Placental abruption is more frequent in women with the angiotensinogen Thr235 mutation.

OBJECTIVE: Obstetrical complications such as preeclampsia, fetal growth restriction, and placental abruption are associated with inadequate placental perfusion. Previous studies have shown that the angiotensinogen (AGT) Thr235 mutation is associated with abnormal remodeling of the uterine spiral arteries and occurs at higher frequencies in preeclampsia. This study was done to evaluate whether the AGT Thr235 mutation increases the risk of placental abruption. MATERIALS AND METHODS: We compared 62 placentas from women who had placental abruption with 240 control patients of similar age and ethnicity. DNA was extracted from paraffin blocks from placentas. AGT Met235Thr mutation status was determined by single fluoresceine labeled probe real-time PCR using a LightCycler system. RESULT: AGT genotypes were divided into three groups: MM (homozygous wild), TT (homozygous mutant), and MT (heterozygous). The constituent ratio of AGT genotype in abrupted placentas (MM 14.5%, MT 43.5%, TT 41.9%) was significantly different from in control group (MM42.5%, MT 39.6%, TT 17.9%) (p<0.001). AGT mutant allele frequency in placental abruption (0.637) was significantly higher than in the control group (0.377) (p<0.001). CONCLUSION: The AGT Thr235 mutation was observed more frequently in placental abruption. AGT Thr235 mutation may be considered a risk factor for placental abruption.

The 'expert patient': empowerment or medical dominance? The case of weight loss, pharmaceutical drugs and the Internet.

Do 'informed' or 'expert' patients challenge dominant traditions in biomedicine or simply adopt these as conventional ways of thinking about body shape and size, illness and health? This paper examines this question in relation to the use of the weight-loss drug Xenical by participants in an Internet forum for obese and overweight people. Ethnographic and interview data from the forum provides evidence that participants share information and support each other as they use Xenical, and in the process emerge as 'expert patients' in relation to their body shape and its treatment. However, it is argued that while an 'expert patient' can be perceived as desirable, enabling the democratisation of healthcare, it can also be constraining. The exchanges between the users in the forum perpetuate a biomedical model of overweight as a condition to be overcome. The discussion critically considers a number of options for the development of the expert patient, including the emergence of an 'informed consumer'.

Repair of coarctation in a right-sided circumflex retroesophageal aortic arch.

We describe an unusual case of a 3-month-old infant with normal cardiac situs and coarctation of the aorta occurring proximal to the right subclavian artery in the presence of a right-sided retroesophageal circumflex aortic arch and aberrant left subclavian artery. Preoperative evaluation with magnetic resonance imaging and conventional aortography led us to surgically approach this lesion through a right thoracotomy with a successful outcome.

Atrial arrhythmia suppression by atrial overdrive pacing: pacemaker Holter assessment.

The purpose of this study was to assess the efficacy of overdrive, single-site right atrial appendage pacing to reduce the burden of atrial fibrillation (AF) when compared with a standard lower rate limit of 60 bpm. This was verified by using the pacemaker's Holter. Eighteen subjects with a pre-implant history of paroxysmal AF and implanted DDDR mode-switching pacemakers were recruited. The pacemaker lower rate limit was programmed in random order to 60, 75 or 90 bpm for three 2-month periods and the amount of AF quantified. In addition, the exercise tolerance (ET), general well being (GWB), functional capacity (FC) and specific symptom prevalence (SSP) were assessed. The main finding of the study was that when ranked according to the amount of AF, there was no significant difference in the amount of AF according to the pacing rate. Six patients failed to tolerate pacing at 90 bpm. There were no differences in the ET, GWB, FC and SSP scores. It is concluded that those clinicians that manage patients with paroxysmal

Genetic expression by fetal chorionic villi during the first trimester of human gestation.

OBJECTIVE: The growth and differentiation of the embryo and the contiguous placental structures are fundamental to human reproduction and survival. Little is known, however, about the genetic control of these processes during early human development. Normal placentation is the result of a well-orchestrated sequence of events that consists of cellular adhesion and limited invasion controlled by relatively unknown genetic processes. We hypothesized that genes expressed by first-trimester chorionic villi constitute critical regulators of placentation and hence of early human development. Our objective was therefore to isolate and characterize genes, both known and unknown, expressed by the human placenta during the first trimester. STUDY DESIGN: Tissues collected consisted of placental material collected during first-trimester elective pregnancy terminations. Fetal chorionic villi were separated grossly from maternal decidual and quickly frozen in liquid nitrogen for ribonucleic acid preservation. Tissues from different gestational ages were kept separate. Total ribonucleic acid was extracted, messenger ribonucleic acid was isolated, and complementary deoxyribonucleic acid was synthesized. Complementary deoxyribonucleic acid was cloned into the ZAP Express lambda vector (Stratagene, La Jolla, Calif). Automated sequencing of random plaques was done. Sequence homology was searched for with the Basic Local Assignment Search Tool to search the Genbank database (National Center for Biotechnology Institute, Bethesda, Md). In the event that a known gene sequence was derived, no further workup was undertaken. If no homology was identified, the complete complementary deoxyribonucleic acid insert was sequenced in its entirety. Novel genes were further characterized by tissue-specific patterns, cellular localization, and chromosomal location. Expression by fetal villi was confirmed by reverse transcriptase polymerase chain reaction. RESULTS: We isolated a number of genes known to be expressed at the maternal-fetal interface. Seventeen of 186 random clones were >1 kilobase in length and did not display homology with known genes, and these may therefore constitute novel genes critical for placentation. One of the clones from a human chorionic villi complementary deoxyribonucleic acid library at 12 weeks' gestation is a 7-kilobase gene that is also abundantly expressed in human fetal brain, lung, liver, and kidney. In situ hybridization localized the transcript to the fetal renal glomerulus. CONCLUSIONS: Our findings indicate that the placenta serves as a rich source for potential novel gene expression. Seventeen clones were >1 kilobase in length and are potential novel genes involved in early first-trimester placentation. One of these 17 potential novel genes is expressed in abundance in several fetal tissues, which suggests a role in early human fetal development. Other potential novel genes are currently being characterized. The powerful molecular techniques that we used to isolate genes expressed by early fetal chorionic villi will lead us to a better understanding of the genetic control of normal human reproduction. They also may be used to study obstetric and other human disease.

Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred.

HHT type 2 (HHT 2) is a multi-system vascular dysplasia caused by a mutation in the ALK-1 gene, but the phenotype has not been well defined. We report on 51 members of an HHT 2 kindred with an ALK-1 gene mutation shown to be associated with the disorder. This ALK-1 mutation was detected in 38 kindred members who were evaluated systematically for associated vascular abnormalities. Pulmonary arteriovenous malformations (AVMs) were found in 6% of those screened, cerebral AVM in 7%, hepatic AVM in 17%, and spinal AVM in 3%. We discuss these and other findings in the 38 affected kindred members, as well as findings in the 13 kindred members in whom the mutation was not detected. This study shows that pulmonary, cerebral, spinal, and hepatic AVMs can all occur in HHT 2. It also adds to the evidence suggesting that pulmonary AVMs are more common in HHT 1 than in HHT 2. We identify a higher prevalence of hepatic AVMs than previously reported in either HHT 1 or 2. This may be specific to the mutation in this kindred, but probably reflects the lack of routine screening for this manifestation. Even in this family in which all affected individuals have the same mutation, the clinical manifestations of HHT and their severity varied tremendously. Intrafamilial variation in expression of HHT is clearly significant, emphasizing the difficulty in establishing the diagnosis in individuals and in sub-typing families when DNA testing is not available.

Genetic factors in recurrent pregnancy loss.

Technologies such as fluorescent in situ hybridization (FISH) are facilitating analysis of tissue that cannot be cultured. Increasing recognition and knowledge of confined placental mosaicism are giving us greater appreciation of the role of aneuploidies in cases of spontaneous and recurrent abortion. Newer molecular analyses suggest important roles for single-gene mutations, X inactivation, and imprinting effects. In the coming years, our increased understanding of the genetics of recurrent spontaneous abortion should result in new and more expedient diagnoses and potential treatments.

Role of MRI in diagnosis of childhood sarcoidosis with fever of unknown origin.

Childhood sarcoidosis is a disease with multisystem organ involvement, and initial presentation as fever of unknown origin (FUO) is relatively common. We describe herein three children (aged 9, 7, and 11 years) with sarcoidosis who were seen initially with FUO. Common clinical and laboratory features include fever of > 2 weeks' duration, weight loss, fatigue, leg pain, anemia, increased erythrocyte sedimentation rate, elevated immunoglobulin G level, negative antinuclear antibodies and rheumatoid factor, and negative purified protein derivative and Candida skin tests. Two patients had iridocyclitis, one had hilar adenopathy, and two had angiotensin-converting enzyme serum levels. All three had no evidence of pulmonary infiltrates on chest radiographs. Bone marrow biopsies for all three were normal, and with no evidence of malignancy. Plain radiographs of the lower extremities and bone scan were normal. Magnetic resonance imaging (MRI) of the lower extremities revealed intact bone architecture and multifocal nodular lesions within the marrow. Bone biopsy from the tibia performed on two patients showed normal bone trabeculae and a solitary noncaseating epithelioid cell granuloma. Noncaseating granuloma was found on reevaluation of the bone marrow biopsy in the third patient. All three patients had negative marrow stains and cultures for fungi and mycobacteria. We conclude that MRI was very useful in the diagnosis of sarcoidosis in children with FUO.

Dofetilide: first of a new generation of class III agents.

Dofetilide (Pfizer, Sandwich, Kent, UK) is a novel, highly specific class III methanesulfonanilide anti-arrhythmic drug. At nanomolar concentrations this agent prolongs both the atrial and ventricular effective refractory periods and action potential duration. Dofetilide's mechanism of action relies on potent blockade of the rapidly activating, inwardly rectifying component of the delayed rectifier potassium current (Ikr), the main current responsible for cardiac repolarisation. Dofetilide does not appear to interact with other cardiac ionic channels, and this explains its minimal effects upon conduction velocity, myocardial contractility and systemic haemodynamics. Dofetilide's mechanism of action makes it suitable for the termination of supraventricular and ventricular tachyarrhythmias. Small scale clinical trials have provided encouraging results, with preliminary data confirming its efficacy in the termination of atrial fibrillation and atrial flutter, and in increasing the electrical threshold for inducible ventricular tachycardia/fibrillation. The results of large scale, randomised, placebo-controlled trials are awaited in order to establish dofetilide's role in clinical practice. Due to its very specific mode of action, dofetilide has very few systemic side-effects. Dofetilide represents a novel and promising new class III agent.

An electrophysiological method for measuring the potassium permeability of the nerve perineurium.

An electrophysiological method is described for measuring the potassium permeability (PK) of the perineurium of the sciatic nerve of the frog. The method is based on the principle of grease-gap recording, in which an insulating compartment separates two surface recording electrodes. The sciatic nerves of frogs Rana temporaria and R. pipiens were isolated and mounted across a five compartment chamber, with Vaseline grease seals on the partitions between compartments. Compartments #1, #2 and #5 contained frog Ringer solution, #4 was filled with Vaseline and formed the grease gap, and #3 was the test compartment in which solutions could be changed. The nerve was stimulated via platinum electrodes in compartments #1 and #2, and DC potentials and compound action potentials (CAP) were recorded between Ag/AgCl electrodes connected through Ringer-agar bridges to compartments #3 and #5. In nerves with undamaged perineurium, changing from normal Ringer to high [K+] Ringer (100 mM, KCl replacing NaCl) for 2 min caused negligible change in DC potential or CAP, indicating that raised [K+] was not reaching the axon surface, and hence that the perineurium was exerting a diffusional restriction on K+ entry. In nerves damaged by stretching or drying, K+ pulses caused a depolarising change in DC potential (delta DC), and corresponding decline in CAP amplitude, consistent with a leaky perineurium allowing K+ entry and axonal depolarisation. Ringer made hypertonic by the addition of 2.5 M sucrose or 5 M NaCl caused increased perineurial permeability to K+. The method was calibrated by measuring the delta DC in response to raised [K+] in the range 5-100 mM [K+] in desheathed nerves; from this calibration curve relating delta DC to endoneurial [K+] it was possible to calculate the change in endoneurial [K+] occurring in intact preparations. The calculations showed that the undamaged perineurium had a PK of < 6.3 x 10(-7) cm.s-1, similar to the value calculated for in situ nerves using radioisotopic techniques, but less than the value reported for isolated perineurial cylinders. The method gives real-time information on the K+ permeability of the nerve perineurium and its modulation by experimental treatments.

Induction of apoptotic cell DNA fragmentation in human cells after treatment with hyperthermia.

The biological significance of apoptosis is becoming increasingly clear. Its relevance in tumor response to treatment as well as recent evidence for its important function as a regulating mechanism in tumorigenesis has also been demonstrated. One of the most prominent biological features of apoptosis is nucleosomal DNA fragmentation. In this communication, we present a study of DNA fragmentation in Raji cells which have been subjected to hyperthermia treatment to induce apoptosis. We found that the induction and onset of fragmentation is swift, and consistent with previous reports that fragmentation must be a rapid event.

Detection of carotid occlusive disease by ultrasonic imaging and pulsed Doppler spectrum analysis.

Ultrasonic imaging of the cervical carotid arteries by ultrasonic arteriography and duplex scanning combined with pulsed Doppler spectrum analysis were investigated in a series of patients undergoing arteriography. By using the ultrasonic image as a guide for precise placement of the pulsed Doppler sample volume, the characteristics of blood flow at points of interest in the carotid arteries could be determined. Audible analysis of the Doppler signal permitted correct diagnosis of 23 of 26 (88%) high-grade stenoses or occlusions with ultrasonic arteriography and 24 of 26 (92%) with duplex scanning. Spectrum analysis of Doppler signals obtained with the duplex scanner detected all of the 22 high-grade stenoses. Spectral abnormalities of a lesser degree also were detected in 18 of 23 vessels (78%) with atherosclerotic plaques which should not have reduced cerebral blood flow. These techniques permit the accurate detection of and the distinction between high-grade stenoses and occlusion, as well as the identification of many plaques which are not large enough to affect intracranial hemodynamics.