Polypharmacy Predicts Onset and Transition of Frailty, Malnutrition, and Adverse Outcomes in Peritoneal Dialysis Patient.

BACKGROUND: Polypharmacy, frailty and malnutrition are known predictors of adverse outcomes in dialysis patients. Little has reported about their interaction and composite prognostic values. We aimed to describe the interaction between polypharmacy, frailty, nutrition, hospitalization, and survival in peritoneal dialysis patients. METHODS: In this prospective cohort study, we recruited 573 peritoneal dialysis patients. Drug burden was measured by medication number and daily pill load. Frailty and nutrition were assessed by the validated Frailty Score (FQ) and Subjective Global Assessment (SGA) respectively. All patients were followed for two years. Primary outcome was all-cause mortality. Secondary outcomes were fall and fracture episodes, hospitalization, change in FQ and SGA. RESULTS: At baseline, each patient took 7.5 ± 2.6 medications with 15.5 ± 8.5 tablets per day. Medication number, but not daily pill load predicted baseline FQ (p = 0.004) and SGA (p = 0.03). Over 2 years, there were 69 fall and 1,606 hospitalization episodes. In addition, 148 (25.8%) patients died, while FQ and SGA changed by 0.73 ± 4.23 and -0.07 ± 1.06 respectively in survivors. Medication number (hospitalization: p = 0.02, survival: p = 0.005), FQ (hospitalization: p < 0.001; survival: p = 0.01) predicted hospitalization and survival. Medication number also predicted fall episodes (p = 0.02) and frailty progression (p = 0.002). Daily pill load did not predict any of these outcomes. CONCLUSIONS: Drug burden is high in peritoneal dialysis patients, and it carries important prognostic implication. Medication number but not pill load significantly predicted onset and progression of frailty, malnutrition, fall, hospitalization, and mortality.

Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism.

Immunostimulatory DNA sequences (ISS) contain unmethylated CpG dinucleotides within a defined motif. Immunization with ISS-based vaccines has been shown to induce high antigen-specific cytotoxic lymphocyte (CTL) activity and a Th1-biased immune response. We have developed a novel ISS-based vaccine composed of ovalbumin (OVA) chemically conjugated to ISS-oligodeoxynucleotide (ODN). Protein-ISS conjugate (PIC) is more potent in priming CTL activity and Th1-biased immunity than other ISS-based vaccines. Cytotoxic lymphocyte activation by ISS-ODN-based vaccines is preserved in both CD4-/- and MHC class II-/- gene-deficient animals. Furthermore, PIC provides protection against a lethal burden of OVA-expressing tumor cells in a CD8+ cell-dependent manner. These results demonstrate that PIC acts through two unique mechanisms: T-helper-independent activation of CTL and facilitation of exogenous antigen presentation on MHC class I. This technology may have clinical applications in cancer therapy and in stimulating host defense in AIDS and chronic immunosuppression.

Microalloying ultrafine grained Al alloys with enhanced ductility.

Bulk ultrafine grained (UFG)/nanocrystal metals possess exceptional strength but normally poor ductility and thermal stability, which hinder their practical applications especially in high-temperature environments. Through microalloying strategy that enables the control of grains and precipitations in nanostructured regime, here we design and successfully produce a highly microstructure-stable UFG Al-Cu-Sc alloy with ~275% increment in ductility and simultaneously ~50% enhancement in yield strength compared with its Sc-free counterpart. Although the precipitations in UFG alloys are usually preferentially occurred at grain boundaries even at room temperature, minor Sc addition into the UFG Al-Cu alloys is found to effectively stabilize the as-processed microstructure, strongly suppress the θ-Al2Cu phase precipitation at grain boundary, and remarkably promote the θ'-Al2Cu nanoparticles dispersed in the grain interior in artificial aging. A similar microalloying strategy is expected to be equally effective for other UFG heat-treatable alloys.

Relationship between changes of glomus cell current and neural response of rat carotid body.

1. Mature rat carotid bodies were harvested and sinus nerve activity was recorded in vitro during superfusion with Ringer saline. Membrane currents of glomus cells were simultaneously recorded using conventional whole cell or perforated-patch whole cell recording. Presumptive glomus cells were identified by the presence of a rapidly activated, voltage-dependent outward current above a threshold of -20 mV. 2. Outward current of presumptive glomus cells was inhibited by tetraethylammonium chloride (TEA) (20 mM) and by verapamil (5-10 microM), consistent with previous studies in which isolated glomus cells were used. Somal capacitance, calculated from the current transient following a step hyperpolarization, was 7.47 +/- 0.54 (SE) pF (n = 52). Membrane resistance for perforated-patch recordings was 820 +/- 187 M omega. 3. In perforated-patch recordings, brief periods of hypoxia (30-45 s) caused a marked increase in nerve activity to 21.6 +/- 2.7 times baseline spiking frequency (n = 59) but no significant change in membrane resistance or outward current. No change in holding current was detected, although the low amplifier gain precluded high-resolution measurement. Similar results were obtained using conventional whole cell recording, except that outward current significantly decreased during hypoxia but failed to recover in the immediate posthypoxia period. 4. TEA (20 mM) rapidly inhibited outward current to 55 +/- 7% (n = 15) of predrug current, but nerve activity only slightly increased to 2.0 +/- 0.3 times baseline spike frequency (n = 15). Brief anoxia (40 s in duration) in the presence of TEA evoked a brisk increase in nerve activity to 30 +/- 13 times baseline frequency (n = 3), demonstrating that organ function was not blocked by TEA. 5. Charybdotoxin (10 nM) significantly reduced outward current by 12.1 +/- 3.0% (n = 11) but did not significantly alter nerve activity, holding current, or membrane resistance. Apamin (100 nM) did not significantly affect nerve activity, membrane resistance, or holding current. Outward current decreased by 11.4 +/- 6.1% (n = 13). 6. These results show a dissociation between changes in glomus cell voltage-gated outward currents and changes in afferent nerve activity. This suggests that modulation of glomus cell K+ current by hypoxia is not the primary step in initiating the nerve response to hypoxia in the rat carotid body.

Immunostimulatory DNA is a potent mucosal adjuvant.

Most proteins delivered to mucosal surfaces fail to induce mucosal or systemic immune responses. We demonstrate that a single intranasal (i.n.) coadministration of a model antigen (beta-galactosidase, beta-gal) with immunostimulatory sequence oligodeoxynucleotide (ISS-ODN) induces a mucosal IgA response equivalent to that induced by i.n. codelivery of beta-gal with cholera toxin (CT). Furthermore, i.n. and intradermal (i.d.) delivery of the beta-gal/ISS-ODN mix stimulates equivalent Th1-biased systemic immune responses with high-level cytotoxic T lymphocyte (CTL) activity. In contrast, i.n. immunization with beta-gal and CT results in a Th2-biased systemic immune response with poor CTL activity. Our data show that i.n. delivery of ISS-ODN provides effective adjuvant activity for the induction of both mucosal and systemic Th1-biased immune responses. This immunization approach deserves consideration in the development of vaccines against mucosal pathogens.

Epstein-Barr virus in oropharyngeal and nasopharyngeal secretions of patients with nasopharyngeal carcinoma and control subjects.

The frequency of oropharyngeal excreters of the Epstein-Barr virus among patients with nasopharyngeal carcinoma in Hong Kong was compared with those of healthy adults in Hong Kong and California. 6 (3%) of 177 patients, 11 (12%) of 92 Hong Kong residents, and 20 (15%) of 132 Californians were excreters. The virus was detected in the nasopharyngeal secretion of only 1 of 67 patients and in 2 of 73 healthy adults. No convincing evidence for neutralizing antibody in the throat wash and nasopharyngeal secretions of the patients could be obtained. Epstein-Barr viral gene sequencing could not be detected in the throat washes from 27 patients with nasopharyngeal carcinoma, 8 patients with infectious mononucleosis, and 15 healthy adults and in the nasopharyngeal secretions of 35 patients and 17 controls. We conclude that patients with nasopharyngeal carcinoma are no more likely to be oropharyngeal or nasopharyngeal excreters of the Epstein-Barr virus than healthy adults. One possible explanation for this unexpected finding is that the virus infections in nasopharyngeal carcinoma cells are predominantly nonproductive.