Angiotensin-converting enzyme (ACE) gene polymorphism in type II diabetic patients with increased albumin excretion rate

Approximately one in three patients with diabetes is at risk of developing kidney disease, despite current methods of treatment. It has long been suspected that diabetic kidney disease has a genetic basis, but this has been difficult to prove. Polymorphisms of the angiotensin-converting enzyme (ACE) gene have been shown to be related to the occurrence of nephropathy in type I diabetic patients. This study showed that there was no association in the ACE genotype frequency and increased albumin excretion rate in type II diabetic patients.     

Spouse Concordance for Alcohol Dependence and Heavy Drinking: Evidence from a Community Sample

Using data from a community sample of 586 married couples, levels of spouse concordance for lifetime and current alcohol dependence and heavy drinking were estimated. In addition, marital quality ratings in concordant and discordant couples were compared. Spouse concordance was significant for lifetime alcohol dependence and for both lifetime and current heavy drinking. Marital quality varied as a function of current heavy drinking and alcohol dependence such that members of couples in which neither spouse drank heavily reported better marital quality than other couples. Furthermore, although marital quality did not differ significantly between concordant and discordant couples, couples concordant for current heavy drinking consistently reported poorer marital quality than other couples.     

Serotonergic modulation of spinal ascending activity and sacral reflex activity evoked by pelvic nerve stimulation in cats

Serotonin (5-HT) may be inhibitory to micturition at a spinal level. A potential mechanism of action for serotonergic inhibition of bladder function is a depression of the ascending limb of the supraspinal reflex mediating micturition. Ascending activity evoked by pelvic nerve stimulation was recorded in the thoracic spinal cord of anesthetized cats. For comparison, spinal reflex activity evoked by pelvic nerve stimulation was recorded on the pudendal nerve. The effects of intrathecal administration of serotonergic agents were examined to determine whether spinal and supraspinal responses to bladder afferent activation were modulated by 5-HT. Methysergide (60 nmol), a non-selective serotonergic antagonist, increased ascending activity by 61±7% and depressed spinal reflex activity by 38±6%. Zatosetron (10 nmol), a 5-HT₃ antagonist had a similar effect on both activities (increased by 93±24% and decreased by 77±7%, respectively). The effect on ascending activity of blocking 5-HT₃ receptors was also confirmed with ICS 205930 and MDL 72222. 2-Methyl-5-HT (800 nmol), a 5-HT₃ agonist, depressed ascending activity to 46±9% of control, but enhanced spinal reflex activity by 73±92%. These results demonstrate that stimulation of 5-HT₃ and methysergide-sensitive 5-HT receptors can inhibit ascending activity and facilitate spinal reflex activity elicited by activation of bladder afferents. It is suggested that descending serotonergic pathways may participate in the spinal coordination of urinary continence.     

Head injury mortality in two centers with different emergency medical services and intensive care

The authors report data collected prospectively on 551 cases of head injury in New Delhi, India, and 822 cases in Charlottesville, Virginia. The mortality rate, adjusted for initial severity of injury, was 11.0% in New Delhi versus 7.2% in Charlottesville (p less than 0.02). There was a striking similarity in mortality rates at both centers when comparing patients with the least severe head injuries and those with the most severe injuries according to the motor score of the Glasgow Coma Scale (GCS M). However, in the group with an abnormal but purposeful motor response (GCS M = 5), the mortality rate was 12.5% in New Delhi versus 4.8% in Charlottesville (p less than 0.01). The relative absence of prehospital emergency care and the delay in admission after head injury in New Delhi are cited as two possible causes for the differences in mortality rates in this subgroup of patients with "moderate" head injuries.     

Detailed gene copy number and RNA expression analysis of the 17q12-23 region in primary breast cancers

Chromosome region 17q12-23 commonly shows an increase in DNA copy number in breast cancers, suggesting that several oncogenes are located at this site. We performed a high-resolution expression array and comparative genomic hybridization analysis of genes mapped to the entire 17q12-23 region, to identify novel candidate oncogenes. We identified 24 genes that showed significant overexpression in breast cancers with gain of 17q12-23, compared to cancers without gain. These genes included previously identified oncogenes, together with several novel candidate oncogenes. FISH analysis using specific gene probes hybridized to tissue arrays confirmed the underlying amplification of overexpressed genes. This high-resolution analysis of the 17q12-23 region indicates that several established and novel candidate oncogenes, including a Wnt-signaling pathway member, are amplified and overexpressed within individual primary breast cancer samples. We were also able to confirm the presence of two apparently separate and reciprocally amplified groups of genes within this region. Investigation of these genes and their functional interactions will facilitate our understanding of breast oncogenesis and optimal management of this disease.     

Beta-defensin genomic copy number is not a modifier locus for cystic fibrosis

Human beta-defensin 2 (DEFB4, also known as DEFB2 or hBD-2) is a salt-sensitive antimicrobial protein that is expressed in lung epithelia. Previous work has shown that it is encoded in a cluster of beta-defensin genes at 8p23.1, which varies in copy number between 2 and 12 in different individuals. We determined the copy number of this locus in 355 patients with cystic fibrosis (CF), and tested for correlation between beta-defensin cluster genomic copy number and lung disease associated with CF. No significant association was found.     

An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line

Metastasis is the major cause of prostate cancer deaths and there is a need for clinically relevant in vivo models allowing elucidation of molecular and cellular mechanisms underlying metastatic behavior. Here we describe the development of a new in vivo model system for metastatic prostate cancer. Pieces of prostate cancer tissue from a patient were grafted in testosterone-supplemented male NOD-SCID mice at the subrenal capsule graft site permitting high tumor take rates. After five serial transplantations, the tumor tissues were grafted into mouse prostates. Resulting tumors and suspected metastatic lesions were subjected to histopathological and immunohistochemical analysis. Samples of metastatic tissue were regrafted in mouse anterior prostates and their growth and spread examined, leading to isolation from lymph nodes of a metastatic subline, PCa1-met. Orthotopic grafting of PCa1-met tissue in 47 hosts led in all cases to metastases to multiple organs (lymph nodes, lung, liver, kidney, spleen and, notably, bone). Histopathological analysis showed strong similarity between orthotopic grafts and their metastases. The latter were of human origin as indicated by immunostaining using antibodies against human mitochondria, androgen receptor, prostate-specific antigen and Ki-67. Spectral karyotyping showed few chromosomal alterations in the PCa1-met subline. This study indicates that transplantable subrenal capsule xenografts of human prostate cancer tissue in NOD-SCID mice can, as distinct from primary cancer tissue, be successfully grown in the orthotopic site. Orthotopic xenografts of the transplantable tumor lines and metastatic sublines can be used for studying various aspects of metastatic prostate cancer, including metastasis to bone.     

Search for intracranial aneurysm susceptibility gene(s) using Finnish families

Background

Cerebrovascular disease is the third leading cause of death in the United States, and about one-fourth of cerebrovascular deaths are attributed to ruptured intracranial aneurysms (IA). Epidemiological evidence suggests that IAs cluster in families, and are therefore probably genetic. Identification of individuals at risk for developing IAs by genetic tests will allow concentration of diagnostic imaging on high-risk individuals. We used model-free linkage analysis based on allele sharing with a two-stage design for a genome-wide scan to identify chromosomal regions that may harbor IA loci.

Methods

We previously estimated sibling relative risk in the Finnish population at between 9 and 16, and proceeded with a genome-wide scan for loci predisposing to IA. In 85 Finnish families with two or more affected members, 48 affected sibling pairs (ASPs) were available for our genetic study. Power calculations indicated that 48 ASPs were adequate to identify chromosomal regions likely to harbor predisposing genes and that a liberal stage I lod score threshold of 0.8 provided a reasonable balance between detection of false positive regions and failure to detect real loci with moderate effect.

Results

Seven chromosomal regions exceeded the stage I lod score threshold of 0.8 and five exceeded 1.0. The most significant region, on chromosome 19q, had a maximum multipoint lod score (MLS) of 2.6.

Conclusions

Our study provides evidence for the locations of genes predisposing to IA. Further studies are necessary to elucidate the genes and their role in the pathophysiology of IA, and to design genetic tests.     

Spotlight on avian coronaviruses

ABSTRACT

Coronaviruses (CoVs) mainly cause enteric and/or respiratory signs. Mammalian CoVs including COVID-19 (now officially named SARS-CoV-2) belong to either the Alphacoronavirus or Betacoronavirus genera. In birds, the majority of the known CoVs belong to the Gammacoronavirus genus, whilst a small number are classified as Deltacoronaviruses. Gammacoronaviruses continue to be reported in an increasing number of avian species, generally by detection of viral RNA. Apart from infectious bronchitis virus in chickens, the only avian species in which CoV has been definitively associated with disease are the turkey, pheasant and guinea fowl. Whilst there is strong evidence for recombination between gammacoronaviruses of different avian species, and between betacoronaviruses in different mammals, evidence of recombination between coronaviruses of different genera is lacking. Furthermore, the recombination of an alpha or betacoronavirus with a gammacoronavirus is extremely unlikely. For recombination to happen, the two viruses would need to be present in the same cell of the same animal at the same time, a highly unlikely scenario as they cannot replicate in the same host!