Schizencephaly in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND AND PURPOSE: The presence of malformations of cortical development in patients with hereditary hemorrhagic telangiectasia has been reported on previous occasions. We evaluated a sample of adults with hereditary hemorrhagic telangiectasia for the presence of malformations of cortical development, spatial coincidence of malformations of cortical development and AVMs, and the coincidence of brain and pulmonary AVMs. MATERIALS AND METHODS: A total of 141 patients 18 years of age or older who were referred to the Augusta University hereditary hemorrhagic telangiectasia clinic and underwent brain MR imaging between January 19, 2018, and December 3, 2020, were identified. MR imaging examinations were reviewed retrospectively by 2 experienced neuroradiologists, and the presence of malformations of cortical development and AVMs was confirmed by consensus. Demographic and clinical information was collected for each case, including age, sex, hereditary hemorrhagic telangiectasia status by the Curacao Criteria, mutation type, presence of malformations of cortical development, presence of brain AVMs, presence of pulmonary AVMs, and a history of seizures or learning disabilities. RESULTS: Five of 141 (3.5%) patients with hereditary hemorrhagic telangiectasia had malformations of cortical development. Two of the 5 patients with polymicrogyria also had closed-lip schizencephaly. One of the patients had a porencephalic cavity partially lined with heterotopic GM. The incidence of spatially coincident polymicrogyria and brain AVMs was 40% (2/5 cases). Of the patients with hereditary hemorrhagic telangiectasia and malformations of cortical development, 4/5 (80%) had pulmonary AVMs and 2/5 (40%) had brain AVMs. CONCLUSIONS: To our knowledge, we are the first group to report the presence of schizencephaly in patients with hereditary hemorrhagic telangiectasia. The presence of schizencephaly and porencephaly lends support to the hypothesis of regional in utero cerebral hypoxic events as the etiology of malformations of cortical development in hereditary hemorrhagic telangiectasia.

The Lateral Ventricles: A Detailed Review of Anatomy, Development, and Anatomic Variations.

The cerebral ventricles have been studied since the fourth century BC and were originally thought to harbor the soul and higher executive functions. During the infancy of neuroradiology, alterations to the ventricular shape and position on pneumoencephalography and ventriculography were signs of mass effect or volume loss. However, in the current era of high-resolution cross-sectional imaging, variation in ventricular anatomy is more easily detectable and its clinical significance is still being investigated. Interpreting radiologists must be aware of anatomic variations of the ventricular system to prevent mistaking normal variants for pathology. We will review of the anatomy and development of the lateral ventricles and discuss several ventricular variations.

Pregnancy intention: how PRAMS data can inform programs and policy. Pregnancy Risk Assessment Monitoring System.

BACKGROUND: In most states, the Pregnancy Risk Assessment Monitoring System (PRAMS) is the only source for state-specific, population-based data on the prevalence of unintended pregnancy among women having a live birth. These data can be used in a variety of ways to inform state policies and programs aimed at the prevention of unintended pregnancy. OBJECTIVES: This paper highlights the programmatic and policy development activities undertaken by three states in relation to unintended pregnancy as well as the role that PRAMS data played in those efforts. RESULTS: Georgia, Oklahoma, and Washington have used PRAMS data to gain support for program initiatives directed at unintended pregnancy, to promote policies aimed at either monitoring or reducing unintended pregnancy, and to acquire additional funds for related programs, such as family planning.

Pregnancy intendedness and physical abuse around the time of pregnancy: findings from the pregnancy risk assessment monitoring system, 1996-1997. PRAMS Working Group. Pregnancy Risk Assessment Monitoring System.

OBJECTIVE: This study examines whether unintended pregnancy is associated with physical abuse of women occurring around the time of pregnancy, independent of other factors. METHODS: In 1996-1997, state-specific population-based data were obtained from the Pregnancy Risk Assessment Monitoring System (PRAMS) from 39,348 women in 14 states who had delivered a live-born infant within the previous 2-6 months. The study questionnaire asked about maternal behaviors and characteristics around the time of pregnancy. RESULTS: Women who had mistimed or unwanted pregnancies reported significantly higher levels of abuse at any time during the 12 months before conception or during pregnancy (12.6% and 15.3%, respectively) compared with those with intended pregnancies (5.3%). Higher rates of abuse were reported by women who were younger, Black, unmarried, less educated, on Medicaid, living in crowded conditions, entering prenatal care late, or smoking during the third trimester. Overall, women with unintended pregnancies had 2.5 times the risk of experiencing physical abuse compared with those whose pregnancies were intended. This association was modified by maternal characteristics, the association was strongest among women who were older, more educated, White, married, not on Medicaid, not living in crowded conditions, receiving first trimester prenatal care, or nonsmoking during the third trimester. CONCLUSIONS: Women with unintended pregnancies are at increased risk of physical abuse around the time of pregnancy compared with women whose pregnancies are intended. Prenatal care can provide an important point of contact where women can be screened for violence and referred to services that can assist them.

The Pregnancy Risk Assessment Monitoring System (PRAMS): methods and 1996 response rates from 11 states.

OBJECTIVES: To determine if the Pregnancy Risk Assessment Monitoring System (PRAMS) is a unique and valuable MCH data source and an effective mechanism for states to collect MCH data, and to assess if recent changes in it have improved efficiency and flexibility. METHODS: Each component of the PRAMS methodology is described: sampling and stratification, data collection, questionnaire, and data management and weighting. To assess effectiveness, we calculated response rates, contact rates, cooperation rates, refusal rates, and questionnaire completion rates. Logistic regression was used to examine the relationship between maternal and infant characteristics and the likelihood of response. Four criteria were defined to measure improvement in PRAMS functioning. RESULTS: Overall response rates for the 11 states in 1996 ranged from 66% to 80%. Cooperation rates were high (85-99%), with contact rates somewhat lower (73-87%). Response rates were higher for women who were older, White, married, had more education, were first-time mothers, and had a normal-birthweight infant. In all states, parity and education were the most consistent predictors of response, followed by marital status and race. Between 1988-1990 and 1996-1999, the number of states and areas participating in PRAMS increased from 6 to 23, response rates improved, and the time for a state to start data collection and to obtain a weighted dataset both decreased. CONCLUSIONS: PRAMS is a unique and valuable MCH data source. The mail/telephone methodology used in PRAMS is an effective means of reaching most women who have recently given birth in the 11 states examined; however, some population subgroups are not reached as well as others. The system has become more efficient and flexible over time and more states now participate.

EPR evidence for the involvement of free radicals in the iron-catalysed decomposition of qinghaosu (artemisinin) and some derivatives; antimalarial action of some polycyclic endoperoxides.

EPR experiments confirm that reaction of qinghaosu and some related endoperoxides with Fe2+ in aqueous acetonitrile leads to the production of carbon-centred radicals derived by rapid rearrangement of first-formed cyclic alkoxyl radicals. Signals obtained from qinghaosu itself with spin-traps DMPO and DBNBS are assigned to the adducts (15) and (16), a finding which accounts for the formation of the major products (11) and (14).

A method to compare costs of drugs and supplies among anesthesia providers: a simple statistical method to reduce variations in cost due to variations in casemix.

BACKGROUND: Comparison of costs among anesthesia providers using "cost per case" does not adjust for variations in casemix (such as the type of procedure and patient condition). The authors propose an alternative method for comparing costs using the American Society of Anesthesiologists' Relative Value Scale (ASARVS) system, which incorporates basic units (for the procedure), modifier units (for the patient's physical condition), "other" units (such as for the placement of invasive monitors), and time units (proportional to the case duration). METHODS: Data were obtained from a series of 3,340 anesthetics performed at a tertiary hospital. Administered and discarded drug, supply, and fluid costs were used. RESULTS: Costs expressed as dollars per ASARVS unit had 54% less variability than costs expressed as dollars per case (P < 0.0001). Pearson correlations between demographic variables and cost per ASARVS unit ranged from -0.10 to 0.13. Total (e.g., quarterly) costs for simulated sets of cases were predicted within 0.0 +/- 2.3% by multiplying (1) their sum of units and (2) a like set of case's sum of costs divided by sum of units. CONCLUSIONS: Costs of anesthetic supplies and drugs of a case were more accurately reported as "cost per unit" than as "cost per case." This method of calculating the cost of anesthetic drugs and supplies has several applications, including (1) comparison of costs among anesthesia providers and (2) benchmarking costs among hospitals and anesthesia groups. By design, anesthesia providers' time is quantified by their ASARVS units. Together anesthesia costs (personnel, supplies, and drugs) are better reported as "cost per unit" than as "cost per case."

Use of an automated anesthesia information system to determine reference limits for vital signs during cesarean section.

INTRODUCTION: We evaluated whether automated anesthesia information systems can be used to calculate reference limits (population-based "normal values") for vital signs. We considered four populations of women undergoing cesarean section: healthy under spinal anesthesia, healthy under general anesthesia, pre-eclamptic/eclamptic under spinal anesthesia, and pre-eclamptic/eclamptic under general anesthesia. METHODS: Reference limits were calculated for each of the study populations by determination of percentiles for: minimum heart rate, maximum heart rate, minimum arterial oxyhemoglobin saturation (SaO2), minimum mean arterial pressure (MAP), maximum MAP, decrease in MAP, and increase in MAP. RESULTS: There was one adverse anesthetic outcome among the 1,300 women in the study; the woman sustained a post-dural puncture headache. The 5th percentiles of SaO2 were at least 95% saturation under spinal versus 90% under general. Under spinal anesthesia, 95th percentiles for decreases in MAP from baseline were 63 mmHg for healthy and 75 mmHg for pre-eclamptic/eclamptic women. Under general anesthesia, the 95th percentiles for maximum MAP were 161 and 177 mmHg, respectively. Two women of the 1,300 patients experienced simultaneously a minimum SaO2 < 92% and minimum MAP < 50 mmHg. DISCUSSION: Automated anesthesia information systems can be used to determine reference limits for vital signs during anesthesia. Reference limits may play a role in malpractice cases when an expert claims that care by an anesthesiologist was sub-standard as shown by vital signs that were not maintained within the normal range during the critical portions of an anesthetic. Automated anesthesia information systems may enhance expert witnesses' clinical judgment.

Lipid peroxidation-dependent chemiluminescence from the cyclization of alkylperoxyl radicals to dioxetane radical intermediates.

This work reveals a novel mechanism for triplet carbonyl formation (and hence chemiluminescence) during lipid peroxidation, whose chemiluminescence has been attributed to both triplet carbonyls and singlet oxygen. As a model for polyunsaturated fatty acid hydroperoxides, we have synthesized 3-hydroperoxy-2,3-dimethyl-1-butene by photooxygenation of tetramethylethylene. One-electron oxidation of this hydroperoxide with heme proteins and peroxynitrite to the corresponding alkylperoxyl radical results in chemiluminescence, both direct and 9,10-dibromoanthracene-2-sulfonate-sensitized, the latter attributed to the formation of triplet acetone. It is postulated that triplet acetone results from the cyclization of the alkylperoxyl radical to a dioxetane radical intermediate followed by its thermolysis. This is supported by EPR spin-trapping experiments in which discrimination between carbon-centered radicals derived from the alkyloxyl and alkylperoxyl radicals is achieved through the use of one-electron oxidants and reductants, e.g., FeII- and TiIII.

A kinetic and ESR investigation of iron(II) oxalate oxidation by hydrogen peroxide and dioxygen as a source of hydroxyl radicals.

The reaction of Fe(II) oxalate with hydrogen peroxide and dioxygen was studied for oxalate concentrations up to 20 mM and pH 2-5, under which conditions mono- and bis-oxalate complexes (Fe[II](ox) and Fe[II](ox)2[2-]) and uncomplexed Fe2+ must be considered. The reaction of Fe(II) oxalate with hydrogen peroxide (Fe2+ + H2O2 --> Fe3+ + .OH + OH-) was monitored in continuous flow by ESR with t-butanol as a radical trap. The reaction is much faster than for uncomplexed Fe2+ and a rate constant, k = 1 x 10(4) M(-1) s(-1) is deduced for Fe(II)(ox). The reaction of Fe(II) oxalate with dioxygen is strongly pH dependent in a manner which indicates that the reactive species is Fe(II)(ox)2(2-), for which an apparent second order rate constant, k = 3.6 M(-1) s(-1), is deduced. Taken together, these results provide a mechanism for hydroxyl radical production in aqueous systems containing Fe(II) complexed by oxalate. Further ESR studies with DMPO as spin trap reveal that reaction of Fe(II) oxalate with hydrogen peroxide can also lead to formation of the carboxylate radical anion (CO2-), an assignment confirmed by photolysis of Fe(II) oxalate in the presence of DMPO.

The bactericidal action of peroxides; an E.P.R. spin-trapping study.

E.P.R. spin trapping has been employed to study radical production during the bactericidal action of three peroxide compounds (peracetic acid, 4-percarboxy-N-isobutyltrimellitimide and magnesium monoperoxyphthalate) upon both Gram negative (Escherichia Coli) and Gram positive (Staphylococcus Aureus) bacteria. Use of the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) has allowed direct detection of both carbon-centred and hydroxyl radicals, which are produced at varying rates for the different bacteria/peracid systems studied. The inhibition of bactericidal action, by DMPO and two antioxidants, Vitamin C and Trolox C, indicates that radicals are the lethal species and evidence is presented which suggests that radical production is internal to the bacterial cell. Hydroxyl radicals are believed to be the lethal species. The effect of added iron chelators and haem protein inhibitors indicates that iron species and haem proteins in particular are involved. A marked variation is found in observed hydroxyl-radical adduct signals with both the nature and concentration of peracid. A strong inverse correlation is found between the concentration of the observed radical adduct signal and the relative strength of the peroxide as a bactericide; use of a stable nitroxide as a radical scavenger confirms that strong bactericides produce radicals at a much faster rate than weak bactericides. Plots of radical generation versus time are correlated with % bacterial kill, offering further evidence that hydroxyl radicals are the lethal species.

Radical-induced damage to bovine serum albumin: role of the cysteine residue.

The reactions of cerium(IV) and the hydroxyl radical [generated from iron(ii)/H2O2] with bovine serum albumin (BSA) have been investigated by EPR spin trapping. With the former reagent a protein-derived thiyl radical is selectively generated; this has been characterized via the anisotropic EPR spectra observed on reaction of this radical with the spin trap DMPO. Blocking of the thiol group results in the loss of this species and the detection of a peroxyl radical, believed to be formed by reaction of oxygen with initially-generated, but undetected, carbon-centred radicals from aromatic amino acids. Experiments with a second spin trap (DBNBS) confirm the formation of these carbon-centred species and suggest that damage can be transferred from the thiol group to carbon sites in the protein. A similar transfer pathway can be observed when hydroxyl radicals react with BSA. Further experiments demonstrate that the reverse process can also occur: when hydroxyl radicals react with BSA, the thiol group appears to act as a radical sink and protects the protein from denaturation and fragmentation through the transfer of damage from a carbon site to the thiol group. Thiol-blocked BSA is shown to be more susceptible to damage than the native protein in both direct EPR experiments and enzyme digestion studies. Oxygen has a similar effect, with more rapid fragmentation detected in its presence than its absence.

An E.S.R. investigation of the reactive intermediate generated in the reaction between FeII and H2O2 in aqueous solution. Direct evidence for the formation of the hydroxyl radical.

The technique of E.S.R. spectroscopy, when employed in conjunction with a continuous flow system, provides direct evidence for the nature of free radicals formed from organic substrates in the presence of FeII and H2O2 in aqueous solution. It is shown, both via the identification of hydroxyl-radical adducts to alkenes and via the observed site-selectivity of radical attack, that the hydroxyl radical is formed as the reactive intermediate in the presence of various chelators (e.g. EDTA, DTPA). This approach also allows the rate constants for the FeII-H2O2 reaction in the presence of the different chelates to be determined; values obtained are in reasonable agreement with most of those measured by other methods. Examples of radical oxidation (by FeIII) and reduction (by FeII) are revealed.

The autoxidation of iron(II) in aqueous systems: the effects of iron chelation by physiological, non-physiological and therapeutic chelators on the generation of reactive oxygen species and the inducement of biomolecular damage.

The ability of various iron(II)-complexes of biological, clinical and chemical interest to reduce molecular oxygen to reactive oxy-radicals has been investigated using complementary oxygen-uptake studies and e.s.r. techniques. It is demonstrated that although the rate of oxygen reduction by a given iron complex is directly related to its redox potential [thus complexes with low values of E0 for the Fe(III)/Fe(II) couple are the most effective reductants of oxygen], the overall ability of an iron(II) complex to induce oxidative biomolecular damage is also determined by its ability to undergo redox-cycling reactions with reducing radicals formed following the reaction of hydroxyl radicals with organic substrates present in the system (e.g. metal-ion chelators and organic buffers). Evidence is presented to suggest that the "Good" buffer MOPS forms a reducing radical following attack by .OH, and hence encourages the autoxidation of iron with the generation of oxy-radicals (as also observed for some of the chelates studied); this may have important implications for the use of such buffers in free-radical studies.

Radical-induced damage to proteins: e.s.r. spin-trapping studies.

The reactions of hydroxyl radicals generated from FeII/H2O2 and CuII/H2O2 redox couples with a variety of proteins (BSA, histones, cytochrome c, lysozyme and protamine) have been investigated by e.s.r. spin trapping. The signals obtained, which are generally anisotropic in nature, characterize the formation of partially-immobilized spin-adducts resulting from attack of the HO. radicals on the protein and subsequent reaction of the protein-derived radicals with the spin trap. Similar spin adducts are observed on incubation of two haem-proteins (haemoglobin and myoglobin) with H2O2 in the absence of added metal ions implying a reaction at the haem centre followed by internal electron transfer reactions. Two strategies have been employed to obtain information about the site(s) of radical damage in these proteins. The first involves the use of a variety of spin traps and in particular DMPO: with this particular trap the broad spectra from largely immobilized radicals show characteristic a(beta-H) values which enable carbon-, oxygen- and sulphur-centred radicals to be distinguished. The second involves the use of enzymatic cleavage of first-formed adducts to release smaller nitroxides, with isotropic spectra, which allow the recognition of beta-proton splittings and hence information about the sites of radical damage to be obtained. These results, which allows backbone and side-chain attack to be distinguished, are in agreement with random attack of the HO. radical on the protein and are in accord with studies carried out on model peptides. In contrast the use of less reactive attacking radicals [N3., .CH(CH3)OH] and oxidising agents (Ce4+) provides evidence for selective attack on these proteins at particular residues.

Model studies of the iron-catalysed Haber-Weiss cycle and the ascorbate-driven Fenton reaction.

Complementary hydroxylation assays and stopped-flow e.s.r. techniques have been employed in the investigation of the effect of various iron chelators (of chemical, biological and clinical importance) on hydroxyl-radical generation via the Haber-Weiss cycle and the ascorbate-driven Fenton reaction. Chelators have been identified which selectively promote or inhibit various reactions involved in hydroxyl-radical generation (for example, NTA and EDTA promote all the reactions of both the Haber-Weiss cycle and the ascorbate-driven Fenton reaction, whereas DTPA and phytate inhibit the recycling of iron in these reactions). The biological chelators succinate and citrate are shown to be relatively poor catalysts of the Haber-Weiss cycle, whereas they are found to be effective catalysts of .OH generation in the ascorbate-driven Fenton reaction. It is also suggested that continuous redox-cycling reactions between iron, oxygen and ascorbate may represent an important mechanism of cell death in biological systems.

The control of iron-induced oxidative damage in isolated rat-liver mitochondria by respiration state and ascorbate.

The reaction of iron (II) with H2O2 is believed to generate highly reactive species (e.g. .OH) capable of initiating biological damage. This study investigates the possibility that the severity of oxidative damage induced by iron in hepatic mitochondria is determined by the level of mitochondrial-H2O2 generation, which is believed to be particularly prominent in state-4 respiration. Iron-induced damage is found to be greater in state-4 than in state-3 respiration. Experiments using uncoupling agents and Ca++ to mimic state-3 conditions indicate that this effect reflects differences in the steady-state oxidation-level of the electron carriers of the respiratory chain (and hence the level of H2O2-generation), rather than changes in redox potential or transportation of the metal-ion. Evidence is also presented for a mechanism in which Fe(II) and H2O2 react inside the mitochondrial matrix. Ascorbate (vitamin C) is shown to be pro-oxidant in this system, except when present at very high concentration when it becomes antioxidant in nature.

Chemical models and radiation damage.

E.s.r. spectroscopy has been used in conjunction with an aqueous flow system to investigate both the metal-catalysed decomposition of hydrogen peroxide to OH. and the subsequent reactions of this radical with a variety of biomolecules. Particular emphasis is placed on the effects of pH and ligand on the FeII-H2O2 reaction and on the sites of attack by OH. in its reaction with pyranose and furanose sugars, sugar phosphates, nucleosides and nucleotides. Attention is focused on subsequent reactions (for example, of radicals formed by attack in the ribofuranose moiety of adenosine) which may be involved in radiation damage.

The oxidation of some polysaccharides by the hydroxyl radical: an e.s.r. investigation.

E.s.r. Experiments employing a flow system in conjunction with the TiIII-H2O2 couple show that dextrans react with the hydroxyl radical (HO.) via indiscriminate attack (except that abstraction of hydrogen atoms from carbons which are both linked by glycosidic bonds and included in the pyranose ring may be inhibited, possibly for steric reasons). Acid- and base-catalysed transformations of first-formed radicals have been demonstrated; the suggestion that such reactions can lead to glycosidic cleavage is supported by viscosity studies which confirm the pH-dependence of radical-initiated degradation. For galacturonan and related compounds, e.s.r. results indicate that reaction with HO. proceeds preferentially via abstraction of the hydrogen on the carbon adjacent to the carboxyl group. The crucial step in the subsequent degradation pathway probably involves a pH-independent rearrangement.