Cerebral Palsy

Loss-of-function of caretaker genes characterizes a group of cancer predisposition diseases that feature cellular hypersensitivity to DNA damage and chromosome fragility; this group includes Fanconi anaemia and Bloom syndrome. The products of the 13 FANC genes (mutated in Fanconi anaemia), which constitute the ‘FANC’ pathway, and BLM (the RecQ helicase mutated in Bloom syndrome) are thought to collaborate during the S phase of the cell cycle, preventing chromosome instability. Recently, BLM has been implicated in the completion of sister chromatid separation during mitosis, a complex process in which precise regulation and execution is crucial to preserve genomic stability. Here we show for the first time a role for the FANC pathway in chromosome segregation during mitotic cell division. FANCD2, a key component of the pathway, localizes to discrete spots on mitotic chromosomes. FANCD2 chromosomal localization is responsive to replicative stress and specifically targets aphidicolin (APH)-induced chromatid gaps and breaks. Our data indicate that the FANC pathway is involved in rescuing abnormal anaphase and telophase (ana-telophase) cells, limiting aneuploidy and reducing chromosome instability in daughter cells. We further address a cooperative role for the FANC pathway and BLM in preventing micronucleation, through FANC-dependent targeting of BLM to non-centromeric abnormal structures induced by replicative stress. We reveal new crosstalk between FANC and BLM proteins, extending their interaction beyond the S-phase rescue of damaged DNA to the safeguarding of chromosome stability during mitosis.

BACKGROUND:: Serum alanine aminotransferase (ALT) levels are commonly used to indicate liver damage. Although elevated levels indicate possible liver injury, abnormalities, or disease, some patients with “normal” ALT levels have minimal to mild liver disease. Recently, ALT reference ranges for adults were queried and revised ranges proposed with lower upper limits of normality. The appropriateness of current paediatric ALT reference ranges is unclear. MATERIAL AND METHODS:: Hepatitis C virus (HCV)-uninfected children from the European Paediatric HCV Network represent a large population of healthy children born to HCV-infected mothers, with ALT observations collected prospectively from birth. Linear regression identified factors associated with ALT levels while accounting for within-child repeated measurements. ALT centiles stratified by sex were calculated using maximum penalized likelihood methods and LMS software. RESULTS:: A total of 1293 HCV-uninfected children had 5011 ALT measurements during follow-up. ALT levels significantly decreased with increasing age, whilst ALT levels were significantly lower in girls than boys. Reference cutoffs representing the 95th centiles before 18 months of age were 60 U/L for boys and 55 U/L for girls, decreasing to 40 U/L for boys and 35 U/L for girls after 18 months of age. CONCLUSIONS:: These reference ranges represent a unique investigation of ALT levels in a healthy child population. We show lower and more detailed age-related cutoffs of normality than available. Additionally, we demonstrate a significant effect of sex on ALT reference ranges, which has not previously been described in children younger than 5 years of age.

Recent technologic advances in multidetector computed tomography have allowed the performance of simultaneous acquisition dual-energy computed tomography (DECT). The advantages of this new technique include simultaneous visualization of lower voltage tube images with improved iodine conspicuity and the performance of material specific imaging, which attempts to differentiate specific materials in the generated images. In this article, we review the concepts and physical principles of DECT using congenital thoracic abnormalities as a substrate for depicting the versatility of DECT.

Anomalous unilateral single pulmonary vein is an extremely rare anomaly of the pulmonary venous system. It is often confused with other pulmonary abnormalities such as hypogenetic lung (scimitar) syndrome, pulmonary varices, pulmonary nodules, and arteriovenous malformations. We present imaging findings including multidetector computerized tomography in a case of anomalous unilateral single pulmonary vein mimicking pulmonary nodules on high-resolution computed tomography of the lungs and scimitar syndrome on chest radiograph in an asthmatic girl.

OBJECTIVE: To prospectively investigate the number, location, and size of ventilation defects and correlate these findings with pulmonary function tests (PFTs) when performing hyperpolarized helium-3 (HP He) magnetic resonance imaging (MRI) of the lung in healthy young adults. MATERIALS AND METHODS: Six healthy adult female volunteers underwent standard PFT and MRI of the lungs after inhalation of HP He. HP He MR images were evaluated by 4 reviewers in consensus. Number, location, and size of ventilation defects were recorded. Locations of ventilation defects included the right upper lobe, right middle lobe, right lower lobe, left upper lobe, left lower lobe, and lingula. Ventilation defects were localized into central, middle, or peripheral portions of the lungs. Size of ventilation defects was categorized with a maximum diameter of either </=3 cm or >3 cm. HP He MRI findings were correlated with PFT results. RESULTS: The study cohort comprised 6 healthy, young adult female volunteers (mean age 22.5 y, range: 20-25 y) who underwent both PFT and HP He MRI. Five (83.3%) out of 6 volunteers had at least 1 ventilation defect (mean=2.3; range: 1-4; 95% confidence interval: 1.3-3.8 defects/patient). Among a total of 14 ventilation defects observed from 5 healthy, young adult volunteers, ventilation defects were observed in left lower lobe in 6 (42.9%), right lower lobe in 3 (21.4%), right upper lobe in 3 (21.4%), and left upper lobe in 2 (14.3%) patients. No ventilation defects were observed in the right middle lobe and lingula. All observed ventilation defects were less than 3 cm in size and peripherally located. There was no correlation between number, location, or size of ventilation defects and PFT results. CONCLUSIONS: Small (</=3 cm) peripherally located ventilation defects can be seen in the majority of healthy, young adult volunteers, and should not be mistaken as abnormalities when evaluating HP He MRI. These ventilation defects are located in the peripheral upper lobes and lower lobes (lower lobes>upper lobes) while sparing right middle lobe and lingula. The number, location, and size of ventilation defects on HP He MRI were not correlated with PFT results in the normal range, which suggests HP He MRI may be more sensitive than PFT for evaluating small ventilation defects in young adults.

Medical examiners often receive cases with limited medical history. Sometimes the medical history received is slightly skewed, or even incorrect. Here we describe a case which was initially referred to the Bexar County Medical Examiner’s Office from a large community hospital as a case of zolpidem overdose. The deceased presented to the hospital with hypertension, elevated temperature, worsening bizarre behavior, and movement irregularities. While in the hospital, the decedent developed seizure-like activity and died approximately 15 hours after admission. A complete autopsy was performed and yielded no significant gross or histologic abnormalities. A full toxicologic analysis revealed therapeutic levels of citalopram and phenytoin. Zolpidem was not present. Further review of the decedent’s medical history as well as information provided by the next of kin revealed that the deceased had been taking diazepam for several years but had recently been switched to alprazolam. The decedent had abruptly stopped taking the alprazolam approximately 4 days before admission when she ran out of the medication, after taking approximately 200 mg in a 6-day period. Given the inconsistent clinical presentation and the findings at autopsy, we suspect that she suffered from benzodiazepine withdrawal and not an overdose as initially reported. Although it is possible that the zolpidem, reportedly taken in the 12 hours before admission, masked the initial symptoms of withdrawal, the constellation of symptoms and signs at presentation are more consistent with benzodiazepine withdrawal than of zolpidem overdose. In this report, we emphasize to the forensic community that one must maintain a high index of suspicion for alternative explanations if the initial report does not seem to fit the presentation or autopsy findings. This case illustrates that although it may take some extra time and effort, further investigation into clinical history can prove crucial to obtaining the correct cause of death and manner of death. This is only the second case within the English literature of death because of benzodiazepine withdrawal.

A 45-year-old man with a past history of hypertension and hyperlipidemia presented with right dorsal pontine hemorrhage manifesting as transient burning pain in the right orbital region, followed by numbness and mild weakness of the left side of the body. Magnetic resonance imaging showed a hyperintense lesion in the right dorsal pons on T(1)-weighted and T(2)-weighted images, but no other abnormalities suggesting vascular lesions in the midbrain, medulla, cerebellum, or cerebrum. These findings were consistent with the subacute stage of small pontine hemorrhage. He was treated to decrease his blood pressure. The symptoms gradually improved and he has suffered neither recurrence of the orbital pain nor migraine for several months after the first episode of headache. The trigeminal nociceptive system in the dorsal lateral pons may be linked to this characteristic pain, as suggested by reports of secondary migraine caused by cavernous hemangioma and arteriovenous malformation, and activation of the dorsal lateral pons during migraine attacks on positron emission tomography.

Familial Juvenile Hyperuricaemic Nephropathy (FJHN), an autosomal dominant disorder, is caused by mutations in the UMOD gene, which encodes Uromodulin, a glycosylphosphatidylinositol (GPI)-anchored protein that is expressed in the thick ascending limb of the loop of Henle, and excreted in the urine. Uromodulin contains 3 epidermal growth factor-like (EGF) domains, a cysteine-rich region which includes a domain of eight cysteines (D8C), and a zona pellucida (ZP) domain. Over 90% of UMOD mutations are missense, and 62% alter a cysteine residue, implicating a role for protein misfolding in the disease. We investigated 20 Northern European FJHN probands for UMOD mutations. Wild-type and mutant Uromodulins were functionally studied by expression in HeLa cells and the use of Western blot analysis and confocal microscopy. Six different UMOD missense mutations (Cys32Trp, Arg185Gly, Asp196Asn, Cys217Trp, Cys223Arg, and Gly488Arg) were identified. Patients with UMOD mutations were phenotypically similar to those without UMOD mutations. The mutant Uromodulins had significantly delayed maturation, retention in the endoplasmic reticulum (ER) and reduced expression at the plasma membrane. However, Gly488Arg, which is the only mutation we identified in the ZP domain, was found to be associated with milder in vitro abnormalities and to be the only mutant Uromodulin detected in conditioned medium from transfected cells, indicating that the severity of the mutant phenotypes may depend on their location within the protein. Thus, FJHN-causing Uromodulin mutants are retained in the ER, with impaired intracellular maturation and trafficking, thereby indicating mechanisms whereby Uromodulin mutants may cause the phenotype of FJHN.

Several lines of functional neuroimaging studies have attributed a role for the insula, a critical component of the brain’s emotional circuitry, in risky decision-making. However, very little evidence yet exists as to whether the insula is necessary for advantageous decision-making under risk, specifically decisions involving uncertain gains and losses. The present study uses a risky decision-making task with lesion patients and healthy controls to investigate the effects of focal insula damage on risk-taking to achieve gains and to avoid losses. Compared to healthy controls, insula lesion patients showed an altered decision-making pattern in domains involving both risky gains and risky losses. Specifically, insula damage was associated with insensitivity to differences in expected value between choice options. Additionally, patients made significantly fewer risky choices than healthy adults in the gain domain. In conjunction with earlier findings, these results suggest that risky decision-making is dependent on the integrity of a neural circuitry that includes several brain regions known to be critical for the experience and expression of emotions, namely the insula, amygdala, and ventromedial prefrontal cortex. However, each neural region seems to provide a distinct contribution to the overall process of decision-making.

As childhood cancer treatment has become more effective, survival rates have improved, and a number of complications have been described while many of these patients reach adulthood. Obesity is a well-recognized late effect, and its metabolic effects may lead to cardiovascular disease. Currently, studies concerning overweight have focused on acute lymphocytic leukemia and brain tumors, since they are at risk for hypothalamic-pituitary axis damage secondary to cancer therapies (cranial irradiation, chemotherapy, and brain surgery) or to primary tumor location. Obesity and cancer have metabolic syndrome features in common. Thus, it remains controversial if overweight is a cause or consequence of cancer, and to date additional mechanisms involving adipose tissue and hypothalamic derangements have been considered, comprising premature adiposity rebound, hyperinsulinemia, leptin regulation, and the role of peroxisome proliferator-activated receptor gamma. Overall, further research is still necessary to better understand the relationship between adipogenesis and hypothalamic control deregulation following cancer therapy.