Magnetic resonance imaging in 122 children with spastic cerebral palsy

The interrelationship between magnetic resonance imaging findings, types of cerebral palsy, and gestation was studied. We analyzed the magnetic resonance imaging of brain in 122 children with spastic cerebral palsy. Forty-three patients had spastic hemiplegia, 61 had spastic diplegia, and 18 had spastic tetraplegia. Magnetic resonance imaging abnormalities were observed in 75% of patients. Periventricular leukomalacia accounted for 66% of abnormalities observed in patients with spastic diplegia; other types of brain lesions were uncommon. In patients with spastic tetraplegia, two types of magnetic resonance imaging abnormalities predominated: congenital brain anomalies and term-type brain injuries, 42% and 33% respectively. Types of magnetic resonance imaging abnormalities were more heterogeneous in patients with spastic hemiplegia. Preterm brain injuries (periventricular leukomalacia and posthemorrhagic porencephaly) were observed often in patients born at preterm but were also observed in patients born at term. Term-type brain injuries (term-type border-zone infarct, basal ganglia-thalamic lesion, subcortical leukomalacia, and multicystic encephalomalacia) were observed only in patients born at or near term. We conclude that magnetic resonance imaging findings for patients with spastic cerebral palsy were closely related to types of cerebral palsy and gestation at birth. Magnetic resonance imaging in patients with perinatal brain injury may reflect pathologic changes and is useful in understanding and evaluating cerebral palsy.     

Death rates of medical school class presidents

Medical professionals often face many competing demands to contribute both to the clinical care of patients and to the public health of society. We studied the long-term survival of doctors graduating from one medical school over one century (n=1521), comparing those who were presidents of their class to those who appeared alphabetically before or alphabetically after the president in the graduating class photograph. Statistics on long-term mortality were obtained from licensing authorities, medical obituaries, professional associations, alumni records, and national physician directories (follow-up 94% complete, median follow-up duration=38 years, total deaths=220). We found that most graduates were male (88%), white (93%), and younger than 30 years at time of graduation (93%). Presidents more frequently made contributions to society than their classmates, as recognized by professional alumni notices (21.9% vs. 13.3%, P<0.001) and Who's Who directory listings (7% vs. 0.5%, P<0.001). Nonetheless, survival after medical school was 2.4 years shorter for presidents than their classmates (49.0 vs. 51.4, P=0.036). The decrease in life-expectancy was unrelated to medical school marks or early career mortality and was accentuated after adjustments for birth year, gender, race, and specialization (P=0.001). We suggest that the type of medical professional who sacrifices themselves for this type of professional prestige may also be the type who fails to look after their health or is otherwise prone to early mortality.     

Ca2+ transient evoked by chemical stimulation is enhanced by PGE2 in vagal sensory neurons: role of cAMP/PKA signaling pathway

The effect of prostaglandin E(2) (PGE(2)) on chemical stimulation-evoked calcium (Ca(2+)) transient was investigated in isolated vagal sensory neurons of the rat using fura-2-based ratiometric Ca(2+) imaging. Application of capsaicin (3 x 10(-8) to 10(-7) M; 15 s) caused a rapid surge of intracellular Ca(2+) concentration in small- and medium-size neurons; the response was reproducible when >10 min elapsed between two challenges and was absent in nominally Ca(2+)-free solution. After pretreatment with PGE(2) (3 x 10(-7) M; 5 min), the peak of this capsaicin-evoked Ca(2+) transient was increased by almost fourfold, and its duration was also prolonged. This augmented response to capsaicin induced by PGE(2) gradually declined but remained higher than control after 15-min washout. Similarly, PGE(2) pretreatment also markedly enhanced the Ca(2+) transients induced by other chemical stimulants to C neurons, such as phenylbiguanide (PBG), adenosine 5'-triphosphate (ATP), and KCl. The Ca(2+) transients evoked by PBG, ATP, and KCl were potentiated after the pretreatment with PGE(2) to 242, 204, and 163% of their control, respectively. This potentiating effect of PGE(2) could be mimicked by forskolin (10(-6) M; 5 min), an activator of adenylyl cyclase, and 8-(4-chlorophenylthio)adenosine-3'-5'-cyclic monophosphate (CPT-cAMP; 3 x 10(-6) M, 10 min), a membrane-permeable cAMP analogue. Furthermore, the potentiating effects of PGE(2), forskolin, and CPT-cAMP were abolished by N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89; 10(-5) M; 15-20 min), a protein kinase A (PKA) inhibitor. In summary, these results show that PGE(2) reversibly potentiates the chemical stimuli-evoked Ca(2+) transients in cultured rat vagal sensory neurons, and this potentiating effect is mediated through the cyclic AMP/PKA transduction cascade.     

A novel ELISPOT assay to enhance detection of antigen-specific T cells employing antigen-presenting cells expressing vector-driven human B7-1

The ELISPOT assay is used to detect T-cell responses in patients enrolled in vaccine clinical trials; it is a relatively sensitive assay that can be performed without in vitro stimulation (IVS) of PBMC. However, this assay may be limited in some cases because of a weak signal 1 (as is the case for tumor-associated antigens [TAA]), or by a limited number of PBMC available from patients. The objective of this study is to enhance the sensitivity of the ELISPOT by increasing the level of signal 2, in this case, B7-1 expression on antigen-presenting cells (APC), allowing for a more sensitive detection of antigen-specific T-cell precursors. C1RA2 cells were used as APC and were uninfected, or infected with either recombinant avipox (fowlpox)-B7-1 (rF-B7-1) or control fowlpox wild-type (FP-WT) vector. The expressions of B7-1, MHC Class II, as well as HLA-A2 on the infected cells were analyzed by flow cytometry. A nearly threefold increase in B7-1 mean fluorescence intensity (MFI) occurred in the rF-B7-1-infected C1RA2 cells with no changes in MHC Class II or HLA-A2 expression. Various PBMC/APC ratios were used to further analyze the use of rF-B7-1-infected C1RA2 cells as APC in the ELISPOT assay. Fewer APC were required to activate PBMC when C1RA2 infected with rF-B7-1 were used as APC. Furthermore, using a PBMC/APC ratio of 1:1, similar detection was achieved using fewer PBMC. In addition, we demonstrated that the reactivity can be blocked by adding anti-B7-1 antibody. We performed the assay using APC on five normal healthy donors. All five donors showed substantial increases in PF to the Flu matrix peptide (Flu peptide) using the rF-B7-1-infected C1RA2 cells. Finally, we evaluated five cancer patients who received a carcinoembryonic antigen (CEA) vaccine-based therapy. Increases in CEA peptide precursors were noted in all five patients using the B7-1-infected APC. In conclusion, we have demonstrated the ability to enhance the sensitivity of the ELISPOT assay through infection of C1RA2 with rF-B7-1.     

Change in olfaction after radiotherapy for nasopharyngeal cancer--a prospective study

PURPOSE: To evaluate the changes in olfactory function in patients with nasopharyngeal carcinoma who have received radiation to the head and neck. MATERIALS AND METHODS: Olfactory function of consecutive patients with nasopharyngeal carcinoma was assessed prospectively before irradiation and serially up to 1 year after radiotherapy by the Sniffin' Sticks (Erlangen, Germany) olfactory function test and by a patient symptom visual analogue scale. RESULTS: Fifty-eight patients were recruited before radiotherapy was commenced. Three patients could not give a reliable response to the Sniffin' Sticks test even in this first assessment, and 7 patients did not return for evaluation after irradiation. Forty-eight patients were available for follow-up assessment. Mean olfactory threshold scores by the Sniffin' Sticks test were found to deteriorate significantly at 12 months when compared with the scores before irradiation (8.3 at 12 months vs 11.5 before irradiation; P =.001). Scores for olfactory discrimination and for identification did not exhibit any significant changes when assessed at 12 months (P >.05 for both). Subjective patient assessment of olfactory function with the visual analogue scale at 12 months did not demonstrate any significant differences when compared with patients' assessment before irradiation (P =.90). An increase in discharge was the only nasal symptom that demonstrated a significant change at 12 months when compared with the assessment before irradiation (P < 001). CONCLUSIONS: Deterioration in olfactory threshold scores was found at 12 months after irradiation and was not noticed by the patients.     

Glial cell line-derived neurotrophic factor family receptors are abnormally expressed in aganglionic bowel of a subpopulation of patients with Hirschsprung's disease

Hirschsprung's disease (HSCR), a congenital disease, is characterized by the absence of ganglion cells in the ganglion plexuses of the caudal most gut. In the aganglionic colon, the plexus remnants are replaced by aggregates of glial cells and hypertrophied nerve fibers. Signaling of glial cell line-derived neurotrophic factor (GDNF)-GFRAs-receptor tyrosine kinase (RET) is crucial for the development and maintenance of ganglion cells. Mutations of genes such as GDNF and RET lead to the perturbation of this signaling pathway, which causes HSCR. To understand the role of GFRAs in ganglion cells and the pathogenesis of HSCR, we intended to determine the specific cell lineages in the enteric nervous system that normally express GFRAs but are affected in HSCR. We studied colon biopsy specimens from 13 patients with HSCR (aged 1 day to 38 months) and 6 age-matched patients without HSCR as normal controls. RT-PCR, in situ hybridization, and immunohistochemistry were performed to examine the expression and cellular distributions of GFRAs in resected bowel segments of normal infants and those with HSCR. In normal infants and normoganglionic colon of patients with HSCR, the expression of GFRA1 was restricted to the glial cells and neurones of the ganglion plexuses. GFRAs expression was found to be markedly reduced in the aganglionic colons of 3 infants with HSCR but was unaffected in the aganglionic colons of 10 other infants with HSCR. Residual GFRA expression was restricted to enteric glial cells in the plexus remnants of the aganglionic colons. Hypertrophied nerve fibers were not found to express GFRA1. We provide the first evidence that abnormal expression of GFRAs in the enteric nervous system may be involved in the pathogenesis of HSCR in a subpopulation of patients.     

Atypical blasts and bone marrow necrosis associated with near-triploid relapse of acute promyelocytic leukemia after arsenic trioxide treatment

The pathologic features of acute promyelocytic leukemia (APL) with t(15;17)(q22;q21) are highly characteristic, which with few exceptions enable a firm diagnosis to be made on morphologic grounds. An APL patient in first relapse presented with large, bizarre circulating blasts and bone marrow necrosis 2 weeks after chemotherapy consolidation for an arsenic trioxide-induced remission. Although a morphologic diagnosis could not be reached, cytogenetic investigations showed a near-triploid clone with t(15;17), confirming APL in second relapse. This case showed that clonal evolution with additional karyotypic aberrations might alter the blast morphology and pathologic features in APL.     

Diffusion-tensor imaging for the detection and quantification of treatment-induced white matter injury in children with medulloblastoma: a pilot study

BACKGROUND AND PURPOSE: Treatment-induced white matter (WM) injury in medulloblastoma survivors, as manifested by deterioration of cognitive function, is prevalent. However, no reliable imaging method exists for early detection and quantification. Our goal was to determine whether anisotropy of WM is reduced in medulloblastoma survivors and whether fractional anisotropy (FA) can be used as an index for evaluation of treatment-induced WM injury. METHODS: We evaluated nine medulloblastoma survivors treated with surgery, cranial irradiation, and chemotherapy by use of diffusion-tensor (DT) imaging and compared FA findings in selected WM sites (cerebellar hemispheres, pons, medulla oblongata, frontal periventricular WM, parietal periventricular WM, and corona radiata) with those of healthy age-matched control subjects. FA maps were compared with conventional T2-weighted images. FA was also compared with age at treatment, time interval since treatment, and deterioration of school performance. The two-tailed paired t test was used to determine statistical significance (P <.05). RESULTS: Significant reduction of FA (P <.05) was seen in all anatomic sites in the patient group compared with FA in control subjects, except in the frontal periventricular WM, even in areas with normal appearance on T2-weighted images. FA reduction ranged from 12.4-19% (mean, 16.5%). Compared with control subjects, posterior fossa and supratentorial WM FA in patients were reduced by 14.6% (SD 1.9%) and 18.4% (SD 0.55%), respectively (P =.029). Reduction of supratentorial WM FA correlated with younger age at treatment (< 5 years), longer interval since treatment (> 5 years), and deterioration of school performance. CONCLUSION: DT imaging and use of the index FA is potentially useful for early detection and monitoring of treatment-induced WM injury in children with medulloblastoma.