Adolescent HIV-1 Transgenic Rats: Evidence for Dopaminergic Alterations in Behavior and Neurochemistry Revealed by Methamphetamine Challenge

Since the introduction of combination antiretroviral therapy (cART) in the mid-90s, the most severe forms of HIV-1-associated neurocognitive disorders (HAND) have diminished. However, milder forms of HAND remain prevalent. Basic and clinical studies implicate alterations in the dopaminergic (DAergic) system in HIV-1 infection. We used the Fischer 344 HIV-1 transgenic (HIV-1 Tg) rat, which expresses 7 of the 9 HIV-1 genes, to examine potential DAergic alterations. Animals were studied beginning at 35 days of age to assess early-onset DAergic alterations, well before any documented neurological symptoms or clinical signs of "wasting". At 48 hr intervals, animals were administered a single dose of methamphetamine (METH) (0, 0.5, 1, 2.5 and 5 mg/kg/ml s.c.) and tested for the auditory startle response (ASR) and prepulse inhibition (PPI), using an auditory prepulse [85dB(A) broad-band noise stimulus] and an auditory startle stimulus [100 dB(A) broad-band noise stimulus] in a sound-attenuating chamber with a continuous 70dB(A) white noise background. The protocol used a 5-min acclimation period, 6 startle trials, and 36 PPI trials [ISIs of 0, 8, 40, 80, 120, and 4000 ms, 6-trial blocks, Latin square design]. As the dose of METH increased, PPI of the startle response decreased. The HIV-1 Tg rats displayed a greater dose-dependency to the METH-induced disruption of PPI compared to non-transgenic controls. Western blot analysis of midbrain extracts revealed lower tyrosine hydroxylase (TH) protein levels and higher monoamine oxidase A (MAO-A) protein levels in HIV-1 Tg rats treated with METH compared to non-transgenic controls. Early-detected cognitive alterations in the preattentive process of sensorimotor gating may have significant predictive utility regarding the progression of DAergic alterations in HIV-1 infection.     

A nitroalkane-based approach to one-pot three-component synthesis of isocryptolepine and its analogs with potent anti-cancer activities

A second generation polyphosphoric acid-mediated one-pot three-component synthesis of indoloquinoline scaffold is developed. This improved version of the process involves electrophilically activated nitroalkanes for the installation of strategic C–C and C–N bonds and ring C assembly. This modification allows the elimination of unnecessary solvent change operations and all steps are carried out in a true, uninterrupted one-pot manner. A further improvement involves the possibility to install an ortho-amino group in situ. A synthetic application of this method is showcased by the concise synthesis of an isocryptolepine alkaloid and its synthetic analogs with potent anticancer activities.

An improved one-pot three-component synthesis involving electrophilically activated nitroalkanes allowed for efficient preparation of indoloquinolines with potent anticancer activities.     

Electrophilically activated nitroalkanes in reaction with aliphatic diamines en route to imidazolines

A novel synthetic methodology for the assembly of imidazolines via an unusual reaction between nitroalkanes and aliphatic 1,2-diamines in the presence of phosphorous acid is described. In contrast to the related highly efficient preparation of benzimidazoles from aromatic amines, this process represents a major synthetic challenge and for a long time was elusive. Analysis of the method limitations is provided.

Imidazolines were assembled via an unusual reaction between nitroalkanes and aliphatic 1,2-diamines in the presence of phosphorous acid.     

AMP-18,一种新发现的胃黏膜保护因子

AMP-18是一种新发现的由胃腺体上皮细胞合成的小分子蛋白质,独特表达于胃黏膜,机体其他部位少见,胃癌组织中表达缺失．AMP-18 由185个氨基酸组成,除去N端信号肽(20个氨基酸)后大小约18 ku,第54-150个氨基酸组成高度保守的结构域(BRICHOS区域)承担主要的生理功能．AMP-18由胃腺体上皮细胞以胞吐的方式分泌到胃黏液中,他的合成和分泌与个体生长发育有关,并受福斯高林、吲哚美辛、地塞米松等药物的影响．目前发现 AMP-18的生理功能主要有促进胃黏膜上皮细胞的有丝分裂,促进细胞的迁徙,促胃肠黏膜损伤的修复,保持胃肠黏膜的完整等．     

Preparation of 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones via base-assisted cyclization of 3-cyanoketones

A convenient preparative method is developed allowing for expeditious assembly of 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones from routinely available inexpensive synthetic precursors. These compounds could not be prepared via the previously known protocols, as 2-aminofuran derivatives were produced instead.

The highly efficient oxidative cyclization of 1,3-diarylsubstituted 3-cyanoketones yielded 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones.     

Clinical and familial study of arrhythmogenic right ventricular cardiomyopathy

Objective　To explore the characteristics of arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods　Seven patients with arrhythmogenic right ventricular cardiomyopathy and 34 members of three families were studied. All patients and family members underwent history collection, clinical examination, electrocardiogram (ECG), two-dimensional echocardiography (2-DE) and a signal averaging electrocardiogram. Programmed ventricular stimulation was performed in five patients. Results　All patients and family members had normal morphologic characteristics and normal function of the left ventricular by 2-DE. Fourteen persons had abnormal findings indicating ARVC. Five had enlargement of the right ventricular with diffused hypocontractility, eight had thin and systolic bulging in the focal anterior wall with hypokinesia and one had bulging of the inferior wall. Twenty-five persons (seven patients and 18 family members) had abnormal findings in ECG. Positive ventricular late potential was recorded in 13 persons (six patients). Two to three monomorphic ventricular tachycardia (VT) with left bundle branch block (LBBB) configurations were induced in five patients. Ventricular fibrillation was induced in two patients during the electrophysiologic study (EPS). Five patients had very high pacing threshold and/or ineffective pacing in one or many regions of the right ventricle. Two members of one family died suddenly. One member was a dwarf with ARVC. Spontaneous VT with a left bundle branch block (LBBB) configuration was recorded in five patients, polymorphic VT with extremely short coupling interval in one, and premature ventricular complexes with LBBB configuration in 12 (six patients). Conclusion　Our familial study strongly suggests that ARVC may be a hereditary disease and it is helpful in the diagnosis and detection of ARVC. The most common manifestations were abnormal structure and function of the right ventricle and abnormal ECG of repolarization and ventricular arrhythmia which originates from the right ventricle.     

HIV-1 protein-mediated amyloidogenesis in rat hippocampal cell cultures

Since the beginning of the highly active antiretroviral therapy (HAART) era, epidemiological evidence indicates an increasing incidence of Alzheimer's (AD)-like brain pathology in aging HIV patients. Emerging evidence warns of potential convergent mechanisms underlying HIV- and Aβ-mediated neurodegeneration. We found that HIV-1 Tat B and gp120 promote the secretion of Aβ 1-42 in primary rat fetal hippocampal cell cultures. Our results demonstrate that the variant of Tat expressed by the neurotropic subtype of HIV-1 virus (HIV-1 clade B) specifically induces both the release of amyloidogenic Aβ 1-42 and the accumulation of cell-bound amyloid aggregates. The results of the research rationalize testing of the ability of β-amyloid aggregation inhibitors to attenuate HIV protein-mediated cognitive deficits in animal models of NeuroAIDS. The long-term goal of the study is to evaluate the potential benefits of anti-amyloidogenic therapies for management of cognitive dysfunction in aging HIV-1 patients.     

Medico-genetic and cytogenetic investigation in family with high predisposition to diffuse intestine polyposis

We revealed a family consisting of 25 persons which displayed high predisposition to malignant diseases of the gastrointestinal tract (GIT): rectal cancer (RC) was diagnosed in 2 patients, large intestine malignant polyposis (LIMP) in 1 patient, large intestine diffuse polyposis (LIDP) in 3 and uterus fibromyoma in 1 patient. Six members of the family were examined cytogenetically with the methaphase method on blood lymphocytes following G-banding of chromosomes. In 2 patients with LIDP was detected 8.7 and 16.7% of hyperaneuploid cells, respectively, and 20% of cells with double minute chromosomes (DMS) were detected in 1 LIDP patient. We suppose, that LIDP development in members of the family is related to the significant increase of proportion of hyperaneuploid and DMS-containing cells.     

Clinical and cytogenetic investigation of a family with high predisposition for intestinal polyps

A medico-genetic investigation of a family, consisting of 25 members, revealed high predisposition to malignant pathology of the gastrointestinal tract: rectal cancer was diagnosed in 2, malignant polyposis of the large intestine--1, diffuse polyposis of the large intestine (DPLI)--3, and uterine fibromyoma--in 1 patient. Six members underwent a cytogenetic examination using the metaphase method for peripheral blood lymphocytes and G-banding of chromosomes. Two patients with DPLI carried 8.7 and 16.7% of hyperaneuploid cells and one--20% of cells with double minute chromosomes (DMS). It is suggested that formation and subsequent significant increase in hyperaneuploid and DMS cells could have been responsible for DPLI development in the family.