Marked thrombocytosis in a child with advanced myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are clonal disorders characterized by ineffective hematopoiesis with rare occurrence in childhood. Conversely to adult affected patients, refractory anemia with ringed sideroblasts and the 5q-syndrome, which are associated with thrombocytosis are virtually absent in the pediatric age group. We describe the case of an 1-year-old boy with advanced MDS, specifically refractory anemia with excess of blasts who presented with leukocytopenia and anemia but marked thrombocytosis at diagnosis. Thrombocytosis resolved without therapy. This case illustrates the relationship between MDS and myeloproliferative disorders.     

Effect of inoculum density on susceptibility of Plesiomonas shigelloides to cephalosporins

OBJECTIVES: Resistance of Plesiomonas shigelloides to cephalosporins at higher cell densities has been reported. We investigated whether these inoculum effects are due to the production of beta-lactamases. METHODS: beta-Lactamase production of five P. shigelloides strains was characterized by activity tests, SDS-PAGE and isoelectric focusing. For all strains, MIC values of different cephalosporins were determined by microdilution methodology using inocula of 1 x 10(5) cfu/mL and 1 x 10(6) cfu/mL. Subsequently, the morphology of cells was determined by light microscopy. For one isolate, kill kinetics of cefpodoxime were determined using batch cultures with the lower and higher inocula. RESULTS: Four of five P. shigelloides strains were shown to be beta-lactamase-positive, producing different amounts of constitutively expressed non-inducible enzymes. Inoculum effects for cephalosporin susceptibility were observed for all strains. Examination of cells revealed a very strong filamentation, with filament sizes ranging from 100 microm up to 2 mm. The kill kinetics with cefpodoxime showed similar killing capacities of the antibiotic at both inoculum sizes. CONCLUSIONS: The reported resistance of P. shigelloides to cephalosporins at higher cell densities is not due to an inoculum-dependent regulation of beta-lactamases, but can be explained by the formation of extensive filaments.     

Increased prevalence of cholelithiasis in Gaucher disease: association with splenectomy but not with gilbert syndrome

GOALS: The purpose of this study is to ascertain the incidence of gallstones among adult patients with type 1 Gaucher disease and whether the presence of the UDPGT1 polymorphism (Gilbert syndrome), increases the incidence of gallstones. BACKGROUND: Cholelithiasis was been observed among patients with type I Gaucher disease with variable frequency. Too, studies have addressed the possibility of an association between Gilbert syndrome and formation of bilirubinate gallstones in hereditary spherocytosis wherein, like Gaucher disease, there is hemolysis of blood cell membranes. METHODS: Medical records of all adult patients with type 1 disease in a referral clinic were reviewed for evidence of gallstones or cholecystectomy. Blood samples were collected for molecular analysis for Gilbert syndrome. RESULTS: Of 323 adult patients, 82 patients (25.4%), 54 women (65.9%) and 28 men (34.1%), had evidence of gallbladder disease (P < 0.001 relative to normal white controls). There was a statistically significant increase (P < 0.001) for all groups above the ages of 20 years other than for men aged 40 to 49 years. There was a statistically significant association between splenectomy and both cholelithiasis (P = 0.022) and Gilbert syndrome (P = 0.002). CONCLUSIONS: This study highlights an increase incidence of cholelithiasis but not Gilbert syndrome among patients with Gaucher disease. Storage of glycolipid per se or an immune reaction to storage, may explain these findings.     

Exposure of anionic phospholipids serves as anti-inflammatory and immunosuppressive signal--implications for antiphospholipid syndrome and systemic lupus erythematosus

In contrast to necrotic cells, the clearance of apoptotic ones usually is an anti-inflammatory process which elicits only a marginal immune response. During apoptosis phosphatidylserine (PS) is exposed on the outer leaflet of the cytoplasmic membrane and serves as target for the PS receptor of phagocytes. The latter is responsible for anti-inflammatory signalling and the induction of TGFbeta. We were interested whether the immunogenicity of apoptotic cells can be increased by masking PS. We observed that treatment of xenogeneic apoptotic cells with annexin V (AxV) significantly increased the humoral immune response against surface epitopes of these cells. Furthermore, AxV-coated irradiated tumour cells were able to elicit a long lasting tumour specific cytotoxic T lymphocyte response. AxV efficiently blocked the uptake of irradiated cells by macrophages but not by dendritic cells. Furthermore, AxV skewed the phagocytosis of irradiated cells towards inflammation. Investigation of patients with autoimmune diseases further supported the role of anionic surface phospholipids for anti-inflammatory clearance of apoptotic cells. Impaired clearance and opsonisation with anti-phospholipid-antibodies are discussed to be responsible for the development of systemic lupus erythematosus and anti-phospholipid-syndrome, respectively. Presentation of cryptic epitopes from late apoptotic cells in a proinflammatory context may challenge T cell tolerance. In addition, accumulation of uncleared apoptotic debris in the germinal centres of lymph nodes may result in the survival of autoreactive B cells.     

Assessment of craniocerebral asymmetries in children by computed tomography

Computed tomographic (CT) scans of 32 children (mean age 2.8±2.5 years) with a wide range of craniocerebral asymmetry (CCA) were analyzed. Hemiparesis and epilepsy were the main clinical presentations. Two-thirds of the patients had brain infarcts. The degree of cerebral and ventricular asymmetry was evaluated by ratios obtained by linear measurements. The patients were divided into two groups according to the index of maximal asymmetry. The incidence of hemiparesis and the width of the cerebral ventricles did not differ in the two groups. This may be due to the fact that most of our patients suffered from perinatal insult to the brain, allowing time for remodeling and palstic changes to occur. The use of measurable structural parameters in craniocerebral asymmetry offers a basis for comparable radiological assessment.     

CT findings in persistent vegetative state following blunt traumatic brain injury

The use of linear measurements in the analysis of CT scans of TBI patients was found to contribute to the understanding of brain damage and were correlated with outcome in severe traumatic close brain injured patients. The purpose of the present study was to analyse the data obtained by the linear measurements on CT studies of TBI patients who remained in persistent vegetative state following blunt head trauma. All 27 patients included in the study were reported to be neurologically normal prior to injury. Thirteen patients, 11 remaining in persistent vegetative state responsive but unaware and two who died, constituted the worst outcome group. Fourteen patients who regained conscious ness, underwent multidisciplinary evaluation when their recovery reached a plateau and were ranked according to severity of residual symptoms and outcome. The degree of correlation with the overall vocational outcome parameter with the various radiological indices was calculated as the Spearman rank correlation coefficient, with correction for tied scores. Fisher's z transformation was used to combine results with those of our previous analysis. Three radiological parameters showed a statistically significant correlation with clinical outcome. These were the right and left septum caudate distance and the cerebroventricular index 2; these showed Spearman rank coefficients of 0.52, 0.45 and 0.48; with two-tailed p-values under 0.01, 0.02 and 0.01 respectively. The width of the third ventricle suggested correlation with the clinical scoring. The findings of the present study point to the impor tance of loss of deep gray matter of the caudate nuclei and widening of the adjacent part of the lateral ventricles in catastrophic brain injury. This finding may highlight the role of localized ischemic changes, in addition to diffuse axonal injury. Values of over 8 mm for the width of the third ventricle and over 11 mm for septum caudate distance are suggestive of catastrophic injury and poor prognosis for recovery.     

Luminal delivery and dosing considerations of local celecoxib administration to colorectal cancer.

The purpose of this study was to develop a biodegradable drug platform composed of chitosan and guar gum and to explore the possibility of using it for local adjuvant or neoadjuvant therapy of colorectal cancer. Celecoxib (Cx), a chemopreventative drug for familial adenomatous polyposis (FAP) and under trial for reducing post surgical colorectal malignancies, was selected as a model drug for this topical system because of the contraindications that are associated with its systemic administration. Films made of chitosan (Ct) and guar gum (GG) were prepared, characterized for equilibrium swelling, mucoadhesion, in vitro and in vivo degradation and loaded with Cx. Short term dosing studies in vitro were performed in the HT-29 colon carcinoma cell line that was incubated with Cx using the MTT test to assess IC50. The impact of a single high dose was evaluated and compared with a repeating low-dose regimen. In vivo dosing experiments with Cx were performed in the perfused intestine of the anaesthetized rat. Measuring tissue LDH assessed epithelium injury. Mechanical, mucoadhesion and in vitro degradation of the polysaccharide films were dictated by manipulating the ratios of Ct and GG. The addition of rat cecal contents to the dissolution medium increased the total Cx released from those films containing high amounts of GG. MTT reduction, a measure of cell proliferation, diminished as a function of increasing drug concentration and exposure time in the HT-29 cell line studies. Local high concentrations of Cx were shown to impede the proliferation of cancer cells directly, while chemoprevention has been demonstrated with low Cx doses. Healthy cells were shown to be sensitive to high Cx doses. Maximum therapeutic efficiency in the context of minimal healthy tissue exposure would thus be predicted utilizing a local delivery system such as the proposed adhesive, biodegradable polysaccharide composites.     

Spectrum of abdominal sonographic findings in 103 pediatric patients with Gaucher disease

The purpose of this study was to catalogue spleen and liver features by US in a cohort of 103 pediatric patients with Gaucher disease, and to document response to enzyme replacement therapy by serial US examination. There were 42 boys and 61 girls, 2 were splenectomized. Forty-eight patients received enzyme replacement therapy (ERT). At presentation all patients evinced organomegaly and 4.9% had focal (splenic or hepatic) lesions (hypo- and hyper-echoic or mixed). Fifteen patients began ERT before 11 years of age. There was a mean liver volume reduction from 230 to 137% after 2 years of ERT, with further reduction of 91% up to 6 years later. Mean spleen volume reduction was 38.4% at 2 years of ERT and a further reduction to 40.8% at last evaluation. Fourteen children began ERT between ages 11 and 16 years. Mean liver reduction was from 230 to 124% at 2 years and further reduction to mean of 104% recently. Mean splenic reduction was 37.7% after 2 years of ERT, with a mean of 43.8% recently (mean 4.5 years later). Organ volume changes in untreated and treated children were documented by US which is the modality of choice for repeat measures in this population. Our results highlight the initial dramatic and then continued response to ERT in pediatric patients with Gaucher disease.     

Gray-white matter discrimination--a possible marker for brain damage in heat stroke?

INTRODUCTION/OBJECTIVE: Heat stroke (HS) is a common medical emergency which carries high morbidity and morality. This study was designed to describe the pattern of central nervous system (CNS) changes as detected by brain CT scan in a case series of six patients suffering from classical and exertional HS. METHODS AND PATIENTS: All the patients were admitted in critical condition during the heat wave in the summer of 1999 in Israel. Each was in deep coma with a measured core temperature of over 40 degrees C upon admission to the emergency department. RESULTS: Aggressive cooling measures decreased the core temperature to <38 degrees C within 30 min following admission. Two patients (33.3%) died. One of the survivors remained in a vegetative state. Brain CT studies carried out within 4 days of admission in all the patients revealed severe loss of gray-white matter discrimination (GWMD) without signs of acute bleed or significant focal lesion, findings that persisted in repeated brain CTs in one patient who remained in a vegetative state. DISCUSSION AND CONCLUSIONS: Loss of GWMD may represent an early and sensitive indication of severe brain damage in patients with severe HS. Further studies in larger groups of patients are warranted in order to determine whether the appearance of GWMD in brain CTs of patients with HS has prognostic value.