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PubMed1986

Leao's spreading depression in the hippocampus explains transient global amnesia. A hypothesis.

Transient global amnesia has been explained by epileptic mechanisms or transient ischemic attacks affecting the hippocampus. None of these two mechanisms appear likely. The animal experimental phenomenon entitled spreading depression of cortical electrical activity (SD) or spreading depression of Leao has been implicated in migraine pathogenesis and may be relevant to transient global amnesia. In experimental animals, SD in the hippocampus causes a temporary functional ablation lasting minutes to hours with full functional recovery. Glutamate, which is present in large amounts in the hippocampus, may experimentally elicit spreading depression, and strong emotional events may possibly liberate glutamate and bring about this reaction in human patients.

Amnesia↗

PubMed1994

Increasing melanoma incidence: putatively explainable by retrotransposons. Experimental contributions of the xiphophorine Gordon-Kosswig melanoma system.

The worldwide accelerating increase of neoplasia in humans is difficult to explain. We use the Xiphophorus tumor model to approach this problem by melanoma provocation with X-rays. Melanoma develops following inappropriate expression of x-erb B-conducted developmental genes and their controllers. These oncodeterminants are inherited according to Mendelian rules. We detected a new type of oncodeterminants that, following a single treatment of embryos with X-rays, generates a self-generating non-Mendelian melanoma transmission and accelerating increase of its incidence in succeeding generations (e.g., 0-->18-->33-->52%). To localize these oncodeterminants, we crossed nonirradiated fish having half of their chromosomes irradiated with nonirradiated fish having none of, half of, or all of their chromosomes irradiated. Because tumor rate and expression in the following generations correspond to the rates of treated chromosomes, we conclude that the new oncodeterminants are distributed over the chromosomes of the fish, where they may increase in the changing generations. By means of xiphophorine-specific retroviral DNA, we isolated two retrotransposons that behave hereditarily like the new transgenerational oncodeterminants. Sequence analysis revealed three ORFs flanked by LTRs containing motives of regulatory sequences typical for known retroviral and retrotransposal LTRs. Pol- and env-resembling sequences are lacking. Southern and in situ hybridization showed their multiple and repetitive nature distributed throughout the chromosomes and indications for their capability to increase in number without further treatment. Their transcripts are expressed in concert with those of most of the other known xiphophorine tumor determinants. Their expression is extremely high in cell cultures from tumorous embryos derived from ancestors treated as embryos with X-rays.

Animals↗

PubMed2006

Explaining differences between hospitals in number of organ donors.

The shortage of donor organs calls for a careful examination of all improvement options. In this study, 80 Dutch hospitals were compared. They provided 868 donors in a 5-year period, constituting 91% of all donors in that period in The Netherlands. Multilevel regression analysis was used to explain the differences between hospitals. Potential explanatory variables were hospital-specific mortality statistics, donor policy and structural hospital characteristics. Of all donors, 81% came from one quarter of the hospitals, mainly larger hospitals. A strong relationship was found between the number of donors and hospital-specific mortality statistics. Hospitals with a neurosurgery department had additional donors. Seven hospitals systematically underperformed over a period of 5 years. If these hospitals were to increase their donor efficiency to their expected value, it would lead to an increase of 10% in the number of donors. Most donors are found in large hospitals, implying that resources to improve donor-recruitment should be channelled to larger hospitals. This study presents an efficient strategy toward a benchmark for hospitals of their organ donation rates. Some larger hospitals performed less well than others. This suggests that there is still room for improvement. There is no evidence for large undiscovered and unused pools of donor organs.

Hospitals↗

PubMed2006

Paradoxical effects of learning the Morris water maze on adult hippocampal neurogenesis in mice may be explained by a combination of stress and physical activity.

Studies in rats that assessed the relation of hippocampus-dependent learning and adult hippocampal neurogenesis suggested a direct regulatory effect of learning on neurogenesis, whereas a similar study in mice had not found such causal link. We here report a substantial decrease of BrdU-positive cells and other measures of adult hippocampal neurogenesis in mice trained in the hidden (HID) or cued version (VIS) of the Morris water maze as compared to untrained animals (CTR). Particularly, cells on advanced stages of neuronal development contributed to this decrease, whereas earlier progenitors (type 2 cells) were not diminished in HID, but were diminished in VIS as compared to CTR. The differential regulation of type 2 cells in HID and VIS may have been caused by a different degree of physical activity, given that a time-yoked control group did not differ from HID, and type 2 cells reportedly constitute the proliferative dentate gyrus population that primarily responds to physical activity. The decrease of hippocampal neurogenesis by water maze training was reversible by pre-exposing animals to the water maze prior to training, suggesting that stress associated with training may have caused the acute downregulation of adult neurogenesis. We propose that in mice the Morris water maze does not provide a pure enough learning stimulus to study the presumed effects of 'learning' on adult neurogenesis. In addition, however, our data show that physical activity that is intricately linked to many cognitive tasks in rodents might play an important role in explaining effects of learning on cellular hippocampal plasticity.

Animals↗

PubMed2006

Weight monitoring of breastfed babies in the United Kingdom--interpreting, explaining and intervening.

Weighing infants in their first 6 months is an important aspect of growth monitoring and a common activity of child health care services worldwide. During the same 6 months, support for establishing breastfeeding and the promotion of continued exclusive breastfeeding are important activities of health professionals. Parents and health professionals may perceive conflicts between achieving both robust growth and continuing breastfeeding. In this narrative review, the literature on weighing breastfed babies in the United Kingdom is examined. A companion paper examined issues of growth charts, scales and weighing frequency and accuracy. This paper considers issues of interpretation of the plotted weight values for individual breastfed babies, noting the complexities of growth patterns, which may lead to difficulties of accurate identification of those individuals whose growth merits further investigation. Little attention has been given to issues of explaining the interpreted growth curves to parents and this issue is explored and noted as of importance for further study. Research evidence on choosing appropriate interventions to improve the growth of breastfed babies is reviewed. The paucity of such evidence leads to suggestions for future study. This review gathers together a wide range of literature from many different perspectives, with the hope of informing weight monitoring practice so that this can both identify infants whose weight may be of concern, and who may need appropriate intervention, and support continued breastfeeding.

Body Weight↗

PubMedDate not supplied

Explaining the thinness of the fresh water lens in the Pleistocene carbonate aquifer on Andros Island, Bahamas.

Two hypotheses are explored to explain the thinness of the fresh water lens on Andros Island, Bahamas. The lens is an order of magnitude thinner than predicted by the Ghyben-Herzberg theory. One hypothesis previously posed in the literature is that the base of the lens is governed by the contact between the Lucayan Formation and the pre-Lucayan limestones. An alternate hypothesis, posed here, is that thinning is caused by the hydraulic influence of low-permeability paleosols in the Lucayan Formation. These hypotheses were explored, along with the influence of recharge and other factors, using a numerical model for variable-density flow and salt transport. In the layered system of grainstones/packstones and paleosols within the Lucayan Formation itself, the velocity vectors are nearly horizontal in the grainstones/packstones, and they are nearly vertical in the paleosols. These strata above the pre-Lucayan, all lower than it in permeability, draw the base of the lens upward to a position well above the contact by significantly reducing pressure within and below the strata relative to hydrostatic pressure. It is the loss of pressure across the paleosols that dramatically thins the fresh water lens, and thus the predominant hydraulic control on lens thickness arises from the existence of paleosols.

Bahamas↗

PubMed1986

Gene conversion. A mechanism to explain HLA-D region and disease association.

In speculating about mechanisms that might give rise to T-cell epitopes appearing within different HLA-DR frameworks, we return to the hypothesis expressed above that suggests that gene-conversion-like events might be involved in shuffling the hypervariable segments of HLA-D region exons into alternative HLA-D region frameworks where they will still be recognized by the T cell (but not typed by conventional serology or mixed lymphocyte typing) as the "disease associated" HLA product. This might well explain the lack of stringent association between rheumatoid arthritis and HLA-DR4. It is possible, through the use of such alloreactive T-cell clones, that we might eventually define subgroups based upon presumed genetic susceptibility markers, which might allow therapeutic or prognostic assignment of patients with seropositive rheumatoid arthritis.

Arthritis, Rheumatoid↗

PubMed1999

Excess retinol intake may explain the high incidence of osteoporosis in northern Europe.

An epidemiologic study of postmenopausal women in Sweden revealed that a chronic excess of retinol intake (> 1.5 mg/day) decreased bone mineral density and increased hip fracture risk. These data provide one explanation for the higher incidence of osteoporosis in Sweden and Norway compared with other European countries. Retinol in fortified milk could explain also the association of high calcium intake and hip fracture incidence in northern Europe because milk is an important source of both nutrients.

Bone Density↗

PubMed1991

Does the occupational structure of the Hunter Region explain the high rates of ischaemic heart disease among its men?

To compare rates of ischaemic heart disease (IHD) among men in occupation groups defined by the new Australian Standard Classification of Occupations (ASCO) and to investigate whether their high mortality rates from IHD in the Hunter Region of New South Wales (NSW) could be explained by its occupational structure, we used official death records and data from the World Health Organization MONICA Project conducted in Newcastle. The study population consisted of men aged 25 to 64 years in NSW and in the Hunter Region for whom occupational information was available. For deaths from IHD between 1984 and 1988 in NSW, indirectly standardised mortality and morbidity ratios (SMRs) were: significantly low for professionals, 66 (95% confidence interval (CI) 60-71) and managers and administrators, 79 (95% CI 74-83); intermediate for paraprofessionals (92), clerks (94) and salesmen and personal service workers (97); and significantly high for tradesmen, 113 (95% CI 107-118), labourers and related workers, 118 (95% CI 113-124) and plant and machine operators and drivers, 125 (95% CI 118-133). Broadly similar patterns were found for IHD deaths and for fatal and nonfatal myocardial infarction in the Hunter Region. When occupation- and age-specific mortality rates from IHD were used to calculate SMRs for the Hunter Region, SMRs for all ASCO groups except paraprofessionals were over 100. Mortality rates for occupational groups classified by ASCO were consistent with well-established differences associated with socioeconomic status.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2005

Epigenetic influences may explain dental differences in monozygotic twin pairs.

BACKGROUND: Comparisons between monozygotic (MZ) co-twins have tended to focus on the similarities between their dentitions rather than differences. The aim of this study was to determine the prevalence of discordant expression for simple hypodontia and supernumerary teeth in MZ twin pairs and to explain how phenotypic differences might occur despite their similar genotypes. METHODS: Records of 278 pairs of MZ twins, including dental casts and radiographs, were examined and the prevalences of discordant expression for missing upper lateral incisors (ULI) or second premolars (PM2), and of mesiodentes, were determined. Zygosities were confirmed by comparisons of blood markers and DNA. RESULTS: There was evidence of at least one missing ULI or PM2 in 24 of the 278 MZ pairs (8.6 per cent), with 21 of these 24 pairs (87.5 per cent) showing discordant expression. Nine of the 278 MZ pairs (3.2 per cent) displayed evidence of mesiodentes, with eight of these nine pairs (88.9 per cent) being discordant. CONCLUSION: Our findings show that differences in the expression of missing or extra teeth occur often between MZ co-twins whose genetic make-up predisposes them to simple hypodontia or mesiodentes. We postulate that minor variations in epigenetic events during odontogenesis may account for these distinct differences.

Adolescent↗

PubMed1986

Can the effects of meptazinol on the guinea-pig isolated ileum be explained by inhibition of acetylcholinesterase?

It has previously been shown that there is a cholinergic component in the antinociceptive action of the opioid analgesic drug meptazinol. In the present study meptazinol was shown to be an inhibitor of acetylcholinesterase in-vitro with a potency one hundredth that of physostigmine. This activity was found to reside only in the (-)-enantiomer of meptazinol. The anticholinesterase activity of meptazinol may explain the increase in the size of the electrically-evoked contraction of the guinea-pig isolated ileum preparation since by using a long pulse width (5 ms) it was found that the (-)-enantiomer of meptazinol modified only the component of the response due to neuronally released acetylcholine and had no direct effect on the smooth muscle. This property of meptazinol may also be responsible for the cholinergic effects of the drug in-vivo.

Animals↗

PubMed1993

Healthy children's understanding of their blood: implications for explaining leukaemia to children.

Explanations of leukaemia to children usually include details of blood function and structure. In study 1, 3-year-olds (N = 25), 4-year-olds (N = 25), and 8-year-olds (N = 27) were interviewed about their understanding of the properties of blood and any occasions when they remembered seeing blood. They were also asked whether other animals and objects had blood or not, and to give reasons for this. Children justified their decisions in three ways: only people have blood, they had seen blood on a particular occasion, or only creatures which shared a human property (walking or talking) could have blood. In study 2, an intervention to increase children's understanding of the function of different blood cells is reported. It was partially successful. Children who reported an incident in which they saw blood were more likely to recall information about the function of red cells, white cells and platelets compared with children who did not report a previous experience (p < .001). In terms of explaining leukaemia to a child, we conclude that explanations should build on previous experience, and not be based simply on chronological age.

Blood↗

PubMed1993

Neither changes in phosphorus metabolite levels nor myosin isoforms can explain the weakness in aged mouse muscle.

1. The contractile force, phosphorus metabolite levels, intracellular pH and myosin isoforms were compared in isolated soleus and extensor digitorum longus (EDL) muscles from young (6 month old) and aged (28 month old) mice, at 23 degrees C. 2. The isometric force per unit cross-sectional area was significantly lower by 21 +/- 5% in soleus muscles from aged mice compared to those from young mice (mean +/- S.E.M., n = 11 and 9 respectively). 3. The EDL muscle contained twice as much total creatine and phosphocreatine as the soleus, 1.7 times as much ATP, and 0.4 times the inorganic phosphate (Pi) per unit weight. The intracellular pH and free ADP levels were not significantly different between these muscle types. 4. There was no significant difference in resting metabolite levels between young and old EDL or soleus despite the difference in mechanical strength. 5. Examination of the expression of myosin isoforms by non-denaturing gel electrophoresis has shown that the percentage of each isoform does not change with respect to age; thus, if there is an atrophic process occurring, it is not fibre type specific. 6. We have determined that neither the Pi levels nor the intracellular pH can explain the differences seen in muscle strength with age. There is also no correlation between muscle weakness and any of the other metabolites responsible for energy transduction (phosphocreatine, ATP or ADP).

Adenosine Diphosphate↗

PubMed1979

Can intrinsic vowel Fo be explained by source/tract coupling?

There is extensive evidence that in the same phonetic environment the voice fundamental frequency (Fo) of vowels varies directly with vowel "height." This Fo difference between vowels could be caused by acoustic interaction between the first vowel formant and the vibrating vocal folds. Since higher vowels have lower first formants than low vowels the acoustic interaction should be greatest for high vowels whose first formant frequencies are closer in frequency to Fo. Ten speakers were used to see if acoustic interaction could cause the Fo differences. The consonant [m] was recorded in the utterances [umu] and [ama]. Although the formant structure of [m] in [umu] and [ama] should not differ significantly, the Fo of each [m] allophone was significantly different. However, the Fo of each [m] allophone did not differ significantly from the Fo of the following vowel. These results did not support acoustic interaction. However, it is quite reasonable to conclude that the Fo variation of [m] was caused by coarticulatory anticipation of the tongue and jaw for the following vowel. Another experiment is offered in order to help explain the physical causes of intrinsic vowel Fo. In this experiment Fo lowering was found at the beginning of vowels following Arabic pharyngeal approximants. This finding indicates that the Fo of pharyngeal constricting vowels, e.g., [ae] and [a], might be lowered as a result of similar articulary movements, viz. tongue compression and active pharyngeal constriction.

Female↗

PubMed2006

Induction of glutathione synthesis explains pharmacodynamics of high-dose busulfan in mice and highlights putative mechanisms of drug interaction.

Busulfan is an example of a drug eliminated through glutathione S-transferase (GST)-catalyzed conjugation with reduced glutathione (GSH). We studied the pharmacokinetics and toxicity of busulfan in C57BL6 mice in correlation with liver GST activity and GSH synthesis by accurate determination of precursors, namely, gamma-glutamyl-cysteine and cysteine. A significantly lower incidence of acute toxicity was observed in mice receiving busulfan 16.5 mg/kg twice a day compared with animals receiving 33 mg/kg once a day. In both cases, a total dose of 132 mg/kg was administered over 4 days. The difference in toxicity was explained by pharmacokinetics since a strong induction of clearance was observed only in animals treated twice daily. Induction of metabolism was correlated with an increase in liver cysteine content and enhanced glutathione synthesis rate, whereas GST activity was unchanged. To our knowledge, this is the first time that in vivo flux of GSH synthesis has been shown to be closely related to a drug plasma clearance and toxicity. These results allow hypothesizing that GSH liver synthesis may directly influence busulfan clearance in humans with possible implications in the occurrence of hepatic veno-occlusive disease.

Animals↗

PubMed2002

The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: a pharmacological analysis in rats.

All atypical antipsychotics avoid extrapyramidal side-effects yet differ in their propensity to cause other side-effects, like prolactin elevation. We proposed that the atypical antipsychotics with a propensity for prolactin elevation would show a higher pituitary versus striatal D2 receptor occupancy. To investigate this hypothesis, we tested four atypical antipsychotics, two that are commonly associated with prolactin elevation (amisulpride and risperidone) and two that are less frequently associated (quetiapine and olanzapine). In particular, we calculated their ED(50) values to increase plasma prolactin and block peripheral pituitary D2 receptors to their ED(50) values to antagonize apomorphine-induced stereotypy and occupy central striatal D2 receptors. All antipsychotics dose dependently increased prolactin levels and antagonized apomorphine-induced stereotypy. However, the central to peripheral potency (ED(50) for apomorphine antagonism to ED(50) for prolactin elevation) differed remarkably across these drugs: amisulpride (21764), risperidone (14), quetiapine (10), and olanzapine (1.7). Compounds displaying a higher peripheral potency brought about higher prolactin levels for a given level of functional central antagonism. This dissociation between central and peripheral effects was explained by the differential occupancy of D2 receptors in the striatum versus in the pituitary [ratio of striatal/pituitary ED(50) values (milligram per kilogram) for D2 occupancy): amisulpride (17/0.026 = 654), risperidone (0.89/0.081 = 14), quetiapine (24/4.1 = 6), olanzapine (0.30/0.43 = 0.7). These results indicate that dissociation between central and peripheral D2 receptor occupancy is a major determinant of the degree of prolactin elevation observed at therapeutic doses.

Animals↗

PubMed2003

Activation of peroxisome proliferator-activated receptor gamma does not explain the antiproliferative activity of the nonsteroidal anti-inflammatory drug indomethacin on human colorectal cancer cells.

The mechanism of the anticolorectal cancer activity of the nonsteroidal anti-inflammatory drug indomethacin is poorly understood. Indomethacin inhibits both cyclooxygenase (COX) isoforms, but it may also act via COX-independent targets. Indomethacin can bind and activate the transcription factor peroxisome proliferator-activated receptor (PPAR) gamma. Moreover, natural and synthetic PPARgamma ligands can induce growth arrest and apoptosis of human colorectal cancer cells in vitro. Therefore, we tested the hypothesis that the antiproliferative activity of indomethacin on human colorectal cancer cells in vitro is explained by a PPARgamma-dependent mechanism of action. Human colorectal cancer cell lines SW480 and HCT116 both expressed functional PPARgamma. Indomethacin directly activated PPARgamma in both cell lines (HCT116 > SW480). A dominant-negative PPARgamma strategy was used to demonstrate that endogenous PPARgamma represses proliferation of HCT116 cells (compatible with tumor suppressor activity) but that the presence of functional PPARgamma is not necessary for the antiproliferative activity (or reduction in cyclin D1 protein) associated with indomethacin in vitro. In summary, indomethacin (>100 microM) directly activates PPARgamma in human colorectal cancer cells. However, PPARgamma activation does not underlie the antineoplastic activity of indomethacin on human colorectal cancer cells in vitro.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2001

Explaining the Weddell Polynya--a large ocean eddy shed at Maud Rise.

Satellite observations have shown the occasional occurrence of a large opening in the sea-ice cover of the Weddell Sea, Antarctica, a phenomenon known as the Weddell Polynya. The transient appearance, position, size, and shape of the polynya is explained here by a mechanism by which modest variations in the large-scale oceanic flow past the Maud Rise seamount cause a horizontal cyclonic eddy to be shed from its northeast flank. The shed eddy transmits a divergent Ekman stress into the sea ice, leading to a crescent-shaped opening in the pack. Atmospheric thermodynamical interaction further enhances the opening by inducing oceanic convection. A sea-ice-ocean computer model simulation vividly demonstrates how this mechanism fully accounts for the characteristics that mark Weddell Polynya events.

Journal Article↗