Conformationally constrained farnesoid X receptor (FXR) agonists: heteroaryl replacements of the naphthalene.

To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.

Regulation of human metabolism by hypoxia-inducible factor.

The hypoxia-inducible factor (HIF) family of transcription factors directs a coordinated cellular response to hypoxia that includes the transcriptional regulation of a number of metabolic enzymes. Chuvash polycythemia (CP) is an autosomal recessive human disorder in which the regulatory degradation of HIF is impaired, resulting in elevated levels of HIF at normal oxygen tensions. Apart from the polycythemia, CP patients have marked abnormalities of cardiopulmonary function. No studies of integrated metabolic function have been reported. Here we describe the response of these patients to a series of metabolic stresses: exercise of a large muscle mass on a cycle ergometer, exercise of a small muscle mass (calf muscle) which allowed noninvasive in vivo assessments of muscle metabolism using (31)P magnetic resonance spectroscopy, and a standard meal tolerance test. During exercise, CP patients had early and marked phosphocreatine depletion and acidosis in skeletal muscle, greater accumulation of lactate in blood, and reduced maximum exercise capacities. Muscle biopsy specimens from CP patients showed elevated levels of transcript for pyruvate dehydrogenase kinase, phosphofructokinase, and muscle pyruvate kinase. In cell culture, a range of experimental manipulations have been used to study the effects of HIF on cellular metabolism. However, these approaches provide no potential to investigate integrated responses at the level of the whole organism. Although CP is relatively subtle disorder, our study now reveals a striking regulatory role for HIF on metabolism during exercise in humans. These findings have significant implications for the development of therapeutic approaches targeting the HIF pathway.

Treatment with intravenous immunoglobulin and steroids may correct severe anemia in hyperhemolytic transfusion reactions: case report and literature review.

Hyperhemolytic transfusion reaction (HHTR) is a serious and potentially life-threatening complication of red blood cell (RBC) transfusion and has been well described in patients with sickle cell disease (SCD) and non-SCD patients. Awareness of this condition is important because subsequent transfusion may exacerbate hemolysis and may lead to a chronic protracted course or even death. If hemolysis is rapid and severe, subsequent transfusion may be necessary. Additional transfusion has been given together with intravenous immunoglobulin (IVIG) and steroids. We report a patient with SCD presented with severe HHTR whose serum contained multiple RBC alloantibodies. On day 2 of admission, the hemoglobin level dropped to 47 g/L. Intravenous immunoglobulin and steroid therapy was commenced. The patient responded and further transfusion was avoided. Review of the literature identified 5 HHTR cases in which transfusion was withheld and IVIG/steroids prescribed. In all of these cases, anemia was corrected and hemolysis resolved without blood transfusion. The reasons why transfusion was withheld and IVIG/steroids treatment prescribed were explored. There is no indication for IVIG in the routine treatment of hemolytic transfusion reactions, but IVIG should be considered as an option for treatment of serious, life-threatening HHTR both in SCD and non-SCD patients.

Transition to adult-oriented health care: perspectives of youth and adults with complex physical disabilities.

INTRODUCTION: The transition to adulthood is extremely difficult for individuals with disabilities. We sought to explore the specific issue of transition to adult-oriented health care in a Canadian context. METHODS: We conducted semi-structured individual interviews with 15 youth and 15 adults with cerebral palsy, spina bifida, and acquired brain injuries of childhood, and their parents (n = 30). Respondents discussed their health care services, their experience with clinical transition, and contributing factors. We analyzed the transcripts using qualitative methods. RESULTS: All participants identified challenges in transition, including: lack of access to health care; lack of professionals' knowledge; lack of information and uncertainty regarding the transition process. Two solutions were identified: early provision of detailed information and more extensive support throughout the clinical transition process. DISCUSSION: The challenges of clinical transition were universal. More extensive information and support is needed during transition to ensure an efficient move to appropriate adult-oriented health care.

Synthesis of novel anilinoquinolines as c-fms inhibitors.

A novel series of potent substituted anilinoquinolines were discovered as c-fms inhibitors. The potency could be manipulated upon modification of the C4 aniline and C7 aryl functionality. Pharmacokinetic analysis identified a metabolically stable analog suitable for further investigative work.

The transition study: a look at youth and adults with cerebral palsy, spina bifida and acquired brain injury.

A group of 100 adults and 190 youth who have cerebral palsy (CP), spina bifida (SB), and acquired brain injuries from childhood (ABIc) participated in a multi-method study focused on the transition to adult health care. The results show that 95% of youth and 61% of adults were living with their parents; 23% of the youth and 55% of adults were employed; and 60% of youth and 42% of adults reported "excellent" or "very good" health. The lowest health scores were reported by adults with SB. These findings provide a starting point for examining health issues specific to youth and young adults with CP, SB, and ABIc.

Synthesis and activity of small molecule GPR40 agonists.

The first report on the identification and structure-activity relationships of a novel series of GPR40 agonists based on a 3-(4-{[N-alkyl]amino}phenyl)propanoic acid template is described. Structural modifications to the original screening hit yielded compounds with a 100-fold increase in potency at the human GPR40 receptor and pEC(50)s in the low nanomolar range. The carboxylic acid moiety is not critical for activity but typically elicits an agonistic response higher than those observed with carboxamide replacements. These compounds may prove useful in unraveling the therapeutic potential of this receptor for the treatment of Type 2 diabetes.

Novel pyrazolopyrimidine derivatives as GSK-3 inhibitors.

A series of [1-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]arylhydrazones were discovered as novel inhibitors glycogen synthase kinase-3 (GSK-3). Based on initial modeling a detailed SAR was constructed. Modification of the interior binding aryl ring (Ar(1)) determined this to be a tight binding region with little room for modification. As predicted from the model, a large variety of modifications could be incorporated into the hydrazone aryl ring. This work led to GSK-3 inhibitors in the low nano-molar range.

Prevalence of tuberculosis, hepatitis B virus, and intestinal parasitic infections among refugees to Minnesota.

OBJECTIVE: The purpose of this study was to define the prevalence of infection with Mycobacterium tuberculosis, hepatitis B virus, and various intestinal parasites among different groups of primary refugees immigrating to Minnesota. METHODS: 2,545 refugees arriving in Minnesota during 1999 received a domestic health examination that included tuberculin skin testing, hepatitis B virus serologic testing, and stool ova and parasite examinations. The Refugee Health Assessment form asked specifically about screening results for amebiasis, ascariasis, clonorchiasis, giardiasis, hookworm, schistosomiasis, strongyloidiasis, and trichuriasis. RESULTS: Forty-nine percent of refugees had a reactive tuberculin test of >or=10 mm induration, with a higher prevalence in males (54%) and refugees >or=18 years of age (63%) (p<0.001). Seven percent had a positive hepatitis B surface antigen, with the highest prevalence in those people from sub-Saharan Africa (8%) (p=0.002) and those refugees >or=18 years of age (9%) (p=0.006). Twenty-two percent had one or more intestinal parasites asked about, including 30% of those refugees <18 years of age (p<0.001). The most commonly reported parasitic infections were trichuriasis (8%) and giardiasis (7%). CONCLUSIONS: Evidence of infection with M. tuberculosis, hepatitis B virus, or one of eight intestinal parasites was present in a substantial proportion of refugees receiving the domestic health assessment. Screening for such infections gives new immigrants the opportunity to receive important medical evaluation and treatment, provides valuable surveillance data, and allows appropriate public health measures to be taken.