The cell tropism of human immunodeficiency virus type 1 determines the kinetics of plasma viremia in SCID mice reconstituted with human peripheral blood leukocytes

Most individuals infected with human immunodeficiency virus type 1 (HIV-1) initially harbor macrophage-tropic, non-syncytium-inducing (M-tropic, NSI) viruses that may evolve into T-cell-tropic, syncytium-inducing viruses (T-tropic, SI) after several years. The reasons for the more efficient transmission of M-tropic, NSI viruses and the slow evolution ofT-tropic, SI viruses remain unclear, although they may be linked to expression of appropriate chemokine coreceptors for virus entry. We have examined plasma viral RNA levels and the extent of CD4+ T-cell depletion in SCID mice reconstituted with human peripheral blood leukocytes following infection with M-tropic, dual-tropic, or T-tropic HIV-1 isolates. The cell tropism was found to determine the course of viremia, with M-tropic viruses producing sustained high viral RNA levels and sparing some CD4+ T cells, dual-tropic viruses producing a transient and lower viral RNA spike and extremely rapid depletion of CD4+ T cells, and T-tropic viruses causing similarly lower viral RNA levels and rapid-intermediate rates of CD4+ T-cell depletion. A single amino acid change in the V3 region of gp120 was sufficient to cause one isolate to switch from M-tropic to dual-tropic and acquire the ability to rapidly deplete all CD4+ T cells.     

Protein density and its influence on metabolite concentration and nitrogen retention by Holstein cows in late gestation

Multiparous Holstein cows in late gestation were used in a completely randomized design to test the effects of prepartum protein supply on prepartum N balance, blood metabolite and hormone concentrations, and postpartum intake and milk production. Cows were assigned to one of three isocaloric diets that differed in amount of total dietary crude protein (CP) (10.6, 12.7, or 14.5% of dry matter) but not in CP degradability or solubility. All diets contained the following ingredients: corn silage, chopped grass hay, ground corn, soybean meal, expeller soybean meal, minerals, and vitamins. Following parturition, all cows were offered a similar diet. Nitrogen balance was measured on d 12 to 7 prior to the expected calving date. Cows were bled on d 5 prior to the expected calving date from just prior to feeding to 8 h postfeeding. As dietary CP increased, plasma glucose concentrations increased linearly, but no change was detected in plasma nonesterified fatty acids or serum insulin concentrations. Nitrogen intake, apparent and true digestibilities, fecal and urinary concentration of and N balance increased as the concentration of dietary protein increased. The efficiency of absorbed protein utilization decreased as protein intake increased. No change in postpartum intake or milk production was observed. An increase in N retention in late gestation cows that were in positive N balance did not increase postpartum milk production.     

Children's use of looking behavior as a cue to detect another's goal

Three studies examined children's understanding of the role that looking behavior plays in revealing another's desired goal. In each study, participants were asked which of 2 objects a protagonist wanted to obtain. Four-year-olds did not infer that an object examined via prolonged looking was more likely to be the protagonist's goal than an object that was either glanced at or inadvertently touched. Instead, they were accurate only when the protagonist looked at one of two potential goals. In contrast, the majority of 6-year-olds (and adults in Experiment 1) consistently regarded prolonged looking as the more important cue of the protagonist's goal. These age differences suggest that development is characterized by an increasing appreciation that goal is revealed by comparative differences in the quality of perceptual connectedness to objects in the world. One explanation for these age differences is that preschoolers are limited in their understanding of the difference between perceiving with full attention and without it.     

Captopril modifies gene expression in hypertrophied and failing hearts of aged spontaneously hypertensive rats

The spontaneously hypertensive rat (SHR) exhibits a transition from stable compensated left ventricular (LV) hypertrophy to heart failure (HF) at a mean age of 21 months that is characterized by a decrease in alpha-myosin heavy chain (alpha-MHC) gene expression and increases in the expression of the atrial natriuretic factor (ANF), pro-alpha1(III) collagen, and transforming growth factor beta1 (TGF-beta1) genes. We tested the hypotheses that angiotensin-converting enzyme inhibition (ACEI) in SHR would prevent and reverse HF-associated changes in gene expression when administered prior to and after the onset of HF, respectively. We also investigated the effect of ACEI on circulating and cardiac components of the renin-angiotensin system. ACEI (captopril 2 g/L in the drinking water) was initiated at 12, 18, and 21 months of age in SHR without HF and in SHR with HF. Results were compared with those of age-matched normotensive Wistar-Kyoto (WKY) rats, and to untreated SHR with and without evidence of HF. ACEI initiated prior to failure prevented the changes in alpha-MHC, ANF, pro-alpha1(III) collagen, and TGF-beta1 gene expression that are associated with the transition to HF. ACEI initiated after the onset of HF lowered levels of TGF-beta1 mRNA by 50% (P<.05) and elevated levels of alpha-MHC mRNA two- to threefold (P<.05). Circulating levels of renin and angiotensin I were elevated four- to sixfold by ACEI, but surprisingly, plasma levels of angiotensin II were not reduced. ACEI increased LV renin mRNA levels in WKY and SHR by two- to threefold but did not influence LV levels of angiotensinogen mRNA. The results suggest that the anti-HF benefits of ACEI in SHR may be mediated, at least in part, by effects on the expression of specific genes, including those encoding alpha-MHC, ANF, TGF-beta1, pro-alpha1(III) collagen, and renin-angiotensin system components.     

Kinematic analysis of shear displacement as a means for operating mechanotransduction channels in the contact region between adjacent stereocilia of mammalian cochlear hair cells

In sensory hair cells of the cochlea, deflection of the stereociliary bundle results in direct mechanical gating of mechanoelectrical transduction channels, a function generally attributed to the tip link running between the tips of short stereocilia and the sides of adjacent taller ones. However, immunocytochemical experiments indicate that the channels may not be associated with the tip link but occur just below it in a region of contact between the stereocilia. To determine whether transduction channels in this location could be operated during physiologically appropriate deflections as effectively by shear displacement as if they were associated with the tip link, a two dimensional kinematic analysis of relative motion between stereocilia has been performed assuming contact between stereocilia is maintained during deflection. Bundle geometry and dimensions were determined from transmission electron micrographs of hair cells from several frequency locations between 0.27 and 13.00 kHz in the guinea-pig cochlea. The analysis indicates that for a 10 nm deflection of the tallest stereocilia of both inner and outer hair cells, i.e. within the range of the maximum sensitivity of mammalian hair bundles, the average shear displacement in the contact region would be 1.6 nm, but that it increases systematically towards higher frequency regions for outer hair cells. This displacement is comparable in magnitude to tip-link elongation for individual stereociliary pairs.     

The surgical risk of pancreas transplantation in the cyclosporine era: an overview

BACKGROUND: Pancreas transplants are still associated with the highest surgical complication rate of all routinely performed solid organ transplants. To date, the impact of serious surgical complications in the cyclosporine era on perioperative patient morbidity, graft and patient survival, and hospital costs has not been analyzed in detail. STUDY DESIGN: We retrospectively studied surgical complications after 445 consecutive pancreas transplants (45% simultaneous pancreas-kidney [SPK], 24% pancreas after kidney [PAK], and 31% pancreas transplant alone [PTA]). Of these, 80% were primary transplants, 20% were retransplants. Cadaver donors were used in 92%, living related donors in 8%. To develop guidelines for their prevention and management, we studied the impact of significant surgical complications (intra-abdominal infections, vascular graft thrombosis, and anastomotic leak) requiring relaparotomy on graft and patient survival. RESULTS: Relaparotomy was required after 32% of all pancreas transplants (SPK: 36%, PAK: 25%, PTA: 16% [p = 0.04]). Perioperative mortality was 9%. Graft and patient survival rates were significantly lower for recipients with (versus without) relaparotomy. The most common procedures were drainage of intra-abdominal abscess with graft necrosectomy (50% of all relaparotomies) and transplant pancreatectomy (34%). The most common causes of relaparotomy were intra-abdominal infection, vascular graft thrombosis, and anastomotic leak. Intra-abdominal infection occurred in 20% (SPK: 18%, PAK: 24%, PTA: 20% [p = NS]). The rate was significantly higher for living related donor (42%) versus cadaver donor (18%) recipients and for those with enteric-drained (39%) versus bladder-drained (18%) transplants. Graft and patient survival rates were significantly lower for recipients with (versus without) intra-abdominal infection. Outcome was better after bacterial (versus fungal) infections. For SPK recipients, those not on dialysis before the transplant had significantly higher graft survival than those on dialysis. Vascular graft thrombosis occurred in 12% of all recipients. The rate was significantly higher for PAK (21%) than for PTA (10%) and SPK (9%) recipients. It was significantly lower for recipients of grafts with donor iliac Y-graft reconstruction (versus all other types of arterial reconstruction) and with right-sided (versus left-sided) graft placement. Of note, patient survival was not different for recipients with versus without vascular graft thrombosis. The incidence of anastomotic or duodenal stump leaks was 10%; of these recipients, 70% required relaparotomy. Patient and graft survival rates were no different for recipients with versus without leaks. CONCLUSIONS: Serious surgical complications occurred in 35% of pancreas recipients and had a significant impact on patient and graft survival. Based on multivariate risk factor analyses, we recommend the following: donors over 45 years and those dying of cerebrocardiovascular disease should not be used; recipients over 45 years and those with a history of cardiac disease should be considered for a kidney transplant alone (KTA); surgical technique for graft procurement, preparation, and implantation should be meticulous; right-sided implantation and arterial Y-graft reconstruction should be performed when possible, since they had the highest success rates; when complications require relaparotomy, the focus must switch from graft salvage to life preservation; and the threshold for pancreatectomy should be low. Diagnosis should be timely, and treatment and relaparotomy expeditious. These cornerstones of success should help decrease the risk of surgical complications and mortality after pancreas transplants.     

The complex pathology of trinucleotide repeats

The expansion of trinucleotide repeat sequences has now been shown to be the underlying cause of at least ten human disorders. Unifying features among these diseases include the unstable behavior of the triplet repeat during germline transmission when the length of the repeat exceeds a critical value. However, the trinucleotide repeat disorders can be divided into two distinct groups. Type I disorders involve the expansion of CAG repeats, which encode an expanded polyglutamine, inserted into the open-reading frame of a gene that is usually quite broadly expressed. Recently, mouse models for type I disorders have been developed and the basis of pathology is under study, both in these models and through biochemical and cell biological approaches. The type II disorders involve repeat expansions in noncoding regions of genes. The mechanisms by which these repeat expansions lead to pathology may be quite diverse.     

PROTEIN-PHYTATE INTERACTIONS IN SOYBEANS. II. MECHANISM OF PROTEIN-PHYTATE BINDING AS AFFECTED BY CALCIUM

Phytate and bovine serum albumin were used in a model system to investigate the mechanism of their binding. Ultrafiltration studies using response surface design showed the association of protein and phytic acid to be highly pH dependent. Under acid conditions, the protein formed an insoluble complex with phytic acid. At pH 3.0, a binding constant of 2.3 times 10⁵ was obtained and it was calculated that there are 78 binding sites of the total 93 basic amino acid residues potentially available. This low pH complex was not disrupted at high temperatures but the presence of calcium ions caused dissolution of the precipitate. Calcium produced different effects at higher pH (> 6). Soluble protein-calcium-phytic acid complexes were formed which were less stable to heat and dissociated above pH 10 at high ionic strength. Since this interaction occurred only in the presence of calcium, a salt linkage is implicated in which divalent cations simultaneously bind to the protein and phytic acid in the form of a soluble complex. It is proposed that either the addition of divalent cations at low pH or sequestering agents at high pH would best effect the removal of phytate from soy products by ultrafiltration.     

Vibrio mimicus infection associated with crayfish consumption, Spokane, Washington, 2010

We report a cluster of severe diarrheal disease caused by Vibrio mimicus infection among four persons who had consumed leftover crayfish the day after a private crayfish boil. Gastrointestinal illness caused by Vibrio mimicus has not been reported previously in Washington State. Three cases were laboratory confirmed by stool culture; using PCR, isolates were found to have ctx genes that encode cholera toxin (CT). Two of the cases were hospitalized under intensive care with a cholera-like illness. The illnesses were most likely caused by cross-contamination of cooked crayfish with uncooked crayfish; however, V. mimicus was not isolated nor were CT genes detected by PCR in leftover samples of frozen crayfish. Clinicians should be aware that V. mimicus can produce CT and that V. mimicus infection can cause severe illness.