Phe19 modification of HDM2-p53 PPI inhibitors to alleviate CYP3A4 metabolism/mechanism-based inhibition liability.

The discovery of potent, bioavailable small molecule inhibitors of p53-HDM2 PPI led us to investigate subsequent modifications to address a CYP3A4 time-dependent inhibition liability. On the basis of the crystal structure of HDM2 in complex with 2, further functionalization of the solvent exposed area of the molecule that binds to Phe19 pocket were investigated as a strategy to modulate the molecule liphophilicity. Introduction of 2-oxo-nicotinic amide at Phe19 proved a viable strategy in obtaining inhibitors exempt from CYP3A4 time-dependent inhibition liability.

Characterizing three shallow-water locations off Goa, India, using passive acoustic data.

In this study, an analysis of the passive acoustic data is carried out for the quantitative characterization of shallow-water acoustic environments from three major estuarine systems of Goa during the months of March and April. The identification of fish sounds was carried out using waveform and peak power spectral densities (PSDs) of the individual fish calls. Fish sound data showed that the toadfish of the Batrachoididae family (Colletteichthys dussumieri species) produced a spectral level 112.27 ± 4.48 dB re 1 µPa2 /Hz at 448.96 ± 40.30 Hz frequency from the mangrove-dominated tidally influenced Mandovi estuary. Similarly, in a coral reef area near Grande Island in the Zuari estuary, Tiger Perch fish from the Terapontidae family (Terapon threaps species) were identified, having spectral levels 106.91 ± 3.08 dB re 1 µPa2 /Hz at 1791.56 ± 106.55 Hz frequency. From the Sal estuary, PSD levels were found to be around 98.24 ± 2.98 dB re 1 µPa2/Hz at 1796.95 ± 72.76 Hz frequency for Tiger Perch of the Terapontidae family (T. threaps species). To characterize the contributions of biophony (fish), geophony (wind and flow, etc.), and anthrophony (boats, etc.), cluster analysis is employed. In the Mandovi estuary, the root-mean-square sound pressure level (SPLrms) of broadband toadfish was a function of the water flow and temperature. In the Zuari estuary, SPLrms was a function of the water temperature and wind, whereas in the Sal estuary, wind mainly influenced the SPLrms.

Core modification of substituted piperidines as novel inhibitors of HDM2-p53 protein-protein interaction.

The discovery of 3,3-disubstituted piperidine 1 as novel p53-HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored. Although some substitutions were tolerated, no significant improvement in potency was observed compared to 1. Incorporation of an allyl side chain at position 2 provided a drastic improvement in binding potency.

Seabed characteristics from ambient noise at three shallow water sites in Northern Indian Ocean.

Ambient noise measurements at three sites along the Indian continental shelf, with different water column and seabed, are analyzed to derive vertical directionality and further estimation of seabed characteristics. Directionality pattern is interpreted using features in the sound speed profiles, in terms of noise notch, surface duct, surface bottom reflections, direct arrivals, and high bottom loss arrivals. Reflection loss estimated from the field directionality is seen to be the same for a particular site and gives an estimate of the sea bottom. Seabed characteristics such as critical angle and reflection coefficient from field directionality correlate well with theoretical estimation using ground truths.

Feeding practices and growth patterns of moderately low birthweight infants in resource-limited settings: results from a multisite, longitudinal observational study.

OBJECTIVES: To describe the feeding profile of low birthweight (LBW) infants in the first half of infancy; and to examine growth patterns and early risk factors of poor 6-month growth outcomes. DESIGN: Prospective observational cohort study. SETTING AND PARTICIPANTS: Stable, moderately LBW (1.50 to <2.50 kg) infants were enrolled at birth from 12 secondary/tertiary facilities in India, Malawi and Tanzania and visited nine times over 6 months. VARIABLES OF INTEREST: Key variables of interest included birth weight, LBW type (combination of preterm/term status and size-for-gestational age at birth), lactation practices and support, feeding profile, birthweight regain by 2 weeks of age and poor 6-month growth outcomes. RESULTS: Between 13 September 2019 and 27 January 2021, 1114 infants were enrolled, comprising 4 LBW types. 363 (37.3%) infants initiated early breast feeding and 425 (43.8%) were exclusively breastfed to 6 months. 231 (22.3%) did not regain birthweight by 2 weeks; at 6 months, 280 (32.6%) were stunted, 222 (25.8%) underweight and 88 (10.2%) wasted. Preterm-small-for-gestational age (SGA) infants had 1.89 (95% CI 1.37 to 2.62) and 2.32 (95% CI 1.48 to 3.62) times greater risks of being stunted and underweight at 6 months compared with preterm-appropriate-for-gestational age (AGA) infants. Term-SGA infants had 2.33 (95% CI 1.77 to 3.08), 2.89 (95% CI 1.97 to 4.24) and 1.99 (95% CI 1.13 to 3.51) times higher risks of being stunted, underweight and wasted compared with preterm-AGA infants. Those not regaining their birthweight by 2 weeks had 1.51 (95% CI 1.23 to 1.85) and 1.55 (95% CI 1.21 to 1.99) times greater risks of being stunted and underweight compared with infants regaining. CONCLUSION: LBW type, particularly SGA regardless of preterm or term status, and lack of birthweight regain by 2 weeks are important risk identification parameters. Early interventions are needed that include optimal feeding support, action-oriented growth monitoring and understanding of the needs and growth patterns of SGA infants to enable appropriate weight gain and proactive management of vulnerable infants. TRIAL REGISTRATION NUMBER: NCT04002908.

Hyperspectral Image Classification Model Using Squeeze and Excitation Network with Deep Learning.

In the domain of remote sensing, the classification of hyperspectral image (HSI) has become a popular topic. In general, the complicated features of hyperspectral data cause the precise classification difficult for standard machine learning approaches. Deep learning-based HSI classification has lately received a lot of interest in the field of remote sensing and has shown promising results. As opposed to conventional hand-crafted feature-based classification approaches, deep learning can automatically learn complicated features of HSIs with a greater number of hierarchical layers. Because HSI's data structure is complicated, applying deep learning to it is difficult. The primary objective of this research is to propose a deep feature extraction model for HSI classification. Deep networks can extricate features of spatial and spectral from HSI data simultaneously, which is advantageous for increasing the performances of the proposed system. The squeeze and excitation (SE) network is combined with convolutional neural networks (SE-CNN) in this work to increase its performance in extracting features and classifying HSI. The squeeze and excitation block is designed to improve the representation quality of a CNN. Three benchmark datasets are utilized in the experiment to evaluate the proposed model: Pavia Centre, Pavia University, and Salinas. The proposed model's performance is validated by a performance comparison with current deep transfer learning approaches such as VGG-16, Inception-v3, and ResNet-50. In terms of accuracy on each class of datasets and overall accuracy, the proposed SE-CNN model outperforms the compared models. The proposed model achieved an overall accuracy of 96.05% for Pavia University, 98.94% for Pavia Centre dataset, and 96.33% for Salinas dataset.

Segmentation and Classification of Glaucoma Using U-Net with Deep Learning Model.

Glaucoma is the second most common cause for blindness around the world and the third most common in Europe and the USA. Around 78 million people are presently living with glaucoma (2020). It is expected that 111.8 million people will have glaucoma by the year 2040. 90% of glaucoma is undetected in developing nations. It is essential to develop a glaucoma detection system for early diagnosis. In this research, early prediction of glaucoma using deep learning technique is proposed. In this proposed deep learning model, the ORIGA dataset is used for the evaluation of glaucoma images. The U-Net architecture based on deep learning algorithm is implemented for optic cup segmentation and a pretrained transfer learning model; DenseNet-201 is used for feature extraction along with deep convolution neural network (DCNN). The DCNN approach is used for the classification, where the final results will be representing whether the glaucoma infected or not. The primary objective of this research is to detect the glaucoma using the retinal fundus images, which can be useful to determine if the patient was affected by glaucoma or not. The result of this model can be positive or negative based on the outcome detected as infected by glaucoma or not. The model is evaluated using parameters such as accuracy, precision, recall, specificity, and F-measure. Also, a comparative analysis is conducted for the validation of the model proposed. The output is compared to other current deep learning models used for CNN classification, such as VGG-19, Inception ResNet, ResNet 152v2, and DenseNet-169. The proposed model achieved 98.82% accuracy in training and 96.90% in testing. Overall, the performance of the proposed model is better in all the analysis.

Incidence and predictors of myocardial infarction after transient ischemic attack: a population-based study.

BACKGROUND AND PURPOSE: Coronary artery disease is the leading cause of death after TIA. Reliable estimates of the risk of MI after TIA, however, are lacking. METHODS: Our purpose was to determine the incidence of and risk factors for MI after TIA. We cross-referenced preexisting incidence cohorts from the Rochester Epidemiology Project for TIA (1985-1994) and MI (1979-2006) to identify all community residents with incident MI after incident TIA. Incidence of MI after TIA was determined using Kaplan-Meier life-table methods. This was compared to the age-, sex-, and period-specific MI incidences in the general population. Proportional hazards regression analysis was used to examine associations between clinical variables and the occurrence of MI after TIA. RESULTS: Average annual incidence of MI after TIA was 0.95%. Relative risk for incident MI in the TIA cohort compared to the general population was 2.09 (95% CI, 1.52-2.81). This was highest in patients younger than 60 years old (relative risk, 15.1; 95% CI, 4.11-38.6). Increasing age (hazard ratio, 1.51 per 10 years; 95% CI, 1.14-2.01), male sex (hazard ratio, 2.19; 95% CI, 1.18-4.06), and the use of lipid-lowering therapy at the time of TIA (hazard ratio, 3.10; 95% CI, 1.20-8.00) were independent risk factors for MI after TIA. CONCLUSIONS: Average annual incidence of MI after TIA is ≈1%, approximately double that of the general population. The relative risk increase is especially high in patients younger than 60 years old. These data are useful for identifying subgroups of patients with TIA at highest risk for subsequent MI.

Prescriptions for self-injectable epinephrine in emergency department angioedema management.

BACKGROUND: Angioedema is often treated in the emergency department (ED). Few studies have evaluated self-injectable epinephrine (SIE) prescribing patterns for angioedema. OBJECTIVES: To describe presentation and management of ED patients with angioedema and determine factors associated with epinephrine administration, hospital admission and SIE prescription. METHODS: We conducted a retrospective cohort study of all ED patients with angioedema between January 2005 and December 2006. RESULTS: Of 63 patients, 39 (61.9%) were female. Median age was 49 years. Precipitating factors were identified in 36 (57.1%) patients. History of other allergic conditions was seen in 37 (58.7%) patients. Seventeen (27.0%) patients received epinephrine, 55 (87.3%) received antihistamines, and 51 (81.0%) received steroids. Epinephrine was administered more commonly in patients with edema of the tongue (risk ratio [RR], 5.28, 95% confidence interval [CI] 1.95-14.33, P = .0003), tightness/fullness of throat (RR, 3.31, 95% CI 1.62-6.76, P = .006), and dyspnea/wheeze (RR, 3.04, 95% CI 1.41-6.59, P = .005). Hospitalization was more common in patients with dyspnea/wheeze (P = .028) and allergic history (P = .006). Thirteen patients (22.0%) were discharged with SIE. An SIE prescription was associated with younger patients (median age, 26 years [interquartile range (IQR) 15-50] vs a median age 57.5 years [IQR 43-68], P = .004) and patients with throat tightness/fullness (RR, 4.2, 95% CI 1.8-9.8, P = .005). CONCLUSION: Patients with respiratory symptoms and allergic history were likely to be admitted. Epinephrine use was more frequent in patients with signs and symptoms of oropharyngeal edema. Younger patients and those with tightness/fullness of throat were likely to be prescribed SIE. Further studies are needed to determine who would benefit from epinephrine use and SIE prescription.

An assessment of the incremental value of the ABCD2 score in the emergency department evaluation of transient ischemic attack.

STUDY OBJECTIVE: We study the incremental value of the ABCD2 score in predicting short-term risk of ischemic stroke after thorough emergency department (ED) evaluation of transient ischemic attack. METHODS: This was a prospective observational study of consecutive patients presenting to the ED with a transient ischemic attack. Patients underwent a full ED evaluation, including central nervous system and carotid artery imaging, after which ABCD2 scores and risk category were assigned. We evaluated correlations between risk categories and occurrence of subsequent ischemic stroke at 7 and 90 days. RESULTS: The cohort consisted of 637 patients (47% women; mean age 73 years; SD 13 years). There were 15 strokes within 90 days after the index transient ischemic attack. At 7 days, the rate of stroke according to ABCD2 category in our cohort was 1.1% in the low-risk group, 0.3% in the intermediate-risk group, and 2.7% in the high-risk group. At 90 days, the rate of stroke in our ED cohort was 2.1% in the low-risk group, 2.1% in the intermediate-risk group, and 3.6% in the high-risk group. There was no relationship between ABCD2 score at presentation and subsequent stroke after transient ischemic attack at 7 or 90 days. CONCLUSION: The ABCD2 score did not add incremental value beyond an ED evaluation that includes central nervous system and carotid artery imaging in the ability to risk-stratify patients with transient ischemic attack in our cohort. Practice approaches that include brain and carotid artery imaging do not benefit by the incremental addition of the ABCD2 score. In this population of transient ischemic attack patients, selected by emergency physicians for a rapid ED-based outpatient protocol that included early carotid imaging and treatment when appropriate, the rate of stroke was independent of ABCD2 stratification.

Insulin for glycaemic control in acute ischaemic stroke.

BACKGROUND: Patients with hyperglycaemia concomitant with an acute stroke have greater stroke severity and greater functional impairment when compared to those with normoglycaemia at stroke presentation. OBJECTIVES: To determine whether maintaining serum glucose within a specific normal range (4 to 7.5 mmol/L) in the first 24 hours of acute ischaemic stroke influences outcome. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (June 2010), CENTRAL (The Cochrane Library 2010, Issue 2), MEDLINE (1950 to June 2010), EMBASE (1980 to June 2010), CINAHL (1982 to June 2010), Science Citation Index (1900 to June 2010), and Web of Science (ISI Web of Knowledge) (1993 to June 2010). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers and SCOPUS. SELECTION CRITERIA: Eligible studies were randomised controlled trials comparing intensively monitored insulin therapy versus usual care in adult patients with acute ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the study characteristics, study quality, and data to estimate the odds ratio (OR) and 95% confidence interval (CI), mean difference (MD) and standardised mean difference (SMD) of outcome measures. MAIN RESULTS: We included seven trials involving 1296 participants (639 participants in the intervention group and 657 in the control group). We found that there was no difference between treatment and control groups in the outcome of death or disability and dependence (OR 1.00, 95% CI 0.78 to 1.28) or final neurological deficit (SMD -0.12, 95% CI -0.23 to 0.00). The rate of symptomatic hypoglycaemia was higher in the intervention group (OR 25.9, 95% CI 9.2 to 72.7). In the subgroup analyses of diabetes mellitus (DM) versus non-DM, we found no difference for the outcomes of death and dependency or neurological deficit. AUTHORS' CONCLUSIONS: With the current evidence, we found that the administration of intravenous insulin with the objective of maintaining serum glucose within a specific range in the first hours of acute ischaemic stroke does not provide benefit in terms of functional outcome, death, or improvement in final neurological deficit and significantly increased the number of hypoglycaemic episodes. Specifically, those who were maintained within a more tight range of glycaemia with intravenous insulin experienced a greater risk of symptomatic and asymptomatic hypoglycaemia than those individuals in the control group.

Matrix metalloproteinase-9 as a marker for acute ischemic stroke: a systematic review.

Matrix metalloproteinase-9 (MMP-9) is a possible marker for acute ischemic stroke (AIS). In animal models of cerebral ischemia, MMP expression was significantly increased and was related to blood-brain barrier disruption, vasogenic edema formation, and hemorrhagic transformation. The definition of the exact role of MMPs after ischemic stroke will have important diagnostic implications for stroke and for the development of therapeutic strategies aimed at modulating MMPs. The objectives of the present study were to determine (1) whether MMP-9 is a possible marker for AIS; (2) whether MMP-9 levels correlate with infarct volume, stroke severity, or functional outcome; and (3) whether MMP-9 levels correlate with the development of hemorrhagic transformation after tissue plasminogen activator (t-PA) administration. The literature was searched using MEDLINE and EMBASE with no year restriction. All relevant reports were included. A total of 22 studies (3,289 patients) satisfied the inclusion criteria. Our review revealed that higher MMP-9 values were significantly correlated with larger infarct volume, severity of stroke, and worse functional outcome. There were significant differences in MMP-9 levels between patients with AIS and healthy control subjects. Moreover, MMP-9 was a predictor of the development of intracerebral hemorrhage in patients treated with thrombolytic therapy. MMP-9 level was significantly increased after stroke onset, with the level correlating with infarct volume, stroke severity, and functional outcome. MMP-9 is a possible marker for ongoing brain ischemia, as well as a predictor of hemorrhage in patients treated with t-PA.

Worse outcome after stroke in patients with obstructive sleep apnea: an observational cohort study.

To evaluate the risk and presence of obstructive sleep apnea (OSA) in patients presenting with acute ischemic stroke, and examine the correlation of OSA with age, sex, ischemic stroke subtype, disability, and death, a prospective cohort study was conducted in all consecutive patients presenting with acute ischemic stroke between June 2007 and March 2008. Exclusion criteria were age < 18 years, refusal of consent for the study, and incomplete questionnaire. The Berlin Sleep Questionnaire was used to identify patients at high risk for OSA. A total of 174 patients with acute ischemic stroke were included; 130 (74.7%) had a modified Rankin Scale (mRS) score ≥ 3 at dismissal, and 11 patients (6.3%) died within 1 month. The Berlin Sleep Questionnaire identified 105 patients (60.4%) at high risk for OSA, along with 7 patients (4%) with a previous diagnosis of OSA. Those with a previous diagnosis of OSA were more likely to die within the first month after stroke (relative risk, 5.3; 95% confidence interval, 1.4-20.1) compared with those without OSA. Patients at high risk for OSA did not demonstrate increased mortality at 30 days (P = 1.0). In multivariate analysis, after adjusting for age and National Institutes of Health Stroke Scale score, previous diagnosis of OSA was an independent predictor of worse functional outcome, that is, worse mRS score at hospital discharge (P = .004). The mRS score was 1.2 points higher (adjusted R², 40%) in those with OSA. Our findings suggest that patients considered at high risk for ischemic stroke should be screened for OSA, the prevalence of which may be as high as 60%. Those with definitive diagnosis of OSA before stroke are at increased risk of death within the first month after an acute ischemic stroke.

Mixed-methods, descriptive and observational cohort study examining feeding and growth patterns among low birthweight infants in India, Malawi and Tanzania: the LIFE study protocol.

INTRODUCTION: Ending preventable deaths of newborns and children under 5 will not be possible without evidence-based strategies addressing the health and care of low birthweight (LBW, <2.5 kg) infants. The majority of LBW infants are born in low- and middle-income countries (LMICs) and account for more than 60%-80% of newborn deaths. Feeding promotion tailored to meet the nutritional needs of LBW infants in LMICs may serve a crucial role in curbing newborn mortality rates and promoting growth. The Low Birthweight Infant Feeding Exploration (LIFE) study aims to establish foundational knowledge regarding optimal feeding options for LBW infants in low-resource settings throughout infancy. METHODS AND ANALYSIS: LIFE is a formative, multisite, observational cohort study involving 12 study facilities in India, Malawi and Tanzania, and using a convergent parallel, mixed-methods design. We assess feeding patterns, growth indicators, morbidity, mortality, child development and health system inputs that facilitate or hinder care and survival of LBW infants. ETHICS AND DISSEMINATION: This study was approved by 11 ethics committees in India, Malawi, Tanzania and the USA. The results will be disseminated through peer-reviewed publications and presentations targeting the global and local research, clinical, programme implementation and policy communities. TRIAL REGISTRATION NUMBERS: NCT04002908 and CTRI/2019/02/017475.

Enhanced T cell responsiveness to Mycobacterium bovis BCG r32-kDa Ag correlates with successful anti-tuberculosis treatment in humans.

Th1 and Th2 cytokines play key role in protection from and pathogenesis of mycobacterial infection and their dynamic changes may predict clinical outcome of the patient. Patients with tuberculosis (TB) have a poorer cellular immune response to recombinant 32-kDa antigen (Ag) of Mycobacterium bovis (r32-kDa M. bovis) than do healthy volunteers. The basis for this observation was studied by evaluating the Th1 (gamma interferon [IFN-γ]) produced in response to the r32-kDa Ag M. bovis by peripheral blood mononuclear cells (PBMC) from patients with pulmonary TB (n=20), extra-pulmonary TB (n=13) and from healthy volunteers (n=9). Recombinant 32-kDa M. bovis stimulated PBMC from TB patients produced significantly lower levels of IFN-γ at 0 month, and increased at 2-4, and 6 months of treatment and were highly significant (p<0.000) compared to the responses in controls. The ratios of IFN-γ to IL-10 were low in patients newly diagnosed and improved both during and after treatment. The present study concludes that the levels of in vitro response to M. bovis BCG r32-kDa Ag leading to the specific release of IFN-γ increased after anti-tuberculosis treatment and seems to reflect the clinical status of the patient, thus reiterating the utility of this antigen in T cell based assays as a surrogate marker of cell mediated responses.

A facile and efficient synthesis of 3,3-dimethyl isopropylidene proline from (+)-3-carene.

A highly efficient and practical route to 3,4-isopropylidene proline I, starting from (+)-3-carene, was developed. The three continuous stereocenters were constructed using the inherent chirality of the starting natural product 2. The overall yield for the 12-step synthesis is 34%. The optimized sequence leading to 1 has been successfully applied on a multigram scale, thereby establishing the practicality of this route.

Towards the second generation of Boceprevir: Dithianes as an alternative P2 substituent for 2,2-dimethyl cycloproyl proline in HCV NS3 protease inhibitors.

Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis and structure-activity relationship studies of inhibitors with (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid 2 as P2 substituent replacing the (1R,2S,5S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor 25 (K(i)( *)=7nM, EC(90)=30nM) with improved rat exposure of 2.56microM h.

P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile.

SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved potency (K(i)( *)=15nM, EC 90=70nM) and pharmacokinetic properties (Rat AUC (PO)=3.52microMh) compared to 1.

Discovery of potent sulfonamide P4-capped ketoamide second generation inhibitors of hepatitis C virus NS3 serine protease with favorable pharmacokinetic profiles in preclinical species.

Hepatitis is a disease characterized by inflammation of the liver, usually producing swelling and, in many cases, permanent damage to liver tissues. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically 3% of the world's population. Boceprevir, SCH 503034, (1) our first generation HCV inhibitor, has already established proof-of- concept and is currently in late stage (phase III) clinical trials. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket by introducing a new sulfonamide moiety and optimization of the P1/P(1)' capping led to the discovery of a novel series of inhibitors of the HCV NS3 serine protease. Optimization of the P(1) residue significantly improved potency and selectivity. The combination of optimal moieties led to the discovery of compound 47 which, in addition to being a potent inhibitor of HCV subgenomic RNA replication, was also found to have good PK profile in rat, dog and monkey.

Acute deep vein thrombus due to May-Thurner syndrome.

A 63-year-old white woman with a history of hypertension, hyperlipidemia, hypothyroidism, and transient ischemic attack, on Premarin, presented with a 2-week history of worsening edema and pain on the left side of the lower extremity associated with purplish discoloration and decreased temperature after a prolonged car travel. Physical examination revealed 2+ edema from the midthigh to the toes associated with purpuric discoloration. All arterial pulses were 4+. Ultrasound examination demonstrated an acute deep vein thrombus extending from the external iliac veins down throughout the visualized veins of the left calf. The patient was started on intravenous heparin and underwent venogram with subsequent thrombolysis. After 48 hours of alteplase infusion, balloon angioplasty was performed and 2 stents were placed in the left common and external iliac veins. Premarin was discontinued and she remains on oral anticoagulation with Coumadin. The patient did well clinically and a second ultrasound showed interval improvement. There is significant family history but no personal history of thrombotic events; however, thrombophilia evaluation is unremarkable.