Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome

Recent reports have suggested that variants in the sortilin-related receptor gene (SORL1) increase the risk of late onset Alzheimer's disease (AD) in Northern European, Hispanic, African–American and Isreali–Arab populations. SORL1 directs trafficking of amyloid precursor protein (APP) and under-expression of SORL1 may lead to over-expression of β amyloid peptides. Adults with Down syndrome (DS) over-express APP and have early onset and high risk for AD. We investigated the relation of seven variants in the gene for SORL1 to age at onset and risk for AD among 208 adults with DS, 45–70 years of age at baseline. Participants were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Homozygosity for the minor T allele in rs556349 and for the minor C allele in rs536360 was associated with later age at onset and reduced risk of AD (HR = 0.26, 95% CI: 0.08–0.86; and HR = 0.40, 95% CI: 0.16–0.98, respectively). Mean age at onset was approximately four years later in individuals who were homozygous for those alleles compared with those who had at least one major allele. These findings indicate a modest association of variants in SORL1 with AD. In addition, we did not observe the same alleles to be associated with AD compared with earlier studies, suggesting that these SNPs are in linkage disequilibrium (LD) with the putative functional variants or that expression of the SORL1 gene and hence its interaction with APP might be modified by the extremely high levels of APP characteristic of Down syndrome. Thus, further studies are needed to identify functional variants that influence risk for AD in this uniquely vulnerable population.     

Differential cardiovascular effects of pharmacological agents in chickens selected for high and low body weight.

This study was conducted to investigate whether there are differences in the autonomic nervous system function of chickens from lines selected for high (HWS) or low body weight (LWS). The cardiovascular response to various pharmacological agents was used as an indicator of autonomic nervous system response. Ten individuals from each line and sex were used in the study. Catheters were introduced into the left brachial artery and vein and connected to a MP100-BIOPAC system to record blood pressure and heart rate (HR). Chickens were injected with phenylephrine, atropine, propranolol, and tetraethylammonium chloride (TEAC). The LWS birds exhibited a greater increase in mean arterial blood pressure (MABP) and a lesser increase in HR than the HWS birds following atropine. The response to atropine showed a line and sex interaction in which male birds had a greater increase in HR than females and LWS females had a lower increase in HR than the HWS females. Injection of phenylephrine following pretreatment with atropine caused a baroreceptor reflex in which males showed a greater decrease in HR than females. In response to the beta-adrenergic receptor blocker propranolol, females displayed a greater decrease in MABP than males and LWS birds had a greater decrease in HR than HWS birds. In response to the autonomic ganglionic blocker TEAC, MABP and HR decreased equally in both lines. The percentage of adrenal and sympathetic impact on regulation of HR showed that LWS females required greater adrenal activity than those from the other subclasses. Although changes in HR and MABP ratios in response to phenylephrine were different between lines, these responses were not different when phenylephrine was given following atropine. This pattern of response suggested that HWS birds had greater parasympathetic nervous system activity in order to maintain cardiovascular function. These results demonstrate that selection for HWS or LWS has resulted in greater parasympathetic and sympathetic nervous system tone in birds from the HWS and LWS birds, respectively, and suggest that differences between the lines could be at the level of the chromaffin tissue in the adrenal gland.     

The value of immunohistochemical detection of P-glycoprotein in breast cancer before and after induction chemotherapy.

We have studied the patterns of P-glycoprotein expression before and after 3 cycles of induction chemotherapy (5-fluorouracil, adriamycin and cyclophosphamide) using immunohistochemically stained paraffin-embedded specimen of 28 patients with locally advanced breast cancer. The frequency of P-glycoprotein expression in untreated breast cancer turned out to be very low: only one out of 28 untreated, biopsy specimen at the time of diagnosis was positive. The frequency of P-glycoprotein expression was markedly increased from 9.1% before chemotherapy to 63.6% after induction chemotherapy (p = 0.006). After 3 cycles of induction chemotherapy, 25 patients had obtained clinical response to chemotherapy (4, CR; 21, PR). Eleven out of 25 tumors (44%) showing clinical response and all three tumors (100%) with minimal response have expressed P-glycoprotein. One out of 6 patients (16.7%) with microscopic residual tumor seen in mastectomy specimen expressed P-glycoprotein, whereas 13 of 22 patients (59.1%) with gross residual tumor showed the presence of P-glycoprotein (p = 0.08). The frequency of intrinsic P-glycoprotein expression in untreated breast cancer was quite low, but approximately half of the patients do acquire P-glycoprotein expression during the cycles of induction chemotherapy. Therefore, the results suggest that the immunohistochemical detection of P-glycoprotein on residual tumor cells after induction chemotherapy can predict acquired drug resistance in breast cancer.     

Negative conversion of antimitochondrial antibody in primary biliary cirrhosis: a case of autoimmune cholangitis

Autoimmune cholangitis is a clinical constellation of chronic cholestasis, histological changes of chronic nonsuppurative cholangitis and the presence of autoantibodies other than antimitochondrial antibody (AMA). It is uncertain whether this entity is definitely different from AMA positive primary biliary cirrhosis (PBC), though it shows some differences. We report a case of autoimmune cholangitis in a 59-year-old woman, who had been previously diagnosed as AMA-positive PBC associated with rheumatoid arthritis, has been converted to an AMA-negative and anticentromere antibody-positive PBC during follow-up. The response to ursodeoxycholic acid treatment is poor except within the first few months, but prednisolone was dropping the biochemical laboratory data.     

Additive Antinociception between Intrathecal Sildenafil and Morphine in the Rat Formalin Test

The possible characteristics of spinal interaction between sildenafil (phosphodiesterase 5 inhibitor) and morphine on formalin-induced nociception in rats was examined. Then the role of the opioid receptor in the effect of sildenafil was further investigated. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. For induction of pain, 50 µL of 5% formalin solution was applied to the hind-paw. Isobolographic analysis was used for the evaluation of drug interaction between sildenafil and morphine. Furthermore, naloxone was intrathecally given to verify the involvement of the opioid receptor in the antinociception of sildenafil. Both sildenafil and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. The isobolographic analysis revealed an additive interaction after intrathecal delivery of the sildenafil-morphine mixture in both phases. Intrathecal naloxone reversed the antinociception of sildenafil in both phases. These results suggest that sildenafil, morphine, and the mixture of the two drugs are effective against acute pain and facilitated pain state at the spinal level. Thus, the spinal combination of sildenafil with morphine may be useful in the management of the same state. Furthermore, the opioid receptor is contributable to the antinocieptive mechanism of sildenafil at the spinal level.     

Isolation of nontoxigenic Vibrio cholerae O group 1 from a patient with severe gastrointestinal disease.

A nontoxigenic strain of Vibrio cholerae O group 1 was isolated in Florida from the stool of a patient with severe diarrhea. The strain had the same hemolytic and unique phage-sensitivity pattern as all toxigenic isolates from recent cases of cholera in Texas and Louisiana. Identical strains were transiently isolated from sewerage systems in two other Florida communities, suggesting that multiple human infections had occurred. This is the first indication that V. cholerae O1 strains which do not produce cholera toxin may be able to cause gastrointestinal disease in humans. The identification of these strains also raises questions about the relationship between toxigenic and nontoxigenic strains of V. cholerae O1 along the Gulf Coast of the United States.     

N(omega)-nitro-L-arginine methyl ester attenuates lithium-induced c-Fos, but not conditioned taste aversion, in rats

Lithium chloride (LiCl) at doses sufficient to induce conditioned taste aversion (CTA) causes c-Fos expression in the relevant brain regions and activates the hypothalamic-pituitary-adrenal (HPA) axis. It has been suggested that nitric oxide (NO) in the central nervous system may play a role not only in the activation of HPA axis but also in CTA learning, and that LiCl may activate the brain NO system. To determine the role of NO in lithium-induced CTA, we examined the lithium-induced CTA, brain c-Fos expression, and plasma corticosterone level with Nomega-nitro-L-arginine methyl ester (L-NAME) pretreatment. Intraperitoneal L-NAME (30 mg/kg) given 30 min prior to LiCl significantly decreased lithium-induced c-Fos expression in the brain regions implicated in CTA learning, such as the hypothalamic paraventricular nucleus (PVN), central nucleus of amygdala (CeA), and nucleus tractus of solitarius. However, either the lithium-induced CTA acquisition or the increase in plasma corticosterone was not attenuated by l-NAME pretreatment. These results suggest that NO may be involved in lithium-induced neuronal activation of the brain regions, but not in the CTA acquisition or the HPA axis activation.     

Posttransplant primary cutaneous Ki-1 (CD30)+/CD56+ anaplastic large cell lymphoma

An anaplastic large cell lymphoma that was negative for Epstein-Barr virus and positive for Ki-1 (CD30) presented as a polypoid scalp mass in a 56-year-old man 16 years after renal transplantation. The lymphoma was of the CD4+ cytotoxic T-cell lineage, and the tumor cells also expressed CD56. Despite reduction in the dose of immunosuppression and localized radiotherapy, the tumor had rapidly progressed to involve the soft tissue of the right hand. Systemic chemotherapy induced complete regression of the soft tissue lesion. This case illustrates that posttransplant primary cutaneous CD30+ anaplastic large cell lymphomas may assume an aggressive clinical course but can still be controlled by systemic chemotherapy.     

Volume variation of mastoid pneumatization in different age groups: a study by three-dimensional reconstruction based on computed tomography images

Although there have been some reports that measured the size of mastoid pneumatization, only a few studies have reported the age-related variations in the mastoid air cell system using three-dimensional (3D) reconstruction techniques of computed tomography (CT) images. We performed a retrospective, cross-sectional study. A 3D reconstruction based on CT images was performed on 199 ears of 102 patients (age range 6–84 years) without otologic disease by a surface-rendering algorithm. The results showed that mastoid pneumatization continued to grow until the third decade. Thereafter, it declined slowly, and then rapidly after the seventh decade. No statistically significant difference was found between male and female or between right and left sides. There was a significant difference between the larger and smaller sides of individuals. The volume measurement technique based on the 3D reconstruction technique reported here is widely available, highly accurate and easy to perform.     

Effects of methylprednisolone on the neural conduction of the motor evoked potentials in spinal cord injured rats

Methylprednisolone(MP), a glucocorticoid steroid, has an anti-inflammatory action and seems to inhibit the formation of oxygen free radicals produced during lipid peroxidation in a spinal cord injury(SCI). However, the effects of MP on the functional recovery after a SCI is controversial. The present study was conducted to determine the effects of MP on the recovery of neural conduction following a SCI. A SCI was produced using the NYU spinal cord impactor. A behavioral test was conducted to measure neurological disorders, and motor evoked potentials (MEPs) were recorded. According to the behavioral test, using BBB locomotor scaling, MP-treated animals showed improved functional recoveries when compared to saline-treated animals. MEP latencies in the MP-treated group were shortened when compared to those in the control group. Peak amplitudes of MEPs were larger in the MP-treated group than those in the control group. The thresholds of MEPs tended to be lower in the MP-treated group than those in the control group. These results suggest that MP may improve functional recovery after a SCI.