Beta-sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12.

beta-Sarcoglycan, a 43 kDa dystrophin-associated glycoprotein, is an integral component of the dystrophin-glycoprotein complex. We have cloned human beta-sarcoglycan cDNA and mapped the beta-sarcoglycan gene to chromosome 4q12. Pericentromeric markers and an intragenic polymorphic CA repeat cosegregated perfectly with autosomal recessive limb-girdle muscular dystrophy in several Amish families. A Thr-to-Arg missense mutation was identified within the beta-sarcoglycan gene that leads to a dramatically reduced expression of beta-sarcoglycan in the sarcolemma and a concomitant loss of adhalin and 35 DAG, which may represent a disruption of a functional subcomplex within the dystrophin-glycoprotein complex. Thus, the beta-sarcoglycan gene is the fifth locus identified (LGMD2E) that is involved in autosomal recessive limb-girdle muscular dystrophy.

Progressive muscular dystrophy in alpha-sarcoglycan-deficient mice.

Limb-girdle muscular dystrophy type 2D (LGMD 2D) is an autosomal recessive disorder caused by mutations in the alpha-sarcoglycan gene. To determine how alpha-sarcoglycan deficiency leads to muscle fiber degeneration, we generated and analyzed alpha-sarcoglycan- deficient mice. Sgca-null mice developed progressive muscular dystrophy and, in contrast to other animal models for muscular dystrophy, showed ongoing muscle necrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of muscle enzymes, increased muscle masses, and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated that the absence of alpha-sarcoglycan resulted in the complete loss of the sarcoglycan complex, sarcospan, and a disruption of alpha-dystroglycan association with membranes. In contrast, no change in the expression of epsilon-sarcoglycan (alpha-sarcoglycan homologue) was observed. Recombinant alpha-sarcoglycan adenovirus injection into Sgca-deficient muscles restored the sarcoglycan complex and sarcospan to the membrane. We propose that the sarcoglycan-sarcospan complex is requisite for stable association of alpha-dystroglycan with the sarcolemma. The Sgca-deficient mice will be a valuable model for elucidating the pathogenesis of sarcoglycan deficient limb-girdle muscular dystrophies and for the development of therapeutic strategies for this disease.

Effect of femtosecond laser irradiation on structure of UV grade fused silica.

A p-polarized femtosecond laser beam was used to irradiate a UV grade fused silica to create microchannels, which are useful for producing optical gratings or micro fluidics devices. The laser irradiated surface was characterized using optical microscope, stylus profiler, SEM, XRD and TEM. A special technique was used to protect the laser irradiated surfaces in preparing cross-sectional TEM samples. The XRD spectra and TEM observation reveal that structure of the fused silica remain amorphous after the femtosecond laser irradiation.

Beta-sarcoglycan: genomic analysis and identification of a novel missense mutation in the LGMD2E Amish isolate.

The sarcoglycan complex is involved in the etiology of four autosomal recessive limb-girdle muscular dystrophies (LGMD2C-F). A missense mutation (T151R) in the beta-sarcoglycan gene on chromosome 4q12 has been shown to cause a mild form of LGMD2E in 11 families from a Southern Indiana Amish community sharing a common haplotype. We now report that two sibs from another Amish family with mild LGMD2E are compound heterozygotes for chromosome 4q12 markers. In order to characterize the genetic defect in this new family, we determined the genomic organization of the beta-sarcoglycan gene. A second missense mutation (R91C) has now been identified in this LGMD2E Amish family. This mutation is also present in the homozygous state in another family of probable Amish ancestry. Finally, analysis of all the components of the dystrophin-glycoprotein complex was performed for the first time on a biopsy from a patient homozygous for the beta-sarcoglycan mutation (T151R). Interestingly, in addition to the loss of the entire sarcoglycan complex, we detected a reduction of alpha-dystroglycan which suggests a role for the sarcoglycan complex in stabilizing alpha-dystroglycan at the sarcolemma.

Identification of muscle-specific calpain and beta-sarcoglycan genes in progressive autosomal recessive muscular dystrophies.

The autosomal recessive forms of limb-girdle muscular dystrophies are encoded by at least five distinct genes. The work performed towards the identification of two of these is summarized in this report. This success illustrates the growing importance of genetics in modern nosology.

Pharmacological properties of a new aziridinylbenzoquinone, RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), in mice.

RH1 (2,5-diaziridinyl-3-(hydroxylmethyl)-6-methyl-1,4-benzoquinone) has shown preferential activity against human tumour cell lines which express high levels of DTD (EC 1.6.99.2; NAD(P)H:quinone oxidoreductase, NQO1, DT-diaphorase) and is a candidate for clinical trials. EO9 (3-hydroxy-5-aziridinyl-1-methyl-2-[1H indole-4,7-dione]prop-beta-en-alpha-ol) is a known substrate for DTD but clinical trials were disappointing, as a result of rapid plasma clearance and reversible dose-limiting kidney toxicity. It is an obvious concern that RH1 does not exhibit the same limitations. We therefore describe the antitumour activity and pharmacology of RH1 in mice and compare its pharmacological characteristics to those of EO9. Significant antitumour activity (P = 0.01) was seen for RH1 (0.5 mg/kg, i.p.) against the high DTD-expressing H460 human lung carcinoma. Pharmacokinetic analysis of RH1 in mice showed a t1/2 of 23 min with an area under the curve of 43.0 ng hr mL(-1) resulting in a calculated clearance of 5.1 mL min(-1), 10-fold slower than EO9. RH1 was also more stable than EO9 in murine blood, where the breakdown was thought to be DTD-related. NADH-dependent microsomal metabolism of RH1 and EO9 in both liver and kidney was slow (<100 pmol/min/g tissue), reflecting the low microsomal DTD expression (<35 nmol/mg/min). Liver cytosol metabolism was rapid for both compounds (>4500 pmol/min/g tissue), although DTD levels were low (21.4+/-0.6 nmol/mg/min). DTD activity in the kidney cytosol was high (125+/-8.2 nmol/mg/min) and EO9 was rapidly metabolised (4396+/-1678 pmol/min/g), but the metabolic rate for RH1 was 7-fold slower (608+/-86 pmol/min/g), even though RH1 was shown to be an excellent substrate for DTD (Vmax = 800 micromol/min/mg and a Km of 11.8 microM). The two DTD substrates RH1 and EO9 are clearly metabolised differently, suggesting that RH1 may have different pharmacological properties to those of EO9 in the clinic.

Angular dispersion compensation for acousto-optic devices used for ultrashort-pulsed laser micromachining.

Ultrashort pulsed laser material processing is a new micromachining method that is gaining interest. Its capability of submicrometer machining has been proved. To obtain high speed and highly flexible beam steering, a two-axis acousto-optic deflector is employed. However, dispersion associated with acoustic-optic interaction will cause serious spatial deformation on the writing spot. The compensation for dispersion is proposed and studied. Experiments show promising results. An additional advantage of the proposed compensation method is that it can also precisely control the pulse number, and, hence improve the quality of ablation.

Psychogenic pain.

Pain is a symptom commonly encountered by the medical profession. After excluding organicity, the possibility of psychogenic mechanisms should be borne in mind. Diagnostic clues in the history and physical examination are outlined. An early referral to the psychiatric services minimises wastage of time and resources but requires skillful handling and sensitivity on the part of the referrer. Patients do not regard themselves as psychologically abnormal and are often resentful and angry when referred for psychiatric evaluation. Principles of management are described with emphasis on establishing an early rapport. Cognitive behavioural methods appear promising but require further evaluation in controlled studies.

Treatment of neurotic disorders.

Neurotic disorders are commonly encountered in psychiatric outpatient clinics. Treatment of the commoner conditions like the anxiety states, depressive, obsessive-compulsive, hypochondrical and phobic neuroses will be described. This includes general supportive measures, pharmacological, cognitive, behavioural and psychodynamic approaches.

A follow up study of patients discharged from the Criminal Procedure Code.

Eighty-six male psychiatric patients discharged from the Criminal Procedure Code over a 5-year period were studied to determine their social, occupational and clinical outcome. The majority were young, single Chinese who had received little education and had suffered from schizophrenia. More than half had been hospitalised for up to 5 years. On discharge many were living with their relatives, 83% were working, 60% were socially isolated and about half were asymptomatic. Factors associated with their outcome were examined.

Why patients fail to attend psychiatric outpatient follow-up: a pilot study.

Patients who failed to attend psychiatric outpatient follow-up were compared with a group of comprising regular attenders. There were 71 defaulters out of 1,664 appointments given during the study period. Schizophrenia was the most common diagnosis. The defaulters did not differ from the controls in terms of age, sex, ethnicity, occupational or marital status. The unemployed were not more likely to be regular, instead, the better educated, shorter intervals between appointments and those given morning appointments were. Those solely on oral medication were more likely to default. The largest proportion gave reasons of work commitments and of not being free to attend; others claimed they had forgotten their appointments or had lost their appointment cards. Patients who said they did not come because they felt well or still had medication were cause for concern because of possible lack of insight and non-compliance with their medication.

A review of offenders remanded in a State Psychiatric Hospital.

Patients remanded over a two-year period to Woodbridge Hospital by Court Order were studied retrospectively. Schizophrenia was the most common diagnosis, theft and robbery the most prevalent offences. Males greatly outnumbered females. There were important gender differences, with males tending to commit sexual offences and females, theft and mischief. Males were less likely to be acquainted with their victims but those who caused hurt were more likely to know their victims. Outrage of modesty and theft were more likely to be committed against strangers. The reconviction rate was 26%, with repeat offenders more likely to commit sexual offences and theft. Patients who had previous psychiatric hospitalisation were more likely to be attending follow-up prior to and after release from remand and were more likely to have schizophrenia. Those assessed to be fit to plead were either fined or given jail sentences. Unsoundness of mind and unfitness to plead were associated with further remand in this hospital.

Panic disorder in Singapore: clinical features and comparisons with generalised anxiety disorder.

Fifty-eight outpatients with panic disorder (PD) were examined to determine their clinical features in comparison with a cohort of 52 patients with generalised anxiety disorder (GAD). Both groups were of comparable age, sex, educational level, marital status and ethnicity. PD patients were more likely to complain of palpitations, breathlessness, chest pain, numbness, choking sensations and especially fear of dying. GAD patients tended to complain of feeling tense, insomnia, headaches, weakness, restlessness and muscle aches. PD patients had greater comorbidity especially with agoraphobia and depression. Contrary to other reports, there were more males than females in both groups but alcohol dependence and suicide attempts were relatively rare. PD symptoms seemed more distressing, caused more social and occupational disruption, led to more requests for medical investigations and earlier psychiatric consultations. These factors seemed to suggest that panic disorder is a more severe illness than generalised anxiety disorder.

Men who commit rape in Singapore.

INTRODUCTION: Rape is regarded as one of the most serious forms of sexual assault, yet there has been a lack of clinical information on convicted rapists in Singapore. This paper attempts to confirm the hypotheses that rapists come from disordered backgrounds, from large families and are poorly educated. We further hypothesize that they are more likely to have a history of antisocial behaviour and to have had recent exposure to pornography. METHODS: Rapists serving sentence in a Singapore prison were compared with 2 control groups, one consisting of violent non-sexual offenders and another comprising non-violent non-sexual offenders. RESULTS: Rapists tended to be men in their late thirties who rape women in their early twenties. A large majority of the rapists and their victims are known to each other. Rapists are more likely to come from large, disordered families, attaining low educational levels but seemingly less antisocial when compared with the controls. More rapists and violent controls reported recent viewing of pornography before committing their offenses. CONCLUSION: The demonstrated similarities between rapists and violent controls lend support to the view that rape is an act of violence carried out in a sexual manner rather than a sexual act violently expressed.

Men who commit statutory rape: how are they different from other rapists?

From an original cohort of 63 rapists serving prison sentences for rape in Singapore, two subgroups were identified, one subgroup who raped females 14 years and younger (an offence that is termed 'statutory rape' or 'SR') and another who raped females 14 years and above (which we term 'non-statutory rape' or 'NSR'). The two subgroups were compared across a broad range of variables. Those who committed SR tended to be older, married, Malay men who were more likely to commit rape in their home or in the home of their victims, and who rated the quality of their sexual relationships more unfavourably than the NSRs. The NSRs were more likely to be single men but with concurrent relationships with different females. NSRs were more likely to report dysfunctional family backgrounds, early conduct problems and were more likely to rape their victims outdoors and late into the night. Although in both subgroups the majority of the victims were known to the rapists, relatives (i.e. step-daughters or daughters) were by far the most common victims of the SR rapists.

A review of outrage of modesty offenders remanded in a state mental hospital.

Minor sexual offences have been increasing over the years. These include parasexual offences such as exhibitionism, frotteurism and its variant. In Singapore, a common minor sexual offence which involves touching, grabbing, kissing or fondling is known as outrage of modesty or molestation. To date no known studies have been made on this subtype of sexual offender. This is a five-year retrospective study looking into the profile of 157 outrage of modestry offenders remanded to Woodbridge Hospital, a state mental hospital. Results showed that schizophrenia was the predominant psychiatric diagnosis amongst the offenders (45.3%) followed by mental retardation (21.7%). Only 28.7% of those suffering from a mental illness experienced active psychiatric symptoms at the time of the sexual offence. Touching, stroking or fondling were the most frequently reported type of molestation (60.5%). The majority of the offences took place between 6 am and 6 pm. Only 15.3% had a past history of sexual offences and the majority (94.9%) were of sound mind at the time of the offence. There were no statistically significant differences between first time and repeat offenders with regard to age, ethnic group, educational level, marital status, diagnoses, place of offence, time and type of offence, soundness of mind and fitness to plead.

The sexual profile of rapists in Singapore.

To our knowledge, this is the first paper that examines the sexual profile of rapists in Singapore. A semi-structured interview based on a questionnaire about sexual habits was conducted on 62 convicted rapists and a control group of 63 prisoners comprising 32 convicted for violent non-sexual offences and 31 for non-violent non-sexual offences. Significantly more rapists masturbated at least once a month and were exposed to pornography within six months before the offence when compared to non-violent controls. Violent controls did not differ significantly from rapists in any aspect of the sexual history. The greater similarity between rapists and violent controls lends support to the concept of rape as a violent rather than sexual offence. A subgroup of 17 'hypersexual' rapists were identified who were either having sex or masturbating very frequently but had still resorted to rape. Compared to the other 46 rapists, the 'hypersexual' rapists were more likely to have fantasised predominantly about rape or bondage and to cite domination, aggression or hostility as reasons for committing rape, suggesting an even stronger element of power and aggression than in their less sexually active counterparts.

A study of outrage of modesty offenders in a Singapore prison.

Outrage of modesty (OOM) offenders cause considerable annoyance and distress to their victims. The offending behaviours include touching, grabbing or fondling of erogenous or non-erogenous parts of the victim's body. The purpose of this study is to examine a prison cohort of OOM offenders and to compare them with a group of OOM offenders who had been remanded in a state mental hospital. All prisoners serving sentence over a two-year study period were interviewed. They were of similar mean age to the hospital cohort but were better educated, more likely to be married and most were working. Victims tended to be young females with an average age of 19 years. Psychotic disorders were rarely present, although 15% had a dissocial personality disorder. Those with previous OOM convictions were likely to have had past psychiatric consultations and were more likely to be unmarried. However, there were no statistically significant differences between convicted first-time offenders and repeat offenders with respect to age, educational level, nature of offences and alcohol consumption. The prisoners were less inclined to commit their offences in the mornings. Breasts and genitalia were the favoured targets for molest action, irrespective of time or place or whether the offence was committed by a first or repeat offender. The offences were often committed along staircases, corridors and in crowded public places.

The sexual habits of males who molest.

To gain better understanding into the causes of molesting behaviour in males, we examined a prison cohort of molesters and compared them with a control group comprising thieves. The molesters were older, had attained a higher educational level and were more likely to be married. They had their initial sexual intercourse at an older age but tended to have multiple sexual relationships and were less likely to report having viewed pornographic material. Three months prior to committing their offences, molesters seemed to engage in less sexual activity. The implications are that molesters had a need for more explicit sexual contact but were unable to sustain ongoing, stable, intimate sexual relationships.

Personality of males charged with outrage of modesty.

Outrage of modesty (OOM) is considered a serious crime in Singapore and offenders are often charged with a period of imprisonment with or without a fine and caning. Previous studies have indicated that non-violent sexual offenders tend to have a socially inhibited personality. No published study has yet been conducted to investigate the personality of OOM offenders. The purpose of the current study was to assess the personality of males charged with outrage of modesty and compare them to a group of males charged with theft using the 16 Personality Factors questionnaire (16PF; Cattell, Eber, and Tatsuoka, 1970). Participants were selected over a two-year study period from a cohort of prisoners serving sentence at Changi Prison. A total of 30 OOM and 22 theft offenders completed the 16PF. All OOM subjects had been charged for molesting an adult female. Unexpectedly, planned comparisons revealed that OOM subjects had marginally higher scores on Factor H (boldness) compared to theft subjects. Exploratory analyses revealed no other significant differences between OOM and theft subjects. Implications of findings and limitations of the study are discussed.