Neonatal Serial Transverse Enteroplasty (STEP): Case Report.

CASE REPORT: Gastroschisis is the most frequent congenital abdominal wall defect. When associated with intestinal atresia (complex gastroschisis), short bowel syndrome may occur. Complicated gastroschisis is the most frequent cause of short bowel syndrome in our series. The serial transverse enteroplasty procedure has been used to lengthen the bowel and achieve intestinal rehabilitation in patients with dilated gut. The use of this technique in the newborn period, for tailoring the bowel while preserving absorptive mucosa, has been recently described. We present a video showing the surgical treatment of an intestinal obstruction produced by a complex intestinal atresia in a newborn baby in whom a primary closure of a gastroschisis had been done at birth. During laparotomy at the 21st day of life, a type IVa intestinal atresia was found, associated with a colonic stenosis. Proximal dilated jejunum was tailored with a serial transverse enteroplasty procedure, as shown in the video. End-to-end jejunal-ileal anastomosis was performed. Postoperative entero-cutaneous fistula occurred and was treated with vacuum-assisted therapy. Enteral feedings were initiated at 15 days after surgery. Parenteral nutrition was withdrawn at 30 days. After 16 months follow-up, actual weight was 8.7 kg (percentile 10% to 25%). The patient remained on full enteral feedings. CONCLUSIONS: In cases of intestinal atresia, short bowel syndrome, and proximal dilated bowel, we propose an aggressive surgical approach to preserve bowel mucosal surface while tailoring the jejunal loop to improve motility. The serial transverse enteroplasty procedure is an acceptable alternative to tailoring methods that resect a segment of the bowel wall.

Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme.

The infiltration of glioma cells into adjacent tissue is one of the major obstacles in the therapeutic management of malignant brain tumours, in most cases precluding complete surgical resection. Consequently, malignant glioma patients almost invariably experience tumour recurrences. Within the brain, glioma cells migrate rapidly either amoeboidly or mesenchymally to invade surrounding structures, in dependence on the extracellular environment. In addition, radiotherapy, frequently applied as adjuvant therapeutic modality, may enhance tumour cell mobility. Here, we show that the receptor tyrosine kinase Mer (MerTK) is overexpressed in glioblastoma multiforme (GBM) and that this is accompanied with increased invasive potential. MerTK expression is maintained in primary GBM-derived tumour spheres under stem cell culture conditions but diminishes significantly in serum-containing cultures with concomitant downregulation of Nestin and Sox2. Depletion of MerTK disrupts the rounded morphology of glioma cells and decreases their invasive capacity. Furthermore, the expression and phosphorylation of myosin light chain 2 are strongly associated with MerTK activity, indicating that the effect of MerTK on glioma cell invasion is mediated by actomyosin contractility. Finally, DNA damage robustly triggers the upregulation and phosphorylation of MerTK, which protects cells from apoptosis. This effect is strongly impaired upon MerTK depletion or overexpression of an inactive MerTK mutant. Collectively, our data suggests that MerTK is a novel therapeutic target in the treatment of the malignant gliomas.

Nanoparticles and surfaces presenting antifungal, antibacterial and antiviral properties.

Here, we present new antimicrobial nanoparticles based on silica nanoparticles (SNPs) coated with a quaternary ammonium cationic surfactant, didodecyldimethylammonium bromide (DDAB). Depending on the initial concentration of DDAB, SNPs immobilize between 45 and 275 µg of DDAB per milligram of nanoparticle. For high concentrations of DDAB adsorbed to SNP, a bilayer is formed as confirmed by zeta potential measurements, thermogravimetry, and diffuse reflectance infrared Fourier transform (DRIFT) analyses. Interestingly, these nanoparticles have lower minimal inhibitory concentrations (MIC) against bacteria and fungi than soluble surfactant. The electrostatic interaction of the DDAB with the SNP is strong, since no measurable loss of antimicrobial activity was observed after suspension in aqueous solution for 60 days. We further show that the antimicrobial activity of the nanoparticle does not require the leaching of the surfactant from the surface of the NPs. The SNPs may be immobilized onto surfaces with different chemistry while maintaining their antimicrobial activity, in this case extended to a virucidal activity. The versatility, relative facility in preparation, low cost, and large antimicrobial activity of our platform makes it attractive as a coating for large surfaces.

PI3Kinase signaling in glioblastoma.

Glioblastoma (GBM) is the most common primary tumor of the CNS in the adult. It is characterized by exponential growth and diffuse invasiveness. Among many different genetic alterations in GBM, e.g., mutations of PTEN, EGFR, p16/p19 and p53 and their impact on aberrant signaling have been thoroughly characterized. A major barrier to develop a common therapeutic strategy is founded on the fact that each tumor has its individual genetic fingerprint. Nonetheless, the PI3K pathway may represent a common therapeutic target to most GBM due to its central position in the signaling cascade affecting proliferation, apoptosis and migration. The read-out of blocking PI3K alone or in combination with other cancer pathways should mainly focus, besides the cytostatic effect, on cell death induction since sublethal damage may induce selection of more malignant clones. Targeting more than one pathway instead of a single agent approach may be more promising to kill GBM cells.

Thymic disorders and myasthenia gravis: genetic aspects.

Myasthenia gravis (MG) is an autoimmune disease characterized by production of antibodies to acetylcholine receptor at the motor end-plate responsible for impairment of neuromuscular transmission. There is general agreement about the involvement of the thymus in the pathogenesis of MG, and thymic pathological changes are commonly found in MG patients. Genetic factors seem to play an important role in susceptibility to MG. As with other autoimmune diseases, genetic predisposition to MG probably involves multiple genes. Ample evidence suggests that genes within the major histocompatibility complex (MHC) are involved in susceptibility to autoimmune diseases. Both data from the literature and our findings indicate that different genes within the MHC could predispose to various forms of MG, and that particularly the tumour necrosis factor genes may play a role in the association between the different thymic disorders and MG.

Course and treatment of myasthenia gravis during pregnancy.

OBJECTIVE: To evaluate the influence of myasthenia gravis (MG) on pregnancy and potential treatment risks for infants and mothers. BACKGROUND: MG frequently affects young women in the second and third decades of life, overlapping with the childbearing years. Knowledge of the potential effects of 1) pregnancy on the course of MG and 2) the use of immunosuppressive drugs during pregnancy is limited, rendering decision-making difficult for both patient and physician. METHODS: We studied 47 women who became pregnant after the onset of MG. Immunosuppressive drugs were administered when MG symptoms were not controlled with anticholinesterases. Sixty-four pregnancies resulted in 55 children and 10 abortions. RESULTS: During pregnancy, MG relapsed in 4 of 23 (17%) asymptomatic patients who were not on therapy before conception; in patients taking therapy, MG symptoms improved in 12 of 31 pregnancies (39%), remained unchanged in 13 (42%), and deteriorated in 6 (19%). MG symptoms worsened after delivery in 15 of 54 (28%) pregnancies. Anti-acetylcholine receptor antibody (anti-AChR ab) was positive in 40 of 47 mothers and was assayed in 30 of 55 newborns; 13 were positive and 5 of 55 (9%) showed signs of neonatal MG (NMG). All affected babies were seropositive. CONCLUSIONS: Pregnancy does not worsen the long-term outcome of MG. The course of the disease is highly variable and unpredictable during gestation and can change in subsequent pregnancies. The occurrence of NMG does not correlate with either maternal disease severity or anti-AChR antibody titer. Immunosuppressive therapy, plasmapheresis, and i.v. human immunoglobulins can be administered safely if needed.

Multiple paraneoplastic diseases associated with thymoma.

Here we report a patient with a lymphoepithelial thymoma who developed in chronological sequence limbic encephalitis, neuromyotonia and myasthenia gravis. The patient presented with limbic encephalitis associated with an invasive thymoma and improved after surgery and cytotoxic therapy. Two months after thymectomy, neuromyotonia associated with hyperhidrosis and mild motor neuropathy occurred and the patient was given plasma-exchange and prednisone therapy. Five months later he developed mild generalised myasthenia gravis. Anti-acetylcholine receptor antibodies, previously repeatedly negative, were found positive at the onset of clinical signs of myasthenia gravis.

Absence of vascular dementia in an autopsy series from a dementia clinic.

OBJECTIVE: The role of cerebrovascular disease in dementia in older people has been the subject of controversy. This study was undertaken to examine the prevalence of vascular disease in a prospective autopsy series of patients with clinically diagnosed dementia. DESIGN: Structured review of clinical and neuropathological examinations. Clinical diagnoses were assigned in accordance with the recommendations of the NINCDS/ADRDA consensus panel. Neuropathological examinations were performed at an academic neuropathology service using published consensus criteria for the diagnosis of Alzheimer's disease and other forms of dementia. SETTING: A subspecialty, outpatient dementia clinic in a university-affiliated suburban American hospital. PARTICIPANTS: Eighty-seven unselected patients coming to autopsy who had undergone clinical dementia evaluation. RESULTS: Dementia could not be attributed to the effects of cerebrovascular disease alone in any of the 87 patients coming to autopsy. Seventy-six (87%) of the patients were found to have Alzheimer's disease (AD), 44 had AD alone, and 32 had AD in combination with cerebrovascular disease (CVD). All of the patients with signs of CVD at autopsy were also found to have some concomitant neurodegenerative disease. The absence of patients in whom vascular dementia could be diagnosed at neuropathology was not the result of recruitment bias. CONCLUSION: Clinicians should maintain a high index of suspicion of AD or other neurodegenerative process in older patients whose presenting complaint is dementia, even in the presence of well documented cerebrovascular disease.

Tumour necrosis factor beta gene polymorphisms in myasthenia gravis.

Genetic analyses indicate that genes within the major histocompatibility complex (MHC) can be involved in susceptibility to autoimmune disease. To investigate the role of the tumour necrosis factor beta (TNFB) gene in myasthenia gravis (MG) susceptibility, we analysed an NcoI polymorphism within the TNFB gene in 63 MG patients and 93 healthy individuals. When patients were subdivided according to thymic pathology, we found differences between MG patients with thymic hyperplasia and thymoma versus controls. In MG patients with thymic hyperplasia we found a positive association with the TNFB*1 allele [Relative risk (RR): 2.6; P < 0.001] and phenotype (RR: 1.8; P < 0.005) and a negative association with the TNFB*2/2 genotype (RR: 0.2; P < 0.001) when compared to the controls. On the other hand, in MG patients with thymoma we found a positive association with the TNFB*2/2 genotype (RR: 5.6; P < 0.01) and a negative association with the TNFB*1 allele (RR: 0.3; P < 0.05) and *1/2 genotype (RR: 0.2; P < 0.01). These data suggest that the two different forms of MG can have different pathogenesis and that the TNFB gene could influence susceptibility to MG.

Juvenile myasthenia gravis with prepubertal onset.

Juvenile myasthenia gravis (JMG) with prepubertal onset is an uncommon disease. We studied 19 patients with age at onset ranging from 1.5 to 9.2 years and compared their clinical characteristics and response to therapy with 114 cases with MG onset after the prepubertal age, up to 20 years. Neither sex prevalence nor autoimmune diseases other than MG were found in younger patients. Although ocular myasthenia was more frequent than in later-onset JMG, children with generalized symptoms were often severely affected and respiratory involvement was present in 8/19 patients. Anti-acetylcholine receptor antibodies were detected at a lower rate and, in contrast with results in older patients, seronegativity was more frequent among children with generalized disease. Three out of six patients with onset before the age of five showed spontaneous remission. Nine prepubertal patients underwent thymectomy and, as most of them also received immunosuppressive therapy, the influence of surgery on disease outcome remains unclear; in no case was thymoma found. This is in contrast to the good results after thymectomy and the presence of thymoma in the later-onset group. Eleven patients in the prepubertal series were treated with immunosuppressive therapy. At the end of follow-up, most patients were in good condition. The frequency of immunosuppressive therapy and the rate of good therapeutic results did not differ from those observed in older patients.