Prognosis factors of short and long-term survival in elderly hospitalized patients after percutaneous endoscopic gastrostomy

OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) is the procedure of choice to achieve long-term enteral nutrition. The risks and benefits of PEG in elderly hospitalized patients have been poorly documented. The objective of this study was to describe the outcome of elderly patients one-year after insertion of a PEG tube.PATIENTS AND METHODS: Hospital records of 73 patients who underwent PEG for enteral nutrition were reviewed retrospectively. Data on patient age and sex, preexisting medical conditions such as dementia or pressure sores, indication for PEG, concomitant infection, complications of PEG and death were obtained from the hospital charts.RESULTS: The main indication for PEG was anorexia (49%). Before insertion of the gastrostomy tube, 44% of the patients had pressure scores, 30% had concomitant infection, 45% had dementia. PEG complications were observed in 51 patients. The survival rate at 1, 6 and 12 months was 0.68 [95% confidence interval - CI 95%: 0.56-0.78], 0.48 [CI 95%: 0.36-0.59] and 0.37 [CI 95%: 0.26-0.48] respectively. The presence of an infectious disease or of pressure sores at the time of PEG tube insertion were independently associated with mortality. Median survival of patients with these two factors was 32 days [CI 95%: 11-98].CONCLUSION: According to these results, the PEG tubes should be inserted with a delay from infectious diseases and before the occurrence of pressure sores.     

Ramipril improves hemodynamic recovery but not microvascular response to ischemia in spontaneously hypertensive rats

BACKGROUND: Angiotensin converting enzyme (ACE) inhibition exerts positive effects on the microvasculature of normotensive animals, although this concept is not universally accepted. Recently, ACE inhibitors have been suggested to be useful for rescue in peripheral ischemia. METHODS: We investigated whether chronic treatment with the ACE inhibitor ramipril may have a positive impact on the defective healing response to ischemia that is typical of spontaneously hypertensive rats (SHR). Unilateral limb ischemia was induced in 20-week-old SHR by surgically removing the left femoral artery. Rats were allowed to regain consciousness and then were randomly allocated to treatment with ramipril (1 mg/kg body weight in drinking water) or vehicle for 28 days. RESULTS: The SHR failed to develop reparative angiogenesis in response to ischemia, thus having inadequate perfusion recovery. Ramipril reduced both tail-cuff systolic blood pressure (180 +/- 7 v 207 +/- 2 mm Hg in the vehicle group at 28 days, P < .05) and intra-arterial mean blood pressure (115 +/- 6 v 135 +/- 5 mm Hg in the vehicle group, P < .05). These effects were associated with increased responsiveness to endothelium-dependent vasodilatation by acetylcholine. Treatment with ramipril did not influence muscular capillary and arteriole density but accelerated the rate of perfusion recovery, leading to complete healing within 28 days after surgery. CONCLUSIONS: These results indicate that ACE inhibition by ramipril may be useful for the treatment of peripheral vascular complications in hypertension.     

Adiponutrin: A new gene regulated by energy balance in human adipose tissue

Adiponutrin is a newly identified nonsecreted adipocyte protein regulated by changes in energy balance in rodents. We documented the influence of energy balance modification on adiponutrin gene expression in humans. We investigated the mRNA expression in sc adipose tissue of nonobese women and in obese women during 2-d very low-calorie diet (VLCD) and subsequent refeeding as well as before and after a VLCD of 3 wk (21-d VLCD). The adiponutrin mRNA levels of the nonobese and obese women were not different (P > 0.05). Two-day VLCD reduced the average level of adiponutrin mRNA expression by 36% (P = 0.0016), whereas refeeding elevated the mRNA level by 31% (P = 0.004). The 3-wk VLCD caused a dramatic 58% fall of the adiponutrin mRNA expression level (P = 0.001). The mRNA level was negatively correlated with fasting glucose (Rho = -0.62; P < 0.0001), and subjects with high adiponutrin mRNA level had an increased insulin sensitivity. Compared with other adipocyte proteins such as leptin and adiponectin, adiponutrin mRNA did not show correlation with either adiposity indexes or with leptin or adiponectin mRNAs. These results indicate that adiponutrin gene expression in humans is highly regulated by changes in energy balance.     

Epidermal growth factor induces the functional expression of dopamine receptors in the GH3 cell line.

GH3 cells are a clonal strain from a rat pituitary tumor that synthesizes and secretes both PRL and GH. The peculiarity of these cells is that they do not express receptors for dopamine; thus the hormone release is insensitive to the inhibitory effect of dopamine and D2 receptor agonists. Exposure of GH3 cells to epidermal growth factor for 4 consecutive days markedly altered the cell morphology, from a spherical appearance to an elongated flattened shape, and increased the cell size. These morphological changes were accompanied by the functional expression of D2 dopamine receptors as shown by the presence of a specific, saturable, and stereoselective high affinity binding for [3H]spiroperidol in epidermal growth factor-treated cells and by the fact that the selective D2 agonist quinpirole recovered the property to inhibit PRL secretion in the cell cultures exposed to the neurotrophic factor. The effect of EGF on the functional expression of D2 receptors was dose dependent (EC50 = 8 pM) and reversible. These data suggest that EGF elicits major effects on the expression of specific genes leading to the differentiation of GH3 cells into lactotroph-like cells endowed with dopamine D2 receptors.     

Apoptosis of naive CD4+ T-cells from HIV-infected patients with poor immune response to HAART is enhanced in vitro by steroid

OBJECTIVE: Because the absence of immune restoration in HIV-infected patients efficiently treated by highly active antiretroviral therapy (HAART) may be due to excessive immune activation, we prospectively studied the effect of hydrocortisone on T-cell apoptosis in a cohort of patients with satisfactory virologic response. METHODS: Apoptosis of T-cell subsets including na?ve CD45RA(+)CD4+ T-cells was determined at baseline and at months 1 and 3 after initiation of HAART. A satisfactory immune response was defined as an increase >100/microL CD4+ T-cells at month 3 compared to baseline. RESULTS: Twenty out of 63 patients showed undetectable viral load at month 3, among whom eight exhibited a satisfactory immune response. Down-regulation spontaneous CD4+T-cell apoptosis was significant in the group of patients with a satisfactory immune response compared to the other patients. However, hydrocortisone up-regulated apoptosis of na?ve CD4+ CD45RA+ T-cells, specifically in group of patients with poor immune response, whatever the time point considered: percentage of apoptotic CD4 T-cells was 16+/-16% without hydrocortisone and 22+/-22% with hydrocortisone at month 1, and respectively, 10+/-9 and 17+/-15% at month 3 (P < 0.05) Hydrocortisone had no impact on CD8+ T-cell apoptosis, whatever the considered group. CONCLUSION: Our results suggest to not use steroid therapy as adjuvant immunotherapy in patients with less than optimal immunologic response to HAART.     

What is the meaning of colorectal transit time measurement?

This study was done to understand the different available methods used to calculate colorectal transit times. A single abdominal radiograph is taken following six successive daily ingestions of the same number of identical radiopaque markers. This method correlates well (P < 0.001) with that using a single ingestion of markers with daily x-ray films until total expulsion. In techniques used to measure colorectal transit time with multiple ingestion of markers, the number of days of ingestion depends on the kinetics of marker defecation. This was found to differ markedly in various groups of control subjects and constipated patients (P < 0.001) and can be used to obtain reliable data, even in subjects with severe constipation. When they ingest 20 markers, constipated patients are found to retain eight or more markers three days after ingestion, and taking a plain film of the abdomen on that day is sufficient to make a diagnosis of constipation. Transit time studies are reproducible from month to month in patients with an irritable bowel syndrome. Control subjects who claim that their bowel habits are not modified by stress have shorter transit times, similar in both sexes, than those who say they are (P <0.001). This may explain why a large percentage of constipated patients have been found by most authors to have normal colorectal transit times. The choice of control subjects is thus a key element in studies of functional bowel motor disorders. Stool frequency and consistency, in health, correlate only to rectosigmoid transit time.     

Investigating the effect of sotalol on the repolarization intervals in healthy young individuals

Background

The dissociation between a drug-induced increase of the QT interval prolongation and an increased risk for ventricular arrhythmias has been suggested by academic investigators and regulatory agencies. Yet, there are no alternative or complimentary electrocardiographic (ECG) techniques available for assessing the cardiotoxicity of novel compounds. In this study, we investigated a set of novel ECG parameters quantifying the morphology of the T-loop. In a group of healthy individuals exposed to sotalol, we compared their drug-induced changes to the drug-induced prolongations of the QTc, QTc apex and T-peak to T-end intervals.

Methods

We implemented a set of parameters describing the morphology of the T loop in its preferential plane. These parameters measure the time interval needed for the heart vector amplitude to change from its maximum value to a time when its amplitude has been reduced by 30%, 50%, and 70%. These measurements are called early repolarization duration (ERD) when they are located before the T-wave apex and late repolarization duration (LRD) when measured after the apex. They depend on both the speed of the repolarization process and the morphology of the T loop. Thirty-nine healthy individuals were exposed to sotalol in a crossover-design study. Sixteen ECGs were recorded per day during 3 days. The first day (day 0) was baseline; a single dose of sotalol (160 mg) was given during day 1, and a double dose was given during day 2 (320 mg). The plasma concentration of the drug was measured just before the ECG recordings.

Results

The values of all investigated parameters revealed a dose-dependent effect of sotalol (in average between parameters, ρ = 0.9, P < .001). Our investigations described profound and statistically significant changes in the morphology of the vectorial T loop for day 1 (peak effect of sotalol: ΔERD_50% = 23 ± 6 msec, P < .05; ΔLRD_50% = 8 ± 3 msec, P = .05) and day 2 (peak effect of sotalol: ΔERD_50% = 51 ± 14 msec, P < .05; ΔLRD_50% = 20 ± 12 msec, P = .05). When investigating the timing of peak drug concentration and peak effect of the drug on the various repolarization parameters, we found asynchrony between ERDs/LRDs (≥3.5 hours after dosing) and QTc/QTc apex profiles (<3.5 hours after dosing), suggesting that the time of maximum prolongation on the repolarization process was not synchronized with the time of maximum drug-induced heterogeneity of repolarization.

Conclusion

This study describes the sotalol-induced changes of the T-loop morphology in healthy individuals based on novel vectocardiographic parameters. These observations might help in improving the next generation of ECG markers for the evaluation of drug cardiotoxicity.     

Dissecting the interface between apicomplexan parasite and host cell: Insights from a divergent AMA–RON2 pair

Plasmodium falciparum and Toxoplasma gondii are widely studied parasites in phylum Apicomplexa and the etiological agents of severe human malaria and toxoplasmosis, respectively. These intracellular pathogens have evolved a sophisticated invasion strategy that relies on delivery of proteins into the host cell, where parasite-derived rhoptry neck protein 2 (RON2) family members localize to the host outer membrane and serve as ligands for apical membrane antigen (AMA) family surface proteins displayed on the parasite. Recently, we showed that T. gondii harbors a novel AMA designated as TgAMA4 that shows extreme sequence divergence from all characterized AMA family members. Here we show that sporozoite-expressed TgAMA4 clusters in a distinct phylogenetic clade with Plasmodium merozoite apical erythrocyte-binding ligand (MAEBL) proteins and forms a high-affinity, functional complex with its coevolved partner, TgRON2_L1. High-resolution crystal structures of TgAMA4 in the apo and TgRON2_L1-bound forms complemented with alanine scanning mutagenesis data reveal an unexpected architecture and assembly mechanism relative to previously characterized AMA–RON2 complexes. Principally, TgAMA4 lacks both a deep surface groove and a key surface loop that have been established to govern RON2 ligand binding selectivity in other AMAs. Our study reveals a previously underappreciated level of molecular diversity at the parasite–host-cell interface and offers intriguing insight into the adaptation strategies underlying sporozoite invasion. Moreover, our data offer the potential for improved design of neutralizing therapeutics targeting a broad range of AMA–RON2 pairs and apicomplexan invasive stages.Phylum Apicomplexa comprises >5,000 parasitic protozoan species, many of which cause devastating diseases on a global scale. Two of the most prevalent species are Toxoplasma gondii and Plasmodium falciparum, the causative agents of toxoplasmosis and severe human malaria, respectively (1, 2). The obligate intracellular apicomplexan parasites lead complex and diverse lifestyles that require invasion of many different cell types. Despite this diversity of target host cells, most apicomplexans maintain a generally conserved mechanism for active invasion (3). The parasite initially glides over the surface of a host cell and then reorients to place its apical end in close contact to the host-cell membrane. After this initial attachment, a circumferential ring of adhesion (termed the moving or tight junction) is formed, through which the parasite actively propels itself while concurrently depressing the host-cell membrane to create a nascent protective vacuole (4).Formation of the moving junction relies on a pair of highly conserved parasite proteins: rhoptry neck protein 2 (RON2) and apical membrane antigen 1 (AMA1). Initially, parasites discharge RON2 into the host cell membrane where an extracellular portion (domain 3; D3) serves as a ligand for AMA1 displayed on the parasite surface (5–8). Intriguingly, recent studies have shown that the AMA1–RON2 complex is an attractive target for therapeutic intervention (9–12). The importance of the AMA1–RON2 pairing is also reflected in the observation that many apicomplexan parasites encode functional paralogs that are generally expressed in a stage-specific manner (13–15). We recently showed that, in addition to AMA1 and RON2, T. gondii harbors three additional AMA paralogs and two additional RON2 paralogs (14, 15): TgAMA2 forms a functional invasion complex with TgRON2 (15), TgAMA3 (also annotated as SporoAMA1) selectively coordinates TgRON2_L2 (14), and TgAMA4 binds TgRON2_L1 (15). Despite substantial sequence divergence, structural characterization of all AMA–RON2D3 complexes solved to date [TgAMA1–TgRON2D3 (16), PfAMA1–PfRON2D3 (17), and TgAMA3–TgRON2_L2D3 (14)] reveal a largely conserved architecture and binding paradigm. Intriguingly, however, sequence analysis indicates that TgAMA4 and TgRON2_L1 are likely to adopt substantially divergent structures with an atypical assembly mechanism.To investigate the functional implications of the AMA4–RON2_L1 complex in T. gondii, we first established that TgAMA4 is part of a highly divergent AMA clade that includes the functionally important malaria vaccine candidate Plasmodium merozoite apical erythrocyte-binding ligand (MAEBL) (18–20) and that TgRON2_L1 displays a similar divergence consistent with coevolution of receptor and ligand. We then show that TgAMA4 and TgRON2_L1 form a high-affinity binary complex and probe its overall architecture and underlying mechanism of assembly using crystal structures of TgAMA4 in the apo and TgRON2_L1D3 bound forms. Finally, we show proof of principle that TgAMA4 and TgRON2_L1 form a functional pairing capable of supporting host-cell invasion. Collectively, our study reveals exceptional molecular diversity at the parasite–host-cell interface that we discuss in the context of the unique invasion barriers encountered by the sporozoite.