Human immunodeficiency virus type 1 Tat protein induces an intracellular calcium increase in human monocytes that requires DHP receptors: involvement in TNF-alpha production

HIV-1 Tat protein, acting at the cell membrane, stimulates the production by human monocytes of TNF-α, a cytokine implicated in both HIV-1 replication and pathogenesis. Here, we analyze, in primary human monocytes, the mechanisms involved in Tat-stimulated calcium mobilization and its relationship with TNF-α production. We show that the Tat protein induces a calcium signal by mobilizing calcium from extracellular stores. This calcium signal is totally blocked when cells are stimulated in the presence of DHP receptor inhibitors such as nimodipine or calcicludine, thus suggesting the implication of this L-type calcium channel. By using RT-PCR amplification, Western blot with antibodies directed against the α1D subunit, binding assays with specific agonists or antagonists, and inhibition with specific antisense oligonucleotides, we show that DHP receptors are expressed and functional in primary human monocytes. Interestingly, we demonstrate that Tat-induced calcium mobilization is tightly linked to TNF-α production, thus indicating that Tat-induced mobilization and TNF-α production are entirely mediated by DHP receptors, as shown by their total inhibition by nimodipine, calcicludine, or anti-α1D antisense oligonucleotides.     

Effect of volume of porogens on the porosity of PLGA scaffolds in pH-controlled environment

Poly(lactic-co-glycolic acid) (PLGA) is a well-studied biodegradable polymer used in drug delivery and other medical applications such as in tissue regeneration. It is often necessary to impart porosity within the scaffold (microparticles) in order to promote the growth of tissue during the regeneration process. Sodium chloride and ammonium bicarbonate have been extensively used as porogens in the generation of porous microstructure. In this study, we compared the effect of volumes (250?μl, 500?μl and 750?μl) of two porogens, sodium chloride (1.71 M) and ammonium bicarbonate (1.71 M), on the porosity of PLGA microparticles.     

Longitudinal Commercial Claims–Based Cost Analysis of Diabetic Retinopathy Screening Patterns

Background

Diabetic retinopathy is one of the most common complications of diabetes. The screening of patients with diabetes to detect retinopathy is recommended by several professional guidelines but is an underutilized service.

Objective

To analyze the relationship between the frequency of retinopathy screening and the cost of care in adult patients with diabetes.

Methods

Truven Health MarketScan commercial databases (2000–2013) were used to identify the diabetic population aged 18 to 64 years for the performance of a 2001–2013 annual trend analysis of patients with type 1 and type 2 diabetes and a 10-year longitudinal analysis of patients with newly diagnosed type 2 diabetes. In the trend analysis, the prevalence of diabetes, screening rate, and allowed cost per member per month (PMPM) were calculated. In the longitudinal analysis, data from 4 index years (2001–2004) of patients newly diagnosed with type 2 diabetes were combined, and the costs were adjusted to be comparable to the 2004 index year cohort, using the annual diabetes population cost trends calculated in the trend analysis. The longitudinal population was segmented into the number of years of diabetic retinopathy screening (ie, 0, 1–4, 5–7, and 8–10), and the relationship between the years of screening and the PMPM allowed costs was analyzed. The difference in mean incremental cost between years 1 and 10 in each of the 4 cohorts was compared after adjusting for explanatory variables.

Results

In the trend analysis, between 2001 and 2013, the prevalence of diabetes increased from 3.93% to 5.08%, retinal screening increased from 26.27% to 29.58%, and the average total unadjusted allowed cost of care for each patient with diabetes increased from $822 to $1395 PMPM. In the longitudinal analysis, the difference between the screening cohorts’ mean incremental cost increase was $185 between the 0- and 1–4–year cohorts (P <.003) and $202 between the 0- and 5–7–year cohorts (P <.023). The cost differences between the other cohorts, including $217 between the 0- and 8–10–year cohorts (P <.066), were not statistically significant.

Conclusions

Based on our analysis, the annual retinopathy screening rate for patients with diabetes has remained low since 2001, and has been well below the guideline-recommended screening levels. For patients with type 2 diabetes, the mean increase in healthcare expenditures over a 10-year period after diagnosis is not statistically different among those with various retinopathy screening rates, although the increase in healthcare spending is lower for patients with diabetes who were not screened for retinopathy compared with patients who did get screened.     

Venetoclax and hypomethylating agents in FLT3-mutated acute myeloid leukemia

FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent in acute myeloid leukemia (AML), and their presence confers adverse risk. FLT3-mutated (FLT3m) AML is a challenging leukemia to manage, particularly in older and unfit patients as well as patients with relapsed/refractory (r/r) disease. We retrospectively analyzed the outcomes of 50 FLT3m AML patients (17 treatment-naïve, 33 r/r) treated with venetoclax (VEN) and hypomethylating agents (HMA). The overall CR/CRi rate with VEN-HMA was 60% (94% in treatment-naïve AML and 42% in r/r AML). Early (60-days) treatment related mortality was 2%. The r/r AML setting was an independent predictor of lower complete response (OR: 0.08; 95%CI: 0.00-0.60, P = .03). Cytogenetics-molecular risk, concurrent mutations, the type of FLT3 mutation (ITD vs TKD), the ITD allelic ratio, the type of HMA, age, prior exposure to HMA and receipt of prior allogeneic transplant did not independently impact response or leukemia-free survival (LFS). Concurrent IDH mutations were associated with lower CR/CRi (P = .01), while ASXL1 or TET2 mutations showed a non-significant association toward higher CR/CRi (P = .07, for both). However, none of the concurrent mutations were an independent predictor for response when adjusted to AML setting. In conclusion, VEN-HMA is associated with encouraging efficacy in FLT3m AML among both newly diagnosed unfit and r/r patients.     

Modulation of the in vivo effects of gabapentin by vigabatrin and SKF89976A

Gabapentin (GBP) has been shown to reduce paired-pulse inhibition in the dentate gyrus of the urethane-anesthetized rat, which is a proconvulsant effect, and to shorten the afterdischarge duration, which is an antiepileptic effect. The mechanism by which GBP exerts these effects is not known, but a number of possibilities have been proposed. Here we tested the ability of vigabatrin (VGB), a GABA transaminase inhibitor, and SKF89976A, a selective GAT-1 blocker, to alter the effectiveness of GBP in the dentate gyrus in urethane-anesthetized adult Sprague-Dawley rats. VGB, alone at 100 mg/kg, had no effect on the evoked potentials or paired-pulse inhibition in the dentate gyrus, but did block lengthening of the afterdischarge. Pretreatment with VGB had no effect on the ability of GBP to reduce paired-pulse inhibition, but blocked the effect of GBP on seizure duration. SKF89976A, alone at 10 mg/kg, increased paired-pulse inhibition and blocked the lengthening of the afterdischarge in the seizure model. Pretreatment with SKF89976A had no effect on the actions of GBP on either paired-pulse inhibition or seizure duration. These results suggest that the action of GBP is not mediated through an inhibition of the GAT-1 transporter and probably not through an increase in basal levels of GABA. The data also suggest that the combination of VGB and GBP may be clinically less effective than the use of GBP alone.     

Modern unicompartmental knee arthroplasty with cement: a three to ten-year follow-up study

BACKGROUND: Unicompartmental arthroplasty is a treatment alternative when only one compartment of the knee is affected with arthritis, but the reported results of this procedure have been variable. The purpose of the present study was to evaluate the results of a modern unicompartmental knee arthroplasty performed with use of a cemented metal-backed prosthesis and surgical instrumentation comparable with that used for total knee replacement. METHODS: The indications for the procedure were osteonecrosis or osteoarthritis associated with full-thickness loss of cartilage that was limited to one tibiofemoral compartment as evaluated on standing and stress radiographs. One hundred and sixty consecutive cemented metal-backed Miller-Galante prostheses in 147 patients were evaluated after a mean duration of follow-up of sixty-six months (range, thirty-six to 112 months). The mean age of the patients at the time of the index procedure was sixty-six years. RESULTS: Three knees were revised because of progression of osteoarthritis in the patellofemoral joint (two knees) or the lateral tibiofemoral compartment (one knee). Two knees had revision of the polyethylene liner. The average Hospital for Special Surgery knee score improved from 59 points preoperatively to 96 points at the time of the review. According to Kaplan-Meier analysis, the ten-year survival rate (with twenty-nine knees at risk) was 94% +/- 3% with revision for any reason or radiographic loosening as the end point. CONCLUSIONS: A modern unicompartmental knee arthroplasty is a valid alternative for patients with unicompartmental tibiofemoral noninflammatory disease. The patient selection must be strict with regard to the status of the patellofemoral joint. The preoperative planning includes stress radiographs to assess the correction of the deformity and the status of the uninvolved compartment. Continued long-term follow-up is necessary to evaluate long-term polyethylene wear.     

Sexual fantasies and impotence. Apropos of 2 cases

Sexual fantasies, drawn of the erotic memory that constitutes himself the long of the sexual history of each, are indispensable, for the good sexual working. Some authors tend to consider the imagination like a "veritable intra psychic erogenous zone". However, people who, for a reason or an another, persisted to avoid all sexual activity before the marriage and to separate all erotic velleity, don't they risk to have an erotic imaginary atrophied, who could sound negatively once on their sexual behaviour, after the marriage, when all is suddenly authorized for them? Through two clinical observations of secondary sexual impotence, we are going to try to show the ominous consequences of such a relentlessness (imposed by the education, the social morals or the religion), against sexual stimulation, on the sexuality. These consequences are more easily observable in men, of the fact of their active role, in the sexual activity. Our purpose is to insist on the necessity to explore the sexual history owing all sexual dysfunction, and to place it in the biographic setting of the impatient; but also and especially to attract the attention on the importance of a precocious sex education, adapted to age, to the personal maturation and the cultural and educational context.