ABSTRACT Objective: This study aimed to present a temporal and spatial analysis of the 2018 measles outbreak in Brazil, particularly in the metropolitan city of Manaus in the Amazon region, and further introduce a new tool for spatial analysis. Methods: We analyzed the geographical data of the residences of over 7,000 individuals with measles in Manaus during 2018 and 2019. Spatial and temporal analyses were conducted to characterize various aspects of the outbreak, including the onset and prevalence of symptoms, demographics, and vaccination status. A visualization tool was also constructed to display the geographical and temporal distribution of the reported measles cases. Results: Approximately 95% of the included participants had not received vaccination within the past decade. Heterogeneity was observed across all facets of the outbreak, including variations in the incubation period and symptom presentation. Age distribution exhibited two peaks, occurring at one year and 18 years of age, and the potential implications of this distribution on predictive analysis were discussed. Additionally, spatial analysis revealed that areas with the highest case densities tended to have the lowest standard of living. Conclusion: Understanding the spatial and temporal spread of measles outbreaks provides insights for decision-making regarding measures to mitigate future epidemics. Objective 201 Brazil region Methods 7000 7 000 7,00 2019 symptoms demographics status cases Results 95 decade presentation peaks 1 age discussed Additionally living Conclusion decisionmaking decision making epidemics 20 700 00 7,0 9 2 70 0 7,

ABSTRACT Objective To investigate the factors influencing carbon dioxide transfer in a system that integrates an oxygenation membrane in series with high-bicarbonate continuous veno-venous hemodialysis in hypercapnic animals. Methods In an experimental setting, we induced severe acute kidney injury and hypercapnia in five female Landrace pigs. Subsequently, we initiated high (40mEq/L) bicarbonate continuous veno-venous hemodialysis with an oxygenation membrane in series to maintain a pH above 7.25. At intervals of 1 hour, 6 hours, and 12 hours following the initiation of continuous veno-venous hemodialysis, we performed standardized sweep gas flow titration to quantify carbon dioxide transfer. We evaluated factors associated with carbon dioxide transfer through the membrane lung with a mixed linear model. Results A total of 20 sweep gas flow titration procedures were conducted, yielding 84 measurements of carbon dioxide transfer. Multivariate analysis revealed associations among the following (coefficients ± standard errors): core temperature (+7.8 ± 1.6 °C, p < 0.001), premembrane partial pressure of carbon dioxide (+0.2 ± 0.1/mmHg, p < 0.001), hemoglobin level (+3.5 ± 0.6/g/dL, p < 0.001), sweep gas flow (+6.2 ± 0.2/L/minute, p < 0.001), and arterial oxygen saturation (-0.5 ± 0.2%, p = 0.019). Among these variables, and within the physiological ranges evaluated, sweep gas flow was the primary modifiable factor influencing the efficacy of low-blood-flow carbon dioxide removal. Conclusion Sweep gas flow is the main carbon dioxide removal-related variable during continuous veno-venous hemodialysis with a high bicarbonate level coupled with an oxygenator. Other carbon dioxide transfer modulating variables included the hemoglobin level, arterial oxygen saturation, partial pressure of carbon dioxide and core temperature. These results should be interpreted as exploratory to inform other well-designed experimental or clinical studies. highbicarbonate venovenous veno venous animals setting pigs Subsequently 40mEq/L 40mEqL mEqL 40mEq L mEq (40mEq/L 725 7 25 7.25 hour model 2 conducted 8 coefficients errors errors) +7.8 78 (+7. 16 1. C °C 0.001, 0001 0.001 , 0 001 0.001) +0.2 02 (+0. 01mmHg mmHg 0.1/mmHg +3.5 35 3 5 (+3. 06gdL gdL g dL 0.6/g/dL +6.2 62 (+6. 02Lminute Lminute minute 0.2/L/minute 0.5 05 (-0. 0.2% 0.019. 0019 0.019 . 019 0.019) lowbloodflow low blood removal removalrelated related oxygenator welldesigned well designed studies 72 7.2 +7. (+7 000 0.00 00 +0. (+0 +3. (+3 +6. (+6 0. (-0 0.2 0.01 01 7. +7 (+ 0.0 +0 +3 +6 (- + (

RESUMO Objetivo Investigar os fatores que influenciam a transferência de dióxido de carbono em um sistema que integra uma membrana de oxigenação em série com terapia de substituição renal contínua com alto teor de bicarbonato em animais hipercápnicos. Métodos Em um ambiente experimental, induzimos lesão renal aguda grave e hipercapnia em cinco porcos Landrace fêmeas. Em seguida, iniciamos terapia de substituição renal contínua com alto teor de bicarbonato (40mEq/L) com uma membrana de oxigenação em série para manter o pH acima de 7,25. Em intervalos de 1 hora, 6 horas e 12 horas após o início da terapia de substituição renal contínua, realizamos uma titulação padronizada do fluxo de gás de varredura para quantificar a transferência de dióxido de carbono. Avaliamos os fatores associados à transferência de dióxido de carbono através da membrana pulmonar com um modelo linear misto. Resultados Realizamos 20 procedimentos de titulação do fluxo de gás de varredura, produzindo 84 medições de transferência de dióxido de carbono. A análise multivariada revelou associações entre os seguintes itens (coeficientes ± erros padrão): temperatura central (+7,8 ± 1,6 °C, p < 0,001), pressão parcial pré-membrana de dióxido de carbono (+0,2 ± 0,1mmHg, p < 0,001), nível de hemoglobina (+3,5 ± 0,6g/dL, p < 0,001), fluxo de gás de varredura (+6,2 ± 0,2L/minuto, p < 0,001) e saturação de oxigênio (-0,5% ± 0,2%, p = 0,019). Entre essas variáveis, e dentro das faixas fisiológicas avaliadas, o fluxo do gás de varredura foi o principal fator modificável que influenciou a eficácia da remoção de dióxido de carbono de baixo fluxo sanguíneo. Conclusão O fluxo do gás de varredura é a principal variável relacionada à remoção de dióxido de carbono durante a terapia de substituição renal contínua com um alto nível de bicarbonato acoplado a um oxigenador. Outras variáveis moduladoras da transferência de dióxido de carbono incluíram o nível de hemoglobina, a saturação de oxigênio, a pressão parcial de dióxido de carbono e a temperatura central. Esses resultados devem ser interpretados como exploratórios para informar outros estudos experimentais ou clínicos bem planejados. hipercápnicos experimental fêmeas seguida 40mEq/L 40mEqL mEqL 40mEq L mEq (40mEq/L 725 7 25 7,25 hora misto 2 8 coeficientes padrão padrão) +7,8 78 (+7, 16 1, C °C 0,001, 0001 0,001 , 0 001 prémembrana pré +0,2 02 (+0, 01mmHg mmHg 1mmHg 0,1mmHg +3,5 35 3 5 (+3, 06gdL gdL 6g dL g 0,6g/dL +6,2 62 (+6, 02Lminuto Lminuto 2L minuto 0,2L/minuto 0,5% 05 (-0,5 0,2% 0,019. 0019 0,019 . 019 0,019) avaliadas sanguíneo oxigenador planejados 72 7,2 +7, (+7 000 0,00 00 +0, (+0 +3, (+3 +6, (+6 0,5 (-0, 0,2 0,01 01 7, +7 (+ 0,0 +0 +3 +6 0, (-0 + ( (-

ABSTRACT From 1913 onwards, the global situation changed from a scenario of nitrogen (N) scarcity to an abundance of ammonia (NH3) produced synthetically via the Haber-Bosch process. Several N compounds have been synthesized since then, with urea becoming the main source of N, accounting for 55 % of current N consumption. However, N efficiency in agroecosystems is low and, normally, N recovery in cultivated plants is less than 50 %. This occurs because a large amount of reactive N is lost to the environment, inducing various forms of pollution, threatening human and environmental health, in addition to causing a negative economic impact on the farmer. The main processes responsible for low N efficiency are NH3 volatilization, leaching, and N denitrification. Considering global NH3 volatilization losses of 14 %, it can be assumed that up to 8.6 million Mg of urea are lost every year in the form of NH3. For each ton of NH3 produced, 1.9 to 3.8 Mg of CO2 is emitted into the atmosphere. Therefore, increasing N use efficiency (NUE) without compromising yield is a necessity and a challenge for crop improvement programs and current management systems, in addition to reducing greenhouse gas emissions. In this context, enhanced efficiency fertilizers (EEFs), which contain technologies that minimize the potential for nutrient losses compared to conventional sources, are an alternative to increasing the efficiency of nitrogen fertilization. Currently, EEFs are classified into three categories: stabilized, slow-release, and controlled-release. This study aims to understand the technologies used to produce EEFs and the factors that govern their availability to plants. This review covers the following topics: the discovery of N, N dynamics in the soil-atmosphere system, N assimilation in plants, strategies to increase NUE in agrosystems, NH3 synthesis, NH3 volatilization losses, N fertilizer technologies, the importance of characterization of EEFs, conventional nitrate or ammonium-based fertilizers to reduce gaseous losses of NH3 and future prospects for the use of N fertilizers in agriculture. 191 onwards (N NH (NH3 HaberBosch Haber Bosch process then 5 consumption However normally environment pollution health farmer leaching denitrification 1 86 8 6 8. 19 9 1. 38 3 3. CO atmosphere Therefore (NUE systems emissions context , (EEFs) sources fertilization Currently categories stabilized slowrelease, slowrelease slow release, release slow-release controlledrelease. controlledrelease controlled release. controlled-release topics soilatmosphere soil system agrosystems synthesis ammoniumbased ammonium based agriculture (NH (EEFs

ABSTRACT Objective: The occurrence of partial remission (honeymoon phase) in type 1 diabetes (T1D) has been associated with a reduced risk of chronic microvascular complications of diabetes. We have published case reports showing that a combination therapy with the DPP-4 inhibitor sitagliptin plus vitamin D3 (VIDPP-4i) can prolong the honeymoon phase in patients with new-onset T1D. In the present case-control study, we investigated the frequency of occurrence of clinical remission (CR) in patients with new-onset T1D after VIDPP-4i treatment. Subjects and methods: In this case-control study, we collected data spanning 10 years from medical records of 46 patients (23 females) recently diagnosed with T1D. Overall, 27 participants with CR (insulin dose-adjusted glycated hemoglobin [IDAA1c] ≤ 9) at 12 or 24 months composed the case group, and 19 participants without CR served as the control group. Chi-square with Yates correction was used to analyze the association between VIDPP-4i use and CR, and odds ratio (OR) was used to determine the chance of CR due to VIDPP-4i treatment exposure. Results: In all, 37 patients (80.4%) experienced CR at some time over 24 months. The mean CR duration was 13.15 ± 9.91 months. Treatment with VIDPP-4i was significantly associated with CR. At 24 months, the OR of CR after VIDPP-4i exposure was 9.0 (95% confidence interval [CI] 2.21-30.18, p = 0.0036). Additionally, 9 (33.6%) and 4 (14.8%) patients in the VIDPP-4i group experienced insulin-free CR at 12 and 24 months, respectively. Conclusion: Therapy with VIDPP-4i was associated with a higher frequency and duration of the honeymoon phase. Randomized controlled trials are needed to confirm these findings. Objective TD T D (T1D DPP4 DPP DPP- VIDPP4i VIDPPi VIDPP 4i i (VIDPP-4i newonset new onset casecontrol study (CR methods 23 (2 females Overall 2 insulin doseadjusted dose adjusted IDAA1c IDAAc IDAA c [IDAA1c Chisquare Chi square (OR Results all 3 80.4% 804 80 (80.4% 1315 13 15 13.1 991 91 9.9 90 0 9. 95% 95 (95 CI [CI 2.2130.18, 2213018 2.21 30.18, 21 30 18 2.21-30.18 0.0036. 00036 0.0036 . 0036 0.0036) Additionally 33.6% 336 33 6 (33.6% 14.8% 148 14 8 (14.8% insulinfree free respectively Conclusion findings ( 80.4 (80.4 131 13. 99 (9 2130 2.2130.18 221301 221 2.2 3018 30.18 2.21-30.1 0003 0.003 003 33.6 (33.6 14.8 (14.8 80. (80. 213 2.2130.1 22130 22 2. 301 30.1 2.21-30. 000 0.00 00 33. (33. 14. (14. (80 2.2130. 2213 30. 2.21-30 0.0 (33 (14 (8 2.2130 2.21-3 0. (3 (1 2.213 2.21-

ABSTRACT Objective: To characterize the pressures, resistances, oxygenation, and decarboxylation efficacy of two oxygenators associated in series or in parallel during venous-venous extracorporeal membrane oxygenation support. Methods: Using the results of a swine severe respiratory failure associated with multiple organ dysfunction venous-venous extracorporeal membrane oxygenation support model and mathematical modeling, we explored the effects on oxygenation, decarboxylation and circuit pressures of in-parallel and in-series associations of oxygenators. Results: Five animals with a median weight of 80kg were tested. Both configurations increased the oxygen partial pressure after the oxygenators. The return cannula oxygen content was also slightly higher, but the impact on systemic oxygenation was minimal using oxygenators with a high rated flow (~ 7L/minute). Both configurations significantly reduced the systemic carbon dioxide partial pressure. As the extracorporeal membrane oxygenation blood flow increased, the oxygenator resistance decreased initially with a further increase with higher blood flows but with a small clinical impact. Conclusion: Association of oxygenators in parallel or in series during venous-venous extracorporeal membrane oxygenation support provides a modest increase in carbon dioxide partial pressure removal with a slight improvement in oxygenation. The effect of oxygenator associations on extracorporeal circuit pressures is minimal. Objective resistances venousvenous venous Methods modeling inparallel inseries Results kg tested ~ ( 7L/minute. 7Lminute Lminute 7L/minute . 7L minute L 7L/minute) Conclusion

RESUMO Objetivo: Caracterizar as pressões, as resistências, a oxigenação e a eficácia da descarboxilação de dois oxigenadores associados em série ou em paralelo durante o suporte com oxigenação veno-venosa por membrana extracorpórea. Métodos: Usando os resultados de insuficiência respiratória grave em suínos associada à disfunção de múltiplos órgãos, ao modelo de suporte com oxigenação por membrana extracorpórea veno-venosa e à modelagem matemática, exploramos os efeitos na oxigenação, descarboxilação e pressões do circuito de associações de oxigenadores em paralelo e em série. Resultados: Testaram-se cinco animais com peso mediano de 80kg. Ambas as configurações aumentaram a pressão parcial de oxigênio após os oxigenadores. O teor de oxigênio da cânula de retorno também foi ligeiramente maior, mas o efeito na oxigenação sistêmica foi mínimo, usando oxigenadores com alto fluxo nominal (~ 7L/minuto). Ambas as configurações reduziram significativamente a pressão parcial de dióxido de carbono sistêmico. Como o fluxo sanguíneo na oxigenação por membrana extracorpórea aumentou, a resistência do oxigenador diminuiu inicialmente, com aumento posterior, com fluxos sanguíneos mais altos, mas pouco efeito clínico. Conclusão: A associação de oxigenadores em paralelo ou em série durante o suporte com oxigenação veno-venosa por membrana extracorpórea proporciona um modesto aumento na depuração da pressão parcial de dióxido de carbono, com leve melhora na oxigenação. O efeito das associações de oxigenadores nas pressões de circuitos extracorpóreos é mínimo. Objetivo resistências venovenosa veno venosa Métodos órgãos matemática Resultados Testaramse Testaram se 80kg kg maior mínimo ~ ( 7L/minuto. 7Lminuto Lminuto 7L/minuto . 7L minuto L 7L/minuto) sistêmico aumentou inicialmente posterior altos clínico Conclusão

RESUMO Objetivo: Avaliar a adesão ao protocolo de profilaxia de úlcera de estresse em pacientes críticos de um hospital universitário terciário. Métodos: Neste estudo de coorte prospectiva, incluímos todos os pacientes adultos admitidos às unidades de terapia intensiva clínica e cirúrgica de um hospital terciário acadêmico. Nosso único critério de exclusão foi a presença de sangramento gastrointestinal alto quando da admissão à unidade de terapia intensiva. Colhemos as variáveis basais e indicações de profilaxia de úlcera de estresse, segundo o protocolo institucional, assim como o uso de profilaxia. Nosso desfecho primário foi a adesão ao protocolo de profilaxia de úlcera de estresse. Os desfechos secundários foram uso apropriado da profilaxia de úlcera de estresse, incidência de sangramento gastrointestinal superior e fatores associados com o uso apropriado da profilaxia de úlcera de estresse. Resultados: Foram incluídos 234 pacientes no período compreendido entre 2 de julho e 31 de julho de 2018. Os pacientes tinham idade de 52 ± 20 anos, sendo 125 (53%) deles cirúrgicos, e o SAPS 3 médio foi de 52 ± 20. No seguimento longitudinal, foram estudados 1.499 pacientes-dias; 1.069 pacientes-dias tiveram indicação de profilaxia de úlcera de estresse, e 777 pacientes-dias tiveram uso profilático (73% de adesão ao protocolo de profilaxia de úlcera de estresse). Dentre os 430 pacientes-dias sem indicações de profilaxia de úlcera de estresse, 242 envolveram profilaxia (56% de uso impróprio de profilaxia de úlcera de estresse). O total de uso apropriado de profilaxia de úlcera de estresse foi de 64%. Fatores associados com prescrição adequada de profilaxia de úlcera de estresse foram ventilação mecânica, com RC 2,13 (IC95% 1,64 - 2,75), e coagulopatia, com RC 2,77 (IC95% 1,66 - 4,60). A incidência de sangramento do trato gastrointestinal superior foi de 12,8%. Conclusão: A adesão ao protocolo de profilaxia de úlcera de estresse foi baixa, e o uso inadequado de profilaxia de úlcera de estresse foi frequente nesta coorte de pacientes críticos.

ABSTRACT Objective: To evaluate adherence to the stress ulcer prophylaxis protocol in critically ill patients at a tertiary university hospital. Methods: In this prospective cohort study, we included all adult patients admitted to the medical and surgical intensive care units of an academic tertiary hospital. Our sole exclusion criterion was upper gastrointestinal bleeding at intensive care unit admission. We collected baseline variables and stress ulcer prophylaxis indications according to the institutional protocol and use of prophylaxis. Our primary outcome was adherence to the stress ulcer prophylaxis protocol. Secondary outcomes were appropriate use of stress ulcer prophylaxis, upper gastrointestinal bleeding incidence and factors associated with appropriate use of stress ulcer prophylaxis. Results: Two hundred thirty-four patients were enrolled from July 2nd through July 31st, 2018. Patients were 52 ± 20 years old, 125 (53%) were surgical patients, and the mean SAPS 3 was 52 ± 20. In the longitudinal follow-up, 1499 patient-days were studied; 1069 patient-days had stress ulcer prophylaxis indications, and 777 patient-days contained prophylaxis use (73% stress ulcer prophylaxis protocol adherence). Of the 430 patient-days without stress ulcer prophylaxis indications, 242 involved prophylaxis (56% inappropriate stress ulcer prophylaxis use). The overall appropriate use of stress ulcer prophylaxis was 64%. Factors associated with proper stress ulcer prophylaxis prescription were mechanical ventilation OR 2.13 (95%CI 1.64 - 2.75) and coagulopathy OR 2.77 (95%CI 1.66 - 4.60). The upper gastrointestinal bleeding incidence was 12.8%. Conclusion: Adherence to the stress ulcer prophylaxis protocol was low and inappropriate use of stress ulcer prophylaxis was frequent in this cohort of critically ill patients.

OBJETIVO: Descrever as manifestações extra-articulares (cardíacas, renais, pulmonares e neurológicas) geralmente não relacionadas às espondiloartrites (EpA) em uma grande coorte de pacientes brasileiros. MÉTODOS: Este estudo retrospectivo analisou 1.472 pacientes com o diagnóstico de EpA atendidos em 29 centros distribuídos pelas cinco principais regiões geográficas do Brasil, integrantes do Registro Brasileiro de Espondiloartrites. Todos os pacientes foram avaliados para a prevalência das principais manifestações extra-articulares (cardíacas, renais, pulmonares e neurológicas), divididas por diagnóstico [espondilite anquilosante (EA), artrite psoriásica (AP), artrite reativa (ARe), artrite associada a doença inflamatória intestinal (DII), EpA indiferenciada (EI) e EpA juvenil] e por forma clínica (axial, periférica, mista e entesítica). RESULTADOS: Dentre os pacientes avaliados com EpA, 963 apresentavam EA, 271 AP, 49 ARe, 48 artrite associada a DII, 98 EI e 43 EpA juvenil. Acometimento cardíaco foi observado em 44 pacientes (3,0%), seguido por acometimento pulmonar em 19 (1,3%), renal em 17 (1,2%) e neurológico em 13 pacientes (0,9%). A maioria dos casos de acometimento visceral ocorreu nos pacientes com EA ou AP e naqueles com forma clínica mista (axial e periférica) e/ou predominantemente axial. CONCLUSÃO: As manifestações extra-articulares cardíacas, renais, pulmonares e neurológicas são muito pouco frequentes nas EpA, variando de 0,9%-3% nesta grande coorte brasileira, estando mais associadas a EA e AP.

OBJECTIVE: To describe the extra-articular manifestations (cardiac, renal, pulmonary, and neurological), usually not related to spondyloarthritis (SpA), in a large cohort of Brazilian patients. MATERIALS AND METHODS: This retrospective study analyzed 1,472 patients diagnosed with SpA and cared for at 29 health care centers distributed in the five major geographic regions in the country, participating in the Brazilian Registry of Spondyloarthritis (BRS). All patients were assessed for the prevalence of major extra-articular manifestations (cardiac, renal, pulmonary, and neurological), classified according to the diagnosis [ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with inflammatory bowel disease (IBD), undifferentiated spondyloarthritis (uSpA), and juvenile SpA], and according to the clinical presentation (axial, peripheral, mixed, and enthesitis). RESULTS: Of the patients with SpA assessed, 963 had AS, 271 PsA, 49 ReA, 48 arthritis associated with IBD, 98 uSpA, and 43 juvenile SpA. Cardiac involvement was reported in 44 patients (3.0%), pulmonary involvement in 19 (1.3%), renal involvement in 17 (1.2%), and neurological involvement in 13 patients (0.9%). Most patients with visceral involvement had AS or PsA, and the mixed (axial + peripheral) and/or predominantly axial clinical form. CONCLUSION: Cardiac, renal, pulmonary, and neurological extra-articular manifestations are quite infrequent in SpA, ranging from 0.9% to 3% in this large Brazilian cohort, and affected predominantly patients with AS and PsA.

Relatamos caso de hipertireoidismo em um homem de 37 anos, no qual a paralisia periódica hipocalêmica apresentou-se como primeiro sintoma desta patologia. Abordamos aspectos do diagnóstico diferencial com outras formas de paralisia periódica e destacamos a necessidade de realizar um correto diagnóstico desta patologia, a fim de evitar complicações clínicas e degeneração muscular permanente.

We report a case of thyrotoxicosis in a 37 year old male, in whom hypocalemic periodic paralysis was the first manifestation of the disease. We comment about the differential diagnosis with other types of periodic paralysis, and the importance of a correct diagnosis to avoid permanent muscle damage.

A doença de Cushing é rara em crianças e sua ocorrência em gêmeos é ainda mais rara. O presente estudo relata a ocorrência de gêmeas idênticas discordantes quanto à doença de Cushing. Uma das gêmeas, desenvolveu síndrome de Cushing aos 10 anos de idade. Sua investigação demonstrou cortisol urinário elevado, ACTH sérico elevado e testes de supressão com dexametasona compatíveis com doença de Cushing. A RMN mostrou macroadenoma hipofisário que foi operado por via transesfenoidal. O estudo imuno-histoquímico confirmou a presença de células produtoras de ACTH. A paciente entrou em remissão clínica e laboratorial desde a cirurgia. Após o desaparecimento dos estigmas do Cushing, a paciente reiniciou ganho estatural, mas permanece menor que sua irmã gêmea. Esta última permanece saudável 4 anos após o início da doença de sua irmã. Este é o terceiro caso do gênero relatado na literatura. Estes achados sugerem que fatores não genéticos estão envolvidos na gênese da doença de Cushing.

Cushing's disease is rare in children and its ocurrence in identical twins is extremely rare. This paper reports on identical twins discordant for Cushing's disease. One of them first presented with a cushingoid phenotype by the age of 10. Her evaluation showed an increased urinary free-cortisol and serum ACTH. Her pattern in the dexametazone supression tests was compatible with Cushing's disease. MRI disclosed a pituitary macroadenoma which was removed by the transesphenoidal approach. Immunohistochemical studies of the tumor showed the presence of ACTH-producing cells. The patient went into clinical and laboratorial remission after surgery. She re-started to grow after the disappearance of the Cushing's phenotype but she is still shorter than her healthy sister. The latter remains disease-free 4 years after her sister's diagnosis. This represents the third such case reported in the literature. Our findings suggest that acquired factors may be responsible for the genesis of Cushing's disease.