Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants

Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section. Infants received no drug or a single dose of TDF at 4 mg/kg of body weight or of TDF at 4 mg/kg plus FTC at 3 mg/kg as soon as possible after birth. All regimens were safe and well tolerated. Maternal areas under the serum concentration-time curve (AUC) and concentrations at the end of sampling after 24 h (C(24)) were similar between the two doses of TDF; the maximum concentrations of the drugs in serum (C(max)) and cord blood concentrations were higher in women delivering via cesarean section than in those who delivered vaginally (P = 0.04 and 0.046, respectively). The median ratio of the TFV concentration in cord blood to that in the maternal plasma at delivery was 0.73 (range, 0.26 to 1.95). Without TDF administration, infants had a median TFV concentration of 12 ng/ml 12 h after birth. Following administration of a single dose of TDF at 4 mg/kg, infant TFV concentrations fell below the targeted level, 50 ng/ml, by 24 h postdose. In HIV-infected pregnant women and their infants, 600 mg of TDF is acceptable as a single dose during labor. Low concentrations at birth support infant dosing as soon after birth as possible. Rapidly decreasing TFV levels in infants suggest that multiple or higher doses of TDF will be necessary to maintain concentrations that are effective for viral suppression.     

Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients

Loss of CD4+ T cells, the hallmark of HIV pathogenesis, was suggested to be partly due to apoptosis. We recently reported that IFN-alpha produced by HIV-1-activated plasmacytoid dendritic cells (pDCs) contributes to CD4+ T cell apoptosis by the TNF-related apoptosis-inducing ligand (TRAIL)/death receptor (DR)5 pathway. Here, we show that HIV-1-induced intracellular expression of IFN-alpha in pDCs is coupled to increased expression of IFN regulatory factor 7 and MyD88 by pDCs in vivo and in vitro. Expression of IFN-alpha was increased in lymphoid tonsillar tissue (LT) of patients with progressive (HIV(prog)) compared with nonprogressive (HIV(NP)) HIV-1 disease and to uninfected controls. LT from HIV(prog) exhibited higher TRAIL and DR5 mRNA levels than LT from HIV(NP) or controls. TRAIL mRNA levels in LT correlated with plasma viral load. We show that HIV-1 induces IFN-alpha and the TRAIL/DR5 apoptotic pathway in LT, suggesting a role for these cytokines in HIV-1 immunopathogenesis.     

Inactivation of p16 INK4a /CDKN2A gene may be a diagnostic feature of large B cell lymphoma leg type among cutaneous B cell lymphomas

The World Health Organization-European Organization for Research and Treatment of Cancer has individualized three main categories among the primary cutaneous B cell lymphoma (PCBCL): leg-type primary cutaneous large B cell lymphoma (PCLBCL leg type), primary cutaneous follicle center lymphoma (PCFCL), and primary cutaneous marginal zone lymphoma (PCMZL). The genetic features of 21 PCBCL cases (six PCLBCL leg type four PCFCL large cells, seven PCFCL small cells, and four PCMZL) were investigated by comparative genomic hybridization (CGH array). Fluorescent in situ hybridization (FISH) analysis was performed to confirm CGH array data and to detect lymphoma-associated gene rearrangements. p14 ( ARF )/p16 ( INK4a ) CDKN2A gene quantification, methylation analysis, and immunohistochemical detection were also performed. CGH array showed a higher number of recurrent genetic imbalances in PCLBCL leg type (mean 62) than in PCFCL large cells (mean 34). PCFCL small cells and PCMZL exhibited fewer chromosomal alterations (mean 24 and 9). FISH analysis provided concordant results with CGH array data in 97% (98 of 101) assays and demonstrated a t(8;14)(q24;q32) in two of six PCLBCL leg type. Recurrent deletions in 9p21 (p14 ( ARF )/p16 ( INK4a ) CDKN2A) were a constant finding in PCLBCL leg type (six of six). Conversely, PCFCL large cells exhibited recurrent 1p36 deletions (four of four) without deletion in 9p21 (zero of four). The diagnostic and prognostic impact of the p16 ( INK4a ) CDKN2A gene status in PCBCL should therefore be confirmed on a larger series.     

Night-time and diastolic hypertension are common and underestimated conditions in newly diagnosed apnoeic patients

BACKGROUND: In newly diagnosed apnoeic patients without a history of hypertension, clinical hypertension is underdiagnosed in at least 40% of the cases. An increase in diastolic blood pressure is the most frequent pattern encountered. OBJECTIVE: To assess clinic and 24-h blood pressure, baroreflex sensitivity and left ventricular mass for identifying the prevalence, the type and the consequences of hypertension in newly diagnosed apnoeic patients. PATIENTS AND METHODS: Fifty-nine unselected patients (age = 48 +/- 12 years, body mass index = 28.1 +/- 4.5 kg/m2) referred to a university hospital sleep laboratory for symptoms suggesting obstructive sleep apnoea were included. Diagnosis of apnoea was accepted when respiratory disturbance index was > or = 15/h of sleep. Blood pressure was considered as normal by their general practitioner and all of them were free of any medication for hypertension. Echocardiography, 24-hour ambulatory blood pressure monitoring and assessment of the baroreflex sensitivity were performed. RESULTS: Forty-two percent of the apnoeic patients demonstrated a clinical hypertension, 34 subjects (58%) had a daytime hypertension, and 45 patients (76%) had a night-time hypertension, using 24-h monitoring. All the daytime hypertensives also had night-time hypertension. Forty-seven of the 59 patients (80%) were hypertensive either in the clinic or using 24-h recording. Diastolic and systolo-diastolic hypertension were the prominent types of hypertension observed both by clinic or ambulatory measurements. Respiratory disturbance index was significantly higher in apnoeic patients suffering isolated diastolic hypertension than in the normotensives (50.9 +/- 26.5/h versus 36.0 +/- 12.3/h, respectively; P = 0.02). The prevalence rate of left ventricular hypertrophy was high (between 15 and 20%) and occurred independently of associated hypertension. Baroreflex sensitivity was altered whatever the type of hypertension and decreased with the severity of obstructive sleep apnoea. CONCLUSION: Hypertension is hugely underdiagnosed in apnoeic patients unknown to be hypertensive. Use of 24-h blood pressure monitoring allowed the diagnosis of twice as much hypertension than did clinical measurement. Even at the beginning of their history of hypertension, apnoeic patients exhibited chronic adaptations of their cardiovascular system, as shown by early changes in baroreflex sensitivity and an increased prevalence of left ventricular hypertrophy.     

Patients aged 90 years or older in the intensive care unit

BACKGROUND: Age is an important prognostic factor in patients admitted to intensive care units (ICUs), but it is not as important as illness severity. However, age seems to remain an important independent triage criterion for ICU admission, and 90 years of age seems to represent a psychological barrier for many ICU physicians. The aim of this preliminary study is to compare the management and outcome of patients aged 90 years or older admitted to a respiratory ICU with those of patients aged 70 years or younger. METHODS: In our matched case-control study over a 6-year period, 36 patients aged 90 years or older (case patients) were selected and matched according to sex with 72 controls chosen in the 20- to 69-year age range. The Simplified Acute Physiology Score (SAPS) II was then computed without using age as a variable. RESULTS: Pre-existing comorbidities were significantly less frequent in cases than in controls (5.1% vs 30.5%, p <.01). Compared to controls, cases were more frequently admitted for cardiac failure (22% vs 7%, p <.05) and less frequently for neurological diseases (0% vs 11%, p <.05). The use of advanced life-support measures in the ICU such as mechanical ventilation, central venous or arterial catheterization, and vasoactive and/or inotropic drugs was not significantly different between case patients and controls. This was also the case for ICU mortality and for the mean duration of ICU and hospital stay. Although there was a trend toward a higher hospital mortality among case patients than among controls, it did not reach statistical significance (47% vs 27%, p =.07). CONCLUSION: Our results reinforce the idea that age alone is not a relevant criterion for ICU admission.     

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.     

Feasibility of outpatient coronary angiography with "ad hoc" angioplasty

To assess the feasibility and safety of coronary angiography combined, where necessary, with ad hoc angioplasty in an outpatient setting; a prospective, single-center study. The first 172 patients (154 men, 59 +/- 11 years) considered at low risk for complications were enrolled for outpatient-coronary angiography with or without angioplasty via a radial approach. The inclusion criteria were clinical, not based on angiography. After angiography/angioplasty, creatinine and troponin were assayed (outside the hospital) within 24h and patients were telephoned and asked about their clinical condition. Angioplasty was performed in 69 (40%) patients and 130 patients (75.6%) were discharged on the same day. In the angioplasty group, a history of coronary dilatation was more common in patients discharged on the same day (p = 0.05), whereas bifurcation lesions were more frequent in subjects who were kept in hospital (p < 0.0001). No serious complications occurred during the study. Of the 42/172 prolonged hospitalizations, eight were due to minor procedural complications, five due to failure of the radial route and three for indications for bypass surgery; the others were kept in for reasons unrelated to a complication (e.g., the examination was performed late in the day, a particularly complex procedure, etc.). Four (3%) of the 24-hour telephone calls led to a visit, but not hospital admission. Overall, performing angiography and "ad hoc" angioplasty in the course of a single outpatient visit makes it possible to foreshorten the hospital stay and increase patient throughput with a given hospital capacity and, this, without increasing clinical risk. Exactly how these patients are selected remains to be defined and may certainly be improved compared to this initial experiment. An outpatient-coronary angiography and ad hoc angioplasty strategy is a viable option with a low risk for patients selected on the basis of simple clinical criteria. It combines the advantages of increased convenience for the patient and lower costs.     

Expiratory-Synchronized Sleep in a Quadriplegic Patient Using Inspiratory Neck Muscles To Breathe

In a patient with C3 quadriplegia causing complete diaphragm paralysis who developed inspiratory neck muscles (INM) hypertrophy to sustain ventilation, spontaneous breathing deeply altered sleep architecture, relegating sleep to the expiratory phase of the ventilatory cycle. A polysomnographic recording performed during mechanical ventilation (without INM activity), showed that sleep was abnormal but unaffected by the respiratory cycle. During spontaneous breathing, the polygraphic recordings showed expiratory microsleep episodes, with inspiratory arousals synchronous to bursts of INM activity. This case report illustrates the powerful adaptability of the respiratory and sleep control systems to maintain each vital function.     

Effects of mild chronic cerebral hypoperfusion and early amyloid pathology on spatial learning and the cellular innate immune response in mice

Understanding the contribution of cerebrovascular factors in the progression of cognitive decline in Alzheimer's disease (AD) is a key step for the development of preventive therapies. Among these factors, chronic cerebral hypoperfusion is an early component of AD pathogenesis that can predict the progression from mild cognitive impairment to AD. Here, we investigated the effects of a protocol of mild chronic cerebral hypoperfusion in the APPswe/PS1 transgenic mouse model of AD. We observed that the permanent occlusion of the right common carotid artery induced spatial learning impairments in young APPswe/PS1 mice, but not in their wild type littermates. Furthermore, the extent of learning deficits strongly correlated with the number of cortical β-amyloid plaques, with the mobilization of monocytes into the blood and with the number of bone marrow-derived microglia in the brain. These results indicate that a mild reduction of cerebral blood flow can selectively induce cognitive deficits at an early stage of amyloid pathology, eliciting a cellular innate immune response, even without causing neuronal death.