Pulmonary artery blood flow patterns in fetuses with pulmonary outflow tract obstruction.

OBJECTIVES: Fetuses with pulmonary outflow tract obstruction (POTO) have altered blood flow to the pulmonary vasculature. We sought to determine whether pulmonary vascular impedance, as assessed by the pulsatility index (PI), is different in fetuses with POTO compared with normal controls. METHODS: Branch pulmonary artery PI was evaluated in age-matched normal control fetuses (n=22) and 20 POTO fetuses (pulmonary stenosis n=15, pulmonary atresia n=5). Pulsed-wave Doppler was performed in the proximal (PA1), mid (PA2) and distal (PA3) branch pulmonary artery. The direction of flow in the ductus arteriosus was noted. The study and control groups were compared with Student's t-test and ANOVA. A linear mixed model evaluated the relationship between PI and ductus arteriosus flow patterns. RESULTS: There was no difference in PI between control, pulmonary stenosis and pulmonary atresia subjects at PA1 and PA2; however, there was a significant difference at PA3. Subjects with pulmonary atresia had a lower PI at PA3 than did controls (P=0.003) and pulmonary stenosis subjects (P=0.003). Subjects with retrograde flow in the ductus arteriosus had lower PIs in PA2 and PA3 than did those with antegrade flow (P=0.01 and 0.005, respectively). The PI in PA3 was lower in fetuses that required prostaglandin postnatally than in those that did not (P=0.008). CONCLUSIONS: Fetuses with pulmonary atresia or severe pulmonary stenosis with retrograde flow in the ductus arteriosus have decreased PI in the distal pulmonary vasculature. Our findings indicate the capacity of the fetal pulmonary vasculature to vasodilate in response to anatomical obstruction of flow.

Comparative analysis of cerebrovascular resistance in fetuses with single-ventricle congenital heart disease.

OBJECTIVE: We sought to determine whether the presence or absence of aortic obstruction impacts cerebrovascular resistance in fetuses with single-ventricle (SV) congenital heart disease (CHD). METHODS: Pulsatility indices (PIs) were recorded for the middle cerebral artery (MCA) and the umbilical artery (UA) from 18 to 40 weeks' gestation in 59 fetuses (163 examinations) with SV-CHD with unobstructed aortic flow, yet decreased pulmonary flow, in 72 fetuses (170 examinations) with obstructed aortic flow and hypoplastic left heart syndrome (HLHS) and in 92 normal fetuses (92 examinations). The cerebral-to-placental resistance (CPR) was calculated as the MCA-PI/UA-PI. Z-scores were generated for the MCA-PI and the UA-PI in order to make comparisons independent of gestational age. Statistical analyses were performed using one-way ANOVA with post-hoc testing. Trends in these variables over the course of gestation were assessed using linear regression and univariate ANOVA. RESULTS: The MCA-PI and the CPR were significantly lower in SV fetuses with aortic obstruction compared with SV fetuses with pulmonary obstruction and with normal fetuses. Moreover, the MCA-PI decreased significantly for SV fetuses with aortic obstruction over the course of gestation. In contrast, the MCA-PI was higher over the course of gestation in SV fetuses with pulmonary obstruction compared with normal fetuses. CONCLUSION: In fetuses with SV-CHD, cerebrovascular resistance varies substantially between fetuses with and without aortic obstruction. Compared with normal fetuses, cerebrovascular resistance is decreased in SV fetuses with aortic obstruction, yet increased in SV fetuses with pulmonary obstruction. In fetuses with SV physiology, inherent differences in cerebral blood flow may underlie postnatal neurodevelopmental outcomes.

Malignant transformation in pediatric spinal intramedullary tumors: case-based update.

BACKGROUND: In children, intramedullary spinal cord neoplasms are rare. These are typically low-grade neuroepithelial tumors, most commonly astrocytomas, ependymomas, and gangliogliomas. Malignant transformation, while common in recurrent adult low-grade gliomas, is an unusual event in pediatric low-grade neoplasms, specifically in intramedullary spinal cord tumors. ILLUSTRATIVE CASES: We report two cases of malignant transformation in low-grade neuroepithelial tumors of the pediatric intramedullary spinal cord. Two children with intramedullary tumors, one with a WHO grade I ganglioglioma and one with a low-grade astrocytoma, were treated surgically, diagnosed histologically, and followed through the course of their disease. Both patients' tumors transformed to higher grades without prior irradiation or chemotherapy, and without a genetic predisposition to tumorigenesis. DISCUSSION: Malignant transformation can occur in low-grade intramedullary neoplasms in children. This is a novel documented event for pediatric intramedullary spinal cord tumors and a rare event for all pediatric low-grade neuroepithelial tumors without induction by irradiation. A survey of the relevant literature reveals an underwhelming number of studies focusing on malignant transformation in children's CNS tumors relative to adults. Further investigation into molecular mechanisms of pediatric low-grade neoplasms may reveal more aggressive tumor sub-variants predisposed to malignant degeneration.

Is there an optimal time for laparoscopic cholecystectomy in acute cholecystitis?

BACKGROUND: Laparoscopic cholecystectomy (LC) is safe in acute cholecystitis, but the exact timing remains ill-defined. This study evaluated the effect of timing of LC in patients with acute cholecystitis. METHODS: Prospective data from the hospital registry were reviewed. All patients admitted with acute cholecystitis from June 1994 to January 2004 were included in the cohort. RESULTS: Laparoscopic cholecystectomy was attempted in 1,967 patients during the study period; 80% were women, mean patient age was 44 years (range, 20-73 years). Of the 1,967 LC procedures, 1,675 were successful, and 292 were converted to an open procedure (14%). Mean operating time for LC was 1 h 44 min (SD +/- 50 min), versus 3 h 5 min (SD +/- 79 min) when converted to an open procedure. Average postoperative length of stay was 1.89 days (+/- 2.47 days) for the laparoscopic group and 4.3 days (+/- 2.2 days) for the conversion group. No clinically relevant differences regarding conversion rates, operative times, or postoperative length of stay were found between patients who were operated on within 48 h compared to those patients who were operated on post-admission days 3-7. CONCLUSIONS: The timing of laparoscopic cholecystectomy in patients with acute cholecystitis has no clinically relevant effect on conversion rates, operative times, or length of stay.

Multifocal vascular tumors in fowl induced by a newly isolated retrovirus.

The morphological features of a spontaneous, multifocal vascular neoplasm of chickens are described. Histologically, the tumor was characterized by areas consisting of freely anastomosing vascular channels with prominent papillary appearance and lined by bland-looking endothelial cells, which alternate with areas resembling cavernous hemangioma. Occasionally solid areas composed of plump, pleomorphic cells were also present. Although there was no clear evidence for metastatic spread, some tumors were obviously invasive. Electron microscopy and immunohistochemistry confirmed the endothelial nature of neoplastic cells, demonstrating in particular pinocytic vesicles, well developed junctional complexes, fragmented basal lamina, occasional Weibel-Palade bodies, and patchy factor VIII-related antigen immunoreactivity. The overall appearance of the tumor was that of a cavernous hemangioma with prominent papillary endothelial hyperplasia. Previously we have shown that the tumor was induced by a newly isolated strain of avian hemangioma retrovirus and in this study we demonstrated typical type C retrovirus particles in the tumor by electron microscopy. It is suggested that this retrovirus-induced avian tumor may serve as a useful model for the study of transformed endothelia and other vascular tumorigenesis.

Germline SDHD mutation in paraganglioma of the spinal cord.

Hereditary paraganglioma of the head and neck is associated with germline mutations in the SDHD gene, which encodes a mitochondrial respiratory chain protein. Paragangliomas of the central nervous system are very rare, occur almost exclusively in the cauda equina of the spinal cord and are considered non-familial. In the present study, we screened 22 apparently sporadic paragangliomas of the cauda equina for SDHD mutations. One spinal paraganglioma and similar cerebellar tumours that developed 22 years later in the same patient contained a missense mutation at codon 12 (GGT-->AGT, Gly-->Ser) and a silent mutation at codon 68 (AGC-->AGT, Ser-->Ser). There was no family history of paragangliomas but DNA from white blood cells of this patient showed the same sequence alterations, indicating the presence of a germline mutation. All other cases of spinal paraganglioma had the wild-type SDHD sequence, except one case with a silent mutation at codon 68 (AGC-->AGT, Ser-->Ser). This is the first observation indicating that inherited SDHD mutations may occasionally cause the development of paragangliomas in the central nervous system.

The contribution of the Israeli trauma system to the survival of road traffic casualties.

BACKGROUND: According to the World Health Organization, over one million people die annually from traffic crashes, in which over half are pedestrians, bicycle riders and two-wheel motor vehicles. In Israel, during the last decade, mortality from traffic crashes has decreased from 636 in 1998 to 288 in 2011. Professionals attribute the decrease in mortality to enforcement, improved infrastructure and roads and behavioral changes among road users, while no credit is given to the trauma system. Trauma systems which care for severe and critical casualties improve the injury outcomes and reduce mortality among road casualties. GOALS: 1) To evaluate the contribution of the Israeli Health System, especially the trauma system, on the reduction in mortality among traffic casualties. 2) To evaluate the chance of survival among hospitalized traffic casualties, according to age, gender, injury severity and type of road user. METHODS: A retrospective study based on the National Trauma Registry, 1998-2011, including hospitalization data from eight hospitals. OUTCOMES: During the study period, the Trauma Registry included 262,947 hospitalized trauma patients, of which 25.3% were due to a road accident. During the study period, a 25% reduction in traffic related mortality was reported, from 3.6% in 1998 to 2.7% in 2011. Among severe and critical (ISS 16+) casualties the reduction in mortality rates was even more significant, 41%; from 18.6% in 1998 to 11.0% in 2011. Among severe and critical pedestrian injuries, a 44% decrease was reported (from 29.1% in 1998 to 16.2% in 2011) and a 65% reduction among bicycle injuries. During the study period, the risk of mortality decreased by over 50% from 1998 to 2011 (OR 0.44 95% 0.33-0.59. In addition, a simulation was conducted to determine the impact of the trauma system on mortality of hospitalized road casualties. Presuming that the mortality rate remained constant at 18.6% and without any improvement in the trauma system, in 2011 there would have been 182 in-hospital deaths compared to the actual 108 traffic related deaths. A 41% difference was noted between the actual number of deaths and the expected number. CONCLUSIONS: This study clearly shows that without any improvement in the health system, specifically the trauma system, the number of traffic deaths would be considerably greater. Although the health system has a significant contribution on reducing mortality, it does not receive the appropriate acknowledgment or resources for its proportion in the fight against traffic accidents.

Epidemiology of Guillain-Barré syndrome.

From 1969 through 1972, a nationwide search for cases of Guillain-Barré syndrome (GBS) is Israel revealed 89 patients. The average annual age-adjusted incidence was 0.75 per 10(5) persons. Overall incidence of the syndrome was similar in Jewish groups of diverse ethnic backgrounds. Arabs had a lower overall incidence than Jews (0.46 per 10(5) persons), perhaps attributable to fewer Arabs at risk in older age groups. Peaks of incidence occurred among individuals over 60 and under 4 years of age when all cases were combined. No clear seasonal or geographic clustering of GBS was evident in Israel during the 4 years of this study. The incidence of GBS in the present study agrees with previous population-based estimates.

Late-onset muscular weakness in phosphofructokinase deficiency due to exon 5/intron 5 junction point mutation: a unique disorder or the natural course of this glycolytic disorder?

Late-onset muscle weakness is rare in glycolytic disorders. There are two reports in the literature of phosphofructokinase (PFK)-deficient Ashkenazi Jews with severe vacuolar myopathy manifesting in late adulthood. The genetic abnormality in these patients is unknown. We report a third patient with a similar syndrome: early-onset exercise intolerance in young childhood and progressive weakness in a limb-girdle distribution appearing at 57 years of age, leading to severe incapacity. Muscle histology showed diffuse vacuolar changes, and muscle fibers contained excess glycogen-like material. Muscle biochemistry was diagnostic for PFK deficiency. DNA analysis from the patient and his family showed that he was homozygous for a recently identified point mutation at the exon 5/intron 5 junction (a G-to-A change); two other family members were heterozygous for this mutation. It is not clear whether late-onset weakness is the natural course for all PFK-deficient patients or whether the exon 5 mutation carries increased risk for this severe myopathy.

The anatomic basis of visual agnosia.

In a patient with associative visual agnosia without alexia, there was bilateral infarction in the distribution of the posterior cerebral arteries, with corticosubcortical lesions in both occipitotemporal regions, sparing the corpus callosum. Bilateral loss of visual-limbic connections may underlie associative visual agnosia, and bilateral lesions of the inferior longitudinal fasciculi may be the necessary and sufficient lesions for this syndrome. Alexia was absent in this case, perhaps because the corpus callosum was intact.

Hereditary leukoencephalopathy and palmoplantar keratoderma: a new disorder with increased skin collagen content.

We report a new neurocutaneous syndrome of apparent autosomal recessive inheritance consisting of early-childhood-onset palmoplantar keratoderma followed in adulthood by progressive tetrapyramidal syndrome and cognitive impairment. Of the four affected siblings, two were available for evaluation. Investigation disclosed cerebral white-matter involvement on MRI and arylsulfatase A pseudodeficiency carrier state, which was also identified in clinically unaffected family members. Since skin biopsies showed dermal connective tissue abnormalities, we studied collagens I, III, and VI biosynthesis. Northern blotting of RNA extracted from cultured skin fibroblasts revealed an increased steady-state messenger RNA (mRNA) level of alpha 1(VI) collagen, whereas no differences were detected for pro alpha 1(I), pro alpha 1(III), and tropoelastin mRNAs. The skin content of collagen and total protein was higher in the patients than in controls. We suggest that an extracellular matrix abnormality may be involved in the pathogenesis of this disorder.

Lipomatous medulloblastoma in adults. A distinct clinicopathological entity.

We report on three patients who presented with a cerebellar medulloblastoma at age 48, 53, and 59 years. Histopathology showed typical features of medulloblastoma, in one case with marked neuronal differentiation. In addition, all neoplasms contained focal accumulations of mature fat cells. Immunoreactivity of adipocytes for S-100 protein, neuron-specific enolase, synaptophysin, microtubule-associated protein-2, and glial fibrillary acidic protein and the lack of immunoreactivity to type IV collagen suggest lipomatous differentiation of neoplastic primitive neuroectodermal cells rather than an admixture of mesenchymal elements. Mitotic activity was low and the growth faction, as determined by the MIB-1 labeling index, was less than 5%. All patients are alive with a recurrence-free interval ranging from 3.5 to 12 years. These three patients and five similar previously reported cases all fit into the concept of the lipomatous medulloblastoma as a new clinicopathological entity characterized by (a) typical features of a cerebellar medulloblastoma with advanced neuronal differentiation, (b) areas of lipomatous differentiation, (c) low proliferative potential, (d) manifestation in adults (mean age, 50 years), and (e) apparent favorable clinical prognosis.

Alpha-fetoprotein suppresses experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE), induced in guinea pigs by immunization with myelin basic protein (MBP) or whole CNS homogenate was successfully treated, as well as partially prevented, by daily administration of fetal alpha-fetoprotein (alpha FP). alpha FP which is produced in high quantities during pregnancy can inhibit both the cell-mediated immune response to MBP and the binding of MBP antibody to the antigen in vitro. It has a non-specific immunosuppressive effect on both the cellular and humoral responses. It is suggested that the ability of alpha FP to suppress an experimental autoimmune disease, as presented in this model of EAE, indicates that clinical remissions of human autoimmune disease during pregnancy may be attributed to the effect of this natural substance.

A monoclonal antibody to SV40 large T-antigen labels a nuclear antigen in JC virus-transformed cells and in progressive multifocal leukoencephalopathy (PML) brain infected with JC virus.

Thirty monoclonal antibodies to SV40 large T-antigen were tested for reactivity on the JC virus-transformed hamster glial cell line known as HJC-15. Two of them (PAb 416 and PAb 108) detected a nuclear antigen in both SV40-transformed CCL 75.1 cells and in HJC-15 cells, but not in control cells lacking T-antigen. These same antibodies also labeled a nuclear antigen in hamster tumor tissue derived from HJC-15 cells. In addition, the monoclonal antibody PAb 416 detected a nuclear antigen in progressive multifocal leukoencephalopathy (PML) tissue infected with JC virus, but not in normal brain tissue or tissue from other neurological diseases. Staining by PAb 416 was reduced by prior incubation with hamster anti-JCV tumor serum, suggesting that the polyclonal antiserum to JCV T-antigen may compete for an epitope at or near the PAb 416 binding site.

A double-label method detects both early (T-antigen) and late (capsid) proteins of JC virus in progressive multifocal leukoencephalopathy brain tissue from AIDS and non-AIDS patients.

A new double-label immunocytochemical method detects JC virus (JCV) early (T-antigen) and late (capsid) proteins simultaneously in cryostat sections of progressive multifocal leukoencephalopathy (PML) brain tissue from both acquired immunodeficiency syndrome (AIDS) and non-AIDS patients. T-antigen is detected with a monoclonal antibody (PAb 416) followed by goat anti-mouse IgG and mouse Clono-PAP, while capsid proteins are detected by a rabbit polyclonal antiserum to capsid proteins followed by biotinylated goat anti-rabbit IgG and streptavidin-alkaline phosphatase conjugate. The substrates are 3,3'-diaminobenzidine and Vector Red I, respectively. With this method some infected glial cells stain for late (capsid) antigens in the nucleus, while others show early protein (large T-antigen) immunoreactivity. The latter are likely to be astrocytes infected abortively or oligodendrocytes in the early stages of a productive JCV infection.

A novel antigen-toxin chimeric protein: myelin basic protein-pseudomonas exotoxin (MBP-PE 40) for treatment of experimental autoimmune encephalomyelitis.

Myelin basic protein (MBP), is a major component of the central nervous system (CNS) myelin. MBP can stimulate T cells that migrate into the CNS, initiating a cascade of events that result in perivascular infiltration and demyelination. EAE is an inflammatory and demyelinating autoimmune disease of the CNS that serves as a model for the human disease Multiple Sclerosis (MS). Taking advantage of the fact that EAE can be mediated by T cells, able to recognize MBP or its peptides, we developed a new approach to target anti-MBP T cells by fusing an MBP-sequence to a toxin. In the new chimeric protein, an oligonucleotide coding for the guinea pig MBP encephalitogenic moiety (residues 68-88) was fused to a cDNA encoding a truncated form of the PE gene (PE40). The chimeric gene termed MBP-PE was expressed in E. coli and highly purified. MBP-PE chimeric protein was cytotoxic to various anti-MBP T cells. Moreover, treatment with the novel MBP-toxin blocked the clinical signs of EAE as well as CNS inflammation and demyelination. A chimeric protein such as MBP-PE40 presents a novel prototype of chimeric proteins, composed of antigen/peptide-toxin, that could prove to be an efficient and specific immunotherapeutic agent for autoimmune diseases in which a known antigen is involved.

SMA type 2 unrelated to chromosome 5q13.

We describe two brothers with clinical and histological findings of type 2 spinal muscular atrophy (SMA) associated with small head circumference (<2%) and normal cognitive development. No survival motor neuron (SMN) or neuronal apoptosis-inhibitory protein (NAIP) deletions were detected in these sibs, and they were discordant for the haplotypes determined by DNA markers flanking the 5q13 SMA locus. These findings support the presence of a distinct anterior horn disease unrelated to 5q13. This entity may have either autosomal recessive or X-linked inheritance.

Splicing mutation in dysferlin produces limb-girdle muscular dystrophy with inflammation.

Mutations in dysferlin were recently described in patients with Miyoshi myopathy, a disorder that preferentially affects the distal musculature, and in patients with Limb-Girdle Muscular Dystrophy 2B, a disorder that affects the proximal musculature. Despite the phenotypic differences, the types of mutations associated with Miyoshi myopathy and Limb-Girdle Muscular Dystrophy 2B do not differ significantly. Thus, the etiology of the phenotypic variability associated with dysferlin mutations remains unknown. Using genetic linkage and mutation analysis, we identified a large inbred pedigree of Yemenite Jewish descent with limb-girdle muscular dystrophy. The phenotype in these patients included slowly progressive, proximal, and distal muscular weakness in the lower limbs with markedly elevated serum creatine kinase (CK) levels. These patients had normal development and muscle strength and function in early life. Muscle biopsies from 4 affected patients showed a typical dystrophic pattern but interestingly, in 2, an inflammatory process was seen. The inflammatory infiltrates included primarily CD3 positive lymphocytes. Associated with this phenotype, we identified a previously undescribed frameshift mutation at nucleotide 5711 of dysferlin. This mutation produced an absence of normal dysferlin mRNA synthesis by affecting an acceptor site and cryptic splicing. Thus, splice site mutations that disrupt dysferlin may produce a phenotype associated with inflammation.

Meningeal carcinomatosis due to basal cell carcinoma.

A case of meningeal carcinomatosis due to metastasizing basal cell carcinoma is reported. The patient was a 34-year-old woman who had a recurrent basal cell carcinoma of the upper eyelid with deep invasion. In spite of extensive surgery and radiotherapy, multiple bone metastases developed, and the patient eventually died of meningeal carcinomatosis. The possible pathogenic mechanisms of meningeal the present case, cancer cells reached the leptomeninges from adjacent vertebral metastases. It is suggested that the possibility of meningeal carcinomatosis should be considered in every patient with cancer and multiple vertebral metastases, particularly when neurologic signs involving the brain, cranial nerves, or spinal nerves are present.

Morphologic analysis of axo-glial membrane specializations in the demyelinated central nervous system.

Axo-glial membrane specializations, occurring in demyelinated spinal cord lesions in guinea pigs with chronic, relapsing experimental allergic encephalitis (EAE) and a case of multiple sclerosis (MS) between naked axons and scarring astrocytes, have been analyzed in transverse and longitudinal sections by transmission electron microscopy. The most common axo-glial specialization was of the desmosome-type and was plaque-like and punctate. It was not related to the region of subaxolemmal densification at the nodes of Ranvier. Synapse-like and gap junctions were also seen, but rarely, between naked axons and astrocytes in chronic EAE. In MS, only desmosome-like specializations were encountered between axons and glia and they were less extensive than in the guinea pig material. Surprisingly, similar chronically demyelinated lesions in the optic nerves of guinea pigs, failed to display axo-glial membrane specializations. It is speculated that their presence in spinal cord lesions is related to the proximity of gray matter and is of relevance to regeneration.