Using food fortification to improve vitamin D bioaccessibility and intakes.

Vitamin D intakes and status are low in many countries due to seasonal UVB exposure variation and the fact that few foods are naturally vitamin D rich. Data modelling studies show that vitamin D intakes increase with food fortification, and countries with mandatory fortification policies have higher vitamin D intakes and status compared to countries without. While many foods can be vitamin D fortified, vitamin D bioavailability differs depending on fortification methods, food structure and composition. Randomised controlled trials (RCT) report that vitamin D2 bioavailability varies between foods, whereas vitamin D3 is bioavailable from many foods. In vitro studies suggest that altering the lipid composition of fortified foods increases vitamin D3 absorption. Olive oil increased vitamin D3 absorption during in vitro digestion compared to other dietary oils. Additionally, when vitamin D3 was incorporated into micelles formed from in vitro digestion of olive oil, more vitamin D3 was absorbed compared to other dietary oils. However, in a human postprandial study, a preformed vitamin D3 micelle dairy drink did not increase vitamin D3 absorption, and a vitamin D3 olive dairy drink increased vitamin D3 absorption in vitamin D insufficient participants only. Action is urgently needed to improve vitamin D intakes and status worldwide. Food fortification improves vitamin D intakes; however, fortification strategies unique to each country are needed. This review will synthesise the literature describing data modelling and intervention trials that assess the safety and efficacy of vitamin D fortification strategies, and those manipulating food composition to alter vitamin D bioavailability from fortified foods. Additionally, RCT examining the impact of vitamin D fortification strategies on vitamin D intakes and status over time are reviewed.

Exercise as a therapeutic intervention for motor and non-motor symptoms in Parkinson's disease: Evidence from rodent models.

Parkinson's disease (PD) is characterised by degeneration of dopaminergic neurons of the nigrostriatal pathway, which leads to the cardinal motor symptoms of the disease - tremor, rigidity and postural instability. A number of non-motor symptoms are also associated with PD, including cognitive impairment, mood disturbances and dysfunction of gastrointestinal and autonomic systems. Current therapies provide symptomatic relief but do not halt the disease process, so there is an urgent need for preventative strategies. Lifestyle interventions such as aerobic exercise have shown potential to lower the risk of developing PD and to alleviate both motor and non-motor symptoms. However, there is a lack of large-scale randomised clinical trials that have employed exercise in PD patients. This review will focus on the evidence from studies on rodent models of PD, for employing exercise as an intervention for both motor and non-motor symptoms.

Assessment of the ability of seaweed extracts to protect against hydrogen peroxide and tert-butyl hydroperoxide induced cellular damage in Caco-2 cells.

The ability of brown seaweed extracts, Ascophyllum nodosum, Laminaria hyperborea, Pelvetia canaliculata, Fucus vesiculosus and Fucus serratus to protect against tert-butyl hydroperoxide (tert-BOOH) induced stress in Caco-2 cells was investigated. Oxidative stress was determined by measuring alteration in the enzymatic activity of catalase (CAT) and superoxide dismutases (SOD) and cellular levels of glutathione (GSH). L. hyperborea, P. canaliculata and F. serratus significantly protected against tert-BOOH induced SOD reduction but did not protect against the reduction in CAT activity or the increased cellular levels of GSH. The ability of F. serratus and F. vesiculosus to protect against H(2)O(2) and tert-BOOH induced DNA damage was also assessed. The DNA protective effects of the two seaweed extracts was compared to those of three metal chelators; deferoxamine mesylate (DFO), 1,10-phenanthroline (o-phen) and 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (BAPTA-AM). F. serratus and F. vesiculosus significantly protected (P<0.05) against H(2)O(2) (50 µM) induced DNA damage but not tert-BOOH induced damage.

Immune activation by a sterile aqueous extract of Cordyceps sinensis: mechanism of action.

Cordyceps sinensis is a fungus that has been used for over 2,000 years in China as a treatment for a variety of conditions including infectious diseases. The available evidence suggests a hypothesis that any efficacy of C. sinensis as an anti-infective therapeutic would be related to a role as an activator of innate immune responses. The objectives of this study were first to investigate the ability of C. sinensis to activate pro-inflammatory responses in macrophages in vitro and induce protective responses against intracellular pathogens in vivo, and second to characterize a method of action. We found that C. sinensis activates murine macrophages to produce a variety of pro-inflammatory cytokines. IFN-gamma synergizes with C. sinensis to amplify this response. Bacterial endotoxin contamination was ruled out as a potential artefact. The evidence presented in this study supports a hypothesis that C. sinensis activates macrophages by engaging Toll-like receptors and inducing mitogen-activated protein kinase (MAPK) pathways characteristic of inflammatory stimuli.

Neuroprotective effects of novel phosphatidylglycerol-based phospholipids in the 6-hydroxydopamine model of Parkinson's disease.

Administration of VP025 (Vasogen Inc.), a novel drug formulation based on phospholipid nanoparticles incorporating phosphatidylglycerol, has previously been shown to have a neuroprotective effect in the brain. We examined the effect of VP025 in a rat model of Parkinson's disease, the 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle. VP025 or phosphate-buffered saline (PBS) was administered to rats 14 days, 13 days and 1 day before the unilateral 6-OHDA lesion. Functional integrity of nigrostriatal dopaminergic neurons was assessed 7 and 21 days later by amphetamine-induced rotational testing and we observed that rotational counts were significantly less in rats that were pretreated with VP025 compared with PBS-pretreated 6-OHDA-lesioned rats. Neurochemical analysis at 10 and 28 days after lesion revealed that VP025 protected against a 6-OHDA-induced decrease in concentrations of striatal dopamine and its metabolites. Immunocytochemical studies of the ipsilateral substantia nigra showed that VP025 significantly inhibited 6-OHDA-induced loss of dopaminergic neurons. We also observed that increases in immunostaining for activated microglia and for activated p38 in dopaminergic neurons of 6-OHDA-lesioned rats were prevented by VP025. This study shows that VP025 has significant protective effects on the 6-OHDA-lesioned nigrostriatal pathway and may therefore have potential for the treatment of Parkinson's disease.

Heparin-binding epidermal growth factor-like growth factor: a component in chromaffin granules which promotes the survival of nigrostriatal dopaminergic neurones in vitro and in vivo.

Chromaffin cells can restore function to the damaged nigrostriatal dopaminergic system in animal models of Parkinson's disease. It has been reported that a protein which is released from chromaffin granules can promote the survival of dopaminergic neurones in vitro and protect them against N-methylpyridinium ion toxicity. This neurotrophic effect has been found to be mediated by astroglial cells and blocked by inhibitors of the epidermal growth factor (EGF) receptor signal transduction pathway. Here we report the identification of bovine heparin-binding EGF-like growth factor (HB-EGF) in chromaffin granules and the cloning of the respective cDNA from bovine-derived adrenal gland. Protein extracts from bovine chromaffin granules were found to promote the survival of embryonic dopaminergic neurones in culture, to the same extent as recombinant human HB-EGF. Furthermore, the neurotrophic action of the chromaffin granule extract could be abolished by antiserum to recombinant human HB-EGF. We also show that intracerebral injection of recombinant human HB-EGF protected the nigrostriatal dopaminergic system in an in vivo adult rat model of Parkinson's disease. Intracerebral administration of this protein at the same time as a 6-hydroxydopamine lesion of the medial forebrain bundle was found to spare dopamine levels in the striatum and tyrosine hydroxylase-immunopositive neurones in the midbrain. This study has found that the main component in chromaffin granules responsible for their neurotrophic effect on dopaminergic neurones is HB-EGF. Furthermore, HB-EGF has significant protective effects on nigrostriatal dopaminergic neurones in vivo, making it a potential candidate for use in the treatment of Parkinson's disease.

Viability of dopaminergic neurones is influenced by serum and astroglial cells in vitro.

Transplantation of embryonic nigral grafts into the striatum of Parkinson's disease patients is not optimal, mainly due to low survival of grafted neurones. Current strategies focus on enhancing neuronal survival by transplanting enriched neuronal cell populations. There is growing evidence for the importance of astroglia in neuronal survival.To characterise the effects of glial cells on dopaminergic neurones, 5-fluoro-2'-deoxyuridine was added to embryonic rat ventral mesencephalic cultures in the presence or absence of serum. The survival and morphology of glial fibrillary acidic protein immunopositive astroglia and tyrosine hydroxylase immunopositive dopaminergic neurones was examined. In serum-containing medium, astroglial cells predominated and 5-fluoro-2'-deoxyuridine had no significant effect on either astroglia or dopaminergic neurone survival. In serum-free medium, astroglial growth was attenuated and numbers were significantly lower in 5-fluoro-2'-deoxyuridine treated compared with untreated cultures. There was no significant difference in the numbers of dopaminergic neurones between 5-fluoro-2'-deoxyuridine treated and untreated cultures. However, by the eighth day in vitro, there were differences in the morphology of these neurones between treated and untreated cultures. This study shows that the use of 5-fluoro-2'-deoxyuridine and serum-free medium can produce a neurone-enriched culture. However, the dopaminergic neurone population present in these cultures appeared to be morphologically dissimilar to those found in control cultures as neurites were retracted and the cell somas of these cells appeared enlarged. These results provide information on the effects of astrocytes on dopaminergic neurones in ventral mesencephalic cultures and thus have implications for transplantation in Parkinson's disease.

The effect of medical education on primary care orientation: results of two national surveys of students' and residents' perspectives.

PURPOSE: To examine changes among a nationally representative sample of students and residents in their orientations toward primary care as reflected in their attitudes toward the psychosocial and technical aspects of medicine and their perceptions of the academic environment for primary care. METHOD: Confidential telephone interviews of stratified national probability samples of first- and fourth-year medical students and residents were conducted in 1994 and 1997. The 1997 survey included 219 students and 241 residents who had also been interviewed in 1994. Participants were asked about their attitudes toward addressing psychosocial issues in medicine and their perceptions of faculty and peer attitudes toward primary care. Responses were compared over time and across groups. RESULTS: Between the first and fourth years of medical school, there was a decline over time in students' reported orientations to socioemotional aspects of patient care (61.6% versus 42.7%, p =.001) and their perceptions that working with psychosocial issues of patients made primary care more attractive (56.3% versus 43.5%, p =.01). This pattern continued for 1997 residents (PGY-3), who were even less likely to say that addressing psychosocial issues made primary care more attractive (26.9%). For fourth-year students in 1994 who became PGY-3 residents in 1997, there was an increased perception that non-primary-care house officers and specialty faculty had positive attitudes toward primary care (20.8% versus 33.0%, p =.005; 28.3% versus 45.7%, p <.0001; respectively). CONCLUSIONS: Between 1994 and 1997 students and residents perceived a positive shift in the attitudes of peers and faculty toward primary care. During the course of their education and training, however, the students experienced an erosion of their orientations to primary care as they progressed through medical school into residency.

Profile of a comprehensive psychiatric emergency program in a New York City municipal hospital.

This paper profiles the services provided, and the patient population treated, in a busy inner city Comprehensive Psychiatric Emergency Program (CPEP) located in Elmhurst, Queens, New York City. For each CPEP component, including the emergency room, extended observation unit and crisis services two years of data are reviewed. A diagnostic profile of patients seen, description of services, patient referrals and dispositions are presented. The children and adolescents treated in the CPEP are described in more detail, focusing on the high frequency of violence to self or others seen in their presenting problems. The CPEP's role in providing comprehensive community based services is discussed.

Incidence of coagulase positive Staphylococcus on beef carcasses in three Australian abattoirs.

The contamination of beef carcasses with coagulase-positive staphylococci (CPS) was studied at three beef abattoirs (A, B and C). The incidence and the number of CPS were determined on cattle hides immediately after slaughter and on three carcass sites (brisket, flank and round) at different points during processing along the slaughter line. The incidence of CPS on cattle hides ranged from 20 to 68.6%. At abattoir A, 6.5% of the carcasses sampled before evisceration were contaminated with CPS, compared to 40% of the carcasses after evisceration. The incidence on carcasses changed little during further processing; however, after chilling for 72 h, the incidence increased to 83%. After evisceration, the brisket and flank areas were more often contaminated than the round. A similar pattern of contamination was observed at abattoir B. At abattoir C, 26.7% of the samples collected before evisceration were contaminated and this fell to 16.7% after evisceration. After chilling for 72 h, the incidence of carcass contamination with CPS increased to 46.7%. The average number of CPS on contaminated carcasses prior to and after overnight chilling was less than 50 colony-forming units (cfu)/cm2 and, after weekend chilling, increased to 64 and 112 cfu/cm2 in abattoirs A and B, respectively. Of the isolates tested, 71.4% produced staphylococcal enterotoxin and 21% could not be classified phenotypically. The hands of workers and environmental sites associated with the evisceration process were examined for CPS at abattoir A. Hands were heavily contaminated and were the likely source of CPS contamination at this abattoir.

Views of managed care--a survey of students, residents, faculty, and deans at medical schools in the United States.

BACKGROUND AND METHODS: Views of managed care among academic physicians and medical students in the United States are not well known. In 1997, we conducted a telephone survey of a national sample of medical students (506 respondents), residents (494), faculty members (728), department chairs (186), directors of residency training in internal medicine and pediatrics (143), and deans (105) at U.S. medical schools to determine their experiences in and perspectives on managed care. The overall rate of response was 80.1 percent. RESULTS: Respondents rated their attitudes toward managed care on a 0-to-10 scale, with 0 defined as "as negative as possible" and 10 as "as positive as possible." The expressed attitudes toward managed care were negative, ranging from a low mean (+/-SD) score of 3.9+/-1.7 for residents to a high of 5.0+/-1.3 for deans. When asked about specific aspects of care, fee-for-service medicine was rated better than managed care in terms of access (by 80.2 percent of respondents), minimizing ethical conflicts (74.8 percent), and the quality of the doctor-patient relationship (70.6 percent). With respect to the continuity of care, 52.0 percent of respondents preferred fee-for-service medicine, and 29.3 percent preferred managed care. For care at the end of life, 49.1 percent preferred fee-for-service medicine, and 20.5 percent preferred managed care. With respect to care for patients with chronic illness, 41.8 percent preferred fee-for-service care, and 30.8 percent preferred managed care. Faculty members, residency-training directors, and department chairs responded that managed care had reduced the time they had available for research (63.1 percent agreed) and teaching (58.9 percent) and had reduced their income (55.8 percent). Overall, 46.6 percent of faculty members, 26.7 percent of residency-training directors, and 42.7 percent of department chairs reported that the message they delivered to students about managed care was negative. CONCLUSIONS: Negative views of managed care are widespread among medical students, residents, faculty members, and medical school deans.

Neuroprotective effects of growth/differentiation factor 5 depend on the site of administration.

Growth/differentiation factor 5 (GDF5) is a neurotrophin which protects the rat nigrostriatal dopaminergic pathway from 6-hydroxydopamine-induced damage. Here we used amphetamine-induced rotational testing, high-performance liquid chromatography and immunocytochemistry to investigate the minimum effective dose of GDF5. We also compared the effectiveness of injecting GDF5 into either the substantia nigra pars compacta (SNpc), the lateral ventricle (LV) or the striatum (or combinations of these sites).

Phage types of Australian isolates of Salmonella enterica subsp. enterica serovar Virchow.

Australian isolates (79) of Salmonella enterica subsp. enterica serovar Virchow (Salmonella Virchow) were characterized by phage typing. Thirteen phage types were identified, of which phage type (PT) 8, representing 54 of 79 isolates, was predominant, as it had been in England and Wales up to 1994 when it was replaced by PT26. Other phage types identified in Australia were distinct from those observed in England and Wales. This suggests that PT8 may be a global phage type, while others may be distinct to particular geographical regions.

Long-term protection of the rat nigrostriatal dopaminergic system by glial cell line-derived neurotrophic factor against 6-hydroxydopamine in vivo.

Glial cell-line-derived neurotrophic factor (GDNF) has been shown to enhance the survival of dopaminergic neurones both in vitro and in vivo, and to protect the rodent dopaminergic system from neurotoxic damage. However, most previous studies have only examined the short-term protective effects of GDNF. We have investigated the long-term effects of GDNF on a 6-hydroxydopamine (6-OHDA)-induced lesion of the rat medial forebrain bundle (MFB), which results in complete and irreversible destruction of the nigrostriatal pathway, and is a robust model of Parkinson's disease. GDNF was administered ipsilaterally above the substantia nigra and into the lateral ventricle immediately before a unilateral 6-OHDA injection into the MFB. The effects of GDNF were examined in vivo by behavioural testing and positron emission tomography (PET) at weekly intervals, for 12 weeks. GDNF prevented the development of amphetamine-induced rotations at all time-points. PET studies, using [11C]-RTI-121 as a tracer for the dopamine transporter, indicated that GDNF prevented 6-OHDA-induced reduction of dopamine reuptake sites in the ipsilateral striatum. Post-mortem neurochemical analysis at 13 weeks after surgery found that GDNF significantly inhibited 6-OHDA-induced loss of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the ipsilateral striatum. Immunocytochemistry showed that GDNF reduced 6-OHDA-induced loss of tyrosine hydroxylase-positive neurones in both the substantia nigra pars compacta and ventral tegmental area. We have shown that a single treatment with GDNF can confer long-term protective effects against a 6-OHDA lesion, which suggests that this factor may be useful for the treatment of Parkinson's disease.

Back-up bone marrow is frequently ineffective in patients with poor peripheral-blood stem-cell mobilization.

PURPOSE: To assess hematologic recovery and procedure-related mortality in patients who received high-dose therapy with stem-cell support, in whom the peripheral-blood stem-cell (PBSC) collection fails (CD34+ cells < 1 x 10(6)/kg). The predictive value of granulocyte-monocyte colony-forming cell (GM-CFC) measurements and the value of bone marrow obtained after PBSC collection failure was assessed. PATIENTS AND METHODS: The study group comprised 324 consecutive patients mobilized with granulocyte colony-stimulating factor (G-CSF) and cyclophosphamide (273 patients), G-CSF with other chemotherapy (37 patients), and G-CSF alone (14 patients). Between one and four aphereses were performed. RESULTS: In 51 of 324 patients, there was failure to obtain 1 x 10(6)/kg CD34+ cells. Twenty-three patients had greater than 1 x 10(5)/kg GM-CFC; 22 patients proceeded to high-dose therapy. Neutrophil recovery occurred within 21 days, but platelet independence was delayed (> 28 days) in eight patients. Of 28 patients with less than 1 x 10(5)/kg GM-CFC, six received high-dose therapy with PBSC alone and five had delayed engraftment. Twelve patients with less than 1 x 10(5)/kg GM-CFC received high-dose therapy supported by bone marrow collected after PBSC collection failure. Eleven patients were assessable for engraftment; four patients had slow (> 21 days) or delayed (> 28 days) neutrophil recovery and eight patients had delayed platelet recovery. In the group of patients who received less than 1 x 10(5)/kg GM-CFC, there were five procedure-related deaths. CONCLUSION: This study shows that delayed hematologic recovery is frequent if less than 1 x 10(6)/kg CD34+ cells are infused after high-dose therapy, particularly with GM-CFC less than 1 x 10(5)/kg. The procedure-related mortality in this latter group is high. In most patients whose PBSC collection contains less than 1 x 10(5)/kg GM-CFC, the use of bone marrow cells does not improve engraftment, which suggests that poor PBSC mobilization usually indicates poor marrow function.

Growth/differentiation factor 5 and glial cell line-derived neurotrophic factor enhance survival and function of dopaminergic grafts in a rat model of Parkinson's disease.

Growth/differentiation factor 5 is a member of the transforming growth factor beta superfamily, which has neurotrophic and neuroprotective effects on dopaminergic neurons both in vitro and in vivo. Here we investigate the effects of growth/differentiation factor 5 on foetal mesencephalic grafts transplanted into a rat model of Parkinson's disease, and compare them with those of glial cell line-derived neurotrophic factor. Mesencephalic tissue was suspended in solutions containing either growth/differentiation factor 5 or glial cell line-derived neurotrophic factor prior to transplantation into the left striatum of rats with 6-hydroxydopamine lesions of the left medial forebrain bundle. Both proteins enhanced graft-induced compensation of amphetamine-stimulated rotations. Positron emission tomography studies showed that both neurotrophins increased graft-induced recovery of striatal binding of [11C]RTI-121, a marker for dopaminergic nerve terminals. Post mortem analysis at 8 weeks after transplantation showed that both neurotrophins significantly increased the survival of grafted dopaminergic neurons. This study shows that growth/differentiation factor 5 is at least as effective as glial cell line-derived neurotrophic factor in enhancing the survival and functional activity of mesencephalic grafts, and thus is an important candidate for use in the treatment of Parkinson's disease.

Attitudes about end-of-life care: a national cross-sectional study.

BACKGROUND: Major concerns have been expressed about the preparation of physicians to provide end-of-life care. Little is known about how well academic health centers prepare students and residents to care for patients at the end-of-life and about the values about end-of-life care transmitted by faculty. METHODS: In 1997, we conducted a telephone survey of a nationally representative sample of first-year medical students (n = 287), fourth-year medical students (n = 173), residents (n = 473), clinical faculty (n = 728), internal medicine residency training directors (n = 143), department chairs (n = 186), and medical school deans (n = 101) within U.S. academic health centers (response rate = 80.2%). RESULTS: U.S. medical students, residents and faculty evaluate themselves as inadequately prepared to provide end-of-life care. Academic health center constituents perceive that providing care at the end of life requires medium to high levels of expertise. Academic health center constituents are divided about whether responsibility for providing care at the end of life rests with generalists or with specialists and view managed care as nearly equivalent to the fee-for-service sector in its capacity to provide excellent end-of-life care. CONCLUSIONS: Academic leaders and faculty, as well as their students, lack confidence in their own skills in providing end-of-life care. They also question the ability of the current and evolving health care delivery system to provide excellent end-of-life care.