Effects of naltrexone are influenced by childhood adversity during negative emotional processing in addiction recovery.

Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependence alone (n=18, alcohol) and in combination with cocaine and/or opioid dependence (n=21, alcohol/drugs) and healthy individuals without a history of alcohol or drug dependence (n=21) were recruited. Participants were alcohol and drug abstinent before entered into this double-blind, placebo-controlled, randomized, crossover study. Functional magnetic resonance imaging was used to investigate brain response while viewing aversive and neutral images relative to baseline on 50 mg of naltrexone and placebo. We found that naltrexone modulated task-related activation in the medial prefrontal cortex and functional connectivity between the anterior cingulate cortex and the hippocampus as a function of childhood adversity (for aversive versus neutral images) in all groups. Furthermore, there was a group-by-treatment-by-condition interaction in the right amygdala, which was mainly driven by a normalization of response for aversive relative to neutral images under naltrexone in the alcohol/drugs group. We conclude that early childhood adversity is one environmental factor that influences pharmacological response to naltrexone. Pharmacotherapy with naltrexone may also have some ameliorative effects on negative emotional processing in combined alcohol and drug dependence, possibly due to alterations in endogenous opioid transmission or the kappa-opioid receptor antagonist actions of naltrexone.

One Health: competing perspectives in an emerging field.

Over the last decade, One Health has attracted considerable attention from researchers and policymakers. The concept argues that the fields of human, animal and environmental health ought to be more closely integrated. Amid a flurry of conferences, projects and publications, there has been substantial debate over what exactly One Health is and should be. This review summarizes the main trends in this emerging discussion, highlighting the fault lines between different perspectives on One Health. Some have shown that One Health's call to synthesize knowledge from different disciplines can lead to better interventions. Others, however, argue that One Health's challenge to existing practice must go further, and set out a vision that foregrounds the social and economic drivers of disease. Meanwhile, recent examples of One Health in practice highlight the potential but also the challenges of institutionalizing cooperation. We also discuss the promise and pitfalls of using complexity theory to tackle multifaceted problems, and consider how the One Health concept has been brought to bear on other issues, such as emerging new technologies. Ultimately, One Health is an important and worthwhile goal, and requires a debate that clarifies both the competing uses and the political nature of the project.

Blastic plasmacytoid dendritic cell neoplasm in an elderly woman.

Blastic plasmacytoid dendritic cell neoplasm (a.k.a. NK cell lymphoma, CD4+CD56+ haematodermic neoplasm) is a rare aggressive tumour that arises from plasmacytoid dendritic cell precursors. We report the first case from Malaysia of a 79-year-old Chinese woman who presented with purpuric plaques and nodules produced by pleomorphic CD4+, CD56+, CD68+, CD123+ and CD303+, but CD2APmononuclear cell infiltrates. Leukemic dissemination occurred and she succumbed to disease without treatment 4 weeks after diagnosis and 9 months after onset of cutaneous disease.

Regulating private health insurance: The reality behind the rhetoric in Uganda.

The continued preponderance of large health budget deficits in low-income countries has led to increasing international debate over the role that private health insurance could play in providing additional financing for health. However, the market failures inherent to insurance constitute a major concern and proponents are now advocating that states employ calculated regulations to offset these tendencies. This article uses an examination of the policy evolution of the Government of Uganda to demonstrate how one low-income country has heeded the call for regulation yet, so far, has remained unable to implement the resulting policies. In doing so, the case study exposes the contradiction underlying the impetus for the state to regulate private health insurance in low-income settings, namely, that while private health insurance is advanced as one response to the failure of the nation state and its inability to provide adequate health services for its population, the same 'failing' state is now being called upon to govern against the market failures inherent to the product.

Multiple sclerosis susceptibility alleles in African Americans.

Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American data set. EVI5 showed the strongest association outside the major histocompatibility complex (rs10735781, OR=1.233, 95% CI=1.06-1.43, P-value=0.006). In addition, RGS1 seems to affect age of onset whereas TNFRSF1A seems to be associated with disease progression. None of the tested variants showed results that were statistically inconsistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry.

Quantifying the effects of forestry practices on the recovery of upland streams and lochs from acidification.

Trends in long-term chemistry data are presented for 37 acidified upland streams and lochs, located in four areas (A, B, C and D) across Scotland, to provide a comparison between recovery rates of moorland catchments and forest catchments at different stages of the management cycle. For all sites, non-marine sulfate (nm-SO(4)) showed a significant decline in annual median concentrations, the greatest decline being in streams draining felled catchments, which showed a 50% greater decline than catchments with moorland or young, aggrading forests. A similar pattern was found for chloride (Cl) concentrations in Area C, which reflected the reduced interception of sea-salt aerosols following clearfelling. However, high elevation moorland sites in Area D also revealed significant declines in Cl while trends in aggrading forest sites in this area were insignificant. Alkalinity (ALK) and pH increased more at sites where felling had taken place than at moorland or young forest sites while aggrading forest catchments appeared to be most resistant to changes in pH and ALK. Associated with these acid-base changes was a corresponding decline in labile aluminium (Al-L) concentrations. The pattern of nitrate (NO(3)) change was especially affected by the timing of felling in forested catchments. Large negative trends in NO(3) at stream sites were associated with felling during the early part of the study period. This downward trend was further enhanced as NO(3) concentrations fell below pre-felling levels as the second rotation crop became established. Few forest sites showed significant increases in NO(3) due to felling in the latter part of the study period. Most moorland loch sites showed a small but significant increase in NO(3,) probably in response to similar increases in N deposition and/or climatic impacts. Dissolved organic carbon (DOC) increased significantly at both forest and moorland sites, however, the extent of these increasing trends appeared to be positively correlated with absolute DOC concentrations. Despite the complex response of streams and lochs during the various stages of the forest cycle, especially for NO(3), both forest and moorland catchments showed generally similar and rapid responses to reductions in S deposition. Nevertheless, forested sites are still more acid and have higher concentrations of toxic forms of Al than moorland sites. Although the proposed emission reductions in Europe are likely to result in a continuing decline in S and N loadings to catchments, the continuing policy of planting second rotation forests in these acidified catchments may, in the long-term, delay or halt chemical and biological recovery. However, in the short-term, any increase in the uptake of N deposition by aggrading forests should help to counteract the acidifying effects of a small increase in the interception of S and N compounds.

Long-term trends in pH, aluminium and dissolved organic carbon in Scottish fresh waters; implications for brown trout (Salmo trutta) survival.

Over the past 30 years upland streams and lochs in Scotland have shown significant signs of recovery from acidification, particularly in terms of declining concentrations of non-marine sulphate (nm-SO(4)). Long-term index sites in central and southwest Scotland reveal a significant decline in the concentration of biologically important components, notably acidity (H(+)) and labile (toxic) forms of aluminium (Al-L), whilst dissolved organic carbon (DOC) and complexed forms of aluminium (AL-NL) have increased significantly. Although these improvements should increase the probability of brown trout survival, and have resulted in increased acid neutralising capacity (ANC) in fishless streams to values close to current critical limits, there is still a relatively poor correlation between ANC and current fish status. Site to site variability appears to be linked to the relative contribution of (H(+)), Al-L and DOC within the critical ANC (ANC(CRIT)) range. It is proposed that ANC(CRIT) should cover a range of ANC values as a function of Al-L concentration. Based on field studies an empirical range of critical ANC values are suggested which better predict the presence of a sustainable brown trout population.

Is postnatal depression a risk factor for sudden infant death?

BACKGROUND: In New Zealand, an association has been shown between postnatal depression and sudden infant death syndrome (SIDS). AIM: To replicate the New Zealand study. DESIGN OF STUDY: Case-control study. SETTING: The city of Sheffield, UK. METHOD: The database of the Sheffield Child Development Study was used Demographic and obstetric data were collected and at one month postpartum the Edinburgh Postnatal Depression Scale (EPDS) was administered. Detailed information on the cause of all infant deaths was available. RESULTS: There were 32,984 live births during the study period (from the year 1988 to 1993) and 42 babies died with the cause registered as SIDS. Multivariate analysis showed that smoking was the most important risk factorfor SIDS (odds ratio [OR] = 7.24, 95% confidence interval [95% CI] = 2.76 to 19.01), followed by a high EPDS (OR = 3.20, 95% CI = 1.46 to 6.99) and residence in an area of poverty (OR = 2.33, 95% CI = 1.06 to 5.11). CONCLUSIONS: The Sheffield data confirm the New Zealand findings. A high EPDS score and, by implication, postnatal depression, may be risk factors for SIDS, however, there are many possible explanations for the association.

Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene.

The xeroderma pigmentosum group D (XPD) protein is a subunit of transcription factor TFIIH with DNA helicase activity. TFIIH has two functions, in basal transcription and nucleotide excision repair. Mutations in XPD that affect DNA repair but not transcription result in the skin cancer-prone disorder, xeroderma pigmentosum (XP). If transcription is also affected, the result is the multi-system disorder trichothiodystrophy (TTD), in which there is no skin cancer predisposition, or in rare cases, XP combined with Cockayne syndrome. Up till now there have been no reports of combined clinical features of XP and TTD. We have now identified two patients with some features of both these disorders. One of these, XP189MA, a 3-year-old girl with sun sensitivity, mental and physical developmental delay, has XPD mutations not previously reported, and barely detectable levels of nucleotide excision repair. The other, XP38BR, a 28-year-old woman with sun sensitivity, pigmentation changes and skin cancers typical of XP, has a mutation that has been identified previously, but only in TTD patients with no features of XP. The level of repair of UV damage in XP38BR is substantially higher than that in other patients with the same mutation. With both patients, polarized light microscopy revealed a 'tiger-tail' appearance of the hair, and amino acid analysis of the hair shafts show levels of sulfur-containing proteins intermediate between those of normal and TTD individuals. Our findings highlight the complexities of genotype-phenotype relationships in the XPD gene.

Characterization of a novel human SMC heterodimer homologous to the Schizosaccharomyces pombe Rad18/Spr18 complex.

The structural maintenance of chromosomes (SMC) protein encoded by the fission yeast rad18 gene is involved in several DNA repair processes and has an essential function in DNA replication and mitotic control. It has a heterodimeric partner SMC protein, Spr18, with which it forms the core of a multiprotein complex. We have now isolated the human orthologues of rad18 and spr18 and designated them hSMC6 and hSMC5. Both proteins are about 1100 amino acids in length and are 27-28% identical to their fission yeast orthologues, with much greater identity within their N- and C-terminal globular domains. The hSMC6 and hSMC5 proteins interact to form a tight complex analogous to the yeast Rad18/Spr18 heterodimer. In proliferating human cells the proteins are bound to both chromatin and the nucleoskeleton. In addition, we have detected a phosphorylated form of hSMC6 that localizes to interchromatin granule clusters. Both the total level of hSMC6 and its phosphorylated form remain constant through the cell cycle. Both hSMC5 and hSMC6 proteins are expressed at extremely high levels in the testis and associate with the sex chromosomes in the late stages of meiotic prophase, suggesting a possible role for these proteins in meiosis.

Retro-inverso prosaptide peptides retain bioactivity, are stable In vivo, and are blood-brain barrier permeable.

Prosaptide (trademark of Myelos Corporation, San Diego, CA) peptides are based on the 14-amino-acid neurotrophic sequence of human prosaposin and, like the parent protein, have potent neurotrophic and neuroprotective properties. We previously examined the in vivo stability of a series of bioactive Prosaptide peptides and designed peptides with increased enzymatic stability in the central and peripheral nervous systems. In this article, we examined the stability, biological activity, and permeability of the blood-brain barrier to retro-inverso Prosaptide peptidomimetics. Retro-inversion both reverses the primary sequence and replaces L-amino acids with D-amino acids. We examined the bioactivity of five peptidomimetics, Prosaptides D1-D5. Prosaptide D1, a peptide containing all D-amino acids with the primary sequence intact, was inactive. However, four retro-inverso peptidomimetics, Prosaptides D2-D5 retained bioactivity in neurite outgrowth and [(35)S]GTPgammaS binding assays. We focused on Prosaptide D4 as a prototypical retro-inverso Prosaptide peptidomimetic for further study. (125)I-Prosaptide D4 remained intact in brain or serum for 60 min after i.v. administration and was transported across the blood-brain barrier with a unidirectional influx constant of 2.5 x 10(-4) ml. g(-1). min(-1). We conclude that retro-inverso Prosaptide peptidomimetics are excellent candidates for development as therapeutics for central nervous system neurodegeneration.

AIT-082, a cognitive enhancer, is transported into brain by a nonsaturable influx mechanism and out of brain by a saturable efflux mechanism.

A fundamental feature of any drug designed to treat a disease of the central nervous system is the ability to cross the blood-brain barrier. Passage across the blood-brain barrier of AIT-082, a cognitive enhancer, was investigated in mice. [(14)C]AIT-082 crossed the blood-brain barrier in young male Swiss-Webster mice with a mean influx constant (K(i)) of 0.6 +/- 0.2 microl g(-1) min(-1). Furthermore, [(14)C]AIT-082 was transported into brain of both young and old male C57BL/6 mice with a K(i) of 0.35 +/- 0.06 and 0.33 +/- 0.02 microl g(-1) min(-1), respectively. There was no significant effect of age or strain on the movement of [(14)C]AIT-082 across the blood-brain barrier in mice. When 110- or 650-fold excess unlabeled AIT-082 was included in the injection solution, the K(i) was not significantly changed in either Swiss-Webster or C57BL/6 mice. This indicated that [(14)C]AIT-082 crossed the blood-brain barrier by a nonsaturable mechanism. The passage of AIT-082 into brain extracellular fluid was confirmed with capillary depletion and microdialysis. The efflux of [(14)C]AIT-082 from brain also was examined. After i.c.v. injection, [(14)C]AIT-082 levels in brain decreased over time with a t(1/2) of 20.0 +/- 1.0 min. Excess unlabeled AIT-082 (600-fold) increased the t(1/2) to 35.5 +/- 3.6 min. Together, these data indicate that AIT-082 moves into brain via a nonsaturable mechanism and is actively transported out of brain.

Designing stable blood-brain barrier-permeable prosaptide peptides for treatment of central nervous system neurodegeneration.

Prosaposin-derived peptides have been proposed as potential therapeutics for neurodegenerative diseases. Previously, we reported that the minimal length for bioactivity was 12 amino acids, and key amino acids were described based on interspecies conservation. In this article, we have further investigated the sequence requirements for bioactive Prosaptide (Myelos Corporation) peptides in terms of length and amino acid identity. The use of Prosaptide peptides for treatment of central nervous system (CNS) disorders requires that they are stable in vivo. Although robust effects of our prototypical peptide Prosaptide TX14(A) have been shown in the peripheral nervous system, minimal success has been achieved when treating the CNS in rats and this may be due to instability of Prosaptide TX14(A) in brain. Herein, we demonstrate that, indeed, Prosaptide TX14(A) is rapidly degraded in the brain and we have attempted to design prosaptides with increased CNS stability. One peptide, Prosaptide TX15-2, shows increased stability in brain and may be of use in the treatment of CNS disorders. With the aim of designing Prosaptide peptides that may be systemically administered for CNS treatment, we have investigated the blood-brain barrier permeability of Prosaptide TX14(A) and TX15-2. Both of these peptides cross the blood-brain barrier via a nonspecific mechanism.

The cancer-free phenotype in trichothiodystrophy is unrelated to its repair defect.

The DNA repair-deficient genetic disorders xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) can both result from mutations in the XPD gene, the sites of the mutations differing between the two disorders. The hallmarks of XP are multiple pigmentation changes in the skin and a greatly elevated frequency of skin cancers, characteristics that are not seen in TTD. XP-D and most TTD patients have reduced levels of DNA repair, but some recent reports have suggested that the repair deficiencies in TTD cells are milder than in XP-D cells. We reported recently that inhibition of intracellular adhesion molecule-1 (ICAM-1) expression by UVB irradiation was similar in normal and TTD cells but increased in XP-D cells, suggesting a correlation between ICAM-1 inhibition and cancer proneness. In the first part of the current work, we have extended these studies and found several other examples, including XP-G and Cockayne syndrome cells, in which increased ICAM-1 inhibition correlated with cancer proneness. However, we also discovered that a subset of TTD cells, in which arg112 in the NH2-terminal region of the XPD protein is mutated to histidine, had an ICAM-1 response similar to that of XP-D cells. In the second part of the work, we have shown that TTD cells with this specific NH2-terminal mutation are more sensitive to UV irradiation than other TTDs, most of which are mutated in the COOH-terminal region, and are indistinguishable from XP-D cells in cell killing, incision breaks, and repair of cyclobutane pyrimidine dimers. Because the clinical phenotypes of these patients do not obviously differ from those of TTDs with mutations at other sites, we conclude that the lack of skin abnormalities in TTD is independent of the defective cellular responses to UV. It is likely to result from a transcriptional defect, which prevents the skin abnormalities from being expressed.

Abnormally high nourishment during sensitive periods results in body weight changes across generations.

OBJECTIVE: This study asked whether a brief period of overnutrition during a developmentally sensitive time could impact the individual's adult weight and that of succeeding generations. RESEARCH METHODS AND PROCEDURES: Female rat pups (F1 generation) were randomly assigned to 1 of 3 groups: (1) a control group that was naturally reared by mothers; (2) another control group implanted with chronic gastric fistulas on postnatal day 4 and fed enough formula to match the growth of the mother-reared group; and (3) an experimental group gastrostomized and infused from day 8 through day 16 with a greater quantity of food than gastrostomy-reared controls (OF). On postnatal day 16, both gastrostomy-reared groups were returned to normal litters. Adult F1 females from overfed and mother-reared groups were bred with normal males to yield an F2 generation. F2 adult females were bred to normal males to produce an F3 generation. RESULTS: When adult, the F1 experimental group was heavier than control groups. F2 adults from OF mothers were smaller than those from the control group. F3 animals from OF grandmothers were heavier at weaning than F3 descendants from mother-reared animals. DISCUSSION: Excess nourishment during a developmentally sensitive period changed the metabolic phenotype of one generation so dramatically that the gestational development and subsequent phenotype of two succeeding generations were also changed. The experiment models fetal effects of gestational diabetes in humans and may help to elucidate how, independent of genetic anomalies, secular changes can be detected across generations.

Conservation of eukaryotic DNA repair mechanisms.

PURPOSE: To discuss the evolutionary conservation of different DNA repair processes. The proteins that carry out base excision repair show a varying degree of structural conservation, but a high level of functional complementation between species, as might be expected for a sequential pathway. In nucleotide excision repair there is a high degree of structural conservation, but few examples of functional complementation because the process involves multiprotein complexes. Repair by homologous recombination involves proteins that are highly conserved structurally. The process of repair of DNA breaks by non-homologous end-joining is conserved in eukaryotes, but the level of sequence identity of several of the proteins is fairly low and some components involved in man do not appear to have sequence homologues in yeast. CONCLUSIONS: All DNA repair processes are highly conserved. The degree of structural and functional conservation varies between the different processes.

1st MRC Human Genetics Symposium: maintenance of genomic stability.

This meeting served to juxtapose the fundamental studies on the distinct pathways which maintain genomic stability with work that addresses the phenotypic consequences of loss of genomic stability in humans. This created an exciting environment where we were prompted to think about the links between fundamental and applied research. It was also a forum where new ideas could be formed that will hopefully fuel interesting research in human disease. As we place the genome projects into perspective, the ideas arising from meetings such as the 1st MRC Human Genetics Symposium might be expected to guide studies that will reveal the molecular defects which underlie some of the more impenetrable phenotypes of human diseases.

Do our patients understand? A comparison of understanding in adult inpatients and schoolchildren.

AIM: To test the assumption that if an explanation about a resuscitation policy is understood by a 12-year-old then it will be understood by an adult patient. METHOD: The comprehension of a paragraph about resuscitation by inpatients was compared to the comprehension of the same paragraph by 12-year-old schoolchildren. RESULTS: The schoolchildren demonstrated better comprehension of a paragraph about resuscitation than the inpatients (p = 0.02). CONCLUSIONS: Schoolchildren, aged 12, in a classroom setting show better comprehension than adult medical and surgical inpatients. This has implications about giving information to patients and seeking consent from them. Persons giving information to patients need to ensure the patients have understood it.