A developmental gradient reveals biosynthetic pathways to eukaryotic toxins in monocot geophytes.

Numerous eukaryotic toxins that accumulate in geophytic plants are valuable in the clinic, yet their biosynthetic pathways have remained elusive. A lead example is the >150 Amaryllidaceae alkaloids (AmAs) including galantamine, an FDA-approved treatment for Alzheimer's disease. We show that while AmAs accumulate to high levels in many tissues in daffodils, biosynthesis is localized to nascent, growing tissue at the base of leaves. A similar trend is found for the production of steroidal alkaloids (e.g. cyclopamine) in corn lily. This model of active biosynthesis enabled elucidation of a complete set of biosynthetic genes for the production of AmAs. Taken together, our work sheds light on the developmental and enzymatic logic of diverse alkaloid biosynthesis in daffodil. More broadly, it suggests a paradigm for biosynthesis regulation in monocot geophytes where plants are protected from herbivory through active charging of newly formed cells with eukaryotic toxins that persist as aboveground tissue develops.

Distinct Hemodynamic Responses That Culminate With Postural Orthostatic Tachycardia Syndrome.

It is of paramount importance to characterize the individual hemodynamic response of patients with postural orthostatic tachycardia syndrome (POTS) to select the best therapeutic intervention. Our aim in this study was to describe the hemodynamic changes in 40 patients with POTS during the head-up tilt test and compare them with 48 healthy patients. Hemodynamic parameters were obtained by cardiac bioimpedance. Patients were compared in supine position and after 5, 10, 15, and 20 minutes of orthostatic position. Patients with POTS demonstrated higher heart rate (74 beats per minute [64 to 80] vs 67 [62 to 72], p <0.001) and lower stroke volume (SV) (83.0 ml [72 to 94] vs 90 [79 to 112], p <0.001) at supine position. The response to orthostatic challenge was characterized by a decrease in SV index (SVI) in both groups (ΔSVI in ml/m2: -16 [-25 to -7.] vs -11 [-17 to -6.1], p = NS). Peripheral vascular resistance (PVR) was reduced only in POTS (ΔPVR in dyne.seg/cm5:-52 [-279 to 163] vs 326 [58 to 535], p <0.001). According to the best cut-off points obtained using the receiver operating characteristic analysis for the variation of SVI (-15.5%) and PVR index (PVRI) (-5.5%), we observed 4 distinct groups of POTS: 10% presented an increase in both SVI and PVRI after the orthostatic challenge, 35% presented a PVRI decrease with SVI maintenance or increase, 37.5% presented an SVI decrease with PVRI maintenance or elevation, and 17.5% presented a reduction in both variables. Body mass index, ΔSVI, and ΔPVRI were strongly correlated with POTS (area under the curve = 0.86 [95% confidence interval 0.77 to 0.92], p <0.0001). In conclusion, the use of appropriate cut-off points for hemodynamic parameters using bioimpedance cardiography during the head-up tilt test could be a useful strategy to identify the main mechanism involved and to select the best individual therapeutic strategy in POTS.

Tertiary Syphilis Masquerading as Oropharyngeal Cancer.

Syphilis is re-emerging in the United States. Treponema pallidum, the spirochete bacterium responsible for syphilis, has immunoevasive properties that facilitate pathogenesis and widespread tissue involvement. Host immune status, particularly the presence of HIV/AIDS, can influence the presentation and severity of the disease. Patients co-infected with HIV and syphilis may develop atypical lesions, including those involving the oropharynx. Any immunocompromised patient with tongue lesions and lymphadenopathy is presumed to have a wide differential diagnosis, and tissue sampling with histopathologic analysis is indicated. We present a patient with gumma of the tongue as the initial manifestation of tertiary syphilis.

Dysautonomia: A Forgotten Condition - Part 1. / Disautonomia: Uma Condição Esquecida ­ Parte 1.

Dysautonomia covers a range of clinical conditions with different characteristics and prognoses. They are classified as Reflex Syndromes, Postural Orthostatic Tachycardia Syndrome (POTS), Chronic Fatigue Syndrome, Neurogenic Orthostatic Hypotension (nOH) and Carotid Sinus Hypersensitivity Syndrome. Reflex (vasovagal) syndromes will not be discussed in this article. Reflex (vasovagal) syndromes are mostly benign and usually occur in patients without an intrinsic autonomic nervous system (ANS) or heart disease. Therefore, they are usually studied separately. Cardiovascular Autonomic Neuropathy (CAN) is the term most currently used to define dysautonomia with impairment of the sympathetic and/or parasympathetic cardiovascular autonomic nervous system. It can be idiopathic, such as multisystemic atrophy or pure autonomic failure, or secondary to systemic pathologies such as diabetes mellitus, neurodegenerative diseases, Parkinson's disease, dementia syndromes, chronic renal failure, amyloidosis and it may also occur in the elderly. The presence of Cardiovascular Autonomic Neuropathy (CAN) implies greater severity and worse prognosis in various clinical situations. Detection of Orthostatic Hypotension (OH) is a late sign and means greater severity in the context of dysautonomia, defined as Neurogenic Orthostatic Hypotension (nOH). It must be differentiated from hypotension due to hypovolemia or medications, called non-neurogenic orthostatic hypotension (nnOH). OH can result from benign causes, such as acute, chronic hypovolemia or use of various drugs. However, these drugs may only reveal subclinical pictures of Dysautonomia. All drugs of patients with dysautonomic conditions should be reevaluated. Precise diagnosis of CAN and the investigation of the involvement of other organs or systems is extremely important in the clinical suspicion of pandysautonomia. In diabetics, in addition to age and time of disease, other factors are associated with a higher incidence of CAN, such poor glycemic control, hypertension, dyslipidemia and obesity. Among diabetic patients, 38-44% can develop Dysautonomia, with prognostic implications and higher cardiovascular mortality. In the initial stages of DM, autonomic dysfunction involves the parasympathetic system, then the sympathetic system and, later on, it presents as orthostatic hypotension. Valsalva, Respiratory and Orthostatic tests (30:15) are the gold standard methods for the diagnosis of CAN. They can be associated with RR Variability tests in the time domain, and mainly in the frequency domain, to increase the sensitivity (protocol of the 7 tests). These tests can detect initial or subclinical abnormalities and assess severity and prognosis. The Tilt Test should not be the test of choice for investigating CAN at an early stage, as it detects cases at more advanced stages. Tilt response with a dysautonomic pattern (gradual drop in blood pressure without increasing heart rate) may suggest CAN. Treatment of patients at moderate to advanced stages of dysautonomia is quite complex and often refractory, requiring specialized and multidisciplinary evaluation. There is no cure for most types of Dysautonomia at a late stage. NOH patients can progress with supine hypertension in more than 50% of the cases, representing a major therapeutic challenge. The immediate risk and consequences of OH should take precedence over the later risks of supine hypertension and values greater than 160/90 mmHg are tolerable. Sleeping with the head elevated (20-30 cm), not getting up at night, taking short-acting antihypertensive drugs for more severe cases, such as losartan, captopril, clonidine or nitrate patches, may be necessary and effective in some cases. Preventive measures such as postural care; good hydration; higher salt intake; use of compression stockings and abdominal straps; portioned meals; supervised physical activity, mainly sitting, lying down or exercising in the water are important treatment steps. Various drugs can be used for symptomatic nOH, especially fludrocortisone, midodrine and droxidopa, the latter not available in Brazil. The risk of exacerbation or triggering supine hypertension should be considered. Chronic Fatigue Syndrome represents a form of Dysautonomia and has been renamed as a systemic disease of exercise intolerance, with new diagnostic criteria: 1 - Unexplained fatigue, leading to occupational disability for more than 6 months; 2 - Feeling ill after exercising; 3 - Non-restorative sleep; 4 - One of the following findings: cognitive impairment or orthostatic intolerance. Several pathologies today have evolved with chronic fatigue, being called chronic diseases associated with chronic fatigue. Postural orthostatic tachycardia syndrome (POTS), another form of presentation of dysautonomic syndromes, is characterized by sustained elevation of heart rate (HR) ≥30 bpm (≥40 bpm if <20 years) or HR ≥120 bpm, in the first 10 minutes in an orthostatic position or during the tilt test, without classical orthostatic hypotension associated. A slight decrease in blood pressure may occur. Symptoms appear or get worse in an orthostatic position, with dizziness, weakness, pre-syncope, palpitations, and other systemic symptoms being common.

O termo disautonomia abrange um conjunto de condições clínicas com características e prognósticos distintos. Classificam-se em síndromes reflexas, síndrome postural ortostática taquicardizante (SPOT), síndrome da fadiga crônica, Hipotensão Ortostática Neurogênica (HON) e a Síndrome da hipersensibilidade do seio carotídeo. As síndromes reflexas (vasovagal) não serão discutidas neste artigo. As síndromes reflexas (vasovagal) são, na maioria das vezes, benignas, e ocorrem usualmente em pacientes sem doença intrínseca do sistema nervoso autônomo (SNA) ou do coração. Por isso, geralmente são estudadas separadamente. O termo neuropatia autonômica cardiovascular (NAC) é o mais utilizado na atualidade para definir as disautonomias com comprometimento do sistema nervoso autônomo cardiovascular simpático e/ou parassimpático. Pode ser idiopática, como a atrofia multissistêmica ou a falência autonômica pura, ou secundária a patologias sistêmicas como diabetes mellitus, doenças neurodegenerativas, doença de Parkinson, síndromes demenciais, insuficiência renal crônica, amiloidose, podendo também acometer idosos. A presença de neuropatia autonômica cardiovascular (NAC) implica em maior gravidade e pior prognóstico em diversas situações clínicas. A detecção de hipotensão ortostática (HO) é um sinal tardio e significa maior gravidade no contexto das disautonomias, definida como hipotensão ortostática neurogênica (HON). Deve ser diferenciada das hipotensões por hipovolemia ou medicamentosas, chamadas de hipotensão ortostática não neurogênica (HONN). A HO pode decorrer de causas benignas, como a hipovolemia aguda, crônica, ou ao uso de diversos fármacos. Esses fármacos podem, entretanto, apenas desmascarar quadros subclínicos de disautonomia. Deve-se reavaliar todos os fármacos de pacientes com quadros disautonômicos. O diagnóstico preciso de NAC e a investigação do envolvimento de outros órgãos ou sistemas é de extrema importância na suspeita clínica de uma pandisautonomia. No diabético, além da idade e do tempo de doença, outros fatores estão associados a maior ocorrência de NAC, como descontrole glicêmico, hipertensão, dislipidemia e obesidade. Entre os pacientes diabéticos, 38­44% podem evoluir com disautonomia, com implicações prognósticas e maior mortalidade cardiovascular. Nas etapas iniciais da DM, a disfunção autonômica envolve o sistema parassimpático, posteriormente o simpático e mais tardiamente manifesta-se com hipotensão ortostática. Os testes de Valsalva, respiratório e ortostático (30:15) são os métodos de padrão ouro para o diagnóstico de NAC. Eles podem ser associados aos testes de variabilidade RR no domínio do tempo, e principalmente da frequência, para aumento da sensibilidade (protocolo dos 7 testes). Esses testes podem detectar alterações iniciais ou subclínicas e avaliar a gravidade e o prognóstico. O teste de inclinação (tilt test) não deve ser o exame de escolha para investigação de NAC em fase inicial, pois detecta casos em fases mais avançadas. A resposta no tilt com padrão disautonômico (queda gradativa da pressão arterial sem aumento da frequência cardíaca) pode sugerir NAC. O tratamento dos pacientes em fases moderadas a avançadas das disautonomias é bastante complexo e muitas vezes refratário, necessitando de avaliação especializada e multidisciplinar. Não há cura para a maioria das disautonomias em fase tardia. Os pacientes com HON podem evoluir com hipertensão supina em mais de 50% dos casos, representando um grande desafio terapêutico. O risco imediato e as consequências da HO devem ter preferência sobre os riscos mais tardios da hipertensão supina e valores maiores que 160/90 mmHg são toleráveis. Medidas como dormir com a cabeceira elevada (20­30 cm), não levantar à noite, uso de anti-hipertensivo de ação curta noturna para casos mais severos, como a losartana, captopril, clonidina ou adesivos de nitratos, podem ser necessários e efetivos em alguns casos. As medidas preventivas como cuidados posturais, boa hidratação, maior ingesta de sal, uso de meias e cintas abdominais compressoras, refeições fracionadas, atividade física supervisionada principalmente sentada, deitada ou exercícios na água são etapas importantes no tratamento. Diversos fármacos podem ser usados para HON sintomática, principalmente a fludrocortisona, a midodrina e a droxidopa. Esses últimas não estão disponíveis no Brasil. O risco de exacerbação ou desencadeamento de hipertensão supina deve ser considerado. A síndrome da fadiga crônica representa uma forma de disautonomia e tem sido renomeada como doença sistêmica de intolerância ao exercício, com novos critérios diagnósticos: 1 - Fadiga inexplicada, levando a incapacidade para o trabalho por mais que 6 meses; 2 - Mal-estar após exercício; 3 - Sono não reparador; 4 - Mais um dos seguintes achados: comprometimento cognitivo ou intolerância ortostática. Várias patologias na atualidade têm evoluído com fadiga crônica, sendo denominadas de doenças crônicas associadas a fadiga crônica. A síndrome postural ortostática taquicardizante (SPOT), outra forma de apresentação das síndromes disautonômicas, é caracterizada por elevação sustentada da frequência cardíaca (FC) ≥30 bpm (≥40 bpm se <20 anos) ou FC ≥120 bpm, nos primeiros 10 minutos em posição ortostática ou durante o tilt test, sem hipotensão ortostática clássica associada. Pode ocorrer leve redução na pressão arterial. Os sintomas manifestam-se ou pioram em posição ortostática, sendo comuns a tontura, fraqueza, pré-síncope, palpitações, além de outros sintomas sistêmicos.

A Pathogen-Responsive Gene Cluster for Highly Modified Fatty Acids in Tomato.

In response to biotic stress, plants produce suites of highly modified fatty acids that bear unusual chemical functionalities. Despite their chemical complexity and proposed roles in pathogen defense, little is known about the biosynthesis of decorated fatty acids in plants. Falcarindiol is a prototypical acetylenic lipid present in carrot, tomato, and celery that inhibits growth of fungi and human cancer cell lines. Using a combination of untargeted metabolomics and RNA sequencing, we discovered a biosynthetic gene cluster in tomato (Solanum lycopersicum) required for falcarindiol production. By reconstituting initial biosynthetic steps in a heterologous host and generating transgenic pathway mutants in tomato, we demonstrate a direct role of the cluster in falcarindiol biosynthesis and resistance to fungal and bacterial pathogens in tomato leaves. This work reveals a mechanism by which plants sculpt their lipid pool in response to pathogens and provides critical insight into the complex biochemistry of alkynyl lipid production.

Reduced Systolic Volume: Main Pathophysiological Mechanism in Patients with Orthostatic Intolerance?

BACKGROUND: Orthostatic intolerance patients' pathophysiological mechanism is still obscure, contributing to the difficulty in their clinical management. OBJECTIVE: To investigate hemodynamic changes during tilt test in individuals with orthostatic intolerance symptoms, including syncope or near syncope. METHODS: Sixty-one patients who underwent tilt test at - 70° in the phase without vasodilators were divided into two groups. For data analysis, only the first 20 minutes of tilting were considered. Group I was made up of 33 patients who had an increase of total peripheral vascular resistance (TPVR) during orthostatic position; and Group II was made up of 28 patients with a decrease in TPVR (characterizing insufficient peripheral vascular resistance). The control group consisted of 24 healthy asymptomatic individuals. Hemodynamic parameters were obtained by a non-invasive hemodynamic monitor in three different moments (supine position, tilt 10' and tilt 20') adjusted for age. RESULTS: In the supine position, systolic volume (SV) was significantly reduced in both Group II and I in comparison to the control group, respectively (66.4 ±14.9 ml vs. 81.8±14.8 ml vs. 101.5±24.2 ml; p<0.05). TPVR, however, was higher in Group II in comparison to Group I and controls, respectively (1750.5± 442 dyne.s/cm5 vs.1424±404 dyne.s/cm5 vs. 974.4±230 dyne.s/cm5; p<0.05). In the orthostatic position, at 10', there was repetition of findings, with lower absolute values of SV compared to controls (64.1±14.0 ml vs 65.5±11.3 ml vs 82.8±15.6 ml; p<0.05). TPVR, on the other hand, showed a relative drop in Group II, in comparison to Group I. CONCLUSION: Reduced SV was consistently observed in the groups of patients with orthostatic intolerance in comparison to the control group. Two different responses to tilt test were observed: one group with elevated TPVR and another with a relative drop in TPVR, possibly suggesting a more severe failure of compensation mechanisms.

Reduced Systolic Volume: Main Pathophysiological Mechanism in Patients with Orthostatic Intolerance? / Volume Sistólico Reduzido: Mecanismo Fisiopatológico Principal em Pacientes com Intolerância Ortostática?

Abstract Background: Orthostatic intolerance patients' pathophysiological mechanism is still obscure, contributing to the difficulty in their clinical management. Objective: To investigate hemodynamic changes during tilt test in individuals with orthostatic intolerance symptoms, including syncope or near syncope. Methods: Sixty-one patients who underwent tilt test at - 70° in the phase without vasodilators were divided into two groups. For data analysis, only the first 20 minutes of tilting were considered. Group I was made up of 33 patients who had an increase of total peripheral vascular resistance (TPVR) during orthostatic position; and Group II was made up of 28 patients with a decrease in TPVR (characterizing insufficient peripheral vascular resistance). The control group consisted of 24 healthy asymptomatic individuals. Hemodynamic parameters were obtained by a non-invasive hemodynamic monitor in three different moments (supine position, tilt 10' and tilt 20') adjusted for age. Results: In the supine position, systolic volume (SV) was significantly reduced in both Group II and I in comparison to the control group, respectively (66.4 ±14.9 ml vs. 81.8±14.8 ml vs. 101.5±24.2 ml; p<0.05). TPVR, however, was higher in Group II in comparison to Group I and controls, respectively (1750.5± 442 dyne.s/cm5 vs.1424±404 dyne.s/cm5 vs. 974.4±230 dyne.s/cm5; p<0.05). In the orthostatic position, at 10', there was repetition of findings, with lower absolute values of SV compared to controls (64.1±14.0 ml vs 65.5±11.3 ml vs 82.8±15.6 ml; p<0.05). TPVR, on the other hand, showed a relative drop in Group II, in comparison to Group I. Conclusion: Reduced SV was consistently observed in the groups of patients with orthostatic intolerance in comparison to the control group. Two different responses to tilt test were observed: one group with elevated TPVR and another with a relative drop in TPVR, possibly suggesting a more severe failure of compensation mechanisms.

Resumo Fundamento: O mecanismo fisiopatológico de pacientes com intolerância ortostática ainda é obscuro, contribuindo para a dificuldade no manejo clínicos desses pacientes. Objetivo: Investigar as alterações hemodinâmicas durante teste de inclinação (tilt teste) em indivíduos com sintomas de intolerância ortostática, incluindo síncope ou pré-síncope. Métodos: Sessenta e um pacientes, com tilt teste a 70º negativo na fase livre de vasodilatador, foram divididos em dois grupos. Para análise dos dados foram considerados apenas os primeiros 20 minutos de inclinação. Grupo I (33 pacientes) que tiveram elevação da resistência vascular periférica total (RVPT) durante posição ortostática e Grupo II (28 pacientes) com queda da RVPT (caracterizando insuficiência de resistência vascular periférica). O grupo controle consistia de indivíduos saudáveis e assintomáticos (24 indivíduos). Os parâmetros hemodinâmicos foram obtidos por um monitor hemodinâmico não invasivo em 3 momentos distintos (posição supina, tilt 10' e tilt 20'), ajustados para idade. Resultados: Na posição supina, o volume sistólico (VS) foi significantemente reduzido tanto no Grupo II quanto no I, quando comparado ao do Grupo controle, respectivamente (66,4 ±14,9 ml vs. 81,8±14,8 ml vs. 101,5±24,2 ml; p<0,05.) A RVPT, no entanto, foi mais elevada no Grupo II, quando comparada a do Grupo I e controles, respectivamente (1750,5± 442 dyne.s/cm5 vs.1424±404 dyne.s/cm5 vs. 974,4±230 dyne.s/cm5; p<0,05). Na posição ortostática, aos 10', houve repetição dos achados, com valores absolutos inferiores de VS Comparado aos controles (64,1±14,0 ml vs 65,5±11,3 ml vs 82,8±15,6 ml; p<0,05). A RVPT, todavia, apresentou queda relativa no Grupo II comparado ao I. Conclusão: Volume sistólico reduzido foi consistentemente observado nos grupos de pacientes com intolerância ortostática, quando comparado ao grupo controle. Foram observadas duas respostas distintas ao teste de inclinação: um grupo com elevação de RVPT e outro com queda relativa desta, indicando, possivelmente, falência mais acentuada dos mecanismos de compensação.

Head and Neck Non-Melanoma Skin Cancer Treated By Superficial X-Ray Therapy: An Analysis of 1021 Cases.

INTRODUCTION: To report a single-institutional experience with the use of Superficial X-Ray Therapy (SXRT) for head and neck non-melanoma skin cancer (N-MSC) and to compare outcomes by prescribed fractionation schedules. MATERIALS AND METHODS: The medical records of 597 patients with 1021 lesions (720 BCC, 242 SCC, 59 SCC in situ) treated with kilovoltage radiation from 1979-2013 were retrospectively reviewed. The majority of patients were treated according to 1 of 3 institutional protocols based on the discretion of the radiation oncologist: 1) 22 x 2.5 Gy; 2) 20 x 2.5 Gy; 3) 30 x 2.0 Gy. "T" stage at first presentation was as follows: Tis (59); T1 (765); T2 (175); T3 (6), T4 (9); Tx, (7). All patients were clinical N0 and M0 at presentation. Chi-square test was used to evaluate any potential association between variables. The Kaplan-Meier method was used to analyze survival with the Log Rank test used for comparison. A Cox Regression analysis was performed for multivariate analysis. RESULTS: The median follow up was 44 months. No significant difference was observed among the 3 prescribed fractionation schemes (p = 0.78) in terms of RTOG toxicity. There were no failures among SCC in situ, 37 local failures (23 BCC, 14 SCC), 5 regional failures (all SCC) and 2 distant failures (both SCC). For BCC, the 5-year LC was 96% and the 10-year LC was 94%. For SCC the corresponding rates of local control were 92% and 87%, respectively (p = 0.03). The use of >2.0 Gy daily was significantly associated with improved LC on multivariate analysis (HR: 0.17; CI 95%: 0.05-0.59). CONCLUSION: SXRT for N-MSC of the head and neck is well tolerated, achieves excellent local control, and should continue to be recommended in the management of this disease. Fractionation schedules using >2.0 Gy daily appear to be associated with improved LC.

Stereotactic body radiation therapy for prostate cancer: Rational and reasonable.

Stereotactic body radiation therapy (SBRT), a treatment procedure that uses large doses per fraction, is currently being used to treat prostate cancer with external radiation therapy in 4 to 5 treatments. Published series in the clinical use of SBRT in patients with localized prostate cancer demonstrate high efficacy within the available follow-up time periods. Rectal and sexual toxicity profiles have been favorable compared with other radiation techniques and surgery. Urinary toxicity profiles might be more comparable to those observed with brachytherapy, more pronounced in the acute setting. SBRT is technically more challenging, requiring precise geometric targeting with in-room image guidance. The use of large doses per fraction potentially provides unique biological effects on both tumor and normal tissues. Immunologic responses in normal tissues, local stromal microenvironment, and specific antigen-presenting cells induced by such high doses likely contribute to effective tumor kill. Ultimately, SBRT for prostate cancer offers significant logistical advantages, with increased convenience to patients and decreased overall cost to the health care delivery system.

Safety and efficacy of stereotactic body radiation therapy in the treatment of pulmonary metastases from high grade sarcoma.

Introduction. Patients with high-grade sarcoma (HGS) frequently develop metastatic disease thus limiting their long-term survival. Lung metastases (LM) have historically been treated with surgical resection (metastasectomy). A potential alternative for controlling LM could be stereotactic body radiation therapy (SBRT). We evaluated the outcomes from our institutional experience utilizing SBRT. Methods. Sixteen consecutive patients with LM from HGS were treated with SBRT between 2009 and 2011. Routine radiographic and clinical follow-up was performed. Local failure was defined as CT progression on 2 consecutive scans or growth after initial shrinkage. Radiation pneumonitis and radiation esophagitis were scored using Common Toxicity Criteria (CTC) version 3.0. Results. All 16 patients received chemotherapy, and a subset (38%) also underwent prior pulmonary metastasectomy. Median patient age was 56 (12-85), and median follow-up time was 20 months (range 3-43). A total of 25 lesions were treated and evaluable for this analysis. Most common histologies were leiomyosarcoma (28%), synovial sarcoma (20%), and osteosarcoma (16%). Median SBRT prescription dose was 54 Gy (36-54) in 3-4 fractions. At 43 months, local control was 94%. No patient experienced G2-4 radiation pneumonitis, and no patient experienced radiation esophagitis. Conclusions. Our retrospective experience suggests that SBRT for LM from HGS provides excellent local control and minimal toxicity.

Prostate-specific antigen bounce after high-dose-rate monotherapy for prostate cancer.

PURPOSE: To characterize the magnitude and kinetics of prostate-specific antigen (PSA) bounces after high-dose-rate (HDR) monotherapy and determine relationships between certain clinical factors and PSA bounce. METHODS AND MATERIALS: Longitudinal PSA data and various clinical parameters were examined in 157 consecutive patients treated with HDR monotherapy between 1996 and 2005. We used the following definition for PSA bounce: rise in PSA ≥threshold, after which it returns to the prior level or lower. Prostate-specific antigen failure was defined per the Phoenix definition (nadir +2 ng/mL). RESULTS: A PSA bounce was noted in 67 patients (43%). The number of bounces per patient was 1 in 45 cases (67%), 2 in 19 (28%), 3 in 2 (3%), 4 in 0, and 5 in 1 (1%). The median time to maximum PSA bounce was 1.3 years, its median magnitude was 0.7, and its median duration was 0.75 years. Three patients (2%) were noted to have PSA failure. None of the 3 patients who experienced biochemical failure exhibited PSA bounce. In the fully adjusted model for predicting each bounce, patients aged <55 years had a statistically significant higher likelihood of experiencing a bounce (odds ratio 2.22, 95% confidence interval 1.38-3.57, P=.001). There was also a statistically significant higher probability of experiencing a bounce for every unit decrease in Gleason score (odds ratio 1.52, 95% confidence interval 1.01-2.04, P=.045). CONCLUSIONS: A PSA bounce occurs in a significant percentage of patients treated with HDR monotherapy, with magnitudes varying from <1 in 28% of cases to ≥1 in 15%. The median duration of bounce is <1 year. More bounces were identified in patients with lower Gleason score and age <55 years. Further investigation using a model to correlate magnitude and frequency of bounces with clinical variables are under way.

No 72-hour pathological boundary for safe early laparoscopic cholecystectomy in acute cholecystitis: a clinicopathological study.

BACKGROUND: The pathological boundary of acute cholecystitis (AC) between early edematous and late chronic fibrotic inflammation beyond 72 h is well-described. Early laparoscopic cholecystectomy (ELC) is safe in AC but the timing still remains controversial. The aim of this study was to analyze the impact of the duration of symptoms on clinical severity, pathology and outcome in patients who underwent laparoscopic cholecystectomy (LC) for AC during the urgent admission. METHODS: A retrospective analysis of a prospectively collected database of 61 patients who underwent LC for AC over a 6-month period was performed. RESULTS: Of 61 patients 21 (34.43%) received ELC at <72 h and 40 (65.57%) received late LC (LLC) at >72 h. Clinically in the ELC group the majority were mild and in the LLC group the majority were moderate and severe in severity grading as per Tokyo guidelines (P<0.001). Surgical findings and histopathology showed no significant difference in the distribution of simple, phlegmonous and gangrenous cholecystitis between both groups (P=0.94). The majority were completed by a standard four port technique and only one required subtotal cholecystectomy. There was no significant difference between operating time, return to normal activities or hospital stay between both groups. There were no conversions to open cholecystectomy, no wound infections, no intra-abdominal collections, no biliary tract injury or mortality in either group. CONCLUSIONS: The degree of inflammatory change in AC is not dependent on time. LC can be safely performed in AC regardless of timing with a standardized surgical strategy in experienced units.

Stereotactic body radiation therapy and 3-dimensional conformal radiotherapy for stage I non-small cell lung cancer: A pooled analysis of biological equivalent dose and local control.

PURPOSE: To determine the relationship between tumor control probability (TCP) and biological effective dose (BED) for radiation therapy in medically inoperable stage I non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Forty-two studies on 3-dimensional conformal radiation therapy (3D-CRT) and SBRT for stage I NSCLC were reviewed for tumor control (TC), defined as crude local control ≥ 2 years, as a function of BED. For each dose-fractionation schedule, BED was calculated at isocenter using the linear quadratic (LQ) and universal survival curve (USC) models. A scatter plot of TC versus BED was generated and fitted to the standard TCP equation for both models. RESULTS: A total of 2696 patients were included in this study (SBRT: 1640; 3D-CRT: 1056). Daily fraction size was 1.2-4 Gy (total dose: 48-102.9) with 3D-CRT and 6-26 (total dose: 20-66) with SBRT. Median BED was 118.6 Gy (range, 68.5-320.3) and 95.6 Gy (range, 46.1-178.1) for the LQ and USC models, respectively. According to the LQ model, BED to achieve 50% TC (TCD50) was 61 Gy (95% confidence interval, 50.2-71.1). TCP as a function of BED was sigmoidal, with TCP ≥ 90% achieved with BED ≥ 159 Gy and 124 Gy for the LQ and USC models, respectively. CONCLUSIONS: Dose-escalation beyond a BED 159 by LQ model likely translates into clinically insignificant gain in TCP but may result in clinically significant toxicity. When delivered with SBRT, BED of 159 Gy corresponds to a total dose of 53 Gy in 3 fractions at the isocenter.

Pseudotumor cerebri and ciprofloxacin: a case report.

INTRODUCTION: We present a case of ciprofloxacin-associated pseudotumor cerebri in a 22-year-old African American woman. Withdrawal of ciprofloxacin in our patient resulted in complete resolution of ciprofloxacin-associated pseudotumor, as evidenced by a normal neuro-ophthalmic examination and a cerebrospinal fluid opening pressure of 140 mmH20. CASE PRESENTATION: A 22-year-old African American woman presented with a headache of two weeks duration, visual blurring and horizontal diplopia after starting ciprofloxacin for pyelonephritis. An ophthalmic examination revealed that she had left eye esotropia, and a picture of the fundus demonstrated bilateral disc swelling without spontaneous venous pulsations. Magnetic resonance imaging of the brain and a magnetic resonance venogram were normal. A diagnostic lumbar puncture demonstrated an elevated opening pressure of 380mmH2O in a supine position. Laboratory examinations, including a cerebrospinal fluid exam, were unremarkable. CONCLUSION: ciprofloxacin-associated pseudotumor can cause chronic disabling headache and visual complications. Therapy is sub-optimal, often symptomatic, insufficient and complicated by side effects. When ciprofloxacin-associated pseudotumor presents in an atypical population, an inciting agent must be suspected because prompt withdrawal of the agent may lead to complete resolution of symptoms and prevent recurrence of similar episodes.

Myelin-associated glycoprotein protects neurons from excitotoxicity.

In addition to supporting rapid nerve conduction, myelination nurtures and stabilizes axons and protects them from acute toxic insults. One myelin molecule that protects and sustains axons is myelin-associated glycoprotein (MAG). MAG is expressed on the innermost wrap of myelin, apposed to the axon surface, where it interacts with axonal receptors that reside in lateral membrane domains including gangliosides, the glycosylphosphatidylinositol-anchored Nogo receptors, and ß1-integrin. We report here that MAG protection extends beyond the axon to the neurons from which those axons emanate, protecting them from excitotoxicity. Compared to wild type mice, Mag-null mice displayed markedly increased seizure activity in response to intraperitoneal injection of kainic acid, an excitotoxic glutamate receptor agonist. Mag-null mice also had larger lesion volumes in response to intrastriatal injection of the excitotoxin NMDA. Prior injection of a soluble form of MAG partially protected Mag-null mice from NMDA-induced lesions. Hippocampal neurons plated on proteins extracted from wild-type rat or mouse myelin were resistant to kainic acid-induced excitotoxicity, whereas neurons plated on proteins from Mag-null myelin were not. Protection was reversed by anti-MAG antibody and replicated by addition of soluble MAG. MAG-mediated protection from excitotoxicity was dependent on Nogo receptors and ß1-integrin. We conclude that MAG engages membrane-domain resident neuronal receptors to protect neurons from excitotoxicity, and that soluble MAG mitigates excitotoxic damage in vivo.