Clostridium perfringens: a rare cause of spondylodiscitis case report and review of the literature.

Presented is a case of a 64-year old male with a unique and yet unreported case of a spondylodiscitis caused by Clostridium perfringens. Becoming symptomatic with massive neurological deficits. Computed tomography (CT) revealed typical signs of spondylodiscitis involving the vertebral body L5 with extensive vacuum phenomenon.

Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation.

Six inherited neurodegenerative diseases are caused by a CAG/polyglutamine expansion, including spinal and bulbar muscular atrophy (SBMA), Huntington's disease (HD), spinocerebellar ataxia type 1 (SCA1), dentatorubral pallidoluysian atrophy (DRPLA) Machado-Joseph disease (MJD or SCA3) and SCA2. Normal and expanded HD allele sizes of 6-39 and 35-121 repeats have been reported, and the allele distributions for the other diseases are comparable. Intergenerational instability has been described in all cases, and repeats tend to be more unstable on paternal transmission. This may present as larger increases on paternal inheritance as in HD, or as a tendency to increase on male and decrease on female transmission as in SCA1 (ref. 15). Somatic repeat instability is also apparent and appears most pronounced in the CNS. The major exception is the cerebellum, which in HD, DRPLA, SCA1 and MJD has a smaller repeat relative to the other brain regions tested. Of non-CNS tissues, instability was observed in blood, liver, kidney and colon. A mouse model of CAG repeat instability would be helpful in unravelling its molecular basis although an absence of CAG repeat instability in transgenic mice has so far been reported. These studies include (CAG) in the androgen receptor cDNA, (CAG) in the HD cDNA, (CAG) in the SCA1 cDNA, (CAG) in the SCA3 cDNA and as an isolated (CAG) tract.

Erythrocyte chimerism after injection of spleen cells into anemic mice of the W-series.

Anemic mice (W(v)W(v)) when injected at birth with a mixture of isologous (genotype W(v)w) and homologous spleen cells, showed an improvement in their peripheral blood picture when adult. Red blood counts, red cell size, and electrophoresis of the hemoglobins indicated that, in some cases, the homologous tissue had become implanted and, in others, the isologous tissue was functioning.

Neural tube defects and sex ratios.

The sex ratio of 147 fetuses with presumed multifactorial neural tube defect (NTD) was studied. Overall, the ratio (males:females) was 0.73 with expected female excess. However, when the NTDs were subdivided according to the site of the lesion, the sex ratios varied. Total craniorachischisis, anencephaly with cervical spina bifida, holoacrania, and thoracic spina bifida showed a greater female excess than that overall; the sex ratio for meroacrania was close to unity, while that for low spinal lesions, particularly those involving the sacrum, showed an extreme bias towards males. These findings are related to the mode of formation of the neural tube. Females seem prone to defects of neurulation and males to defects in canalization. An explanation for these findings is suggested in possible sex differences in rate of early embryonic development.

Conjoined twins discordant for cleft lip and palate.

Female thoraco-omphalopagus twins were of equal size and had similar abnormalities related to the twinning site. However, one twin was more severely affected and also had cleft lip and palate which the co-twin did not have. The implications of this are discussed.

Neural tube defects: are neurulation and canalization forms causally distinct?

Neural tube defects (NTD) may be separated according to the overall location and probable embryological origin into 2 groups: upper or neurulation defects, and lower or canalization defects. Evidence as to whether these 2 forms are causally related or distinct was sought from 2 sources. Families with more than one NTD individual were studied to examine whether there was concordance within sibships for these 2 types of lesion. Seven of the 38 sibships were discordant (18%). Eight of the 10 cases of NTD that had arisen despite maternal periconceptional vitamin supplementation were neurulation defects and 2 were canalization defects. Both observations suggest that upper and lower types of NTD are causally related, and offer no support for the suggestion that they are distinct.

Multi-site neural tube closure in humans and maternal folate supplementation.

A group of 13 individuals with neural tube defects (NTD) despite maternal periconceptional folate supplementation was examined to determine precisely which closure sites along the neural tube had failed during embryogenesis. All the common forms of NTD, and thus all the usual closure sites, were represented. This suggests that folate deficiency does not act specifically on one region of the neural tube; rather, it may be more generally involved in the cause of human NTD.

Sex, neural tube defects, and multisite closure of the human neural tube.

While neural tube defects (NTD) overall have a female sex bias, this does not apply to all sites along the neuraxis. The findings regarding sex and NTD in a series of midtrimester fetuses are reviewed, and then analysed in terms of the recent hypothesis that during embryogenesis of the human neural tube there are multiple closure sites, rather than a single zipping up process. Females more often than males tend to have craniorachischisis, spina bifida involving the thorax, the holoacrania form of anencephaly, anencephaly and cervical spina bifida and encephalocoeles, while males more often than females have spina bifida affecting the lower spine. Meroacrania occurs equally in both sexes. Other sources indicate that there is a male bias in frontoethmoidal encephalocoeles. Since sex seems to be a factor that is differentially associated with lack of closure of specific areas of the neural tube, it would seem to support the notion that there are multiple closure sites in the human neural tube. However, no association was found between a particular sex and either the type of NTD which have an isolated abnormality or those NTD associated with developmental abnormalities of other body systems.

Unusual case of Smith-Lemli-Opitz syndrome "type II".

We describe a fetus with abnormalities suggestive, but not typical, of severe Smith-Lemli-Opitz syndrome (SLO). Biochemical studies demonstrated that there was a defect of cholesterol biosynthesis similar to that recently discovered in children with SLO. The findings in this fetus extend even further the wide spectrum of abnormalities of the SLO phenotype, and emphasize that a genetic pathological examination and biochemical studies should always be undertaken on atypical cases, especially fetuses.

Chondrodysplasia punctata: another possible X-linked recessive case.

A 22-week fetus who had died in utero had a markedly hypoplastic nose and other facial abnormalities, short fingers, hypoplastic nails, and small phallus. Radiologically there was symmetrical cartilaginous stippling of the vertebral column, femoral heads, calcanei and elbows typical of chondrodysplasia punctata (CP), and metacarpal shortness and tiny pyramidal phalanges. The several causally different forms of CP are tabulated. Differential diagnosis suggests that the present case, which does not have limb shortness, could be a case of X-linked recessive brachytelephalangic chondrodysplasia punctata.

Two sibs with anophthalmia and pulmonary hypoplasia (the Matthew-Wood syndrome).

We describe two sibs with pulmonary hypoplasia and anophthalmia; one also had a number of other malformations. Only one other broadly similar case could be found in the literature, and it was an isolated occurrence. The condition is named the Matthew-Wood syndrome.

Dominant optic atrophy, Kjer type. Linkage analysis and clinical features in a large British pedigree.

OBJECTIVES: To perform DNA linkage studies in an extensive 5-generation British pedigree with dominant optic atrophy and to validate the efficacy of domiciliary screening for affected members. METHODS: Family members received a domiciliary examination based on corrected visual acuity, color vision, visual field defects, and optic disc appearance; DNA linkage analysis was performed using 7 microsatellite markers on 3q27-qter. RESULTS: Based on the results of the ophthalmic examination, 15 members could be classified as definitely affected, 1 probably affected, and 25 unaffected. Two-point linkage analysis gave significant maximum lod scores at theta [corrected] = 0.00, with the markers D3S3669, D3S3590, and D3S3642. A haplotype segregating with the disease was identified in affected individuals, including the probably affected subject. Informative meioses defined the disease interval between markers D3S1601 and D3S1265. CONCLUSIONS: Domiciliary screening was effective in identifying all 16 affected members of a British family with dominant optic atrophy. The typical clinical features were present. The location of the OPA1 gene in this new British family seems to be in the 3q27-28 region and is the same as that reported in Danish, Cuban, and French families, suggesting no genetic heterogeneity in this disorder.

Arylsulphatase A pseudodeficiency in vascular dementia and Alzheimer's disease.

The carrier rates of a genetic marker for arylsulphatase A pseudodeficiency (ASA-PD) were determined in three series of patients with vascular dementia (VaD) or Alzheimer's disease (AD). In the first community-based sample, the 1524 + 95A-->G mutation, which is known to be associated with ASA-PD, was present in 35% of VaD cases and none of the AD cases. In a second sample of cases drawn from a Dementia Register, the mutation rates were 18% (VaD) and 16% (AD). Brain DNA from a post-mortem sample revealed the ASA-PD mutation in 60% of VaD cases and 34% of AD cases. These rates are higher than previous studies of culturally similar populations and suggest that ASA-PD may be a risk factor for dementia.

Gel electrophoresis of maternal and fetal serum cholinesterases from normal pregnancies and of those affected by neural tube defects.

The cholinesterase isozymes of maternal and fetal sera from normal pregnancies and those in which the fetus had a neural tube defect were studied using flat-bed vertical polyacrylamide gel electrophoresis. Normal maternal and fetal sera had multiple bands of cholinesterase activity, including the two bands in the position of those found in amniotic fluid from NTD pregnancies. The one difference between maternal and fetal sera was that the faster of these two "amniotic fluid bands" was acetylcholinesterase in fetal serum, as in the neural tube defect amniotic fluids, but non-specific cholinesterase in maternal serum. In artificial mixtures this difference could be used to differentiate between maternal and fetal blood-contamination of amniotic fluids, but in samples naturally contaminated at amniocentesis this test did not always agree with the Kleihauer findings. Both maternal and fetal sera had additional weak acetylcholinesterase activity in the most anodally migrating enzyme bands, but all other enzyme activity was non-specific cholinesterase. No difference was observed in the isozymes of fetal serum from normal fetuses and those with neural tube defects, or of maternal serum from normal and neural tube defect pregnancies.

Value of glial fibrillary acidic protein determination in amniotic fluid for prenatal diagnosis of neural tube defects.

Glial fibrillary acidic protein (GFAp), an intracellular protein specific to astrocytes of the central nervous system, was determined by 2-site immunoradiometric assay in amniotic fluid from 78 pregnancies with a normal, and 100 with an abnormal outcome. GFAp was not detectable in any of the normal pregnancies, but there were measurable, and so raised, levels in 23 out of 25 cases of anencephaly and 4 out of 7 cases of spina bifida, which therefore allowed prenatal diagnosis. GFAp was also increased in 4 of 6 cases of fetal intrauterine death, but not in other congenital malformations associated with elevated alphafetoprotein levels or abnormal acetylcholinesterase banding pattern, such as exomphalos, other gastrointestinal malformations or renal abnormalities. GFAp is therefore specific for diagnosing open neural tube defects. The determination of GFAp in amniotic fluid was slightly less efficient overall than AFP for the prenatal diagnosis of neural tube defects, but can be a useful ancillary test and has the advantage of specificity.

Effects of tobacco smoke inhalation on the developing mouse embryo and fetus.

Pregnant C57BL or mutant curly tail mice were exposed to tobacco smoke in a smoking machine for 10 min, three times a day, either on the day of conception (day 0) and days 1 and 2, or on days 3, 4, and 5, or from day 0 through day 17. In the first two cases, the embryonic development was subsequently assessed on day 9. Both periods of exposure were associated with a dose-related retardation in embryonic growth, but it was more marked with exposure on days 0, 1, and 2. It would seem, therefore, that even brief episodes of maternal smoking are detrimental to the very early embryo, and even if smoking is stopped, the effects persist at least for some days and there is no immediate catch-up growth. In the mice exposed continuously for 17 days, the fetuses were studied on day 18: there was a significant reduction in fetal body weight in both types of mice. There was also a reduction in the number of skeletal ossification centres, showing that additionally, there was developmental delay. In C57BL mice, one rib abnormality occurred, but no major congenital malformations; however, in the curly tail mutants, 60% of which normally have a curly tail or an open neural tube defect, there was a modest increase in the frequency of open spina bifida and exencephaly. A few minor rib abnormalities also occurred, and one case of cleft lip with cleft palate. These results indicate that tobacco smoke, while detrimental to the developing fetus, is not a potent teratogen in the mouse, but that it may have minor effects in those individuals genetically predisposed to an abnormality. This may have implications for humans, and may explain the generally inconclusive findings regarding congenital malformations in the children of women who smoke during pregnancy. In all experiments, the detrimental effects were seen with both higher tar cigarettes (tar and nicotine yields: 12.9 and 1.19 mg/cigarette, respectively) and lower tar cigarettes (4.8 and 0.54 mg/cigarette respectively), so tobacco modification is not really beneficial to the developing fetus.

The spinal cord lesion in human fetuses with myelomeningocele: implications for fetal surgery.

Recently produced experimental evidence suggests that secondary traumatic injury and degenerative changes, acquired in utero, to the openly exposed neural tissue may be primarily responsible for the massive neurological deficit associated with myelomeningocele (MMC). The goal of this study was to examine the morphology of human fetuses with MMC to determine if acquired trauma to the spinal cord could be identified. The MMC lesions with surrounding tissues from 10 human fetuses ranging in gestational age between 19 and 23 weeks were prepared with serial histological sections. The MMC lesions were characterized by an open vertebral arch, an open dura mater fused laterally to the dermis, and an open pia mater fused laterally to the epidermis. The spinal cord was exposed, without any meningeal, bony, or cutaneous covering, and was resting on the dorsal aspect of the abnormal arachnoid sac created by the fusion of the meninges to the cutaneous tissues. The exposed neural tissue had undergone varying degrees of recent traumatic injury as a result of its exposed position, ranging from nearly complete preservation of neural elements in four cases to nearly complete loss in two cases. The neural tissue remaining in the MMC with partial loss contained hemorrhages and abrasions from recent injury, suggesting that injury occurred during passage through the birth canal. The presence of dorsal and ventral parts of the cord with nerve roots and ganglia demonstrated that these structures had formed during development and that the loss of tissue by injury was a secondary change. The results support the concept that performing in utero surgery could protect the exposed but initially well-developed and uninjured cord, prevent secondary neural injury, and preserve neural function in the human fetus with myelomeningocele.

Ultrastructural changes in 9-day old mouse embryos following maternal tobacco smoke inhalation.

Mice were exposed to tobacco smoke inhalation for three ten-minute episodes on days 6, 7 and 8 of pregnancy. The effects of a higher tar cigarette (tar 12.9 mg, nicotine 1.19 mg, carbon monoxide 9.01 mg/cigarette) and a modified brand (4.8, 0.54 and 4.03 mg/cigarette respectively) were compared. Specific cells of the embryos were examined by scanning and transmission electron microscopy on day 9, 20 hours after the last smoking episode. Cells of the neural plate, surface ectoderm, pericardium and heart all showed marked surface changes with the higher tar cigarettes which suggested depressed metabolic activity. The changes were sometimes less marked with lower tar cigarettes but not in all cell types. Transmission electron microscopy of the neural tube also showed that significant changes were associated with the higher tar cigarettes, particularly of the mitochondria which became elongate and the cristae more common and less distinct. These findings suggest that maternal smoking may cause anoxia in the embryo, and that the cellular changes this produces persist even 20 hours after smoking has ceased. However, cell counts of sections of the closed neural tube showed no change in the total cell number or number of dead cells or alteration in the mitotic index with either type of cigarette. Cigarette modification does reduce to some extent the detrimental effects of maternal smoking observed in the embryo, but it is by no means all-embracing.

Neural tube defects, chromosome abnormalities and multiple closure sites for the human neural tube.

The hypothesis that during human embryogenesis there is multi-site closure of the neural tube, with possibly regionally distinct genetic control, is examined in the light of the neural tube defects (NTD) observed in trisomy 13, trisomy 18 and triploidy which survive at least to the mid-trimester. In a series of mid-trimester fetuses examined post-mortem, there were two spina bifidas in 25 cases of trisomy 13; eight spina bifidas and one anencephalic among 38 trisomy 18 individuals; and three spina bifidas in 13 triploids. Not only was there a predominance of spina bifida, but all the spina bifidas were similar in location along the neuraxis: regardless of chromosome constitution, they were all sacral or lumbosacral. A survey of the literature confirms this finding. While this regionally distinct type of NTD is not specific to a particular chromosome abnormality and thus by implication to any particular gene, it does seem to be specific to an imbalance caused by an excess of genetic material of a type which permits survival past the first few post-conception weeks, and thus lends some support to the hypothesis.