Cerebral Palsy

OBJECTIVE:: Two females with severe anorexia nervosa (BMI of 10) were seen with marked abnormalities in their liver function tests before the initiation of refeeding. These paradoxically resolved with progressive refeeding and weight restoration. METHOD:: Clinical observation during regimented medical stabilization and refeeding of two patients with severe anorexia nervosa with frequent monitoring of liver function tests. RESULTS:: Normalization of liver function tests ensued as caloric intake increased and weight gain progressed. DISCUSSION:: Although classically liver function test elevations occur during refeeding, as a manifestation of excessive calories and fat deposition in the liver, they may also be elevated due to severe malnutrition before refeeding has commenced and improved as refeeding occurs. (c) 2009 by Wiley Periodicals, Inc. Int J Eat Disord 2009.

Multiple case reports have described pregnancy in phencyclidine hydrochloride (PCP) abusers. Characteristic clinical symptoms of PCP-exposed infants have revealed neurobehavioral or physical abnormalities. We designed this study to evaluate whether chronic prenatal exposure to PCP during the last 2 weeks of gestation in rats produces alterations of hippocampal neurogenesis in offspring. Rats received repeated subcutaneous injection of PCP (5 mg/kg) once daily during the last 2 weeks of gestation. Control animals received subcutaneous injection of physiological saline during gestation. Dams receiving repeated PCP administrations showed markedly increased locomotor activities on days 1, 5, and 10 during the last 2 weeks of gestation. At 21 days after birth, 5-bromo-2′-deoxyuridine (BrdU)-positive cells of offspring were counted in the granule cell layer (GCL) and subgranular zone of the dentate gyrus. The numbers of BrdU-positive cells in the GCL in male and female offspring of the PCP-treated group were significantly increased by approximately 77% compared with those from the control group. At 56 days, the number of surviving BrdU-positive cells also remained to be increased by 74% in the GCL in PCP-treated group. At 21 days, locomotor activities of offspring in the PCP-treated group were significantly decreased by approximately 30% compared with those in the control group. However, neuronal differentiation of newly formed cells and cell survival were not influenced at 5 weeks after BrdU injections. Some altered biochemical or physiological conditions of offspring from dams receiving repeated PCP injections during pregnancy could influence changes in cell proliferation in the GCL of offspring during early development. Changes to cell proliferation in the hippocampus may affect behavioral abnormalities during infancy in offspring. Synapse 63:729-736, 2009. (c) 2009 Wiley-Liss, Inc.

DKK1 is a negative regulator in the Wnt signal transduction pathway. It can inhibit the pathway’s activation. Previous studies in some malignant tumors revealed the possibility that DKK1 is involved in tumorigenesis inducing abnormalities of the Wnt signal pathway. In this study, we showed that in benign and malignant endometrium, DKK1 exhibited novel expression profiles and invasiveness-related biology function: DKK1 was expressed in both glandular epithelium and matrix of two kinds of endometrium tissues and mostly distributed in the cytoplasm and epicytes of endometrial carcinoma (EC) Ishikawa cell line. DKK1 expression level in EC was significantly lower than that in benign endometrium. The expression correlated well with histology and clinical stage of EC. Exogenous DKK1 suppressed invasiveness of EC cells. Taken together, DKK1 is involved in genesis and early phase of EC by suppressing the invasiveness via the Wnt signal pathway. It shows promise as a biomarker for screening the progression of EC.

The objective of the paper was to evaluate the influence of antimony (5(+)) on electrocardiographic changes in children with visceral leishmaniasis. The study was based on weekly ECGs analysis of 87 children treated, from April 2001 to May 2006, with antimoniate N-methyl glucamine. Eligible subjects included children from 6 months to 12 years of age with weight of 6-34 kg. Forty-five children (52%) were males and forty-two (48%) were females. The cardiac response to antimony was significantly milder compared to the adult populations, so the usage of meglumine antimoniate is safer. Thus, during treatment sinus rhythm was maintained without ectopic beats. No changes were observed in the P wave and in PR interval. The QRS complex remained unaltered during the treatment, the amplitude being increased. The Sokolow;s indexes exceeded normal values in one child on the first week and in eight children on the fourth. The prolongation of QTc occurred in ten patients. The T wave flattening was observed in seven children on the first week. In total, ECG abnormalities were detected in 34.4% of treatment courses, while in adults they were reported in 53.8%. Antimony therapy needs ECG monitoring of the cardiac function in order to prevent complications.

The purpose was to assess the diagnostic accuracy of a hand-held Doppler ultrasound (US) machine for the bedside detection of liver and vascular abnormalities after liver transplantation in the intensive care unit. The IRB approved this study, and written informed consent was obtained from all patients or the patient’s legal representative. Any liver transplant recipient at our institution who needed a bedside Doppler US examination in the intensive care unit was eligible. Patients underwent routine grey-scale, colour, and spectral Doppler US examinations of the liver with a conventional machine, which was taken as the reference method, and with a hand-held machine on the same day. Examinations followed one another and were performed in a blinded fashion by two radiologists. Over a 4-month period, 24 consecutive patients (16 men, median age 54 years old; 16 cadaveric and 8 living related right liver transplantations) underwent 43 examinations with both conventional and hand-held machines. Image quality and overall satisfaction scores of grey-scale were lower with the hand-held than with the conventional machine. The hand-held was similar to the conventional machine for assessing the patency of portal veins, hepatic veins and the IVC in all patients but one. The hand-held machine failed to detect signals in the right branch of the hepatic artery and in the hilum in two and one cases, respectively. There was no abnormal hepatic arterial flow with the conventional machine in any of the patients, and the results were the same with the hand-held machine. Total examination time was significantly longer with the hand-held machine. The hand-held US machine had a high diagnostic accuracy for both parenchymal and vascular analyses compared with a conventional US machine in the bedside assessment of post-liver transplant patients.

Cytological cancer screening that targets genetic or epigenetic abnormalities may be a viable alternative to morphological screening. Detecting cancer cells by specific genetic markers helps their easy detection in cytological samples. We recently established the telomerase-specific replication-selective adenovirus OBP-401, in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted upstream of the E1 genes, and in which the green fluorescent protein (GFP) gene is driven by the CMV promoter. This virus selectively replicates only in telomerase-positive cells, expressing GFP, and therefore may be a tool for cancer screening. In the present study, we first confirmed that cytological samples can easily be infected with OBP-401, allowing visualization of GFP-positive cells under fluorescent microscopy 24 h after infection. After 32 cytological samples from patients with cervical, endometrial or ovarian cancers were infected with OBP-401, GFP signals were detected in 31 (96%) of the samples. However, some normal endometrial scrapings exhibited GFP-signals, possibly due to endometrial glandular cells with constitutive telomerase activity. The ability of OBP-401 to enrich cancer cells was then tested. Cytological samples containing cervical or endometrial cancer cells were infected with OBP-401, and GFP-positive cells were sorted by flow cytometry; DNA was extracted from the GFP-positive cells. Direct DNA sequencing or methylation-specific PCR identified cancer-derived mutations or hypermethylations of tumor suppressor genes more efficiently than analyses using crude cytological samples. Thus, OBP-401-based sorting of GFP-positive cells successfully enriched cancer cells, allowing efficient detection of genetic or epigenetic abnormalities in cytological samples.

Acute lymphoblastic leukemia (ALL) cells at relapse are frequently more resistant to treatment than primary clones and this may be caused by further genetic changes in the ALL cells at relapse. These acquired genomic abnormalities have not been fully characterized. To examine the additional genomic alterations of ALL at relapse, we performed single nucleotide polymorphism genomic microarry (SNP-chip) analysis on 14 ALL bone marrow samples at initial diagnosis, remission and relapse. Only two cases at initial diagnosis had a normal appearing genome by SNP-chip. All 14 cases had genomic alterations at relapse; and 10 of these had additional genomic abnormalities not present at diagnosis. Deletion of either the INK4A/ARF gene (2 cases) or the NF2 gene (2 cases) at 22q12.2 was an acquired genomic change at relapse. Loss of heterozygosity with normal copy number [uniparental disomy (UPD)] was detected in 3 cases as an additional genomic change at relapse. Interestingly, several genomic alterations, especially deletions, detected at initial diagnosis, disappeared at relapse, suggesting the ALL cells at relapse were minor clones at initial diagnosis and emerged at relapse. For several cases, trisomy at initial diagnosis changed to either UPD (2 cases) or normal appearing genome (2 cases). Further, we found disruption of PTPRD gene occurring at intron 23 as an additional genomic abnormality in one case. In summary, additional genomic changes are very common events in ALL at relapse; whether these abnormalities are associated with resistance to treatment remains to clarified in further studies.

Treatment of patients affected by advanced or inoperable GIST was revolutionized by the use of the tyrosine kinase inhibitors. Despite the fact that most patients have a good durable response of disease, they develop a resistance to treatments after a median time of 24 months. The acquired resistance is an emerging aspect in medical oncology especially in the era of target therapies. The aim of this review is to report all known mechanisms of secondary resistance to tyrosine kinase inhibitors and to highlight their clinical implications. In general, they may be divided in mechanisms related to the acquisition of new molecular abnormalities associated to KIT and PDGFRA receptor signalling pathway, such as the loss of KIT expression, the genomic amplification of KIT, the activation of an alternative downstream signalling pathways such as AKT/mTOR and the acquisition of new receptor mutations, and other mechanisms different to KIT/PDGFRA receptors. Future research perspectives on target therapy and early resistance evaluation are also discussed.

SUMMARY:: Polymicrogyria (PMG), a malformation of cortical organization, may, occasionally, be associated with electrical status epilepticus of sleep and focal electrical status. The aim of this study was to better characterize the latter association. This was an historic cohort study. Inclusion criteria were diagnosis of PMG on neuroimaging and presence of focal electrical status on EEG. Focal electrical status was considered when patients presented with continuous epileptiform abnormalities over a focal area on awakeness, which became bilateral and synchronous during sleep. Interictal EEGs lasted for at least 20 minutes and up to 4 hours and were performed during awakeness and sleep. Neuroimaging findings were classified as holosylvian PMG and hemispheric PMG. All patients, except one, had asymmetric neuroimaging findings, mostly on the right side. All patients had partial motor seizures, which were easily controlled with antiepileptic drugs in two of them. Despite seizure control, their EEGs still registered focal electrical status. The other four patients presented with atonic seizures and/or atypical absences. All patients showed awakeness focal electrical status that was activated by sleep. Focal electrical status is a different EEG pattern from other continuous electrographical patterns previously described, such as electrical status epilepticus of sleep, continuous epileptiform discharges, and rhythmic epileptiform discharges. Each one has its own peculiarity. Focal electrical status seems to be associated with asymmetric and extensive PMG.

Telomere capture, a rare event that stabilizes chromosome breaks, is associated with certain genetic abnormalities in humans. Studies pertaining to the generation, maintenance, and biological effects of telomere formation are limited in metazoans. A mutation, mu2(a), in Drosophila melanogaster decreases the rate of repair of double strand DNA breaks in oocytes, thus leading to chromosomes that have lost a natural telomere and gained a new telomere. Amino acid sequence, domain architecture, and protein interactions suggest that MU2 is an ortholog of human MDC1. The MU2 protein is a component of meiotic recombination foci and localizes to repair foci in S2 cells after irradiation in a manner similar to that of phosphorylated histone variant H2Av. Domain searches indicated that the protein contains an N-terminal FHA domain and a C-terminal tandem BRCT domain. Peptide pull-down studies showed that the BRCT domain interacts with phosphorylated H2Av, while the FHA domain interacts with the complex of MRE11, RAD50, and NBS. A frameshift mutation that eliminates the MU2 BRCT domain decreases the number and size of meiotic phospho-H2Av foci. MU2 is also required for the intra-S checkpoint in eye-antennal imaginal discs. MU2 participates at an early stage in the recognition of DNA damage at a step that is prerequisite for both DNA repair and cell cycle checkpoint control. We propose a model suggesting that neotelomeres may arise when radiation-induced chromosome breaks fail to be repaired, fail to arrest progression through meiosis, and are deposited in the zygote, where cell cycle control is absent and rapid rounds of replication and telomere formation ensue.