Echinococcus Species Infections among Wild Canids in Pennsylvania, USA.

Echinococcus species are zoonotic tapeworms that can impact the health of wildlife, domestic animals, livestock, and humans. Two species of interest in North America are Echinococcus multilocularis and Echinococcus canadensis (Echinococcus granulosus sensu lato). The primary wildlife definitive hosts for E. multilocularis and E. canadensis are similar, including red foxes (Vulpes vulpes), gray foxes (Urocyon cinereoargenteus), coyotes (Canis latrans), and wolves (Canis lupus). These two Echinococcus spp. use different intermediate hosts, including small mammals for E. multilocularis and artiodactylids for E. canadensis. Although historically absent from much of the eastern US, recent reports in new US states (e.g., Virginia, Vermont, Maine, Missouri) highlight the need for Echinococcus spp. surveillance in this region. During 2019-2020, 308 gastrointestinal tracts were collected from wild canids in Pennsylvania and microscopically screened for adult Echinococcus species. Two coyotes (2/155) were co-infected with both E. multilocularis and E. canadensis as determined by molecular confirmation. No red foxes (n=137) or gray foxes (n=16) were positive. These data indicate both Echinococcus species are present in Pennsylvanian coyotes, highlighting the need to better understand the ecological and epidemiological consequences for human and animal health.

Characterization of the genetics and epidemiology of Brugia sp. in domestic dogs in Chad, Africa.

Neglected tropical diseases pose a threat to domestic animal health, as domestic animals can serve as reservoirs for certain zoonotic parasitic infections, including Guinea worm (Dracunculus medinensis) and lymphatic filariasis. Surveillance for these parasites in domestic animals is needed to understand infection prevalence and transmission cycles, with the goal of instituting appropriate interventions. The goal of this research was to report our finding of Brugia sp. infection in dogs from Chad, Africa, and to characterize the genetics and epidemiology of the parasite. During a recent Chadian canine pathogen surveillance project, we identified Brugia sp. infections in a total of 46 out of 428 dogs (10.7%) sampled at three time points in 2019-2020. We found high levels of sequence similarity to B. malayi and B. pahangi based on amplification of 18S rRNA, 5.8S rRNA, and ITS-2 regions. Phylogenetic analysis of 18S rRNA gene sequences placed the Chadian Brugia sp. in a clade with other Brugia spp. but grouped it separately from both B. malayi and B. pahangi. Analysis of Hha I sequences showed the greatest similarity with B. patei, a parasite previously reported from dogs, cats, and wildlife hosts in Kenya. Epidemiologic analysis using generalized linear regression modeling found significantly higher odds of Brugia sp. detection among dogs in villages in southern Chad compared to those in the northern region. Further, within the northern region, there were higher odds of detection in the dry season, compared to the wet season, which is consistent with the ecology of a presumably mosquito-borne parasite. The same 428 dogs were tested for Dirofilaria immitis antigen using a commercial assay (IDEXX SNAP 4Dx) at the earliest time point of the study, with 119 dogs testing positive. However, no association was noted between Brugia infection and a dog being positive for Di. immitis antigen, with only seven of the 119 Di. immitis antigen-positive dogs being Brugia-positive. This is the first report of Brugia sp. in domestic dogs in Chad and additional research is needed to definitively identify the species present, elucidate transmission, and understand potential risks to canine and human health.

Notoedric mange (Notoedres centrifera) in two species of free-ranging rabbits from Florida, USA.

Mange is a contagious skin disease caused by different mite species affecting numerous domestic and wild animals, worldwide. This report details notoedric mange in an eastern cottontail (Sylvilagus floridanus) and in a marsh rabbit (Sylvilagus palustris) from Florida, USA. Clinical examination revealed similar gross lesions including poor nutritional condition, multifocal alopecia and hyperkeratosis. Skin scrapings from both rabbits revealed numerous subcutaneous mites identified as Notoedres centrifera, a species previously only associated with rodents, primarily squirrels. Mites from both rabbits were identified based on morphology and confirmed by sequencing the internal transcribed spacer-2 (ITS-2) region. These cases emphasize the need for continued surveillance and accurate diagnostic evaluation to determine the cause and characterization of the skin disease, while distinguishing it from other potential pathogens that may manifest similarly in rabbits, such as Notoedres cati, Sarcoptes scabiei or Psoroptes cuniculi.

Risk factors for Toxoplasma gondii seropositivity in the Old Order Amish.

Toxoplasma gondii (T. gondii) is an important human disease-causing parasite. In the USA, T. gondii infects >10% of the population, accrues economic losses of US$3.6 billion/year, and ranks as the second leading culprit of foodborne illness-related fatalities. We assessed toxoplasmosis risk among the Old Order Amish, a mostly homogenous population with a high prevalence of T. gondii seropositivity, using a questionnaire focusing on food consumption/preparation behaviours and environmental risk factors. Analyses were conducted using multiple logistic regression. Consuming raw meat, rare meat, or unpasteurised cow or goat milk products was associated with increased odds of seropositivity (unadjusted Odds Ratios: 2.192, 1.613, and 1.718 , respectively). In separate models by sex, consuming raw meat, or consuming unpasteurised cow or goat milk products, was associated with increased odds of seropositivity among women; washing hands after touching meat with decreased odds of seropositivity among women (adjusted OR (AOR): 0.462); and cleaning cat litterbox with increased odds of seropositivity among men (AOR: 5.241). This is the first study to assess associations between behavioural and environmental risk factors and T. gondii seropositivity in a US population with high seroprevalence for T. gondii. Our study emphasises the importance of proper food safety behaviours to avoid the risk of infection.

Association of plasma nitrite levels with obesity and metabolic syndrome in the Old Order Amish.

OBJECTIVES: Plasma nitrite is a metabolite of nitric oxide and reflects endogenous nitric oxide synthase (NOS) activity. Although plasma nitrites were previously linked with obesity and metabolic syndrome (MetS), the direction of association remains inconsistent, possibly due to sample heterogeneity. In a relatively homogeneous population, we hypothesized that nitrite levels will be positively associated with overweight/obesity and MetS. METHODS: Fasting nitrite levels were measured in 116 Old Order Amish (78% women). We performed age-and-sex-adjusted ancovas to compare nitrite levels between three groups (a) overweight/obese(-)MetS(-), (b) overweight/obese(+)MetS(-) and (c) overweight/obese(+)MetS)(+). Multivariate linear regressions were conducted on nitrite associations with continuous metabolic variables, with successive adjustments for demographics, body mass index, C-reactive protein and neopterin. RESULTS: Nitrite levels were higher in the obese/overweight(+)MetS(+) group than in the other two groups (p < 0.001). Nitrites were positively associated with levels of triglycerides (p < 0.0001), total cholesterol (p = 0.048), high-density lipoprotein/cholesterol ratio (p < 0.0001) and fasting glucose (p < 0.0001), and negatively correlated with high-density lipoprotein-cholesterol (p < 0.0001). These associations were robust to adjustments for body mass index and inflammatory markers. CONCLUSION: Further investigation of the connection between obesity/MetS and plasma nitrite levels may lead to novel dietary and pharmacological approaches that ultimately may contribute to reducing the increasing burden of obesity, MetS and cardiovascular morbidity and mortality.

A pilot investigation of differential neuroendocrine associations with fronto-limbic activation during semantically-cued list learning in mood disorders.

BACKGROUND: Decreased volume and disrupted function in neural structures essential for memory formation (e.g. medial temporal lobe and prefrontal cortex) are common among individuals with depression. Hypothalamic-pituitary-axis function, as reflected by measurement of cortisol levels, is linked to neural activity during memory encoding in healthy people. However, it is not as well understood whether cortisol is associated with alterations in fronto-temporal recruitment during memory encoding in depression. METHODS: In this pilot study, we evaluated associations between cortisol and neural activation during memory encoding in 62 adults (18-65 years) with mood disorders (MD; n = 39, 66.7% female), including major depression (n = 28) and bipolar I disorder (n = 11), and healthy controls (HC; n = 23, 43.5% female). Participants provided salivary cortisol samples before and after completing a semantically-cued list-learning task during 3-Tesla fMRI. Links between pre-scan cortisol (and cortisol change) and activation during encoding were evaluated using block and event-related models. RESULTS: Overall, pre-scan cortisol level was positively associated with greater engagement of fronto-limbic activation during the encoding block. However, in MD, pre-scan cortisol was associated with attenuated activation during encoding in medial frontal, superior and middle temporal gyri, insula, lingual gyrus, and claustrum relative to HCs. Cortisol-related attenuation of activation in MD was also observed during encoding of words subsequently recalled in the ventral anterior cingulate, hypothalamus, and middle temporal gyrus. By and large, cortisol change (pre/post scan) predicted the same pattern of findings in both block and event-related contrasts. LIMITATIONS: Although analyses accounted for variations in scanner time of day, circadian alterations in cortisol may have introduced variability into the results. CONCLUSIONS: Pre-scan cortisol may selectively interfere with recruitment of important fronto-temporal memory circuitry in mood disorders. The inverted associations between cortisol and neural function in MD relative to HC also elucidate potentially unique pathophysiological markers of mood disorders.

CE/BZA effects on bone and quality of life in European postmenopausal women: a pooled analysis.

OBJECTIVES: To evaluate the efficacy of conjugated estrogens/bazedoxifene (CE/BZA) on bone mineral density (BMD), bone turnover markers (BTM), and menopause-specific quality of life (MENQOL) in European women. METHODS: Data through 12 months were pooled from two double-blind, randomized, controlled trials in non-hysterectomized postmenopausal women who received CE/BZA or placebo. Women from European study sites with evaluable BMD (n = 60), BTM (n = 56), and MENQOL questionnaire (n = 236) data were included and compared with 1523 women from US study sites (n = 730 with evaluable data for bone outcomes). RESULTS: At month 12, CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg, respectively, significantly improved BMD (adjusted difference vs. placebo) in lumbar spine (2.5%, 2.9%; both p ≤ 0.011) and total hip (1.7%, 2.2%, both p ≤ 0.002), significantly improved serum BTMs (osteocalcin: -31.1%, -33.1%; C-telopeptide: -48.5%, -36.8%) vs. placebo (osteocalcin: 6.7%, C-telopeptide: 4.2%; all p < 0.001), and significantly improved MENQOL vasomotor function scores (-2.1, -2.2) vs. placebo (-0.7; both p < 0.001). No significant treatment × subpopulation interactions were observed for any of the outcomes. CONCLUSIONS: Twelve-month CE/BZA treatment prevented bone loss and improved vasomotor function in European postmenopausal women. Findings were similar to those in the subpopulation of women enrolled at US study sites.

Decoupling of the amygdala to other salience network regions in adolescent-onset recurrent major depressive disorder.

BACKGROUND: Recent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes. METHOD: Resting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted. RESULTS: Young adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN. CONCLUSIONS: This is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

Effect of endoscopic forceps on quality of duodenal mucosal biopsy in healthy dogs.

BACKGROUND: Limited data exist regarding influence of endoscopic forceps on duodenal mucosal biopsy quality and adequacy for histologic examination/assessment in dogs. HYPOTHESIS/OBJECTIVES: Hypothesizing that larger forceps would procure superior specimens, we evaluated effect of 6 disposable forceps on duodenal biopsy weight, depth, crush artifact, and adequacy for histologic examination/assessment. ANIMALS: Seventeen healthy adult dogs. METHODS: Prospective study. Two operators each obtained 4 duodenal specimens from each dog with each forceps. Lightest sample discarded. One pathologist evaluated blindly other 3 specimens. A total of 612 specimens evaluated. Results analyzed by one-way ANOVA of forceps effects with dog as blocking factor. Posthoc pairwise comparisons examined with Tukey's test when indicated. RESULTS: Biopsies performed with large capacity forceps heavier (10.56 ± 0.90 and 11.6 ± 0.62 mg (mean ± SD) versus 5.55 ± 0.53 to 8.61 ± 0.49; P < .0001) and adequacy for histologic examination/assessment superior to standard oval and 'pediatric' (scores 2.52 ± 0.41 and 2.58 ± 0.37 versus 2.08 ± 0.33 and 2.14 ± 0.29; P < .0001). No statistically significant difference in depth scores. Large capacity forceps with spike associated with less crush artifact than all smaller forceps (scores 1.19 ± 0.16 versus 1.38 ± 0.21 to 1.52 ± 0.21; P < .0001). In same size forceps, presence of spike had no effect on crush artifact and adequacy for histologic examination/assessment (P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Large capacity forceps are superior, providing higher quality and greater numbers of samples achieving adequacy for histologic examination/assessment. Choice of endoscopic biopsy forceps for duodenal samples influences sample volume and diagnostic utility.

Isolation of lactobacilli with probiotic properties from the human stomach.

AIMS: Recent evidence suggests that the human gastric microbiota is much more diverse than previously thought. The aim of this study was to assess the potential for isolating lactobacilli from the human stomach. METHODS AND RESULTS: Lactobacilli were selectively cultured from gastric biopsies from 12 patients undergoing routine endoscopy. Lactobacilli were present in four of 12 biopsies. We isolated, in total 10 different strains representing five species (Lactobacillus gasseri, L. fermentum, L. vaginalis, L. reuteri and L. salivarius). The 10 isolates varied greatly in their ability to inhibit the growth of two Gram-positive bacteria and two Gram-negative bacteria. Furthermore, the acid and bile resistance profiles of the 10 isolates spanned a wide range. CONCLUSIONS: Five different Lactobacillus species were cultured from human gastric biopsies for the first time. SIGNIFICANCE AND IMPACT OF THE STUDY: Diverse Lactobacillus species are more prevalent in the human stomach than previously recognized, representing an untapped source of bacteria with beneficial probiotic and/or biotechnological properties.

Predictors of well-being among significant others of persons with multiple sclerosis.

OBJECTIVE: To examine patient and significant other characteristics as predictors of significant other well-being. METHODS: A total of 74 persons with multiple sclerosis (MS) and their significant others participated. Executive functioning was measured using neuropsychological tests. Awareness of cognitive deficit was measured as the discrepancy between the patient's reports of their abilities and objective test results. Awareness of functional deficit was measured as the discrepancy between the patient's and significant other's reports of the patient's functional abilities. Patient neurobehavioral disturbance was measured using a significant-other rated questionnaire. Significant other perceived social support and well-being (ie, psychological distress, life satisfaction, and general health status) were assessed using questionnaires filled out by the significant other. RESULTS: Executive dysfunction, neurobehavioral disturbance, and lack of awareness of functional deficits in patients were associated with poor well-being outcomes; whereas, lack of awareness of cognitive deficits was only weakly related to well-being. Social support was associated with positive well-being outcomes. CONCLUSIONS: Diminished insight regarding functional limitations may increase significant others' supervisory burden as patients attempt activities independently, whereas lack of awareness of cognitive deficits may not be directly associated with behavior-relevant impairments that significant others find distressing. Social support appears to be a powerful aid in diffusing the distress among significant others of MS patients.

Relationship between vascular calcification and bone mineral density in the Old-order Amish.

Vascular calcification and osteoporosis are common age-related processes that are influenced by both genetic and nongenetic factors. Whether common genes underlie these processes is not known. We measured coronary artery calcification (CAC), aortic calcification (AC), and bone mineral density (BMD) in 682 men and women from large Old-Order Amish families. We assessed the heritabilities of these traits and then evaluated, using variance decomposition procedures, whether variation in the traits was influenced by a common set of genes (i.e., pleiotropy). Significant heritabilities were detected for BMD of the femoral neck and spine (0.65, 0.63) and CAC and AC (0.43, 0.42). Mean BMD did not differ significantly across quartiles of either CAC or AC in either sex. In neither the total group nor any single subgroup (men, women, postmenopausal women) did any of the genetic or environmental correlations between BMD and vascular calcification achieve statistical significance. However, subjects with a history of cardiovascular disease (CVD) events had significantly lower BMD at the femoral neck compared to subjects who reported no prior history of CVD (age-, sex-, body mass index-, and family structure-adjusted P = 0.003). We detected no evidence for shared genes affecting the joint distribution of bone and vascular calcification. However, our results do reveal a lower BMD in subjects with a prior history of CVD in the Old-Order Amish.

Brain activation patterns associated with working memory in relapsing-remitting MS.

BACKGROUND: Patients with multiple sclerosis (MS) show changes in brain activation patterns during visual and motor tasks that include decreases in the typical local network for a function and increases in other brain regions. OBJECTIVE: To determine whether brain activation patterns associated with working memory are affected by MS. METHODS: Activation of working memory circuitry was examined using an fMRI n-back task in adults with mild relapsing-remitting MS (RRMS; n = 10) and demographically matched healthy controls (n = 10). RESULTS: Group differences in brain activation emerged during both low- and high-demand conditions (p < 0.001). Overall, patients showed less activation than controls in core prefrontal and parietal regions of working memory circuitry, and greater activation in other regions within and beyond typical working memory circuitry, including bilateral medial frontal, cingulate, parietal, bilateral middle temporal, and occipital regions. CONCLUSIONS: Relative to controls, patients with mild RRMS showed shifts in brain activation patterns within and beyond typical components of working memory circuitry.

Cryptogenic epilepsy: an infectious etiology?

PURPOSE: Cryptogenic epilepsy, the group of epilepsy syndromes for which an etiology is unknown, comprises approximately 20% of all epilepsy syndromes. We selected patients in this subgroup of epilepsy and tested them for evidence of Toxoplasma gondii IgG antibodies by the enzyme-linked immunosorbent assay. T. gondii is found in up to 20% of the U.S. population forming dormant brain cysts in the latent bradyzoite form. We investigated the hypothesis that dormant T. gondii infection might be associated with cryptogenic epilepsy. METHODS: We selected patients with cryptogenic epilepsies and tested them for evidence of T. gondii IgG antibodies by the enzyme-linked immunosorbent assay. A control group was also tested for comparison. RESULTS: We have found a statistically-significant elevation of T. gondii antibodies among cryptogenic epilepsy patients as compared to controls [59% increase in optical density (OD), p = 0.013]. This association persisted after adjustment for subjects' gender and age in a multiple logistic regression model; however, it was no longer as statistically significant. CONCLUSIONS: Our results suggest that chronic T. gondii infection with brain cysts may be a cause of cryptogenic epilepsy.

Evaluation of clarithromycin resistance and cagA and vacA genotyping of Helicobacter pylori strains from the west of Ireland using line probe assays.

The prevalence of clarithromycin resistance-associated mutations, the cytotoxin-associated gene (cagA), and the various vacuolating cytotoxin (vacA) genotypes was determined in 50 gastric biopsy specimens from Helicobacter pylori-infected patients, using line probe assays. The clarithromycin resistance-associated mutation A2143G was detected in H. pylori strains from 26% of the specimens, which suggested that the high rate of H. pylori treatment failure in Ireland may be partly attributable to the presence of these mutations. All strains examined carried the vacA s1 genotype, and 76% were cagA positive. Of these 50 specimens, 13 (26%) carried H. pylori strains with vacA midregion genotype m1, 29 (58%) carried strains that were m2, 1 (2%) was infected by a strain that was positive for both m1 and m2, and 7 (14%) carried strains that could not be typed.

The female condom and STDs: design of a community intervention trial.

OBJECTIVES: The main purpose of this study is to compare sexually transmitted disease (STD) prevalence in cohorts of women with and without access to female condoms. METHODS: Six matched pairs of communities were identified from Kenya tea, coffee and flower plantations. One community within each pair was randomly selected to receive the female condom intervention. Approximately 160 eligible women were enrolled at each site. Female condom communities underwent an education program on use of female and male condoms and STDs, comprising group meetings, puppetry and other folk media, and training of clinic service providers and community outreach workers. Control communities received similar information on use of male condoms (freely available at all sites). At baseline, participants were tested for cervical gonorrhea and chlamydia and vaginal trichomoniasis, to be repeated at 6 and 12 months. The study has 80% power to detect a 10% prevalence difference, assuming an aggregate STD prevalence of 20% with 25% loss to follow-up and intracluster correlation of 0.03. RESULTS: Among 1929 women at baseline, the mean age was 33.1 years; 78% had never used a male condom. The prevalences of gonorrhea, chlamydia and trichomoniasis were 2.6%, 3. 2% and 20.4%, respectively (23.9% overall). The intracluster correlation based on these data was near zero. CONCLUSIONS: Comparable pairs of study sites have been selected. STD prevalence is sufficiently high, and the variation between sites is acceptably low. The study is feasible as designed.

Genotyping of cagA and vacA, Lewis antigen status, and analysis of the poly-(C) tract in the alpha(1,3)-fucosyltransferase gene of Irish Helicobacter pylori isolates.

Much work has focused on trying to identify markers in Helicobacter pylori that might allow the eventual disease outcome of an infection to be predicted. In this study we examined the cagA and vacA genotype, and Lewis status in a panel of 43 Irish H. pylori clinical isolates, and investigated a possible correlation with disease pathology. In addition, differences in the poly-(C) tract of the alpha(1,3)-fucosyltransferase gene were examined to identify a possible correlation with gene expression. Only three of 43 isolates were cagA-negative, whereas the remaining 40 isolates, independent of pathology, were cagA-positive. In all the strains we examined, the vacA signal-sequence was type s1a. For the vacA mid-region 12/43 isolates were type m1 and 31/43 isolates were type m2. These data, and examination of isolates from different pathology groups, suggests that there is no correlation between virulence and vacA genotype in the Irish population of H. pylori isolates. Western blotting of whole cell lysates from 32 H. pylori isolates showed 3/32 displayed only the Le(x) epitope, 12/32 only the Le(y), 13/32 both epitopes and 4/32 neither epitope. No apparent association between Lewis phenotype and disease pathology was evident. A range of lengths of poly-(C) tract were observed in the alpha(1, 3)-fucosyltransferase gene, however the length of the tract in an isolate did not correlate with the Lewis structures present. We conclude that future studies on H. pylori pathogenesis should not alone focus on the importance of molecular markers, but also on the host response, including genetic background and immune responsiveness.

Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs.

BACKGROUND: Although improved epicardial blood flow (as assessed with either TIMI flow grades or TIMI frame count) has been related to reduced mortality after administration of thrombolytic drugs, the relationship of myocardial perfusion (as assessed on the coronary arteriogram) to mortality has not been examined. METHODS AND RESULTS: A new, simple angiographic method, the TIMI myocardial perfusion (TMP) grade, was used to assess the filling and clearance of contrast in the myocardium in 762 patients in the TIMI (Thrombolysis In Myocardial Infarction) 10B trial, and its relationship to mortality was examined. TMP grade 0 was defined as no apparent tissue-level perfusion (no ground-glass appearance of blush or opacification of the myocardium) in the distribution of the culprit artery; TMP grade 1 indicates presence of myocardial blush but no clearance from the microvasculature (blush or a stain was present on the next injection); TMP grade 2 blush clears slowly (blush is strongly persistent and diminishes minimally or not at all during 3 cardiac cycles of the washout phase); and TMP grade 3 indicates that blush begins to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). There was a mortality gradient across the TMP grades, with mortality lowest in those patients with TMP grade 3 (2.0%), intermediate in TMP grade 2 (4.4%), and highest in TMP grades 0 and 1 (6.0%; 3-way P=0.05). Even among patients with TIMI grade 3 flow in the epicardial artery, the TMP grades allowed further risk stratification of 30-day mortality: 0.73% for TMP grade 3; 2.9% for TMP grade 2; 5.0% for TMP grade 0 or 1 (P=0.03 for TMP grade 3 versus grades 0, 1, and 2; 3-way P=0.066). TMP grade 3 flow was a multivariate correlate of 30-day mortality (OR 0.35, 95% CI 0.12 to 1.02, P=0.054) in a multivariate model that adjusted for the presence of TIMI 3 flow (P=NS), the corrected TIMI frame count (OR 1.02, P=0.06), the presence of an anterior myocardial infarction (OR 2.3, P=0.03), pulse rate on admission (P=NS), female sex (P=NS), and age (OR 1.1, P<0.001). CONCLUSIONS: Impaired perfusion of the myocardium on coronary arteriography by use of the TMP grade is related to a higher risk of mortality after administration of thrombolytic drugs that is independent of flow in the epicardial artery. Patients with both normal epicardial flow (TIMI grade 3 flow) and normal tissue level perfusion (TMP grade 3) have an extremely low risk of mortality.