Atypical onset of symptoms in Huntington disease: severe cognitive decline preceding chorea or other motor manifestations.

OBJECTIVE: To describe the onset of Huntington disease (HD) in a patient with atypical progression of symptoms. BACKGROUND: The authors report the case of a 39-year-old man with severe cognitive impairment and diffuse cortical atrophy before the onset of motor manifestations or symptoms of an extrapyramidal movement disorder. METHOD: Clinical examinations, neuropsychologic assessments, magnetic resonance imaging, electroencephalogram, and genetic testing were conducted. RESULTS AND CONCLUSIONS: Although HD was eventually confirmed through genetic testing, chorea was not part of the clinical picture until well after the patient had developed a frank dementia, with a decline in global intellectual functioning, memory deficits, slowed information processing speed, and executive dysfunction. This case indicates HD may present with atypical clinical features in the early course of the disease, and warrants diagnostic consideration in patients with early dementia of unknown etiology.     

Development and validation of a multivariate predictor of mortality in very low birth weight

Accurate prognosis is critical to the design of all prospective research aimed at improving survival. Predictions based on birth weight, gestational age, or any other single variable, fail to take into account the potentially important contribution of other factors. In order to develop a practical and accurate multivariate model, we studied all singleton pregnancies resulting in viable liveborn infants who weighed less than or equal to 1500 g at birth during 1984 and 1985 at the New York Hospital-Cornell Medical Center. When gestational age, birth weight, and/or crown-heel length were considered, no maternal characteristics were significant predictors of mortality. The model with the maximal predictive accuracy (84.5%) used birth weight and 5-minute Apgar score to calculate a probability of mortality. This prognostic model was then validated in a separate cohort of singletons born in 1986. We conclude that clinical trials should require stratification before randomization, using the calculated probability of mortality, rather than birth weight or gestational age alone. Given the ability of models, such as the one presented here, to generate reasonable estimates of mortality, this information might also be used in the clinical setting to assist parents and physicians in individualized decision-making processes for a given infant.     

Chromosome triplication found across the tribe Brassiceae

We have used an approximately 8.7-Mb BAC contig of Arabidopsis thaliana Chromosome 4 to trace homeologous chromosome regions in 21 species of the family Brassicaceae. Homeologs of this segment could be identified in all tested species. Painting of pachytene chromosomes of Calepina, Conringia, and Sisymbrium species (2n = 14, 16), traditionally placed in tribe Brassiceae, showed one homeologous copy of the Arabidopsis contig, while the remaining taxa of the tribe (2n = 14-30) revealed three, and three Brassica species (2n = 34, 36, and 38) and Erucastrum gallicum (2n = 30) had six copies corresponding to the 8.7-Mb segment. The multiple homeologous copies corresponded structurally to the Arabidopsis segment or were rearranged by inversions and translocations within the diploidized genomes. These chromosome rearrangements accompanied by chromosome fusions/fissions led to the present-day chromosome number variation within the Brassiceae. Phylogenetic relationships based on the chloroplast 5'-trnL (UAA)-trnF(GAA) region and estimated divergence times based on sequence data of the chalcone synthase gene are congruent with comparative painting data and place Calepina, Conringia, and Sisymbrium outside the clade of Brassiceae species with triplicated genomes. Most likely, species containing three or six copy pairs descended from a common hexaploid ancestor with basic genomes similar to that of Arabidopsis. The presumed hexaploidization event occurred after the Arabidopsis-Brassiceae split, between 7.9 and 14.6 Mya.     

Susceptibility of corneal allografts and xenografts to antibody-mediated rejection

The effects of passive transfer of antisera containing cytotoxic antibodies to allo- and xenoantigens on survival of corneal allografts and xenografts were evaluated in experimental models. Corneas from allogeneic B10 or xenogeneic rat Lewis donors were grafted orthotopically into BALB/c mice. Recipient mice were treated with donor-specific antisera administered at the period of grafting or at 2 weeks after transplantation. Rejection was determined by the severity of corneal opacity using a standard scoring system. Treatment of graft recipients with donor-specific antisera accelerated the onset of graft rejection and significantly shortened survival times of both corneal allografts and xenografts. Corneal xenografts, which had been accepted after treatment with anti-CD4 monoclonal antibody, were acutely rejected by the passive transfer of antiserum against xenoantigens. The results suggest that corneal grafts are vulnerable to antibody-dependent immunity and that cytotoxic antibodies against graft donor antigens can mediate rejection of both corneal allografts and xenografts.     

Lesion of posterior parietal cortex in rats does not disrupt place avoidance based on either distal or proximal orienting cues

A current topic in neurobiology is the study of the role of various brain structures in processing of spatial information. The present study was aimed at elucidating the role of the rat posterior parietal cortex in performing a place avoidance task. Two variants of the task were used: an arena frame task, in which animals were trained to avoid a sector defined by local cues bound to the surface of a rotating arena, and the room frame task, in which the shock sector was defined with respect to distal room landmarks. The results showed that both control and lesioned rats were able to efficiently solve both tasks, while locomotion was not altered. These results suggest that the posterior parietal cortex is not crucial for the processing of either proximal or distal cues in place avoidance.     

Anti-beta(2)-glycoprotein I antibodies in children with atopic dermatitis

beta(2)-Glycoprotein I (beta(2)GPI) appears to be the major antigen for antiphospholipid antibodies (aPL) in patients with antiphospholipid syndrome (APS). In early infancy, virtually all children initiate transient immune response to non-pathogenic nutritional antigens, which fails to terminate in children with atopic diseases. To examine the possibility that a prolonged immune response to beta(2)GPI could also spread to the human protein, antibodies against human beta(2)GPI (anti-beta(2)GPI) were determined in 93 randomly selected children with different allergic diseases. A high frequency (42%) of IgG anti-beta(2)GPI was found in children with atopic dermatitis (AD), but not in those with other allergic diseases. Anti-beta(2)GPI in children with AD were exclusively of the IgG1 subclass and bound to bovine beta(2)GPI as well, but not to either beta(2)GPI combined with the phospholipid cardiolipin. The epitopes were identified in domain V of beta(2)GPI and the antibody binding was abolished upon the specific proteolytic cleavage of the phospholipid-binding C-terminal loop in domain V of beta(2)GPI. These results indicated that the epitopes for anti-beta(2)GPI in children with AD most likely resided in close vicinity of the phospholipid-binding site of beta(2)GPI. The epitopic difference from anti-beta(2)GPI in APS may explain presumed non-thrombogenicity of anti-beta(2)GPI in children with AD.     

Expression and potential role of fibroblast growth factor 2 and its receptors in human embryonic stem cells

Although the detection of several components of the fibroblast growth factor (FGF) signaling pathway in human embryonic stem cells (hESCs) has been reported, the functionality of that pathway and effects on cell fate decisions are yet to be established. In this study we characterized expression of FGF-2, the prototypic member of the FGF family, and its receptors (FGFRs) in undifferentiated and differentiating hESCs; subsequently, we analyzed the effects of FGF-2 on hESCs, acting as both exogenous and endogenous factors. We have determined that undifferentiated hESCs are abundant in several molecular-mass isoforms of FGF-2 and that expression pattern of these isoforms remains unchanged under conditions that induce hESC differentiation. Significantly, FGF-2 is released by hESCs into the medium, suggesting an autocrine activity. Expression of FGFRs in undifferentiated hESCs follows a specific pattern, with FGFR1 being the most abundant species and other receptors showing lower expression in the following order: FGFR1 --> FGFR3 --> FGFR4 --> FGFR2. Initiation of differentiation is accompanied by profound changes in FGFR expression, particularly the upregulation of FGFR1. When hESCs are exposed to exogenous FGF-2, extracellular signal-regulated kinases are phosphorylated and thereby activated. However, the presence or absence of exogenous FGF-2 does not significantly affect the proliferation of hESCs. Instead, increased concentration of exogenous FGF-2 leads to reduced outgrowth of hESC colonies with time in culture. Finally, the inhibitor of FGFRs, SU5402, was used to ascertain whether FGF-2 that is released by hESCs exerts its activities via autocrine pathways. Strikingly, the resultant inhibition of FGFR suppresses activation of downstream protein kinases and causes rapid cell differentiation, suggesting an involvement of autocrine FGF signals in the maintenance of proliferating hESCs in the undifferentiated state. In conclusion from our data, we propose that this endogenous FGF signaling pathway can be implicated in self-renewal or differentiation of hESCs.     

Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells.

Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The 'dioxin-like' PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the 'non-dioxin-like' compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 muM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.     

Investigation of Solid Dosage Form Components Interaction Using Orthogonal Techniques- Discovery of New Forms of Sodium Stearyl Fumarate

Physical or chemical interactions between drug product (DP) components can occur during manufacturing and/or upon storage; and may alter DP shelf life and performance. In this work a new Powder X-ray Diffraction (PXRD) peak was observed in DP under accelerated storage conditions. Due to the complex drug product matrix (including API, polymer, fillers, super disintegrant and lubricant), it was challenging to pinpoint the component(s) responsible for the new peak. In addition to PXRD, other orthogonal techniques including Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), Solid State Nuclear Magnetic Resonance (SSNMR) and Infrared (IR) spectroscopy were employed in this investigation to understand the root cause mechanistically. Specifically, multi nuclei SSNMR (¹H, ²³Na, ¹³C) was instrumental in delineating the components of the matrix. We identified the root cause to be an acid base reaction occurring in the DP, whereby sodium ion in sodium stearyl fumarate (SSF) is replaced by proton leading to SSF form conversion. We also identified commercially available SSF to be a hydrate that can dehydrate to an anhydrous form upon heating. In general, the same techniques can be used to investigate interactions of any multi component solid dosage forms.