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Background Micronutrient supplementation is recommended in Ebola virus disease (EVD); however, there are limited data on therapeutic impacts of specific micronutrients. Objective To evaluate the association between vitamin A supplementation and mortality in EVD. Methods This retrospective cohort included patients with EVD admitted to 5 International Medical Corps Ebola Treatment Units (ETUs) in 2 countries during 2014-2015. Protocolized treatments with micronutrients were used at all ETUs: however, because of resource constraints, only a subset of patients received vitamin A. Standardized data on demographics, clinical characteristics, malaria status, and Ebola viral loads (cycle threshold values) were collected. The outcome of interest was mortality between cases treated with 200,000 IU of vitamin A on care days 1 and/or 2, and those not. Propensity scores based on the first 48 h of care were derived using covariates of age, ETU duration, malaria status, cycle threshold values, and clinical symptoms. Patients were matched 1:1 using nearest neighbors with replacement. Mortality between cases treated and not treated with vitamin A was compared using generalized estimating equations to calculate RR with associated 95% CI. Results There were 424 cases analyzed, of which 330 (77.8%) were treated with vitamin A. The mean age was 30.5 y and 40.3% were men. The most common symptoms were diarrhea (85.6%), anorexia (80.7%), and abdominal pain (76.9%). Mortality proportions among cases treated and not treated with vitamin A were 55.0% and 71.9%, respectively. In the propensity-matched analysis, mortality was significantly lower among cases receiving vitamin A (RR = 0.77, 95% CI: 0.59, 0.99; P = 0.041). In a subgroup analysis of patients treated with multivitamins already containing vitamin A, additional vitamin A supplementation did not impact mortality. Conclusion Early vitamin A supplementation was associated with reduced mortality in patients with EVD, and should be further studied and considered for use in future epidemics.

Background Intravenous fluid (IVF) is a frequently recommended intervention in Ebola virus disease (EVD), yet its impact on patient outcomes remains unclear. Methods This retrospective cohort study evaluated patients with EVD admitted to 5 Ebola treatment units (ETUs) in West Africa. The primary outcome was the difference in 28-day survival between cases treated and not treated with IVF. To control for demographic and clinical factors related to both IVF exposure and survival, cases were compared using propensity score matching. To control for time-varying patient and treatment factors over the course of ETU care, a marginal structural proportional hazards model (MSPHM) with inverse probability weighting was used to assess for 28-day survival differences. Results Among 424 EVD-positive cases with data for analysis, 354 (83.5%) were treated with IVF at some point during their ETU admission. Overall, 146 (41.3%) cases treated with IVF survived, whereas 31 (44.9%) cases not treated with any IVF survived (P = .583). Matched propensity score analysis found no significant difference in 28-day survival between cases treated and not treated with IVF during their first 24 and 48 hours of care. Adjusted MSPHM survival analyses also found no significant difference in 28-day survival for cases treated with IVF (27.3%) compared to those not treated with IVF (26.9%) during their entire ETU admission (P = .893). Conclusions After adjustment for patient- and treatment-specific time-varying factors, there was no significant difference in survival among patients with EVD treated with IVF as compared to those not treated with IVF.

Background Empiric antimalarial treatment is a component of protocol-based management of Ebola virus disease (EVD), yet this approach has limited clinical evidence for patient-centered benefits. Methods This retrospective cohort study evaluated the association between antimalarial treatment and mortality among patients with confirmed EVD. The data was collected from five International Medical Corps operated Ebola Treatment Units (ETUs) in Sierra Leone and Liberia from 2014 through 2015. The standardized protocol used for patient care included empiric oral treatment with combination artemether and lumefantrine, twice daily for three days; however, only a subset of patients received treatment due to resource variability. The outcome of interest was mortality, comparing patients treated with oral antimalarials within 48-h of admission to those not treated. Analysis was conducted with logistic regression to generate adjusted odds ratios (aORs). Multivariable analyses controlled for ETU country, malaria rapid diagnostic test result, age, EVD cycle threshold value, symptoms of bleeding, diarrhea, dysphagia and dyspnea, and additional standard clinical treatments. Results Among the 424 cases analyzed, 376 (88.7%) received early oral antimalarials. Across all cases, mortality occurred in 57.5% (244). In comparing unadjusted mortality prevalence, early antimalarial treated cases yielded 55.1% mortality versus 77.1% mortality for those untreated (p = 0.005). Multivariable analysis demonstrated evidence of reduced aOR for mortality with early oral antimalarial treatment versus non-treatment (aOR = 0.34, 95% Confidence Interval: 0.12, 0.92, p = 0.039). Conclusion Early oral antimalarial treatment in an EVD outbreak was associated with reduced mortality. Further study is warranted to investigate this association between early oral antimalarial treatment and mortality in EVD patients.

Background Unsafe abortion is a leading cause of maternal mortality. In Afghanistan, which has experienced decades of armed conflict and where abortion is highly restricted, maternal mortality is high at 638 maternal deaths per 100,000 live births. Post-abortion care (PAC) is a lifesaving package of interventions to reduce morbidity and mortality related to induced or spontaneous abortion, but is rarely provided and often of poor quality, particularly in humanitarian settings. In July 2018, we conducted a study to identify the factors that influence access to and use of PAC services at Sharana Provincial Hospital. Methods In-depth interviews (IDIs) were conducted with ten women who had received PAC services at Sharana Hospital, and eight focus group discussions (FGDs) were conducted with 40 married women and 40 married men aged 18–45 from four villages surrounding Sharana Hospital. Results PAC clients and community participants discussed similar barriers to seeking PAC, including cost, distance to the health facility, the need for male accompaniment to seek care, perceived and actual quality of care, stigma and shame. Despite the mentioned stigma around abortion, community members expressed willingness to help women to receive PAC. Conclusions Our results suggest that while some barriers are not unique to PAC, others, especially those related to stigma around abortion, may be specific to PAC. It is important for the Ministry of Public Health and its partners to prioritize addressing these barriers to ensure that women have access to this critical life-saving care.

Conflict and mass displacement into Protection of Civilian (POCs) sites in South Sudan led to the breakdown of community and family structures, increasing women and girls' vulnerability to gender-based violence and exacerbating already poor sexual and reproductive health outcomes. As one component of a study on post-abortion care, this study explores community perceptions of unintended pregnancy and abortion in a POC in Juba. Four focus group discussions were conducted with 36 women and married men aged 18-45 living in the POC. Although initial reactions to induced abortion were generally negative, participants discussed that unintended pregnancy and induced abortion appeared to have increased during the current conflict. Their discussion of abortion became less condemnatory as they described changes in people's situation due to war, including instability and poverty, transactional sex, disruption of marital norms, rape, and low contraceptive use. This is one of the first studies to investigate community perceptions and practices related to unintended pregnancy and abortion in South Sudan. Despite the beliefs that these are taboo topics, the discussions provide an opening to reduce abortion stigma. To ensure lasting stigma reduction, investment in women and girls to improve gender equity is needed.

Background In the aftermath of the devastating 2015 earthquakes in Nepal, three non-governmental organizations collaborated to develop a program responding to the immediate mental health and psychosocial support (MHPSS) needs in three severely affected districts: Dhading, Gorkha, and Sindhuli. The program was implemented between April 2015 and February 2017 and aimed to (i) strengthen health worker capacity to provide integrated MHPSS services; and (ii) increase access to mental health services. This paper describes the program's implementation and the results of a pragmatic evaluation of the program's overall reach, effectiveness, and lessons learned. Methods The mixed-methods evaluation used routine program data, quantitative data from pre- and post-tests conducted with trainees and service users, and qualitative data from stakeholder interviews and focus group discussions. Results A total of 1041 health workers received MHPSS training and supervision. Participants demonstrated significant improvements in skills, knowledge, and self-rated perceived competency. Trainees went on to provide MHPSS services to 3422 people. The most commonly identified presenting problems were epilepsy (29%) and depression (26%). A total of 67% of service users reported being ‘completely satisfied’ with the services received and 83% of those experiencing severe functional impairments on enrollment demonstrated improvement after receiving services. Conclusions Despite operational challenges, the program successfully engaged both laypeople and health workers to provide MHPSS in the aftermath of the crisis. Lessons learned can inform the planning and implementation of future training and integration programs to provide large-scale MHPSS efforts in humanitarian settings.

To evaluate the association between oral third-generation cephalosporin antibiotic treatment and mortality in Ebola virus disease (EVD).This retrospective cohort studied EVD-infected patients admitted to five Ebola Treatment Units in Sierra Leone and Liberia during 2014-15. Empiric treatment with cefixime 400 mg once daily for five days was the clinical protocol; however, due to resource variability, only a subset of patients received treatment. Data on sociodemographics, clinical characteristics, malaria status and Ebola viral loads were collected. The primary outcome was mortality compared between cases treated with cefixime within 48 h of admission to those not treated within 48 h. Propensity scores were derived using clinical covariates. Mortality between treated and untreated cases was compared using propensity-matched conditional logistic regression and bootstrapped log-linear regression analyses to calculate an odds ratio (OR) and relative risk (RR), respectively, with associated 95% confidence intervals (CI).Of 424 cases analysed, 360 (84.9%) met the cefixime treatment definition. The mean age was 30.5 years and 40.3% were male. Median cefixime treatment duration was 4 days (IQR: 3, 5). Among cefixime-treated patients, mortality was 54.7% (95% CI: 49.6-59.8%) vs. 73.4% (95% CI: 61.5-82.7%) in untreated patients. In conditional logistic regression, mortality likelihood was significantly lower among cases receiving cefixime (OR = 0.48, 95% CI: 0.32-0.71; P = 0.01). In the bootstrap analysis, a non-significant risk reduction was found with cefixime treatment (RR = 0.82, 95% CI: 0.64-1.16, P = 0.11).Early oral cefixime may be associated with reduced mortality in EVD and warrants further investigation.Evaluer l'association entre le traitement antibiotique oral avec des céphalosporine de troisième génération et la mortalité dans la maladie au virus Ebola (MVE). MÉTHODES: Cette étude de cohorte rétrospective a été menée chez des patients infectés par la maladie au virus Ebola admis dans cinq unités de traitement Ebola en Sierra Leone et au Libéria en 2014-2015. Le traitement empirique avec Cefixime 400 mg une fois par jour pendant cinq jours était le protocole clinique. Cependant, en raison de la variabilité des ressources, seul un sous-ensemble de patients a reçu un traitement. Des données sur la sociodémographie, les caractéristiques cliniques, le statut du paludisme et les charges virales d'Ebola ont été collectées. Le critère principal était la mortalité comparée entre les cas traités au céfixime dans les 48 heures suivant l'admission et ceux non traités dans les 48 heures. Les scores de propension ont été dérivés à l'aide de covariables cliniques. La mortalité entre les cas traités et non traités a été comparée à l'aide d'analyses de régression logistique conditionnelle et de régression log-linéaire bootstrapées pour calculer respectivement un rapport de cotes (OR) et un risque relatif (RR), avec des intervalles de confiance (IC) à 95% associés. RÉSULTATS: Sur 424 cas analysés, 360 (84,9%) répondaient à la définition du traitement au céfixime. L'âge moyen était de 30,5 ans et 40,3% étaient des hommes. La durée médiane du traitement par le céfixime était de 4 jours (IQR: 3, 5). Parmi les patients traités au Cefixime, la mortalité était de 54,7% (IC95%: 49,6 à 59,8%) vs 73,4% (IC95%: 61,5 à 82,7%) chez les patients non traités. Dans la régression logistique conditionnelle, la probabilité de mortalité était significativement plus faible parmi les cas recevant du céfixime (OR = 0,48 ; IC95%: 0,32 à 0,71; P = 0,01). Dans l'analyse bootstrap, une réduction du risque non significative a été trouvée avec le traitement au céfixime (RR = 0,82, IC95%: 0,64 à 1,16 ; P = 0,11).Le céfixime par voie orale rapide peut être associé à une mortalité réduite dans la MVE et mérite une investigation plus approfondie.

Background Experiments in vitro have shown that the drug amodiaquine may inhibit Ebola virus activity. During the Ebola virus disease (EVD) epidemic in West Africa in 2014–2016, 2 mass drug administrations (MDAs) of artesunate-amodiaquine (ASAQ) were implemented to decrease the burden of malaria. The objective of this study was to assess the effect of the ASAQ MDAs on the mortality of patients with EVD. Methods A retrospective cohort design was used to analyze mortality data for patients with EVD admitted to 5 Ebola treatment units in Liberia and Sierra Leone. Patients admitted to the ETUs during the time period of ASAQ’s therapeutic effect from areas where the MDA was implemented were matched to controls not exposed to ASAQ, using a range of covariates, including malaria co-infection status, and a logistic regression analysis was performed. The primary outcome was Ebola treatment unit mortality. Results A total of 424 patients with EVD had sufficient data for analysis. Overall, the mortality of EVD patients was 57.5%. A total of 22 EVD patients were exposed to ASAQ during the MDAs and were found to have decreased risk of death compared with those not exposed in a matched analysis, but this did not reach statistical significance (relative risk, 0.63; 95% confidence interval, 0.37–1.07; P = .086). Conclusions There was a non–statistically significantly decreased risk of mortality in EVD patients exposed to ASAQ during the 2 MDAs as compared with EVD patients not exposed to ASAQ. Further prospective trials are needed to determine the direct effect of ASAQ on EVD mortality., Experiments in vitro have shown that amodiaquine may inhibit Ebola virus activity. This study found a non-statistically significant decreased risk of death for patients with Ebola Virus Disease exposed to amodiaquine during mass drug administration of artesunate-amodiaquine in the 2014-15 West African Ebola outbreak suggesting possible therapeutic effect of amodiaquine and need for further trials of this drug in patients with Ebola Virus Disease.

OBJECTIVE Fluid loss during Ebola virus disease (EVD) infections from gastrointestinal dysfunction leads to volume depletion. It is possible that high environmental temperatures may exacerbate volume depletion or interfere with the provision of medical care by providers in full personal protective equipment. We investigated the effect of environmental temperature on case fatality. METHODS The International Medical Corps (IMC) operated five Ebola Treatment Units (ETUs) in Liberia and Sierra Leone during the 2014-2016 epidemic. Demographic and outcomes variables for 465 patients with EVD were sourced from a de-identified, quality-checked clinical database collected by IMC. Daily environmental temperature data for Liberia and Sierra Leone were collected from a publicly available database (Weather Underground). Mean daily environmental temperatures were averaged across each patient's ETU stay and environmental temperature thresholds were determined. Multiple logistic regression was utilised, with forward variable selection and threshold for entry of P < 0.1. Statistical significance was defined as P < 0.05. The following variables were analysed as potential confounders: age, sex, ETU, length of ETU operation and date of treatment. RESULTS Case fatality was 57.6% among patients diagnosed with EVD. Analysis of case fatality across environmental temperature quintiles indicated a threshold effect; the optimal threshold for average environmental temperature during a patient's ETU stay was determined empirically to be 27.4 °C (81.3 °F). Case fatality was significantly greater for patients with average environmental temperatures above the threshold (70.4%) vs. below (52.0%) (P < 0.001). In multiple regression, patients with average environmental temperature above the threshold during their ETU stay were significantly more likely to die than patients below the threshold (aOR = 2.5, 95% CI 1.6-3.8, P < 0.001). This trend was observed only among patients treated in white tent ETUs, and not in ETUs with aluminium roofs. DISCUSSION These findings suggest that an average environmental temperature above 27.4 °C (81.3 °F) during patients' ETU stay is associated with greater risk of death among patients with EVD. Further studies should investigate this effect. These results have potential implications for reducing case fatality through improved ETU construction or other temperature control methods within ETUs during future outbreaks.

Introduction:Micronutrient supplementation is recommended in Ebola Virus Disease (EVD). However, there is limited data on its therapeutic impacts. This study evaluated the association between vitamin A supplementation and mortality outcomes in EVD patients.Methods:This retrospective cohort study accrued patients with EVD admitted to five International Medical Corps run Ebola Treatment Units (ETU) in two countries from 2014-2015. Protocolized treatments with antimicrobials and micronutrients were used at all ETUs. However, due to resource limitations and care variations, only a subset of patients received vitamin A. Standardized data on demographics, clinical characteristics, malaria status, and Ebola virus RT-PCR cycle threshold (CT) values were collected. The outcome of interest was mortality compared between cases treated with 200,000 International Units of vitamin A on care days one and two and those not. Propensity scores (PS) based on the first 48-hours of care were derived using the covariates of age, duration of ETU function, malaria status, CT values, symptoms of confusion, hemorrhage, diarrhea, dysphagia, and dyspnea. Treated and non-treated cases were matched 1:1 based on nearest neighbors with replacement. Covariate balance met predefined thresholds. Mortality proportions between cases treated and untreated with vitamin A were compared using generalized estimating equations to calculate relative risks (RR) with associated 95% confidence intervals (CI).Results:There were 424 cases analyzed, with 330 (77.8%) being vitamin A-treated cases. The mean age was 30.5 years and 57.0% were female. The most common symptoms were diarrhea (86%), anorexia (81%), and vomiting (77%). Mortality proportions among cases untreated and treated with vitamin A were 71.9% and 55.0%, respectively. In a propensity-matched analysis, mortality was significantly lower among cases receiving vitamin A (RR = 0.77 95%; CI:0.59-0.99; p = 0.041).Discussion:Early vitamin A supplementation was associated with reduced mortality in EVD patients and should be provided routinely during future epidemics.

[¹³¹I]meta-iodobenzylguanidine ([¹³¹I]MIBG) is the most commonly used treatment for metastatic pheochromocytoma and paraganglioma. It enters the chromaffin cells via the membrane norepinephrine transporter; however, its success has been modest. We studied the ability of histone deacetylase (HDAC) inhibitors to enhance [¹²³I]MIBG uptake by tumors in a mouse metastatic pheochromocytoma model. HDAC inhibitors are known to arrest growth, induce differentiation and apoptosis in various cancer cells, and further inhibit tumor growth. We report the in vitro and in vivo effects of two HDAC inhibitors, romidepsin and trichostatin A, on the uptake of [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in mouse pheochromocytoma (MPC) cells by using the transporter-blocking agent desipramine and the vesicular-blocking agent reserpine. HDAC inhibitors increased [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in significantly increased uptake of [(18)F]fluorodopamine positron emission tomography (PET) in pheochromocytoma liver metastases (19.1 ± 3.2% injected dose per gram of tumor (%ID/g) compared to liver metastases in pretreatment scans 5.9 ± 0.6%; P

Pheochromocytomas are chromaffin cell-derived neuroendocrine tumors. There is presently no cure for metastatic pheochromocytoma and no reliable way to distinguish malignant from benign tumors before the development of metastases. In order to successfully manage pheochromocytoma, it is necessary to better understand the biological determinants of tumor behavior. For this purpose, we have recently established a mouse model of metastatic pheochromocytoma using tail vein injection of mouse pheochromocytoma (MPC) cells. We optimized this model modifying the number of cells injected, length of trypsin pre-treatment, and incubation temperature and duration for the MPC cells before injection, and by serial passage and re-selection of tumors exhibiting the metastatic phenotype. We evaluated the effect of these modifications on tumor growth using serial in vivo Magnetic Resonance Imaging studies. These results show that number of cells injected, the pre-injection incubation temperature, and duration of trypsin treatment are important factors to produce faster growing, more aggressive tumors that yielded secondary metastatic lesions. Serial harvest, culture and re-selection of metastatic liver lesions produced even more aggressive pheochromocytoma cells that retained their biochemical phenotype. Microarray gene expression comparison and quantitative real-time PCR of these more aggressive cells to the MPC-parental cell line identified genes that may be important for the metastatic process.

We compared functional imaging modalities including positron emission tomography (PET) with 6-[18F]-fluorodopamine ([18F]-DA) against [123I]-metaiodobenzylguanidine ([123I]-MIBG) and somatostatin receptor scintigraphy (SRS) with [111In]-pentetreotide (Octreoscan) in non-metastatic and metastatic pheochromocytoma (PHEO). Methods: We studied 25 men and 28 women (mean age±SD: 44.2±14.2 years) with biochemically-proven non-metastatic (n: 17) or metastatic (n: 36) PHEO. Evaluation included anatomical imaging with computed tomography (CT) and/or magnetic resonance imaging (MRI) and functional imaging that included at least two nuclear medicine modalities: [18F]-DA PET, [123I]-MIBG scintigraphy, or SRS. Sensitivity of functional imaging vs. anatomical imaging was assessed on a per-patient and on a per-region basis. Results For this available cohort, on a per patient basis, overall sensitivity (combined for non-metastatic and metastatic PHEO) was 90.2% for [18F]-DA PET, 76.0% for [123I]-MIBG scintigraphy, and 22.0% for SRS. On a per-region basis, overall sensitivity was 75.4% for [18F]-DA PET, 63.4% for [123I]-MIBG scintigraphy, and 64.0% for SRS.

Objective: Human pheochromocytoma tumor cells express glucagon receptors, and bolus i.v. glucagon injection rapidly increases plasma epinephrine levels, suggesting that glucagon can directly stimulate adrenomedullary secretion. In this study, we tested whether the catecholamine secretory response to glucagon was present in bovine chromaffin cells or exclusive to the tumor cells. Design and Methods: Adrenomedullary cells were cultured in 24-well plates (10 6 cells per well). After 48 - 72 hours, wells were incubated for 1-20 minutes with (1) incubation medium (control), (2) catecholamine secretagogues (nicotine or potassium ion), or (3) glucagon (10 - 8 to 10 - 5 M). After incubation, catecholamine contents in medium and cells were assayed by high-pressure liquid chromatography with electrochemical detection. Fractional release rates of epinephrine, norepinephrine, and dopamine were calculated and compared to controls. Reverse-transcriptase PCR was performed to compare expression of mRNA of the glucagon receptor in chromaffin cells and pheochromocytoma cells. Results: Nicotine and potassium evoked time-dependent release of epinephrine, norepinephrine, and dopamine. Glucagon did not affect catecholamine secretion at any concentration. Reverse-transcriptase PCR failed to detect mRNA for glucagon receptor in bovine adrenomedullary cells, but did detect it in human pheochromocytoma cells. Conclusions: In contrast to pheochromocytoma tumor cells, bovine adrenomedullary chromaffin cells do not express the glucagon receptor, and therefore do not secrete catecholamines in response to glucagon.

[¹³¹I]meta-iodobenzylguanidine ([¹³¹I]MIBG) is the most commonly used treatment for metastatic pheochromocytoma and paraganglioma. It enters the chromaffin cells via the membrane norepinephrine transporter; however, its success has been modest. We studied the ability of histone deacetylase (HDAC) inhibitors to enhance [¹²³I]MIBG uptake by tumors in a mouse metastatic pheochromocytoma model. HDAC inhibitors are known to arrest growth, induce differentiation and apoptosis in various cancer cells, and further inhibit tumor growth. We report the in vitro and in vivo effects of two HDAC inhibitors, romidepsin and trichostatin A, on the uptake of [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in mouse pheochromocytoma (MPC) cells by using the transporter-blocking agent desipramine and the vesicular-blocking agent reserpine. HDAC inhibitors increased [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in significantly increased uptake of [(18)F]fluorodopamine positron emission tomography (PET) in pheochromocytoma liver metastases (19.1 ± 3.2% injected dose per gram of tumor (%ID/g) compared to liver metastases in pretreatment scans 5.9 ± 0.6%; P0.001). Biodistribution analysis after inhibitors treatment confirmed the PET results. The uptake of [(123)I]MIBG was significantly increased in liver metastases 9.5 ± 1.1% compared to 3.19 ± 0.4% in untreated control liver metastases (P0.05). We found that HDAC inhibitors caused an increase in the amount of norepinephrine transporter expressed in tumors. HDAC inhibitors may enhance the therapeutic efficacy of [(131)I]MIBG treatment in patients with advanced malignant pheochromocytoma and paraganglioma.

Signs and symptoms associated with pheochromocytomas are predominantly caused by catecholamine excess, but tend to be highly variable and non-specific. In this study, we evaluated 23 male and 35 female pheochromocytoma patients for symptoms and signs of pheochromocytoma with special regard to gender-related differences in presentation. Total symptom score comparison between genders showed significant differences (12.0 vs. 7.8, P-value 0.0001). Female patients reported significantly more headache (80% vs. 52%), dizziness (83% vs. 39%), anxiety (85% vs. 50%), tremor (64% vs. 33%), weight change (88% vs. 43%), numbness (57% vs. 24%), and changes in energy level (89% vs. 64%). Females and males displayed comparable biochemical phenotypes (60% and 65% noradrenergic phenotype, respectively). Use of alpha- and/or beta-blockade between males and females did not differ significantly. Subgroup analyses and multiple regression analysis revealed gender differences to be irrespective of benign or malignant disease, use of adrenoceptor-blockade, age and biochemical phenotype. We conclude female patients have significantly more self-reported pheochromocytoma signs and symptoms than male patients irrespective of biochemical phenotype and tumor presentation which may be related to distinct catecholamine receptor sensitivity. Clinicians should be aware of these complaints in female pheochromocytoma patients and offer adequate treatment if indicated.

Recombinant adenoviruses (rAd) have been widely used as gene transfer vectors both in the laboratory and in human clinical trials. In the present study, we investigated the effects of adenoviral-mediated gene transfer in primary bovine adrenal chromaffin cells (BACC) and a murine pheochromocytoma cell line (MPC). Cells were infected with one of three nonreplicating E1/E3-deleted (E1(-)/E3(-)) rAd vectors: Ad.GFP, expressing a green fluorescent protein (GFP); Ad.null, expressing no transgene; or Ad.C2.TK, expressing the herpes simplex virus-1 thymidine kinase gene (TK). Forty-eight hours after exposure to Ad.GFP, the percentage of GFP-expressing BACC ranged from 23.5-97% in a dose-dependent manner and similarly from 1.06-84.4% in the MPC, indicating that adrenomedullary cells are a potentially valuable target for adenoviral-mediated gene transfer. Ultrastructural analysis, however, revealed profound changes in the nucleus and mitochondria of cells infected with rAd. Furthermore, infection of BACC with Ad.null was accompanied by a time- and dose-dependent decrease in cell survival due to the vector alone. Specific whole-cell norepinephrine uptake was also decreased in a time- and dose-dependent fashion in BACC. Infection of MPC cells with the Ad.C2.TK vector sensitized them to the cytotoxic effect of the antiviral drug ganciclovir, in direct proportion to the fraction of cells infected with the virus. We conclude that rAd may alter the structural and functional integrity of adrenomedullary cells, potentially interfering with the normal stress response. At the same time, in light of their ability to effectively deliver and express genes in pheochromocytoma cells, they may be applicable to the gene therapy of adrenomedullary tumors.

Mitochondrial research has influenced concepts in anthropology, human physiology and pathophysiology. We present here direct evidence that human recombinant viruses can localize in mitochondria to disrupt their integrity. This finding, while opening new perspectives in viral gene therapy, may provide new insights into the pathogenesis, prevention and treatment of viral diseases. In addition, it may advance the current understanding of cell evolution.