The utility of dopamine transporter scans for diagnosing Parkinsonian disorders

Introduction Dopamine transporter scans are increasingly being used in the diagnosis of clinically undefined Parkinsonism. Aims To assess the indications for imaging usage and its impact on future clinical management. Methods Retrospective review of scans ordered and their corresponding results over a five-year period. A chart review was carried out on a cohort of scans to assess changes in clinical management. Results One hundred and eighty scans (69% of total) were reported as showing evidence of dopaminergic deficit. A chart review in 81 patients showed a change in clinical management in 53 patients (65%). Scans were ordered inappropriately in 34 patients (13%). Discussion 123I-FP-CIT SPECT scans are being more frequently ordered and if used correctly can alter clinical management. Increased education on indications for use is required to reduce waste of resources and risk to patients.

Timing of Therapeutic Hypothermia for Inborn and Outborn Infants with Neonatal Encephalopathy.

Therapeutic hypothermia is now the standard of care for infants with moderate to severe hypoxic ischaemic encephalopathy. Sixty-three infants received therapeutic hypothermia at Cork University Maternity Hospital (CUMH) from 2010-2014. Median gestational age was 40 weeks. Eighteen (29%) infants were Sarnat grade 3, 41(65%) grade 2 and 4(6%) grade 1. Nineteen outborn infants arrived in CUMH at a median (IQR) age of 310 (270, 420) minutes. Four (21%) outborn infants were within the target temperature range on arrival. Median (IQR) time (minutes) from birth to achieve target temperature was 136 (90, 195) for inborn and 300 (240, 360) for outborn infants (p < .01). Overall, 35 (56%) infants had electrical seizures, 42 (74%) had a normal MRI at a median (IQR) age of 7(6,9) days and the median(IQR) length of stay was 9 (7,11) days. Although no difference in seizures or MRI findings was seen, passive cooling does not achieve consistent temperature control for outborn infants.

Hhex regulates Kit to promote radioresistance of self-renewing thymocytes in Lmo2-transgenic mice.

Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute leukemias, in particular poor prognosis early T-cell precursor-like (ETP-) acute lymphoblastic leukemia (ALL). The primary effect of Lmo2 is to cause self-renewal of developing CD4(-)CD8(-) (double negative, DN) T cells in the thymus, leading to serially transplantable thymocytes that eventually give rise to leukemia. These self-renewing thymocytes are intrinsically radioresistant implying that they may be a source of leukemia relapse after therapy. The homeobox transcription factor, Hhex, is highly upregulated in Lmo2-transgenic thymocytes and can phenocopy Lmo2 in inducing thymocyte self-renewal, implying that Hhex may be a key component of the Lmo2-induced self-renewal program. To test this, we conditionally deleted Hhex in the thymi of Lmo2-transgenic mice. Surprisingly, this did not prevent accumulation of DN thymocytes, nor alter the rate of overt leukemia development. However, deletion of Hhex abolished the transplantation capacity of Lmo2-transgenic thymocytes and overcame their radioresistance. We found that Hhex regulates Kit expression in Lmo2-transgenic thymocytes and that abrogation of Kit signaling phenocopied loss of Hhex in abolishing the transplantation capacity and radioresistance of these cells. Thus, targeting the Kit signaling pathway may facilitate the eradication of leukemia-initiating cells in immature T-cell leukemias in which it is expressed.

Bilateral inferior vena cava filter insertion in a patient with duplication of the infrarenal vena cava.

BACKGROUND: Inferior vena cava (IVC) filter insertion is a commonly performed procedure for indications such as recurrent pulmonary emboli or contraindication to anticoagulation. Symptomatic duplication of the IVC is exceedingly rare with only a handful of cases being described in the literature. AIM: We report an unusual case of a patient with symptomatic duplication of the IVC. RESULT: A 53-year-old woman presented at our hospital for resection of a cerebral metastasis from a non-small cell lung cancer following a recent diagnosis of bilateral lower limb deep venous thrombosis. This required perioperative reversal of anticoagulation and IVC filter insertion. Conventional venography performed during filter insertion documented the existence of a duplicated IVC. CONCLUSION: We present a case of a symptomatic duplication of the IVC requiring filter insertion. We review the developmental anatomy of the IVC along with the diagnostic findings and management strategies available.

Cost-effectiveness analysis of different imaging strategies for diagnosis of haemophilic arthropathy.

SUMMARY: Physiotherapy and radiography of the joints are standard diagnostic strategies for assessment of haemophilic arthropathy. The use of ultrasonography as an adjunct tool for early diagnosis of haemophilic arthropathy may optimize factor replacement therapy. The objective of this study was to compare costs and effectiveness of physiotherapy, radiography and ultrasonography (intervention strategy, IS) with physiotherapy and radiography alone (standard care strategy, SCS) for diagnosing soft tissue and osteocartilaginous changes in haemophilic joints. We retrospectively compared costs and effectiveness of IS vs. SCS in knees, ankles and elbows of 31 children (age range, 4-17 years) with haemophilia A (n = 30) or B (n = 1) (IS, n = 11; SS, N = 20). Direct health care costs were measured from the provincial health care perspective. Effectiveness was measured by false-negative (FN) rates in each study arm by comparing presence or absence of abnormalities of physiotherapy and imaging exams to the reference standard measure (MRI). In scenario 1, all diagnostic tests matched with MRI. In scenario 2, at least one diagnostic test matched with MRI. The IS was more costly [incremental cost/100 patients, Canadian (CND) $4987] and more effective (incremental effectiveness, FNs/100 patients for scenario 1, -4.09, and for scenario 2, -41) for both scenarios. The incremental cost-effectiveness ratios for scenario 1 and for scenario 2 were CND$1166 and CDN$116 per FN result averted per 100 patients, respectively. In conclusion, in the short-term, the incorporation of ultrasonography in a test set for diagnosis of haemophilic arthropathy substantially improved the diagnostic performance of this test set, however at an increased cost.

A method to establish the relationship between chronological age and stage of union from radiographic assessment of epiphyseal fusion at the knee: an Irish population study.

Characteristic changes during epiphyseal union provide a skeletal age, which when compared with age-based standards provides an estimation of chronological age. Currently there are no data on epiphyseal union for the purposes of age estimation specific to an Irish population. This cross-sectional study aims to investigate the relationship between stage of epiphyseal union at the knee joint and chronological age in a modern Irish population. A novel radiographic method that sub-divides the continuum of development into five specific stages of union is presented. Anteroposterior and lateral knee radiographs of 148 males and 86 females, aged 9-19 years, were examined. Fusion was scored as Stage 0, non-union; Stage 1, beginning union; Stage 2, active union; Stage 3, recent union; or Stage 4, complete union. Stage of epiphyseal union is correlated with chronological age in both males and females. Mean age gradually increases with each stage of union and also varies between male and female subjects. A statistically significant difference in mean age was recorded between stages when compared to the previous stage, for the three epiphyses. Irish children are comparable to those from previously published studies with epiphyseal union in females occurring earlier than males. A significant difference was noted between the mean age of union for males and females for each of Stages 1 and 2 for the femur and Stages 0, 1, 2 and 3 for the tibia and the fibula. The results also suggest that the stages of union occur at earlier ages in this Irish population. Implementation of standardized methodology is necessary to investigate if this is due to a secular or population variation in maturation or to a methodology which clearly identifies five stages of union.

Immunocytochemical characterization of murine Hex, a homeobox-containing protein.

A polyclonal antibody against a glutathione S:-transferase fusion protein containing the 76 COOH-terminal amino acids of Hex, a divergent homeobox gene, was raised in rabbits. Western blot and immunofluorescence reveal that Hex is a 35-37-kD soluble protein present both in the nucleus and cytoplasm of transfected and nontransfected cultured cells as well as in whole mouse embryo. Confocal microscopy of whole mount immunostained mouse embryos at E7. 5 and E8.5 demonstrates that Hex is differentially localized in the cytoplasm and nucleus of definitive endoderm, developing blood islands, and hepatic diverticulum. In particular, in the region of the foregut that gives rise to the liver, Hex expression is nuclear in the endodermal cells of the hepatic diverticulum, whereas expression is primarily cytoplasmic in cells lateral to the liver-forming region. This suggests that nuclear localization of Hex is involved in early hepatic specification and that compartmentalization of Hex protein plays an important role in its function during mouse development.

Hex expression suggests a role in the development and function of organs derived from foregut endoderm.

Hex is a divergent homeobox gene expressed as early as E4.5 in the mouse and in a pattern that suggests a role in anterior-posterior patterning. Later in embryogenesis, Hex is expressed in the developing thyroid, lung, and liver. We now show Hex expression during thymus, gallbladder, and pancreas development and in the adult thyroid, lung, and liver. At E10.0, Hex is expressed in the 3rd pharyngeal pouch, from which the thymus originates, the endodermal cells of liver that are invading the septum transversum, the thyroid, the dorsal pancreatic bud, and gallbladder primoridum. At E13.5, expression is maintained at high levels in the thyroid, liver, epithelial cells lining the pancreatic and extrahepatic biliary ducts and is present in both the epithelial and mesenchymal cells of the lung. Expression in the thymus at this age is less than in the other organs. In the E16.5 embryo, expression persists in the thyroid, pancreatic, and bile duct epithelium, lung, and liver, with thymic expression dropping to barely detectable levels. By E18.5, expression in the thyroid and bile ducts remains high, whereas lung expression is markedly decreased. At this age, expression in the pancreas and thymus is no longer present. Finally, we show the cell types in the adult thyroid, lung, and liver that express Hex in the mature animal. Our results provide more detail on the potential role of Hex in the development of several organs derived from foregut endoderm and in the maintenance of function of several of these organs in the mature animal.

Divergent homeobox gene hex regulates promoter of the Na(+)-dependent bile acid cotransporter.

The divergent homeobox gene Hex is expressed in both developing and mature liver. A putative Hex binding site was identified in the promoter region of the liver-specific Na(+)-bile acid cotransporter gene (ntcp), and we hypothesized that Hex regulates the ntcp promoter through this site. Successive 5'-deletions of the ntcp promoter in a luciferase reporter construct transfected into Hep G2 cells confirmed a Hex response element (HRE) within the ntcp promoter (nt -733/-714). Moreover, p-CMHex transactivated a heterologous promoter construct containing HRE multimers (p4xHRELUC), whereas a 5-bp mutation of the core HRE eliminated transactivation. A dominant negative form of Hex (p-Hex-DN) suppressed basal luciferase activity of p-4xHRELUC and inhibited activation of this construct by p-CMHex. Interestingly, p-CMHex transactivated the HRE in Hep G2 cells but not in fibroblast-derived COS cells, suggesting the possibility that Hex protein requires an additional liver cell-specific factor(s) for full activity. Electrophoretic mobility shift assays confirmed that liver and Hep G2 cells contain a specific nuclear protein that binds the native HRE. We have demonstrated that the liver-specific ntcp gene promoter is the first known target of Hex and is a useful tool for evaluating function of the Hex protein.

HNF3beta and GATA-4 transactivate the liver-enriched homeobox gene, Hex.

The orphan homeobox gene, Hex, has a limited domain of expression which includes the developing and adult mouse liver. Hex is expressed in the developing liver coincident with the forkhead/winged helix transcription factor, Hepatocyte Nuclear Factor 3beta (HNF3beta). Although preliminary characterization of the mouse Hex promoter has recently been reported, the identity of the molecular regulators that drive liver expression is not known. We hypothesized that putative HNF3beta and GATA-4 elements within the Hex promoter would confer liver-enriched expression. A series of Hex promoter-driven luciferase reporter constructs were transfected in liver-derived HepG2 and fibroblast-like Cos cells+/-HNF3beta or GATA expression plasmids. The Hex promoter region from nt -235/+22 conferred basal activity in both HepG2 and Cos cells, with the region from -103/+22 conferring liver-enriched activity. HNF3beta and GATA-4 transactivated the promoter via response elements located within nt -103/+22, whereas Sp1 activated the -235/+22 construct. Mutation of the HNF3 element significantly reduced promoter activity in HepG2 cells, whereas this element in isolation conferred HNF3beta responsiveness to a heterologous promoter. Electrophoretic mobility shift assays were performed to confirm transcription factor:DNA binding. We conclude that HNF3beta and GATA-4 contribute to liver-enriched expression of Hex.

Pain management and weaning from narcotics and sedatives.

Over the last 10 years, there has been a fundamental change in physicians' attitudes toward analgesia and sedation in pediatrics. In this time, basic and clinical research have provided a wealth of information. In this paper we review important advances registered in the past year, including new molecular and physiological mechanisms of antinociception and sedation, behavioral and psychoemotional implications of pain, and advances in the clinical practice of pediatric analgesia and sedation. Fortunately, the attitude of physicians toward these matters has changed significantly and much more attention is now paid to the alleviation of pain and provision of adequate sedation. However, there remains, according to most estimates, incongruity between these advances and what is practiced clinically.

Use of high-frequency and nonconventional ventilation for respiratory failure.

Over the past several years, many new strategies have evolved for improving the care of patients with acute lung injury and respiratory failure. Although many of these new modalities remain unproven, some show much promise for decreasing the morbidity and mortality seen in critically ill patients who need assisted ventilation. In this review, we discuss recent data concerning four of these modalities: high frequency ventilation, prone positioning, tracheal gas insufflation, and partial liquid ventilation.

Fetal lung mRNA levels of Hox genes are differentially altered by maternal diabetes and butyrate in rats.

Diabetes is known to be associated with delayed lung development in humans and in experimental animals. This includes delayed expression of surfactant apoproteins. An important component of the metabolic abnormalities in diabetes is elevated levels of analogs of butyric acid, and the effects of diabetes on surfactant apoproteins can be reproduced by exposure of fetal rat lung explants to butyrate. Dexamethasone has the opposite effects on lung development. In humans, antenatal exposure to dexamethasone results in a lower incidence of RDS, whereas in experimental animals, dexamethasone increases the expression of surfactant apoproteins. A subset of Hox genes are expressed in developing lung, and their level of expression decreases with advancing gestation. We hypothesized that: 1) lungs of fetuses of rats with streptozotocin-induced diabetes would have altered levels of expression of Hox genes, 2) the effect would be mediated in part through elevated levels of butyrate, and 3) dexamethasone would reverse the effect. We tested our hypotheses in vivo using fetuses from streptozotocin-treated rats and in vitro by treating lung explants from normal rats with sodium butyrate. Streptozotocin treatment increased expression of Hoxb-5 at 18 d of gestation, but did not affect Hoxa-5 expression. This was associated with a 20-fold increase in alpha-aminobutyrate levels. Dexamethasone tended to reverse this effect. In contrast, butyrate treatment of explants decreased the expression of Hoxa-5 and Hoxb-5. We conclude that diabetes alters expression of Hox genes, but that the effect of butyrate on lung development, and in particular on surfactant apoprotein expression, is independent of its effects on Hox genes.

Retinoic acid increases surfactant protein mRNA in fetal rat lung in culture.

Retinoic acid has both early or immediate (within hours) and late (after days) effects on gene expression. We studied the early effects of retinoic acid on the surfactant protein (SP) genes. Exposure of fetal rat lung explants to all trans-retinoic acid for 4 h resulted in a significant dose-dependent increase in SP-A, -B, and -C mRNA with markedly different dose-response characteristics. The maximal (2.5x) increase in SP-A mRNA was observed with 10(-10) M retinoic acid, whereas treatment with 10(-5) M resulted in a tendency to decreased levels. In contrast, maximal stimulation of SP-C (6x) was noted at 10(-5) M retinoic acid and that of SP-B (2x) at 10(-7) to 10(-5) M retinoic acid. Similar differences in the dose-response characteristics of SP-A and SP-C were observed with 9-cis-retinoic acid. A retinoic acid response element consensus sequence was identified in the rat SP-A gene; we hypothesize that retinoic acid-receptor complexes act directly on the SP-A gene via this response element.

Expression of Hoxb genes in the developing mouse foregut and lung.

Lung development in the mouse begins at embryonic day 9.5 (E9.5) when lung buds form in the foregut. Subsequently, there is extensive branching and cellular differentiation that depends upon specific epithelial-mesenchymal interactions. Homeobox genes are expressed in specific temporo-spatial patterns in the developing embryo and are known to be involved in axial patterning and specification of regional identity. Using whole mount in situ hybridization and immunohistochemistry, we studied the expression of Hoxb-1, b-2, b-3, b-4 and b-5 in the E9.5-E14.5 foreguts and lungs. Our results show that in E9.5 branchial arches and foregut, Hoxb genes are expressed in overlapping spatial domains and the anterior boundaries of these domains correspond to the position of a particular gene in the cluster-genes on the 3' end of the cluster are expressed more anteriorly in the branchial arches and foregut and those on the 5' end are expressed more posteriorly. Three of the genes, Hoxb-3, b-4, and b-5, are highly expressed in the foregut where the lung buds form. In contrast, in E10.5-E14.5 lung, there are two patterns of Hoxb gene expression. Hoxb-3 and b-4 are expressed in the mesenchyme of the trachea, mainstem bronchi, and distal lung, whereas Hoxb-2 and b-5 mRNA are present only in the mesenchyme of the distal lung buds. These results suggest that specific combinations of Hoxb gene expression are important in lung development and that Hoxb genes may be involved in specifying the differences between proximal (trachea and main bronchi) and distal (lung bud) mesenchyme.

Identification of Hox genes in newborn lung and effects of gestational age and retinoic acid on their expression.

Hox genes are sequence-specific DNA transcription factors, which are important in embryonic development and are expressed in a number of fetal tissues, including the lung. Additionally, retinoic acid (RA) has been shown to modulate Hox gene expression in a number of cell types. The specific aims of this study were to 1) identify those Hox genes expressed in newborn mouse lung using reverse transcription-polymerase chain reaction (RT-PCR), 2) study the ontogeny of Hox gene expression in fetal mouse and rat lung by Northern analysis using cDNAs for mouse Hox genes, and 3) study the effects of RA on whole lung Hox mRNA levels in cultured fetal rat lung explants. Our data show that 16 different homeobox genes are expressed in newborn mouse lung. This includes seven Hox genes not previously identified in lung, as well as the divergent homeobox gene Hex. Steady-state mRNA levels of Hox A5 (Hox 1.3), B5 (Hox 2.1), B6 (Hox 2.2), and B8 (Hox 2.4) decrease with advancing gestational age in mouse lungs (E14 to adult). Similarly, Hox A5, B5, and B6 follow the same decreasing pattern of expression with advancing gestational age in rat lungs (E15 to adult). RA treatment of E17 rat lung explants in culture resulted in a significant dose- and time-dependent increase in Hox A5, B5, and B6 mRNA levels. The highest mRNA levels were seen in explants treated with 1 x 10(-5) M RA for 4-16 h. We conclude that there are many homeobox genes expressed in developing rodent lung and that their mRNA levels are affected by both gestational age and RA.