The impact of a nationwide hands-on workshop on the diagnostic rates and management of obstetrical anal sphincter Injuries in Israel.

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.

Fetal optic nerve sheath measurement as a non-invasive tool for assessment of increased intracranial pressure.

OBJECTIVES: 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). METHODS: In this cross-sectional study ONSD was measured sonographically in three fetuses (aged 23, 24 and 35 gestational weeks) with intracranial findings associated with increased intracranial pressure (ICP; dural thrombosis and intracranial tumors) as well as 42 healthy controls matched for GA ± 1 week (aged 22-25 and 34-36 weeks). For fetal eye assessment, transabdominal and transvaginal routes and high-resolution transducers were used for optimal visualization depending on fetal position. Measurements were made using an axial view at the level of the orbits, with the fetal face positioned towards the transducer. The ONSD was measured 1.5 or 2 mm behind the papilla (depending on GA) in all fetuses. Mean ± 2 SD ONSD of controls were calculated for each GA and compared with data from the three fetuses with intracranial pathology. RESULTS: In the 42 normal fetuses, ONSD increased 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. ONSD measurements of the three cases were above mean + 2 SD of values obtained from healthy controls at the same GA and also exceeded values of fetuses that were 1 week older. CONCLUSIONS: Fetal ONSD measurement is feasible using a technique similar to that used in adults and children. ONSD enlargement was observed in all three fetuses with intracranial lesions and may be an early tool with which to diagnose increased ICP.

PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome.

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.

Polyradiculopathy in sarcoidosis.

We present three new and 14 retrospective cases of polyradiculopathy in sarcoidosis. Of these, 71% had weakness and 59% areflexia of the lower extremities, and 35% had sphincter dysfunction. Cases often were associated with central nervous system sarcoidosis. All cases involved thoracolumbar or lumbosacral roots, except a single case of cervical polyradiculopathy. Of 14 treated patients, nine improved with corticosteroids, laminectomy, or both. Polyradiculopathy complicating sarcoidosis: (1) is uncommon; (2) primarily involves thoracic and lumbar roots; (3) may arise from contiguous, hematogenous, or gravitational nerve root sleeve seeding; (4) may be asymptomatic; and (5) may improve with corticosteroids. Differential diagnosis of weakness in patients with sarcoidosis should include nerve root involvement from the primary process by direct sarcoid involvement.

Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31.

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 is neuroprotective after transient middle cerebral artery occlusion in male rats.

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.

Increased resistance of the collagen in avian dystrophic muscle to collagenolytic attack: evidence for increased crosslinking.

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.

The role of collagen crosslinking in the increased stiffness of avian dystrophic muscle.

The resting tension and stiffness in the range of sarcomere lengths 2.4-3.6 microns 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) less than heterozygote (003/433) less than dystrophic homozygote (433/433) chickens, with the data from the heterozygotes being halfway between the two homozygotes, thus exhibiting a semi-dominant inheritance pattern. In separate experiments, lathyrism was induced by treating normal (412/412) and dystrophic (413/413) chickens with alpha-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.

Thyroid function in the elderly.

Many differences in thyroid function exist between elderly and younger populations. Although serum T4 levels probably do not change with age, serum T3 levels appear to decline. Hyperthyroidism in the geriatric population may be atypical and is characterized by anorexia and constipation. The pulse rate is often slower than in younger patients. Apathetic hyperthyroidism mainly occurs in older patients. The cause of hyperthyroidism is usually toxic multinodular goiter. Isolated T3 or T4 elevations may be seen. RAIU is often normal. Hypothyroidism is common in the elderly. TSH is a reliable indicator, but the significance of mild elevations (less than 20 microU/ml) is unclear. Serum antithyroid antibodies are unreliable in the definitive diagnosis of hypothyroidism. Acute and chronic illnesses occur frequently in older patients and have varied and important effects on thyroid function tests. Low T3 and both low T4 and low T3 are seen. High T4 syndrome may be more common in older patients than in younger patients. It is also seen in psychiatric populations. TSH levels are usually normal but may be mildly elevated.

"Crack" cocaine-associated stroke.

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.

Cerebral venous thrombosis with lupus anticoagulants. Report of two cases.

Lupus anticoagulants are circulating autoantibodies, primarily directed against phospholipids, that prolong the partial thromboplastin time. They have been previously associated with systemic arterial and venous thrombosis and arterial stroke, but not with cerebral venous thrombosis. We describe 2 young patients with cerebral venous thrombosis documented by intravenous digital subtraction angiography in whom a lupus anticoagulant was demonstrated. Both patients improved with corticosteroid and anticoagulant therapy.

Recurrent stroke associated with thymoma and anticardiolipin antibodies.

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.

Stiffness and contractile properties of avian normal and dystrophic muscle bundles as measured by sinusoidal length perturbations.

Both tension and stiffness as a function of muscle length were measured under relaxing conditions on isolated small bundles of chemically skinned myofibers from normal and dystrophic chicken pectoral muscles. It was shown that the dystrophic muscle was stiffer than normal muscle and developed more tension for the same amount of stretch. A fraction of stiffness was not removed by extraction with either 0.6 M KI or with 5 M guanidine HCl mixed with 1% mercaptoethanol. The stiffness of dystrophic muscle was also unaffected by treatment with bacterial collagenase under conditions that destroyed the stiffness of tendon. Nyquist plots of normal and dystrophic muscles during calcium-activated isometric contraction were very similar and were characteristic of fast-twitch muscle, as evidenced by three clear exponential processes. The normal appearance of the Nyquist plot of dystrophic muscle demonstrates that cross-bridge function is not altered, and the characteristic slowing of contraction and relaxation is not a consequence of a fast-to-slow transformation of muscle types. The increased stiffness of dystrophic muscle may be a very fundamental change in the biomechanics of dystrophy. We postulate that the stiffness is mediated by an altered form of collagen, which is collagenase-resistant by virtue of excessive crosslinking.

The interaction of unregulated actin and myosin in avian muscular dystrophy.

The presence of an altered form of the heavy chain component of myosin subfragment-1 (S-1) in avian dystrophic pectoral muscle was confirmed by Triton-urea-acetic acid polyacrylamide gel electrophoresis. The potential functional significance of this altered form of S-1 was evaluated by measuring the ATPase activity of the unregulated acto-S-1 complex using all possible pairwise combinations of actin and S-1 from normal (N) and dystrophic (D) muscle. (NN, DD, ND, DN, where the first letter designates the actin and the second letter the S-1). With conventionally purified actin and S-1, NN not equal to DD not equal to ND not equal to DN, implying both N actin not equal to D actin and N S-1 not equal to D S-1 functionally. An alternate purification scheme for actin resulted in preparations from normal and dystrophic muscles of actin Mg-polymers with the same rheology (viscosity vs shear rate) and critical concentration for polymerization. When these actins were combined with more highly purified preparations of S-1, the adenosine triphosphatase (ATPase) activity of the acto-S-1 complex did not vary with changes in the pairwise composition and responded similarly to variation of the actin or adenosine triphosphate (ATP) concentration. In experiments with actin activation of intact myosin, no differences were observed between myosin from normal vs dystrophic muscle. The different isozymes of myosin present in normal and dystrophic chicken pectoral muscles are functionally equivalent as ATPases in their interactions with unregulated actin.

31P-NMR studies of normal and dystrophic chicken muscle.

Phosphorus-31 nuclear magnetic resonance (31P-NMR) analysis was performed on normal (line 412) and dystrophic (line 413) superficial pectoralis muscles excised from chickens between 15 and 116 days after hatching. An apparent alteration in dystrophic muscle energy metabolism was abolished by pretreatment with curare and was attributed to muscle hyperexcitability. Time-dependent 31P-NMR studies demonstrated no apparent difference in the overall tissue adenosine triphosphatase (ATPase) activity of dystrophic as compared to normal muscle. After 55 days of age, a resonance signal attributed to serine ethanolamine phosphodiester (SEPDE) was observed only in dystrophic muscle. Adding the paramagnetic cation Mn2+ to the buffer surrounding the muscle resulted in an approximate 80% decrement in the dystrophic SEPDE signal without apparent alteration of the other phosphatic signals in either the normal or dystrophic muscle. This would argue against any generalized membrane defect in dystrophic chicken muscle and suggest that SEPDE is in a compartment accessible to Mn2+.

Acute subdural hematomas with lupus anticoagulant (procoagulant inhibitor).

A patient with systemic lupus erythematosus (SLE) and circulating "lupus anticoagulant" (procoagulant inhibitor) developed both hemorrhagic microinfarction of the brain characteristic of SLE and massive bilateral, fatal, isodense subdural hematomas.