PET measurement of cardiac and nigrostriatal denervation in Parkinsonian syndromes.

Scintigraphic imaging with (123)I-metaiodobenzylguanidine ((123)I-MIBG) has demonstrated extensive losses of cardiac sympathetic neurons in idiopathic Parkinson's disease (IPD). In contrast, normal cardiac innervation has been observed in (123)I-MIBG studies of multiple-system atrophy (MSA) and progressive supranuclear palsy (PSP). Consequently, it has been hypothesized that cardiac denervation can be used to differentiate IPD from MSA and PSP. We sought to test this hypothesis by mapping the distribution of cardiac sympathetic neurons in patients with IPD, MSA, and PSP by using PET and (11)C-meta-hydroxyephedrine ((11)C-HED). Also, the relationship between cardiac denervation and nigrostriatal denervation was investigated by measuring striatal presynaptic monoaminergic nerve density with PET and (11)C-dihydrotetrabenazine ((11)C-DTBZ). METHODS: (11)C-HED and (11)C-DTBZ scans were obtained for patients with IPD (n = 9), MSA (n = 10), and PSP (n = 8) and for age-matched control subjects (n = 10). Global and regional measurements of (11)C-HED retention were obtained to assess the extent of cardiac sympathetic denervation. (11)C-DTBZ binding was measured in the caudate nucleus, anterior putamen, and posterior putamen. RESULTS: As expected, extensive cardiac denervation was observed in several of the patients with IPD. However, substantial cardiac denervation was also seen in some patients with MSA and PSP. (11)C-DTBZ studies demonstrated striatal denervation in all patients with IPD and in most patients with MSA and PSP. No correlation was found between cardiac (11)C-HED retention and striatal (11)C-DTBZ binding. CONCLUSION: Cardiac sympathetic denervation was found to occur not only in IPD but also in other movement disorders, such as MSA and PSP. This finding implies that scintigraphic detection of cardiac sympathetic denervation cannot be used independently to discriminate IPD from other movement disorders, such as MSA and PSP. Cardiac sympathetic denervation was not correlated with striatal denervation, suggesting that the pathophysiologic processes underlying cardiac denervation and striatal denervation occur independently in patients with parkinsonian syndromes. These findings provide novel information about central and peripheral denervation in patients with neurodegenerative disorders.     

Dependence of cardiac 11C-meta-hydroxyephedrine retention on norepinephrine transporter density.

The norepinephrine analog (11)C-meta-hydroxyephedrine (HED) is used with PET to map the regional distribution of cardiac sympathetic neurons. HED is rapidly transported into sympathetic neurons by the norepinephrine transporter (NET) and stored in vesicles. Although much is known about the neuronal mechanisms of HED uptake and retention, there is little information about the functional relationship between HED retention and cardiac sympathetic nerve density. The goal of this study was to characterize the dependence of HED retention on nerve density in rats with graded levels of cardiac denervation induced chemically with the neurotoxin 6-hydroxydopamine (6-OHDA). METHODS: Thirty male Sprague-Dawley rats were divided into 6 groups, and each group was administered a different dose of 6-OHDA: 0 (controls), 7, 11, 15, 22, and 100 mg/kg intraperitoneally. One day after 6-OHDA injection, HED (3.7-8.3 MBq) was injected intravenously into each animal and HED concentrations in heart and blood at 30 min after injection were determined. Heart tissues were frozen and later processed by tissue homogenization and differential centrifugation into a membrane preparation for in vitro measurement of cardiac NET density. A saturation binding assay using (3)H-mazindol as the radioligand was used to measure NET density (maximum number of binding sites [B(max)], fmol/mg protein) for each heart. RESULTS: In control animals, NET B(max) was 388 +/- 23 fmol/mg protein and HED heart uptake (HU) at 30 min was 2.89% +/- 0.35 %ID/g (%ID/g is percentage injected dose per gram tissue). The highest 6-OHDA dose of 100 mg/kg caused severe cardiac denervation, decreasing both NET B(max) and HED HU to 8% of their control values. Comparing values for all doses of 6-OHDA, HED retention had a strong linear correlation with NET density: HU = 0.0077B(max) -0.028, r(2) = 0.95. CONCLUSION: HED retention is linearly dependent on NET density in rat hearts that have been chemically denervated with 6-OHDA, suggesting that HED retention is a good surrogate measure of NET density in the rat heart. This finding is discussed in relation to clinical observations of the dependence of HED retention on cardiac nerve density in human subjects using PET.     

Management of symptomatic chronic extra-axial fluid collections in pediatric patients.

The records of 103 pediatric patients having symptomatic chronic extra-axial fluid collections treated at Children's Hospital of Los Angeles from 1977 to 1988 were reviewed. Patients were treated with observation, serial percutaneous needle drainage, drainage through burr holes, drainage into a closed external drainage system, or subdural to peritoneal shunt. If the initial treatment was not effective, additional forms of treatment were instituted. Shunts, ultimately used in 73% of the patients, proved to be the most effective treatment. Of the group with shunts, the extra-axial fluid was unilateral in 20% and bilateral in 80%. In those patients with bilateral effusions, no difference in efficacy of shunts was seen in patients treated with bilateral versus unilateral shunts. Of the 75 patients with shunts, 12% required a shunt revision for progressive or recurrent symptoms. Shunt infections occurred in 3% of the patients, necessitating removal of the shunt and treatment with antibiotics. Eosinophilia in the subdural fluid was associated with shunt obstruction requiring revision. The shunt was never removed in 51% of patients with no untoward effects. This study demonstrates that the most efficacious treatment of symptomatic chronic extra-axial fluid collections in children is a unilateral subdural to peritoneal shunt. The shunt need not be removed after resolution of the fluid collections.     

β-Methyl-15-p-iodophenylpentadecanoic acid metabolism and kinetics in the isolated rat heart

The use of 15-p-iodophenyl--methyl-pentadecanoic acid (Me-IPPA) as an indicator of long chain fatty acid (LCFA) utilization in nuclear medicine studies was evaluated in the isolated, perfused, working rat heart. Time courses of radioctivity (residue curves) were obtained following bolus injections of both Me-IPPA and its straight chain counterpart 15-p-iodophenyl-pentadecanoic acid (IPPA). IPPA kinetics clearly indicated flow independent impairment of fatty acid oxidation caused by the carnitine palmitoyltransferase I inhibitor 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). In contrast, Me-IPPA kinetics were insenstive to changes in fatty acid oxidation rate and net utilization of long chain fatty acid. Analysis of radiolabeled species in coronary effluent and heart homogenates showed the methylated fatty acid to be readily incorporated into complex lipids but a poor substrate for oxidation. POCA did not significatly alter metabolism of the tracer, suggesting that the tracer is poorly metabolized beyond Me-IPPA-CoA in the oxidative pathway.     

Phylogenetic analysis of the spirochetes Borrelia parkeri and Borrelia turicatae and the potential for tick-borne relapsing fever in Florida

Isolates of Borrelia turicatae, Borrelia parkeri, and the Florida canine borrelia (FCB) were examined to further phylogenetically characterize the identities of these spirochetes in the United States. DNA sequences of four chromosomal loci (the 16S rRNA gene, flaB, gyrB, and glpQ) were determined for eight isolates of B. turicatae and six isolates of B. parkeri, which grouped the spirochetes into two distinct but closely related taxa (>98% sequence identity) separate from Borrelia hermsii. The FCB was clearly separated with the group identified as B. turicatae, confirming this bacterium as a relapsing fever spirochete. Therefore, the potential for tick-borne relapsing fever in humans and other animals exists in Florida and future efforts are needed to determine the enzootic hosts and distribution of this spirochete in the southeastern United States. Analysis of plasmids demonstrated both linear and circular forms in B. turicatae but only linear plasmids in B. parkeri, which should be of interest to investigators concerned with plasmid diversity and evolution within this group of spirochetes.     

De novo 13q partial duplication identified by cytogenetic, biochemical and molecular approaches

A 3.5-month-old female infant manifesting dysmorphic facies, developmental delay and failure to thrive was referred for cytogenetic evaluation. Peripheral lymphocytes revealed three chromosomally distinct cell lines: 46,XX/46,XX,10p+/47,XX,10p+,+mar. Dermal fibroblasts revealed only the 46,XX,10p+cell line. High resolution G-, R-, and Q-banding suggested that the extra chromosomal material (10p+) represented a duplication of the segment 13q14----13qter. Parental karyotypes were normal. As absolute identification of de novo chromosomal abnormalities, based solely on cytogenetic studies, is sometimes difficult, both biochemical and molecular approaches were undertaken to elucidate this abnormality in more detail. Dosage effects were examined using esterase D (localized to 13q14.1) and the DNA probes p1E8 and p9A7 (localized to 13q22 and 13q31/32, respectively). These studies suggested the presence of only 2 copies of esterase D, but 3 copies of both DNA probes, allowing identification of the breakpoint at 13q14.2.     

Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress

Aging degrades hematopoietic stem cell (HSC) functions, including stress response; however, the involved molecular pathways are incompletely defined. Murine BM conditionally deleted for One-Twenty-Two-1 (Ott1), is able to maintain lifelong hematopoiesis and has preserved numbers of long-term HSCs, yet cannot repopulate nor sustain itself after transplantation against a competitor even when Ott1 is excised after engraftment. We show, specifically under replicative stress, that Ott1-deleted HSCs have a significant reduction of the G(0) cell-cycle fraction associated with self-renewal and undergo early failure. Therefore, Ott1 is required to preserve HSC quiescence during stress but not steady-state hematopoiesis. Reduced tolerance of replicative stress, increased myeloid potential, and greater absolute numbers are mutual characteristics of both Ott1-deleted and aged HSCs, and comparison of their gene expression profiles reveals a shared signature. Ott1-deleted HSCs share multiple aging-associated physiologic changes, including increases in NF-κB activation and DNA damage. Loss of Ott1 causes increased reactive oxygen species; however, antioxidant treatment does not rescue the competitive defect, indicating the existence of additional essential Ott1-dependent HSC pathways. In conclusion, our data establish a requirement for Ott1 in stress hematopoiesis and suggest that Ott1-dependent processes may converge with those affected by aging.     

Linking global climate and temperature variability to widespread amphibian declines putatively caused by disease

The role of global climate change in the decline of biodiversity and the emergence of infectious diseases remains controversial, and the effect of climatic variability, in particular, has largely been ignored. For instance, it was recently revealed that the proposed link between climate change and widespread amphibian declines, putatively caused by the chytrid fungus Batrachochytrium dendrobatidis (Bd), was tenuous because it was based on a temporally confounded correlation. Here we provide temporally unconfounded evidence that global El Niño climatic events drive widespread amphibian losses in genus Atelopus via increased regional temperature variability, which can reduce amphibian defenses against pathogens. Of 26 climate variables tested, only factors associated with temperature variability could account for the spatiotemporal patterns of declines thought to be associated with Bd. Climatic predictors of declines became significant only after controlling for a pattern consistent with epidemic spread (by temporally detrending the data). This presumed spread accounted for 59% of the temporal variation in amphibian losses, whereas El Niño accounted for 59% of the remaining variation. Hence, we could account for 83% of the variation in declines with these two variables alone. Given that global climate change seems to increase temperature variability, extreme climatic events, and the strength of Central Pacific El Niño episodes, climate change might exacerbate worldwide enigmatic declines of amphibians, presumably by increasing susceptibility to disease. These results suggest that changes to temperature variability associated with climate change might be as significant to biodiversity losses and disease emergence as changes to mean temperature.     

Antenatal detection of cystic hygroma

Ultrasonographic evaluation, as a routine component of prenatal care, has significantly contributed to in utero assessment of pregnancy status. The detection of fetal abnormalities by ultrasound, however, has raised clinical questions and created parental dilemmas concerning the outcomes of such pregnancies. A relatively frequent anomaly observed on routine ultrasonographic examination is the posterior nuchal cystic hygroma. We report the prenatal detection of 16 cases of cystic hygromata and an analysis of a survey of the world's literature including an additional 155 cases. The information available from these 171 cases allows a clearer picture of the prognosis for fetuses in whom posterior cystic hygroma is detected in utero. Regarding outcome, 73.2 per cent of cases were terminated at the parents' request; 37 cases (22.6 per cent) resulted in fetal death in utero prior to any intervention. Only 7 per cent of continuing pregnancies resulted in live-born infants. Of the 142 cases with available cytogenetic findings, 22 per cent had normal karyotypes; 58 per cent had a karyotype associated with Turner syndrome phenotype; while autosomal trisomies and various structural abnormalities made up the remaining 20 per cent. Even among those fetuses with normal chromosomes, various physical anomalies were detected. Fetal hydrops was present in 66 per cent of the 102 cases with pertinent information. For those fetuses demonstrating cystic hygroma and normal karyotypes, Mendelian syndromes must be considered in the differential diagnosis. Alpha-fetoprotein evaluation of both maternal serum and amniotic fluid was not helpful in determining prognosis of these fetuses. The ultrasonographic finding of a posterior nuchal cystic hygroma, with or without accompanying fetal hydrops, is a valid indicator for a poor outcome of such pregnancies.     

Gene therapy for PNET

Summary A new era has been reached in cancer therapeutics in which the techniques of molecular biology can be applied to human brain tumors. Ongoing studies are determining the best vector system with which to deliver genes to cells. Choices include the retroviral, adenoviral, and Herpes simplex virus vector systems. The optimum mode of delivering the vector specifically to the tumor is being explored through intravenous, intra-arterial, and direct intra-tumoral injections. Finally, efforts to achieve adequate vector expression throughout an entire tumor are being realized with our greater understanding of vector design and gene expression. The PNET may be amenable in the future to gene therapy strategies because of its rapid proliferative potential, its tendency to spread within the CSF pathways, and its high recurrence rate. In this regard, a number of novel strategies for treating PNET are described herein.