Fatal metabolic stroke in a child with propionic acidemia 11 years post liver transplant

Propionic acidemia is a rare autosomal recessive inborn error of metabolism caused by a deficiency of propionyl CoA carboxylase which often manifests with frequent metabolic decompensations and risk of neurological injury. Outcomes with medical therapy remain suboptimal. Liver transplantation has been shown to be a therapeutic option for patients and results in a milder phenotype of the disease and partial correction of the enzyme defect. Liver transplantation has been increasingly reported over the last decade and experience in managing these patients is improving. Long-term outcomes are generally good; however, the risk of complications still exists despite transplantation. We report a child who presented with a fatal metabolic stroke 11 years post liver transplant without any biochemical evidence of decompensation. We highlight the need to closely monitor these patients lifelong despite liver transplantation and maintain multidisciplinary working between hepatology and metabolic clinicians.     

Irreversible effects of trichloroethylene on the gut microbial community and gut‐associated immune responses in autoimmune‐prone mice

The developing immune system is particularly sensitive to immunotoxicants. This study assessed trichloroethylene (TCE)‐induced effects on the gut microbiome and cytokine production during the development in mice. Mice were exposed to TCE (0.05 or 500 μg/mL) at the levels that approximate to environmental or occupational exposure, respectively. Mice were subjected to a continuous developmental exposure to these doses encompassing gestation, lactation and continuing directly in the drinking water postnatally for 154 days (PND154) or PND259. To observe persistence of the effect TCE was removed from the drinking water in a subset of mice on PND154 and were provided regular drinking water until the study terminus (PND259). Abundance of total tissue‐associated bacteria reduced only in mice exposed to TCE until PND259. The ratio of Firmicutes/Bacteroidetes did not alter during this continuos exposure; however, cessation of high‐dose TCE at PND154 resulted in the increased abundance Bacteroidetes at PND259. Furthermore, high‐dose TCE exposure until PND259 resulted in a lower abundance of the genera Bacteroides and Lactobaccilus and increased abundance of genus Bifidobactrium and bacterial family Enterobacteriaceae. TCE exposure until PND154 showed significant changes in the production of interleukin‐33; that might play a dual role in maintaining the balance and homeostasis between commensal microbiota and mucosal health. At PND259, interleukin‐3, granulocyte‐macrophage colony‐stimulating factor and Eotaxin were altered in both, the continuous exposure and cessation groups, whereas only a cessation group had a higher level of KC that may facilitate infiltration of neutrophils. The irreversible effects of TCE after a period of exposure cessation suggested a unique programming and potential toxicity of TCE even at the environmental level exposure.     

The lipoprotein lipase gene serine 447 stop variant influences hypertension-induced left ventricular hypertrophy and risk of coronary heart disease

LVH [LV (left ventricular) hypertrophy] is an independent risk factor for CHD (coronary heart disease). During LVH, the preferred cardiac energy substrate switches from FAs (fatty acids) to glucose. LPL (lipoprotein lipase) is the key enzyme in triacylglycerol (triglyceride) hydrolysis and supplies FAs to the heart. To investigate whether substrate utilization influences cardiac growth and CHD risk, we examined the association between the functional LPL S447X (rs328) variant and hypertension-induced LV growth and CHD risk. LPL-X447 has been shown to be more hydrolytically efficient and would therefore release more free FAs than LPL-S477. In a cohort of 190 hypertensive subjects, LPL X447 was associated with a greater LV mass index [85.2 (1.7) in S/S compared with 91.1 (3.4) in S/X+X/X; P=0.01], but no such association was seen in normotensive controls (n=60). X447 allele frequency was higher in hypertensives with than those without LVH {0.14 [95% CI (confidence interval), 0.08-0.19] compared with 0.07 (95% CI, 0.05-0.10) respectively; odds ratio, 2.52 (95% CI, 1.17-5.40), P=0.02}. The association of LPL S447X with CHD risk was then examined in a prospective study of healthy middle-aged U.K. men (n=2716). In normotensive individuals, compared with S447 homozygotes, X447 carriers were protected from CHD risk [HR (hazard ratio), 0.48 (95% CI, 0.23-1.00); P=0.05], whereas, in the hypertensives, X447 carriers had increased risk [HR, 1.54 (95% CI, 1.13-2.09) for S/S (P=0.006) and 2.30 (95% CI, 1.53-3.45) for X447+ (P<0.0001)] and had a significant interaction with hypertension in CHD risk determination (P=0.007). In conclusion, hypertensive LPL X447 carriers have increased risk of LVH and CHD, suggesting that altered FA delivery constitutes a mechanism through which LVH and CHD are associated in hypertensive subjects.     

Measuring SSRI occupancy of SERT using the novel tracer [123I]ADAM: a SPECT validation study

Purpose Serotonergic brain regions play a crucial role in the modulation of emotion, and serotonergic dysfunction may contribute to several neurological disorders. [¹²³I]ADAM is a novel SPECT tracer which binds with high affinity to serotonin transporters (SERT). The objective of this study was to compare different methods for the quantification of tracer binding and to develop a simplified single-scan protocol for this tracer, as well as to investigate its potential for characterisation of the transporter occupancy versus plasma concentration curve of a selective serotonin re-uptake inhibitor (SSRI).Methods Dynamic SPECT scans were performed on 16 healthy volunteers after administration of 150 MBq [¹²³I]ADAM. Data were acquired from the time of injection until 5.5 h after injection in 30- or 45-min sessions. Each subject was scanned twice: with and without pre-treatment with the SSRI citalopram in various dosage regimens. The plasma concentration of citalopram (C_p) was determined from venous samples. Images were reconstructed by filtered back-projection with scatter and attenuation correction. Tracer binding was quantified for midbrain, striatum and thalamus using cerebellum as a reference region. Quantification was done by kinetic modelling, graphical analysis and multi-linear regression, as well as by the ratio method, with binding potential (BP₂) as the outcome measure. The SERT occupancy by citalopram was determined relative to the baseline scan for each subject, and the occupancy versus C_p curve was fitted with the E_max model.Results The highest binding of [¹²³I]ADAM was in midbrain (mean baseline BP₂±SD=1.31±0.29), with lower binding in thalamus (0.79±0.16) and striatum (0.66±0.13). There was good agreement between BP₂ values obtained by different quantification methods. Using the ratio method, the best agreement with kinetic modelling was obtained with data from the time interval [200,260] min after injection. The fitting of the midbrain occupancy curve yielded a maximum occupancy of 84% and a plasma concentration required to reach 50% of the maximum of 2.5 ng/ml, with a goodness-of-fit variability of 13% (SD).Conclusion Binding of [¹²³I]ADAM to SERT in midbrain can be quantified with a single scan starting 200 min after injection. However, the variability of estimated occupancy values may be too high for critical assessment of occupancy of SERT by SSRI.     

Why does man have a quadratus plantae? A review of its comparative anatomy

Quadratus plantae is a muscle in the sole of the foot, typically originating from the calcaneus and inserting into the posterolateral surface of the tendons of flexor digitorum longus. It is implicated in heel pain, claw toe deformity and diabetic polyneuropathy. Phylogenetic considerations suggest that quadratus plantae is getting bulkier, implying its significance in human locomotion. Is it simply an accessory flexor that brings the line of pull of flexor digitorum longus in line with the long axis of the foot, as its name would suggest? We cite evidence from electromyographic studies that suggest it actually acts as a primary toe flexor in voluntary movements, being preferentially recruited over flexor digitorum longus. From comparative anatomical considerations it also seems likely that quadratus plantae is an intrinsic evertor of the foot. Eversion is an important evolutionary asset, especially in erect bipedalism. Human electromyographic experiments have yet to confirm this. However, they do suggest that quadratus plantae functions to resist extension of the toes during the stance phase of locomotion, which serves to increase the stability of the foot. Future electromyographic experiments may provide more information on the role of quadratus plantae in human locomotor evolution and in foot eversion in particular.     

Adhesion, chemotaxis, and aggregation of Walker carcinosarcoma cells in response to products of resorbing bone

Cells from the Walker 256 carcinosarcoma, a rat breast tumor with a propensity to metastasize to bone, were labeled with [131I]5-iodo-2'-deoxyuridine and then added to 96-hour organ cultures of fetal Sprague-Dawley rat calvaria that had been prelabeled with 45Ca and incubated with various stimulators or inhibitors of resorption. In conditioned media from resorbing bone cultures, the number of cells that attached to the bone surfaces correlated with the degree of bone resorption (r = 0.65; P less than .005). The attachment response was maximal after 180 minutes of cocultivation and was inhibited by preincubation of the tumor cells with 10(-5) M cytochalasin B. Cellular attachment appeared to be promoted by a trypsin-sensitive factor released into the organ culture medium from resorbing bones. Enhanced tumor cell attachment did not appear to be related to a change in the surface properties of the resorbing bone, since it was not observed when the conditioned media were replaced with fresh medium. Furthermore, tumor cells placed in conditioned medium demonstrated increased attachment to plastic surfaces and formed aggregates. While there was a direct correlation between the ability of conditioned medium to promote cellular adhesion and chemotactic migration (r = 0.85; P less than .05), the factors responsible for chemotaxis and adhesion could be separated by gel filtration. The release of such factors from resorbing bones may promote the formation of secondary bone tumors, since in this system attachment of unlabeled cells was followed by proliferation of tumor cells and evidence of bone invasion.     

Assessment of regional left ventricular function: accuracy and reproducibility of positioning standard short-axis sections in cardiac MR imaging

The assessment of regional left ventricular (LV) function with cardiac magnetic resonance (MR) cine techniques requires a standardized section positioning. A simple selective short-axis method for selective positioning of three short-axis sections (basal, midcavity, apical) was tested for its accuracy, compared with accepted criteria, in 21 volunteers (mean age, 32 years +/- 11) and in 23 patients with myocardial infarction (mean age, 56 years +/- 12). Reproducibility of section positioning and of regional LV parameters was tested in the volunteers. Among the six accuracy criteria defined for standard sections, the selective short-axis approach had an average accuracy of 90.9% in volunteers and 87.7% in patients, compared with 92.1% and 90.6%, respectively, for a multisection approach covering the whole LV. There was very good reproducibility of the selected intersection gap (r = 0.89, P < .001) and of measured midcavity end-diastolic diameters in vertical (r = 0.83, P < .001) and horizontal (r = 0.85, P < .001) long-axis orientations. The proposed method produces standardized short-axis section positions that meet the recommendations for cardiac imaging. The study was approved by the local ethics committee, and all subjects gave written informed consent.     

Tolerance of MRI vs. SPECT myocardial perfusion studies--a patient survey

PURPOSE: To compare patients' perceived satisfaction and tolerance of magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) myocardial perfusion imaging. MATERIALS AND METHODS: A questionnaire was sent retrospectively to 41 patients who had undergone both SPECT and MRI myocardial perfusion scans at our institution. The questionnaire assessed SPECT and MRI separately, and in a separate section compared the tests directly. The answers were scored and analyzed for statistical significance by the use of Wilcoxon signed-ranks and chi2 tests. RESULTS: Thirty-five completed questionnaires were returned. In a direct comparison, 12 patients (34%) preferred MRI overall, nine (26%) preferred SPECT, and 14 (40%) expressed no preference. The ratings for the overall comfort of the scans were similar, with a score of 5.8 for SPECT and 5.7 for MRI (on a scale of 1-10). More patients stated a preference for MRI on scan comfort, duration, and safety (no statistical significance), but it was less well rated than SPECT for space on the scanner (P = 0.008). Three patients (9%) stated that they would not have an MRI scan again, while two patients (6%) said they would not repeat a SPECT scan. CONCLUSION: MRI myocardial perfusion imaging represents an acceptable alternative to SPECT with respect to patient tolerance and satisfaction.     

Epidemiology of dengue in Sri Lanka before and after the emergence of epidemic dengue hemorrhagic fever

Before 1989, dengue epidemiology in Sri Lanka was characterized by frequent transmission of all four dengue serotypes but a low incidence of dengue hemorrhagic fever (DHF). After 1989, cases of DHF dramatically increased. Here we present the results of epidemiologic studies conducted in Colombo, Sri Lanka before and after epidemic emergence of DHF in 1989. We compared the proportion of dengue cases among people with fever attending clinics from 1980 to 1984 and in 1997 and 1998 to determine if an increase in dengue transmission was associated with more DHF cases being reported. We also compared the relative distribution of dengue virus serotypes circulating in Colombo before and after the emergence of DHF. We detected no significant differences in dengue as a proportion of fever cases or in serotype distribution between the pre and post-DHF periods. We conclude that an increase in virus transmission or a change in circulating serotypes does not explain the epidemic emergence of DHF in Sri Lanka.