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كتاب أكسفورد المختصر في الطب النفسي
هذا الكتاب غني عن التعريف فهو معروف على المستوى الدولي والعربي منذ صدور طبعته الأول وحتى الطبعة الحالية السابعة، والتي تحتوي على الطب النفسي بشكله المعاصر. كتاب أكسفورد المختصر في الطب النفسي معترف به بشكل واسع، هو كتاب أساسي للمتدربين في الطب النفسي، ويقف هذا الكتاب متميزا فوق التنافس. واكتسب زخما على مدى سبع طبعات، يتميز الكتاب بالسلاسة والسهولة، السلطة والبصيرة وهذه نادرا ما تجدها في الكتب المرجعية، مما يجعل عملية اكتساب المعلومات منة فعالة وممتعة. الكتاب يقدم استهلالا لكل المواضيع السريرية، والاختصاصات الفرعية، والاضطرابات النفسية الأساسية الكبيرة المطلوبة للأطباء المتدربين في الطب النفسي. طول صفحات الكتاب، يؤكد المؤلفون على المهارات السريرية الأساسية المطلوبة لاستكمال تقييم وفهم حالة المريض. مناقشة أشكال العلاج المتاحة تشمل بالإضافة إلى الدلائل العلمية المشاكل العملية في تدبير المرضى في إطار الأسرة والمجتمع. تم إعطاء الانتباه الكامل للجوانب الأخلاقية والقانونية من خلال المقاربة المستندة على الدليل للممارسة التي تقدم في هذا الكتاب. الكتاب يعطي ظهورا متساويا للتقسيم الدولي العاشر للأمراض، والتقسيم الأمريكي الخامس، وهذا يجعل الكتاب مفيدا للممارسين في كل أنحاء العالم، وهذا التوجه للعالمية تم تدعيمه بفصل عن الصحة النفسية العالمية. ولاستعراض الكتاب وفصوله فإنه يقع في ستة وعشرين فصلا، تغطي كافة جوانب الطب النفسي بداية بالأعراض والعلامات النفسية التي تساعد في التعرف على الاضطرابات المختلفة من شكوى المريض ومن يحيط به إلى المظاهر التي يراها الطبيب أثناء الفحص، إلى التصنيف بأشكاله وأنواعه مع التركيز على التصنيف الدولي العاشر والأمريكي الخامس، والتقييم للحالة الذي لا بد أن يقوم به من يقيم الحالة، فالأخلاقيات والقوانين المدنية ذات العلاقة.
Book
Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence
This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a ‘genetic cytoarchitecture’ would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications.
Journal Article
The neurobiology of D-amino acid oxidase and its involvement in schizophrenia
D
-amino acid oxidase (DAO) is a flavoenzyme that metabolizes certain
D
-amino acids, notably the endogenous
N
-methyl
D
-aspartate receptor (NMDAR) co-agonist,
D
-serine. As such, it has the potential to modulate the function of NMDAR and to contribute to the widely hypothesized involvement of NMDAR signalling in schizophrenia. Three lines of evidence now provide support for this possibility: DAO shows genetic associations with the disorder in several, although not all, studies; the expression and activity of DAO are increased in schizophrenia; and DAO inactivation in rodents produces behavioural and biochemical effects, suggestive of potential therapeutic benefits. However, several key issues remain unclear. These include the regional, cellular and subcellular localization of DAO, the physiological importance of DAO and its substrates other than
D
-serine, as well as the causes and consequences of elevated DAO in schizophrenia. Herein, we critically review the neurobiology of DAO, its involvement in schizophrenia, and the therapeutic value of DAO inhibition. This review also highlights issues that have a broader relevance beyond DAO itself: how should we weigh up convergent and cumulatively impressive, but individually inconclusive, pieces of evidence regarding the role that a given gene may have in the aetiology, pathophysiology and pharmacotherapy of schizophrenia?
Journal Article
What causes aberrant salience in schizophrenia? A role for impaired short-term habituation and the GRIA1 (GluA1) AMPA receptor subunit
The
GRIA1
locus, encoding the GluA1 (also known as GluRA or GluR1) AMPA glutamate receptor subunit, shows genome-wide association to schizophrenia. As well as extending the evidence that glutamatergic abnormalities have a key role in the disorder, this finding draws attention to the behavioural phenotype of
Gria1
knockout mice. These mice show deficits in short-term habituation. Importantly, under some conditions the attention being paid to a recently presented neutral stimulus can actually increase rather than decrease (sensitization). We propose that this mouse phenotype represents a cause of aberrant salience and, in turn, that aberrant salience (and the resulting positive symptoms) in schizophrenia may arise, at least in part, from a glutamatergic genetic predisposition and a deficit in short-term habituation. This proposal links an established risk gene with a psychological process central to psychosis and is supported by findings of comparable deficits in short-term habituation in mice lacking the NMDAR receptor subunit
Grin2a
(which also shows association to schizophrenia). As aberrant salience is primarily a dopaminergic phenomenon, the model supports the view that the dopaminergic abnormalities can be downstream of a glutamatergic aetiology. Finally, we suggest that, as illustrated here, the real value of genetically modified mice is not as ‘models of schizophrenia’ but as experimental tools that can link genomic discoveries with psychological processes and help elucidate the underlying neural mechanisms.
Journal Article
Dopaminergic modulation of regional cerebral blood flow: An arterial spin labelling study of genetic and pharmacological manipulation of COMT activity
•We examined whether groups that differ in the activity of catechol-O-methyltransferase (COMT), either genetically or as the result of a pharmacological challenge, show differences in regional cerebral blood flow (CBF).•COMT genotype influenced frontal CBF, whilst COMT inhibition altered CBF in parietal and temporal regions.•Our findings demonstrate that both acute and trait differences in dopamine signalling influence regional CBF.•We recommend the inclusion of CBF measures in fMRI studies of the impact of dopaminergic manipulations on BOLD signal.
Dopamine has direct and complex vasoactive effects on cerebral circulation. Catechol-O-methyltransferase (COMT) regulates cortical dopamine, and its activity can be influenced both genetically and pharmacologically. COMT activity influences the functional connectivity of the PFC at rest, as well as its activity during task performance, determined using blood oxygen level-dependent (BOLD) fMRI. However, its effects on cerebral perfusion have been relatively unexplored. Here, 76 healthy males, homozygous for the functional COMT Val158Met polymorphism, were administered either the COMT inhibitor tolcapone or placebo in a double-blind, randomised design. We then assessed regional cerebral blood flow at rest using pulsed arterial spin labelling. Perfusion was affected by both genotype and drug. COMT genotype affected frontal regions (Val158 > Met158), whilst tolcapone influenced parietal and temporal regions (placebo > tolcapone). There was no genotype by drug interaction. Our data demonstrate that lower COMT activity is associated with lower cerebral blood flow, although the regions affected differ between those affected by genotype compared with those altered by acute pharmacological inhibition. The results extend the evidence for dopaminergic modulation of cerebral blood flow. Our findings also highlight the importance of considering vascular effects in functional neuroimaging studies, and of exercising caution in ascribing group differences in BOLD signal solely to altered neuronal activity if information about regional perfusion is not available.
Journal Article
Geographical distribution of red and green Noctiluca scintillans
The dinoflagellate Noctiluca scintillans is one of the most important and abundant red tide organisms and it is distributed world-wide. It occurs in two forms. Red Noctiluca is heterotrophic and fills the role of one of the microzooplankton grazers in the foodweb. In contrast, green Noctiluca contains a photosynthetic symbiont Pedinomonas noctilucae (a prasinophyte), but it also feeds on other plankton when the food supply is abundant. In this review, we document the global distribution of these two forms and include the first maps of their global distribution. Red Noctiluca occurs widely in the temperate to sub-tropical coastal regions of the world. It occurs over a wide temperature range of about 10°C to 25°C and at higher salinities (generally not in estuaries). It is particularly abundant in high productivity areas such as upwelling or eutrophic areas where diatoms dominate since they are its preferred food source. Green Noctiluca is much more restricted to a temperature range of 25°C–30°C and mainly occurs in tropical waters of Southeast Asia, Bay of Bengal (east coast of India), in the eastern, western and northern Arabian Sea, the Red Sea, and recently it has become very abundant in the Gulf of Oman. Red and green Noctiluca do overlap in their distribution in the eastern, northern and western Arabian Sea with a seasonal shift from green Noctiluca in the cooler winter convective mixing, higher productivity season, to red Noctiluca in the more oligotrophic warmer summer season.
Journal Article
Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis
Two main pieces of neurobiological evidence are adduced to support an early neurodevelopmental component to schizophrenia. Firstly, an abnormal distribution of neurons, especially interstitial white matter neurons (IWMNs). Secondly, decreased expression of reelin, a key developmental signalling molecule. Although influential, neither result is wholly established, and a possible link between them has not been examined. We addressed both issues, in superior temporal cortex, in 12 subjects with schizophrenia and 14 controls. The distribution and density of IWMNs, immunostained with the neuronal marker NeuN, was increased in the superficial white matter in schizophrenia (+16%;
P
=0.03). IWMN density in deep white matter was unaffected. Using
in situ
hybridization, reelin mRNA was found to be expressed by many IWMNs, layer I neurons, and scattered interneurons. Superficial IWMNs (
P
=0.008) and layer I neurons (
P
=0.036) both expressed less reelin mRNA per cell in schizophrenia, with a trend for deep IWMNs (
P
=0.055). In conclusion, we replicated findings of increased IWMN density, and of decreased reelin expression, in schizophrenia. The loss of reelin reflects, at least partly, its decreased expression by IWMNs. These findings together support neurodevelopmental theories of the disorder, and indicate a link between reelin and IWMNs in this process, consistent with evidence from the heterozygous reeler mutant mouse. The alterations may contribute to the aberrant synaptic connectivity seen in schizophrenia. However, the functional implications of the abnormalities, as well as the mechanisms involved, remain to be fully elucidated.
Journal Article
Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801
It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by
Cre
-mediated knockout of the corresponding gene
Grin1
(
Grin1
ΔPV
mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that
Grin1
ΔPV
mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals,
Grin1
ΔPV
mice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in
Grin1
ΔPV
mice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated
Grin1
ΔPV
mice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease.
Journal Article
The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology
The neuropathological features of schizophrenia are suggestive of a developmentally induced impairment of synaptic connectivity. Semaphorin 3A (sema3A) might contribute to this process because it is a secreted chemorepellant which regulates axonal guidance. We have investigated sema3A in the cerebellum (an area in which expression persists in adulthood), and measured its abundance in 16 patients with schizophrenia and 16 controls. In adults, sema3A was predominantly localized to the inner part of the molecular layer neuropil, whereas infants and rats showed greater labelling of Purkinje cell bodies. Sema3A was increased in schizophrenia, as shown by enzyme-linked immunosorbent assay (+28%;
P
<0.05) and immunohistochemistry (+45%;
P
<0.01). We also measured reelin mRNA, since reelin is involved in related developmental processes and is decreased in other brain regions in schizophrenia. Reelin mRNA showed a trend reduction in the subjects with schizophrenia (−26%;
P
=0.07) and, notably, was negatively correlated with sema3A. Sema3A also correlated negatively with synaptophysin and complexin II mRNAs. The results show that sema3A is elevated in schizophrenia, and is associated with downregulation of genes involved in synaptic formation and maintenance. In this respect, sema3A appears to contribute to the synaptic pathology of schizophrenia, perhaps via ongoing effects of persistent sema3A elevation on synaptic plasticity. The findings are consistent with an early neurodevelopmental origin for the disorder, and the reciprocal changes in sema3A and reelin may be indicative of a pathogenic mechanism that affects the balance between trophic and inhibitory factors regulating synaptogenesis.
Journal Article