A novel nonsense mutation in the EYA1 gene associated with branchio-oto-renal/branchiootic syndrome in an Afrikaner kindred.

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by the associations of hearing loss, branchial arch defects and renal anomalies. Branchiootic (BO) syndrome is a related disorder that presents without the highly variable characteristic renal anomalies of BOR syndrome. Dominant mutations in the human homologue of the Drosophila eyes absent gene (EYA1) are frequently the cause of both BOR and BO syndromes. We report a South African family of Afrikaner descent with affected individuals presenting with pre-auricular abnormalities and either hearing loss or bilateral absence of the kidneys. Genetic analysis of the pedigree detected a novel EYA1 heterozygous nonsense mutation in affected family members but not in unaffected family members or a random DNA panel. Through mutational analysis, we conclude that this particular mutation is the cause of BOR/BO syndrome in this family as a result of a truncation of the EYA1 protein that ablates the critical EYA homologous region. To the best of our knowledge, this is the first case of BOR/BO syndrome reported in Africa or in those of the Afrikaner descent.

A review of trabeculectomy in East Asian people--the influence of race.

Glaucoma is the leading cause of irreversible blindness worldwide. East Asians account for approximately half of all glaucoma sufferers. It is likely that trabeculectomy will be needed for many of these people as the intraocular pressure is to be maintained at a satisfactorily low level. The eyes of East Asian people differ in some aspects from those of other races. This review describes the natural history of the eye after trabeculectomy in East Asians.

A pilot study of a system for grading of drainage blebs after glaucoma surgery.

PURPOSE: To develop and evaluate a novel bleb grading scheme for clinical and photographic evaluation. METHOD: A system for grading bleb photographs using widely applicable parameters was designed, and reference color photographs printed. A prospective masked agreement study was undertaken comparing slit lamp examination with mono and stereo photographs; 36 eyes of 28 patients with previous glaucoma surgery were graded according to defined parameters on a 1 to 10 scale clinically at the slit lamp by four ophthalmologists and two optometrists. Standardized stereo and mono photographs of the blebs were taken on the same day. The photographs were graded at least one week later in a masked fashion by the same observers, with grading of mono and stereo photographs also separated by one week. Analysis was performed to determine the variability and agreement between slit lamp results and photographic results, and to identify the presence of systematic bias. RESULTS: High levels of agreement were found between slit lamp and both stereo and mono photographs for vascularity indices, bleb wall thickness, and bleb elevation. Lower levels of agreement were found for the relative components of demarcated versus diffuse areas of the bleb, and for the total width of the bleb. The interquartile range for the median difference between slit lamp and photograph grading was -1.0 to 1.0 for all criteria except diffuse component (-2.0 to 2.0), and the median difference for all scores was 0.0. The median interobserver difference for all criteria was 0.0; the quartile range for all scores was between -0.5 and 1.0 except for diffuse component and width assessments whose quartiles fell in the -1.75 to 1.0 range. Examiners agreed with photographic grading within +/- 1 in more than 80% of gradings for vascularity and bleb height, within +/- 1 in more than 75% of gradings for bleb wall thickness, within +/- 2 in 61% of bleb width assessments, and +/- 2 in 59% of diffuse component. CONCLUSION: This bleb grading system is reproducible clinically and photographically. High levels of agreement between scores for photographs versus slit lamp examination were found for most categories, with good interobserver agreement for both photograph and slit lamp grading. Further refinement of scoring and reference photographs is required for optimization, especially for grading of bleb morphology.

Provision of MRI can significantly reduce CT collective dose.

The purpose of this study was to investigate the proportion of patients currently being investigated by CT that could be investigated by MRI with a potential reduction in exposure to ionizing radiation. The health detriment arising from the radiation dose associated with CT has been quantified in terms of the number of likely cases of serious health effects. The results show that a significant saving in the collective radiation dose is possible, with an associated detriment of between 0.23 and 0.33 cases of cancer or severe hereditary effects averted in one imaging department every year. In selecting the balance of provision of MRI and CT facilities, the health detriment associated with the radiation dose from CT should be considered.

Development and validation of measures of social phobia scrutiny fear and social interaction anxiety.

The development and validation of the Social Phobia Scale (SPS) and the Social Interaction Anxiety Scale (SIAS) two companion measures for assessing social phobia fears is described. The SPS assesses fear of being scrutinised during routine activities (eating, drinking, writing, etc.), while the SIAS assesses fear of more general social interaction, the scales corresponding to the DSM-III-R descriptions of Social Phobia--Circumscribed and Generalised types, respectively. Both scales were shown to possess high levels of internal consistency and test-retest reliability. They discriminated between social phobia, agoraphobia and simple phobia samples, and between social phobia and normal samples. The scales correlated well with established measures of social anxiety, but were found to have low or non-significant (partial) correlations with established measures of depression, state and trait anxiety, locus of control, and social desirability. The scales were found to change with treatment and to remain stable in the face of no-treatment. It appears that these scales are valid, useful, and easily scored measures for clinical and research applications, and that they represent an improvement over existing measures of social phobia.

The etiology of acrophobia and its relationship to severity and individual response patterns.

The acquisition of acrophobia in a large clinical sample was investigated. 148 patients from a university-based height phobia clinic and 148 age and sex matched non-phobic controls served as Ss. Subjects were assessed with a battery of measures including the Acrophobia Questionnaire [Cohen, D. C. (1977), Behavior Therapy, 18, 17-23], self-rating of severity [Marks, I.M. & Mathews, A. M. (1979) Behaviour Research and Therapy, 17, 263-267] global rating of severity [Michelson, L. (1986), Behaviour Research and Therapy, 24, 263-275], origins questionnaire [Menzies, R. G. & Clarke, J. C. (1993a) Behaviour Research and Therapy, 31, 355-365], and a height avoidance test. Results obtained question the significance of simple associative-learning events in the acquisition of fear of heights. Only 11.5% of fearful Ss were classified as directly conditioned cases. Furthermore, no differences between groups were found in the proportion of Ss who knew other height-fearfuls, had experienced relevant associative-learning events, or the ages at which these events had occurred. Finally, no relationships between mode of acquisition and severity or individual response patterns were obtained. In general, the data were consistent with the non-associative, Darwinian accounts of fear acquisition that continue to attract theorists from a variety of backgrounds [e.g. Bowlby, J. (1975) Attachment and Loss; Clarke, J.C. & Jackson, J. A. (1983) Hypnosis and behavior therapy: the treatment of anxiety and phobia; Marks, I. M. (1987) Fears, phobias and rituals: panic, anxiety and their disorders; Menzies, R. G. & Clarke, J. C. (1993a), (1993b) Behaviour Research and Therapy, 31, 499-501; Menzies, R. G. & Clarke, J. C. (1995)].

Parathyroid hormone/parathyroid hormone related peptide receptor gene transcripts are expressed from tissue-specific and ubiquitous promoters.

Parathyroid hormone (PTH) and PTH related peptide (PTHrP) stimulate diverse physiological responses in a number of tissues by binding to the same receptor. We have previously cloned the gene encoding the mouse PTH/PTHrP receptor (PTHR), and have identified a promoter region. The first exon transcribed from this promoter contains untranslated sequence and is followed by an exon encoding signal sequence and the first amino acids of the mature polypeptide. We have now identified and characterized a second promoter region, located > 3 kb upstream of the original. Four partial cDNA clones, amplified from mouse kidney RNA by reverse transcription followed by the polymerase chain reaction, contain sequence corresponding to two previously unidentified exons composed of untranslated sequence. The second (3') of the two exons is spliced to the previously identified signal sequence exon. These cDNAs are highly homologous to the 5' end of a cDNA isolated from human kidney, strongly suggesting that the promoter region is conserved between mouse and humans. RNase protection and primer extension experiments have identified several transcriptional start sites extending over a region of approximately 100 bp. Unlike the previously identified promoter, this promoter is not (G+C)-rich. It lacks a consensus TATA element, but does contain a consensus CCAAT box. We have determined the expression patterns of both promoters by RNase protection with total and poly A+ RNA from several mouse tissues. The newly identified promoter is highly tissue specific, being strongly active in kidney and weakly active in liver, but not expressed in the other tissues studied. The previously identified (G+C)-rich promoter is expressed in all tissues studied. This indicates that the PTHR gene expression is controlled by regulatory signals specific to kidney and liver, as well as signals functioning in a wide variety of cell types. These results may provide insight into certain defects in PTH signalling found in humans.

Danger expectancies and insight in acrophobia.

Differences between phobic and normal subject perceptions of danger were examined. Fifty-nine height phobic patients and a matched set of normal controls gave danger ratings before and during a height avoidance test on a triple extension ladder. Before the test acrophobic patients: (1) gave higher estimates of the probability of falling from the ladder than normals did; (2) gave higher estimates of the injuries that would result from falling, and; (3) believed their excessive levels of anticipated anxiety were more reasonable and appropriate to the demands of the situation than did normals. In addition, during the height avoidance test the differences between the two groups grew as phobic danger estimates increased while control group estimates did not. Finally, moderate, but inconsistent, relationships were obtained between phobic danger ratings and anxiety and avoidance. The implications of these findings for expectancy models of anxiety are discussed. The results challenge the view that phobic patients have complete insight into the inappropriateness of their own distress.

Involvement of multiple Cryptococcus neoformans strains in a single episode of cryptococcosis and reinfection with novel strains in recurrent infection demonstrated by random amplification of polymorphic DNA and DNA fingerprinting.

We compared the abilities of random amplification of polymorphic DNA and DNA fingerprinting, with oligonucleotide probes, to type five pairs of Cryptococcus neoformans clinical isolates recovered from five separate human immunodeficiency virus-positive patients in London, England. The two techniques had comparable discriminatory abilities when applied to these isolates. A total of eight different isolate types were demonstrated in these patients. No isolate type was observed in more than one patient. Two of the isolate pairs recovered from single episodes of cryptococcosis within 1 day of each other were genotypically indistinguishable by both methods. The other three pairs of isolates were all distinguishable. One of these isolate pairs was obtained from a single episode of cryptococcosis, while the other two were obtained from recurrent infections. These results indicate that multiple strains of C. neoformans may be responsible for a single episode of cryptococcosis and that recurrent infection may occur as a result of reinfection with a novel strain.

Molecular cloning of the gene encoding the mouse parathyroid hormone/parathyroid hormone-related peptide receptor.

The parathyroid hormone/parathyroid hormone-related peptide receptor (PTHR) is a G-protein-coupled receptor containing seven predicted transmembrane domains. We have isolated and characterized recombinant bacteriophage lambda EMBL3 genomic clones containing the mouse PTHR gene, including 10 kilobases of the promoter region. The gene spans > 32 kilobases and is divided into 15 exons, 8 of which contain the transmembrane domains. The PTHR exons containing the predicted membrane-spanning domains are heterogeneous in length and three of the exon-intron boundaries fall within putative transmembrane sequences, suggesting that the exons did not arise from duplication events. This arrangement is closely related to that of the growth hormone releasing factor receptor gene, particularly in the transmembrane region, providing strong evidence that the two genes evolved from a common precursor. Transcription is initiated principally at a series of sites over a 15-base-pair region. The proximal promoter region is highly (G+C)-rich and lacks an apparent TATA box or initiator element homologies but does contain CCGCCC motifs. The presumptive amino acid sequence of the encoded receptor is 99%, 91%, and 76% identical to those of the rat, human, and opossum receptors, respectively. There is no consensus polyadenylation signal in the 3' untranslated region. The poly(A) tail of the PTHR transcript begins 32 bases downstream of a 35-base-long A-rich sequence, suggesting that this region directs polyadenylylation.

The "medicinal effect": a possible mechanism in the development of severe alcohol dependence.

An examination of the change in attractiveness of a flavor subsequent to pairing with recuperation from malaise was undertaken. Forty-five subjects consumed a flavor after the rotation-induced motion sickness at two different intervals. Twenty-four consumed, on three separate conditioning trials, the paired flavor immediately as malaise began to decline (short-delay group), the remainder, when malaise had completely diminished (long-delay group). All subjects also consumed an unpaired flavor the morning after each session. Analysis of variance revealed that the paired flavor was rated as more highly attractive than the unpaired flavor, and this effect was only present in the short delay group. These results were taken as supporting the existence of conditioned flavor preferences in humans and interpreted as a possible learning mechanism in the development of severe alcohol dependence.

The etiology of childhood water phobia.

The origins of 50 clinical cases of childhood water phobia were investigated. All Ss had sought treatment at a university-based water phobia clinic. During screening, an origins questionnaire was administered to each attending parent. Parents were asked to indicate the most influential factor in the onset of their child's concern from a list of alternatives covering all three of Rachman's (Behaviour Research and Therapy, 15, 375-387, 1977) pathways to fear. Only one parent could recall classical conditioning episodes at the onset of their child's phobia. In contrast, the majority of parents (56%) claimed their child's concern had always been present, even on their first encounter with water. The data are taken to support a non-associative model of onset. Differences with previous studies in which classical conditioning has accounted for the majority of cases are discussed in terms of the differing definitions of conditioning used across studies.

The etiology of fear of heights and its relationship to severity and individual response patterns.

The acquisition of fear of heights in an undergraduate student sample was investigated. Height-fearful (n = 50) and non-fearful (n = 50) groups were formed on the basis of extreme scores to the heights item on the FSS-III (Wolpe & Lang, Behaviour Research and Therapy, 2, 27-30, 1964). Subjects were then assessed with a battery of measures including the Acrophobia Questionnaire (Cohen, Behaviour Therapy, 18, 17-23, 1977), self-rating of severity (Marks & Mathews, Behaviour Research and Therapy, 17, 263-267, 1979), global rating of severity (Michelson, Behaviour Research and Therapy, 24, 263-275, 1986), and a new comprehensive origins questionnaire constructed by the authors. Results obtained question the significance of simple associative-learning events in the acquisition of fear of heights. Only 18% of fearful Ss were classified as directly conditioned cases. Furthermore, no differences between groups were found in the proportion of Ss who knew other height-fearfuls, had experienced relevant associative-learning events, or the ages at which these events had occurred. Finally, no relationships between mode of acquisition and severity or individual response patterns were obtained. In general, the data were consistent with the non-associative, Darwinian accounts of fear acquisition that continue to attract theorists from a variety of backgrounds (e.g. Bowlby, Attachment and loss. London: Penguin, 1975; Clarke & Jackson, Hypnosis and behaviour therapy: The treatment of anxiety and phobias. New York: Springer, 1983; Marks, Fears, phobias and rituals: Panic anxiety and their disorders. New York, Oxford Univ. Press, 1987). Differences with previous studies in which classical conditioning has accounted for the majority of cases are discussed in terms of the methodological differences across studies.

A comparison of in vivo and vicarious exposure in the treatment of childhood water phobia.

The effectiveness of in vivo exposure and vicarious exposure in reducing children's phobic anxiety and avoidance of water was investigated. Forty-eight water phobic children between the ages of 3 and 8 yr were randomly assigned to one of four groups: (1) in vivo exposure plus vicarious exposure (IVVE); (2) vicarious exposure (VE); (3) in vivo exposure (IVE); and (4) assessment only control. All subjects in the treatment groups received three individually administered treatment sessions. At the conclusion of treatment it was found that the IVE condition had produced statistically and clinically significant gains that had generalized to another situation involving water, and were largely maintained over a period of 3 months. In contrast, the VE condition did not lead to statistically greater treatment benefits than those observed in the control subjects. Furthermore, there was no significant difference between the IVVE condition and the IVE condition in their level of improvement from pre- to post-treatment. Hence, by post-treatment, vicarious exposure had not only failed to produce benefits when used on its own, but had also failed to enhance the benefits achieved through in vivo exposure. However, a tendency for the vicarious component to enhance the maintenance of treatment benefits was found at follow-up. The implications of these findings are discussed.

Alcohol and recreational drug use by HIV-seropositive homosexual men.

The objectives of this study were to describe the patterns of alcohol and recreational drug use of HIV-seropositive homosexual men and to determine the effect of alcohol use on HIV risk-taking behaviour. Of particular interest was the effect of knowledge of HIV status on these behaviours. Information on alcohol and drug use was obtained from 485 HIV-seropositive homosexual and bisexual men presenting to a HIV-antibody testing and medical management clinic. Heavy alcohol use was common, with 46.2% reporting consumption of six or more standard drinks on one day recently. Men who knew that they were HIV infected drank significantly more than those men who had yet to learn of their HIV status at the time of interview. There was clear evidence in this study for a role of alcohol use in HIV risk-taking behaviour. Almost one-third (27%) of the HIV-seropositive men reported unprotected anal intercourse during the previous 3 months with approximately one-third of these (27/76, 35.5%) nominating alcohol as contributing to their high HIV-risk behaviour.