Median liver lobe of woodchuck as a model to study hepatic outflow obstruction: a pilot study

Background: Hepatic vein outflow obstruction represents an important clinical problem in living‐liver transplantation. An animal model is required to study the influence of outflow obstruction on the intrahepatic regulation of liver perfusion and the subsequent effects on liver injury and recovery during liver regeneration. The size of woodchucks enables the use of standard clinical imaging procedures. Aim: This study aims at describing hepatic vascular and territorial anatomy of the woodchuck liver based on a virtual three‐dimensional (3D) visualization of the hepatic vascular tree. Methods: Woodchucks (n=6) were subjected to an all‐in‐one computed tomography (CT) after contrasting the vascular and the biliary tree. CT‐images were used for 3D‐reconstruction of hepatic and portal veins and calculation of the corresponding portal and hepatic vein territories and their respective volume using hepavision (MeVisLab). A virtual resection was performed following the Cantlie‐line and territories at risk were calculated. Results: The median lobe of the woodchuck liver has a similar vascular supply and drainage as the human liver with two portal (right and left median portal vein) and three hepatic veins (left, middle and right median hepatic vein). The corresponding portal and hepatic vein subterritories are of a similar relative size compared with the human liver. Virtual splitting of the median lobe of the woodchuck liver revealed areas at risk of focal outflow obstruction, as observed clinically. Conclusion: The median liver lobe of the woodchuck represents, to a small extent, the hepatic vascular anatomy of the human liver and is therefore a suitable potential model to correlate repeated imaging of impaired liver perfusion with histomorphological findings of liver damage and regeneration.     

Effect of aromatase inhibition on serum levels of sclerostin and dickkopf-1, bone turnover markers and bone mineral density in women with breast cancer

Purpose

While their negative impact on bone health is well established, the effects of aromatase inhibition (AI) on Wnt inhibitors and osteoprotegerin (OPG) are unknown. The aim of the study was to investigate the effects of AI on serum levels of sclerostin, DKK-1 and OPG, as well as their associations with PINP and CTX as markers of bone turnover and bone mineral density (BMD) assessed by DXA.

Methods

We conducted a prospective longitudinal analysis of 70 postmenopausal women with hormone receptor-positive early breast cancer (BC) treated with anastrozole. All measurements were performed at baseline, 12 and 24 months of treatment. We measured the association of the investigated variables with circulating bone turnover markers, as well as with the BMD.

Results

After 24 months of AI therapy, sclerostin and OPG concentrations increased from 29.5 pmol/l (SD = 15.1) and 6.8 pmol/l (SD = 2.2) at baseline to 43.2 pmol/l (SD = 20.6) (p < 0.001) and 7.4 pmol/l (SD = 2.2) (p = 0.028), respectively. DKK-1 levels decreased from 34.3 pmol/l (SD = 13.5) at baseline to 29.7 pmol/l (SD = 12.3) at the 24-month visit (p = 0.005). Sclerostin levels significantly correlated with PTH, OPG and BMD of the lumbar spine, while DKK-1 correlated with the BMD of the femoral neck and of the total hip.

Conclusions

The observed increase in sclerostin levels indicates a central role of osteocytes in bone turnover in women with BC.     

Executive Dysfunction Early Postnatal Biomarkers among Children Born Extremely Preterm

Journal of Neuroimmune Pharmacology - We evaluated the relationship between blood levels of inflammatory and neurotrophic proteins during the first postnatal month in 692 children born before the...     

Utilization of Health Care Services and Satisfaction with Care in Adults Affected by Disorders of Sex Development (DSD)

BACKGROUND

Disorders of sex development (DSD) are a heterogeneous group of rare genetic disorders of sex determination or differentiation. Evidence-based guidelines concerning gender assignment and surgical and hormonal treatment are limited for many DSD entities, and health care is highly fragmented across various sub-specialties and settings. A lack of informed consent, secrecy about the condition, shame, and impaired sexual and psychosocial functioning may affect satisfaction with care.

OBJECTIVES

The main goal of this study was to describe satisfaction with care in individuals with DSD and to identify factors associated with low satisfaction with care.

METHODS / MAIN MEASURES

Using both biological (chromosomes) and social categories (sex of rearing), we classified participants according to the nomenclature of the European Society for Pediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society (ESPE/LWPES) consensus statement. We used standardized measures to assess satisfaction with care (CSQ-8), health-related quality of life (SF-36), psychological symptoms (BSI), and gender identity (FGI), in addition to self-constructed questionnaires probing experiences with health care and access to self-help groups.

PARTICIPANTS

A total of 110 adults were recruited between January 2005 and December 2007 in four study centers in Germany, Austria, and German-speaking Switzerland.

RESULTS

Reports of half the participants scored below the cut-off indicating low quality of care. Women with XX DSD conditions and virilization (i.e., congenital adrenal hyperplasia) reported the highest scores for satisfaction with care, and women with XY DSD conditions and complete lack of androgen effects reported the lowest scores. Satisfaction with care was positively associated with indicators of psychological well-being.

CONCLUSIONS

Satisfaction with care is lowest among participants with the rarest conditions, highlighting the lack of evidence-based recommendations and the lack of coordination of care. Associations of satisfaction and well-being indicate the need to ensure access to mental health services.

     

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Methicillin-resistant Staphylococcus aureus (MRSA) is the most frequent cause of hospital-acquired infection, which manifests as surgical site infections, bacteremia, and sepsis. Due to drug-resistance, prophylaxis of MRSA infection with antibiotics frequently fails or incites nosocomial diseases such as Clostridium difficile infection. Sortase A is a transpeptidase that anchors surface proteins in the envelope of S. aureus, and sortase mutants are unable to cause bacteremia or sepsis in mice. Here we used virtual screening and optimization of inhibitor structure to identify 3-(4-pyridinyl)-6-(2-sodiumsulfonatephenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole and related compounds, which block sortase activity in vitro and in vivo. Sortase inhibitors do not affect in vitro staphylococcal growth yet protect mice against lethal S. aureus bacteremia. Thus, sortase inhibitors may be useful as antiinfective therapy to prevent hospital-acquired S. aureus infection in high-risk patients without the side effects of antibiotics.The gram-positive bacterium Staphylococcus aureus colonizes the human skin and nares yet also causes invasive diseases such as skin and soft tissue infections, osteomyelitis, pneumonia, bacteremia, sepsis, and endocarditis (1). Methicillin-resistant S. aureus (MRSA) acquired resistance against many different drugs, including β-lactam, cephalosporin, fluoroquinolone, aminoglycoside, tetracycline, macrolide, trimethoprim-sulfamethoxazole, and vancomycin antibiotics (2). In the United States, MRSA isolates are responsible for >50% of S. aureus infections in hospitals and long-term care facilities (3). Individuals at high risk of MRSA infection include very-low-birth-weight neonates, elderly, and patients with indwelling catheters, endotracheal intubation, medical implantation of foreign bodies (prosthetic joints, implants and heart valves), trauma, surgical procedures, diabetes, dialysis, and immunosuppressive or cancer therapy (4). Antibiotic prophylaxis is designed to mitigate the risk of S. aureus infection, especially in surgical patients; however, this frequently fails due to drug resistance (5). Importantly, antibiotic therapy suppresses human microbiota and promotes Clostridium difficile infection, which is also associated with increased morbidity and mortality (6, 7). Several trials for vaccines and immune therapeutics were designed to prevent MRSA infection in hospital settings; these efforts have thus far failed to meet their study end points (4).Surface proteins of S. aureus are secreted as precursors with C-terminal sorting signals that are cleaved by sortase A (SrtA) between the threonine (T) and the glycine (G) residues of their LPXTG motif (8, 9). The active site cysteine residue of sortase forms an acyl enzyme intermediate that is relieved by the nucleophilic attack of the amino group (pentaglycine crossbridge) in peptidoglycan synthesis precursors (10). Surface proteins attached to peptidoglycan precursors are subsequently incorporated into the cell wall envelope and displayed on the staphylococcal surface (9). Genome sequencing revealed that all S. aureus isolates encode 17–21 surface proteins with LPXTG sorting signals, which fulfill diverse functions during the infectious process (11). SrtA mutants cannot assemble surface proteins into their envelope and are unable to form abscess lesions in organ tissues or cause lethal bacteremia when inoculated into the bloodstream of mice (12, 13). In contrast, mutations that abrogate the expression of secreted virulence factors may cause attenuation but do not abrogate the ability of S. aureus to cause infectious diseases (12).We reasoned that small molecule inhibitors blocking SrtA may be useful as antiinfectives to prevent S. aureus infection without affecting the growth of other bacteria. If so, such compounds could be used to reduce the incidence of MRSA infections without the side effects of antibiotics.     

Differences in Methylmercury and Inorganic Mercury Biomagnification in a Tropical Marine Food Web

Methylmercury (MeHg), inorganic mercury (Hg_inorg) and their biomagnification factors (BMF) were evaluated along a non-degraded Brazilian bay food web. Highly significant differences (p < 0.0001) were found between MeHg and Hg_inorg concentrations among all organisms (microplankton, shrimp, fish and dolphin). MeHg increased with increasing trophic position while Hg_inorg did not present the same pattern. BMF values for MeHg were higher than 1 for all trophic interactions from source to consumer, indicating that MeHg was transferred more efficiently and biomagnified over the entire web. Only one BMF exceeding one was observed for Hg_inorg (27) between microplankton and their consumer, planktivorous fish. BMF values for Hg_inorg were significantly different than those found for MeHg (20) at the base of the food web.     

Kosteneffektivität eines krankenkassengestützten Case-Management-Programms für Patienten mit affektiven Störungen

Objective

Health economic evaluation of a health insurance based case management intervention for persons with mood to severe depressive disorders from payers’ perspective. Intervention intended to raise utilization rates of outpatient health services.

Methods

Comparison of patients of one German health insurance company in two different regions/states. Cohort study consists of a control region offering treatment as usual. Patients in the experimental region were exposed to a case management programme guided by health insurance account manager who received trainings, quality circles and supervisions prior to intervention. Utilization rates of ambulatory psychiatrist and/or psychotherapist should be increased. Estimation of incremental cost effectiveness ratio (ICER) was intended.

Results

Intervention yielded benefits for patients at comparable costs. A conservative estimation of the ICER was 44,16 €. Maximum willingness to pay was 378,82 € per year. Sensitivity analyses showed that this amount of maximum willingness to pay can be reduced to 34,34 € per year or 2,86 € per month due to cost degression effects.

Conclusions

The intervention gains increasing cost effectiveness by the number of included patients and case managers. Cooperation between health insurances is suggested in order to minimize intervention cost and to maximize patient benefits. Results should be confirmed by individual longitudinal data (bottom-up approach) first.