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Hap1 was originally identified as a neuronal protein that interacts with huntingtin, the Huntington’s disease (HD) protein. Later studies revealed that Hap1 participates in intracellular trafficking in neuronal cells and that this trafficking function can be adversely affected by mutant huntingtin. Hap1 is also present in pancreatic β-cells and other endocrine cells; however, the role of Hap1 in these endocrine cells remains unknown. Using the Cre-loxP system, we generated conditional Hap1 knockout mice to selectively deplete the expression of Hap1 in mouse pancreatic β-cells. Mutant mice with Hap1 deficiency in pancreatic β-cells had impaired glucose tolerance and decreased insulin release in response to intraperitoneally injected glucose. Using cultured pancreatic β-cell lines and isolated mouse pancreatic islets, we confirmed that decreasing Hap1 could reduce glucose-mediated insulin release. Electron microscopy suggested that there was a reduced number of insulin-containing vesicles docked at the plasma membrane of pancreatic islets in Hap1 mutant mice following intraperitoneal glucose injection. Glucose treatment decreased the phosphorylation of Hap1A in cultured β-cells and in mouse pancreatic tissues. Moreover, this glucose treatment increased Hap1’s association with kinesin light chain and dynactin p150, both of which are involved in microtubule-dependent trafficking. These studies suggest that Hap1 is important for insulin release from β-cells via dephosphorylation that can regulate its intracellular trafficking function.

An expanded polyglutamine tract (>37 glutamines) in the N-terminal region of huntingtin (htt) causes htt to accumulate in the nucleus, leading to transcriptional dysregulation in Huntington disease (HD). In HD knock-in mice that express full-length mutant htt at the endogenous level, mutant htt preferentially accumulates in the nuclei of striatal neurons, which are affected most profoundly in HD. The mechanism underlying this preferential nuclear accumulation of mutant htt in striatal neurons remains unknown. Here, we report that serine 16 (S16) in htt is important for the generation of small N-terminal fragments that are able to accumulate in the nucleus and form aggregates. Phosphorylation of N-terminal S16 in htt promotes the nuclear accumulation of small N-terminal fragments and reduces the interaction of N-terminal htt with the nuclear pore complex protein Tpr. Mouse brain striatal tissues show increased S16 phosphorylation and a decreased association between mutant N-terminal htt and Tpr. These findings provide mechanistic insight into the nuclear accumulation of mutant htt and the selective neuropathology of HD, revealing potential therapeutic targets for treating this disease.

The function of the brainstem Hap1–Ahi1 complex in the regulation of feeding behavior was investigated. When mice were fasted or treated with 2-deoxy-d-glucose (2-DG), Hap1–Ahi1 was significantly upregulated. By using streptozotocin (STZ) to decrease the circulating insulin in mice, Hap1–Ahi1 was significantly increased. Furthermore, intra-brain injection of insulin decreased the expression of Hap1–Ahi1 in the brainstem. Moreover, when we knocked down the expression of brainstem Hap1 by RNAi, the mice showed decreased food intake and lower body weights. Collectively, our results indicate that the Hap1–Ahi1 complex in the brainstem works as a sensor for insulin signals in feeding control.Structured summaryAhi1 physically interacts with Hap1: shown by anti bait coimmunoprecipitation (view interactions 1, 2)

Recent studies suggest that the human Abelson helper integration site-1 ( AHI1 ) gene on chromosome 6 is associated with susceptibility to schizophrenia and autism, two common neuropsychological disorders with depression symptoms. Mouse Ahi1 protein is abundant in the hypothalamus and amygdala, which are important brain regions for controlling emotion. However, the neuronal function of Ahi1 remains unclear. With the Cre–loxP system, we created a mouse model that selectively reduces Ahi1 expression in neuronal cells. Mice with neuronal Ahi1 deficiency show reduced TrkB level in the brain and depressive phenotypes, which can be alleviated by antidepressant drugs or by overexpression of TrkB in the amygdala. Ahi1 deficiency promotes the degradation of endocytic TrkB and reduces TrkB signaling in neuronal cells. Our findings suggest that impaired endocytic sorting and increased degradation of TrkB can induce depression and that this impaired pathway may serve as a previously uncharacterized therapeutic target for depression.

The ubiquitin–proteasome system (UPS) is responsible for clearing most soluble proteins in the cytoplasm and nucleus. Recent studies reveal that the UPS function is critical for maintaining synaptic plasticity and transmission and that the UPS dysfunction is associated with axonal degeneration and impaired synaptic transmission. In this chapter, we will focus on the role of the UPS in synapses and the association of UPS impairment with neurological disorders. Since protein misfolding causes several neurological disorders that show synaptic dysfunction during the early stages of disease, understanding the involvement of the synaptic UPS in neurological disorders may help determine effective strategies for treating neurological disorders caused by the accumulation of misfolded proteins.

Neurodegeneration is a hallmark of many neurological diseases, including Alzheimer's, Parkinson's and the polyglutamine diseases, which are all caused by misfolded proteins that accumulate in neuronal cells of the brain. Although apoptosis is believed to contribute to neurodegeneration in these cases, genetic mouse models of these diseases often fail to replicate apoptosis and overt neurodegeneration in the brain. Using nuclear transfer, we generated transgenic Huntington's disease (HD) pigs that express N-terminal (208 amino acids) mutant huntingtin with an expanded polyglutamine tract (105Q). Postnatal death, dyskinesia and chorea-like movement were observed in some transgenic pigs that express mutant huntingtin. Importantly, the transgenic HD pigs, unlike mice expressing the same transgene, displayed typical apoptotic neurons with DNA fragmentation in their brains. Also, expression of mutant huntingtin resulted in more neurons with activated caspase-3 in transgenic pig brains than that in transgenic mouse brains. Our findings suggest that species differences determine neuropathology and underscore the importance of large mammalian animals for modeling neurological disorders.

To study the relationship between 637A/G gene polymorphisms of the transporter associated with antigen processing 1 gene and nasopharyngeal carcinomas (NPC) and to find out the susceptible genes of NPC in Han population in Yunnan Province, China.Two hundred and thirty-three cases with NPC and 296 cases matched cancer-free controls were genotyped for the TAP1 637A/G polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Epstein-Barr virus infection was detected by PCR. The adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated by using unconditional logistic regression model.Contrast with homozygous TAP1 637 AA, G allele significantly increasing risk of NPC was associated with homozygous 637 GG OR = 4.26 (95%CI were 2.08 - 8.66, P0.001) and heterozygous 637 AG OR = 1.56 (95%CI were 1.12 - 2.33, P0.05). The subjects at least having one TAP1 637 G allele had OR of 1.88 (95%CI were 1.35 - 2.82, P0.001). Furthermore, EBV infection may increase the risk of developing NPC interacting with TAP1 637 A/G polymorphism OR = 2.76(95% CI were 1.69 - 4.63, P0.001).The TAP1 637G allele is associated with the NPC in Han population in Yunnan China, EBV pathogenesis in NPC might be facilitated by polymorphisms in the TAP1 proteins.

The prolate spheroidal reflector antenna focuses pulsed radiation in the near field with a small beam-width, allowing for applications such as target detection. We have investigated the use of two identical antennas for signal transmitting and receiving to detect a moving target behind obstacles, such as human movement behind a wall. The coverage area was found to be 10 m × 7 m. We have also investigated the use of the focusing antenna in a confocal configuration for the detection of stationary targets. We show that decreasing the focal spot size by adding a dielectric lens enables us to resolve targets smaller than diffraction limit.

An expanded polyglutamine (polyQ) domain in the N-terminal region of huntingtin (htt) causes misfolding and accumulation of htt in neuronal cells and the subsequent neurodegeneration of Huntington’s disease (HD). Clearing the misfolded htt is critical for preventing neuropathology, and this process is mediated primarily by both the ubiquitin –p roteasome system (UPS) and autophagy. Although overexpression of mutant htt can inhibit UPS activity in cultured cells, mutant htt does not inhibit global UPS activity in the brains of HD transgenic mice. These findings underscore the importance of investigating the function of the UPS and autophagy in the brain when mutant proteins are not overexpressed. When cultured PC12 cells were treated with either UPS or autophagy inhibitors, more N-terminal mutant htt fragments accumulated via inhibition of the UPS. Furthermore, in HD CAG repeat knock-in mouse brain, inhibiting the UPS also resulted in a greater accumulation of N-terminal, but not full-length, mutant htt than inhibiting autophagy did. Our findings suggest that impairment of the UPS may be more important for the accumulation of N-terminal mutant htt and might therefore make an attractive therapeutic target.

Huntingtin-associated protein-1 (Hap1) is a neuronal protein that associates with huntingtin, the Huntington disease protein. Although Hap1 and huntingtin are known to be involved in intracellular trafficking, whether and how the impairment of Hap1-associated trafficking leads to neurological pathology and symptoms remain to be seen. As Hap1 is enriched in neuronal cells in the brain, addressing this issue is important in defining the role of defective intracellular trafficking in the selective neuropathology associated with Hap1 dysfunction. Here, we find that Hap1 is abundantly expressed in orexin (hypocretin)-producing neurons (orexin neurons), which are distinctly distributed in the hypothalamus and play an important role in the regulation of feeding and behavior. We created conditional Hap1 knock-out mice to selectively deplete Hap1 in orexin neurons via the Cre-loxP system. These mice show process fragmentation of orexin neurons and reductions in food intake, body weight, and locomotor activity. Sucrose density gradient fractionation reveals that loss of Hap1 in the mouse brain also reduces the distribution of trafficking protein complexes and cargo proteins in the fractions that are enriched in synaptosomes. These results suggest that Hap1 is critical for the transport of multiple proteins to the nerve terminals to maintain the integrity of neuronal processes and that selective disruption of the processes of orexin neurons can cause abnormal feeding and locomotor activity.

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in brain development and synaptic plasticity. It is synthesized as a precursor (pro-BDNF), sorted into the secretory pathway, transported along dendrites and axons, and released in an activity-dependent manner. Mutant Huntingtin with expanded polyglutamine (polyQ) and the V66M polymorphism of BDNF reduce the dendritic distribution and axonal transport of BDNF. However, the mechanism underlying this defective transport remains unclear. Here, we report that Huntingtin-associated protein-1 (HAP1) interacts with the prodomain of BDNF and that the interaction was reduced in the presence of polyQ-expanded Huntingtin and BDNF V66M. Consistently, there was reduced coimmunoprecipitation of pro-BDNF with HAP1 in the brain homogenate of Huntington disease. Pro-BDNF distribution in the neuronal processes and its accumulation in the proximal and distal segments of crushed sciatic nerve and the activity-dependent release of pro-BDNF were abolished in HAP1−/− mice. These results suggest that HAP1 may participate in axonal transport and activity-dependent release of pro-BDNF by interacting with the BDNF prodomain. Accordingly, the decreased interaction between HAP1 and pro-BDNF in Huntington disease may reduce the release and transport of BDNF Refereed/Peer-reviewed

Neuropeptide Y, peptide YY, and pancreatic polypeptide are homologous 36-amino acid peptides that differ from most other peptide transmitters by having a relatively rigid conformation in aqueous solutions, defined as the pancreatic polypeptide fold, and a critical C-terminal tyrosine amide. These peptides serve as gastrointestinal hormones and neurotransmitters. A cDNA encoding a novel G protein-coupled receptor activated by neuropeptide Y was cloned from Drosophila by use of degenerate oligonucleotide primers and polymerase chain reaction amplification of cDNA prepared from transcripts expressed early in embryogenesis. The cDNA encodes a protein of 449 amino acids with the characteristics of a G protein-coupled receptor and shares significant amino acid identity with mammalian tachykinin receptors. When expressed in Xenopus oocytes, the PR4 protein is activated by mammalian neuropeptides in the order: peptide YY greater than neuropeptide Y much greater than pancreatic polypeptide. Northern analysis showed that PR4 receptor is expressed at equivalent levels in adult Drosophila head and body and that the expression of the PR4 receptor is regulated during development. The molecular characterization of this receptor should lead to a better understanding of the functional role of this important family of hormone receptors in adult organisms and during development.

TATA binding protein (TBP), a universal transcription factor, is broadly required by nuclear RNA polymerases for the initiation of transcription. TBP contains a polymorphic polyglutamine tract in its N-terminal region, and expansion of this tract leads to spinocerebellar ataxia type 17 (SCA17), one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine expansion in the affected proteins. The expanded polyglutamine proteins are ubiquitously expressed, but cause selective and characteristic neurodegeneration in distinct brain regions in each disease. Unlike many other polyglutamine proteins, whose functions are not yet fully understood, TBP is a well-characterized transcription factor that is restricted to the nucleus. Thus, investigating how mutant TBP mediates neuropathology should help elucidate the mechanisms by which transcriptional dysregulation contributes to neuronal dysfunction and/or neurodegeneration in polyglutamine diseases. To this end, we characterized cellular and mouse models expressing polyQ-expanded TBP. The cell model exhibits characteristic features of neuronal dysfunction, including decreased cell viability and defective neurite outgrowth. We found that the high-affinity nerve growth factor receptor, TrkA, is down-regulated by mutant TBP in cells. Down-regulation of TrkA also occurs in the cerebellum of SCA17 transgenic mice prior to Purkinje cell degeneration. Mutant TBP binds more Sp1, reduces its occupancy of the TrkA promoter and inhibits the activity of the TrkA promoter. These findings suggest that the transcriptional down-regulation of TrkA by mutant TBP contributes to SCA17 pathogenesis.

The clinical evaluation of neural transplantation as a potential treatment for Huntington's disease (HD) was initiated in an attempt to replace lost neurons and improve patient outcomes. Two of 3 patients with HD reported here, who underwent neural transplantation containing striatal anlagen in the striatum a decade earlier, have demonstrated marginal and transient clinical benefits. Their brains were evaluated immunohistochemically and with electron microscopy for markers of projection neurons and interneurons, inflammatory cells, abnormal huntingtin protein, and host-derived connectivity. Surviving grafts were identified bilaterally in 2 of the subjects and displayed classic striatal projection neurons and interneurons. Genetic markers of HD were not expressed within the graft. Here we report in patients with HD that ( i ) graft survival is attenuated long-term; ( ii ) grafts undergo disease-like neuronal degeneration with a preferential loss of projection neurons in comparison to interneurons; ( iii ) immunologically unrelated cells degenerate more rapidly than the patient's neurons, particularly the projection neuron subtype; ( iv ) graft survival is attenuated in the caudate in comparison to the putamen in HD; ( v ) glutamatergic cortical neurons project to transplanted striatal neurons; and ( vi ) microglial inflammatory changes in the grafts specifically target the neuronal components of the grafts. These results, when combined, raise uncertainty about this potential therapeutic approach for the treatment of HD. However, these observations provide new opportunities to investigate the underlying mechanisms involved in HD, as well as to explore additional therapeutic paradigms.

There are nine inherited neurodegenerative disorders caused by polyglutamine (polyQ) expansion in various disease proteins. Although these polyglutamine proteins have different functions and are localized in different subcellular regions, all the polyQ diseases share a common pathological feature: the nuclear accumulation of polyQ disease proteins and the formation of inclusions. The nuclear accumulation of polyQ proteins in turn leads to gene transcriptional dysregulation and neuropathology. Here we will discuss potential mechanisms behind the nuclear accumulation of mutant polyQ proteins, since an understanding of how polyQ proteins accumulate in the nucleus could help elucidate the pathogenesis of these diseases and develop their treatment.

The aim of this study was to investigate the susceptibility and prognostic implications of the cyclin D1 gene (CCND1) G870A polymorphism to nasopharyngeal carcinomas (NPC) in Han population in Yunnan China.Two hundred and forty one cases with NPC and 271 matched cancer-free controls were genotyped for the CCND1 G870A polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. The adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated by using unconditional logistic regression model. Overall survival was assessed using univariate and multivariate analyses.Contrast with homozygous CCND1 G870G, A allele significantly increasing risk of NPC was associated with homozygous A870A (OR = 4.79, 95% CI 2.77 - 8.28, P0.001) and heterozygous A870G (OR = 1.72, 95% CI 1.10 - 2.68, P = 0.017). The subjects at least having one CCND1 870A allele had OR of 2.40 (95% CI 1.59 - 3.63, P0.001). Furthermore, smoking may increase the risk of developing NPC interacting with CCND1 G870A polymorphism. Kaplan-Meier analysis and Cox regression analysis demonstrated that the five-year survival rate of subjects with AA, AG and GG genotype was 56.2%, 78.5% and 81.4% (AA vs GG, P = 0.003; AA vs AG, P = 0.012; AG vs GG, P = 0.132), but not independent prognostic factor in NPC (P = 0.501).The CCND1 870A allele is associated with the NPC in Han population in Yunnan China, meanwhile, showed a significant prognosis for those patients.

The SH3 domain of human AHI1 was cloned and expressed in Escherichia coli. The protein was purified by affinity and size-exclusion chromatography and was crystallized using the sitting-drop vapour-diffusion method at 293 K. A complete data set was collected to 2.5 A resolution at 110 K. The crystal belonged to space group P4(1)2(1)2, with unit-cell parameters a = 67.377, b = 67.377, c = 98.549 A.

We identified clones encoding a Drosophila receptor for tachykinin-like peptides by low stringency screening of an embryonic cDNA library with probes from the bovine substance K receptor. The cDNAs encode a seven transmembrane domain protein (DTKR) of 519 amino acids with 40-48% amino acid identity to mammalian tachykinin receptors within transmembrane regions. Xenopus oocytes injected with DTKR cRNAs showed selective responses to vertebrate substance P, its agonists and not to other vertebrate tachykinin peptides. These responses were eliminated by treatment of oocytes with pertussis toxin. In the adult fly, Northern and PCR analysis demonstrated preferential expression of DTKR in the head; in situ hybridization indicated that DTKR is accumulated in the cell bodies of neurons in the adult CNS. The levels of DTKR transcript are regulated during development. Northern and PCR amplification analysis showed that while DTKR transcripts are present at all stages, high levels of expression occur in later stages of embryogenesis (starting at 10-14 h), coinciding with the beginning of major periods of neural development. Whole mount embryo in situ hybridization demonstrated that DTKR is expressed at these later stages of embryogenesis (11-15 h) in the brain and in a specific subset of neurons in each neuromere of the developing ventral ganglion. The gene encoding DTKR was mapped by in situ hybridization to a single location at 99D on the right arm of chromosome 3. These observations demonstrate that the tachykinin family of peptide transmitters and their receptors represent an evolutionarily ancient form of cellular communication within the nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic myeloid leukemia (CML) represents the first human malignancy successfully treated with a tyrosine kinase inhibitor (TKI; imatinib). However, early relapses and the emergence of imatinib-resistant disease are problematic. Evidence suggests that imatinib and other inhibitors may not effectively eradicate leukemic stem/progenitor cells, and that combination therapy directed to complimentary targets may improve treatment. Abelson helper integration site 1 (Ahi-1)/AHI-1 is a novel oncogene that is highly deregulated in CML stem/progenitor cells where levels of BCR-ABL transcripts are also elevated. Here, we demonstrate that overexpression of Ahi-1/AHI-1 in murine and human hematopoietic cells confer growth advantages in vitro and induce leukemia in vivo, enhancing effects of BCR-ABL. Conversely, RNAi-mediated suppression of AHI-1 in BCR-ABL–transduced lin−CD34+ human cord blood cells and primary CML stem/progenitor cells reduces their growth autonomy in vitro. Interestingly, coexpression of Ahi-1 in BCR-ABL–inducible cells reverses growth deficiencies exhibited by BCR-ABL down-regulation and is associated with sustained phosphorylation of BCR-ABL and enhanced activation of JAK2–STAT5. Moreover, we identified an AHI-1–BCR-ABL–JAK2 interaction complex and found that modulation of AHI-1 expression regulates phosphorylation of BCR-ABL and JAK2–STAT5 in CML cells. Importantly, this complex mediates TKI response/resistance of CML stem/progenitor cells. These studies implicate AHI-1 as a potential therapeutic target downstream of BCR-ABL in CML.

To detect the expression of vessel endothelial growth factor C (VEGF-C) and microlymphatic vessel density (MLVD) and probe the relationship between lymphangiogenesis and lymph node micrometastasis in nasopharyngeal carcinoma.The expression of VEGF-C, was evaluated in 58 cases with nasopharyngeal carcinoma and 20 samples of nasopharyngitis tissues by immunohistochemical staining SP methods. The MLVD in tumor was counted by immunostaining with the specific antibody lymphatic vessel endothelial hyaluronic acid receptor 1 and analyzed with clinicopathologic parameters.The positive rate of VEGF-C was 84.5% and 15.0% respectively in nasopharyngeal carcinoma and nasopharyngitis tissues, there was significant difference between them (chi2 = 32.309, P0.01). The microlymphatic vessel density was (28.6 +/- 6.2) pieces per field and (10.5 +/- 3.0) pieces per field respectively in nasopharyngeal carcinoma and nasopharyngitis tissues, there was significant difference between them (t = 12.491, P0.01). The expression of VEGF-C and the MLVD were significantly higher in nasopharyngeal carcinoma and in lymph node metastasis group than in no-metastasis group. The expression of VEGF-C was positively correlated with MLVD (t =3.512, P0.01), lymph node metastasis (chi2 =7.715, P0.01, r =0.712) and clinical stage (chi2 =4.250, P0.05, r =0.481).In nasopharyngeal carcinoma, the expression rate of VEGF-C was high. VEGF-C expression was positively correlated with MLVD and lymph node metastasis and tumor staging. It was explained that VEGF-C attached itself to the emergence and infiltration and transfer of NPC. There was close correlation between the expression of VEGF-C and MLVD. It was explained that the expression of VEGF-C in NPC was correlated to neoplasm lymphangiogenesis and that VEGF-C played a vital role in the progression of NPC. VEGF-C was likely to a potential target of anticancer therapy.

A number of neurodegenerative diseases, including Alzheimer's, Parkinson's, and polyglutamine diseases, are characterized by the age-dependent formation of intracellular protein aggregates and neurodegeneration. Although there is some debate surrounding the role of these aggregates in neurotoxicity, the formation of aggregates is known to reflect the accumulation of misfolded and toxic proteins. The degradation of misfolded proteins occurs mainly via the ubiquitin-proteasome and autophagy pathways. In neuronal cells, polyglutamine protein inclusions are present predominantly in the nucleus, which is not accessible to autophagy. It remains unclear how the ubiquitin-proteasomal and autophagy pathways remove misfolded proteins in the different subcellular regions of neurons, where disease proteins become misfolded and aggregated in an age-dependent manner. Here we discuss the key findings to date about the roles of the ubiquitin-proteasome system and autophagy in polyglutamine diseases. Understanding how these two pathways function to clear mutant polyglutamine proteins will further the development of effective treatments for polyglutamine and other neurodegenerative diseases.

The transport of vesicles in neurons is a highly regulated process, with vesicles moving either anterogradely or retrogradely depending on the nature of the molecular motors, kinesins and dynein, respectively, which propel vesicles along microtubules (MTs). However, the mechanisms that determine the directionality of transport remain unclear. Huntingtin, the protein mutated in Huntington's disease, is a positive regulatory factor for vesicular transport. Huntingtin is phosphorylated at serine 421 by the kinase Akt but the role of this modification is unknown. Here, we demonstrate that phosphorylation of wild-type huntingtin at S421 is crucial to control the direction of vesicles in neurons. When phosphorylated, huntingtin recruits kinesin-1 to the dynactin complex on vesicles and MTs. Using brain-derived neurotrophic factor as a marker of vesicular transport, we demonstrate that huntingtin phosphorylation promotes anterograde transport. Conversely, when huntingtin is not phosphorylated, kinesin-1 detaches and vesicles are more likely to undergo retrograde transport. This also applies to other vesicles suggesting an essential role for huntingtin in the control of vesicular directionality in neurons.

A number of mouse models expressing mutant huntingtin (htt) with an expanded polyglutamine (polyQ) domain are useful for studying the pathogenesis of Huntington's disease (HD) and identifying appropriate therapies. However, these models exhibit neurological phenotypes that differ in their severity and nature. Understanding how transgenic htt leads to variable neuropathology in animal models would shed light on the pathogenesis of HD and help us to choose HD models for investigation. By comparing the expression of mutant htt at the transcriptional and protein levels in transgenic mice expressing N-terminal or full-length mutant htt, we found that the accumulation and aggregation of mutant htt in the brain is determined by htt context. HD mouse models demonstrating more severe phenotypes show earlier accumulation of N-terminal mutant htt fragments, which leads to the formation of htt aggregates that are primarily present in neuronal nuclei and processes, as well as glial cells. Similarly, transgenic monkeys expressing exon-1 htt with a 147-glutamine repeat (147Q) died early and showed abundant neuropil aggregates in swelling neuronal processes. Fractionation of HD150Q knock-in mice brains revealed an age-dependent accumulation of N-terminal mutant htt fragments in the nucleus and synaptosomes, and this accumulation was most pronounced in the striatum due to decreased proteasomal activity. Our findings suggest that the neuropathological phenotypes of HD stem largely from the accumulation of N-terminal mutant htt fragments and that this accumulation is determined by htt context and cell-type-dependent clearance of mutant htt.

To observe the clinical therapeutic effect of Airening Suppository (ARN) on carcinoma fever.Adopting randomized and double-blinded method, 54 patients with carcinoma fever were randomly assigned to the observation group and the control group, who were treated respectively with ARN and indomethacin suppository by anal administering, 7 days as one treatment course. The effect on body temperature on patients and side effect occurred were observed 7 days after discontinuation of the medication, and patients' serum tumor necrosis factor alpha (TNF-alpha), interleukin-1beta were determined by RIA, routine test of blood, urine and stool, liver and renal function were tested as well. Body temperature, changes of clinical symptoms, and adverse reaction were observed.The effective rate of fever abating was 86.7% in the observation group and 66.7% in the control group, showing significant difference between them (chi2 = 8.06, P0.05). After treatment, serum levels of TNF-alpha and IL-1beta in the observation group were much lower than those in the control group (t = 7.477, t = 3.492, P0.01). Besides, patients' chief clinical symptoms and quality of life were markedly improved in the observation group (t =4.71, P0.05, chi2 =7.38, P0.05), all better than those in the control group (P0.05). No evident effect on peripheral blood figure, or harmful impact on heart, liver and kidney function was found.Airening Suppository has a standing and stable fever abating effect in treating cancerous fever with no obvious adverse reaction, so it is worthy of clinical use and spreading.

Huntington's disease (HD) is caused by polyglutamine (polyQ) expansion in huntingtin (htt), a large (350 kDa) protein that localizes predominantly to the cytoplasm. Proteolytic cleavage of mutant htt yields polyQ-containing N-terminal fragments that are prone to misfolding and aggregation. Disease progression in HD transgenic models correlates with age-related accumulation of soluble and aggregated forms of N-terminal mutant htt fragments, suggesting that multiple forms of mutant htt are involved in the selective neurodegeneration in HD. Although mitochondrial dysfunction is implicated in the pathogenesis of HD, it remains unclear which forms of cytoplasmic mutant htt associate with mitochondria to affect their function. Here we demonstrate that specific N-terminal mutant htt fragments associate with mitochondria inHdh(CAG)150 knock-in mouse brain and that this association increases with age. The interaction between soluble N-terminal mutant htt and mitochondria interferes with thein vitroassociation of microtubule-based transport proteins with mitochondria. Mutant htt reduces the distribution and transport rate of mitochondria in the processes of cultured neuronal cells. Reduced ATP level was also found in the synaptosomal fraction isolated fromHdh(CAG)150 knock-in mouse brain. These findings suggest that specific N-terminal mutant htt fragments, before the formation of aggregates, can impair mitochondrial function directly and that this interaction may be a novel target for therapeutic strategies in HD.

A polyglutamine repeat expansion of more than 36 units in a protein called huntingtin (htt) is the only known cause of Huntington's disease (HD). The expanded repeat length is inversely correlated with the age-at-onset (AAO), however, the onset age among HD patients with CAG repeats below 60 units varies considerably. In addition to environmental factors, genetic factors different from the expanded CAG repeat length can modify the AAO of HD. We hypothezised that htt interacting proteins might contribute to this variation in the AAO and investigated human htt-associated protein-1 (HAP1) using genetic and functional assays. We identified six polymorphisms in the HAP1 gene including one that substitutes methionine (M441) for threonine (T441) at amino acid 441. Analyzing 980 European HD patients, we found that patients homozygous for the M441 genotype show an 8-year delay in the AAO. Functional assays demonstrated that human M441-HAP1 interacts with mutant htt more tightly than does human T441-HAP1, reduces soluble htt degraded products and protects against htt-mediated toxicity. We thus provide genetic and functional evidence that the M441-HAP1 polymorphism modifies the AAO of HD.

Huntington disease is caused by polyglutamine expansion in huntingtin, a 350 kD protein that is ubiquitously expressed and widely distributed at the subcellular level. Recently, Kaltenbach et al. identified a large collection of novel huntingtin-interacting proteins, several of which modify mutant huntingtin toxicity in Drosophila. Thus, the interaction of mutant huntingtin with certain protein partners can influence its toxicity and therefore the severity and/or progression of Huntington disease.

To provide anatomic data for clinical use of reversed submental island flap in reconstruction of buccal and facial defects.Twenty cadavers with 40 sides of head and neck which were fixed by formalin and perfused by red emulsion, 6 fresh cadavers which were perfused by coloring agent were dissected, observed and measured.The diameter of the submental artery, the superior lip artery and the inferior lip artery at their origins were respectively (1.42 +/- 0.30) mm (x +/- s, same at below), (1.34 +/- 0.35) mm and (1.34 +/- 0.27) mm respectively. The realistic distance from the origin of inferior and superior lip arteries to the origin of submental artery were (50.13 +/- 13.79) mm and (92.09 8.73) mm, respectively. However, the straight distances from the origin of inferior and superior lip arteries to the origin of submental artery were (35.19 +/- 9.18) mm, (64.99 +/- 5.24) mm, respectively. There were rich anastomoses between both facial arteries, and the facial arteries also anastomosed richly with the ophthalmic artery and the superficial temporal artery. On the marginal mandibular plane, the facial vein ran closely with the artery, the marginal mandibular branch of the facial nerve crossed superficially to the facial blood vessels; superior to this plane, the vein ran 1 cm behind the artery. The buccal branches of the facial nerve crossed superficially to the facial vein and ran into the muscles behind or across the facial artery. The facial vein anastomosed richly with the ophthalmic vein and the maxillary vein.There is anatomic feasibility for the reconstruction of buccal and facial defects by using pedicled submental reversed island flap. The reversing point of the flap ought to be at the cheilion plane or inferiorly. Anatomy, regional

To evaluate the effect of induction chemotherapy on the patients with moderate tongue squamous cell carcinoma and to investigate the factors that influence prognosis of these patients.One hundred and twenty two patients with moderate tongue squamous cell carcinoma (stage II-III, T2-3 N0/T1-3N1), treated from Jan. 1990 to Dec. 1999 were retrospectively reviewed. Among them, 69 and 53 patients were received operation alone and operation after induction chemotherapy respectively [cisplatin + 5-fluorouracil + bleomycin-A5 (PBF), 17 cases; bleomycin-A5, 36 cases]. Survival rate was estimated by Kaplan-Meier method. Multivariate analysis by the Cox proportional hazard model.The mean follow-time of all patients were (79.9 +/- 49.8) (x +/- s) months (range: 7 to 177 months), and 45 patients died (including 5 lost to follow up) , 66 of 77 patients alive followed more than 5 years. The overall 3-year and 5-year survival rate were 79.4% and 69. 0% respectively. The overall 3-year and 5-year free-disease survival rate were 71.7% and 66. 3% respectively. The survival rate of 3-year and 5-year was 82.5% and 73.1% respectively for the group of operation alone; 82.4% and 70.1% respectively for the group of operation after induction chemotherapy with PBF, 72.2% and 61.1% respectively for the group of operation after induction chemotherapy with bleomycin-A5; and there were no significant difference between the above three groups (chi2 = 0.42, P = 0.8106). The locoregional recurrence rate were 30.4%, 41.2% and 38.9% for the operation alone group, operation after PBF induction chemotherapy group and operation after bleomycin-A5 induction chemotherapy group respectively. No significant benefit on decreasing locoregional recurrence (chi2 = 1.148, P = 0.563) or distant metastasis rate (chi2 = 2.305, P = 0.316) were found by induction chemotherapy by univariate analysis. Using multivariate analysis, risk factor that independently influence survival was the recurrence.Risk factors that independently influence survival of moderate tongue squamous cell carcinoma was the locoregional recurrence. No significant benefit on improving survival rate or decreasing locoregional recurrence or metastasis rate were found by induction chemotherapy, there was no difference between the two induction chemotherapy schemes on the survival rate or locoregional recurrence or metastasis rate of these patients.

DNP, a nitramine, has been studied with regard to the kinetics and mechanism of thermal decomposition, using thermogravimetry (TG), differential thermal analysis (DTA), infrared (IR) spectroscopy, and differential scanning calorimetry (DSC). The IR spectra of DNP have also been recorded and the kinetics of thermolysis has been followed by non-isothermal TG. The activation energy of the solid-state process was determined using Flynn–Wall–Ozawa method. The actual reaction mechanism obeyed nucleation and growth model, Avramie Erofeev function (n = 1) with integral form G(α) = −ln(1 − α) (α = 0.10–0.65). Ea and A were determined to be 116.51 kJ/mol and 1010.52 s−1. The T/Jump FT-IR analysis showed that CH2O, NO2, and NO are produced in larger amounts than CO2 and HCN. The cleavage of the N–N and C–N bond appears to be the primary step in the thermolysis of DNP.

Huntington disease (HD) is caused by expansion of a polyglutamine (polyQ) domain in the protein known as huntingtin (htt), and the disease is characterized by selective neurodegeneration. Expansion of the polyQ domain is not exclusive to HD, but occurs in eight other inherited neurodegenerative disorders that show distinct neuropathology. Yet in spite of the clear genetic defects and associated neurodegeneration seen with all the polyQ diseases, their pathogenesis remains elusive. The present review focuses on HD, outlining the effects of mutant htt in the nucleus and neuronal processes as well as the role of cell-cell interactions in HD pathology. The widespread expression and localization of mutant htt and its interactions with a variety of proteins suggest that mutant htt engages multiple pathogenic pathways. Understanding these pathways will help us to elucidate the pathogenesis of HD and to target therapies effectively.

Understanding basic neuronal mechanisms hold the hope for future treatment of brain disease. The 1st international conference on synapse, memory, drug addiction and pain was held in beautiful downtown Toronto, Canada on August 21-23, 2006. Unlike other traditional conferences, this new meeting focused on three major aims: (1) to promote new and cutting edge research in neuroscience; (2) to encourage international information exchange and scientific collaborations; and (3) to provide a platform for active scientists to discuss new findings. Up to 64 investigators presented their recent discoveries, from basic synaptic mechanisms to genes related to human brain disease. This meeting was in part sponsored by Molecular Pain, together with University of Toronto (Faculty of Medicine, Department of Physiology as well as Center for the Study of Pain). Our goal for this meeting is to promote future active scientific collaborations and improve human health through fundamental basic neuroscience researches. The second international meeting on Neurons and Brain Disease will be held in Toronto (August 29-31, 2007). © 2006 Bi et al; licensee BioMed Central Ltd.

To explore the feasibility of endoscope-assisted thyroidectomy with minimal neck incision.Endoscope-assisted thyroid surgeries had been accomplished through incision above sternal notch and in submental area respectively from August 2003 to August 2005, including 11 partial lobectomy, 3 lobectomy, 2 two-sides partial lobectomy, 1 isthmectomy.In this group, 12 cases approached through above sternal notch, 5 cases approached through the submental area, and all were successful. The mean length of incisions was 2.3 cm (range from 1.5 cm to 3.0 cm). No one was converted to open surgery. The mean time of operation was 61.3 minutes (range from 30 minutes to 120 minutes). The mean volume of hemorrhage during the operation was 15.6 ml (range from 10 to 40 ml). The mean volume of drainage of post-operation was 22.5 ml (range from 6 ml to 40 ml). The mean length of stay was 4. 5 days (range from 3 days to 6 days). There were no hoarseness and no low serum calcium. Following visits were performed after operation from 1 month to 12 months, and there were no stiff feelings on skin. The cosmetic outcomes of the incisions were good, except 1 case for scar physique.Endoscope-assisted thyroidectomy was safe and feasible with good cosmetic outcome. The selection of approach with minimal incision depends on the location of neoplasm.

The pathophysiology of Huntington’s disease reflects actions of mutant Huntingtin (Htt) (mHtt) protein with polyglutamine repeats, whose N-terminal fragment translocates to the nucleus to elicit neurotoxicity. We establish that the nuclear translocation and associated cytotoxicity of mHtt reflect a ternary complex of mHtt with GAPDH and Siah1, a ubiquitin-E3-ligase. Overexpression of GAPDH or Siah1 enhances nuclear translocation of mHtt and cytotoxicity, whereas GAPDH mutants that cannot bind Siah1 prevent translocation. Depletion of GAPDH or Siah1 by RNA interference diminishes nuclear translocation of mHtt.

The hypothalamus responds to circulating leptin and insulin in the control of food intake and body weight. A number of neurotransmitters in the hypothalamus, including gamma-aminobutyric acid (GABA), also have key roles in feeding. Huntingtin-associated protein 1 (Hap1) is expressed more abundantly in the hypothalamus than in other brain regions, and lack of Hap1 in mice leads to early postnatal death. Hap1 is also involved in intracellular trafficking of the GABA(A) receptor. Here, we report that fasting upregulates the expression of Hap1 in the rodent hypothalamus, whereas intracerebroventricular administration of insulin downregulates Hap1 by increasing its degradation through ubiquitination. Decreasing the expression of mouse hypothalamic Hap1 by siRNA reduces the level and activity of hypothalamic GABA(A) receptors and causes a decrease in food intake and body weight. These findings provide evidence linking hypothalamic Hap1 to GABA in the stimulation of feeding and suggest that this mechanism is involved in the feeding-inhibitory actions of insulin in the brain.

To discuss how the diagnosis, misdiagnosis and different treatment modalities affect the prognosis of the patients with extranodal NK-T cell lymphoma-nasal type.A retrospective study was made on the clinical characteristics, treatment modality, short-term effect, and survival rate of 68 patients with extranodal NK-T cell lymphoma-nasal type. Among them,60 patients staged I(E) were subdivided into single therapy group of 20 cases( radiation therapy 9 cases, chemotherapy 11 cases) and combined therapy group of 40 cases (9 cases with radiation therapy + chemotherapy, 12 cases with chemotherapy + radiation therapy,19 cases with chemotherapy + radiation therapy + chemotherapy). Eight patients staged IV(E) included 3 cases with radiation therapy alone and 5 cases with chemotherapy and radiation therapy.The rate of misdiagnosis of whole group is 66. 2% (45/68), and the rate of misoperated patients accounted for 52. 9% (36/68). The CR rate of radiation therapy was 94. 4% (17/18) for limited disease in I(E) group compared 61.9% (26/42) for out-cavity disease in I(E) group, of which the difference is significant (P =0. 012). The 1-years, 3-years and 5-years survival rate of the I(E) intra-cavity group were 100%, 77.8%, 59.8%, and those of ex-cavity group were 80.1%, 48.5% and 14.6%, respectively. The 1, 3 and 5-years survival rate of IV(E) group were 17.5%, 0.0% and 0.0%. The difference of survival was significance among the above 3 groups (P = 0. 000). The 1, 3, 5-years survival rate of 60 I(E) patients with single therapy were 68.4%, 22.8% and 7.6% respectively; and that of combined therapy group were 94.9%, 81.1% and 52.4% respectively, which was significant difference (P = 0. 000). The survival difference among the radiation therapy + chemotherapy group, chemotherapy + radiation therapy group and chemotherapy + radiation therapy + chemotherapy group were not significant (P = 0.088).The early clinical manifestation of extranodal NK-T cell lymphoma-nasal type is not typical,which is easy to be misdiagnosed and mistreated. Early therapy is the key,which can achieve good location control. Diseased stage I(E) out-cavity and above should be treated with combined therapy.

Huntington disease (HD) is characterized by the preferential loss of striatal medium-sized spiny neurons (MSNs) in the brain. Because MSNs receive abundant glutamatergic input, their vulnerability to excitotoxicity may be largely influenced by the capacity of glial cells to remove extracellular glutamate. However, little is known about the role of glia in HD neuropathology. Here, we report that mutant huntingtin accumulates in glial nuclei in HD brains and decreases the expression of glutamate transporters. As a result, mutant huntingtin (htt) reduces glutamate uptake in cultured astrocytes and HD mouse brains. In a neuron–glia coculture system, wild-type glial cells protected neurons against mutant htt-mediated neurotoxicity, whereas glial cells expressing mutant htt increased neuronal vulnerability. Mutant htt in cultured astrocytes decreased their protection of neurons against glutamate excitotoxicity. These findings suggest that decreased glutamate uptake caused by glial mutant htt may critically contribute to neuronal excitotoxicity in HD.

Huntingtin-associated protein-1 (HAP1) was initially identified as an interacting partner of huntingtin, the Huntington disease protein. Unlike huntingtin that is ubiquitously expressed throughout the brain and body, HAP1 is enriched in neurons, suggesting that its dysfunction could contribute to Huntington disease neuropathology. Growing evidence has demonstrated that HAP1 and huntingtin are anterogradely transported in axons and that the abnormal interaction between mutant huntingtin and HAP1 may impair axonal transport. However, the exact role of HAP1 in anterograde transport remains unclear. Here we report that HAP1 interacts with kinesin light chain, a subunit of the kinesin motor complex that drives anterograde transport along microtubules in neuronal processes. The interaction of HAP1 with kinesin light chain is demonstrated via a yeast two-hybrid assay, glutathione S-transferase pull down, and coimmunoprecipitation. Furthermore, HAP1 is colocalized with kinesin in growth cones of neuronal cells. We also demonstrated that knocking down HAP1 via small interfering RNA suppresses neurite outgrowth of PC12 cells. Analysis of live neuronal cells with fluorescence microscopy and fluorescence recovery after photobleaching demonstrates that suppressing the expression of HAP1 or deleting the HAP1 gene inhibits the kinesin-dependent transport of amyloid precursor protein vesicles. These studies provide a molecular basis for the participation of HAP1 in anterograde transport in neuronal cells.

Huntingtin-associated protein 1 (HAP1) was originally found to be localized in neurons and is thought to play an important role in neuronal vesicular trafficking and/or organelle transport. Based on functional similarity between neuron and endocrine cell in vesicular trafficking, we examined the expression and localization of HAP1 in the rat endocrine system using immunohistochemistry. HAP1-immunoreactive cells are widely distributed in the anterior lobe of the pituitary, scattered in the wall of the thyroid follicles, or clustered in the interfollicular space of the thyroid gland, exclusively but diffusely distributed in the medullae of adrenal glands, and selectively located in the pancreas islets. HAP1-containing cells were also found in the mucosa of stomach and small intestine with a distributive pattern similar to that of gastrointestinal endocrine cells. However, no HAP1-immunoreactive cell was found in the cortex of the adrenal gland, the testis, and the ovary. In the posterior lobe of the pituitary, HAP1-immunoreactive products were not detected in the cell bodies but in many stigmoid bodies, one kind of non-membrane-bound cytoplasmic organelle with a central or eccentric electron-lucent core. HAP1-immunoreactive stigmoid bodies were also found in the cytoplasm of endocrine cells in the thyroid gland, the medullae of adrenal gland, the pancreas islets, the stomach, and small intestine. The present study demonstrates that HAP1 is selectively expressed in part of the small peptide-, protein-, and amino-acid analog and derivative-secreting endocrine cells but not in steroid hormone-secreting cells, suggesting that HAP1 is also involved in intracellular trafficking in certain types of endocrine cells.

To analysis the reasons of the reoperation of thyroid neoplasm and the efficiency of the surgery and to explore the diagnosis of thyroid neoplasm in order to choose the rational surgical method.Reoperation of thyroid cancers were performed in 128 patients from Oct. 1992 to Oct. 2000. The causes of reoperation were thyroid cancer remnants and persistence of the micro carcinoma The type of reoperation includes: 1. completion of lobectomy and isthmectomy or subtotal thyroidectomy. Radical neck dissection or modified neck dissection were indicated for the neck of lymph node metastasis. 2. completion of lobectomy and isthmectomy and modified neck dissection or selective neck dissection for patient with thyroid micro carcinoma. Preoperative fine needle aspiration (FNA) (10 cases), intra-operative frozen section (FS) (55 cases), FNA and FS (13 cases) were done in 78 patients who first visited our hospital, with pure (solitary) thyroid nodule suspected thyroid carcinoma clinically. The results of the above examinations were compared with postoperative pathological results.For the patients with reoperation, the rate of remained cancer was 68.8% (88/128) which was confirmed by pathological results. The occurring of complication was 23.4% (30/128). Laryngeal recurrent nerve paralysis was accounted for 2. 3% and transient postoperative hypocalcemia occurred in 19.5%. Five patients developed local recurrence and 3 had neck metastasis the following up. The 5-, 10-year survival rates of these patients were 92.0% (101/110) and 86.9% (17/20) respectively. The diagnostic accuracy of preoperative FNA, intra-operative FS, FNA and FS were 90.0%, 87.3% and 92.3% respectively.The rate of postoperative residual carcinoma in thyroid was relatively higher because of misdiagnosis and inadequate operation. It was necessary to take active and reasonable reoperation. Reoperation added to surgical complications. Increasing preoperative diagnostic accuracycarrying out standard, adequate surgical treatment are the essence to decrease surgical complication.

In postmortem Huntington's disease brains, mutant htt is present in both nuclear and cytoplasmic compartments. To dissect the impact of nuclear and extranuclear mutant htt on the initiation and progression of disease, we generated a series of transgenic mouse lines in which nuclear localization or nuclear export signal sequences have been placed N-terminal to the htt exon 1 protein carrying 144 glutamines. Our data indicate that the exon 1 mutant protein is present in the nucleus as part of an oligomeric or aggregation complex. Increasing the concentration of the mutant transprotein in the nucleus is sufficient for and dramatically accelerates the onset and progression of behavioral phenotypes. Furthermore, nuclear exon 1 mutant protein is sufficient to induce cytoplasmic neurodegeneration and transcriptional dysregulation. However, our data suggest that cytoplasmic mutant exon 1 htt, if present, contributes to disease progression.

To investigate serum CA(125) levels and the value of serum CA(125) in differential diagnosis of benign pelvic mass.We retrospectively analyzed 492 patients with benign pelvic mass, including 237 cases of benign ovarian tumor and 255 other benign gynecological diseases. Sixty cases of ovarian epithelial cancer were randomly chosen as control group.The median of serum CA(125) in patients with pelvic tuberculosis, uterine adenomyosis, ovarian endometriosis and ovarian fibroma were all higher than the cut-off level of CA(125) (35 kU/L), being 465.0, 88.9, 59.0 and 44.5 kU/L, respectively. Those of ovarian epithelial cancer patients were significantly higher than in benign pelvic mass (P0.01). The highest value of CA(125) among all the benign cases was 1281.0 kU/L, which was seen in a case of ovarian thecoma. The highest median value was 465.0 kU/L, detected in a patient with pelvic tuberculosis.Serum CA(125) levels in some benign pelvic mass are higher than the cut-off level of CA(125), such as pelvic tuberculosis, uterine adenomyosis, ovarian fibroma and ovarian endometriosis. The medians of serum CA(125) in benign pelvic mass are much lower than in ovarian epithelial cancer. Serum CA(125) is of significance in the differential diagnosis between hysteromyoma and uterine adenomyosis.

Huntington's disease is caused by a polyglutamine expansion in the protein huntingtin. Several studies suggest that huntingtin and its associated protein HAP1 participate in intracellular trafficking and that polyglutamine expansion affects vesicular transport. A study now provides new evidence that HAP1 is also involved in the endocytosis of membrane receptors. These studies offer insight into the normal function of HAP1 and its involvement in Huntington's disease.

SummaryExpanded polyglutamine (polyQ) proteins in Huntington’s disease (HD) as well as other polyQ disorders are known to elicit a variety of intracellular toxicities, but it remains unclear whether polyQ proteins can elicit pathological cell-cell interactions which are critical to disease pathogenesis. To test this possibility, we have created conditional HD mice expressing a neuropathogenic form of mutant huntingtin (mhtt-exon1) in discrete neuronal populations. We show that mhtt aggregation is a cell-autonomous process. However, progressive motor deficits and cortical neuropathology are only observed when mhtt expression is in multiple neuronal types, including cortical interneurons, but not when mhtt expression is restricted to cortical pyramidal neurons. We further demonstrate an early deficit in cortical inhibition, suggesting that pathological interactions between interneurons and pyramidal neurons may contribute to the cortical manifestation of HD. Our study provides genetic evidence that pathological cell-cell interactions elicited by neuropathogenic forms of mhtt can critically contribute to cortical pathogenesis in a HD mouse model.

Huntington’s disease results from a polyglutamine expansion in the N-terminal region of huntingtin (htt). This abnormality causes protein aggregation and leads to neurotoxicity. Despite its widespread expression in the brain and body, mutant htt causes selective neurodegeneration in Huntington’s disease patient brains. However, Huntington’s disease mouse models expressing mutant htt do not have obvious neurodegeneration despite significant neurological symptoms. Most Huntington’s disease mouse models display the accumulation of toxic N-terminal mutant htt fragments in both the nucleus and neuronal processes, suggesting that these subcellular sites are hotspots for the early neuropathology of Huntington’s disease. Intranuclear htt affects gene expression and may cause neuronal dysfunction. Mutant htt in neuronal processes affects axonal transport and induces degeneration, and these effects may be more relevant to the selective neurodegeneration in Huntington’s disease. Growing evidence has also suggested that mutant htt mediates multiple pathological pathways. This review discusses the early pathological changes identified in Huntington’s disease cellular and animal models. These changes may be the causes of neurode-generation.

To analyze the clinical characteristics of female pelvic tuberculosis for the differentiation from ovary carcinoma.Twenty patients who were confirmed having pelvic tuberculosis from March 1994 to May 2002 were retrospectively studied.Poor economic condition, history of tuberculosis or contact with tuberculosis, and fever were among the most important factors in differentiating pelvic tuberculosis from advanced ovarian cancer. Pelvic mass and ascites were present in all of the 20 patients, abdominal distension in 16, abdominal pain in 12, fever in 16, lost of weight in 13, and diarrhea in 6. The level of serum CA125 ranged from 65 U/L to 1,069 U/L. Peritoneal effusion cytology was studied in 16 cases before operation.The clinical differentiation of female pelvic tuberculosis from ovary carcinoma was difficult. Pelvic tuberculosis should be considered in young women presented with pelvic mass, ascites, fever, an elevated CA125 level and negative cytology, and with a history of tuberculosis or contact with tuberculosis.