The management of congenital and acquired problems of the distal radioulnar joint in children

Pain in the ulnar aspect of the pediatric wrist is an uncommon problem; however, when pain does occur it is usually the result of antecedent bony trauma or an underlying skeletal abnormality, which may lead to ulnar-sided wrist pain of varying etiology. The clinician must to be able to identify these entities within the pediatric wrist in order to make the appropriate diagnosis and plan for surgical intervention to prevent ongoing damage to the distal radioulnar joint (DRUJ). This article reviews the etiology, clinical presentation, and treatment strategies for the management of the unique problems that can affect the pediatric and adolescent DRUJ.     

Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved beta-cell function: extension of a randomized, double-blind, phase II trial

BACKGROUND: Treatment with DiaPep277, a peptide derived from HSP60, has been shown to preserve beta-cell function in non-obese diabetic mouse (NOD) mice and in a trial with newly diagnosed human patients with type 1 diabetes treated over a 10-month period. This article extends the clinical trial observations to a total of 20 months of treatment to determine the safety and the effects of repeated doses of DiaPep277 on endogenous insulin secretion, metabolic control, and exogenous insulin requirements. METHODS: Thirty-five male patients (aged 16-58) with a basal C-peptide greater than 0.1 nmol/L were assigned to periodic treatment with DiaPep277 (1 mg) or placebo for a 12-month treatment and 18-month observation protocol, later extended to an additional year of treatment. Stimulated C-peptide, HbA1c, and an exogenous insulin dose were the clinical endpoints. RESULTS: At 18 months, stimulated C-peptide concentrations had fallen in the placebo group (p = 0.0005) but were maintained in the DiaPep277 group. The need for exogenous insulin was higher in the placebo group than in the DiaPep277 group. Mean HbA1c concentrations were similar in both groups. After extension of the study, patients continuing treatment with DiaPep277 and those switched from placebo to DiaPep277 manifested a trend towards a greater preservation of beta-cell function compared to patients maintained on or switched to placebo. The safety profile of DiaPep277 was similar between the treatment and placebo groups, and no drug-related adverse events occurred. CONCLUSIONS: Periodic treatment of subjects with DiaPep277 over 2 years was safe and associated preservation of endogenous insulin secretion up to 18 months was observed.     

Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: a randomised, double-blind phase II study

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a T-cell-mediated autoimmune disease that leads to the destruction of insulin-producing beta cells. Treatment with DiaPep277, a peptide derived from heat-shock protein 60 (hsp60), has been found to slow the deterioration of beta-cell function after clinical onset of diabetes in NOD mice and human adults. Our aim was to evaluate the efficacy and safety of DiaPep277 treatment in attenuating beta-cell destruction in children with recent-onset T1DM. METHODS: A prospective, randomized, double-blind, phase II design was used. The sample included 30 children (19 males) aged 7-14 years who had been diagnosed with T1DM from 53 to 116 days previously, and had basal C-peptide concentrations above 0.1 nmol/L. The children were randomized to receive subcutaneous injections of 1 mg DiaPep277 (15 patients) or 40 mg mannitol (placebo) at entry and at 1, 6, and 12 months. The duration of follow-up was 18 months. The groups were compared for stimulated C-peptide level, exogenous insulin dose, and HbA1c concentration. RESULTS: C-peptide levels similarly decreased over time in the DiaPep277- and placebo-treated patients. There was no significant difference in insulin dose or HbA1c concentration between the groups at any time point. No serious drug-related adverse effects were recorded throughout the study period. CONCLUSIONS: One-year treatment with DiaPep277 at a dosage of 1 mg is safe for use and well tolerated in children with recent-onset T1DM. However, it appears to have no beneficial effect in preserving beta-cell function or improving metabolic control.     

A dual role for interleukin-1 in hippocampal-dependent memory processes

Ample research demonstrates that pathophysiological levels of the pro-inflammatory cytokine interleukin-1 (IL-1) produces detrimental effects on memory functioning. However, recent evidence suggests that IL-1 may be required for the normal physiological regulation of hippocampal-dependent memory. To substantiate the physiological role of IL-1 in learning and memory we examined the induction of IL-1 gene expression following a learning experience, and the effects of IL-1 signaling blockade, by either genetic or pharmacological manipulations, on memory functioning. We show that IL-1 gene expression is induced in the hippocampus 24h following fear-conditioning in wild type mice, but not in two mouse strains with impaired IL-1 signaling. Moreover, we report that mice with transgenic over-expression of IL-1 receptor antagonist restricted to the CNS (IL-1raTG) display impaired hippocampal-dependent and intact hippocampal-independent memory in the water maze and fear-conditioning paradigms. We further demonstrate that continuous administration of IL-1ra via osmotic minipumps during prenatal development disrupt memory performance in adult mice, suggesting that IL-1 plays a critical role not only in the formation of hippocampal-dependent memory but also in normal hippocampal development. Finally, we tested the dual role of IL-1 in memory by intracerebroventricular (ICV) administration of different doses of IL-1beta and IL-1ra following learning, providing the first systematic evidence that the involvement of IL-1 in hippocampal-dependent memory follows an inverted U-shaped pattern, i.e., a slight increase in brain IL-1 levels can improve memory, whereas any deviation from the physiological range, either by excess elevation in IL-1 levels or by blockade of IL-1 signaling, results in impaired memory.     

EUS-guided FNA diagnostic yield of malignancy in solid pancreatic masses: a benchmark for quality performance measurement

BACKGROUND: The diagnostic yield of EUS-guided FNA (EUS-FNA) of solid pancreatic masses is a potential benchmark for EUS-FNA quality, because the majority of EUS-FNA of solid pancreatic masses should be diagnostic for malignancy. OBJECTIVES: To determine the cytologic diagnostic rate of malignancy in EUS-FNA of solid pancreatic masses and to determine if variability exists among endoscopists and centers. DESIGN: Multicenter retrospective study. PATIENTS: EUS centers provided cytology reports for all EUS-FNAs of solid, noncystic, >or=10-mm-diameter, solid pancreatic masses during a 1-year period. MAIN OUTCOME MEASUREMENT: Cytology diagnostic of pancreatic malignancy. RESULTS: A total of 1075 patients underwent EUS-FNA at 21 centers (81% academic) with 41 endoscopists. The median number of EUS-FNA of solid pancreatic masses performed during the year per center was 46 (range, 4-177) and per endoscopist was 19 (range, 1-97). The mean mass dimensions were 32 x 27 mm, with 73% located in the head. The mean number of passes was 3.5. Of the centers, 90% used immediate cytologic evaluation. The overall diagnostic rate of malignancy was 71%, 95% confidence interval 0.69%-0.74%, with 5% suspicious for malignancy, 6% atypical cells, and 18% negative for malignancy. The median diagnostic rate per center was 78% (range, 39%-93%; 1st quartile, 61%) and per endoscopist was 75% (range, 0%-100%; 1st quartile, 52%). LIMITATIONS: Retrospective study, participation bias, and varying chronic pancreatitis prevalence. CONCLUSIONS: (1) EUS-FNA cytology was diagnostic of malignancy in 71% of solid pancreatic masses and (2) endoscopists with a final cytologic diagnosis rate of malignancy for EUS-FNA of solid masses that was less than 52% were in the lowest quartile and should evaluate reasons for their low yield.     

Brain injury impairs dentate gyrus inhibitory efficacy

Every 23 s, a person sustains a traumatic brain injury in the United States leaving many patients with substantial cognitive impairment and epilepsy. Injury-induced alterations in the hippocampus underpin many of these disturbances of neurological function. Abnormalities in the dentate gyrus are likely to play a major role in the observed pathophysiology because this subregion functions as a filter impeding excessive or aberrant activity from propagating further into the circuit and following experimental brain injury, the dentate gyrus becomes more excitable. Although alteration in excitation or inhibition could mediate this effect in the dentate gyrus, we show a key role played by an impairment of GABA(A)ergic inhibition. The efficacy of GABA(A)-mediated inhibition depends on a low [Cl-]i that is maintained by neuronal K-Cl co-transporter 2 (KCC2). Using fluid percussion injury (FPI) in the mouse, we demonstrate significant reductions in KCC2 protein and mRNA expression in the dentate gyrus that causes a depolarizing shift in GABA(A) reversal potential, due to impaired chloride clearance, resulting in reduced inhibitory efficiency. This study elucidates a novel mechanism underlying diminished dentate gyrus inhibitory efficacy and provides an innovative target for the development of potential therapeutics to restore the severe pathological consequences of traumatic brain injury.     

Disparate host response and donor survival after the transplantation of mesenchymal or neuroectodermal cells to the intact rodent brain

BACKGROUND: To circumvent ethical and legal complications associated with embryonic cell sources, investigators have proposed the use of nonneural donor sources for use in neural transplantation strategies. Leading candidate sources include autologous marrow stromal cells (MSCs) and fibroblasts, which are mesodermal derivatives. However, we recently reported that MSCs transplanted to the adult brain are rapidly rejected by an inflammatory response. Whether extrinsic variables or intrinsic mesenchymal traits stimulated inflammation and rejection is unknown. To determine the future utility of these cells in neural transplantation, we have now performed a systematic analysis of MSC transplantation to the brain. METHODS: To examine the effects of extrinsic variables on transplantation, green fluorescent protein (GFP)-expressing rat MSCs, cultured under distinct conditions, were transplanted stereotactically to the normal adult rat striatum, and donor survival and the host response was compared. To examine whether intrinsic donor traits promoted rejection, 50,000 GFP-expressing rat MSCs, fibroblasts, or astrocytes were transplanted stereotactically to the adult rat striatum and graft survival and the host response was compared. RESULTS: Irrespective of preoperative culture conditions, MSCs elicited an inflammatory response and were rejected by 14 days, indicating acute rejection was not mediated by culture conditions. Comparison of MSC, fibroblast, or astrocyte grafts revealed that mesenchymal derivatives, MSCs and fibroblasts, elicited an inflammatory response and were rapidly rejected, whereas neuroectodermal astrocytes demonstrated robust survival in the absence of inflammation. CONCLUSIONS: Our findings suggest that intrinsic characteristics of mesenchymal cells may stimulate host inflammation, and thus may not represent an ideal donor source for transplantation to the adult brain.     

Astroblastoma presenting with intracerebral hemorrhage misdiagnosed as dural arteriovenous fistula: review of a rare entity

BACKGROUND: Astroblastoma is one of the most unusual types of tumors whose histogenesis has been recently clarified. It occurs mainly among children and young adults. It is grossly well demarcated and shows histologically characteristic perivascular pseudorosettes with frequent vascular hyalinization. Immunohistochemically, the tumor cells show diffuse strong positivity for GFAP, S-100 protein, vimentin, as well as neuron-specific enolase and focal positivity for EMA. CASE DESCRIPTION: Our patient is a 33-year-old gentleman who presented with intraparenchymal hemorrhage in the left temporal lobe. A 4-vessel cerebral angiogram revealed a dural AVF in the left posterior temporal area. The lesion was resected, and pathology showed a GFAP-positive lesion with prominent astroblastoma rosettes. There was abundant hemosiderin consistent with a prior hemorrhage. Because of its high degree of proliferation, the presence of astroblastic pseudorosettes, prominent perivascular hyalinization, regional hyaline changes, and pushing borders with regard to the adjacent brain, the tumor was considered anaplastic. CONCLUSIONS: Astroblastoma is a rare pure pathologic entity--a distinct form of astrocytic gliomas. The diagnosis of astroblastoma is often difficult because of the astroblastic aspects that can be found in astrocytic tumors, in ependymomas, and in nonneuroepithelial tumors. The natural history seems to be between astrocytomas and glioblastomas. Total resection and radiation therapy seem to be the advisable treatments.