Detection of SARS-CoV-2 in aerosols in long term care facilities and other indoor spaces with known COVID-19 outbreaks.

Coronavirus outbreaks are likely to occur in crowded and congregate indoor spaces, and their effects are most severe in vulnerable long term care facilities (LTCFs) residents. Public health officers benefit from tools that allow them to control COVID-19 outbreaks in vulnerable settings such as LTCFs, but which could be translated in the future to control other known and future virus outbreaks. This study aims to develop and test a methodology based on detection of SARS-CoV-2 in aerosol samples collected with personal pumps that could be easily implemented by public health officers. The proposed methodology was used to investigate the levels of SARS-CoV-2 in aerosol in indoor settings, mainly focusing on LTCFs, suffering COVID-19 outbreaks, or in the presence of known COVID-19 cases, and targeting the initial days after diagnosis. Aerosol samples (N = 18) were collected between November 2020 and March 2022 in Castelló (Spain) from LTCFs, merchant ships and a private home with recently infected COVID-19 cases. Sampling was performed for 24-h, onto 47 mm polytetrafluoroethylene (PTFE) and quartz filters, connected to personal pumps at 2 and 4 L/min respectively. RNA from filters was extracted and SARS-CoV-2 was determined by detection of regions N1 and N2 of the nucleocapsid gene alongside the E gene using RT-PCR technique. SARS-CoV-2 genetic material was detected in 87.5% samples. Concentrations ranged ND-19,525 gc/m3 (gene E). No genetic traces were detected in rooms from contacts that were isolated as a preventative measure. Very high levels were also measured at locations with poor ventilation. Aerosol measurement conducted with the proposed methodology provided useful information to public health officers and contributed to manage and control 12 different COVID-19 outbreaks. SARS-CoV-2 was detected in aerosol samples collected during outbreaks in congregate spaces. Indoor aerosol sampling is a useful tool in the early detection and management of COVID-19 outbreaks and supports epidemiological investigations.

Clinical factors predictive for histological aggressiveness of basal cell carcinoma: A prospective study of 2274 cases.

INTRODUCTION: Since surgery is the first-line treatment for basal cell carcinomas (BCC), the histological aggressiveness of the disease must be clinically predicted in order to apply optimal safety margins that ensure a high rate of complete resection while minimising the risk of recurrence. OBJECTIVES: To evaluate clinical predictive factors of histological aggressiveness of BCC, we conducted a national prospective multi-centre study. METHODS: All consecutive patients presenting for BCC surgery were included, and standardised clinical data collected, and slides were submitted for review. Trabecular, micronodular and morpheaform BCCs were classified as aggressive. RESULTS: Of the 2710 cases included, 2274 were histologically confirmed. Clinical subtyping was correct in 49.9% of superficial BCCs, 86.2% of nodular BCCs and only 22% of aggressive BCCs. By multivariate analysis, aggressive BCCs were more frequently ulcerated (45%), indurated (70%), showed adherence (8.6%), and were associated with high-risk anatomical zones (50.3%, P<0.0001). These predictive clinical features may be helpful for decision making.

Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients.

Background: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods: In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRß sequencing. Results: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-ß and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1ß concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients.

BACKGROUND: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves. RESULTS: Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P =  0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P =  0.013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P =  0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P =  0.001) and NSCLC (P =  0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression. CONCLUSIONS: Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.

Utility of neurological smears for intrasurgical brain cancer diagnostics and tumour cell percentage by DESI-MS.

Analysis of neurological smears by desorption electrospray ionization mass spectrometry (DESI-MS) is an emerging diagnostic strategy for intraoperative consultation in brain tumor resection. DESI-MS allows rapid sampling while providing accurate diagnostic information. We assess the chemical homogeneity of neurological smears using DESI-MS imaging and the quality of rapid DESI-MS diagnosis.

[Emergency transcranial doppler ultrasound: predictive value for the development of symptomatic vasospasm in spontaneous subarachnoid hemorrhage in patients in good neurological condition]. / Ultrasonografía doppler transcraneal urgente: utilidad predictiva del vasoespasmo sintomático en la hemorragia subaracnoidea espontánea en pacientes con buena situación neurológica.

PURPOSE: To examine the predictive value of an early transcranial Doppler ultrasound (TCD) study performed in the emergency department in patients with spontaneous subarachoniod hemorrhage (SAH) in good neurological condition, in order to know which patients are at high risk of developing delayed cerebral ischemia (DCI). DESIGN: A descriptive observational study was carried out involving a period of 3 years. SETTING: Critical Care and Emergency Department. PATIENTS: The study consecutively included patients with SAH of grade I-III on the Hunt and Hess scale. VARIABLES OF INTEREST: DCI (decrease of 2 points in GCS or focal deficit), Mean Velocity (MV) of middle cerebral arteries (MCA), Lindegaard Index (IL). Sonographic vasospasm pattern (SVP) was considered if MCA-MV>120cm/sc and IL>3. RESULTS: The mean age of the 122 patients was 54.1±13.7 years; 57.3% were women. SVP was detected in 24 patients (19.7%), although high velocities patterns (HVP) were present in 38 patients (31.1%). DCI developed in 21 patients (MV183+/-49cm/sc), all with previous SVP. In this group MV increased 22+/-5cm/sc/day during the first 3 days. The group without HVP (84 patients/MV of 67+/-16.6cm/sc), compared with DCI group, showed differences in highest MV (p<0.001), and also ΔMV/day (8.30+/-4,5cm/sc Vs 22+/-5cm/sc) during the first 3 days (p=0.009). In our series, ROC analysis selected the best cut-off value for ΔMV/day as 21cm/sc (p<0.001). CONCLUSION: During the first 3 days, an increase of 21cm/s/24h in MCA-MV was associated with the development of symptomatic vasospasm. TCD is a useful tool for the early detection of patients at risk of DCI after SAH.

Chemosterilant bait stations coupled with sterile insect technique: an integrated strategy to control the Mediterranean fruit fly (Diptera: Tephritidae).

During 2008 and 2009, the efficacy of the combination of two Mediterranean fruit fly, Ceratitis capitata (Wiedemann) (Diptera: Tephritidae), control techniques, sterile insect technique (SIT) and a chemosterilant bait station system (Adress), was tested in three crops: citrus (Citrus spp.), stone fruit (Prunus spp.), and persimmon (Diospyros spp.). Two thousand sterile males were released per ha each week in the whole trial area (50,000 ha, SIT area). For 3,600 ha, within the whole trial area, 24 Adress traps per ha were hung (SIT + Adress area). Ten SIT + Adress plots and 10 SIT plots in each of three different fruit crops were arranged to assess Mediterranean fruit fly population densities and fruit damage throughout the trial period. To evaluate the efficacy of each treatment, the male and female populations were each monitored from August 2008 to November 2009, and injured fruit was assessed before harvest. Results showed a significant reduction in the C. capitata population in plots treated with both techniques versus plots treated only with the SIT. Likewise, a corresponding reduction in the percentage of injured fruit was observed. These data indicate the compatibility of these techniques and suggest the possibility of using Adress coupled with SIT to reduce C. capitata populations in locations with high population densities, where SIT alone is not sufficiently effective to suppress fruit fly populations to below damaging levels.

Cutaneous facial sinus tract of dental origin.

Cutaneous sinus tract on the head and neck area in a child may originate from dental disease. A high degree of clinical suspicion and complementary tests are often needed, as the diagnosis is usually not straight forward. Anatomical correlation is also useful in tracing the affected tooth or teeth. We present the case of a boy with a facial sinus tract that originated from periapical abscesses of maxillary molars.

Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes.

Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.

First report of Trypanosoma vivax infection in dairy cattle from Costa Rica.

An outbreak of haemoparasitoses occurred from October 2007 to July 2008 in cattle from the district of Rio Cuarto, province of Alajuela, Costa Rica. Fifty animals of various ages out of 450 Brown Swiss were affected. The animals presented fever, severe anemia, jaundice, abortion or premature birth, loss of appetite, decrease milk production and accentuated weight loss in a short period of time. Haemoparasites were observed in the blood smears: Anaplasma marginale was present in 17 animals (60.7%); Trypanosoma vivax in nine (32.1%) and Babesia bovis in two (7.1%). Three of the animals (10.7%) had a mixed infection with T. vivax and A. marginale. After treatment, all the animals were clinically recovered and subsequent blood samplings showed no parasites. Data suggest that the outbreak might be related to a decrease in the availability and quality of the pastures due to very heavy rainfalls during the year 2007, as well as an increase in the abundance of Boophilus microplus and Stomoxys calcitrans. This is the first report of the presence of T. vivax in Costa Rica.

The first account of the mating disruption technique for the control of California red scale, Aonidiella aurantii Maskell (Homoptera: Diaspididae) using new biodegradable dispensers.

Semiochemical-based pest management programs have been increasingly used to provide environmentally friendly methods for the control of major insect pests. The efficacy of the mating disruption technique has been demonstrated for several moth pests. Unfortunately, not many experiments on mating disruption to control diaspididae species have been documented. In this work, biodegradable dispensers for mating disruption with increasing pheromone loads were used in order to study the potential of this technique for the control of Aonidiella aurantii Maskell. Field trial results demonstrated that dispensers loaded with 50 mg (a.i.) (20 g ha-1) and 100 mg (a.i.) (40 g ha-1) of sex pheromone were the most suitable, achieving significant reductions in male catches, compared to an untreated plot. In treated plots, virtually a 70% reduction in damage to fruit was recorded. Pheromone release profiles of all the dispensers were also studied under field conditions. We found that emission values >250 microg day-1 were the most suitable. This study suggests a new biodegradable dispenser capable of interfering with normal A. aurantii chemical communication. The use of mating disruption as a control method against A. aurantii is discussed.

Leukocyte and platelet counts as prognostic values of testicular germ cell tumours. / Valor pronóstico del recuento de leucocitos y plaquetas, en tumores testiculares de células germinales.

INTRODUCTION: The immune system plays an essential role in the organism's response to cancer. Several haematological markers can influence prognosis and survival of patients. The objective of this study is to determine their prognostic value in testicular germ cell tumours. MATERIAL AND METHODS: Retrospective cohort study on 164 patients with germ cell tumours. Clinical, analytical, histological and evolutionary data were collected. The absolute neutrophil and absolute platelet counts, neutrophil-lymphocyte (NLR), platelet-lymphocyte and lymphocyte-monocyte ratios were estimated at diagnosis. The association that these markers can have with the classic prognostic factors, as well as their effect on prognosis and survival, have been analysed. RESULTS: 17.7% had NLR>4 and 14.6% ANC>8000/µL. These patients presented higher percentages of residual disease and stage II-III tumours. Patients with elevated absolute neutrophil showed also higher percentages of progression and exitus. 7.3% presented absolute platelet >400000/µL. These patients obtained higher rates of residual disease, nonseminomatous and stage III tumours. 28.4% showed platelet-lymphocyte values>150. This data was associated to higher percentages of residual disease, progression, stage II and III tumours and seminomatous tumours. 83.3% had an lymphocyte-monocyte >3. These patients presented: higher tumour markers in normal range, decreased residual disease rates and higher percentages of stage I and II tumours. The mean survival time was shorter in patients with NLR>4 and absolute neutrophil >8,000/µL. The ROC curves showed significance in the prediction of progression and values of lymphocyte-monocyte >3, and prediction of survival and values NLR>4. CONCLUSION: Our results indicate that the analysed haematological markers are associated with poor prognoses at diagnosis. Therefore, their use in daily clinical practice can be a valuable tool in the diagnosis and prognosis of patients with testicular germ cell tumours.

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells.

The surface phenotype CD3-NK1.1+DX5+CD11c(int)B220+GR1- has been recently ascribed to a novel subset of mouse leukocytes termed interferon (IFN)-producing killer dendritic cells (IKDCs) that shares functions with natural killer (NK) cells and DCs. Interleukin-15 (IL-15) is critical for NK cells but its relationship with IKDC remained unexplored. An expression cassette encoding human IL-15 (hIL-15) has been transferred by hydrodynamic injection into the liver of mice, resulting in transient expression of the cytokine that is detectable during the first 48 h. hIL-15 hydrodynamic gene transfer resulted in an expansion of NK cells and IKDCs. Relative expansions of IKDCs were more dramatic in the IL-15 gene-transferred hepatic tissue than in the spleen. Adoptively transferred DX5+ cells comprising both NK cells and IKDCs proliferated in response to hydrodynamic injection of hIL-15, indicating that quantitative increases are at least in part the result of proliferation from already differentiated cells. Expansion is accompanied by enhanced cytolytic activity and increased expression of TRAIL and CD137 (4-1BB), without augmenting interferon-gamma production. The effects of a single hydrodynamic injection surpassed those of two intraperitoneal doses of the recombinant protein. The novel functional link between circulating IL-15 and IKDCs opens new possibilities to study the biology and applications of this minority cell subset.

[New treatments for renal carcinoma]. / Nuevos tratamientos para el carcinoma renal.

Renal cell carcinoma presents several unique features, which distinguish it from other tumours. The increase in survival that has been described in patients with renal cell carcinoma following nephrectomy breaks a classical rule of oncology, which states that surgery of the primary tumour has no role in the treatment of patients with advanced disease. Together with melanoma, it is the only tumour in which immunomodulatory treatments with drugs such as interleukin-2 produces a clinical benefit to patients. In randomized trials treatment of metastatic renal cell carcinoma with high dose interleukin-2 has confirmed its ability to induce long-term complete responses, which in practice can be considered equivalent to cure. Lastly, renal cell carcinoma is being used as a clinical model to demonstrate the role of several targeted treatments, with over 30 novel agents under development. It has been the first tumour type in which treatment with angiogenesis inhibitors has shown a clinical benefit. This article reviews the most relevant aspects of renal cell carcinoma, including epidemiology, prognostic factors, clinical presentation, molecular bases and the current status of development of the most relevant novel treatments for this disease.

Conversion from calcineurin inhibitors to everolimus in kidney transplant recipients with malignant neoplasia.

Cancer has been reported to be more common among kidney transplant recipients than waiting-list patients or the general population. Use of anticalcineurin agents and azathioprine are relevant risk factors. Nine renal allograft recipients (seven men and two women) of mean age 67.6 (55-77) years and mean time after transplantation of 30.7 (58-216) months were switched to everolimus-based immunosuppression because of the presence of biopsy-proven malignancies (eight patients) or neurological tacrolimus toxicity (one patient). One patient with posttransplant lymphoproliferative disease also received chemotherapy with a good evolution at 6 months. He showed an initial increase in the protein to creatinine ratio (peak 3.3 mg/mg at 3 months) that was controlled by increasing the enalapril dose. One patient with skin cancer and severe atheromatosis (baseline SCr 2.5 mg/dL, creatinine clearance 17 mL/min, and protein to creatinine ratio 3.2 mg/mg), had cyclosporine and everolimus overlapped for 25 days, showing a continued poor evolution requiring dialysis initiation at 3 months after switch. The other six patients with recurrent skin cancers had good cancer evolution, with no new skin tumors and regression of skin lesions in three, including not biopsied actinic keratosis. Sudden switching from calcineurin inhibitors to everolimus is safe and may be used in long-term transplant recipients with malignancies. In patients with advanced chronic nephropathy this approach appeared to be less beneficial.

[The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases]. / El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB) para terapia de enfermedades malignas e infecciones virales crónicas.

Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start.

Electrolytic disorders, hyperosmolar states, and lactic acidosis in brain-dead patients.

Despite the use of well-accepted protocols for donor maintenance, the severe electrolytic disorders are not infrequent with deleterious consequences to the organs. The objective of our survey was to determine the incidence of episodes of electrolyte disorders among brain-dead patients (despite of rigid protocols of maintenance) and the rate of anaerobic metabolism in these patients (suggestive of an occult systemic hypoperfusion). The study group of 50 brain-dead patients underwent therapy to maintain normal arterial pressure, urine output, and body temperature. Standard monitoring for brain-dead patients was followed, except for a frequent evaluation of electrolytes, including glucose, sodium, potassium, phosphorus, osmolality, base excess, and lactate plasma levels. Our results demonstrate that with frequent determinations of electrolytes, despite following strict protocols of maintenance, there was a high incidence of hyperglycemia, hypophosphotemia, hypokaemia, and hyperosmolality. Interesting findings were the high incidence of elevated lactate, and the relationship between lactate levels and bases deficit as well as hypernatremia. It can be concluded that, even following rigid protocols, the maintenance of brain-dead patients demands a close evaluation of electrolyte levels. Our results also suggest that the inclusion in the monitoring protocol of anerobic metabolism data including lactate levels can help to avoid occult ischemia of organs, and consequently improve their quality for transplantation.

Fine tuning of magnetite nanoparticle size distribution using dissymmetric potential pulses in the presence of biocompatible surfactants and the electrochemical characterization of the nanoparticles.

The effects of varying the surfactant concentration and the anodic pulse potential on the properties and electrochemical behaviors of magnetite nanoparticles were investigated. The nanoparticles were synthesized with an electrochemical method based on applying dissymmetric potential pulses, which offers the advantage that can be used to tune the particle size distribution very precisely in the range of 10 to 50 nm. Under the conditions studied, the surfactant concentration directly affects the size distribution, with higher concentrations producing narrower distributions. Linear voltammetry was used to characterize the electrochemical behavior of the synthesized nanoparticles in both the anodic and cathodic regions, which are attributed to the oxidation of Fe(2+) and the reduction of Fe(3+); these species are part of the spinel structure of magnetite. Electrochemical impedance spectroscopy data indicated that the reduction and oxidation reactions of the nanoparticles are not controlled by the mass transport step, but by the charge transfer step. The sample with the highest saturation magnetization was that synthesized in the presence of polyethylene glycol.

CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations.

The authors report the CYP2D6 inhibitory effects of fluoxetine, paroxetine, sertraline, and venlafaxine in an open-label, multiple-dose, crossover design. Twelve CYP2D6 extensive metabolizers were phenotyped, using the dextromethorphan/dextrorphan (DM/DX) urinary ratio, before and after administration of fluoxetine 60 mg (loading dose strategy), paroxetine 20 mg, sertraline 100 mg, and venlafaxine 150 mg. Paroxetine, sertraline, and venlafaxine sequences were randomized with 2-week washouts between treatments; fluoxetine was the last antidepressant (AD) administered. Comparing within groups, baseline DM/DX ratios (0.017) were significantly lower than DM/DX ratios after treatment (DM/DXAD) with fluoxetine (0.313, p < 0.0001) and paroxetine (0.601, p < 0.0001) but not for sertraline (0.026, p = 0.066) or venlafaxine (0.023, p = 0.485). Between groups, DM/DXAD ratios were significantly higher for fluoxetine and paroxetine compared to sertraline and venlafaxine. No differences between DM/DXAD ratios were found for fluoxetine and paroxetine although more subjects phenocopied to PM status after receiving the latter (42% vs. 83%; chi 2 = 4.44, p = 0.049, df = 1). Similarly, no differences between DM/DXAD ratios were found for sertraline and venlafaxine. Of note, the DM/DXAD for 1 subject was much lower after treatment with paroxetine (0.058) compared to fluoxetine (0.490), while another subject exhibited a much lower ratio after treatment with fluoxetine (0.095) compared to paroxetine (0.397). Significant correlations between AD plasma concentration and DM/DXAD were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine. In addition, DM/DXAD correlated with baseline isoenzyme activity for paroxetine, sertraline, and venlafaxine groups. These results demonstrate the potent, but variable, CYP2D6 inhibition of fluoxetine and paroxetine compared to sertraline and venlafaxine. CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity, and these correlations merit further investigation.

Identification by CT scan of ischemic stroke patients with high risk of brain death.

The identification of patients with high risk of evolution to brain death is one of the more important tasks of transplant coordination teams. Although most of pool of potential donors come from the group of patients who suffer a head injury or hemorrhagic stroke, the procurement of organs from brain-dead patients suffering an ischemic stroke as the cause of brain damage must also be considered. The main objective of this study was to investigate the radiological signs that in the CT scan of admission to a neurological ICU are more frequently associated with progression to brain death. We studied the CT scans of 15 brain-dead patients after an ischemic stroke versus the scans of 15 recovered patients admitted to ICU with the same diagnosis. The radiological signs included: insular ribbon sign, hyperintensities inside the big arteries of the base of the skull, hemispheric hypodensities, midline shift, and compression of the cerebrospinal fluid spaces. There were two signs significantly associated with brain death: midline shifts and the compression of the ambiens cistern. It may be concluded that analysis of the CT scan at admission of patients with an ischemic stroke in the ICU can predict the risk of evolution to brain death.