Aim The aim was to evaluate the influence of a half day, hands-on, workshop on the detection and repair of obstetric anal sphincter injuries (OASIs). Method Starting in February 2011, hands-on workshops for the diagnosis and repair of OASIs were delivered by trained urogynaecologists in departments of tertiary medical centres in Israel. The structure of the hands-on workshop resembles the workshop organized at the International Urogynecological Association annual conferences. Participants included medical staff, midwives and surgical residents from each medical centre. We collected data regarding the rate of OASIs, 1 year before and 1 year following the workshop, in 11 medical centres. The study population was composed of parturients with the following inclusion criteria: singleton pregnancy, vertex presentation and vaginal delivery. Pre-viable preterm gestations (< 24 weeks), birth weight < 500 g, stillborn, and those with major congenital anomalies, multifoetal pregnancies, breech presentations and caesarean deliveries were excluded from the analysis. Results In the reviewed centres, 70 663 (49.3%) women delivered prior to the workshop (pre-workshop group) and 72 616 (50.7%) women delivered following the workshop (post-workshop group). Third- or fourth-degree perineal tears occurred in 248 women (0.35%) before the workshop, and in 328 (0.45%) following the workshop, a significant increase of 28.7% (P = 0.002). The increase in diagnosis was significant also in women with third-degree tears alone, 226 women (0.32%) before the workshop and 298 (0.41%) following the workshop, an increase of 28.3% (P = 0.005). Conclusion The detection rate of OASIs has significantly increased following the hands-on workshop. The implementation of such programmes is crucial for increasing awareness and detection rates of OASI following vaginal deliveries.

Optic nerve sheath diameter (ONSD) enlargement has been described as an early marker of increased intracranial pressure in fetuses with intracranial lesions A decrease in the diameter can suggest optic nerve hypoplasia. The aim of this study was to establish ONSD nomograms based on gestational age. A prospective, multicenter, cross-sectional study was performed including 382 normal singleton fetuses with gestational age ranging from 16 to 38 weeks. The technique for measurement of the ONSD using 2D sonography followed the previous description published by our group, using high-resolution real-time ultrasound with 5–9 or 7-12MHz transducers. Nomograms were produced using multilevel statistical analysis, according to the Royston and Wright method. At least one side ONSD was successfully measured in all fetuses enrolled in the study. The linear regression model was best fitted to estimate the 5th, 50th, and 95th percentile range of the ONSD at each gestational week. Fetal ONSD gradually increased with GA with fitted equation (mean 0,8 mm by 16 weeks and 3,6mm by 38 weeks of gestation). We have provided nomograms for the assessment of the fetal ONSD. This is a useful non-invasive tool and may provide a solid basis for a multidisciplinary approach, management and counseling of intracranial conditions associated with abnormal ONSD.

The aims of this study were to describe the sonographic technique for the assessment of the fetal optic nerve sheath in normal fetuses and to report three fetuses with space occupying intracranial lesions and enlarged optic nerve sheath diameters (ONSD), compared to normal fetuses. The preferred view for the fetal eye sonographic assessment is through an axial plane at the level of the lens with the face positioned towards the transducer. The images obtained are similar to the ones depicted in postnatal ophthalmic sonography. Transabdominal and transvaginal routes may be used for the examination. The ONSD was measured in normal fetuses and paired by gestational age ( ± 1 week) to 3 fetuses with intracranial findings suspected of producing an increase in intracranial pressure (ICP) (1 dural thrombosis and 2 intracranial tumors). The mean diameters ± 2 SD were calculated for each gestational week. In the 42 normal fetuses the ONSD showed an increase from 1.2 mm at 23 weeks to 2.6 mm at 36 weeks. The measurements at 36 weeks correlated well with those observed in newborns. When comparing the ONSD measurements of these three fetuses to normal fetuses paired for gestational age, we found that all values were above two standard deviations of the normal range. Fetal ONS measurement is feasible using a technique similar to the one performed in adults and children. We were able to demonstrate ONS enlargement in 3 fetuses with intracranial lesions potentially leading to increased ICP.

To describe the sonographic technique for assessment of the fetal optic nerve sheath and to report on three fetuses with intracranial lesions and enlarged optic nerve sheath diameter (ONSD) compared with normal controls matched for gestational age (GA).

Inherited distal myopathies represent a heterogeneous group of skeletal muscle disorders. One type of adult-onset, progressive autosomal dominant distal myopathy, frequently associated with dysphagia and dysphonia, has been mapped to chromosome 5q31 in a North American pedigree (vocal cord and pharyngeal weakness with distal myopathy; VCPDM). We recently identified a second large VCPDM family of Bulgarian descent and performed fine mapping of the critical interval. Sequencing of positional candidate genes revealed precisely the same non-conservative S85C missense mutation affecting an interspecies conserved residue in the MATR3 gene in both families (Senderek et al., Am J Human Genet, in press). MATR3 is expressed in skeletal muscle and encodes matrin 3, a component of the proteinaceous network that extends throughout the nucleus and has been termed the nuclear matrix. Different disease related haplotype signatures in the two families provide evidence that two independent mutational events at the same position in MATR3 cause VCPDM. Histopathological and electron microscopical analysis of two muscle biopsies revealed reduced matrin 3 immunoreactivity of muscle fiber nuclei and myonuclear degeneration as well as autophagic vacuoles in affected muscle fibers.

Corticobasal ganglionic degeneration (CBGD) is a progressive neurological disorder characterized by gradual nerve cell loss and atrophy of the cerebral cortex and basal ganglia. Symptoms of the disorder include verbal apraxia and language disturbances along with bradykinesia and rigidity. There have been no reports to date of acquired or neurogenic stuttering associated with CBGD. We describe a patient whose initial symptom of CBGD was stuttering which worsened as her disease progressed. Neuroimaging including PET scans revealed poor metabolic functioning of the right basal ganglia. This finding, along with bilateral atrophy of the frontal and parietal lobes likely contributed to the disturbance of motor sequencing skills and led to the development and worsening of stuttering, apraxia of speech and swallowing, and eventual aphasia and cognitive decline. We suggest that neurogenic stuttering may be an additional symptom of CBGD.

Distal myopathies represent a heterogeneous group of inherited skeletal muscle disorders. One type of adult-onset, progressive autosomal dominant distal myopathy, frequently associated with dysphagia and dysphonia, has been mapped to chromosome 5q31 in a North American pedigree (vocal cord and pharyngeal weakness with distal myopathy; VCPDM). We report the identification of a second large VCPDM family of Bulgarian descent and fine mapping of the critical interval. Sequencing of positional candidate genes revealed precisely the same non-conservative S85C missense mutation affecting an interspecies conserved residue in the MATR3 gene in both families. MATR3 is expressed in skeletal muscle and encodes matrin 3, a component of the proteinaceous network that extends throughout the nucleus and has been termed the nuclear matrix. Different disease related haplotype signatures in the two families provide evidence that two independent mutational events at the same position in MATR3 cause VCPDM. Histopathological and electron microscopical analysis of two muscle biopsies revealed reduced matrin 3 immunoreactivity of muscle fiber nuclei and myonuclear degeneration as well as autophagic vacuoles in affected muscle fibers. Our data establish proof-of-principle that the nuclear matrix is crucial for normal skeletal muscle structure and function and put VCPDM on the growing list of monogenic disorders associated with the nuclear proteome.

Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family ( P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family ( P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients ( P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR ( P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone ( P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

Distal myopathy refers to a heterogeneous group of disorders in which the initial manifestations are weakness and atrophy of the hands and feet. We report a family segregating an autosomal dominant distal myopathy, with multiple affected individuals in whom vocal cord and pharyngeal weakness may accompany the distal myopathy, without involvement of the ocular muscles. To our knowledge, this pedigree displays a distinct distal myopathy with the added features of pharyngeal and vocal cord dysfunction (VCPDM) that has not been previously reported. We mapped the MPD2 gene for VCPDM to chromosome 5q within a 12-cM linkage interval between markers D5S458 and D5S1972 in a large pedigree (a maximum LOD score of 12.94 at a recombination fraction of 0 for D5S393) and combined genome screening and DNA pooling successfully adapted to fluorescent markers. This technique provides for the possibility of fully automated genome scans.

Progesterone (PROG) is a neurosteroid, possessing a variety of functions in the central nervous system. Exogenous PROG has been shown to reduce secondary neuronal loss in conjunction with attenuated brain edema after cerebral contusion and to reduce brain edema after focal cerebral ischemia. In the present study, we assessed the neuroprotective potential of PROG in a model of focal cerebral ischemia in the rat. Forty-eight male Wistar rats were randomly assigned to 4 groups, i.e. pretreatment with water soluble PROG, or dimethyl sulfoxide (DMSO) dissolved PROG, or DMSO as control or delayed treatment with DMSO dissolved PROG. Middle cerebral artery occlusion (MCAO) was induced by insertion of an intraluminal suture and reperfusion was performed by withdrawing the suture. Pretreatments were initiated 30 min before MCAO via intraperitoneal injection. Delayed treatment was initiated upon reperfusion following 2 h of MCAO. Infarct volume, body weight loss, and neurological deficit were measured 48 h after MCAO. Pre- and delayed treatment with DMSO dissolved PROG resulted in a 39% (P < 0.05) and 34% (P < 0.05) reduction in cerebral infarction, respectively, along with decreased body weight loss and improved neurological function as compared to control animals, whereas no statistically significant reduction in infarct volume by water soluble PROG was found. We demonstrated that administration of PROG to the male rat before or 2 hours after onset of MCAO reduces ischemic cell damage and improves physiological and neurological function 2 days after stroke. These results suggests potential therapeutic properties of PROG in the management of stroke.

The resting tension and stiffness in the range of sarcomere lengths 2.4–3.6 μm were studied in highly inbred normal and dystrophic chicken pectoral muscle bundles, and the results were compared with the collagen content and the extent of crosslinkage of the collagen. All parameters increased in the order normal homozygote (003/003) < heterozygote (003/433) < dystrophic homozygote (433/433) chickens, with the data from the heterozygotes being halfway between the two homozygotes, thus exhibiting a semidominant inheritance pattern. In separate experiments, lathyrism was induced by treating normal (412/412) and dystrophic (413/413) chickens with α‐acetoaminonitrile, an inhibitor of lysyl oxydase, the enzyme responsible for the initiation of collagen crosslinkage formation. These experiments showed that the tension and stiffness in response to passive stretch did not change with lathyrism in normal muscles, whereas the tension and stiffness decreased significantly with lathyrism in dystrophic muscles. The collagen content did not change with lathryrism in both normal and dystrophic muscles. These results indicate that the increased content of collagen crosslinkages is the basis for the increased resting tension and stiffness in the dystrophic muscles of the chicken, and that the effects can be reversed by treatment with an inhibitor of collagen crosslinkage formation.

To the Editor. —In a recent article1concerning the benefit of prednisone therapy on the course of Duchenne muscular dystrophy, the authors indicate that glucocorticoids have also been shown to result in "a significant slowing or arrest in the progression of muscle weakness" in "autosomal recessive" muscular dystrophy in the chicken. While it is indeed remarkable that glucocorticoids are beneficial in both forms of muscular dystrophy, there are several important misconceptions about dystrophy in the chicken that should be corrected. First, muscular dystrophy in the chicken does not result in progressive muscular weakness. Biomechanical studies of chemically skinned avian dystrophic muscle fiber bundles have shown that increased resting stiffness rather than an impairment of active contraction is the fundamental biomechanical abnormality in this animal form of muscular dystrophy.2There was no difference in the calcium-activated isometric tension in normal vs dystrophic avian pectoral muscle fiber bundles. Thus, there is

Fibrous collagen from normal (line 412) and dystrophic (line 413) chicken pectoral muscles was examined for susceptibility to bacterial collagenase by a pH-stat titration method to assess the kinetics of peptide bond hydrolysis. These experiments showed that there was a profound difference in the kinetics of hydrolysis using fibrous collagen purified from normal and dystrophic muscle. Although normal collagen was readily hydrolyzed by the collagenase, dystrophic collagen was not hydrolyzed in the presence of 200 microM Ca and was hydrolyzed slowly in the presence of 5 mM Ca. At this high Ca concentration, the Km for collagenase was six times higher in dystrophic collagen than in normal, whereas the maximum reaction rate (Vmax) remained the same. After CNBr digestion, peptides from both sources were readily hydrolyzed by collagenase in the presence of 200 microM Ca, and there was no noticeable difference in the reaction kinetics. The above results were not modified whether the chicken was sacrificed on day 4 or day 98 post-hatching, and the insusceptibility to collagenase preceded the clinical manifestations of dystrophy. The structure of both fibrous and CNBr-treated collagen from normal and dystrophic muscle was compared. One and two-dimensional gel electrophoreses showed identical peptide maps. Gel filtration of CNBr peptides showed in the excluded volume the presence of twice as much high-molecular-weight (presumably crosslinked) peptides from dystrophic collagen compared with normal. We conclude that the intermolecular crosslinks are more extensively formed in dystrophic collagen and that this increased crosslinking results in the increased resistance of the dystrophic collagen to collagenase.

A 44-year-old woman developed recurrent thrombotic cerebral cortical infarctions. IgG and IgM anticardiolipin antibodies were found, as was a thymoma. To our knowledge, these antiphospholipid antibodies, which may inhibit prostacyclin formation and alter platelet function, have not been previously associated with this thymic neoplasm, an association we believe is not coincidental.

We present three cases of "crack" cocaine-associated stroke, together with a review of cocaine-associated cerebrovascular complications. Unlike previously reported cases tentatively associating ischemic stroke with cocaine, our patients had no other potential causes for their strokes. Although the exact mechanism of cocaine-related stroke remains uncertain, both disordered neurogenic control of the cerebral circulation as well as systemic factors (ie, acute hypertension) may play a role.