Herpesvirus-encoded GPCRs rewire cellular signaling

Viral G-protein-coupled receptors (vGPCRs) are chemokine receptor homologues encoded by the Herpes- and Capripoxviridae. They are thought to have been hijacked from the host genome during the course of evolution. These vGPCRs play different roles in the viral lifecycle and associated pathologies. Three members of the Herpesviridae, Kaposi sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) are capable of setting up persistent latent infections in humans. Two of the herpesviruses, KSHV and EBV, are associated with cancer, while HCMV may have an oncomodulary effect.     

The relationship between CR3 deficiency and neutrophil actin assembly

Polymorphonuclear leukocytes (PMN) with a deficiency of the complement receptor type 3 (CR3) membrane glycoprotein family have impairments in the ability to adhere to surfaces as well as chemotactic and phagocytic defects, processes that require a functional contractile apparatus. PMN from the patient with neutrophil actin dysfunction (NAD) displayed similar functional characteristics to those with CR3 deficiency suggesting the two disorders may be the same disease. In order to evaluate the relationship between CR3 deficiency and actin assembly, actin filament assembly was measured in PMN from six previously reported homozygotes (two severe and four moderate CR3-deficient patients) as well as five heterozygotes for CR3 deficiency. PMN from all patients had normal unstimulated concentrations of F-actin and after exposure to the chemotactic peptide FMLP (5 x 10(-7) mol/L for 5 to 40 seconds at 25 degrees C) assembled actin normally. Pretreatment of normal PMN with concentrations of monoclonal anti-alpha CR3 antibody, capable of blocking PMN adherence, also failed to impair FMLP- induced actin filament assembly. CR3 glycoprotein expression was measured in PMNs from the mother, father, and older sister of the NAD patient (N Engl J Med 291:1093, 1974). Actin filament assembly was recently shown to be defective in PMNs from all three family members. The total concentrations of the alpha and beta CR3 subunits were below normal in PMN detergent extracts from the mother (25% of simultaneous controls) and older sister (56% of control). PMN surface expression of these two subunits was also found to be depressed (mother, 50%; older sister, 63% of control). These findings suggest these two NAD family members are heterozygote carriers for CR3 deficiency as well as NAD. Simultaneous studies of the father, however, demonstrated normal total concentrations of both the alpha and beta CR3 subunits (126% of controls) as well as normal surface expression of both subunits after phorbol myristate acetate stimulation and incubation at 37 degrees C (mean, 112% of controls) but slightly lower than normal levels after FMLP stimulation (mean, 83%). These findings indicate that CR3 deficiency generally is not associated with defective actin filament assembly and support the conclusion that NAD represents a unique kindred in which PMN actin function differs from previously reported genotypes of CR3 deficiency.     

Four categories of gamma-globin gene triplications: DNA sequence comparison of low G gamma and high G gamma triplications

The human fetal gamma chains are produced by closely linked G gamma and A gamma genes, and unequal crossing over between them leads to gamma gene deletions and triplications. Nine gamma gene triplications from seven ethnic groups were analyzed for G gamma and hemoglobin F (Hb F) values of heterozygotes and for the presence of polymorphic XmnI restriction sites 5' to the gamma genes. Four categories of triplication were found: I had low G gamma and low Hb F values and lacked XmnI sites 5' to the three gamma genes [---]. II had high G gamma and slightly elevated Hb F values but was also [---]. III was similar to II, except that XmnI was [+--]. IV had very high G gamma and slightly elevated Hb F values, and XmnI was [++-]. One case each of triplications I and IV were cloned into Charon 35. For both, the two 5' gamma gene code for G gamma chain, while the 3' gamma gene codes for A gamma chain. DNA sequencing showed that the unequal crossover occurred between 472 and 398 base pairs (bp) 5' to the gamma gene Cap sites (- 472 and -398) for the type IV triplication and between -271 and codon 136 for the type I triplication. In addition, type I had a 4-bp deletion of AGCA from -225 to -222. The high G gamma values of the type IV triplication are explained by its -G gamma-G gamma-A gamma-gene arrangement and the XmnI sites 5' to the G gamma genes. We hypothesize that the low G gamma value of the type I triplication, which is also -G gamma-G gamma-A gamma-, is due to inactivation of the middle G gamma gene by the AGCA deletion at -225 to -222.     

A classification tree for predicting recurrent falling in community-dwelling older persons

OBJECTIVES: To develop a classification tree for predicting the risk of recurrent falling in community-dwelling older persons using tree-structured survival analysis (TSSA). DESIGN: A prospective cohort study. SETTING: A community in the Netherlands. PARTICIPANTS: One thousand three hundred sixty-five community-dwelling older persons (>/=65) from the Longitudinal Aging Study Amsterdam (LASA). MEASUREMENTS: In 1995, physical, cognitive, emotional, and social aspects of functioning were assessed. Subsequently, a prospective fall follow-up, specifically on recurrent falls (two falls within 6 months) was conducted for 3 years. RESULTS: The classification tree included 11 end groups differing in risk of recurrent falling based on a minimum of two and a maximum of six predictors. The first split in the tree involved two or more falls versus fewer than two falls in the year preceding the interview. Respondents with two or more falls in the year preceding the interview (n=193) and with at least two functional limitations (n=98) had a 75% risk of becoming a recurrent faller, whereas respondents with fewer than two functional limitations were further divided into a group with regular dizziness (n=11, risk of 68%) and a group with no regular dizziness (n=84, risk of 30%). In respondents with fewer than two falls in the year preceding the interview (n=1,172), the risk of becoming a recurrent faller varied between 9% and 70%. Predictors in this branch of the tree were low performance, low handgrip strength, alcohol use, pain, high level of education, and high level of physical activity. CONCLUSION: This classification tree included 11 end groups differing in the risk of recurrent falling based on specific combinations of a maximum of six easily measurable predictors. The classification tree can identify subjects who are eligible for preventive measures in public health strategies.     

Ballooning Your Way in Altered Anatomy ERCP: Ready for Deductive Learning

Digestive Diseases and Sciences -