bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Porphyria Presenting with Mental Symptoms
Authors: Hare E. H.
Published: August 2008

Acute porphyria is a rare disease in this country. Although a typical case was described in the Journal of Mental Science over 50 years ago (Campbell, 1898), Petrie (1948) could find only three cases reported in Britain between 1940 and 1948; since then at least six more cases have been reported. The disease is relatively common in Scandinavia and, to a less extent, in North America—a distribution for which Discombe (1948) has suggested an explanation in terms of relative emigration rates.
Report on Short-Action Muscle Relaxant Ro/3/0386 in E.C.T.
Authors: Saffery W. A.
Published: August 2008

The use of muscle relaxants as a help in minimizing the hazards of E.C.T. has been reported by a number of workers (Hobson and Prescott, 1947; Davies and Lewis, 1949; Shepherd and Watts, 1949; Smith and Thomas, 1951; and Thompson and Norton, 1951). From these observations the value of such substances in reducing the muscular force of electrically-induced convulsions is clear. Nevertheless the trial of a new substance was embarked upon in order to establish whether it approaches more closely the ideal drug for the purpose.
Gargoylism (Hurler's Disease): A Neuropathological Report
Authors: Naidoo D.
Published: August 2008

Hurler's disease is characterized by chondro-dystrophic skeletal changes, corneal opacities, hepatosplenomegaly and mental defect. The skeletal changes are such that the patient presents a large head, grotesque facies, deformed limbs and kyphosis.
Rorschach Validation. II: The Validity of Colour Shock in the Diagnosis of Neuroticism
Authors: Keehn J. D.
Published: August 2008

Having stated the case for the atomistic approach to Rorschach validation (Keehn, 21), we must now turn to an examination of the methods and results of the application of the approach to a single Rorschach sign.
The Significance of Brain Acetylcholine
Authors: Crossland J.
Published: August 2008

Until a few years ago there existed a sharp dichotomy of opinion between the pharmacologists, who, on the basis of their experiments, assigned to acetylcholine the role of universal synaptic transmitter, and the electrophysiologists, who denied that this substance could effect the transfer of excitation from one conducting element to another. It is, however, now generally agreed that, certainly at the neuromuscular junction, and probably also at ganglionic and some—but not all—central synapses, acetylcholine does indeed exert a primary transmitter action. It must be added that recognition of this fundamental action has been hastened as a result of recent experiments by those very electrophysiologists (such as Eccles and his colleagues) who previously supported exclusively electrical hypotheses of nervous transmission. For this reason the assumption which is implicit throughout this paper that the acetylcholine in brain is concerned in maintaining central synaptic transmission is likely to go unchallenged and requires no detailed justification here.
The use of Short-Acting Relaxants in E.C.T.
Authors: Monro A. B. , Kirkland Anne K. , Gillie A. , McNeill D. L. M.
Published: August 2008

Since the introduction of curare to modify the contractions in E.C.T., the use of relaxants has become standard psychiatric practice. These substances reduce the risk of fractures and enable treatment to be given to patients who would otherwise be denied it owing to risks arising from concomitant physical disease. During recent years great efforts have been made to simplify the technique of muscle relaxation, in particular to evolve a method which is short in duration, free from undesirable side-effects and easy in use. In this short paper we give a description of our experience with three drugs recently introduced, namely, Suxamethonium Bromide or Brevidil “M” which we used in 111 treatments, Suxethonium Bromide or Brevidil “E” (70 treatments), and Suxamethonium Chloride or Scoline (653 treatments). These choline succinic ester derivatives have similar characteristics which can be considered together.
The High Incidence of Huntington's Chorea in the Duchy of Cornwall
Authors: Bickford J. A. R. , Ellison R. M.
Published: August 2008

When one finds a legend associated with a disease it may be accepted as a general rule that little is known about its true cause. This is exemplified by Huntington's chorea, of which it is said that the original case was a man who imitated Christ's agony on the Cross. A great deal of work has been done on this complaint, but much of it has been to do no more than to confirm the findings of Abel Huntington, who recognized its hereditary nature in 1797.
The Relative Roles of Individual Psycho-Therapy and Group Psycho-Therapy in the Industrial Neurosis Unit
Authors: Merry Julius
Published: August 2008

The Industrial Neurosis Unit of Belmont Hospital has one hundred beds, two-thirds of which are occupied by males. The vast majority of the patients are chronic psycho-neurotics and psychopathic personalities, who show poor social adjustment. The material treated here is what is usually labelled as “hopeless.” Letters from Out-Patient Departments, seeking admission are prefaced, “We know this is a hopeless case …,” or “If you cannot help him then there is no hope for him …,” etc. During the four years of its existence the Industrial Unit has evolved and practised a variety of techniques of group psycho-therapy, in addition to the orthodox psychological and physical treatments available in modern psychiatric hospitals. More and more importance is being attached to the value of group methods here, to the extent that some doctors, after taking a brief history, thereafter employ group-therapy exclusively. This paper is an attempt to discuss the relative values and roles of therapy carried out at individual and group levels in the Industrial Unit.
Primitive forms of Response to the Matrices Test
Authors: Bromley D. B.
Published: August 2008

I. Problem and Method.

Recent work on the psychology of intelligence and thinking suggests that perceptual types of intelligence tests are inadequate for dealing with psychiatric cases, young children, old people, mental defectives, and primitive peoples. The argument is that, in these groups, intellectual processes have either deteriorated from or failed to develop to that level with which most perceptual intelligence tests are concerned. The methods of scoring also assume that the correct answers are always reached in the same way, but this is by no means always the case, as Goldstein and Scheerer (1941, p. 14) have pointed out. The studies of Werner (1948), Piaget (1951), Goldstein (1940), Hanfmann and Kasanin (1942), Rapaport (1951), Moursy (1952)et al.show convincing evidence that cognition can take place at different “levels.” The exact determination of the number, nature, and scope of the different levels remains a task for the future, since the present situation is confused, to say the least.
Psychological Test Performance in Patients Over Sixty. I. Senile Psychosis and the Affective Disorders of Old Age
Authors: Roth Martin , Hopkins Barbara
Published: August 2008

Affective disturbances are a common consequence of organic brain lesions of varying aetiology, and it is to be expected that the differentiation between affective symptoms of “functional” origin and those resulting from organic lesions would become an increasingly difficult problem in an age-range which is particularly susceptible to pathological cerebral changes. In fact the classical accounts of mental disorder in old age convey the impression, by their emphasis on the depressive form of senile psychosis, that an affective disorder appearing in senescence is commonly the manifestation of some cerebral degenerative process. This is one of the sources of the widely prevalent view in contemporary clinical practice that there is a large group of cases in which dementia and a depressive (and less often a manic) symptom-complex are associated. The overlap being large, an ill-defined line of demarcation is held to exist in old age between the organic degenerative diseases and the affective illnesses of a “functional” kind.
Some Considerations on the Phenomenon of Aggression
Authors: Tolsma F. J.
Published: August 2008

When we pass under review the theoretical concepts of aggression three main types stand out clearly, which are fairly representative of prevalent opinions.
The Korsakov Syndrome in Spontaneous Subarachnoid Haemorrhage
Authors: Walton John N.
Published: August 2008

The amnestic-confabulatory symptom-complex to which the eponymous title of Korsakov's syndrome is usually given was probably first described by the Swedish physician Magnus Huss (1807–90), who spent the greater part of his lifetime in the study of alcoholism. There is, however, no doubt that Korsakov's (1890) paper on the subject gave an excellent description of the syndrome, and stressed the fact that whereas it often developed in patients with alcoholism and polyneuritis, numerous other metabolic and neurological disorders could be complicated by the characteristic mental changes. Indeed, in Korsakov's (1890) own series of cases alcoholics were in the minority. One of the neurological conditions in which the syndrome has been described significantly often is spontaneous subarachnoid haemorrhage. The first reports of the association were probably those of Flatau (1918 and 1921), and it was discussed in some detail by Goldflam (1923) and Herman (1925 and 1926). Each of these authors described the mental symptoms exhaustively but gave no actual case-histories; the first fully documented cases in the literature were the two reported by Hall (1929). Single cases have since been described by Cubitt (1930), Popow (1930) and Kulkow (1935), and in 1939 Tarachow gave an extensive review of the literature and reported an additional 3 cases. It is remarkable that since 1939 the association has received little attention, although it has been mentioned by Sands (1941) and Meadows (1951).
The Backward Baby
Authors: Kirman Brian H.
Published: August 2008

Interest in this problem on the part of parents, sociologists and paediatricians, among others, has grown of recent years. So much is this so that the casual observer might well conclude that there had been a real increase in backwardness, and that anxious parents now have a more genuine cause for anxiety on this score than was the case a generation ago. This view indeed is held by certain well established authorities in the fields of education and psychology, for example Burt and Professor Godfrey Thompson, who have expressed gloomy views about the intelligence of the nation. Moreover, considerable publicity by means of wireless broadcasts or otherwise has been given to these prognostications. It is not therefore surprising that many parents should be concerned as to whether their offspring will after all prove to be something less of a genius than they had anticipated. The smaller size of modern families is also a factor in increasing paternal anxiety. I say paternal advisedly, since it is more often the male parent, especially in middle-class circles, who has set his heart on his child being an infant prodigy. With only one string to his bow, the whole tension of paternal ambition is concentrated in a single object. Moreover in these days of compulsory examinations at the age of eleven, together with widespread coaching for the intelligence tests which form part of the examination, the unfortunate, innocent babe is barely able to lift a mug or a spoon when his rattle is whisked away and replaced by a host of constructional toys designed on similar lines to modern American intelligence tests. The slightest failure in performance or slackening of interest is liable to produce a state akin to panic in the proud parent, who has just been comparing notes about his prodigy with the owner of another (but naturally, somewhat inferior) budding genius next door.
The Mental Capacity in Achondroplasia
Authors: Morris J. V. , MacGillivray R. C.
Published: August 2008

Achondroplasia (micromelia, chondrodystrophia foetalis) has been defined as “an absence, arrest or perversion of the normal process of endochondral ossification of the most definite and universal character in every element of the skeleton, in which the process normally takes place during intrauterine life” (Symington and Thomson, 1892).
Mongolism in One of Twins
Authors: Morris J. V. , MacGillivray R. C.
Published: August 2008

It has been suggested that mongolism results from damage to the germ plasm from gametic mutation or the fertilization of an abnormal ovum, the theory being mainly based on the study of twins, one or both of whom has been found to be mongoloid (Benda, 1947).
A Girl of Mongoloid Appearance and Normal Intelligence
Authors: Cant W. H. P. , Gerrard J. W. , Richards B. W.
Published: August 2008

During a domiciliary visit one of us encountered a child who appeared to be a typical mongol and who nevertheless behaved remarkably intelligently. This child was later shown to numerous colleagues, among them the late Sir Leonard Parsons, who spontaneously suggested that she was a “mongol.” The combination of mongoloid features, which she exhibits, and normal intelligence is of sufficient interest, we feel, to be recorded.
The Bristol Psychiatric Day Hospital
Authors: Aron K. W. , Smith S.
Published: August 2008

In April, 1946, an experimental form of hospitalization for psychiatric patients was set up in Montreal.∗ This form of hospital, described by Ewen Cameron (1947), admitted any type of patient, the only criterion being that they should be well enough to stay at home over-night. To such an institution he gave the name of Day Hospital. At about the same time J. Bierer (1951) was experimenting in the same direction in this country. in connection with his attempt to extend the principles of “social psychiatry” to the everyday treatment of patients. Since then there have been several other short communications on the subject such as those of A. E. Moll (1951) and H. Gilmore (1952).
The Effects of Temporal Lobe Lesions on Behaviour in Paranoid States
Authors: Oldham A. J.
Published: August 2008

The effects of temporal lobe lesions on behaviour have recently received considerable attention. There is reason to believe that certain types of abnormal behaviour are related to neurophysiological disturbances localized in the temporal lobes (Hill and Watterson, 1942; Rey, Pond and Evans, 1949). The effects of excisions of the temporal lobes on behaviour have been studied in animals (Klüver and Bucy, 1938), and in human subjects (Penfield and Flanigan, 1950; Bailey and Gibbs, 1951), while those of therapeutic incisions have been described by Obrador (1947). They appear to have certain features in common with those resulting from lesions of the frontal lobes. However, knowledge in this field is still in its infancy, and the following two cases in which temporal lobe lesions supervened upon paranoid states are therefore considered as worthy of interest. They were observed at the Professorial Unit of the Bethlem Royal and Maudsley Hospitals.
Some Factors in the Aetiology of Maladjustment in Children
Authors: Holman Portia
Published: August 2008

The Education Act of 1944 lays on the Local Education Authorities the duty of providing special educational treatment for certain categories of children distinguished as “handicapped.” Included under this heading are maladjusted pupils. These are defined (by regulations) as “pupils who show evidence of emotional instability or psychological disturbance and require special educational treatment to effect their personal, social or educational readjustment.” This definition is, in the words of The Times (1950), “broadly based,” and has indeed been a source of confusion. The first clause asserts a proposition which is very nearly circular, since “emotional instability” and “psychological disturbance” stand as much in need of definition as maladjustment. The second clause makes for even greater uncertainty. Is it intended to indicate that only some children showing evidence of psychological disturbance or emotional instability need “personal, social or educational readjustment”? The suggestion that this can be effected by special educational treatment has led to much bewilderment. Presumably what is intended is that these children have, in common with other handicapped children, a need for special educational treatment, and also a need for personal, social and educational readjustment. For no other class of handicapped pupils is it suggested that the handicap can be treated by education, however widely this term is conceived or however specialized to the particular needs of the handicapped child.
Disorientation for Age
Authors: Zangwill O. L.
Published: August 2008

It has often been noticed that patients in amnesic states are prone to underestimate their age. In cases of Korsakov's psychosis this under-estimation may be very gross, and its extent appears to be determined, in part at least, by the duration of retrograde amnesia (Meggendorfer, 1928). A similar, if less extreme, under-estimation of age may also occur in the early stages of recovery after head-injury. In a recent study Weinstein and Kahn (1951) refer to this phenomenon as disorientation for age and adduce some striking examples. Thus one of their patients, a woman of over 70, insisted that she was 38. These authors do not, however, attempt a systematic analysis of this facet of disorientation.
Visual Agnosia and Alternating Dominance; Analysis of a Case
Authors: Klein R. , Stack J. J.
Published: August 2008

The case here described is of interest in that it concerns a young man of good intelligence who presented a disorder limited to visual-gnostic functions; this is noteworthy as the majority of the cases described are elderly patients and there are usually other than visual gnostic functions involved. The case has special circumstances of additional significance. The patient had lost the sight of his right eye in infancy and he was a definite right-handed man; the damage involved the right hemisphere; this exceptional coincidence raises interesting problems of hemispheric dominance.
New Data on Marriage and Mental Disease: The Incidence of Psychoses in the Widowed and the Divorced
Authors: Ødegård Ørnulv
Published: August 2008

It may be regarded as an established fact that the incidence of mental disorder is much higher in the single than in the married. In a previous paper two possible explanations were discussed: 1. There is a selection by marriage, whereby individuals who are personally and socially handicapped tend to remain single. Among such possible marriage handicaps there are certain personality traits which correlate markedly with a predisposition towards certain forms of mental disease, in particular schizophrenia.
Experiences and Results in Prefrontal Leucotomy: a Clinical Study of 339 Leucotomized Patients
Authors: Kostič Slobodan
Published: August 2008

From October, 1947, to October, 1952, we have had the opportunity of performing prefrontal leucotomy on 339 patients at the Neurosurgical Clinic in Belgrade. As this operation is of importance in the treatment of mental disease we consider it necessary to report our experiences and our results.
Type I Membrane Klotho Expression Is Decreased and Inversely Correlated to Serum Calcium in Primary Hyperparathyroidism
Authors: Björklund Peyman , Krajisnik Tijana , Åkerström Göran , Westin Gunnar , Larsson Tobias E.
Published: August 2008

Context: The type I membrane protein Klotho was recently shown to mediate PTH secretion in parathyroid cells in response to low extracellular calcium. In contrast, Klotho inhibits PTH secretion indirectly through the action of fibroblast growth factor-23. Abnormal Klotho expression in parathyroid disorders remains to be elucidated.

Objective: The aim of the study was to determine: 1) Klotho expression in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT) compared to normal tissue; and 2) its relation to the serum calcium and PTH levels.

Design: Surgically removed parathyroid glands (n = 40) and four normal parathyroid tissue specimens were analyzed for Klotho mRNA and protein levels by quantitative real-time PCR and immunohistochemistry. In vitro effects of calcium on Klotho mRNA expression were studied in bovine parathyroid cells.

Results: Klotho mRNA levels were significantly decreased (n = 23) or undetectable (n = 17) in parathyroid adenomas compared to normal tissues (P < 0.001). Reduced Klotho protein expression was confirmed by immunohistochemistry. Klotho mRNA levels were inversely correlated to serum calcium (r = −0.97; P < 0.0001), and calcium dose-dependently decreased Klotho mRNA expression in normal parathyroid cells in vitro (P < 0.01). Serum calcium was the only significant marker of Klotho expression in multivariate analysis with calcium, phosphate, PTH, and adenoma weight as independent variables.

Conclusions: Parathyroid Klotho expression is decreased or undetectable in pHPT. We provide evidence that 1) serum calcium is strongly associated with parathyroid Klotho expression in pHPT; and 2) abnormal PTH secretion in hypercalcemic pHPT subjects is mediated by Klotho-independent mechanisms.
BRAFV600E Mutation and Outcome of Patients with Papillary Thyroid Carcinoma: A 15-Year Median Follow-Up Study
Authors: Elisei Rossella , Ugolini Clara , Viola David , Lupi Cristiana , Biagini Agnese , Giannini Riccardo , Romei Cristina , Miccoli Paolo , Pinchera Aldo , Basolo Fulvio
Published: August 2008

Background: The BRAFV600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). The role of BRAFV600E mutation as a poor prognostic factor has been controversially reported in series with short-term follow-ups. In this study we verified the prognostic value of the BRAFV600E mutation in PTC patients with a long-term follow-up.

Methods: We studied 102 PTC patients with a median follow-up of 15 yr. The BRAFV600E mutation was analyzed by PCR-single-strand conformational polymorphism and sequencing. The correlation between the presence/absence of the BRAFV600E mutation, clinicopathological features, and outcome of PTC patients were evaluated.

Results: The BRAFV600E mutation was found in 38 of 102 (37.3%) PTC patients, and was significantly more frequent in patients older than 60 yr (P = 0.02), in advanced stages (P = 0.03), and in cases with vascular invasion (P = 0.02). At univariate analysis the worst outcome for PTC patients was significantly correlated with clinicopathological features (i.e. age, tumor size, extrathyroid extension, lymph node and distant metastases, advanced stage, vascular endothelial growth factor expression, and vascular invasion) and the BRAFV600E mutation (P < 0.002). However, at multivariate analysis only the BRAFV600E mutation showed an independent correlation with the worst outcome (P = 0.03). Moreover, the survival curves of PTC patients showed a lower percentage of survivors in the BRAFV600E-mutated group (P = 0.015).

Conclusions: In this study the BRAFV600E mutation correlated with the worst outcome for PTC patients, who were not only at a higher risk not to be cured but also for death. In particular, the BRAFV600E mutation was demonstrated to be a poor prognostic factor independent from other clinicopathological features.
Loss-of-Function Mutations in the Genes Encoding Prokineticin-2 or Prokineticin Receptor-2 Cause Autosomal Recessive Kallmann Syndrome
Authors: Abreu Ana Paula , Trarbach Ericka Barbosa , de Castro Margaret , Frade Costa Elaine Maria , Versiani Beatriz , Matias Baptista Maria Tereza , Garmes Heraldo Mendes , Mendonca Berenice Bilharinho , Latronico Ana Claudia
Published: August 2008

Context: Physiological activation of the prokineticin pathway has a critical role in olfactory bulb morphogenesis and GnRH secretion in mice.

Objective: To investigate PROK2 and PROKR2 mutations in patients with hypogonadotropic hypogonadism (HH) associated or not with olfactory abnormalities.

Design: We studied 107 Brazilian patients with HH (63 with Kallmann syndrome and 44 with normosmic HH) and 100 control individuals. The coding regions of PROK2 and PROKR2 were amplified by PCR followed by direct automatic sequencing.

Results: In PROK2, two known frameshift mutations were identified. Two brothers with Kallmann syndrome harbored the homozygous p.G100fsX121 mutation, whereas one male with normosmic HH harbored the heterozygous p.I55fsX56 mutation. In PROKR2, four distinct mutations (p.R80C, p.Y140X, p.L173R, and p.R268C) were identified in five patients with Kallmann syndrome and in one patient with normosmic HH. These mutations were not found in the control group. The p.R80C, p.L173R, and p.R268C missense mutations were identified in the heterozygous state in the HH patients and in their asymptomatic first-degree relatives. In addition, no mutations of FGFR1, KAL1, GnRHR, KiSS-1, or GPR54 were identified in these patients. Notably, the new nonsense mutation (p.Y140X) was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous for this severe defect.

Conclusion: We expanded the repertoire of PROK2 and PROKR2 mutations in patients with HH. In addition, we show that PROKR2 haploinsufficiency is not sufficient to cause Kallmann syndrome or normosmic HH, whereas homozygous loss-of-function mutations either in PROKR2 or PROK2 are sufficient to cause disease phenotype, in accordance with the Prokr2 and Prok2 knockout mouse models.
High-Circulating Leptin Levels Are Associated with Greater Risk of Hypertension in Men Independently of Body Mass and Insulin Resistance: Results of an Eight-Year Follow-Up Study
Authors: Galletti F. , D'Elia L. , Barba G. , Siani A. , Cappuccio F. P. , Farinaro E. , Iacone R. , Russo O. , De Palma D. , Ippolito R. , Strazzullo P.
Published: August 2008

Background: We previously reported a significant association between plasma leptin (LPT) concentration and blood pressure (BP), which was partly independent of serum insulin levels and insulin resistance. The aims of this study were to detect whether serum LPT levels predict the development of hypertension (HPT) in the 8-yr follow-up investigation of a sample of an adult male population (the Olivetti Heart Study), and to evaluate the role of body mass index (BMI) and insulin resistance in this putative association.

Patients and Methods: The study population was made up of 489 untreated normotensive subjects examined in 1994–1995 (age: 50.1 ± 6.7 yr; BMI: 26.3 ± 2.8 kg/m2; BP: 120 ± 10/78 ± 6 mm Hg; and homeostatic model assessment index: 2.1 ± 1.6).

Results: The HPT incidence over 8 yr was 35%. The participants with incident HPT had similar age but higher BMI (P < 0.001), serum LPT (P < 0.001), and BP (P < 0.01) at baseline. One sd positive difference in baseline serum LPT log was associated at univariate analysis with a 49% higher rate of HPT [95% confidence interval (CI) 22–83; P < 0.001]). In three different models of multivariable logistical regression analysis, LPT was respectively associated with a 41% greater risk to develop HPT (95% CI 15–74; P < 0.001) upon adjustment for age and baseline BP, with a 48% (95% CI 20–81) greater risk when adding the homeostatic assessment model index to the model, and with 33% greater risk (95% CI 6–67; P < 0.02) upon adjustment for BMI.

Conclusions: In this sample of originally normotensive men, circulating LPT level was a significant predictor of the risk to develop HPT over 8 yr, independently of BMI and insulin resistance.
Mechanism of flagellar oscillation–bending-induced switching of dynein activity in elastase-treated axonemes of sea urchin sperm
Authors: Hayashi Shuichi , Shingyoji Chikako
Published: August 2008

Oscillatory movement of eukaryotic flagella is caused by dynein-driven microtubule sliding in the axoneme. The mechanical feedback from the bending itself is involved in the regulation of dynein activity, the main mechanism of which is thought to be switching of the activity of dynein between the two sides of the central pair microtubules. To test this, we developed an experimental system using elastase-treated axonemes of sperm flagella, which have a large Ca2+-induced principal bend (P-bend) at the base. On photoreleasing ATP from caged ATP, they slid apart into two bundles of doublets. When the distal overlap region of the slid bundles was bent in the direction opposite to the basal P-bend, backward sliding of the thinner bundle was induced along the flagellum including the bent region. The velocity of the backward sliding was significantly lower than that of the forward sliding, supporting the idea that the dynein activity alternated between the two sides of the central pair on bending. Our results show that the combination of the direction of bending and the conformational state of dynein-microtubule interaction induce the switching of the dynein activity in flagella, thus providing the basis for flagellar oscillation.
Versatile DNA damage detection by the global genome nucleotide excision repair protein XPC
Authors: Hoogstraten Deborah , Bergink Steven , Ng Jessica M. Y. , Verbiest Vincent H. M. , Luijsterburg Martijn S. , Geverts Bart , Raams Anja , Dinant Christoffel , Hoeijmakers Jan H. J. , Vermeulen Wim , Houtsmuller Adriaan B.
Published: August 2008

To investigate how the nucleotide excision repair initiator XPC locates DNA damage in mammalian cell nuclei we analyzed the dynamics of GFP-tagged XPC. Photobleaching experiments showed that XPC constantly associates with and dissociates from chromatin in the absence of DNA damage. DNA-damaging agents retard the mobility of XPC, and UV damage has the most pronounced effect on the mobility of XPC-GFP. XPC exhibited a surprising distinct dynamic behavior and subnuclear distribution compared with other NER factors. Moreover, we uncovered a novel regulatory mechanism for XPC. Under unchallenged conditions, XPC is continuously exported from and imported into the nucleus, which is impeded when NER lesions are present. XPC is omnipresent in the nucleus, allowing a quick response to genotoxic stress. To avoid excessive DNA probing by the low specificity of the protein, the steady-state level in the nucleus is controlled by nucleus-cytoplasm shuttling, allowing temporally higher concentrations of XPC in the nucleus under genotoxic stress conditions.
Genetic Testing for Warfarin Therapy Initiation
Authors: Hynicka Lauren M , Cahoon William D , Bukaveckas Bonny L
Published: August 2008

Objective

To review the literature regarding the efficacy of genetic testing for determining the appropriate initial dose of warfarin and the effect that this testing has on the safety and efficacy of therapy.

Data Sources:

Searches of MEDLINE (1966–May 2008) and Cochrane Database (1993–May 2008) were conducted using the search terms warfarin, anticoagulation, pharmacogenomics, pharmacogenetics, CYP2C9, VKORC1, and interindividual variability. Limits included articles written in English with human subjects. Additional data were identified through bibliographic reviews.

Study Selection And Data Extraction:

All English-language articles identified from the data sources were evaluated. Studies were eligible for inclusion if they evaluated the efficacy of pharmacogenomic testing to improve outcomes with initiation of warfarin therapy.

Data Synthesis:

The use of warfarin presents numerous challenges in clinical practice. Four studies (N = 38, 48, 200, 297) evaluating the efficacy of genetic testing for determining the initial dose of warfarin therapy have been published. Results show that time to therapeutic international normalized ratio (INR) and time to stable warfarin dose are similar regardless of genotype. When conventional warfarin dosing was compared with pharmacogenomic-based dosing, no significant difference was seen between groups in terms of time spent within the target INR range (41.5% vs 41.7%; no p value reported). Similar results were found in a subsequent study in which patients receiving conventional dosing were outside their target INR range 33.1% of the time compared with 30.7% of the lime for patients whose dose was guided by pharmacogenomics (p = 0.47).

Conclusions:

There is growing evidence that variant alleles for CYP2C9 and VKORC1 genotypes account for a proportion of the variability seen in warfarin dosing. The currently available literature related to the use of pharmacogenomic testing in the initiation of warfarin therapy does not show improved outcomes in either safety or efficacy with warfarin therapy and therefore does not support the routine use of pharmacogenomic testing when initiating warfarin therapy.
Prediction of Incident Hip Fracture Risk by Femur Geometry Variables Measured by Hip Structural Analysis in the Study of Osteoporotic Fractures
Authors: Kaptoge Stephen , Beck Thomas J , Reeve Jonathan , Stone Katie L , Hillier Teresa A , Cauley Jane A , Cummings Steven R
Published: August 2008

The role of bone tissue's geometric distribution in hip fracture risk requires full evaluation in large population-based datasets. We tested whether section modulus, a geometric index of bending strength, predicted hip fracture better than BMD. Among 7474 women from the Study of Osteoporotic Fractures (SOF) with hip DXA scans at baseline, there were 635 incident hip fractures recorded over 13 yr. Hip structural analysis software was used to derive variables from the DXA scans at the narrow neck (NN), intertrochanter (IT), and shaft (S) regions. Associations of derived structural variables with hip fracture were assessed using Cox proportional hazard modeling. Hip fracture prediction was assessed using the C-index concordance statistic. Incident hip fracture cases had larger neck-shaft angles, larger subperiosteal and estimated endosteal diameters, greater distances from lateral cortical margin to center of mass (lateral distance), and higher estimated buckling ratios (p < 0.0001 for each). Areal BMD, cross-sectional area, cross-sectional moment of inertia, section modulus, estimated cortical thickness, and centroid position were all lower in hip fracture cases (p < 0.044). In hip fracture prediction using NN region parameters, estimated cortical thickness, areal BMD, and estimated buckling ratio were equivalent (C-index = 0.72; 95% CI, 0.70, 0.74), but section modulus performed less well (C-index = 0.61; 95% CI, 0.58, 0.63; p < 0.0001 for difference). In multivariable models combining hip structural analysis variables and age, effects of bone dimensions (i.e., lateral distance, subperiosteal diameter, and estimated endosteal width) were interchangeable, whereas age and neck-shaft angle were independent predictors. Several parsimonious multivariable models that were prognostically equivalent for the NN region were obtained combining a measure of width, a measure of mass, age, and neck-shaft angle (BMD is a ratio of mass to width in the NN region; C-index = 0.77; 95% CI, 0.75, 0.79). Trochanteric fractures were best predicted by analysis of the IT region. Because section modulus failed to predict hip fracture risk as well as areal BMD, the thinner cortices and wider bones among those who fractured may imply that simple failure in bending is not the usual event in fracture. Fracture might require initiation (e.g., by localized crushing or buckling of the lateral cortex).
A Haplotype-Based Analysis of the LRP5 Gene in Relation to Osteoporosis Phenotypes in Spanish Postmenopausal Women
Authors: Agueda Lídia , Bustamante Mariona , Jurado Susana , Garcia-Giralt Natalia , Ciria Manel , Saló Guillem , Carreras Ramon , Nogués Xavier , Mellibovsky Leonardo , Díez-Pérez Adolfo , Grinberg Daniel , Balcells Susana
Published: August 2008

LRP5 encodes the low-density lipoprotein receptor-related protein 5, a transmembrane protein involved in Wnt signaling. LRP5 is an important regulator of osteoblast growth and differentiation, affecting bone mass in vertebrates. Whether common variations in LRP5 are associated with normal BMD variation or osteoporotic phenotypes is of great relevance. We used a haplotype-based approach to search for common disease-associated variants in LRP5 in a cohort of 964 Spanish postmenopausal women. Twenty-four SNPs were selected, covering the LRP5 region, including the missense changes p.V667M and p.A1330V. The SNPs were genotyped and evaluated for association with BMD at the lumbar spine (LS) or femoral neck (FN) and with osteoporotic fracture, at single SNP and haplotype levels, by regression methods. Association with LS BMD was found for SNP 1, rs312009, located in the 5′-flanking region (p = 0.011, recessive model). SNP 6, rs2508836, in intron 1, was also associated with BMD, both at LS (p = 0.025, additive model) and FN (p = 0.031, recessive model). Two polymorphisms were associated with fracture: SNP 11, rs729635, in intron 1, and SNP 15, rs643892, in intron 5 (p = 0.007 additive model and p = 0.019 recessive model, respectively). Haplotype analyses did not provide additional information, except for haplotype “GC” of the block located at the 3′end of the gene. This haplotype spans intron 22 and the 3′ untranslated region and was associated with FN BMD (p = 0.029, one copy of the haplotype versus none). In silico analyses showed that SNP 1 (rs312009) lies in a putative RUNX2 binding site. Electro-mobility shift assays confirmed RUNX2 binding to this site.
Excitatory Effects of the Puberty-Initiating Peptide Kisspeptin and Group I Metabotropic Glutamate Receptor Agonists Differentiate Two Distinct Subpopulations of Gonadotropin-Releasing Hormone Neurons
Authors: Dumalska Iryna , Wu Min , Morozova Elena , Liu Rongjian , van den Pol Anthony , Alreja Meenakshi
Published: August 2008

Activation of the G-protein-coupled receptor GPR54 by kisspeptins during normal puberty promotes the central release of gonadotropin-releasing hormone (GnRH) that, in turn, leads to reproductive maturation. In humans and mice, a loss of function mutations of GPR54 prevents the onset of puberty and leads to hypogonadotropic hypogonadism and infertility. Using electrophysiological, morphological, molecular, and retrograde-labeling techniques in brain slices prepared fromvGluT2-GFPandGnRH-GFPmice, we demonstrate the existence of two physiologically distinct subpopulations of GnRH neurons. The first subpopulation is comprised of septal GnRH neurons that colocalize vesicular glutamate transporter 2 and green fluorescent protein and is insensitive to metabotropic glutamate receptor agonists, but is exquisitely sensitive to kisspeptin which closes potassium channels to dramatically initiate a long-lasting activation in neurons from prepubertal and postpubertal mice of both sexes. A second subpopulation is insensitive to kisspeptin but is uniquely activated by group I metabotropic glutamate receptor agonists. These two physiologically distinct classes of GnRH cells may subserve different functions in the central control of reproduction and fertility.
Frontal Cortex Mediates Unconsciously Triggered Inhibitory Control
Authors: van Gaal Simon , Ridderinkhof K. Richard , Fahrenfort Johannes J. , Scholte H. Steven , Lamme Victor A. F.
Published: August 2008

To further our understanding of the function of conscious experience we need to know which cognitive processes require awareness and which do not. Here, we show that an unconscious stimulus can trigger inhibitory control processes, commonly ascribed to conscious control mechanisms. We combined the metacontrast masking paradigm and the Go/No-Go paradigm to study whether unconscious No-Go signals can actively trigger high-level inhibitory control processes, strongly associated with the prefrontal cortex (PFC). Behaviorally, unconscious No-Go signals sometimes triggered response inhibition to the level of complete response termination and yielded a slow down in the speed of responses that were not inhibited. Electroencephalographic recordings showed that unconscious No-Go signals elicit two neural events: (1) an early occipital event and (2) a frontocentral event somewhat later in time. The first neural event represents the visual encoding of the unconscious No-Go stimulus, and is also present in a control experiment where the masked stimulus has no behavioral relevance. The second event is unique to the Go/No-Go experiment, and shows the subsequent implementation of inhibitory control in the PFC. The size of the frontal activity pattern correlated highly with the impact of unconscious No-Go signals on subsequent behavior. We conclude that unconscious stimuli can influence whether a task will be performed or interrupted, and thus exert a form of cognitive control. These findings challenge traditional views concerning the proposed relationship between awareness and cognitive control and stretch the alleged limits and depth of unconscious information processing.
Semicircular Canal Size Determines the Developmental Onset of Angular Vestibuloocular Reflexes in LarvalXenopus
Authors: Lambert François M. , Beck James C. , Baker Robert , Straka Hans
Published: August 2008

Semicircular canals have been sensors of angular acceleration for 450 million years. This vertebrate adaptation enhances survival by implementing postural and visual stabilization during motion in a three-dimensional environment. We used an integrated neuroethological approach in larvalXenopusto demonstrate that semicircular canal dimensions, and not the function of other elements, determines the onset of angular acceleration detection. Before angular vestibuloocular function in either the vertical or horizontal planes, at stages 47 and 48, respectively, each individual component of the vestibuloocular system was shown to be operational: extraocular muscles could be activated, central neural pathways were complete, and canal hair cells were capable of evoking graded responses. ForXenopus, a minimum semicircular canal lumen radius of 60 μm was necessary to permit endolymph displacement sufficient for sensor function at peak accelerations of 400°/s2. An intra-animal comparison demonstrated that this size is reached in the vertical canals earlier in development than in the horizontal canals, corresponding to the earlier onset of vertical canal-activated ocular motor behavior. Because size constitutes a biophysical threshold for canal-evoked behavior in other vertebrates, such as zebrafish, we suggest that the semicircular canal lumen and canal circuit radius are limiting the onset of vestibular function in all small vertebrates. Given that the onset of gravitoinertial acceleration detection precedes angular acceleration detection by up to 10 d inXenopus, these results question how the known precise spatial patterning of utricular and canal afferents in adults is achieved during development.
Bilateral Speech Comprehension Reflects Differential Sensitivity to Spectral and Temporal Features
Authors: Obleser Jonas , Eisner Frank , Kotz Sonja A.
Published: August 2008

Speech comprehension has been shown to be a strikingly bilateral process, but the differential contributions of the subfields of left and right auditory cortices have remained elusive. The hypothesis that left auditory areas engage predominantly in decoding fast temporal perturbations of a signal whereas the right areas are relatively more driven by changes of the frequency spectrum has not been directly tested in speech or music. This brain-imaging study independently manipulated the speech signal itself along the spectral and the temporal domain using noise-band vocoding. In a parametric design with five temporal and five spectral degradation levels in word comprehension, a functional distinction of the left and right auditory association cortices emerged: increases in the temporal detail of the signal were most effective in driving brain activation of the left anterolateral superior temporal sulcus (STS), whereas the right homolog areas exhibited stronger sensitivity to the variations in spectral detail. In accordance with behavioral measures of speech comprehension acquired in parallel, change of spectral detail exhibited a stronger coupling with the STS BOLD signal. The relative pattern of lateralization (quantified using lateralization quotients) proved reliable in a jack-knifed iterative reanalysis of the group functional magnetic resonance imaging model. This study supplies direct evidence to the often implied functional distinction of the two cerebral hemispheres in speech processing. Applying direct manipulations to the speech signal rather than to low-level surrogates, the results lend plausibility to the notion of complementary roles for the left and right superior temporal sulci in comprehending the speech signal.
Multiple RIBEYE–RIBEYE Interactions Create a Dynamic Scaffold for the Formation of Synaptic Ribbons
Authors: Magupalli Venkat Giri , Schwarz Karin , Alpadi Kannan , Natarajan Sivaraman , Seigel Gail M. , Schmitz Frank
Published: August 2008

Synaptic ribbons are large, dynamic structures in the active zone complex of ribbon synapses and important for the physiological properties of these tonically active synapses. RIBEYE is a unique and major protein component of synaptic ribbons. The aim of the present study was to understand how the synaptic ribbon is built and how the construction of the ribbon could contribute to its ultrastructural plasticity. In the present study, we demonstrate that RIBEYE self-associates using different independent approaches (yeast two-hybrid analyses, protein pull downs, synaptic ribbon–RIBEYE interaction assays, coaggregation experiments, transmission electron microscopy and immunogold electron microscopy). The A-domain [RIBEYE(A)] and B-domain [RIBEYE(B)] of RIBEYE contain five distinct sites for RIBEYE–RIBEYE interactions. Three interaction sites are present in the A-domain of RIBEYE and mediate RIBEYE(A)–RIBEYE(A) homodimerization and heterodimerization with the B-domain. The docking site for RIBEYE(A) on RIBEYE(B) is topographically and functionally different from the RIBEYE(B) homodimerization interface and is negatively regulated by nicotinamide adenine dinucleotide. The identified multiple RIBEYE–RIBEYE interactions have the potential to build the synaptic ribbon: heterologously expressed RIBEYE forms large electron-dense aggregates that are in part physically associated with surrounding vesicles and membrane compartments. These structures resemble spherical synaptic ribbons. These ribbon-like structures coassemble with the active zone protein bassoon, an interaction partner of RIBEYE at the active zone of ribbon synapses, emphasizing the physiological relevance of these RIBEYE-containing aggregates. Based on the identified multiple RIBEYE–RIBEYE interactions, we provide a molecular mechanism for the dynamic assembly of synaptic ribbons from individual RIBEYE subunits.
Detection of a complete autoimmune regulator gene deletion and two additional novel mutations in a cohort of patients with atypical phenotypic variants of autoimmune polyglandular syndrome type 1
Authors: Podkrajšek Katarina Trebušak , Milenković Tatjana , Odink Roelof J , Claasen-van der Grinten Hedi L , Bratanič Nina , Hovnik Tinka , Battelino Tadej
Published: August 2008

Objective

Autoimmune polyglandular syndrome type 1 (APS-1) is characterised by multiple autoimmune diseases. Detection of autoimmune regulator (AIRE) gene mutations facilitates timely and precise diagnosis.

Design

AIRE mutation detection was performed in a cohort of 11 patients. Two did not meet clinical APS-1 criteria and several started with atypical presentation.

Methods

Sequencing and TaqMan genotyping were used to identify AIRE mutations. Complete AIRE deletion was confirmed and framed by real-time PCR, long-range amplification and analysis of the microsatellite markers.

Results

Seven different mutations were detected, three were novel: c.892G>A in exon 8, silent mutation c.462A>T in exon 3 most likely affecting splicing, and a complete deletion of a single AIRE allele ((?_68)_(1567-14_?)del). Novel (chronic otitis) and rare (systemic juvenile rheumatoid arthritis, autoimmune bronchiolitis, epilepsy) clinical presentations were observed.

Conclusions

AIRE mutation detection was valuable in the diagnostics of APS-1 in patients with atypical presentation. Chronic otitis media possibly broadened the cluster of APS-1 manifestations.