus, it is exposed only on the matrix side, where it could participate directly in organellar translation and localize Cox2p synthesis by virtue of its functional interaction with the COX2 mRNA 5'-untranslated leader. We also found that Pet111p is present at levels limiting the synthesis of Cox2p by examining the effect of altered PET111 gene dosage in the nucleus on expression of a reporter gene, cox2::ARG8(m), that was inserted into mitochondrial DNA. The level of the reporter protein, Arg8p, was one-half that of wild type in a diploid strain heterozygous for a pet111 deletion mutation, whereas it was increased 2.8-fold in a strain bearing extra copies of PET111 on a high-copy plasmid. Thus, Pet111p could play dual roles in both membrane localization and regulation of Cox2p synthesis within mitochondria.

Differential toxicities of anticancer agents among DNA repair and checkpoint mutants of Saccharomyces cerevisiae.

Most cytotoxic anticancer agents damage DNA directly, interfere with DNA metabolism or chromosome segregation, and are particularly toxic in dividing cells. Although a considerable amount of information on the mechanisms of action of these agents is available, the molecular bases for selective tumor cell killing by chemotherapy are largely unknown. Many genetic alterations found in sporadic and hereditary cancers affect functions in DNA repair and cell cycle control and result in sensitivity to DNA damaging agents. We have therefore set out to determine the effects of these cancer mutations on sensitivity or resistance to various chemotherapeutic agents. Because most of the affected genes are well conserved among eukaryotes, we have carried out a comprehensive analysis of a panel of isogenic yeast strains, each defective in a particular DNA repair or cell cycle checkpoint function, for sensitivity to the Food and Drug Administration-approved cytotoxic anticancer agents. Widely different toxicity profiles were observed for 23 agents and X-rays, indicating that the type of DNA repair and cell cycle checkpoint mutations in individual tumors could strongly influence the outcome of a particular chemotherapeutic regimen.

Chronic orofacial muscle pain: a new approach to diagnosis and management.

The initial data from this study indicate that there are clearly identifiable chronic muscle pain conditions in the form of localized pain; myofascial pain or regional pain conditions; and fibromyalgia or generalized pain conditions. A clear difference exists between the prevalence of these conditions in male and female patients, with a higher percentage of female patients suffering generalized pain problems and temporomandibular problems. Generalized or localized pain appears to be an individual variant of a similar problem and pain patients may have a genetically determined vulnerability associated with bacterial toxins, particularly within the genitourinary tract. It appears that in fibromyalgia there is an underlying genetic factor that causes abnormalities in the muscle metabolic cycle, and preliminary data suggest that lipid anomalies predispose to fibromyalgia and possibly chronic fatigue syndrome. Patients report infectious events at/or around onset in more than 60 percent of cases. Seventy percent of fibromyalgic cases report orofacial pain.

In vivo analysis of Saccharomyces cerevisiae COX2 mRNA 5'-untranslated leader functions in mitochondrial translation initiation and translational activation.

We have used mutational and revertant analysis to study the elements of the 54-nucleotide COX2 5'-untranslated leader involved in translation initiation in yeast mitochondria and in activation by the COX2 translational activator. Pet111p. We generated a collection of mutants with substitutions spanning the entire COX2 5'-UTL by in vitro mutagenesis followed by mitochondrial transformation and gene replacement. The phenotypes of these mutants delimit a 31-nucleotide segment, from -16 to -46, that contains several short sequence elements necessary for COX2 5'-UTL function in translation. The sequences from -16 to -47 were shown to be partially sufficient to promote translation in a foreign context. Analysis of revertants of both the series of linker-scanning alleles and two short deletion/ insertion alleles has refined the positions of several possible functional elements of the COX2 5'-untranslated leader, including a putative RNA stem-loop structure that functionally interacts with Pet111p and an octanucleotide sequence present in all S. cerevisiae mitochondrial mRNA 5'-UTLs that is a potential rRNA binding site.

TFIIIR is an isoleucine tRNA.

Promoter-specific transcription by silkworm RNA polymerase III is dependent on several transcription factors (TFs) in addition to the polymerase itself. The activities present in silk gland nuclear extracts that are necessary to reconstitute transcription from class III genes in vitro have been resolved into several partially purified components. These include TFIIIR, which is unusual because it is composed of RNA. Here, we identify the RNA that provides TFIIIR activity as silkworm tRNA(IleIAU). This conclusion is based on copurification of tRNA(IleIAU) with TFIIIR activity, TFIIIR activity in synthetic tRNA(Ile), and hybrid selection of TFIIIR activity by antisense tRNA(IleIAU). We have tested the ability of a variety of other tRNAs to stimulate transcription and find that TFIIIR activity is highly specific to silkworm tRNA(IleIAU).

tRNA(IleIAU) (TFIIIR) plays an indirect role in silkworm class III transcription in vitro and inhibits low-frequency DNA cleavage.

tRNA(IleIAU) provides an activity, originally called TFIIIR, necessary to reconstitute transcription by silkworm RNA polymerase III in vitro from partially purified components. Here we report studies on the role of tRNA(IleIAU) in in vitro transcription. We show that tRNA(IleIAU) does not act positively but, rather, is required to prevent the action of a transcriptional inhibitor. We also show that the presence of tRNA(IleIAU) in transcription reaction mixtures prevents low-frequency DNA cleavage by the TFIIIB fraction. Studies on the mechanism of transcriptional inhibition suggest that this DNA cleavage could cause transcriptional inhibition through trans-inactivation of transcription machinery. The ability to block DNA cleavage, like the ability to facilitate transcription, is highly specific to silkworm tRNA(IleIAU).

A class III transcription factor composed of RNA.

It is generally assumed that the machinery that transcribes genes is composed entirely of polypeptides. However, in vitro transcription by silkworm RNA polymerase III requires a transcription factor that is not a polypeptide. This component, TFIIIR, is distinct from the previously identified transcription components: RNA polymerase III, and the accessory factors TFIIIA, TFIIIB, TFIIIC, and TFIIID. The newly discovered TFIIIR is a macromolecule that appears to be composed of RNA. It is resistant to heat, detergent, phenol, protease, and deoxyribonuclease, but it is sensitive to alkali and ribonuclease.