A Rare Case of Duodenal Adenocarcinoma With Brain Metastasis.

Small bowel malignancies are relatively rare, accounting for only 3% of all gastrointestinal cancers. Duodenum is the most common location among small bowel cancers, followed by Jejunum and then Ileum. Duodenal adenocarcinoma produces vague symptoms, leading to late presentation and a poor prognosis compared to similarly staged colon cancer. It is rare to have brain metastasis in duodenal adenocarcinoma, and not many case reports have been reported. Only approximately 6% of patients with gastrointestinal malignancy have brain metastasis. Here, we present a case of a 64-year-old female patient diagnosed initially with stage IV duodenal adenocarcinoma presenting with duodenal mass, abdominal lymphadenopathy, and liver metastasis. She had excellent systemic control for over two years with systemic chemotherapy, with a close to complete response on follow-up imaging. She presented with a 2 cm left frontal mass biopsy consistent with duodenal adenocarcinoma metastasis. She underwent resection of the left frontal tumor and gamma knife to the resection cavity. She continues to have good systemic control of disease. This case highlights the rare possibility of brain metastasis with duodenal adenocarcinoma, especially in patients who have good systemic control with chemotherapy.

Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma.

PURPOSE: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Global Circumferential and Radial Strain Among Patients With Immune Checkpoint Inhibitor Myocarditis.

BACKGROUND: Global circumferential strain (GCS) and global radial strain (GRS) are reduced with cytotoxic chemotherapy. There are limited data on the effect of immune checkpoint inhibitor (ICI) myocarditis on GCS and GRS. OBJECTIVES: This study aimed to detail the role of GCS and GRS in ICI myocarditis. METHODS: In this retrospective study, GCS and GRS from 75 cases of patients with ICI myocarditis and 50 ICI-treated patients without myocarditis (controls) were compared. Pre-ICI GCS and GRS were available for 12 cases and 50 controls. Measurements were performed in a core laboratory blinded to group and time. Major adverse cardiovascular events (MACEs) were defined as a composite of cardiogenic shock, cardiac arrest, complete heart block, and cardiac death. RESULTS: Cases and controls were similar in age (66 ± 15 years vs 63 ± 12 years; P = 0.20), sex (male: 73% vs 61%; P = 0.20) and cancer type (P = 0.08). Pre-ICI GCS and GRS were also similar (GCS: 22.6% ± 3.4% vs 23.5% ± 3.8%; P = 0.14; GRS: 45.5% ± 6.2% vs 43.6% ± 8.8%; P = 0.24). Overall, 56% (n = 42) of patients with myocarditis presented with preserved left ventricular ejection fraction (LVEF). GCS and GRS were lower in myocarditis compared with on-ICI controls (GCS: 17.5% ± 4.2% vs 23.6% ± 3.0%; P < 0.001; GRS: 28.6% ± 6.7% vs 47.0% ± 7.4%; P < 0.001). Over a median follow-up of 30 days, 28 cardiovascular events occurred. A GCS (HR: 4.9 [95% CI: 1.6-15.0]; P = 0.005) and GRS (HR: 3.9 [95% CI: 1.4-10.8]; P = 0.008) below the median was associated with an increased event rate. In receiver-operating characteristic (ROC) curves, GCS (AUC: 0.80 [95% CI: 0.70-0.91]) and GRS (AUC: 0.76 [95% CI: 0.64-0.88]) showed better performance than cardiac troponin T (cTnT) (AUC: 0.70 [95% CI: 0.58-0.82]), LVEF (AUC: 0.69 [95% CI: 0.56-0.81]), and age (AUC: 0.54 [95% CI: 0.40-0.68]). Net reclassification index and integrated discrimination improvement demonstrated incremental prognostic utility of GRS over LVEF (P = 0.04) and GCS over cTnT (P = 0.002). CONCLUSIONS: GCS and GRS are lower in ICI myocarditis, and the magnitude of reduction has prognostic significance.

Prospective randomized study comparing outcome of myocardial protection with Del-Nido Cardioplegia versus Saint Thomas Cardioplegia in adult cardiac surgical patients.

Objectives: To compare the effectiveness of Del-Nido cardioplegia as myocardial protective agent with Saint Thomas cardioplegia in adult cardiac surgical patients. Methods: This prospective randomized study was conducted in cardiac surgery department of Bahawal Victoria hospital Bahawalpur, from October 2020 to March 2021. Eighty adult patients who underwent primary Isolated coronary artery bypass grafting (CABG) or isolated Valve surgery requiring cardiopulmonary bypass were randomly divided into Del Nido (DN, n=40) and Saint Thomas (ST, n=40) groups. Data regarding operative and post-operative variables such as cardiopulmonary bypass (CPB) and aortic cross clamp (AXC) times, inotropic requirements, resumption of sinus rhythm, need for electrical defibrillation, post-operative CKMB, blood requirement and ICU stay were noted. Results: CPB and AXC times were statistically insignificantly different. Resumption of Sinus rhythm was seen significantly in more patients of DN group (95%) than in ST group (72.5%) [p-value 0.05]. Less patients of DN group (5%) were candidates of electrical defibrillation than ST group (17.5%) [p-value <0.001). Post- operative CKMB values were significantly lower in DN group as compared to ST group (30.5±22.6 IU vs 50.5±50.28 IU, p value.008). Blood transfusion was significantly lower in DN group; 50% versus 80% in ST group (p-value 0.005). Ventilation time was significantly less in DN group than ST group (165.95±48.09 minutes versus 165.95±48.09 minutes respectively, p-value 0.03). While ICU stay was also less in DN group; 5.2±0.8 days versus 6.05±1.6 days in ST group (p-value 0.003). Conclusion: Del-Nido cardioplegia is a reliable and better myocardial protective agent than Saint Thomas cardioplegia in adult cardiac surgical procedures.

Surgical outcome of repair of aortic valve prolapse and regurgitation associated with ventricular septal defect.

OBJECTIVE: To analyze the outcome of repair of aortic valve disease associated with various types of ventricular septal defect. METHODS: In a retrospective observational study design, data of seventy-two patients of ventricular septal defect (VSD) associated with aortic valve prolapse (AVP) and aortic regurgitation (AR) who was operated in Punjab Institute of cardiology from May 2016 to April 2020 was collected. Depending on presence of AR, all patients were divided in four groups. Group-I (VSD and AVP but no AR) had fifteen patients. Only VSD was closed in this group. Group-II (VSD and Mild AR) had forty patients, only VSD was closed in this group as well. Group-III (VSD and Moderate AR) had ten patients, VSD closure and aortic valve repair was done. Group-IV (VSD and severe AR) had seven patients. Aortic valve was repaired in five patients and replaced (AVR) in two patients along with VSD closure. Associated anomalies were addressed as well. RESULTS: Group-I: Twelve out of fifteen patients (80%) showed no post-operative AR. While two patients (13.3%) showed Trace AR. Single patient (6.6%) showed mild AR. There results were unchanged after mean follow up of 36 months. Group-II: Eight out of forty patients (20%) had no AR, while eight (20%) had trace AR. Twenty-three (57.5%) patients had mild AR. Single (2.5%) patient had moderate AR. After follow up of 24 months the patient with moderate AR progressed to severe AR. We are planning to do Aortic Valve Replacement (AVR) in this case. Rest of cases showed no progression of disease. Group-III: Two out of ten patients (20%) had no AR, four (40%) had trace AR, while four (40%) had mild AR. Mean follow up was 42 months (2.5 years). Neither trace nor mild AR progressed to severe or moderate AR. Group-IV: Among seven patients, five underwent repair while two had AVR. Out of five patients who underwent aortic valve repair, four patients (57.1%) were declared mild AR, while severe AR was converted to moderate AR in single patient (14.28%). Mean follow up was 18 months. The moderate AR patient has progressed to severe AR for last six months and we are planning to do AVR in this patient. Postoperative echo of patients with AVR showed adequately functioning aortic valve with AVPG mean 10 mmHg and 15 mm Hg respectively, with no residual AR. CONCLUSIONS: Aortic regurgitation associated with VSD is a congenital lesion with continuously active aortic valve disease resulting in significant morbidity and mortality. Early diagnosis, effective treatment and meticulous follow up decelerate and in most cases arrest the disease process.

Electrocardiographic features of immune checkpoint inhibitor associated myocarditis.

BACKGROUND: Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis. METHODS: From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested. RESULTS: Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39). CONCLUSIONS: The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.

Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor-Associated Myocarditis.

BACKGROUND: Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited. OBJECTIVES: This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis. METHODS: In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. RESULTS: Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across all patients, mean z-scores for T1 and T2 values were 2.9 ± 1.9 (p < 0.001) and 2.2 ± 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1 (1,079.0 ± 55.5 ms vs. 1,000.3 ± 22.1 ms; p < 0.001) and T2 (56.2 ± 4.9 ms vs. 49.8 ± 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91 (95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE. CONCLUSIONS: The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis.

Palbociclib-Induced Pneumonitis: A Case Report and Review of the Literature.

The treatment of metastatic breast cancer has undergone significant changes in recent years. New classes of medications have been approved by the Food and Drug Administration (FDA) for use in clinical practice to extend progression-free survival and overall survival along with increasing response rate. Here, we present a case report of pneumonitis as a rare side effect of palbociclib in the treatment of metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (ERBB2-) breast cancer in addition to endocrine therapy. We also review the literature for other reports of pneumonitis during treatment with palbociclib. Through this case report and review of the literature, we aim to shed light on this rare side effect of palbociclib along with its successful management.

Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis.

AIMS: Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented. METHODS AND RESULTS: From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE. CONCLUSION: These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.

Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis.

BACKGROUND: There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis. OBJECTIVES: This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis. METHODS: This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death. RESULTS: Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8). CONCLUSIONS: GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.

Rare Presentation of a Rare Disease: Signet-Ring Cell Gastric Adenocarcinoma in Rothmund-Thomson Syndrome.

Rothmund-Thomson syndrome (RTS) is an exceedingly infrequent genetic disorder characterized by a multitude of skin findings collectively known as poikiloderma. In normal cells, the RECQL4 gene is involved in DNA replication and repair. RTS is caused by a mutation in the RECQL4 gene, which results in increased predilection to develop various malignancies. Osteosarcomas and skin cancers are typically associated with this syndrome. We present a rare case of signet-ring cell gastric adenocarcinoma in a patient with RTS.

Case Report: Neuroendocrine Tumor With Cardiac Metastasis.

Neuroendocrine tumors (NETs), also known as carcinoid tumors, are a heterogeneous group of neoplasms that arise from cells throughout the neuroendocrine system, most commonly arising from the gastrointestinal (GI) tract, lungs, and bronchi. Myocardial carcinoid metastasis is rare with an incidence among metastatic carcinoid patients of 4%. They are generally asymptomatic and detected incidentally. Infiltrative myocardial metastasis secondary to carcinoid tumor is exceedingly rare with only single-digit cases reported in the literature. We report the case of a 65-years-old female with a newly diagnosed ileal neuroendocrine tumor as well as heart failure due to infiltrative myocardial metastasis.

Influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors.

BACKGROUND: Influenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs. METHODS: Patients on ICIs who developed myocarditis (n = 101) (cases) were compared to ICI-treated patients (n = 201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6 months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death. RESULTS: The FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p = 0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p = 0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p = 0.10) including lower rates of pneumonitis (12 vs. 36%, p = 0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p = 0.002). CONCLUSION: The rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.

Doubly committed Subarterial Ventricular Septal defect repair: An experience of 51 cases.

OBJECTIVE: To review the surgical outcome of doubly committed subarterial (DCSA) ventricular septal defect repair. METHOD: Data of 51 patients of doubly committed sub arterial Ventricular septal defect from January 2012 to June 2017 that were referred to Chaudhary Pervaiz Elahi institute of Cardiology Multan was retrospectively reviewed using electronic database. All patients were operated by first author. In our study, we segregated patients into four main groups depending on presence or absence of aortic structural defect and degree of aortic valve regurgitation. Group-A comprised of nineteen (37%) patients who neither had aortic structural nor functional abnormality while Group-B had six (11.7%) patients, having aortic valve cusp prolapse without aortic regurgitation. Group-C and Group-D consists of seventeen (33.3%) and nine (17.6%) patients respectively depending upon degree of aortic regurgitation. Furthermore, six (11.7%) patients among these 51 had associated defects as well. RESULTS: Group-A patients had no aortic valve regurgitation post operatively and at follow up of 22.6 months (1.8 years) as well. In Group-B, aortic valve was not addressed and aortic regurgitation was also not present post operatively or on follow up of 33.6 months (2.8 years). Similarly, in Group-C aortic valve was not addressed, these patients also did not show progression of disease on regular follow up of 18 months (1.5 year). While, in Group-D, eight patients underwent aortic valve repair and one patient had aortic valve replacement. Aortic regurgitation improved significantly in all patients of this group and remained unchanged on follow up of 22.7 months (1.8 years). CONCLUSION: Early closure of doubly committed subarterial ventricular septal defect with appropriate management of aortic valve disease can halt the process of disease progression.

Review - Glycyrrhiza glabra L. (Liquorice).

Medicinal plants are being used for treating various diseases. According to World Health Organization 80% of the world population depends on indigenous medicinal plant remedies. Herbal medicine employs fruits, vegetables, as dry materials or their extracts for the treatment of different diseases and health maintenance. Glycyrrhiza glabra (Liquorice) has been used in Europe since prehistoric times. It is well documented in written form starting with the ancient Greeks. Glycyrrhizin is the major active constituent obtained from liquorice roots, one of the most widely used in herbal preparations for the treatment of liver complaints. The plant is used as anti-inflammatory, spasmolytic, laxative, anti-depressive, anti-ulcer and anti-diabetic. The present review focuses Glycyrrhiza glabra distribution, ethno botany, ethno pharmacology, chemical constituents, medicinal uses, cultivation and trade. Plant requires a lot of attention as it has been reduced in population due to over-use in Baluchistan. The plant conservationists should consider this herb as priority species and should start its cultivation on the commercial scale to fulfill the requirements of the local markets and pharmaceutical industries as well as reduce the pressure on the wild plants.

The role of CD40L and VEGF in the modulation of angiogenesis and inflammation.

Recently, there has been growing interest in deciphering the role of angiogenesis in the progression of atherogenesis. Importantly, CD40-CD40L interactions are of significant relevance because of their involvement in both angiogenesis and atherosclerotic development. Previously, we have shown that recombinant soluble CD40 ligand (rsCD40L) stimulates auto-inflammatory CD40L synthesis and reactive oxygen species (ROS) generation in vascular cells. In the current study, we demonstrate that redox-mediated CD40-CD40L interaction can enhance vascular endothelial growth factor (VEGF)-induced angiogenesis, endothelial migration, and actin polymerization processes. Interestingly, the addition of exogenous VEGF leads to cleavage of de novo CD40L produced in endothelial cells following rsCD40L treatment. Using inhibitor and silencing RNA-based experiments, it was observed that VEGF-induced protease, calpain 2, was responsible for the cleavage of de novo CD40L. While our in vivo experiments using a matrigel plug assay indicate a VEGF and CD40L induced enhancement of angiogenesis, our studies also identify a novel mechanism by which VEGF can abrogate CD40L-mediated inflammation. Together, these studies reveal a new pathway by which VEGF-CD40L interactions can regulate the angiogenic and inflammatory process depending on the specific environment.

Hypoxia influences CD40-CD40L mediated inflammation in endothelial and monocytic cells.

The interaction between CD40 and its ligand (CD40L) has been implicated in the pathogenesis of atherosclerosis and is recognized as a central event in the development of immuno-inflammatory processes. Our previous studies have shown that the CD40-CD40L interaction modulates platelet, neutrophil, and endothelial reactive oxygen species (ROS) generation. Hypoxia, known to be associated with tissue ischemia and inflammation, also influences the ROS production and changes the cellular redox state. However, the effect of hypoxia on CD40-CD40L mediated vascular inflammation is unknown. We have investigated whether hypoxia influences CD40-CD40L mediated vascular inflammatory responses, ROS production, and cellular interactions. We found that hypoxia significantly enhances the inflammatory effect of CD40L in both endothelial and monocytic cells (THP1). CD40-CD40L interaction in the presence of hypoxia induces ROS production, the synthesis of an inflammatory adhesive protein intercellular adhesion molecule 1 (ICAM1) and activates stress response proteins (p38 MAP kinase and HSP27), indicating that CD40L mediates the induction of oxidative stress in these cells. Importantly, we found that the effects of CD40L can be transmitted between HUVECs and monocytic THP1 cells through intercellular CD40-CD40L interaction and these processes are augmented under hypoxia. Together, these data indicate that under hypoxic conditions the CD40-CD40L interaction significantly influences adhesion molecule expression, stress generation, actin polymerization, and monocytic adhesion to endothelial cells in addition to changes in signaling. In summary, we show that hypoxia can alter CD40-CD40L mediated endothelial-monocyte interaction, playing a significant role in vascular inflammation and cellular adhesion processes.

CD40-CD40 ligand interactions in oxidative stress, inflammation and vascular disease.

CD40 ligand (CD40L) and its receptor CD40 participate in numerous inflammatory pathways that contribute to multiple pathophysiological processes. A role for CD40-CD40L interactions has been identified in atherosclerosis, and such interactions are known to destabilize atherosclerotic plaques by inducing the expression of cytokines, chemokines, growth factors, matrix metalloproteinases and pro-coagulant factors. The CD40-CD40L interaction has also been implicated in immune system disorders. Recent studies have suggested that CD40-CD40L interactions regulate oxidative stress and affect various signaling pathways in both the immunological and cardiovascular systems. Here, we discuss the emerging role of CD40-CD40L-mediated processes in oxidative stress, inflammatory pathways and vascular diseases. Understanding the roles and regulation of CD40-CD40L-mediated oxidative signaling in immune and non-immune cells could facilitate the development of therapeutics targeting diverse inflammatory diseases.

Pattern of nosocomial infection in two intensive care units of a tertiary care hospital in Karachi.

OBJECTIVE: To determine the pattern of nosocomial infections in two ICUs' of a teaching hospital in terms of frequency, common sites of infection, the pathogens involved and the antibiotic sensitivity patterns. DESIGN: Observational study. PLACE AND DURATION OF STUDY: It was conducted in two medical ICUs (Neurology and Nephrology) of a public tertiary care hospital i.e. Civil Hospital, Karachi, from June to November 2004. PATIENTS AND METHODS: Data was collected prospectively on patients suspected to have developed nosocomial infection after 48 hours of admission to the ICU according to objective. RESULTS: There were 101 cases of suspected nosocomial infection out of a total of 254 patients. The frequency of nosocomial infection was 39.7%. UTI developed in 44.6%, while 27% had blood stream infection, and 21% had pneumonia. Each of the three major sites of infection was strongly associated with the use of invasive devices. Escherichia (E.) coli was the most common organism isolated followed by Pseudomonas aeruginosa and Klebsiella. E. coli and Klebsiella showed a maximum sensitivity to Imipenem followed by Tazocin (pipericillin + tazobactam). Pseudomonas aeruginosa was sensitive to Amikacin and Fosfomycin. CONCLUSION: The high frequency of nosocomial infection suggests that more strict measures regarding invasive devices should be taken in future to control the infection and limit the emergence of antibiotic resistant organisms.