Preening cups in duck housing are associated with an increase in central dopamine activity that suggests a negative affective state.

Preening cups are a form of environmental enrichment that provides Pekin ducks a semi-open water source to express their natural behaviors. We recently observed that preening cups may increase feather pecking behaviors in ducks. Thus, we set out to determine if this form of enrichment can impact the affective state of Pekin ducks. To accomplish this goal, we evaluated the effect of preening cups on serotonin (5-HT) and dopamine (DA) turnover via mass spectrometry and their respective synthetic enzyme gene expression via qRT-PCR. Our study investigated the link between aggressive pecking with levels and activity of brain 5-HT and DA. Brain 5-HT and DA levels and activity have been established for decades to be associated with affective states. Grow-out Pekin ducks (n = 260) were housed at Purdue and raised per industry standards. On day 18, brains were collected from ducks in pens before preening cups were placed (PRE, n = 6) and, again on day 43, in pens with (PC, n = 6) and without (CON, n = 6) preening cups. Brains were dissected into right and left halves, then further microdissected into 4 brain areas: caudal mesencephalon (CM), rostral mesencephalon (RM), diencephalon (DI), and forebrain (FB). The right hemisphere was used for mass spectrometry to determine the neurotransmitter concentration (ng/mg of tissue) and those concentrations were applied to neurotransmitter turnover equations. There were no differences across treatments for 5-HT turnover in any brain area. There were differences in DA turnover across age (P = 0.0067) in the CM and across treatments (P = 0.003) in the RM. The left hemisphere of the brain was used to perform qRT-PCR on the genes of 5-HT and DA production enzymes. Within the CM, day 43 duck brains had increased (P = 0.022) tryptophan hydroxylase and tyrosine hydroxylase relative mRNA levels. All other brain areas showed no differences. Our data suggest that ducks housed with preening cups and that showed increased feather pecking are associated with increased brain DA activity. The increased DA in the brain may lead to a predisposition for increased aggression in the form of feather pecking.

Sea level anomalies affect the ocean circulation at abyssal depths.

Abyssal channels are the key points controlling bottom circulation of the World Ocean. They provide meridional transport of the coldest Antarctic Bottom Water between deep-water basins influencing the meridional overturning circulation and the climate on a global scale. Here we show that the synoptic variability of deep-water flows including blocking abyssal currents between deep ocean basins is related to sea level anomalies observed over the channels. Our results demonstrate that processes at the ocean surface have a more significant connection with the bottom circulation than it was considered earlier. This study opens a discussion of the importance of mesoscale eddies and air-sea interactions on water exchange between abyssal basins, meridional heat transport in the ocean, and possible responses of the ocean to the observed sea level rise in a changing climate.

Preening cups increase apparent wet preening behaviors, but have no impact on other behaviors, body condition, growth, or body morphometrics of grow-out Pekin ducks.

Preening cups may be a form of open water that would allow ducks to express preening behaviors. We set out to test the hypothesis that preening cups would not have detrimental effects on ducks or their environment. Control pens (N = 6, 65 ducks/pen) had nipple lines while experimental pens (N = 6, 65 ducks/pen) had the same nipple line plus one preening cup (PC). Body weights of 30 ducks per pen, and body condition scores on 50 ducks per pen were recorded weekly. On d 18 and 43, 5 ducks per pen were euthanized and their spleens, Bursas, liver, and uropygial glands were weighed. Behavior data were collected using scan sampling with video being recorded for 72 continuous hours at 4 different ages: 25 d, 30 d, 36 d, and 40 d. Body morphometrics were analyzed by 2-way ANOVA with repeated measures. Body condition scoring was analyzed by Pearson's chi-square. The GLIMMIX procedure (SAS 9.4) was used for behavioral analyses to examine treatment differences in the proportion of ducks performing dry preening, wet preening, eating, drinking, standing, and laying down. Feather pecking, feather picking, preening conspecifics (also known as allopreening), dunking head, and drinking from preening cup were analyzed using PROC LOGISTIC with the Firth bias correction for quasi-complete separation and odds ratios were calculated. More PC ducks housed with PC performed wet preening compared to control ducks (25 d: F1,26 = 6.90, P = 0.0143; 30, 36, and 40 d; F1,78 = 24.53, P < 0.0001). Ducks in the PC group were also more likely to lay down compared to controls (25 d: F1,33 = 4.95, P = 0.0330). No differences were observed for any other behavior, body condition score, body weight or morphometrics at any age. Although ducks in the preening cup group showed an increase in wet preening, our data suggest that open water is not necessary to maintain feather condition or uropygial gland size.

Diagnosis, prevention, and treatment of bone fragility in people living with HIV: a position statement from the Swiss Association against Osteoporosis.

Life expectancy of people living with HIV (PLWH) is reaching similar length as in the general population. Accordingly, age-related comorbidities, including osteoporosis, are increasing. Fracture risk is higher and increases approximately 10 years earlier in PLWH. Classical risk factors of bone fragility are highly prevalent in PLWH but factors specific for HIV infection itself and the type of antiretroviral therapy (ART) (triple combination antiretroviral therapy) regimen (especially tenofovir and protease inhibitors) also contribute to bone loss. The majority of bone loss occurs during virus activity and at initiation of ART (immune reconstitution) and is associated with an increase of bone resorption (upregulation RANKL). Recent data indicate that calcium and vitamin D supplements as ART initiation lower BMD loss. The reduction of tenofovir plasma concentrations with tenofovir alafenamide attenuates BMD loss but it remains unknown whether it will contribute to reduce fracture risk. Hence, special considerations for the management of bone fragility in PLWH are warranted. Based on the current state of epidemiology and pathophysiology of osteoporosis in PLWH, we provide the consensus of the Swiss Association against Osteoporosis on best practice for diagnosis, prevention, and management of osteoporosis in this population. Periodic assessment of fracture risk is indicated in all HIV patients and general preventive measures should be implemented. All postmenopausal women, men above 50 years of age, and patients with other clinical risk for fragility fractures qualify for BMD measurement. An algorithm clarifies when treatment with bisphosphonates and review of ART regimen in favour of more bone-friendly options are indicated.

CT-based evaluation of volumetric bone density in fragility fractures of the pelvis-a matched case-control analysis.

This matched case-control study compared the computed tomography (CT)-based regional bone density of patients with fragility fractures of the sacrum to a control without fracture. Patients with a sacral fracture demonstrated a significantly lower regional bone density of the sacrum, the sacral bone density not being correlated with the BMD by DXA of the spine. INTRODUCTION: The aim of this study is to compare the computed tomography-based regional bone density measured by Hounsfield units (HUs) in patients with and without fragility fractures of the sacrum. METHODS: Patients aged ≥ 50 years with a fragility fracture of the sacrum were compared to patients of similar age and gender who had a fall from standing height without fracture (n = 46). A matched case-control analysis was conducted by retrospective chart review and assessment of areal bone mineral density by lumbar DXA and by volumetric regional HU measurements in uncalibrated CT scans of the sacrum. RESULTS: Patients with a sacral fracture (age 74 ± 11 years) showed a lower bone density in the body of S1 (HU 85 ± 22) when compared to the matched control group without fracture (age 73 ± 10 years, HU 125 ± 37, p < 0.001). The CT-based bone density of S1 did not correlate with the DXA values of the lumbar spine (r = 0.223, p = 0.136), and lumbar spine T-scores did not differ between the groups (- 2.0 ± 1.3 vs. - 1.9 ± 1.2, p = 0.786). All measurements are based on uncalibrated scans, and absolute HU values are restricted to scans made on Siemens SOMATOM Force or SOMATOM Edge scanners. CONCLUSIONS: Patients with fragility fractures of the sacrum demonstrated a lower regional volumetric bone density of the sacrum when compared to a cohort without a fracture. Local sacral volumetric bone density as measured by CT seems to be independent from the areal BMD as measured by DXA of the lumbar spine. LEVEL OF EVIDENCE: level III.

Novel routes to electromagnetic enhancement and its characterisation in surface- and tip-enhanced Raman scattering.

Quantitative understanding of the electromagnetic component in enhanced Raman spectroscopy is often difficult to achieve on account of the complex substrate structures utilised. We therefore turn to two structurally simple systems amenable to detailed modelling. The first is tip-enhanced Raman scattering under electron scanning tunnelling microscopy control (STM-TERS) where, appealing to understanding developed in the context of photon emission from STM, it is argued that the localised surface plasmon modes driving the Raman enhancement exist in the visible and near-infrared regime only by virtue of significant modification to the optical properties of the tip and sample metals (gold here). This is due to the strong dc field-induced (∼109 V m-1) non-linear corrections to the dielectric function of gold via the third order susceptibility term in the polarisation. Also, sub-5 nm spatial resolution is shown in the modelling. Secondly, we suggest a novel deployment of hybrid plasmonic waveguide modes in surface enhanced Raman scattering (HPWG-SERS). This delivers strong confinement of electromagnetic energy in a ∼10 nm oxide 'gap' between a high-index dielectric material of nanoscale width (a GaAs nanorod and a 100 nm Si slab are considered here) and a metal, yielding a monotonic variation in the Raman enhancement factor as a function of wavelength with no long-wavelength cut-off, both features that contrast with STM-TERS.

Effect of Twice-Yearly Denosumab on Prevention of Bone Mineral Density Loss in De Novo Kidney Transplant Recipients: A Randomized Controlled Trial.

We conducted an open-label, prospective, randomized trial to assess the efficacy and safety of RANKL inhibition with denosumab to prevent the loss of bone mineral density (BMD) in the first year after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 2 weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine areal BMD (aBMD) increased by 4.6% (95% confidence interval [CI] 3.3-5.9%) in 46 patients in the denosumab group and decreased by -0.5% (95% CI -1.8% to 0.9%) in 44 patients in the control group (between-group difference 5.1% [95% CI 3.1-7.0%], p < 0.0001). Denosumab also increased aBMD at the total hip by 1.9% (95% CI, 0.1-3.7%; p = 0.035) over that in the control group at 12 months. High-resolution peripheral quantitative computed tomography in a subgroup of 24 patients showed that denosumab increased volumetric BMD at the distal tibia and radius (all p < 0.05). Biomarkers of bone turnover (C-terminal telopeptide of type I collagen, procollagen type I N-terminal propeptide) markedly decreased with denosumab (all p < 0.0001). Episodes of cystitis and asymptomatic hypocalcemia occurred more often with denosumab, whereas graft function, rate of rejections, and incidence of opportunistic infections were similar. In conclusion, denosumab increased BMD in the first year after kidney transplantation but was associated with more frequent episodes of urinary tract infection.

Language mapping in healthy volunteers and brain tumor patients with a novel navigated TMS system: evidence of tumor-induced plasticity.

OBJECTIVE: This article explores the feasibility of a novel repetitive navigated transcranial magnetic stimulation (rnTMS) system and compares language mapping results obtained by rnTMS in healthy volunteers and brain tumor patients. METHODS: Fifteen right-handed healthy volunteers and 50 right-handed consecutive patients with left-sided gliomas were examined with a picture-naming task combined with time-locked rnTMS (5-10 Hz and 80-120% resting motor threshold) applied over both hemispheres. Induced errors were classified into four psycholinguistic types and assigned to their respective cortical areas according to the coil position during stimulation. RESULTS: In healthy volunteers, language disturbances were almost exclusively induced in the left hemisphere. In patients errors were more frequent and induced at a comparative rate over both hemispheres. Predominantly dysarthric errors were induced in volunteers, whereas semantic errors were most frequent in the patient group. CONCLUSION: The right hemisphere's increased sensitivity to rnTMS suggests reorganization in language representation in brain tumor patients. SIGNIFICANCE: rnTMS is a novel technology for exploring cortical language representation. This study proves the feasibility and safety of rnTMS in patients with brain tumor.

A new approach for corticospinal tract reconstruction based on navigated transcranial stimulation and standardized fractional anisotropy values.

PURPOSE: To establish a novel approach for fiber tracking based on navigated transcranial magnetic stimulation (nTMS) mapping of the primary motor cortex and to propose a new algorithm for determination of an individualized fractional anisotropy value for reliable and objective fiber tracking. METHODS: 50 patients (22 females, 28 males, median age 58 years (20-80)) with brain tumors compromising the primary motor cortex and the corticospinal tract underwent preoperative MR imaging and nTMS mapping. Stimulation spots evoking muscle potentials (MEP) closest to the tumor were imported into the fiber tracking software and set as seed points for tractography. Next the individual FA threshold, i.e. the highest FA value leading to visualization of tracts at a predefined minimum fiber length of 110 mm, was determined. Fiber tracking was then performed at a fractional anisotropy value of 75% and 50% of the individual FA threshold. In addition, fiber tracking according to the conventional knowledge-based approach was performed. Results of tractography of either method were presented to the surgeon for preoperative planning and integrated into the navigation system and its impact was rated using a questionnaire. RESULTS: Mapping of the motor cortex was successful in all patients. A fractional anisotropy threshold for corticospinal tract reconstruction could be obtained in every case. TMS-based results changed or modified surgical strategy in 23 of 50 patients (46%), whereas knowledge-based results would have changed surgical strategy in 11 of 50 patients (22%). Tractography results facilitated intraoperative orientation and electrical stimulation in 28 of 50 (56%) patients. Tracking at 75% of the individual FA thresholds was considered most beneficial by the respective surgeons. CONCLUSIONS: Fiber tracking based on nTMS by the proposed standardized algorithm represents an objective visualization method based on functional data and provides a valuable instrument for preoperative planning and intraoperative orientation and monitoring.

[Parathyroid dysfunction and rheumatic manifestations]. / Nebenschilddrüse und Rheumatologische Manifestationen.

Parathyroid dysfunction, leading to severe clinical symptoms and radiographic changes, has decreased over the last years due to routine laboratory checks including serum calcium levels. Thus, abnormal calcium levels are detected early in the course of the disease and the underlying cause treated accordingly. Hyperparathyroidism often leads to osteoporosis and low-trauma fractures. When evaluating secondary osteoporosis analysis of calcium, phosphate and intact parathyroid hormone levels are mandatory. Osteitis fibrosa cystica and brown tumors are less frequent findings of hyperparathyroidism. However, in patients with arthritis or bone symptoms, hyperparathyroidism has to be evaluated as a possible reason. Other manifestations of hyperparathyroidism include myopathy, tendon ruptures and unspecific symptoms of the muscles and skeleton. Gout as well as pseudogout may be associated with hyperparathyroidism. Hypoparathyroidism may cause musculoskeletal diseases mimicking ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. Myopathies are sometimes induced by hypoparathyroidism. An association between systemic lupus erythematosus and hypoparathyroidism seems to exist.

Tumour-infiltrating lymphocytes and survival in patients with adenocarcinoma of the oesophagus.

INTRODUCTION: Tumor-infiltrating lymphocytes (TILs) and forkhead box transcription factor positive (FoxP3(+)) regulatory T-lymphocytes (TREGs) have been analyzed in a variety of tumors but not in oesophageal adenocarcinoma. PATIENTS AND METHODS: Tissue from 130 adenocarcinomas of the oesophagus was re-evaluated in the centre and periphery of tumour, respectively, using immunohistochemical staining with anti-CD3, anti-CD4, anti-CD8, anti-CD25 and anti-FoxP3 antibodies. Patients were stratified according neoadjuvant treatment. 106 patients proceeded directly to surgery and 24 underwent pre-operative radio-chemotherapy (RCT). RESULTS: In patients without RCT, TILs were found significantly more frequently in the periphery with the exception of CD25(+) cells. Patients with centrally low counts of FoxP3(+) TREGs had higher tumour stages than patients with high counts (p < 0.011). The number of FoxP3(+) TREGs was significantly associated with the number of CD8(+) cells (centre: p < 0.001, periphery: p = 0.002). The multivariate regression analysis identified UICC stage (IIB/III vs. I/IIA, hazard ratio 2.6, p = 0.011) and completeness of resection (no vs. yes, hazard ratio 2.3, p = 0.015) as independent predictors of survival. RCT significantly reduced the number of TREGs in the centre (p = 0.016) but not the number of the other TILs. CONCLUSION: UICC stage and completeness of resection but none of the TILs were prognostic markers for long-term survival. We found no morphologic evidence that TREGs suppress immunological response, represented by the infiltration of CD8(+) cells. Preoperative RCT affected the centre of tumours more than the periphery, which may indicate that it does not inhibit the host-to-tumour reaction. RCT affects TREGs more than the other TILs.

Metformin induces glucose uptake in human preadipocyte-derived adipocytes from various fat depots.

To evaluate the effect of metformin on basal and insulin-induced glucose uptake in subcutaneous and visceral preadipocyte-derived adipocytes from obese and non-obese patients, preadipocytes were obtained from subcutaneous and visceral fat depots during abdominal surgery. Differentiation efficiency was evaluated by measurement of intracellular triglyceride accumulation. Preadipocyte-derived adipocytes were treated with metformin (1 mM) for 24 h with or without the addition of insulin (100 nM) for 20 min and glucose uptake was measured. In cells from each donor, intracellular triglyceride accumulation was more abundant in subcutaneous preadipocyte-derived adipocytes than in visceral preadipocyte-derived adipocytes (p < 0.001). Insulin stimulated glucose uptake in subcutaneous preadipocyte-derived adipocytes from both non-obese and obese patients (p < 0.001 vs. basal). In visceral preadipocyte-derived adipocytes, insulin did not increase basal glucose uptake. In subcutaneous preadipocyte-derived adipocytes from non-obese and obese patients, metformin alone increased glucose uptake to 2.7 +/- 0.2 (p < 0.001) and 2.1 +/- 0.1 fold (p < 0.001) respectively. Metformin increased glucose uptake in visceral preadipocyte-derived adipocytes from non-obese (1.7 +/- 0.1 fold vs. basal, p < 0.001) and obese (2.0 +/- 0.2 fold vs. basal, p < 0.001) patients. Combined treatment with metformin and insulin increased glucose uptake in subcutaneous preadipocyte-derived adipocytes from both non-obese and obese patients (p < 0.001 vs. insulin alone). In preadipocyte-derived adipocytes glucose uptake is induced by metformin independent of the fat depot origin of the preadipocytes (subcutaneous or visceral) and the obesity state of the patients (non-obese or obese). In adipocytes, metformin seems to induce glucose uptake independent of insulin suggesting an alternative mechanism of action of this drug.

Influence of neoadjuvant radio-chemotherapy on tumor-infiltrating lymphocytes in squamous esophageal cancer.

INTRODUCTION: Data on influence of radio-chemotherapy (RCT) on tumor-infiltrating lymphocytes (TILs) is scarce and no study addressed this issue in esophageal squamous cell cancer (SCC) so far. METHODS: Tumor specimens of 49 patients with SCC were re-evaluated with immunohistochemical staining with anti-CD3, anti-CD4, anti-CD8, anti-CD25 and anti-FOXP3 antibodies. Lymphocytes were counted in one high power field (0.189 mm(2)) at the periphery and in the centre of tumors. RESULTS: 21 patients received preoperative RCT, 28 proceeded directly to surgery. There was no significant difference in survival between the two groups (median survival 23.2 months vs. 22.1 months, log rank test p=n.s.). Cox regression analysis showed that no variable had a significant effect on survival. The infiltrating pattern of TILs revealed higher numbers peripherally independent of the administration of RCT. There was a significant decrease in all cell numbers except CD4(+) cells in the centre of the tumors after RCT (CD3(+)p=0.005; CD8(+)p=0.02; CD25(+)p=0.01; FoxP3(+)p=0.01). There were fewer TILs in the periphery after RCT; however, this difference only reached significance in FoxP3(+) cells (p=0.01). CONCLUSION: Neoadjuvant RCT reduced the number of TILs in esophageal SCC. This was primarily seen in the centre of tumors and suggests that the effect of RCT on immunological response is located in the centre of tumors.

Volume-controlled vs no/short-term drainage after axillary lymph node dissection in breast cancer surgery: a meta-analysis.

It is unknown whether there are any clinically relevant differences between volume-controlled (<30-50 ml/24h across trials) vs no/short-term drainage after axillary lymph node dissection in breast cancer surgery on outcomes such as seroma formation, wound infection or length of hospital stay. Randomised controlled trials comparing volume-controlled drainage vs no or short-term drainage after axillary lymph node dissection in breast cancer surgery were identified systematically using Pubmed, EMBASE and The Cochrane library. Trial data were reviewed and extracted independently by two reviewers in a standardised unblinded manner. Six randomised controlled trials which included a total of 561 patients fulfilled our inclusion criteria. Patients randomised to volume-controlled drainage were less likely to develop clinically relevant seromas compared to patients randomised to no/short-term drainage. There was, however, no difference in wound infections between patients treated with volume-controlled drainage and patients with no or short-term drainage. Patients randomised to volume-controlled drainage stayed significantly longer in hospital than patients randomised to no/short-term drainage. Based on available evidence, clinically relevant seromas occur more frequently in patients treated with no/short-term drainage. However, no/short-term drainage after axillary lymph node dissection does not lead to an increase in wound infections and is associated with shorter hospital stay.

How psychiatrists inform themselves and their patients about risks and benefits of antipsychotic treatment.

OBJECTIVE: In order to choose the best treatment option, physicians have to inform themselves and their patients about both the benefits and risks of available treatment options equally. Our study aims to investigate whether psychiatrists actually do conduct such a balanced information search and presentation. METHOD: Psychiatrists' information search and information presentation to a patient with schizophrenia were studied using two separate experiments. In both, participants were presented with hypothetical case vignettes and descriptions of fictitious antipsychotics. RESULTS: When searching for information, psychiatrists looked more for risks than benefits of antipsychotic treatment options (t = -3.4, df = 74, P = 0.001). However, when informing a patient, they named more benefits than risks (t = 17.1, df = 224, P < 0.001). CONCLUSION: The risk-biased information search presumably follows the principle of 'primum non nocere'. The benefit-biased information presentation might be motivated by the wish to persuade patients to accept the proposed therapy.

Sclerosing skin disorders in association with multiple sclerosis. Coincidence, underlying autoimmune pathology or interferon induced?

OBJECTIVES: To describe and analyse the manifestation of sclerosing skin disorders in patients with multiple sclerosis (MS). CASE REPORTS: We describe three patients with relapsing-remitting MS who developed skin sclerosis while receiving interferon (IFN)-beta treatment and review nine further cases of systemic sclerosis (SSc) in MS from the literature. Of all 12 patients reported, eight had limited cutaneous SSc, three had diffuse cutaneous SSc and one patient had an antisynthetase syndrome. Localised scleroderma such as morphoea was not described. The mean age at diagnosis was 25.2 years for MS (range 12 to 51) and 38.3 years for SSc (range 16 to 66). Eleven patients developed SSc after the onset of MS and manifested with skin sclerosis after a mean of 14.9 years (range 1 to 45). In five patients IFN-beta was commenced before the development of skin sclerosis (mean 4.6 years, range 1 to 8 years). There was no relationship between the onset of skin sclerosis and MS activity. With the exception of one individual, all patients had antinuclear antibodies. CONCLUSIONS: Sclerosing skin disorders may develop in the course of MS. The relatively early age of SSc onset in patients with MS suggests a genetic predisposition and/or an IFN-associated trigger.

Randomized clinical trial of Lichtenstein's operation versus mesh plug for inguinal hernia repair.

BACKGROUND: Two of the most commonly used open prosthetic tension-free techniques for inguinal hernia repair are Lichtenstein's operation and the mesh plug repair. The technique of choice remains a subject of ongoing debate. The objective of the present investigation was to compare the two surgical procedures with respect to associated morbidity and recurrence rates. METHODS: Five hundred and ninety-five patients with 700 primary or recurrent inguinal hernias were randomized to undergo either Lichtenstein's operation or mesh plug repair. The primary endpoint of the investigation was the recurrence rate 1 year after surgery. Secondary endpoints were perioperative complications and reoperation rates. RESULTS: At 12-month follow-up, 597 hernia repairs (85.3 per cent) were evaluated. There were no significant differences regarding recurrence rates and perioperative complications. However, there was a significant difference in the overall reoperation rate between the two treatment groups, with 13 reoperations (4.2 per cent) in the Lichtenstein group and four (1.4 per cent) in the mesh plug group (P = 0.047). CONCLUSION: Lichtenstein's operation and the mesh plug repair are comparable with respect to perioperative complications and recurrence rates.

Intravenous administration of an AAV-2 vector for the expression of factor IX in mice and a dog model of hemophilia B.

Previous experiments have demonstrated the stable expression of factor IX (FIX) protein in mice and canine models of hemophilia B following portal vein gene transfer with a recombinant adeno-associated virus (rAAV) vector encoding FIX. Here, we present the results of studies that further optimized the rAAV vector transgene cassette used to express FIX and explored the use of the less-invasive intravenous (i.v.) route of vector administration for the treatment of hemophilia B. First, a liver-specific promoter was evaluated in conjunction with cis-acting regulatory elements in mice. Constructs that included both the beta-globin intron and the woodchuck hepatitis virus post-transcriptional regulatory element resulted in the highest level of FIX expression in vivo. Using this optimized vector, we demonstrate that i.v. injection was feasible for hepatic gene transfer in mice, achieving 70-80% of portal vein expression levels of FIX. In further studies using the Chapel Hill strain of hemophilia B dogs, we demonstrate for the first time FIX expression and partial correction of the bleeding disorder following i.v. administration of an AAV vector.

Hormone replacement therapy: what is the evidence today?

Based on the most recent studies, it clearly appears that long-term hormone replacement therapy (HRT) prevents fractures but does not improve established coronary artery disease. In addition, HRT leads to a small increase in breast cancer incidence and to a decrease in colorectal cancer incidence. HRT increases the incidence of venous thrombosis, pulmonary embolisms and strokes. As a consequence, HRT can no longer be recommended for primary or secondary prevention of cardiovascular diseases. In addition, it was also demonstrated that HRT was not able to improve cognitive functions and prevent dementia. Therefore regarding daily clinical practice, HRT certainly remains useful to control the symptoms of oestrogen deficiency in recently menopausal patients, but it should definitively no longer be recommended for long-term treatment.