Selective activation of central thalamic fiber pathway facilitates behavioral performance in healthy non-human primates.

Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat enduring cognitive dysfunctions in structurally brain injured (SBI) patients. However, the mechanisms of CT-DBS that promote restoration of cognitive functions are unknown, and the heterogeneous etiology and recovery profiles of SBI patients contribute to variable outcomes when using conventional DBS strategies,which may result in off-target effects due to activation of multiple pathways. To disambiguate the effects of stimulation of two adjacent thalamic pathways, we modeled and experimentally compared conventional and novel 'field-shaping' methods of CT-DBS within the central thalamus of healthy non-human primates (NHP) as they performed visuomotor tasks. We show that selective activation of the medial dorsal thalamic tegmental tract (DTTm), but not of the adjacent centromedian-parafascicularis (CM-Pf) pathway, results in robust behavioral facilitation. Our predictive modeling approach in healthy NHPs directly informs ongoing and future clinical investigations of conventional and novel methods of CT-DBS for treating cognitive dysfunctions in SBI patients, for whom no therapy currently exists.

Medicine in motion: Opportunities, challenges and data analytics-based solutions for traditional medicine integration into western medical practice.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional pharmacopeias have been developed by multiple cultures and evaluated for efficacy and safety through both historical/empirical iteration and more recently through controlled studies using Western scientific paradigms and an increasing emphasis on data science methodologies for network pharmacology. Traditional medicines represent likely sources of relatively inexpensive drugs for symptomatic management as well as potential libraries of new therapeutic approaches. Leveraging this potential requires hard evidence for efficacy that separates science from pseudoscience. MATERIALS AND METHODS: We performed a review of non-Western medical systems and developed case studies that illustrate the epistemological and practical translative barriers that hamper their transition to integration with Western approaches. We developed a new data analytics approach, in silico convergence analysis, to deconvolve modes of action, and potentially predict desirable components of TM-derived formulations based on computational consensus analysis across cultures and medical systems. RESULTS: Abstraction, simplification and altered dose and delivery modalities were identified as factors that influence actual and perceived efficacy once a medicine is moved from a non-Western to Western setting. Case studies on these factors highlighted issues with translation between non-Western and Western epistemologies, including those where epistemological and medicinal systems drive markets that can be epicenters for zoonoses such as the novel Coronavirus. The proposed novel data science approach demonstrated the ability to identify and predict desirable medicinal components for a test indication, pain. CONCLUSIONS: Relegation of traditional therapies to the relatively unregulated nutraceutical industry may lead healthcare providers and patients to underestimate the therapeutic potential of these medicines. We suggest three areas of emphasis for this field: First, vertical integration and embedding of traditional medicines into healthcare systems would subject them to appropriate regulation and evidence-based practice, as viable integrative implementation mode. Second, we offer a new Bradford-Hill-like framework for setting research priorities and evaluating efficacy, with the goal of rescuing potentially valuable therapies from the nutraceutical market and discrediting those that are pseudoscience. Third, data analytics pipelines offer new capacity to generate new types of TMS-inspired medicines that are rationally-designed based on integrated knowledge across cultures, and also provide an evaluative framework against which to test claims of fidelity and efficacy to TMS made for nutraceuticals.

Myrcene and terpene regulation of TRPV1.

Nociceptive Transient Receptor Potential channels such as TRPV1 are targets for treating pain. Both antagonism and agonism of TRP channels can promote analgesia, through inactivation and chronic desensitization. Since plant-derived mixtures of cannabinoids and the Cannabis component myrcene have been suggested as pain therapeutics, we screened terpenes found in Cannabis for activity at TRPV1. We used inducible expression of TRPV1 to examine TRPV1-dependency of terpene-induced calcium flux responses. Terpenes contribute differentially to calcium fluxes via TRPV1 induced by Cannabis-mimetic cannabinoid/terpenoid mixtures. Myrcene dominates the TRPV1-mediated calcium responses seen with terpenoid mixtures. Myrcene-induced calcium influx is inhibited by the TRPV1 inhibitor capsazepine and Myrcene elicits TRPV1 currents in the whole-cell patch-clamp configuration. TRPV1 currents are highly sensitive to internal calcium. When Myrcene currents are evoked, they are distinct from capsaicin responses on the basis of Imax and their lack of shift to a pore-dilated state. Myrcene pre-application and residency at TRPV1 appears to negatively impact subsequent responses to TRPV1 ligands such as Cannabidiol, indicating allosteric modulation and possible competition by Myrcene. Molecular docking studies suggest a non-covalent interaction site for Myrcene in TRPV1 and identifies key residues that form partially overlapping Myrcene and Cannabidiol binding sites. We identify several non-Cannabis plant-derived sources of Myrcene and other compounds targeting nociceptive TRPs using a data mining approach focused on analgesics suggested by non-Western Traditional Medical Systems. These data establish TRPV1 as a target of Myrcene and suggest the therapeutic potential of analgesic formulations containing Myrcene.

Short communication: Identifying challenges and opportunities for improved nutrient management through the USDA's Dairy Agroecosystem Working Group.

Nutrient management on US dairy farms must balance an array of priorities, some of which conflict. To illustrate nutrient management challenges and opportunities across the US dairy industry, the USDA Agricultural Research Service Dairy Agroecosystems Working Group (DAWG) modeled 8 confinement and 2 grazing operations in the 7 largest US dairy-producing states using the Integrated Farm System Model (IFSM). Opportunities existed across all of the dairies studied to increase on-farm feed production and lower purchased feed bills, most notably on large dairies (>1,000 cows) with the highest herd densities. Purchased feed accounted for 18 to 44% of large dairies' total operating costs compared with 7 to 14% on small dairies (<300 milk cows) due to lower stocking rates. For dairies with larger land bases, in addition to a reduction in environmental impact, financial incentives exist to promote prudent nutrient management practices by substituting manure nutrients or legume nutrients for purchased fertilizers. Environmental priorities varied regionally and were principally tied to facility management for dry-lot dairies of the semi-arid western United States (ammonia-N emissions), to manure handling and application for humid midwestern and eastern US dairies (nitrate-N leaching and P runoff), and pasture management for dairies with significant grazing components (nitrous oxide emissions). Many of the nutrient management challenges identified by DAWG are beyond slight modifications in management and require coordinated solutions to ensure an environmentally and economically sustainable US dairy industry.

We think you can dance! A pilot randomised controlled trial of dance for nursing home residents with moderate to severe dementia.

OBJECTIVES: To evaluate the feasibility of a dance program for people with moderate to severe dementia living in nursing homeswith regards to recruitment and retention, assessment tools, intervention safety, attendance and engagement. DESIGN: Pilot randomised controlled trial with assessments at weeks 0, 16 and 32. SETTING: A nursing home in Sydney, Australia. INTERVENTIONS: Experienced dance teachers conducted dance groups (intervention) or music appreciation and socialisation groups (control) for 45min, three times a week for 16 weeks. MAIN OUTCOME MEASURES: Descriptive statistics for recruitment and retention, adverse events and attendance and engagement. RESULTS: Recruitment was smooth, attrition was17% over 32 weeks. Engagement during the sessions was high, and no serious falls or behavioural incidents occurred. Average attendance was poorer than anticipated for dance groups (67%) in comparison to music groups (89%). A ceiling effect on the Severe Impairment Battery and the logistical challenges of the Clinical Global Impression of Change meant they may not be optimal tools. CONCLUSIONS: It is feasible to conduct a study of group dance for people with moderate to severe dementia in residential care. Choice of attention control condition should be reconsidered.

Should an increase in cerebral neurochemicals following head kicks in full contact karate influence return to play?

BACKGROUND: Cerebral neurochemicals are markers of traumatic brain injury (TBI). OBJECTIVES: The aim of the study was to determine whether kicks to the head (KTH) in full contact karate significantly increased serum concentrations of protein S-100B, and neurone specific enolase (NSE). Kicks to the body (KTB) were also quantified to asses muscle tissue injury. Muscle damage was assessed by analysis of serum total creatine kinase (CK). METHODS: Twenty-four full contact karate practitioners were observed and filmed during actual competition and divided into two main groups post event: (1) Kicks to the head and body group (KTH): n = 12; mean ± SD; age, 30.4 ± 6.7 years; height, 1.74 ± 0.1 m; weight, 79.1 ± 2.1 kg; and (2): Kicks to the body group (KTB): n = 12; mean ± SD; age, 28.2 ± 6.5 years; height, 1.75 ± 0.1 m; weight, 79.2 ± 1.7 kg. The KTH group received direct kicks to the head, while group KTB received kicks and punches to the body. Blood samples were taken before and immediately post-combat for analysis of serum S-100B, NSE, CK and cardiac troponin. RESULTS: Significant increases in serum concentrations of S-100B (0.12 ± 0.17 vs. 0.37 ± 0.26, µg.L(-1)) and NSE (11.8 ± 4.1 vs. 20.2 ± 9.1 ng.mL(-1)) were encountered after combat in the KTH group and CK (123 ± 53 vs. 184 ± 103 U.L(-1)) in the KTB group (all P <0.05). CONCLUSIONS: Head kicks in full contact karate cause elevation of neurochemical markers associated with damaged brain tissue. The severity of injury is related to the early post-traumatic release of protein S-100B and NSE. The early kinetics and appearance post injury can reflect intracranial pathology, and suggest S-100B and NSE are extremely sensitive prognostic markers of TBI.

Differential regulation of calcium signalling pathways by components of Piper methysticum ('Awa).

Kava is a soporific, anxiolytic and relaxant in widespread ritual and recreational use throughout the Pacific. Traditional uses of kava by indigenous Pacific Island peoples reflect a complex pharmacopeia, centered on GABA-ergic effects of the well-characterized kavalactones. However, peripheral effects of kava suggest active components other than the CNS-targeted kavalactones. We have previously shown that immunocytes exhibit calcium mobilization in response to traditionally prepared kava extracts, and that the kavalactones do not induce these calcium responses. Here, we characterize the complex calcium-mobilizing activity of traditionally prepared and partially HPLC-purified kava extracts, noting induction of both calcium entry and store release pathways. Kava components activate intracellular store depletion of thapsigargin-sensitive and -insensitive stores that are coupled to the calcium release activated (CRAC) current, and cause calcium entry through non-store-operated pathways. Together with the pepper-like potency reported by kava users, these studies lead us to hypothesize that kava extracts contain one or more ligands for the transient receptor potential (TRP) family of ion channels. Indeed, TRP-like conductances are observed in kava-treated cells under patch clamp. Thus TRP-mediated cellular effects may be responsible for some of the reported pharmacology of kava.

A consideration of the paradigm of exercise physiology.

Exercise physiology, in terms of the history of biological sciences, is quite young and has a rather tumultuous history - as it spans physical education, health & medicine, sport science, and biology. This has led to the development of differing definitions, research approaches, practices and goals. This is easily seen in the presence of competing and non-universally adopted definitions of fitness. Such internal inconsistencies portray to the outside world a discipline experiencing the problems associated with a changing paradigm. Every science requires the presence of a paradigm that both describes and guides the evolution of thinking, experimentation, and the application of such. It is argued here that exercise physiology has been operating without benefit of a satisfactory and relevant paradigm. A further proposition is that the required disciplinary definitions derived from an articulated paradigm are also absent. A paradigmatic scheme based on biological dogma is presented along with proposed definitions.

Medicinal lavender modulates the enteric microbiota to protect against Citrobacter rodentium-induced colitis.

Inflammatory bowel disease, inclusive of Crohn's disease and ulcerative colitis, consists of immunologically mediated disorders involving the microbiota in the gastrointestinal tract. Lavender oil is a traditional medicine used to relieve many gastrointestinal disorders. The goal of this study was to examine the therapeutic effects of the essential oil obtained from a novel lavender cultivar, Lavandula×intermedia cultivar Okanagan lavender (OLEO), in a mouse model of acute colitis caused by Citrobacter rodentium. In colitic mice, oral gavage with OLEO resulted in less severe disease, including decreased morbidity and mortality, reduced intestinal tissue damage, and decreased infiltration of neutrophils and macrophages, with reduced levels of TNF-α, IFN-γ, IL-22, macrophage inflammatory protein-2α, and inducible nitric oxide synthase expression. This was associated with increased levels of regulatory T cell populations compared with untreated colitic mice. Recently, we demonstrated that the composition of the enteric microbiota affects susceptibility to C. rodentium-induced colitis. Here, we found that oral administration of OLEO induced microbiota enriched with members of the phylum Firmicutes, including segmented filamentous bacteria, which are known to protect against the damaging effects of C. rodentium. Additionally, during infection, OLEO treatment promoted the maintenance of microbiota loads, with specific increases in Firmicutes bacteria and decreases in γ-Proteobacteria. We observed that Firmicutes bacteria were intimately associated with the apical region of the intestinal epithelial cells during infection, suggesting that their protective effect was through contact with the gut wall. Finally, we show that OLEO inhibited C. rodentium growth and adherence to Caco-2 cells, primarily through the activities of 1,8-cineole and borneol. These results indicate that while OLEO promoted Firmicutes populations, it also controlled pathogen load through antimicrobial activity. Overall, our results reveal that OLEO can protect against colitis through the microbial-immunity nexus and that a pharmacological agent, in this case OLEO, alters the normal enteric microbiota.

A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis.

OBJECTIVE: Higher latitude, lower ultraviolet exposure, and lower serum 25-hydroxyvitamin D (25OHD) correlate with higher multiple sclerosis (MS) prevalence, relapse rate, and mortality. We therefore evaluated the effects of high-dose vitamin D2 (D2) in MS. METHODS: Adults with clinically active relapsing-remitting MS (RRMS) were randomized to 6 months' double-blind placebo-controlled high-dose vitamin D2, 6,000 IU capsules, dose adjusted empirically aiming for a serum 25OHD 130-175 nM. All received daily low-dose (1,000 IU) D2 to prevent deficiency. Brain MRIs were performed at baseline, 4, 5, and 6 months. Primary endpoints were the cumulative number of new gadolinium-enhancing lesions and change in the total volume of T2 lesions. Secondary endpoints were Expanded Disability Status Scale (EDSS) score and relapses. RESULTS: Twenty-three people were randomized, of whom 19 were on established interferon or glatiramer acetate (Copaxone) treatment. Median 25OHD rose from 54 to 69 nM (low-dose D2) vs 59 to 120 nM (high-dose D2) (p = 0.002). No significant treatment differences were detected in the primary MRI endpoints. Exit EDSS, after adjustment for entry EDSS, was higher following high-dose D2 than following low-dose D2 (p = 0.05). There were 4 relapses with high-dose D2 vs none with low-dose D2 (p = 0.04). CONCLUSION: We did not find a therapeutic advantage in RRMS for high-dose D2 over low-dose D2 supplementation. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that high-dose vitamin D2 (targeting 25OHD 130-175 nM), compared to low-dose supplementation (1,000 IU/d), was not effective in reducing MRI lesions in patients with RRMS.

Impact of in situ chemical oxidation on contaminant mass discharge: linking source-zone and plume-scale characterizations of remediation performance.

A large-scale permanganate-based in situ chemical oxidation (ISCO) effort has been conducted over the past ten years at a federal Superfund site in Tucson, AZ, for which trichloroethene (TCE) is the primary contaminant of concern. Remediation performance was assessed by examining the impact of treatment on contaminant mass discharge, an approach that has been used for only a very few prior ISCO projects. Contaminant mass discharge tests were conducted before and after permanganate injection to measure the impact at the source-zone scale. The results indicate that ISCO caused a significant reduction in mass discharge (approximately 75%). The standard approach of characterizing discharge at the source-zone scale was supplemented with additional characterization at the plume scale, which was evaluated by examining the change in contaminant mass discharge associated with the pump-and-treat system. The integrated contaminant mass discharge decreased by approximately 70%, consistent with the source-zone-scale measurements. The integrated mass discharge rebounded from 0.1 to 0.2 kg/d within one year after cessation of permanganate injections, after which it has been stable for several years. Collection of the integrated contaminant mass discharge data throughout the ISCO treatment period provided a high-resolution, real-time analysis of the site-wide impact of ISCO, thereby linking source-zone remediation to impacts on overall risk. The results indicate that ISCO was successful in reducing contaminant mass discharge at this site, which comprises a highly heterogeneous subsurface environment. Analysis of TCE sediment concentration data for core material collected before and after ISCO supports the hypothesis that the remaining mass discharge is associated in part with poorly accessible contaminant mass residing within lower-permeability zones.

Randomized control trial investigating the influence of coffee on heart rate variability in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Cardiac autonomic dysfunction post ST-segment elevation myocardial infarction (STEMI) has been linked to an excess risk of premature cardiovascular morbidity and mortality above those with normal autonomic function post-STEMI. AIM: The aim of this study was to evaluate the effect of acute ingestion of coffee on autonomic function and cardiovascular outcomes in patients with acute STEMI. DESIGN: Randomized control trial. METHODS: We randomized 103 patients with acute STEMI, admitted to our Coronary Care Unit, to receive regular coffee (caffeinated) or de-caffeinated coffee using a randomized controlled double-blinded design. Heart rate variability was assessed 5 days post-STEMI to assess the effect of caffeine on autonomic function. RESULTS: In the group randomized to regular coffee, parasympathetic activity increased by up to 96% (P = 0.04) after 5 days. There was no detrimental effect of regular coffee on cardiac rhythm post-STEMI. CONCLUSION: Coffee ingestion is associated with an increase in parasympathetic autonomic function immediately post-STEMI. Coffee was found to be safe and not associated with any adverse cardiovascular outcomes in the short term.

Suppression of ochratoxin biosynthesis by naturally occurring alkaloids.

The effects of four alkaloids on the biosynthesis of ochratoxin A (OTA), ochratoxin B (OTB) and citrinin were examined on four OTA-producing aspergilli: Aspergillus auricomus, A. sclerotiorum and two isolates of A. alliaceus. Piperine and piperlongumine, natural alkaloids of Piper longum, significantly inhibited OTA production at 0.001% (w/v) for all aspergilli examined. Piperine and piperlongumine affected the polyketide synthesis step of OTA production and inhibited production of citrinin. Curcumin, a constituent of tumeric, completely inhibited mycelial growth of A. alliaceus isolate 791 at 0.1% (w/v) and decreased OTA production by approximately 70% at 0.01% (w/v). Sesamin, a constituent of sesame oil, inhibited OTA and OTB production by 60 and 45%, respectively, at 0.1% (w/v), showing its effect was on chloroperoxidase and polyketide synthase activity. The potential advantage of these natural products to reduce ochratoxin contamination of agricultural commodities is discussed.

Consumption of black tea or coffee and risk of ovarian cancer.

The goal of this study was to investigate the associations between ovarian cancer risk and usual consumption of black tea, regular coffee, or decaffeinated coffee. Using a hospital-based case-control design, participants included 414 women with primary epithelial ovarian, fallopian, or peritoneal cancer and 868 age- and region-matched women with nonneoplastic conditions. All participants completed a comprehensive epidemiologic questionnaire. Black tea consumption was associated with a linear decline in ovarian cancer risk (P for trend 0.03), with individuals consuming two or more cups daily experiencing a 30% decline in risk (adjusted OR 0.70, 95% CI 0.51-0.97). Similar declines were noted among individuals consuming two or more cups of decaffeinated coffee daily (adjusted OR 0.71, 95% CI 0.51-0.99; P for trend 0.002). However, no association was noted between any level of regular coffee consumption and risk of ovarian cancer. The chemoprotective effects of phytochemicals in black tea and decaffeinated coffee may be important, although the effects of phytochemicals in regular coffee may be counteracted by the elevated risk associated with its higher caffeine content.

Soil and surface runoff phosphorus relationships for five typical USA midwest soils.

Excessively high soil P can increase P loss with surface runoff. This study used indoor rainfall simulations to characterize soil and runoff P relationships for five Midwest soils (Argiudoll, Calciaquaoll, Hapludalf, and two Hapludolls). Topsoil (15-cm depth, 241-289 g clay kg(-1) and pH 6.0-8.0) was incubated with five NH4H2PO4 rates (0-600 mg P kg(-1)) for 30 d. Total soil P (TPS) and soil-test P (STP) measured with Bray-P1 (BP), Mehlich-3 (M3P), Olsen (OP), Fe-oxide-impregnated paper (FeP), and water (WP) tests were 370 to 1360, 3 to 530, 10 to 675, 4 to 640, 7 to 507, and 2 to 568 mg P kg(-1), respectively. Degree of soil P saturation (DPS) was estimated by indices based on P sorption index (PSI) and STP (DPSSTP) and P, Fe, and Al extracted by ammonium oxalate (DPSox) or Mehlich-3 (DPSM3). Soil was packed to 1.1 g cm(-3) bulk density in triplicate boxes set at 4% slope. Surface runoff was collected during 75 min of 6.5 cm h(-1) rain. Runoff bioavailable P (BAP) and dissolved reactive P (DRP) increased linearly with increased P rate, STP, DPSox, and DPSM3 but curvilinearly with DPSSTP. Correlations between DRP or BAP and soil tests or saturation indices across soils were greatest (r > or = 0.95) for FeP, OP, and WP and poorest for BP and TPS (r = 0.83-0.88). Excluding the calcareous soil (Calciaquoll) significantly improved correlations only for BP. Differences in relationships between runoff P and the soil tests were small or nonexistent among the noncalcareous soils. Routine soil P tests can estimate relationships between runoff P concentration and P application or soil P, although estimates would be improved by separate calibrations for calcareous and noncalcareous soils.

Antifungal constituents of northern prickly ash, Zanthoxylum americanum mill.

Leaf, fruit, stem, bark and root of Zanthoxylum americanum were investigated for antifungal activity with 11 strains of fungi representing diverse opportunistic and systemic pathogens, including Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. All extracts demonstrated a broad spectrum of antifungal activity and inhibited at least eight fungal species in a disk diffusion assay (600 microg/disk). Antifungal activity was light-dependent, with fruit and leaf extracts most active in general. The presence of light-mediated compounds, such as psoralen, 8-methoxypsoralen and imperatorin in extracts of different organs was confirmed by RP-HPLC. A high furanocoumarin content was detected in fruit and leaf and low furanocoumarin levels were found in bark and wood. A high positive correlation was observed between total furanocoumarin content and fungal inhibition zones (r2=0.902, p<0.001). The results provide a phytochemical basis for the very widespread use of Z. americanum in indigenous North American ethnomedical tradition for conditions that may be related to fungal infections.

Metabonomics in preclinical drug development.

Metabonomics has emerged as a key technology in preclinical drug discovery and development. The technology enables noninvasive systems assessment of untoward effects induced by candidate compounds characterising a broad spectrum of biological responses on an individual animal basis in a relatively rapid-throughput fashion, thus making it an ideal addition to early preclinical safety assessment. However, the implementation and interpretation of the technology and data it generates is not something that should be trivialised. Proper expertise in biological sciences, analytical sciences (nuclear magnetic resonance and/or mass spectrometry) and chemometrics should all be considered necessary prerequisites. If these factors are properly considered, the technology can add significant value as a tool for preclinical toxicologists.

Inactivation of Ebola virus with a surfactant nanoemulsion.

Hemorrhagic fever caused by Ebola virus (EBO) is a highly contagious infection. This necessitates that the contaminated instruments, clothes, and hospital premises must be completely disinfected. Nanoemulsions are a new form of disinfectant composed of detergents and vegetable oil suspended in water. The antiviral activity of nanoemulsion ATB has been investigated against EBO. The nanoemulsion was tested against two preparations of EBO (strain Zaire) obtained from Vero cell culture fluid (EBO-zc) and from blood of infected monkeys (EBO-zb). The nanoemulsion ATB was virucidal against both preparations of EBO, inactivating the purified virus within 20 min even when diluted 1:100 with the growth medium. Inactivation of the virus in tissue preparations was also complete, but required 1:10 dilutions with media or higher. After treatment with ATB (10 and 1% concentrations), no EBO was apparent even after two passages in Vero cell culture. These data indicate that the nanoemulsion is an effective disinfectant for EBO. Because of the excellent biocompatibility of nanoemulsions, studies are planned to determine whether the nanoemulsion-killed virus is suitable for developing a vaccine against EBO.

Early diagnosis of colonic carcinoma: a haemorrhagic complication after the use of tissue plasminogen activator.

Haemorrhagic complications of thrombolytic therapy for myocardial infarction are common. A 68 year old man presented with a myocardial infarction and was started on tissue plasminogen activator. Soon after he experienced rectal bleeding and a barium enema showed a small carcinoma in the colon, which was treated surgically. It is important that gastrointestinal bleeding secondary to thrombolysis is always investigated for an underlying cause.