Characterization of mice lacking the multidrug resistance protein MRP2 (ABCC2)

The multidrug resistance protein Mrp2 is an ATP-binding cassette (ABC) transporter mainly expressed in liver, kidney, and intestine. One of the physiological roles of Mrp2 is to transport bilirubin glucuronides from the liver into the bile. Current in vivo models to study Mrp2 are the transporter-deficient and Eisai hyperbilirubinemic rat strains. Previous reports showed hyperbilirubinemia and induction of Mrp3 in the hepatocyte sinusoidal membrane in the mutant rats. In addition, differences in liver cytochrome P450 and UGT1a levels between wild-type and mutant rats were detected. To study whether these compensatory mechanisms were specific to rats, we characterized Mrp2(-/-) mice. Functional absence of Mrp2 in the knockout mice was demonstrated by showing increased levels of bilirubin and bilirubin glucuronides in serum and urine, a reduction in biliary excretion of bilirubin glucuronides and total glutathione, and a reduction in the biliary excretion of the Mrp2 substrate dibromosulfophthalein. To identify possible compensatory mechanisms in Mrp2(-/-) mice, the expression levels of 98 phase I, phase II, and transporter genes were compared in liver, kidney, and intestine of male and female Mrp2(-/-) and control mice. Unlike in Mrp2 mutant rats, no induction of Mrp3 in Mrp2(-/-) mice was detected. However, Mrp4 mRNA and protein in liver and kidney were increased approximately 6- and 2-fold, respectively. Phenotypic analysis of major cytochrome P450-mediated activities in liver microsomes did not show differences between wild-type and Mrp2(-/-) mice. In conclusion, Mrp2(-/-) mice are a new valuable tool to study the role of Mrp2 in drug disposition.     

A controlled national survey in France of health-related challenges for persons with Down syndrome

Despite recent research on the impact of disability on function, little information is available to evaluate the need for daily support in persons with Down syndrome. The aim of this study was to evaluate the prevalence and relative degree of difficulty experienced by this population in routine hygiene and health care when compared to their siblings. A proxy French language questionnaire was used for this cross-sectional survey of 199 persons with Down syndrome and 153 siblings (mean age 12.3 years, range < or = 1-48). Individuals in the study group had significantly more difficulty performing all activities related to routine hygiene and health care, and were 2-22 times more likely to need help than the control group. Certain acts of routine health care were performed more regularly by those in the study group (6/12 items), and specialist medical and paramedical visits were more regular (OR = 7-44). Increased difficulty and need for help in performing acts of basic self-care may reduce autonomy and social integration for persons with Down syndrome. Recommendations are made in relation to the training of caregivers and health professionals.     

Volume expansion with albumin compared to gelofusine in children with severe malaria: results of a controlled trial

Objectives:     

Neuroleptics antagonize nalbuphine antianalgesia.

To evaluate the role of sigma receptors in the sexually dimorphic antianalgesic effect of agonist-antagonist kappa opioids, 2 neuroleptics, haloperidol, a sigma receptor antagonist, and chlorpromazine, which has minimal effect at sigma receptors, were administered with the agonist-antagonist kappa opioid nalbuphine in patients with postoperative pain. Before surgical extraction of bony impacted mandibular third molar teeth, patients received haloperidol (1 mg), chlorpromazine (10 mg), or placebo by oral administration. After surgery, the pain intensity did not differ significantly between the 3 treatment groups, suggesting lack of analgesic effect produced by either haloperidol or chlorpromazine. All patients were then administered nalbuphine (5 mg, intravenous). As previously reported, the group that did not receive a preoperative neuroleptic exhibited sexually dimorphic analgesia, with women experiencing greater analgesia than men. Antianalgesia was also observed, with men experiencing late onset increased pain compared with baseline, starting approximately 1 hour after nalbuphine administration. Both neuroleptics blocked nalbuphine antianalgesia, resulting in enhanced analgesia and elimination of the sex differences. Because chlorpromazine and haloperidol enhanced nalbuphine analgesia and eliminated sexual dimorphism, the receptor at which neuroleptics act to antagonize the "antianalgesia" might be a common site of action to both drugs. PERSPECTIVE: This study demonstrates that neuroleptics can block the antianalgesic effect of agonist-antagonist kappa opioids. These findings could help inform the development of novel analgesics.     

Higher in utero and perinatal HIV infection risk in girls than boys

OBJECTIVE: This study analyzed mother-to-child HIV transmission rates by sex and exposure time for babies born to HIV-infected, untreated African women. METHODS: Data were analyzed from 2 independent studies done in Malawi during the 1990s. Infections were established by polymerase chain reaction on blood samples. Odds ratios (ORs) for transmission were examined by period at risk: in utero (infected in umbilical cord blood), perinatal (infected in 1st postnatal blood > or =4 weeks), and postnatal (later postnatal infection). RESULTS: Among 1394 singleton births, girls were more likely to become infected than boys. For in utero transmission, the OR was 1.4 (95% CI: 0.9 to 2.2). For transmission during early life (umbilical cord blood not available) the OR was 2.7 (95% CI: 1.5 to 4.9). However, transmission risks in the perinatal and postnatal infection periods did not differ in boys and girls. Among 303 tested twin-birth pairs, girls were at higher risk than boys for in utero (OR: 2.6; 95% CI: 1.2 to 5.8) and perinatal (OR: 1.9; 95% CI: 1.0 to 3.7) infection. Recognized mother-to-child transmission risk factors did not explain the higher risk of infection in girls. CONCLUSIONS: Girls were at higher risk of early (in utero and perinatal) HIV infection than boys. It is proposed that minor histocompatibility reactions between maternal lymphocytes and infant Y chromosome-derived antigens reduce the risk of HIV transmission in boys.     

The management of abuse: 2. Child abuse

The role of the GDP and the dental team in the recognition and management of child abuse is discussed. Information on the current legislation and protocols for referral are provided. CLINICAL RELEVANCE: This paper discusses child abuse and offers information and practical advice for the dental team.     

Gender differences in how men and women who are referred for IVF cope with infertility stress

BACKGROUND: Men and women use a variety of coping strategies to manage stress associated with infertility. Although previous research has helped us understand these coping processes, questions remain about gender differences in coping and the nature of the relationship between coping and specific types of infertility stress. METHODS: This study examined the coping behaviours of 1026 (520 women, 506 men) consecutively referred patients at a University-affiliated teaching hospital. Participants completed the Ways of Coping Questionnaire, Fertility Problem Inventory and the Dyadic Adjustment Scale. RESULTS: Women used proportionately greater amounts of confrontative coping, accepting responsibility, seeking social support and escape/avoidance when compared with men, whereas men used proportionately greater amounts of distancing, self-controlling and planful problem-solving. For men and women, infertility stress was positively related to escape/avoidance and accepting responsibility and negatively related to seeking social support, planful problem-solving and distancing. CONCLUSIONS: By analysing relative coping scores, this study identified key gender differences in how men and women cope with infertility. This was particularly true for men's coping processes that had previously remained hidden because of less frequent use of coping strategies when compared with women.     

Characterisation of the associations and impact of symptoms in primary biliary cirrhosis using a disease specific quality of life measure

BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) patients experience significant impairment to quality of life (QOL). Studies to date examining relative contributions of different symptoms to QOL impairment in PBC, and biological associations have been limited by the unavailability of appropriate disease specific symptom quantification modalities. METHODS: We applied the PBC-40, a recently developed, multi-domain disease specific QOL measure, to 54 PBC patients to explore the inter-relationship of different symptoms, their biological associations, and correlation with physical functioning measured by accelerometry. RESULTS: Two discrete and unrelated symptom complexes in PBC were identified focused on fatigue (together with cognitive and emotional dysfunction and other symptoms) and itch, with social dysfunction associating with both complexes. We confirmed no correlation between symptom severity and biological parameters of disease severity. There was a strong inverse correlation between physical activity (assessed over 6 days) and fatigue (P<0.005), but not between physical activity and Itch. Patients averaging <7,500 steps per day had over 75% higher fatigue scores than patients averaging >7,500 steps. CONCLUSIONS: We have demonstrated two independent symptom complexes in PBC centred around fatigue and itch, neither is associated with biological parameters of activity, and the fatigue-centred complex is associated with objective impairment of physical functioning.