Percutaneous mechanical thrombectomy in the treatment of acute iliofemoral deep vein thrombosis: a systematic review.

BACKGROUND: Conventional treatment of deep vein thrombosis (DVT) of the lower extremities by anticoagulation alone has been proven to be insufficient to prevent recurrence and post-thrombotic syndrome (PTS). Early restoration of venous patency and preservation of valvular function by endovascular surgery has been advocated. The aim of this study was to review the efficacy and safety of percutaneous mechanical thrombectomy (PMT) against catheter-directed thrombolysis (CDT) in the treatment of acute iliofemoral DVT. METHODS: Three hundred sixty-nine articles were identified through screening of the PubMed, EMBASE, and Cochrane databases from January 2006 to December 2016. RESULTS: Fifteen retrospective studies and one prospective registry, totalling 1170 patients, were recruited for qualitative synthesis. The venous patency rate ranged from 75% to 100% with mean follow-up of 12.3 months. The rates of PTS and recurrent DVT were less than 17% and 15%, respectively. The overall mortality rate was 0.26%. Compared with CDT, PMT was shown to reduce PTS at 1 year (Villalta score: 2.1 ± 3.0 in the PMT group and 5.1 ± 4.1 in the CDT group, P=0.03) and bleeding complications (packed cells transfused: 0.2 ± 0.3 units in the pharmacomechanical thrombectomy group and 1.2 ± 0.7 units in the CDT group, P<0.05). CONCLUSION: Percutaneous mechanical thrombectomy is a safe and effective treatment for acute iliofemoral DVT in terms of restoration of venous patency, prevention of DVT recurrence, and PTS. Compared with CDT alone, PMT offers a lower risk of PTS and bleeding complications.

Maternal hyperglycemia in singleton pregnancies conceived by IVF may be modified by first-trimester BMI.

STUDY QUESTION: Does IVF independently increase the risk of gestational diabetes mellitus (GDM) and is this increase in risk modified by maternal body mass index? SUMMARY ANSWER: IVF appears to be an independent risk factor for GDM and elevated blood glucose levels in overweight women (BMI > 25 kg/m2). WHAT IS KNOWN ALREADY: IVF has been associated with increased risk of GDM, but most previous studies did not adequately assess confounding or effect modification by other risk factors. STUDY DESIGN, SIZE, DURATION: Cross-sectional study using data from 1089 women with singleton pregnancies who participated in a Singaporean birth cohort study (GUSTO) and received a 75 g oral glucose tolerance test (OGTT) at 26-28 weeks gestation. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1089 women (n = 1013 conceived spontaneously, n = 76 conceived through IVF) with singleton pregnancies received a 75 g OGTT at 26-28 weeks gestation. Fasting and 2 h postprandial blood glucose levels were assayed. World Health Organization criteria (1999) standard criteria were used to classify GDM: ≥7.0 mmol/L for fasting and/or ≥7.8 mmol/L for 2-h postprandial plasma glucose levels, which was the clinical guideline in use during the study. MAIN RESULTS AND THE ROLE OF CHANCE: IVF pregnancies had nearly double the odds of GDM (OR = 1.83, 95% CI: 1.03-3.26) and elevated fasting (mean difference = 0.12 mmol/L, 95% CI: 0.00-0.24) and OGTT 2-h blood glucose levels (mean difference = 0.64 mmol/L, 95% CI: 0.27-1.01), after adjusting for commonly recognized risk factors for GDM. After stratification by first-trimester BMI, these increased risks of GDM (OR = 3.54, 95% CI: 1.44-8.72) and elevated fasting (mean difference = 0.39 mmol/L, 95% CI: 0.13-0.65) and 2-h blood (mean difference = 1.24 mmol/L, 95% CI: 0.56-1.91) glucose levels were significant only in the IVF group who is also overweight or obese (BMI > 25 kg/m2). LIMITATIONS REASONS FOR CAUTION: One limitation of our study is the absence of a 1 h post-OGTT plasma glucose sample, as we were using the 1999 WHO diagnostic criteria (the clinical guideline in Singapore) at the time of our study, instead of the revised 2013 WHO diagnostic criteria. Our cohort may not be representative of the general Singapore obstetric population, although participants were recruited from the two largest maternity hospitals in the country and include both private and subsidized patients. WIDER IMPLICATIONS OF THE FINDINGS: IVF appears to be an independent risk factor for GDM and elevated blood glucose levels in overweight women. Our findings reinforce the need to advise overweight or obese women contemplating IVF to lose weight before the procedure to reduce their risk of GDM and hyperglycemia-related adverse outcomes arising therefrom. In settings where universal GDM screening is not routine, overweight or obese women who conceive by IVF should be screened. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Program and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC), Singapore (NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014). Additional funding was provided by the Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR). K.M.G. and Y.S.C. have received lecture fees from Nestle Nutrition Institute and Danone, respectively. K.M.G., Y.S.C. and S.Y.C. are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec and Danone. The other authors have nothing to disclose. The other authors have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Hydrogen sulfide protects testicular germ cells against heat-induced injury.

OBJECTIVE: The present study was designed to investigate whether H2S can protect testicular germ cells against heat exposure induced injury and the underlying mechanisms. RESULTS: It was found that all three H2S generating enzymes, cystathionine ß-synthase (CBS), cystathionine γ-lysase (CSE), and 3-mercaptopyruvate sulfurtransferase (3 MST), were expressed in mouse testicular tissue. Three episodes of heat exposure (42 °C, 30 min/day, 3 days) significantly decreased endogenous H2S production and down-regulated the expression of CBS and CSE in testes. In primary cultured testicular germ cells, exogenous application of NaHS (an H2S donor) attenuated heat stress (42 °C, 30 min) induced cell death and apoptosis. This was mediated by the inhibitory effects of H2S on cytochrome C release and the ratio of the Bax/Bcl-2. NaHS also improved mitochondrial function by decreasing oxygen consumption and increasing ATP production. NaHS treatment also stimulated SOD activity and reduced ROS production. CONCLUSIONS: Our results revealed both physiological and pharmacological roles of H2S in testicular germ cells. Exogenous application of H2S may protect germ cells by preservation of mitochondrial function and stimulation of anti-oxidant activity.

Fabrication and laser patterning of polystyrene optical oxygen sensor films for lab-on-a-chip applications.

We present a novel and simple method for patterning oxygen-sensitive polystyrene thin films and demonstrate its potential for integration with microfluidic lab-on-a-chip devices. Optical oxygen sensing films composed of polystyrene with an embedded luminescent oxygen-sensitive dye present a convenient option for the measurement of oxygen levels in microfluidic and lab-on-a-chip devices; however, patterning and integrating the films with poly(dimethylsiloxane) (PDMS) microfluidic devices has proven difficult due to a residue after dry etch patterning that inhibits subsequent PDMS bonding. Our new method uses mask-less laser ablation by a commercial laser ablation system to define the outline of the structures and subsequent bulk film removal by aqueous lift-off. Because the bulk film is peeled or lifted off of the substrate rather than etched, the process is compatible with standard PDMS plasma bonding. We used ToF-SIMS analysis to investigate how laser ablation facilitates this fabrication process as well as why dry etching polystyrene inhibits PDMS plasma bonding. The results of this analysis showed evidence of chemical species formed during the laser ablation and dry etching processes that can produce these effects. Our new method's mask-less nature, simplicity, speed, and compatibility with PDMS bonding make it ideally suited for single-use lab-on-a-chip applications. To demonstrate the method's compatibility with PDMS microfluidics, we also present a demonstration of the sensors' integration into a microfluidic oxygen gradient generator device.

Anti-Müllerian hormone versus antral follicle count for defining the starting dose of FSH.

This pilot study compared the efficacy and safety of two simple dosing algorithms, one based on anti-Müllerian Hormone (AMH) and the other on the antral follicle count (AFC), to determine the starting dose of recombinant FSH (rFSH) for ovarian stimulation in 348 women. Patients were randomized to a predefined AMH- or AFC-based algorithm. The proportion of cycles with the desired response was similar when rFSH dose was determined using AMH or AFC (35.2% versus 28.4%). There was a significant difference between the groups in the proportion of cycles with a hyperresponse (8.6% and 17.4%, but the incidence of ovarian hyperstimulation syndrome was similar (1.1% and 4.6%). There were no significant differences between two groups in outcomes, including implantation (19.3% versus 19.0%), clinical pregnancy (38.0% versus 46.9%), multiple pregnancy (16.5% versus 15.2%) and miscarriage (7.0% versus 8.3%). However, statistically significant differences in ovarian response were evident among the AMH and AFC subgroups: for AMH, Desired and Hypo; for AFC, Hypo and Hyper. This pilot study provides information for developing protocols to further validate the use of either AMH or AFC to guide the starting dose of rFSH in ovarian stimulation. The ideal outcome for couples undergoing IVF treatment is the birth of a healthy baby. One factor that might influence this is retrieving an adequate number of eggs, which are obtained using various treatment protocols. A group of drugs called gonadotrophins have been used for more than 20years to stimulate the ovaries to produce eggs. However, the dose to start treatment has not been clearly defined. A few studies have looked at ways to use the best gonadotrophin dose for each woman, but to be useful in the clinic any approach needs to be simple and easy to use. This study compared the effectiveness and safety of two simple approaches to determining the starting dose of recombinant FSH (rFSH) for ovarian stimulation in women undergoing IVF. One was based on the concentration of a hormone secreted by developing eggs (anti-Müllerian hormone; AMH) and the other on the number of developing follicles (antral follicle count; AFC). The number of cycles achieving the desired response in terms of number of eggs was similar when rFSH dose was guided using AMH or AFC, and the incidence of ovarian hyperstimulation syndrome was also similar. In addition, rates of clinical pregnancy, multiple pregnancy and miscarriage did not differ between the two groups. However, patients with low AMH concentrations or low AFC had a poor response to ovarian stimulation. This pilot study provides useful information from which new studies can further assess these approaches to personalizing treatment during IVF.

Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice.

beta-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-beta precursor protein (APP) leading to the generation of amyloid-beta peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1(+/-) mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1(-/-) mice with impaired processing of NRG1. We demonstrate that BACE1(-/-) mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1(-/-) mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1(-/-) mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders.

Subserosal adenomyotic cysts and peritoneal inclusion cysts - Unusual differential diagnoses of multicystic pelvic masses: A review of two cases.

BACKGROUND: Multiloculated pelvic cysts are commonly misdiagnosed as ovarian tumors or malignancies. We report 2 patients diagnosed with subserosal adenomyotic cysts and peritoneal inclusion cysts, mimicking multiloculated pelvic tumors. We discuss their clinical presentation, investigations, operation findings, and histopathology, present a literature review. CASES: Case 1 was a 44-year-old patient with abnormal uterine bleeding. Imaging showed an enlarging multiloculated cystic structure over the right uterine wall. She underwent a diagnostic laparoscopy and right salpingo-ophorectomy. Intra-operatively, she was found to have multiple subserosal uterine cysts, diagnosed as adenomyotic cysts on histology.Case 2 was a 50-year-old patient with history of laparoscopic cystectomy done 20 years ago. She was incidentally found to have a multiloculated cystic lesion in the pelvis. The lesion was located midline, anterior and superior to the uterus and bladder. She underwent a total abdominal hysterectomy, bilateral salpingo-ophorectomy, and bladder peritonectomy. Intra-operatively, multiple cystic lesions were noted over the anterior and fundus of uterus, bladder peritoneum, and pelvic side walls. The condition was confirmed to be peritoneal inclusion cysts on histology. CONCLUSION: Subserosal adenomyotic cysts are a rare presentation of adenomyosis. They typically occur in premenopausal women. Treatment is usually by hormonal medications or surgical excision.Many patients with peritoneal inclusion cysts have a history of peritoneal insults. Surgical excision is the most commonly described management as they often mimic malignancy. Both conditions are unusual presentations of multiloculated pelvic masses. A high recurrence rate is found, hence long-term follow-up with imaging is essential.

Characterization of dominant and recessive assembly-defective mutations in mouse neurofilament NF-M.

We have generated a set of amino- and carboxy-terminal deletions of the neurofilament NF-M gene and determined the molecular consequences of forced expression of these mutant constructs in mouse fibroblasts. To follow the expression of mutant NF-M subunits in transfected cells, a 12 amino acid epitope (from the human c-myc protein) was expressed at the carboxy terminus of each mutant. We show that NF-M molecules missing up to 90 or 70% of the nonhelical carboxy-terminal tail or amino-terminal head domains, respectively, incorporate readily into an intermediate filament network comprised either of vimentin or NF-L, whereas deletions into either the amino- or carboxy-terminal alpha-helical rod region generate assembly-incompetent polypeptides. Carboxy-terminal deletions into the rod domain invariably yield dominant mutants which rapidly disrupt the array of filaments comprised of NF-L or vimentin. Accumulation of these mutant NF-M subunits disrupts vimentin filament arrays even when present at approximately 1% the level of the wild-type subunits. In contrast, the amino-terminal deletions into the rod produce pseudo-recessive mutants that perturb the wild-type NF-L or vimentin arrays only modestly. The inability of such amino-terminal mutants to disrupt wild-type subunits defines a region near the amino-terminal alpha-helical rod domain (residues 75-126) that is required for the earliest steps in filament assembly.

The rod domain of NF-L determines neurofilament architecture, whereas the end domains specify filament assembly and network formation.

Neurofilaments, assembled from NF-L, NF-M, and NF-H subunits, are the most abundant structural elements in myelinated axons. Although all three subunits contain a central, alpha-helical rod domain thought to mediate filament assembly, only NF-L self-assembles into 10-nm filaments in vitro. To explore the roles of the central rod, the NH2-terminal head and the COOH-terminal tail domain in filament assembly, full-length, headless, tailless, and rod only fragments of mouse NF-L were expressed in bacteria, purified, and their structure and assembly properties examined by conventional and scanning transmission electron microscopy (TEM and STEM). These experiments revealed that in vitro assembly of NF-L into bona fide 10-nm filaments requires both end domains: whereas the NH2-terminal head domain promotes lateral association of protofilaments into protofibrils and ultimately 10-nm filaments, the COOH-terminal tail domain controls lateral assembly of protofilaments so that it terminates at the 10-nm filament level. Hence, the two end domains of NF-L have antagonistic effects on the lateral association of protofilaments into higher-order structures, with the effect of the COOH-terminal tail domain being dominant over that of the NH2-terminal head domain. Consideration of the 21-nm axial beading commonly observed with 10-nm filaments, the approximate 21-nm axial periodicity measured on paracrystals, and recent cross-linking data combine to support a molecular model for intermediate filament architecture in which the 44-46-nm long dimer rods overlap by 1-3-nm head-to-tail, whereas laterally they align antiparallel both unstaggered and approximately half-staggered.

Neurofilaments are obligate heteropolymers in vivo.

Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons. Using DNA transfection and mice expressing NF transgenes, we find that despite the ability of NF-L alone to assemble into short filaments in vitro NF-L cannot form filament arrays in vivo after expression either in cultured cells or in transgenic oligodendrocytes that otherwise do not contain a cytoplasmic intermediate filament (IF) array. Instead, NF-L aggregates into punctate or sheet like structures. Similar nonfilamentous structures are also formed when NF-M or NF-H is expressed alone. The competence of NF-L to assemble into filaments is fully restored by coexpression of NF-M or NF-H to a level approximately 10% of that of NF-L. Deletion of the head or tail domain of NF-M or substitution of the NF-H tail onto an NF-L subunit reveals that restoration of in vivo NF-L assembly competence requires an interaction provided by the NF-M or NF-H head domains. We conclude that, contrary to the expectation drawn from earlier in vitro assembly studies, NF-L is not sufficient to assemble an extended filament network in an in vivo context and that neurofilaments are obligate heteropolymers requiring NF-L and NF-M or NF-H.

Assembly properties of dominant and recessive mutations in the small mouse neurofilament (NF-L) subunit.

We have generated a set of amino- and carboxy-terminal deletions of the NF-L neurofilament gene and determined the assembly properties of the encoded subunits after coexpression with vimentin or wild-type NF-L. NF-L molecules missing greater than 30% (31 amino acids of the head) or 90% (128 amino acids of the tail) failed to incorporate into intermediate filament networks. Carboxy-terminal deletions into the rod domain yield dominant mutants that disrupt arrays assembled from wild-type subunits, even when present at levels of approximately 2% of the wild-type subunits. Even mutants retaining 55% of the tail (61 amino acids) disrupt normal arrays when accumulated above approximately 10% of wild-type subunits. Since deletion of greater than 90% of the head domain produces "recessive" assembly incompetent subunits that do not affect wild-type filament arrays, whereas smaller deletions yield efficient network disruption, we conclude that some sequence(s) in the head domain (within residues 31-87) are required for the earliest steps in filament assembly. Insertional mutagenesis in the nonhelical spacer region within the rod domain reveals that as many as eight additional amino acids can be tolerated without disrupting assembly competence.

Increasing neurofilament subunit NF-M expression reduces axonal NF-H, inhibits radial growth, and results in neurofilamentous accumulation in motor neurons.

The carboxy-terminal tail domains of neurofilament subunits neurofilament NF-M and NF-H have been postulated to be responsible for the modulation of axonal caliber. To test how subunit composition affects caliber, transgenic mice were generated to increase axonal NF-M. Total neurofilament subunit content in motor and sensory axons remained essentially unchanged, but increases in NF-M were offset by proportionate decreases in both NF-H and axonal cross-sectional area. Increase in NF-M did not affect the level of phosphorylation of NF-H. This indicates that (a) in vivo NF-H and NF-M compete either for coassembly with a limiting amount of NF-L or as substrates for axonal transport, and (b) NF-H abundance is a primary determinant of axonal caliber. Despite inhibition of radial growth, increase in NF-M and reduction in axonal NF-H did not affect nearest neighbor spacing between neurofilaments, indicating that cross-bridging between nearest neighbors does not play a crucial role in radial growth. Increase in NF-M did not result in an overt phenotype or neuronal loss, although filamentous swellings in perikarya and proximal axons of motor neurons were frequently found.

Subunit composition of neurofilaments specifies axonal diameter.

Neurofilaments (NFs), which are composed of NF-L, NF-M, and NF-H, are required for the development of normal axonal caliber, a property that in turn is a critical determinant of axonal conduction velocity. To investigate how each subunit contributes to the radial growth of axons, we used transgenic mice to alter the subunit composition of NFs. Increasing each NF subunit individually inhibits radial axonal growth, while increasing both NF-M and NF-H reduces growth even more severely. An increase in NF-L results in an increased filament number but reduced interfilament distance. Conversely, increasing NF-M, NF-H, or both reduces filament number, but does not alter nearest neighbor interfilament distance. Only a combined increase of NF-L with either NF-M or NF-H promotes radial axonal growth. These results demonstrate that both NF-M and NF-H play complementary roles with NF-L in determining normal axonal calibers.

Combinatorial morphogenetic and mechanical cues to mimic bone development for defect repair.

Endochondral ossification during long bone development and natural fracture healing initiates by mesenchymal cell condensation, directed by local morphogen signals and mechanical cues. Here, we aimed to mimic development for regeneration of large bone defects. We hypothesized that engineered human mesenchymal condensations presenting transforming growth factor-ß1 (TGF-ß1) and/or bone morphogenetic protein-2 (BMP-2) from encapsulated microparticles promotes endochondral defect regeneration contingent on in vivo mechanical cues. Mesenchymal condensations induced bone formation dependent on morphogen presentation, with BMP-2 + TGF-ß1 fully restoring mechanical function. Delayed in vivo ambulatory loading significantly enhanced the bone formation rate in the dual morphogen group. In vitro, BMP-2 or BMP-2 + TGF-ß1 initiated robust endochondral lineage commitment. In vivo, however, extensive cartilage formation was evident predominantly in the BMP-2 + TGF-ß1 group, enhanced by mechanical loading. Together, this study demonstrates a biomimetic template for recapitulating developmental morphogenic and mechanical cues in vivo for tissue engineering.

An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.

Mutations in Cu/Zn superoxide dismutase (SOD1) cause a subset of cases of familial amyotrophic lateral sclerosis. Four lines of mice accumulating one of these mutant proteins (G37R) develop severe, progressive motor neuron disease. At lower levels of mutant accumulation, pathology is restricted to lower motor neurons, whereas higher levels cause more severe abnormalities and affect a variety of other neuronal populations. The most obvious cellular abnormality is the presence in axons and dendrites of membrane-bounded vacuoles, which appear to be derived from degenerating mitochondria. Since multiple lines of mice expressing wild-type human SOD1 at similar and higher levels do not show disease, the disease in mice expressing the G37R mutant SOD1 must arise from the acquisition of an adverse property by the mutant enzyme, rather than elevation or loss of SOD1 activity.

Effects of PS1 deficiency on membrane protein trafficking in neurons.

We have examined the trafficking and metabolism of the beta-amyloid precursor protein (APP), an APP homolog (APLP1), and TrkB in neurons that lack PS1. We report that PS1-deficient neurons fail to secrete Abeta, and that the rate of appearance of soluble APP derivatives in the conditioned medium is increased. Remarkably, carboxyl-terminal fragments (CTFs) derived from APP and APLP1 accumulate in PS1-deficient neurons. Hence, PS1 plays a role in promoting intramembrane cleavage and/or degradation of membrane-bound CTFs. Moreover, the maturation of TrkB and BDNF-inducible TrkB autophosphorylation is severely compromised in neurons lacking PS1. We conclude that PS1 plays an essential role in modulating trafficking and metabolism of a selected set of membrane and secretory proteins in neurons.

An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos.

Mutations in presenilin 1 (PS1) cosegregate with approximately 25% of early onset familial Alzheimer's disease (FAD) pedigrees. A variety of in vitro and in vivo paradigms have established that one mechanism by which PS1 variants cause AD is by elevating the production of highly amyloidogenic Abeta1-42/43 peptides. PS1 is homologous to sel-12, a C. elegans protein that facilitates signaling mediated by the Notch/lin-12 family of receptors. Wild-type human PS1 complements an egg-laying defect in C. elegans lacking sel-12, while FAD-linked PS1 variants exhibit reduced rescue activity. These data suggested that mutant PS1 may cause disease as a result of reduction in PS1 function. To test the function of FAD-linked PS1 in mammals, we examined the ability of the A246E PS1 variant to complement the embryonic lethality and axial skeletal defects in mice lacking PS1. Finally, to examine the influence of reduced PS1 levels on Abeta production, we quantified Abeta1-42/43 peptide levels in PS1 heterozygous null mice (PS1[+/-] mice). We now report that both human wild-type and A246E PS1 efficiently rescue the phenotypes observed in PS1(-/-) embryos, findings consistent with the view that FAD-linked PS1 mutants retain sufficient normal function during mammalian embryonic development. Moreover, the levels of Abeta1-42/43 and Abeta1-40 peptides between PS1(+/-) and control mice are indistinguishable. Collectively, these data lead us to conclude that mutant PS1 causes AD not by loss of normal PS1 function but by influencing amyloid precursor protein (APP) processing in a manner that elevates Abeta1-42/43 production.

Menopause, hormone therapy and cardiovascular and cerebrovascular disease.

INTRODUCTION: Cardiovascular disease is the leading cause of death and morbidity among postmenopausal women, and oestrogen deficiency may be an important factor in its development. The role of oestrogen replacement in preventing cardiovascular disease is controversial. The aim of this descriptive review is to analyse the available data and to recommend evidence-based practice guidelines pertaining to hormone therapy in the context of cardiovascular and cerebrovascular health. MATERIALS AND METHODS: Relevant clinical trials were identified by computerised literature search. The collated data were presented to fellow gynaecologists for review, analysis of results and discussion in a series of meetings dedicated to finding the best evidence in menopause management. The evidence was used to formulate clinical practice guidelines for the management of women with significant cardiovascular risk factors. RESULTS: Evidence from animal studies and observational trials supported a cardio-protective effect of postmenopausal hormone therapy. More recent randomised clinical trial data have shown no significant reduction of coronary heart disease, and have confirmed a higher incidence of stroke and venous thromboembolism. CONCLUSIONS: The evidence is widely divergent regarding postmenopausal hormone therapy and cardiovascular risk. More consistent data are available reporting an increased risk in the incidence of venous thromboembolism and stroke. It is important to be clear about the indications of hormone use and to utilise alternative modalities to promote cardiovascular health in the postmenopausal population.