Cerebral Palsy

The first menstrual cycles following menarche are often caracterized by irregular and/or heavy bleeding. The adolescent patient may be worried by these episodes of bleeding. In 50-80% of cases these are anovulatory bleeding due to the immaturity of the gonadotrophic axis. Nevertheless pathologies such as von Willebrand disease, genital infection, polycystic ovary syndrom, eating disorders, a tumor or a pregnancy may be diagnosed by bleeding abnormalities. The challenge for the physician is to distinguish between bleeding abnormalities secondary to anovulation and pathologies where investigations and specific follow-up is mandatory. Adolescents who experience abnormal bleeding must be counceled according to their perceptions and expectations.

Although extrapyramidal diseases are commonly thought to solely affect the (extrapyramidal) motor system, non-motor symptoms such as behavioural abnormalities, dysautonomia, sleep disturbances and sensory dysfunctions are also frequently observed. Autonomic dysfunction as an important clinical component of extrapyramidal disease (idiopathic Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies) is often not formally assessed and thus frequently misdiagnosed. Symptoms of autonomic dysfunction in general impact more on quality of life than motor symptoms. Appropriate symptom-oriented diagnosis and symptomatic treatment as part of an interdisciplinary approach can provide a great benefit for the patient. Unfortunately, double-blind, randomised, controlled studies are scarce with the consequence that most recommendations are not based on the highest level of evidence. This review presents a limited overview on the treatment of cardiovascular, gastrointestinal, urogenital and sudomotor autonomic dysfunctions in various extrapyramidal syndromes. © Georg Thieme Verlag KG Stuttgart · New York.

Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition to hematologic malignancies during childhood. NS is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. More recently, a single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. PTPN11, BRAF and RAF1 mutations also account for approximately 95% of LEOPARD syndrome, a condition which resembles NS phenotypically but is characterized by multiple lentigines dispersed throughout the body, café-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy and sensorineural hearing deficits. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.

Objective: To evaluate the potential toxicity of repeated intravitreal injections of bevacizumab in rabbit eyes.Design: Randomized, placebo-controlled experimental animal study.Participants: Fourteen chinchilla rabbits; 12 assigned to the experimental group and 2 assigned to the normal control group.Methods: Three sequential, biweekly, intravitreal injections of bevacizumab in doses of 2.5 mg/0.1 mL or 5.0 mg/0.2 mL were performed on each rabbit. Evaluations included intraocular pressure (IOP), aqueous flare, B-scan ultrasound, fundus photography, ultrasound biomicroscopy, electroretinography (ERG), and visually evoked potentials (VEPs) performed at baseline and during the follow-up period. The eyes were enucleated at 1 week and 4 weeks after the last intravitreal injection, and underwent light and electron microscopic evaluations, as well as testing for apoptotic activity.Results: After intravitreal injections, no changes were found by regular clinical observation and IOP tests. There was no significant difference in the anterior chamber inflammatory activity evaluated by the laser flare meter. No evidence of retinal toxicity was seen after intravitreal bevacizumab at doses of 2.5 and 5.0 mg by either ERG or flash VEPs. Electron microscopy did show the presence of inflammatory cells and some ultrastructural changes in the photoreceptor cells in the 5.0 mg experimental group 1 week after the third injection. Mild to moderate apoptosis of photoreceptors was detected in the 5.0 mg group at the same time.Conclusions: The biweekly, multiple intravitreal injections of bevacizumab did not result in evidence of toxicity in regular clinical and functional observations at both 2.5 mg and 5.0 mg doses. The 5.0 mg dose may induce transient inflammation, ultrastructural abnormalities, and apoptosis.

Ankylosis of the temporomandibular joint (TMJ) is a severe disorder that leads to jaw function impairment and restricted mouth opening. Management of TMJ ankylosis poses a challenge to surgeons concerned because of the high rate of recurrence. The surgical approach to TMJ ankylosis can be performed according to different techniques and modalities. This report presents a case of a bilateral posttraumatic TMJ ankylosis that showed limited mouth opening (27 mm) along with dental occlusion abnormalities, and both TMJs showed severe fibro-osseous ankylosis. Bilateral gap arthroplasty was performed, and passive interincisal mouth opening of at least 47 mm was achieved after 15 days of physiotherapy. Eight months later, bilateral split ramus osteotomy was performed to correct the residual retrognathia and malocclusion. The outcome of the patient’s treatment was satisfactory. Wide gap arthroplasty if followed by vigorous physiotherapy may be sufficient in treating TMJ ankylosis and prevent recurrence in adults.

MCL-1, a pro-survival member of the BCL-2 family, was previously shown to have functions in ATR-dependent Chk1 phosphorylation following DNA damage. To further delineate these functions, we explored possible differences in DNA damage response caused by lack of MCL-1 in mouse embryo fibroblasts (MEFs). As expected, Mcl-1(-/-) MEFs had delayed Chk1 phosphorylation following etoposide treatment, compared to wild type MEFs. However, their response to hydroxyurea, which causes a G(1)/S checkpoint response, was not significantly different. In addition, appearance of gamma-H2AX was delayed in the Mcl-1(-/-) MEFs treated with etoposide. We next investigated whether MCL-1 is present, together with other DNA damage response proteins, at the sites of DNA damage. Immunoprecipitation of etoposide-treated extracts with anti-MCL-1 antibody showed association of MCL-1 with gamma-H2AX as well as NBS1. Immunofluorescent staining for MCL-1 further showed increased co-staining of MCL-1 and NBS1 following DNA damage. By using a system that creates DNA double strand breaks at specific sites in the genome, we demonstrated that MCL-1 is recruited directly adjacent to the sites of damage. Finally, in a direct demonstration of the importance of MCL-1 in allowing proper repair of DNA damage, we found that treatment for two brief exposures to etoposide , followed by periods of recovery, which mimics the clinical situation of etoposide use, resulted in greater accumulation of chromosomal abnormalities in the MEFs that lacked MCL-1. Together, these data indicate an important role for MCL-1 in coordinating DNA damage mediated checkpoint response, and have broad implications for the importance of MCL-1 in maintenance of genome integrity.

Objective The subsets and the polarization of lymphocytes in bone marrow from low-risk myelodysplastic syndrome (MDS) were studied and compared with those from patients with aplastic anemia (AA). Methods A total of 34 patients with low-risk MDS (IPSS score</=1.0) who presented abnormal chromosomes and 16 patients with AA were enrolled in this study. We determined T lymphocyte subsets, T cells polarization status, and the percentages of NK cells and of B lymphocytes in bone marrow and compared these parameters between the two groups of patients. As controls, 24 patients with high-risk MDS (IPSS score>1.0) presenting abnormal chromosomes and 22 healthy/benign hematologic disease subjects were used. Results In low-risk MDS/AA patients, the percentage of CD3+ lymphocytes was significantly increased compared to controls (p=0.006 and p=0.001), while the percentage of CD19+ lymphocytes was significantly decreased (p<0.001 and p=0.002); there were no significant differences between MDS/AA and normal controls in other parameters; For low-risk MDS patients, the polarization status of bone marrow CD4+ cells toward Th1 (Th1/Th2) and of CD8+ cells toward Tc1 (Tc1/Tc2) was stronger than that for AA patients (p=0.05 and p<0.001). Other parameters did not show significant differences; Regardless of the predominance of CD4 or CD8 T cells, all patients with low-risk MDS were accompanied with elevated Tc1 polarization (Tc1/Tc2). Conclusion In both AA and MDS, the number of total T lymphocytes increased. However, polarization towards Th1 and Tc1 was obviously stronger in MDS patients than in AA patients. This might be related to T cell stimulation from the clones of malignant hematopoietic cells.

Background Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different PEX genes. This includes PEX16, which encodes an integral peroxisomal membrane protein involved in peroxisomal membrane assembly. PEX16-defective patients have been reported to have a severe clinical presentation. Fibroblasts from these patients displayed a defect in the import of peroxisomal matrix and membrane proteins, resulting in a total absence of peroxisomal remnants. Objective To report on six patients with an unexpected mild variant peroxisome biogenesis disorder due to mutations in the PEX16 gene. Patients presented in the preschool years with progressive spastic paraparesis and ataxia (with a characteristic pattern of progressive leucodystrophy and brain atrophy on MRI scan) and later developed cataracts and peripheral neuropathy. Surprisingly, their fibroblasts showed enlarged, import-competent peroxisomes. Results Plasma analysis revealed biochemical abnormalities suggesting a peroxisomal disorder. Biochemical variables in fibroblasts were only mildly abnormal or within the normal range. Immunofluorescence microscopy revealed the presence of import-competent peroxisomes, which were increased in size but reduced in number. Subsequent sequencing of all known PEX genes revealed five novel apparent homozygous mutations in the PEX16 gene. Conclusions An unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene, with a relatively mild clinical phenotype and an unexpected phenotype in fibroblasts, was identified. Although PEX16 is involved in peroxisomal membrane assembly, PEX16 defects can present with enlarged import-competent peroxisomes in fibroblasts. This is important for future diagnostics of patients with a peroxisomal disorder.

‘Ion channelopathies’ have emerged in the past decade as a new cause of several neurological diseases. These Mendelian disorders are caused by mutations in genes that encode ion channel subunits and are often characterised by paroxysmal attacks of brain or muscle dysfunction, interspersed with periods of clinical normality. Andersen-Tawil syndrome is one of the rarest and is characterised clinically by the triad of periodic paralysis, cardiac dysrhythmias and skeletal abnormalities. Mutations in a potassium channel gene, KCNJ2 which encodes the potassium channel, Kir2.1, underlie the disorder. Here, the authors describe a patient and review the clinical spectrum and genetic features of the disorder.

The purpose of this study was to identify the clinical and thin-section CT findings in patients with acute Klebsiella pneumoniae pneumonia (KPP) alone and with concurrent infection. We retrospectively identified 160 patients with acute KPP who underwent chest thin-section CT examinations between August 1998 and August 2008 at our institutions. The study group comprised 80 patients (54 male, 26 female; age range 18-97 years, mean age 61.5) with acute KPP alone, 55 (43 male, 12 female; age range 46-92 years, mean age 76.0) with KPP combined with methicillin-resistant Staphylococcus aureus (MRSA) and 25 (23 male, 2 female; age range 56-91 years, mean age 72.7) with KPP combined with Pseudomonas aeruginosa (PA). Underlying diseases in patients with each type of pneumonia were assessed. Parenchymal abnormalities were evaluated along with enlarged lymph nodes and pleural effusion. In patients with concurrent pneumonia, underlying conditions such as cardiac diseases, diabetes mellitus and malignancy were significantly more frequent than in patients with KPP alone. The mortality rate in patients with KPP combined with MRSA or PA was significantly higher than in those with KPP alone. In concurrent KPP, CT findings of centrilobular nodules, bronchial wall thickening, cavity, bronchiectasis, nodules and pleural effusion were significantly more frequent with concurrent pneumonia than in those with KPP alone.