Advances in computer-assisted single-photon emission computed tomography (SPECT) for epilepsy surgery in children

Epilepsy surgery has emerged as an important option in the treatment of children with epilepsy that is refractory to antiepileptic drug management. The cornerstone of successful surgery is accurate localization of the brain region of seizure onset. Traditional techniques of seizure onset localization, e.g. surface electroencephalography (EEG) recording and magnetic resonance imaging (MRI), allow accurate localization in a significant number of patients. When the focus of seizure onset is not apparent from these non-invasive techniques, other methods of localization, e.g. intracranial EEG recording, may be needed before resection of the focus. Single-photon emission computed tomography (SPECT) is a nuclear medicine blood-flow technique that has been used to identify a region of epileptogenic brain associated with low blood flow in the resting state (interictal SPECT) or increased blood flow at the time of seizure activity (ictal SPECT). This report describes the validation and utility of a computer-assisted method of subtracting the interictal from the ictal SPECT scans and co-registering the difference image on the MRI. This method, called subtraction ictal SPECT co-registered on MRI (SISCOM), is used in guiding the location and the extent of intracranial electrode implantation, or in obviating the need for the implantation in some cases.     

Female circumcision (female genital mutilation): a problem for brachytherapy in cervical cancer

Female circumcision is a traditional practice common in African countries. It involves partial or total removal of external female genitalia. It has led to many complications, in particular, the scarring of the external genitalia. The consequence is a very narrow introitus making the intracavitary brachytherapy treatment component difficult when these women develop cancer of cervix. We present two such cases from our institution. Our aim is to make the radiation and gynecological oncologists, both in developed and developing countries, aware of this practice and the problems they can encounter in the management of such cases. Intracavitary brachytherapy is an important component in the potentially curative role of radiation therapy for cervical cancer. Every effort should be made to ensure that the sequelae of genital mutilation does not deprive these women of the same standard of care as the general population.     

A phase I and pharmacokinetic study of paclitaxel poliglumex (XYOTAX), investigating both 3-weekly and 2-weekly schedules.

PURPOSE: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. EXPERIMENTAL DESIGN: Nineteen patients were investigated on the 3-weekly phase Ia study and 11 patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. RESULTS: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m(2) (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m(2). Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m(2). Pharmacokinetic investigations indicated a prolonged half-life of >100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m(2) in phase Ia and one in a patient with gastric carcinoma at 175 mg/m(2) in phase Ib. CONCLUSION: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.     

Gilbert's syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn

OBJECTIVE: Prolonged neonatal jaundice, beyond day 14 of life, is very common and of concern to the clinician. The aim of this study was to investigate whether a genetic mutation in the bilirubin UGT1A1 gene, which has been associated with Gilbert's syndrome in adults, is a contributory factor in prolonged neonatal jaundice. STUDY DESIGN: Blood was collected from 85 term newborns with unexplained hyperbilirubinemia, and DNA was prepared. The neonates were divided into 6 groups depending on whether they were breast-fed or bottle-fed and whether they had acute, prolonged, or very prolonged jaundice. UGT1A1 TATA promoter genotyping (DNA test for Gilbert's syndrome) was performed on all samples, and analysis of the entire UGT1A1 coding sequence was performed in a representative sample (11 of 26) of very prolonged cases. RESULTS: In addition to the known common UGT1A1 TATA alleles (TA6 and TA7), a novel TATA allele (TA5) in a neonate with very prolonged jaundice was identified. Statistical analysis of the TATA genotype distributions within the group of breast-fed neonates revealed significant differences among the acute, prolonged, and very prolonged subgroups (.05 > P >.01): the incidence of familial hyperbilirubinemia genotypes (7/7 and 5/7) is 5 times greater in very prolonged cases (31%) relative to acute cases (6%). Neonates with prolonged jaundice from family pedigrees were observed to demonstrate the Gilbert's phenotype as children or young adults. CONCLUSIONS: A genetic predisposition to develop prolonged neonatal hyperbilirubinemia in breast-fed infants is associated with TATA box polymorphism of the UGT1A1 gene and will be recognized as Gilbert's syndrome in adulthood.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Sustained stoichiometric imbalance and its ecological consequences in a large oligotrophic lake

Considerable attention is given to absolute nutrient levels in lakes, rivers, and oceans, but less is paid to their relative concentrations, their nitrogen:phosphorus (N:P) stoichiometry, and the consequences of imbalanced stoichiometry. Here, we report 38 y of nutrient dynamics in Flathead Lake, a large oligotrophic lake in Montana, and its inflows. While nutrient levels were low, the lake had sustained high total N: total P ratios (TN:TP: 60 to 90:1 molar) throughout the observation period. N and P loading to the lake as well as loading N:P ratios varied considerably among years but showed no systematic long-term trend. Surprisingly, TN:TP ratios in river inflows were consistently lower than in the lake, suggesting that forms of P in riverine loading are removed preferentially to N. In-lake processes, such as differential sedimentation of P relative to N or accumulation of fixed N in excess of denitrification, likely also operate to maintain the lake’s high TN:TP ratios. Regardless of causes, the lake’s stoichiometric imbalance is manifested in P limitation of phytoplankton growth during early and midsummer, resulting in high C:P and N:P ratios in suspended particulate matter that propagate P limitation to zooplankton. Finally, the lake’s imbalanced N:P stoichiometry appears to raise the potential for aerobic methane production via metabolism of phosphonate compounds by P-limited microbes. These data highlight the importance of not only absolute N and P levels in aquatic ecosystems, but also their stoichiometric balance, and they call attention to potential management implications of high N:P ratios.

The emergence of the Anthropocene era has been marked by major changes in all of Earth’s major biogeochemical cycles (1). For example, fluxes of carbon (C) (as CO₂) to the atmosphere have increased by ∼14% during the last 120 y largely due to fossil fuel combustion. Fluxes of nitrogen (N) into the biosphere have increased by at least 100% due to application of the Haber-Bosch reaction for fertilizer production, land use change favoring N-fixing legumes, and conversion of atmospheric N₂ to available forms (NO_x) by high temperature combustion of petroleum and fossil gas (2). Finally, large-scale mining of phosphorus (P)-rich geological deposits for production of fertilizers has amplified rates of P cycling in the biosphere by ∼400% (1). Each of these perturbations has biophysical and ecological impacts at differing time and space scales. For C, its accumulation in the atmosphere has altered Earth’s radiative balance, warming the planet and perturbing precipitation patterns globally. Amplified inputs of reactive N to the Earth system enter the hydrosphere and, thus, potentially lead to overenrichment of lakes, rivers, and coastal oceans across broad regions. Amplifications of P inputs often impair water quality at watershed and local scales (3), stimulating phytoplankton production and contributing, along with N, to harmful algal blooms, fish kills, and “dead zones” (4, 5). These differential amplifications and their contrasting spatial scales indicate that ecosystems are experiencing not only absolute changes in biogeochemical cycling, but also perturbations in the relative inputs and outputs of biologically important elements (6). Studies of elemental coupling and uncoupling in ecosystems are not yet widespread, but emerging work has shown how C, N, and P are differentially processed as they pass through watersheds (7).The potential for differential alteration in supplies of N and P to aquatic ecosystems suggests that understanding the nutrient status of a water body requires knowledge of not only absolute supplies of limiting nutrients, but also their relative proportions (i.e., their N:P stoichiometry). This work has been facilitated in recent years by the emergence of the theory of ecological stoichiometry (8). For example, seminal work by Redfield (9) found that N:P ratios in marine organic matter were tightly constrained around 16:1 (molar, here and throughout), a value that may represent the central tendency for the N:P ratio of phytoplankton undergoing balanced growth in which major pools of N (protein) and P (RNA) are produced at the same rate (10). In lakes, N:P ratios show much wider variation—around a value of ∼30—perhaps reflecting the biogeochemical connections of lakes to terrestrial systems where N:P ratios have a similar value and range of variation (11). Nevertheless, this classic “Redfield ratio” of 16:1 can be thought of as representing a balanced nutrient supply for primary producers in pelagic ecosystems. When the ratios of N and P supplied deviate from this balanced ratio, primary limitation of growth by N (when N:P is low) or by P (when N:P is high) can occur. For example, phytoplankton growth in lakes with imbalanced total N: total P (TN:TP) ratios that exceed 30:1 is generally P limited (12). Disproportionate inputs of N relative to P from atmospheric deposition can increase lake TN:TP ratios and shift lake phytoplankton from N to P limitation (13), inducing P limitation in zooplankton (14). Imbalanced N:P ratios in nutrient supplies can also shift the competitive advantage among phytoplankton and enhance production of potentially toxic compounds during harmful algal blooms. For example, skewed supplies of N relative to P can increase production of N-rich secondary compounds by phytoplankton, while disproportionate inputs of P relative to N can induce production of C-based toxins (15). High N:P ratios can also enhance proliferation of fungal parasites of phytoplankton (16).Imbalanced N:P ratios can impact aquatic ecosystems in other ways. For example, they can alter the functioning of food webs. In particular, shifts in nutrient supply regimes that enhance P limitation can impede energy flow in trophic interactions because biomass of P-limited primary producers is of low quality for animals due to its low P content (8). Ecosystem shifts to high N:P ratios and more prevalent P limitation can also impact the cycling of the greenhouse-active gas methane (CH₄) because phosphate limitation can result in production of methane under aerobic conditions in both marine and freshwater phytoplankton and bacteria (17, 18). Both chemoheterotrophic and photoautotrophic bacteria (e.g., Pseudomonas, SAR11, Trichodesmium, Synechococcus) can metabolize organic P compounds, called phosphonates, to acquire P. Microbial cleavage of one type of phosphonate, methylphosphonic acid (MPn), to acquire P results in formation of methane (17). While it is likely that anaerobic methane production due to oxygen depletion in response to P-driven eutrophication is the dominant process connecting P to methane dynamics, the significance of aerobic phosphonate metabolism to global methane cycles remains to be assessed. However, contributions are potentially large, given the prevalence of P limitation in both freshwater and marine ecosystems. In light of emerging trends that suggest overall increases in ecosystem N:P ratios due to human impacts (6), these trophic and biogeochemical impacts of stoichiometric imbalance show that it is critical to consider not only absolute levels of nutrients, but also their stoichiometry. In particular, high N:P ratios can accentuate P limitation, causing a suite of ecological impacts that, currently, are poorly described.In this paper, we illustrate the utility of stoichiometric approaches by combining analyses of long-term records of nutrient supply and dynamics, together with contemporary experiments, to examine how imbalances in N:P stoichiometry (e.g., strong divergence from classic Redfield proportions) influence plankton ecology and biogeochemistry across multiple scales in Flathead Lake, a large lake in western Montana. The lake is itself relatively unperturbed by human impacts and, thus, maintains low overall nutrient levels. However, the strong stoichiometric imbalance that we describe makes Flathead Lake appropriate for assessing ecosystem consequences of what appear to be general trends of increasing N:P ratios in global ecosystems (6). Numerous limnological properties of the lake and its inflow rivers have been monitored continuously for several decades, including concentrations of various forms of N and P. Thus, these time-series data allow us not only to assess long-term variability or stability in the stoichiometry of N and P in the lake and its river inflows over decadal time scales, but also to connect its stoichiometry with potential consequences for nutrient limitation, food web dynamics, and biogeochemical cycling under low-nutrient conditions.     

Secondary hypertrophic osteoarthropathy an unusual cause of arthritis in childhood

Although an uncommon occurrence in childhood, hypertrophic osteoarthropathy secondary to tumors—most commonly to osteogenic sarcoma with pulmonary metastasis—may cause severe joint pain and swelling. The syndrome should be considered in the differential diagnosis of acute arthritis in childhood.     

Association between neuromelanin-sensitive MRI signal and psychomotor slowing in late-life depression

Late-life depression (LLD) is a prevalent and disabling condition in older adults that is often accompanied by slowed processing and gait speed. These symptoms are related to impaired dopamine function and sometimes remedied by levodopa (L-DOPA). In this study, we recruited 33 older adults with LLD to determine the association between a proxy measure of dopamine function—neuromelanin-sensitive magnetic resonance imaging (NM-MRI)—and baseline slowing measured by the Digit Symbol test and a gait speed paradigm. In secondary analyses, we also assessed the ability of NM-MRI to predict L-DOPA treatment response in a subset of these patients (N = 15) who received 3 weeks of L-DOPA. We scanned a further subset of these patients (N = 6) with NM-MRI at baseline and after treatment to preliminarily evaluate the effects of L-DOPA treatment on the NM-MRI signal. We found that lower baseline NM-MRI correlated with slower baseline gait speed (346 of 1807 substantia nigra–ventral tegmental area (SN-VTA) voxels, P_corrected = 0.038), particularly in the more medial, anterior, and dorsal SN-VTA. Secondary analyses failed to show an association between baseline NM-MRI and treatment-related changes in gait speed, processing speed, or depression severity (all P_corrected > 0.361); we however found preliminary evidence of increases in the NM-MRI signal 3 weeks post-treatment with L-DOPA compared to baseline (200 of 1807 SN-VTA voxels; P_corrected = 0.046), although the small sample size of these preliminary analyses warrants caution in their interpretation and future replications. Overall, our findings indicate that NM-MRI is sensitive to variability in gait speed in patients with LLD, suggesting this non-invasive MRI measure may provide a promising marker for dopamine-related psychomotor slowing in geriatric neuropsychiatry.Subject terms: Cognitive neuroscience, Depression, Biomarkers