Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.

The alarming reduction in drug effectiveness against bacterial infections has created an urgent need for the development of new antibacterial agents that circumvent bacterial resistance mechanisms. We report here a series of DNA gyrase and topoisomerase IV inhibitors that demonstrate potent activity against a range of Gram-positive and selected Gram-negative organisms, including clinically-relevant and drug-resistant strains. In part 1, we present a detailed structure activity relationship (SAR) analysis that led to the discovery of our previously disclosed compound, REDX05931, which has a minimum inhibitory concentration (MIC) of 0.06 µg mL-1 against fluoroquinolone-resistant Staphylococcus aureus. Although in vitro hERG and CYP inhibition precluded further development, it validates a rational design approach to address this urgent unmet medical need and provides a scaffold for further optimisation, which is presented in part 2.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2.

Building on our previously-reported novel tricyclic topoisomerase inhibitors (NTTIs), we disclose the discovery of REDX07965, which has an MIC90 of 0.5 µg mL-1 against Staphylococcus aureus, favourable in vitro pharmacokinetic properties, selectivity versus human topoisomerase II and an acceptable toxicity profile. The results herein validate a rational design approach to address the urgent unmet medical need for novel antibiotics.

Assessing and managing patients with musculoskeletal conditions.

This article discusses the anatomy and physiology of the musculoskeletal system and some common presenting complaints. Examination techniques and principles of nursing care are considered.

Neurovascular assessment.

The ability to carry out a neurovascular assessment on a patient's limb is an important skill for all registered nurses. All nurses, whether working in primary or acute care environments, are exposed to patients who have sustained injury or trauma to a limb or have a cast or restrictive bandages in place. The ability to detect a compromised limb through careful observation enables prompt referral and subsequent treatment, which may otherwise result in a permanent deficit. This article discusses the importance of undertaking neurovascular observations providing a step-by-step guide for the reader.

BrainImageJ: a Java-based framework for interoperability in neuroscience, with specific application to neuroimaging.

The Human Brain Project consortium continues to struggle with effective sharing of tools. To facilitate reuse of its tools, the Stanford Psychiatry Neuroimaging Laboratory (SPNL) has developed BrainImageJ, a new software framework in Java. The framework consists of two components-a set of four programming interfaces and an application front end. The four interfaces define extension pathways for new data models, file loaders and savers, algorithms, and visualization tools. Any Java class that implements one of these interfaces qualifies as a BrainImageJ plug-in-a self-contained tool. After automatically detecting and incorporating new plug-ins, the application front end transparently generates graphical user interfaces that provide access to plug-in functionality. New plug-ins interoperate with existing ones immediately through the front end. BrainImageJ is used at the Stanford Psychiatry Neuroimaging Laboratory to develop image-analysis algorithms and three-dimensional visualization tools. It is the goal of our development group that, once the framework is placed in the public domain, it will serve as an interlaboratory platform for designing, distributing, and using interoperable tools.

Indirect prediction of fetal lung maturity. Value of ultrasonographic colonic and placental grading.

OBJECTIVE: To correlate fetal morphometrics with studies of fetal lung maturity. STUDY DESIGN: One hundred six patients undergoing amniocentesis for fetal lung maturity studies were examined prospectively. Eighty-four patients were normal (79%), and 22 were diabetic (21%). Fetal morphometrics were obtained prior to amniocentesis. The fetal colon and placenta were graded. Discriminant analysis was used to identify variables that were predictive of a mature lecithin/sphingomyelin ratio and the presence of phosphatidylglycerol (PG). All patients delivered within 48 hours of amniocentesis. RESULTS: In the normal group, 28 (33%) fetuses had a grade 3 colon, which was 68% sensitive and 98% specific for a mature amniocentesis. A grade 3 colon was the single best predictor of a mature amniocentesis (P < .001). Twenty-five (29%) fetuses had a grade 3 placenta, which was 64% sensitive and 96% specific for a mature amniocentesis (P < .005). Diabetes did not influence colonic grading since a grade 3 colon was present in seven (32%) patients (47% sensitivity and 100% specificity for PG) (P < .02). Interexaminer and intraexaminer variability for the study was excellent, kappa = 1.0 (P < .001). CONCLUSION: Colonic and placental stage 3 grading are reliable and reproducible ultrasonographic scales that can help predict the findings of fetal lung maturity studies.

Syntelencephaly in an infant of a diabetic mother.

Here we report on an infant of a diabetic mother (IDM) with midline interhemispheric "fusion" (MIF), or syntelencephaly. This is a rare anomaly characterized by segmental failure of cleavage of the cerebral hemispheres and other brain structures in the posterior frontal and parietal regions, with a normal interhemispheric fissure anterior and posterior to the "fused" region. While there is obvious overlap with holoprosencephaly (HPE), this condition differs from HPE in that the midline "fusion" in MIF is complete but segmental, while the structural brain anomalies seen in the HPE spectrum progress smoothly in severity in a posterior to anterior "fusion." However, while it is apparent that there are key distinctions between MIF and HPE, in all likelihood they arise from a similar pathogenetic mechanisms. We therefore suggest that MIF is a distinct variant of the HPE spectrum of midline brain anomalies. Given the known increased incidence of HPE in IDMs, MIF is likely a maternal diabetes-associated malformation.

Prenatal myocardial infarction suspected by fetal echocardiography.

Myocardial infarction is rare in the newborn period. We describe a case in which myocardial infarction was suspected at 25 weeks of gestation by fetal echocardiography. There was an aneurysm of the left ventricular apex with paradoxical motion and bulging of the left ventricular free wall during systole. The diagnosis was confirmed by postnatal electrocardiogram, vectorcardiogram, and thallium myocardial perfusion imaging.

Cornual heterotopic pregnancy and cornual resection after in vitro fertilization/embryo transfer. A report of two cases.

BACKGROUND: Heterotopic pregnancy occurs in about 1% of pregnancies achieved with assisted reproductive technologies. The incidence of cornual pregnancy is approximately 1% of all ectopics. CASES: Two patients became pregnant after treatment with IVF-ET. Both presented during the first trimester with evidence of an acute abdomen and ultrasonographic suspicion for cornual heterotopic pregnancies. The diagnoses were confirmed by laparoscopy, and treatment was undertaken with laparotomy with cornual resection. Both delivered viable infants by cesarean section; the first patient delivered a twin gestation at 28 weeks and the second a singleton pregnancy at 37 weeks. All infants were doing well two months after delivery. CONCLUSION: Abnormal pregnancies can be detected after IVF-ET with careful follow-up, transvaginal ultrasound studies, serial hCG measurements and pelvic examinations. Cornual heterotopic pregnancies can be successfully treated with cornual resection, especially in cases presenting during the second trimester or when there is clinical evidence of an acute abdomen. All deliveries should be performed by cesarean section at term prior to labor or when tocolysis for premature labor has failed.

The accuracy of antenatal ultrasonography in identifying renal abnormalities.

OBJECTIVE: To determine the accuracy of measuring antenatal renal pelvic diameter for prediction of renal abnormalities. RESEARCH DESIGN: Prospective evaluation of all pregnant women undergoing ultrasonography. SETTING: A teaching hospital providing primary and referral maternity care. PARTICIPANTS: Fifty-six pregnant women with suspected fetal hydronephrosis or cystic lesions identified from 7500 ultrasonograms over 3 years. METHODS: Antenatal renal pelvic diameter was measured in the anteroposterior dimension. Neonates underwent postnatal ultrasonography after day 3 of life; if the results were abnormal, a cystogram and renal diuretic scan were obtained. RESULTS: None of 50 kidneys 15 mm or smaller in anteroposterior pelvic diameter had obstruction; 11 (79%) of 14 kidneys larger than 15 mm were obstructed or demonstrated vesicoureteral reflux. Of 12 kidneys believed to be multicystic before birth, five (42%) proved to have hydronephrosis. CONCLUSIONS: Since the majority of fetuses with suspected hydronephrosis proved to be normal, parents should not be unduly alarmed by the physician. Renal pelvic diameter of more than 15 mm is strongly predictive of hydronephrosis. Since severe hydronephrosis is treatable and can be mistaken for a multicystic kidney antenatally, full radiologic evaluation is needed soon after birth.

Clinical associations of variable decelerations during reactive nonstress tests.

Six hundred ninety-three patients at or beyond 30 weeks' gestation with reactive nonstress tests (NSTs) were divided into groups based on the occurrence of variable decelerations of 15 seconds or more in duration and of 20 or more beats per minute in severity. Ultrasound examination within a month of testing showed no increases in nuchal cord localization or decreased amniotic fluid volumes in a subgroup of 181 patients. Fetuses with antepartum variable decelerations were more likely to demonstrate similar decelerations in labor (P less than .001), to undergo operative delivery for a diagnosis of "distress" (P less than .05), to require intensive care nursery admission (P less than .01), and to be small for gestational age (P less than .01). No significant differences were noted in frequency of nuchal or other cord entanglements, overall cesarean section rate, or low pH or Apgar score values. We conclude that variable decelerations in the absence of other alarming NST findings may aid in identifying patients at risk for adverse perinatal occurrences, although factors other than nuchal cord placement or oligohydramnios may be responsible.

Use of intravenous immune globulin in pregnant women with common variable hypogammaglobulinemia.

Two patients with common variable hypogammaglobulinemia were treated with immune serum globulin during pregnancy. An intravenous immune serum globulin preparation was used in the last trimester of pregnancy. Both patients tolerated this preparation well and had an uneventful pregnancy. The two term newborns were healthy and had cord blood IgG levels likely to be the result of transplacental transfer of the intravenous immune serum globulin preparation. During pregnancy there is an increase in the IgG distribution space due to plasma volume expansion. Therefore, pregnancy is an indication for these immune serum globulin preparations that can be administered at high doses intravenously in order to confer adequate protection to the mother and the newborn.

Thiocyanate and drinking during pregnancy.

Alcohol appears to have a relatively direct effect in decreasing fetal growth; however, it also appears that other factors associated with alcohol consumption may also contribute to lowered birthweight. Three studies have suggested that beverage source of alcohol may be a determinant of decreased intrauterine growth and that beer may have a comparatively greater effect than wine and liquor. Since beer is reported to contain thiocyanate (SCN), a substance which has been implicated as a determinant of fetal growth retardation in relation to cigarette smoking, we studied maternal and fetal serum SCN levels in 82 pregnancies. After controlling for maternal characteristics, gestational age, and tobacco and marijuana use, the quantity of beer consumed was found to have a significant positive correlation with fetal serum SCN (p less than 0.005). Consumption of other types of alcoholic beverages was not significantly associated with elevated fetal serum SCN, although the numbers of wine and liquor drinkers in this study were limited. Further research is warranted to explore the possibility that the correlation of beer consumption with increased SCN might provide at least one explanation for the reported linkage of diminished fetal growth and beer drinking.