Structure, histone deacetylase, and antiprotozoal activities of apicidins B and C, congeners of apicidin with proline and valine substitutions.

[structure: see text]. Isolation and structure elucidation of two novel cyclic tetrapeptides that show a variety of potent antiprotozoal activities by reversibly inhibiting HDAC have been reported. These are the new members of a unique family of cyclic tetrapeptides that do not require the electrophilic alpha-epoxyketone moiety of HC-toxin, trapoxin A, or chlamydocin for their potent activities against HDAC and the malarial parasite.

Candelalides A-C: novel diterpenoid pyrones from fermentations of Sesquicillium candelabrum as blockers of the voltage-gated potassium channel Kv1.3.

[figure: see text] Blockers of the voltage-gated potassium channel Kv1.3 are potential immunosuppressants. Candelalides A-C are three novel diterpenoid pyrones that block this channel. The structure, stereochemistry, and activity against Kv1.3 are described.

A brief intervention for prenatal alcohol use: an in-depth look.

About 20% of pregnant women will drink alcohol, even though no universally safe level of prenatal alcohol consumption has been established. This study of 123 alcohol screen-positive pregnant women receiving a brief intervention in the 16th week of gestation examines the relationship of drinking goals, reasons for the goals, recognition of situations increasing risk of drinking, and subsequent antepartum consumption. While women who named abstinence as their antepartum drinking goal were more likely not to be consuming alcohol at the time of study enrollment (chi(2) = 16.80, df = 1, p =.001), current drinkers who named abstinence as their goal did reduce subsequent prenatal alcohol use (chi(2) = 10.04, df = 1, p =.002). All current drinkers who indicated fetal alcohol syndrome as a reason not to drink reduced their subsequent alcohol consumption (chi(2) = 11.04, df = 1, p =.001). Future efforts may include the partners and support systems of pregnant women in education or intervention programs to reduce prenatal alcohol consumption to enhance their effectiveness.

Correolide and derivatives are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium channels.

The voltage-gated potassium channel, Kv1.3, is specifically expressed on human lymphocytes, where it controls membrane potential and calcium influx. Blockade of Kv1.3 channels by margatoxin was previously shown to prevent T cell activation and attenuate immune responses in vivo. In the present study, a triterpene natural product, correolide, was found to block Kv1.3 channels in human and miniswine T cells by electrophysiological characterization. T cell activation events, such as anti-CD3-induced calcium elevation, IL-2 production, and proliferation were inhibited by correolide in a dose-dependent manner. More potent analogs were evaluated for pharmacokinetic profiles and subsequently tested in a delayed-type hypersensitivity (DTH) response to tuberculin in the miniswine. Two compounds were dosed orally, iv, or im, and both compounds suppressed DTH responses, demonstrating that small molecule blockers of Kv1.3 channels can act as immunosuppressive agents in vivo. These studies establish correolide and its derivatives as novel immunosuppressants.

Prenatal alcohol consumption. Self versus collateral report.

The reservations expressed about the accuracy of patient self-reports of drinking may be heightened when obtaining information about prenatal alcohol consumption, which may be subject to fears of social or medical disapproval. Thus, clinicians may seek collateral reports to confirm patients' reports during this critical time. The purpose of this study is to compare the self and collateral reports of antepartum alcohol consumption by 247 pregnant women, obtained shortly after the initiation of prenatal care, and again after delivery. Collateral reports of subjects were exceeded by the subjects' self-reports of alcohol consumption before pregnancy and in the antepartum.

The TWEAK: application in a prenatal setting.

OBJECTIVE: The TWEAK is a screening instrument used to identify women who are risk drinkers. Potential limitations of previous studies of the TWEAK in the prenatal setting include indirect administration of the instrument to minority, indigent pregnant women. The purpose of this study is to assess the efficacy of the TWEAK when it is given directly to a sample of pregnant women of different socioeconomic backgrounds. METHOD: The original TWEAK, with two different tolerance questions, was administered to a sample of 135 pregnant women enrolled in a study of alcohol use during pregnancy at the obstetrics practices of the Brigham and Women's Hospital in Boston, Massachusetts. RESULTS: The TWEAK, using the first tolerance question (number of drinks before feeling the first effects of alcohol) with the cut point set at more than two drinks, had the best predictive ability for lifetime alcohol diagnoses and risk drinking. The sensitivity of the TWEAK can be increased if the cut point for the first tolerance question is set at two drinks, with some loss of specificity and predictive ability. Medical record assessment was the least sensitive but most specific method of identifying alcohol use by pregnant women. CONCLUSIONS: The TWEAK has promise as a screening instrument for identifying risk drinking during pregnancy. Future work should include testing in other clinical populations.

Identifying prenatal alcohol use: screening instruments versus clinical predictors.

The purpose of this study is to compare the accuracy of screening instruments with clinical predictors in the identification of prenatal alcohol use. 350 women initiating prenatal care at the Brigham and Women's Hospital (Boston, MA) completed the T-ACE, AUDIT, and SMAST. The predictive accuracy of each was compared using Receiver Operating Characteristic (ROC) curve analysis. The T-ACE, AUDIT, and clinical predictors alone correctly identified 65 to 70% of current drinkers, whereas the SMAST alone performed only slightly better than chance. The predictive ability of the T-ACE was further improved with the addition of clinical predictors.

Identification and biochemical characterization of a novel nortriterpene inhibitor of the human lymphocyte voltage-gated potassium channel, Kv1.3.

A novel nortriterpene, termed correolide, purified from the tree Spachea correae, inhibits Kv1.3, a Shaker-type delayed rectifier potassium channel present in human T lymphocytes. Correolide inhibits 86Rb+ efflux through Kv1.3 channels expressed in CHO cells (IC50 86 nM; Hill coefficient 1) and displays a defined structure-activity relationship. Potency in this assay increases with preincubation time and with time after channel opening. Correolide displays marked selectivity against numerous receptors and voltage- and ligand-gated ion channels. Although correolide is most potent as a Kv1.3 inhibitor, it blocks all other members of the Kv1 family with 4-14-fold lower potency. C20-29-[3H]dihydrocorreolide (diTC) was prepared and shown to bind in a specific, saturable, and reversible fashion (Kd = 11 nM) to a single class of sites in membranes prepared from CHO/Kv1.3 cells. The molecular pharmacology and stoichiometry of this binding reaction suggest that one diTC site is present per Kv1.3 channel tetramer. This site is allosterically coupled to peptide and potassium binding sites in the pore of the channel. DiTC binding to human brain synaptic membranes identifies channels composed of other Kv1 family members. Correolide depolarizes human T cells to the same extent as peptidyl inhibitors of Kv1.3, suggesting that it is a candidate for development as an immunosuppressant. Correolide is the first potent, small molecule inhibitor of Kv1 series channels to be identified from a natural product source and will be useful as a probe for studying potassium channel structure and the physiological role of such channels in target tissues of interest.

Brief intervention for alcohol use in pregnancy: a randomized trial.

AIMS: To assess the impact of a brief intervention on antepartum alcohol consumption. DESIGN: A randomized clinical trial. SETTING: The obstetrics practices of the Brigham and Women's Hospital in Boston, MA, USA. PARTICIPANTS: Two hundred and fifty eligible women initiating prenatal care. INTERVENTION: A comprehensive assessment of alcohol use (assessment only, AO) or the same comprehensive assessment with a brief intervention (BI). MEASUREMENT: Demographic background and obstetric history of subjects, current and lifetime use of alcohol and substances, composite Addiction Severity Index scores, and antepartum alcohol use. FINDINGS: Of the 250, 247 (99%) subjects provided information on their antepartum drinking. Both the AO and BI groups had reductions in antepartum alcohol consumption, but differences in reductions by group were not statistically significant (p > 0.05). Risk of antepartum drinking after either the AO or BI was increased nearly threefold if the subject had any prenatal alcohol consumption before assessment (p = 0.0001). For the 143 subjects who were abstinent pre-assessment, however, those who received the BI maintained higher rates of abstinence (86% versus 72%, p = 0.04). CONCLUSIONS: After a comprehensive assessment of alcohol use, subjects in both the AO and BI groups reduced their antepartum alcohol consumption. The importance of screening for prenatal alcohol use is underscored by the findings that any prenatal alcohol consumption increases the risk of continued antepartum drinking.

Resorcylic acid lactones: naturally occurring potent and selective inhibitors of MEK.

A resorcylic acid lactone, L-783,277, isolated from a Phoma sp. (ATCC 74403) which came from the fruitbody of Helvella acetabulum, is a potent and specific inhibitor of MEK (Map kinase kinase). L-783,277 inhibits MEK with an IC50 value of 4 nM. It weakly inhibits Lck and is inactive against Raf, PKA and PKC. L-783,277 is an irreversible inhibitor of MEK and is competitive with respect to ATP. L-783,290, the trans-isomer of L-783,277, was isolated from the same culture and evaluated together with several semi-synthetic resorcylic acid lactone analogs. A preliminary structure-activity relationship is presented. Several independent cell-based assays have been carried out to study the biological activities of these resorcylic acid lactone compounds and a brief result summary from these studies is presented.

Pregnant women with negative alcohol screens do drink less. A prospective study.

The authors examined the antepartum alcohol consumption of 100 women with negative alcohol screens as they initiated prenatal care. Subjects completed a comprehensive assessment of their alcohol use at 15.7 +/- 4.9 weeks gestation and again 2 months after delivery, with 96% follow-up. The majority (87%) were abstinent in the 90-day period before study enrollment, while pregnant. Moreover, 92% drank no alcohol in the interval between study enrollment and delivery. These results are compared with the antepartum alcohol consumption of 250 women with positive alcohol screens. Routine prenatal screening can efficiently identify those at risk for alcohol consumption in the antepartum.

Alcohol use and pregnancy: improving identification.

OBJECTIVE: To test the effectiveness of a four-item prenatal-alcohol-use, self-administered screening questionnaire that asks about tolerance to alcohol, being annoyed by other's comments about drinking, attempts to cut down, and having a drink first thing in the morning ("eye-opener") (T-ACE) in an ethnically and socioeconomically diverse sample. METHODS: Two hundred fifty T-ACE-positive and 100 T-ACE-negative women completed a comprehensive assessment of their alcohol use after initiating prenatal care at the Brigham and Women's Hospital in Boston, Massachusetts. This comprehensive assessment, which included the Alcohol Use Disorders Identification Test and the Short Michigan Alcoholism Screening Test as comparisons to the T-ACE, generated three criterion standards: Diagnostic and Statistical Manual of Mental Disorders, Third Ed., Revised (DSM-III-R), lifetime alcohol diagnoses, risk drinking (regularly having more than one fluid ounce of alcohol per drinking day before pregnancy), and current drinking. RESULTS: T-ACE-positive pregnant women were more likely than T-ACE-negative women to satisfy DSM-III-R criteria for lifetime alcohol diagnoses (40% versus 14%, P < .001) and risk drinking (39% versus 8%, P < .001) and to have current alcohol consumption (43% versus 13%, P < .001). In contrast, obstetric staff members documented only 33 (9%) women as using alcohol at any time, even though nearly all subjects (96%) were asked about drinking upon initiation of prenatal care. CONCLUSION: The T-ACE was the most sensitive screen for lifetime alcohol diagnoses, risk drinking, and current alcohol consumption. It outperformed obstetric staff assessment of any alcohol use by pregnant women enrolled in the study.

Coprophilin: an anticoccidial agent produced by a dung inhabiting fungus.

Coprophilin, a decalin pentanedienoic acid methyl ester, was isolated from an unidentified fungus by bioassay guided separation. It inhibited (MIC = 1.5 microM) the growth of Eimeria tenella in an in vitro assay. The isolation, structure elucidation, absolute stereochemistry and biology are described.

Firefly "femmes fatales" acquire defensive steroids (lucibufagins) from their firefly prey.

Female fireflies of the genus Photuris, the so-called firefly "femmes fatales," prey on male fireflies of the genus Photinus. The females are able to entrap the males by faking the flash signal characteristics of the Photinus female. We found that by feeding on Photinus males, Photuris females gain more than nutrients. They also acquire defensive steroidal pyrones called lucibufagins, which are contained in Photinus but which Photuris fireflies are unable to produce on their own. Photuris females that eat Photinus males or lucibufagin are rejected by Phidippus jumping spiders. Lucibufagin itself proved to be a deterrent to such spiders. Field-collected Photuris females contain lucibufagin in varying amounts. The more lucibufagin they contain the more unacceptable they are to Phidippus.

Women and alcohol abuse in primary care. Identification and intervention.

Female problem drinkers are less likely than men to be identified in the primary care setting. The authors studied 24 adult women attending a general, internal medicine clinic to assess the efficiency of self-reports of alcohol consumption when compared with physician identification and other measures and the impact of a brief intervention on alcohol consumption. Despite the high rate of lifetime (79%) and current (67%) alcohol diagnoses, no patient was in alcohol treatment. Physician identification of alcohol problems was least sensitive but most specific, when compared with other measures. Brief intervention, as offered in this study, did not appear to modify alcohol consumption.

Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase.

A novel fungal metabolite, apicidin [cyclo(N-O-methyl-L-tryptophanyl-L -isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally active in vivo against Plasmodium berghei malaria in mice. Many Apicomplexan parasites cause serious, life-threatening human and animal diseases, such as malaria, cryptosporidiosis, toxoplasmosis, and coccidiosis, and new therapeutic agents are urgently needed. Apicidin's antiparasitic activity appears to be due to low nanomolar inhibition of Apicomplexan histone deacetylase (HDA), which induces hyperacetylation of histones in treated parasites. The acetylation-deacetylation of histones is a thought to play a central role in transcriptional control in eukaryotic cells. Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents.

Evaluation of a hospital-based youth violence intervention.

To decrease adolescent morbidity and mortality and improve the quality of life, a violence-prevention consultation is offered to hospitalized victims of nondomestic violence. The context is a violence-prevention team approach to patient assessment, treatment, and follow-up. Psychoeducational counseling emphasizes the individual through a cognitive behavioral approach and also recognizes the individual in the proximal social setting through referrals to community resources. The in-hospital component draws on the health beliefs model, self-efficacy, the theory of reasoned action and their synergy with cognitive mediation theory as expressed in developmental psychology. The target group for the intervention is adolescents (12-17 years of age) who have been victims of violent assaults severe enough to warrant treatment at a Level One trauma center. The six steps in the intervention are to (1) review and assess the incident, (2) review the patient's conflict-resolution strategies and introduce nonviolent alternatives, (3) provide information on the prevalence of violence/homicide and determine the patient's risk status, (4) explore the patient's coping skills and support system, (5) develop a plan to stay safe, and (6) refer patient to services for follow-up activities. Approximately 15 study participants are identified each month, half of whom are randomly assigned to receive the intervention. Over the 12-month recruitment interval, approximately 180 adolescent patients will be identified. Baseline data are collected through hospital intake procedures and chart reviews. A battery of standardized measures supplemented by a brief structured, closed-ended interview is collected four months after the youths leave the hospital. Preliminary baseline data for 39 youths are reported. The "typical" youth is a 16-year-old African-American male. Even though nearly one third of victims had been shot, the typical patient was injured in a fight during which he was kicked, bitten, or beaten with or without a blunt instrument. The majority of incidents involved only one attacker who was known to the victim. Nearly half the injuries were precipitated by an argument or fight. No statistically significant differences between intervention subjects and nonintervention controls in terms of baseline variables have been observed. For inner-city adolescent victims of violent assaults, a hospital-based intervention offers a unique opportunity for reduction of the incidence of reinjury. We describe the elements of the intervention, including the theoretical basis and implementation; detail the overall evaluation design including modifications; and present preliminary analyses of baseline data.

A novel antiviral agent which inhibits the endonuclease of influenza viruses.

A novel anti-influenza virus compound, flutimide, was identified in extracts of a recently identified fungal species, Delitschia confertaspora (F. Pelaez, J.D. Polishook, M. Valldosera, and J.Guarro, Mycotaxon 50:115-122, 1994). The compound, a substituted 2,6-diketopiperazine, selectively inhibited the cap-dependent transcriptase of influenza A and B viruses and had no effect on the activities of other polymerases. Similar to the 4-substituted 2,4-dioxobutanoic acids, a series of transcriptase inhibitors which we described previously (J. Tomassini, H. Selnick, M.E. Davies, M.E. Armstrong, J. Baldwin, M. Bourgeois, J.Hastings, D. Hazuda, J. Lewis, W. McClements, G. Ponticello, E. Radzilowski, G. Smith, A. Tebben, and A. Wolfe, Antimicrob. Agents Chemother. 38:2827-2837, 1994), this inhibitor, which is a natural product, affected neither the initiation nor the elongation of influenza virus mRNA synthesis, but it specifically targeted the cap-dependent endonuclease of the transcriptase. Additionally, the compound was inhibitory to the replication of influenza A and B viruses in cell culture. The selective antiviral properties of this compound further demonstrate the utility of influenza virus endonuclease as a target of antiviral agents.

Ophiobolin M and analogues, noncompetitive inhibitors of ivermectin binding with nematocidal activity.

A series of ophiobolins were isolated from a fungal extract based on their nematocidal activity. These compounds are non-competitive inhibitors of ivermectin binding to membranes prepared from the free-living nematode, Caenorhabditis elegans, with an inhibition constant of 15 microM. The ophiobolins which were most potent in the biological assays, ophiobolin C and ophiobolin M, were also the most potent compounds when evaluated in a C. elegans motility assay. These data suggest that the nematocidal activity of the ophiobolins is mediated via an interaction with the ivermectin binding site. The isolation, structure and biological activity of ophiobolins have been described.