Assessment of an AI-based tool for population-wide collection of placental morphological data.

OBJECTIVES: Automated placental assessment could allow accurate and timely morphological/pathological measurements at scale. We undertook a pilot study using an artificial intelligence-based assessment system (AI-PLAX) to ascertain the potential of a state-wide rollout as part of Generation Victoria, assessing the impact of time post-delivery, user, and technology used for image capture, on a range of derived placental data. STUDY DESIGN: Ten placentas were imaged by three different users and imaging technologies (iPad, iPhone, Samsung) at (0 h), 24 h, and 48 h post-delivery. Using AI-PLAX, disc size (short and long length, perimeter, area), shape (normal, abnormal), cord insertion type (central, eccentric), cord coiling, abruption (retroplacental hematoma), and meconium staining were determined. RESULTS: When analysing the maternal surface of the placenta, time in cold storage post-delivery had modest effects on placental dimensions, with decreases in the short length (24-48 h: -3.7 %), disc area (0-24 h: 4.7 % and 0-48 h: -7.4 %), and perimeter (0-48 h: -3.8 %) observed. There was marginal impact on placental dimensions when the placenta was imaged by different users, including long length (+1.9 %), disc area (+2.9 %), and perimeter (+2.0 %). Measures of placental size were not impacted by the type of technology used to capture the images. When analysing the fetal surface of the placenta, more variance in placental size measures were observed between users. Abruption detection was not affected by any parameter. Time between delivery and imaging impacted apparent meconium staining - likely reflecting changes in fetal surface colour over time. Meconium staining was not affected by technology or user. CONCLUSIONS: This study supports the feasibility of the collection of placenta images for later morphological analysis by AI-PLAX, with measures obtained minimally influenced by time in cold storage, user imaging the placenta, or technology to capture the images.

Activator protein-1 regulation of murine aldehyde dehydrogenase 1a1.

Previously we demonstrated that aldehyde dehydrogenase (ALDH) 1a1 is the major ALDH expressed in mouse liver and is an effective catalyst in metabolism of lipid aldehydes. Quantitative real-time polymerase chain reaction analysis revealed a ≈2.5- to 3-fold induction of the hepatic ALDH1A1 mRNA in mice administered either acrolein (5 mg/kg acrolein p.o.) or butylated hydroxylanisole (BHA) (0.45% in the diet) and of cytosolic NAD⁺-dependent ALDH activity. We observed ≈2-fold increases in ALDH1A1 mRNA levels in both Nrf2⁺/⁺ and Nrf2⁻/⁻ mice treated with BHA compared with controls, suggesting that BHA-induced expression is independent of nuclear factor E2-related factor 2 (Nrf2). The levels of activator protein-1 (AP-1) mRNA and protein, as well as the amount of phosphorylated c-Jun were significantly increased in mouse liver or Hepa1c1c7 cells treated with either BHA or acrolein. With use of luciferase reporters containing the 5'-flanking sequence of Aldh1a1 (-1963/+27), overexpression of c-Jun resulted in an ≈4-fold induction in luciferase activity, suggesting that c-Jun transactivates the Aldh1a1 promoter as a homodimer and not as a c-Jun/c-Fos heterodimer. Promoter deletion and mutagenesis analyses demonstrated that the AP-1 site at position -758 and possibly -1069 relative to the transcription start site was responsible for c-Jun-mediated transactivation. Electrophoretic mobility shift assay analysis with antibodies against c-Jun and c-Fos showed that c-Jun binds to the proximal AP-1 site at position -758 but not at -1069. Recruitment of c-Jun to this proximal AP-1 site by BHA was confirmed by chromatin immunoprecipitation analysis, indicating that recruitment of c-Jun to the mouse Aldh1a1 gene promoter results in increased transcription. This mode of regulation of an ALDH has not been described before.

Histone H3K4 trimethylation by MLL3 as part of ASCOM complex is critical for NR activation of bile acid transporter genes and is downregulated in cholestasis.

The nuclear receptor Farnesoid x receptor (FXR) is a critical regulator of multiple genes involved in bile acid homeostasis. The coactivators attracted to promoters of FXR target genes and epigenetic modifications that occur after ligand binding to FXR have not been completely defined, and it is unknown whether these processes are disrupted during cholestasis. Using a microarray, we identified decreased expression of mixed lineage leukemia 3 (MLL3), a histone H3 lysine 4 (H3K4) lysine methyl transferase at 1 and 3 days of post-common bile duct ligation (CBDL) in mice. Chromatin immunoprecipitation analysis (ChIP) analysis revealed that H3K4me3 of transporter promoters by MLL3 as part of activating signal cointegrator-2 -containing complex (ASCOM) is essential for activation of bile salt export pump (BSEP), multidrug resistance associated protein 2 (MRP2), and sodium taurocholate cotransporting polypeptide (NTCP) genes by FXR and glucocorticoid receptor (GR). Knockdown of nuclear receptor coactivator 6 (NCOA6) or MLL3/MLL4 mRNAs by small interfering RNA treatment led to a decrease in BSEP and NTCP mRNA levels in hepatoma cells. Human BSEP promoter transactivation by FXR/RXR was enhanced in a dose-dependent fashion by NCOA6 cDNA coexpression and decreased by AdsiNCOA6 infection in HepG2 cells. GST-pull down assays showed that domain 3 and 5 of NCOA6 (LXXLL motifs) interacted with FXR and that the interaction with domain 5 was enhanced by chenodeoxycholic acid. In vivo ChIP assays in HepG2 cells revealed ligand-dependent recruitment of ASCOM complex to FXR element in BSEP and GR element in NTCP promoters, respectively. ChIP analysis demonstrated significantly diminished recruitment of ASCOM complex components and H3K4me3 to Bsep and Mrp2 promoter FXR elements in mouse livers after CBDL. Taken together, these data show that the "H3K4me3" epigenetic mark is essential to activation of BSEP, NTCP, and MRP2 genes by nuclear receptors and is downregulated in cholestasis.

Endometrial safety of ultra-low-dose Vagifem 10 microg in postmenopausal women with vaginal atrophy.

OBJECTIVE: The objective of the study was to evaluate the endometrial safety of a 10 microg estradiol vaginal tablet in the treatment of vaginal atrophy in postmenopausal women. METHODS: A total of 336 healthy, non-hysterectomized, postmenopausal women (age 59.5 +/- 6.16 years, 9.4 +/- 5.9 years from last menses) were treated with a 10 microg estradiol vaginal tablet for 12 months (once daily for 2 weeks and then twice weekly for 50 weeks). Endometrial histology was analyzed at baseline and at the end of the trial. RESULTS: Of the 336 enrolled subjects, 292 (86.9%) completed the 52-week study. All 336 subjects received an endometrial biopsy at baseline, and 283 had biopsy results at week 52, when 258 out of the 283 biopsy samples were classified as 'atrophic' or 'inactive' endometrium. There were 21 with 'no tissue' despite a repeat biopsy attempt to obtain endometrial tissue, one had insufficient tissue with endometrial thickness >4 mm, one was 'weakly proliferative' and two revealed polyps. No cases of endometrial hyperplasia or endometrial cancer were reported. The mean endometrial thickness decreased from 2.04 mm (n = 334) from study start to 1.94 mm (n = 293) after 52 weeks, and the estradiol levels remained at the low postmenopausal level. CONCLUSIONS: After 12 months of treatment with the 10 microg estradiol vaginal tablet, there was no suggestion of endometrial stimulation and no cases of endometrial hyperplasia or cancer reported. This study provides reassuring data on the endometrial safety of treatment with the 10 microg estradiol vaginal tablet for 1 year in a large group of postmenopausal, non-hysterectomized women with vaginal atrophy.

Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy.

BACKGROUND: Although multiple reports have documented the influence of CYP2C9 and VKORC1 variants on warfarin dose, risk of over-anticoagulation and hemorrhage, their influence on anticoagulation maintenance and individual proportion of time spent in target INR range (PPTR) is limited. Moreover the potential benefit of genotype-guided dosing implemented after initiation of therapy in a racially diverse population has not been explored. Herein we present the influence of CYP2C9 and VKORC1 C1173T on warfarin response during the first 30 days of therapy. METHODS: Warfarin dose was empirically determined in 250 African Americans 271 European Americans. The influence of CYP2C9 and VKORC1 on rate of INR increase, anticoagulation maintenance, risk of over-anticoagulation, and change in dose over 30 days was evaluated after adjustment for socio-demographic, lifestyle and clinical factors. Possession of variant VKORC1 (+/- variant CYP2C9) genotype was associated with a more rapid attainment of target INR and higher frequency of dose adjustments. Patients possessing variant genotypes spent less time in target range. However adjustment for rate of INR increase rendered the association non-significant. European Americans (but not African Americans) possessing variant VKORC1 (+/- variant CYP2C9) genotype had a higher risk of over-anticoagulation. Neither CYP2C9 nor VKORC1 influenced the risk of minor hemorrhage. CYP2C9 and VKORC1 explained 6.3% of the variance in dose change over the first 30 days of therapy demonstrating that the usefulness of genotype-guided dosing may extend beyond first day of therapy. CONCLUSION: The benefit of genotype-based dose prediction may extend beyond first few days of therapy. Whether genotype-guided dosing will decrease the risk of over-anticoagulation, improve anticoagulation control and most importantly improve outcomes for chronic warfarin users remains to be proven.

Validation of the Vectra H1 portable three-dimensional photogrammetry system for facial imaging.

Three-dimensional (3D) surface imaging using stereophotogrammetry has become increasingly popular in clinical settings, offering advantages for surgical planning and outcome evaluation. The handheld Vectra H1 is a low-cost, highly portable system that offers several advantages over larger stationary cameras, but independent technical validation is currently lacking. In this study, 3D facial images of 26 adult participants were captured with the Vectra H1 system and the previously validated 3dMDface system. Using error magnitude statistics, 136 linear distances were compared between cameras. In addition, 3D facial surfaces from each system were registered, heat maps generated, and global root mean square (RMS) error calculated. The 136 distances were highly comparable across the two cameras, with an average technical error of measurement (TEM) value of 0.84mm (range 0.19-1.54mm). The average RMS value of the 26 surface-to-surface comparisons was 0.43mm (range 0.33-0.59mm). In each case, the vast majority of the facial surface differences were within a ±1mm threshold. Areas exceeding ±1mm were generally limited to facial regions containing hair or subject to facial microexpressions. These results indicate that 3D facial surface images acquired with the Vectra H1 system are sufficiently accurate for most clinical applications.

Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa.

Metabolism of the antimalarial drug amodiaquine (AQ) into its primary metabolite, N-desethylamodiaquine, is mediated by CYP2C8. We studied the frequency of CYP2C8 variants in 275 malaria-infected patients in Burkina Faso, the metabolism of AQ by CYP2C8 variants, and the impact of other drugs on AQ metabolism. The allele frequencies of CYP2C8*2 and CYP2C8*3 were 0.155 and 0.003, respectively. No evidence was seen for influence of CYP2C8 genotype on AQ efficacy or toxicity, but sample size limited these assessments. The variant most common in Africans, CYP2C8(*)2, showed defective metabolism of AQ (threefold higher K(m) and sixfold lower intrinsic clearance), and CYP2C8(*)3 had markedly decreased activity. Considering drugs likely to be coadministered with AQ, the antiretroviral drugs efavirenz, saquinavir, lopinavir, and tipranavir were potent CYP2C8 inhibitors at clinically relevant concentrations. Variable CYP2C8 activity owing to genetic variation and drug interactions may have important clinical implications for the efficacy and toxicity of AQ.

Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins.

Phagocytes generate H2O2 for use by a secreted heme enzyme, myeloperoxidase, to kill invading bacteria, viruses, and fungi. We have explored the possibility that myeloperoxidase might also convert L-tyrosine to a radical catalyst that cross-links proteins. Protein-bound tyrosyl residues exposed to myeloperoxidase, H2O2, and L-tyrosine were oxidized to o,o'-dityrosine, a stable product of the tyrosyl radical. The cross-linking reaction required L-tyrosine but was independent of halide and free transition metal ions; the heme poisons azide and aminotriazole were inhibitory. Activated neutrophils likewise converted polypeptide tyrosines to dityrosine. The pathway for oxidation of peptide tyrosyl residues was dependent upon L-tyrosine and was inhibited by heme poisons and catalase. Dityrosine synthesis was little affected by plasma concentrations of Cl- and amino acids, suggesting that the reaction pathway might be physiologically relevant. The requirement for free L-tyrosine and H2O2 for dityrosine formation and the inhibition by heme poisons support the hypothesis that myeloperoxidase catalyzes the cross-linking of proteins by a peroxidative mechanism involving tyrosyl radical. In striking contrast to the pathways generally used to study protein oxidation in vitro, the reaction does not require free metal ions. We speculate that protein dityrosine cross-linking by myeloperoxidase may play a role in bacterial killing or injuring normal tissue. The intense fluorescence and stability of biphenolic compounds may allow dityrosine to act as a marker for proteins oxidatively damaged by myeloperoxidase in phagocyte-rich inflammatory lesions.

DOHaD at the intersection of maternal immune activation and maternal metabolic stress: a scoping review.

The prenatal environment is now recognized as a key driver of non-communicable disease risk later in life. Within the developmental origins of health and disease (DOHaD) paradigm, studies are increasingly identifying links between maternal morbidity during pregnancy and disease later in life for offspring. Nutrient restriction, metabolic disorders during gestation, such as diabetes or obesity, and maternal immune activation provoked by infection have been linked to adverse health outcomes for offspring later in life. These factors frequently co-occur, but the potential for compounding effects of multiple morbidities on DOHaD-related outcomes has not received adequate attention. This is of particular importance in low- or middle-income countries (LMICs), which have ongoing high rates of infectious diseases and are now experiencing transitions from undernutrition to excess adiposity. The purpose of this scoping review is to summarize studies examining the effect and interaction of co-occurring metabolic or nutritional stressors and infectious diseases during gestation on DOHaD-related health outcomes. We identified nine studies in humans - four performed in the United States and five in LMICs. The most common outcome, also in seven of nine studies, was premature birth or low birth weight. We identified nine animal studies, six in mice, two in rats and one in sheep. The interaction between metabolic/nutritional exposures and infectious exposures had varying effects including synergism, inhibition and independent actions. No human studies were specifically designed to assess the interaction of metabolic/nutritional exposures and infectious diseases. Future studies of neonatal outcomes should measure these exposures and explicitly examine their concerted effect.

Incidence and prevalence of type 2 diabetes mellitus with HIV infection in Africa: a systematic review and meta-analysis.

OBJECTIVES: This systematic review aims to investigate the incidence and prevalence of type 2 diabetes mellitus (T2DM) in patients with HIV infection in African populations. SETTING: Only studies reporting data from Africa were included. PARTICIPANTS: A systematic search was conducted using four databases for articles referring to HIV infection and antiretroviral therapy, and T2DM in Africa. Articles were excluded if they reported data on children, animals or type 1 diabetes exclusively. MAIN OUTCOME MEASURES: Incidence of T2DM and prevalence of T2DM. Risk ratios were generated for pooled data using random effects models. Bias was assessed using an adapted Cochrane Collaboration bias assessment tool. RESULTS: Of 1056 references that were screened, only 20 were selected for inclusion. Seven reported the incidence of T2DM in patients with HIV infection, eight reported the prevalence of T2DM in HIV-infected versus uninfected individuals and five reported prevalence of T2DM in HIV-treated versus untreated patients. Incidence rates ranged from 4 to 59 per 1000 person years. Meta-analysis showed no significant differences between T2DM prevalence in HIV-infected individuals versus uninfected individuals (risk ratio (RR) =1.61, 95% CI 0.62 to 4.21, p=0.33), or between HIV-treated patients versus untreated patients (RR=1.38, 95% CI 0.66 to 2.87, p=0.39), and heterogeneity was high in both meta-analyses (I2=87% and 52%, respectively). CONCLUSIONS: Meta-analysis showed no association between T2DM prevalence and HIV infection or antiretroviral therapy; however, these results are limited by the high heterogeneity of the included studies and moderate-to-high risk of bias, as well as, the small number of studies included. There is a need for well-designed prospective longitudinal studies with larger population sizes to better assess incidence and prevalence of T2DM in African patients with HIV. Furthermore, screening for T2DM using gold standard methods in this population is necessary. TRIAL REGISTRATION NUMBER: PROSPERO42016038689.

Percutaneous vascular interventions in renal artery diseases.

Renal artery stenosis (RAS) is a progressive manifestation of atherosclerosis. It is associated with hypertension and progressive renal failure. Noninvasive testing includes renal artery duplex, computed tomographic angiography (CTA) and magnetic resonance angiography (MRA). Percutaneous transluminal renal angioplasty and stenting (PTRAS) is indicated for significant atherosclerotic RAS while percutaneous transluminal renal angioplasty (PTRA) is indicated for fibromuscular dysplasias (FMD) associated with the proper clinical indications. PTRAS is associated with a high technical success rate and an acceptable adverse event and restenosis rate. PTRAS appears to improve control of hypertension and renal preservation. All patients should be followed clinically and with periodic duplex ultrasonography. Restenosis is treated with repeat angioplasty and occasionally stenting. Current and future areas of investigation will involve distal protection and drug eluting stents.

Metabolism of 2-acetylaminofluorene by two 3-methylcholanthrene-inducible forms of rat liver cytochrome P-450.

The present study examines the contribution of two major 3-methylcholanthrene (3-MC)-inducible forms of rat liver cytochrome P-450 (P-448MC and P-448HCB) to the metabolism of 2-acetylaminofluorene (AAF). In a reconstituted enzyme system, purified rat liver P-448MC metabolized AAF at a 10-fold greater rate than P-448HCB. The major metabolites produced by cytochrome P-448MC were 3-hydroxy (OH) (30%), 5-OH (24%), 7-OH (22%), and 9-OH (10%). N-OH-AAF (3%) was a minor metabolite. In contrast, P-448HCB catalyzed the N-hydroxylation of AAF preferentially (15% of total metabolites). The other primary metabolites formed by this isozyme were 7-OH-AAF (30%), 5-OH-AAF (29%), and 9-OH-AAF (25%). Cytochrome P-448HCB catalyzed the formation of less 3-OH-AAF (7%) than did P-448MC (30%). Since cytochrome P-448HCB is immunochemically related to P-448MC, specific antisera to both isozymes were made by immunoabsorption with the appropriate antigen bound covalently to Sepharose. Anti-P-448MC inhibited AAF metabolism approximately 43% in microsomes from 3-MC-induced male rats and 30% in microsomes from rats treated with 3,4,5,3',4',5'-hexachlorobiphenyl (HCB), another 3-MC-type inducer. Anti-P-448HCB inhibited total metabolism of AAF by only 22 and 38% in microsomes from 3-MC- and HCB-induced rats. However, anti-P-448HCB inhibited N-hydroxylation by 60% in both 3-MC- and HCB-induced microsomes. Anti-P-448MC did not inhibit N-hydroxylation. Neither antibody affected AAF metabolism in control microsomes. These data suggest that, in rat liver, two 3-MC-inducible izozymes of cytochrome P-450 metabolize AAF; however, N-hydroxylation is catalyzed primarily by one of these isozymes, cytochrome P-448HCB.

Dose-response relationships for chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a rat tumor promotion model: quantification and immunolocalization of CYP1A1 and CYP1A2 in the liver.

The mechanisms responsible for the braod spectrum of effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are not entirely clear but seem to involve an initial interaction with the Ah receptor. A major uncertainty in risk assessment for TCDD is the lack of adequate dose-response relationships following chronic exposure to TCDD. Induction of cytochrome P-450 enzymes (CYP1A1 and CYP1A2) is one of the most sensitive responses to TCDD and its structural analogues. We have used a two-stage model for hepatocarcinogenesis in female Sprague-Dawley rats to evaluate dose-response relationships for induction of CYP1A1 and CYP1A2 in diethylnitrosamine-initiated as well as in noninitiated rats. After initiation with a single dose of diethylnitrosamine, TCDD was administered biweekly by p.o. gavage at doses equivalent to 3.5, 10.7, 35.7, and 125 ng/kg/day for 30 weeks. CYP1A1 and CYP1A2 concentrations were quantified in hepatic microsomes by radioimmunoassay and localized in hepatic tissue slices by immunohistochemical techniques. Radioimmunoassay data revealed a maximum induction of 200-fold for CYP1A1 and 10-fold for CYP1A2 and there were no statistically significant differences between initiated and noninitiated rats. Induction at the lowest dose (3.5 ng/kg/day) was 20-fold for CYP1A1 and 3-fold for CYP1A2. Mathematical analysis indicates that the best fit of the induction data are inconsistent with a threshold for this response. There was a linear relationship between administered dose and TCDD liver concentration over the entire dose range of the study. This indicates that induction of CYP1A2 does not significantly alter the distribution of TCDD in our chronic dosing regimen. Immunolocalization of CYP1A1 and CYP1A2 revealed the same localization and induction pattern for both isozymes in the cytoplasm of hepatocytes. However, the hepatic distribution pattern was not uniform with the most intense staining observed around central veins. These studies help to clarify dose-response relationships for dioxin-mediated effects and demonstrate different sensitivity of hepatocytes to the effects of TCDD.

Echocardiographic demonstration of outlet strut fracture of a Björk-Shiley mitral prosthesis.

Fracture of the outlet strut of the Björk-Shiley mitral valve prosthesis has been recognized with increasing frequency, prompting recall of unimplanted valves manufactured before March 1982. Presenting dramatically with acute severe pulmonary edema and low cardiac output, strut fracture is frequently a fatal complication. This case report documents the first reported echocardiographic demonstration of occluder disc dislodgment secondary to outlet strut fracture with survival after emergency valve replacement.

Hemodynamic importance of systolic ventricular interaction, augmented right atrial contractility and atrioventricular synchrony in acute right ventricular dysfunction.

To delineate the determinants of right ventricular performance with acute right ventricular dysfunction, surgical electrical isolation of the right ventricular free wall was produced in 13 dogs. During atrioventricular (AV) pacing, hemodynamic and wall motion measurements were normal. When not paced, the right ventricular free wall became asystolic, resulting in a depressed and bifid right ventricular systolic pressure (33 +/- 5 to 18 +/- 4 mm Hg) and decreased left ventricular systolic pressure (100 +/- 18 to 80 +/- 18 mm Hg) and stroke volume (14 +/- 4 to 10.3 +/- 3.5 ml) (all p less than 0.05). Ultrasound demonstrated right ventricular free wall dyskinesia, increased right ventricular end-diastolic size (155 +/- 13% of control), but decreased left ventricular size (69 +/- 11% of control) (both p less than 0.05). Right atrial pressure increased (5.8 +/- 2.5 to 7.6 +/- 2.8 mm Hg, p less than 0.05) with an augmented A wave and blunted Y descent, indicating pandiastolic right ventricular dysfunction. The septum demonstrated reversed curvature in diastole and bulged paradoxically into the right ventricle during early systole, generating the initial peak of right ventricular pressure and reducing its volume. Later, posterior septal motion coincided with maximal left ventricular pressure and the second peak of the right ventricular waveform. Left ventricular pacing alone led to further decreases in right ventricular systolic pressure and size, left ventricular systolic pressure and stroke volume. The previously augmented A wave was replaced by a prominent V wave. Therefore, when contractility of its free wall is acutely depressed, right ventricular performance is dependent on left ventricular-septal contractile contributions transmitted by the septum.(ABSTRACT TRUNCATED AT 250 WORDS)

Right atrial ischemia exacerbates hemodynamic compromise associated with experimental right ventricular dysfunction.

To determine the importance of right atrial function with acute right ventricular dysfunction, sequential right ventricular and right atrial ischemia were induced in 15 dogs. Right ventricular ischemia resulted in right ventricular free wall dyskinesia, right ventricular dilation by ultrasound, elevated right ventricular filling pressure and paradoxic septal motion. There were decrements in right ventricular systolic pressure (28.9 +/- 5.5 to 25.5 +/- 4.6 mm Hg) (p less than 0.05 for these and all subsequent values) and stroke work (5.66 +/- 0.94 to 2.66 +/- 0.62 g.m/m2), resulting in reductions in left ventricular preload, systolic pressure (123 +/- 11 to 97 +/- 12 mm Hg) and stroke volume (24.2 +/- 4.3 to 19.1 +/- 5.2 ml). Right atrial contractility was augmented, as indicated by increases in peak A wave amplitude (ratio of peak A wave to mean right atrial pressure 1.22 +/- 0.02 to 1.46 +/- 0.3) and right atrial stroke work (0.11 +/- 0.02 to 0.25 +/- 0.05 g.m/m2). Right atrial ischemia depressed right atrial contraction, as indicated by decreased A wave amplitude (ratio of peak A wave to mean right atrial pressure 1.46 +/- 0.3 to 1.04 +/- 0.2) and stroke work (0.25 +/- 0.05 to 0.04 +/- 0.01 g.m/m2).(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of left ventricular function and systolic ventricular interaction to right ventricular performance during acute right heart ischemia.

To determine whether modulation of systolic ventricular interaction influences right ventricular performance during right heart ischemia, the effects of septal ischemia and inotropic stimulation were studied in 15 dogs in an open chest preparation. Right coronary branch occlusions led to right ventricular dilation and free wall dyskinesia, reversed septal curvature and reduced left ventricular diastolic volume. In systole, the septum thickened but bulged paradoxically into the right ventricle generating an active but depressed right ventricular systolic pressure (28.9 +/- 5.5 to 22.1 +/- 4.5 mm Hg), with associated decreases in right ventricular stroke work (5.66 +/- 0.94 to 1.92 +/- 0.53 g.m/m2) and left ventricular systolic pressure (123 +/- 11 to 80 +/- 10 mm Hg). Septal ischemia induced systolic septal thinning, left ventricular dilation and decreased left ventricular systolic pressure (80 +/- 10 to 55 +/- 10 mm Hg) and stroke work. Although the extent of paradoxic septal displacement increased, there were further decrements in right ventricular systolic pressure (22.1 +/- 4.5 to 18.7 +/- 4.3 mm Hg) and stroke work (1.92 +/- 0.53 to 0.7 +/- 0.2 g.m/m2). Dopamine infusion augmented left ventricular free wall contraction and increased left ventricular systolic pressure (55 +/- 10 to 172 +/- 17 mm Hg) and stroke work. Although systolic septal thinning persisted, the extent of paradoxic septal displacement increased strikingly and, despite continued right ventricular free wall dyskinesia, right ventricular systolic pressure increased (18.7 +/- 4.3 to 39.6 +/- 6.2 mm Hg) as did right ventricular stroke work (0.7 +/- 0.2 to 7 +/- 1.6 g.m/m2).(ABSTRACT TRUNCATED AT 250 WORDS)

Volume loading improves low cardiac output in experimental right ventricular infarction.

To evaluate the effect of volume loading in the low output state associated with right ventricular infarction, isolated right ventricular infarction was produced in seven dogs with the pericardium intact. Volume loading and pericardiotomy were then sequentially performed. After the production of right ventricular infarction, right ventricular systolic pressure decreased by 25%, aortic pressure by 36% and cardiac output by 32%. Right ventricular ejection fraction decreased by 57%, but left ventricular ejection fraction did not change significantly. Left ventricular transmural pressure and diastolic size decreased, and right ventricular diastolic size increased. Intrapericardial pressure increased and equalization of diastolic pressures was noted. Volume loading resulted in increased right ventricular systolic pressure and stroke work, increased aortic pressure and cardiac output and increased transmural pressure and diastolic size in both ventricles. Pericardiotomy resulted in further increases in right and left ventricular filling, stroke work and cardiac output, as well as resolution of equalized diastolic pressures. These results indicate that cardiac output in experimental right ventricular infarction increases with volume loading, which enhances left ventricular preload by augmenting right ventricular output. Elevated intrapericardial pressure affects filling of both ventricles and may play a role in the pathophysiology of low cardiac output in right ventricular infarction.

Malaria. A city hospital experience.

We reviewed the charts of 24 patients with malaria seen at the Queens Hospital Center, Jamaica, NY, over the past five years. Twenty-three patients were foreign citizens. Eighteen patients were infected with Plasmodium vivax and six with Plasmodium falciparum. Malaria was suspected on admission in 19 of the 23 hospitalized patients. Five patients were admitted with unrelated diagnoses, and four of these experienced diagnostic delay. All diagnoses were confirmed with thin blood smears. Twenty-one patients were febrile, and 18 patients had prominent gastrointestinal tract symptoms. Serum glucose level was increased in nine patients, and hypoglycemia occurred in one. Four patients also had intestinal parasites. Malaria should be suspected in travelers with gastrointestinal tract symptoms, and patients with malaria may have other parasitic infections. Most patients with P vivax infections can be treated as outpatients, since the course is usually uncomplicated.

Cochlear gene delivery through an intact round window membrane in mouse.

Cochlear gene transfer studies in animal models have utilized mainly two delivery methods: direct injection through the round window membrane (RWM) or intracochlear infusion through a cochleostomy. However, the surgical trauma, inflammation, and hearing loss associated with these methods lead us to investigate a less invasive delivery method. Herein, we studied the feasibility of a vector transgene-soaked gelatin sponge, Gelfoam, for transgene delivery into the mouse cochlea through an intact RWM. The Gelfoam absorbed with liposomes and adenovirus, but not with adeno-associated virus (AAV), was successful in mediating transgene expression across an intact RWM in a variety of cochlear tissues. The Gelfoam technique proved to be an easy, atraumatic, and effective, but vector-dependent, method of delivering transgenes through an intact RWM. Compared with the more invasive gene delivery methods, this technique represents a safer and a more clinically viable route of cochlear gene delivery in humans.