Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study.

PURPOSE: At the time of diagnosis, metastatic dissemination of tumor cells via the lymphatic system has occurred in nearly all patients with inflammatory breast cancer (IBC). The objective of this study was twofold: (a) to determine which is the most suitable marker of lymph vessels in primary breast tumors and (b) to compare histomorphometric lymph vessel variables in IBC and non-IBC. EXPERIMENTAL DESIGN: Serial sections of 10 IBCs and 10 non-IBCs were immunostained for D2-40, LYVE-1, podoplanin, and PROX-1. Relative lymph vessel area, lymph vessel perimeters, and counts and lymphatic endothelial cell proliferation (LECP) were then measured in D2-40/Ki-67 double-immunostained sections of 10 normal breast tissues, 29 IBCs, and 56 non-IBCs. RESULTS: D2-40 was the most suitable antibody for staining peritumoral and intratumoral lymph vessels. D2-40-stained intratumoral lymph vessels were present in 80% of non-IBCs and 82.8% of IBCs (P = 0.76). In non-IBC, lymph vessels located in the tumor parenchyma were smaller and less numerous than those at the tumor periphery (P < 0.0001) whereas in IBC, intratumoral and peritumoral variables were not significantly different. The mean relative tumor area occupied by lymph vessels was larger in IBC than in non-IBC (P = 0.01). LECP at the tumor periphery was higher in IBC than in non-IBC: median LECP was 5.74% in IBC versus 1.83% in non-IBC (P = 0.005). CONCLUSIONS: The high LECP in IBC suggests that lymphangiogenesis contributes to the extensive lymphatic spread of IBC.     

Pharmacy residency training in academic medical centers.

PURPOSE: A survey of U.S. academic medical centers (AMCs) was conducted to identify the most important and challenging issues in pharmacy residency training. METHODS: A questionnaire addressing program characteristics and residency training concerns was sent electronically to pharmacy directors at 130 AMCs that are members or associate members of the University HealthSystem Consortium (UHC). Residency coordinators for both pharmacy practice and specialized programs were asked to complete the questionnaire, with input from other pharmacists involved in the residency program. Respondents were asked to rate the importance and degree of challenge for all issues on a 5-point Likert scale, where 1 = least important or least challenging and 5 = most important or most challenging. RESULTS: Responses were received from hospitals representing over 60% of all residency positions offered by UHC member hospitals. Recruitment was rated the most important issue (mean importance score, 4.8) facing residency programs in AMCs, but with over 85% of budgeted positions filled, programs appear to be successful in overcoming this concern. The most challenging issue (mean challenge score, 4.2) was compliance with the evaluation and documentation elements of the ASHP Residency Learning System (RLS), a system often used to meet requirements for pharmacy practice residency accreditation. The completion of resident research requirements was ranked as both an important and a challenging issue (mean importance score, 4.5; mean challenge score, 3.9). CONCLUSION: A survey of AMCs showed that they offered a wide variety of pharmacy residency programs and filled most budgeted resident positions. Resident recruitment, the RLS, and research requirements are the most important and challenging residency concerns facing the respondents.     

Nephrotoxicity and hepatotoxicity of 1,1-dichloro-2,2-difluoroethylene in the rat. Indications for differential mechanisms of bioactivation

1,1-Dichloro-2,2-difluoroethylene (DCDFE) produced marked nephrotoxicity in rats upon an i.p. dose of 150 mumole/kg. At doses higher than 375 mumole/kg, DCDFE also produced hepatotoxicity. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, appeared to be slightly nephrotoxic in Wistar rats. Nevertheless it exerted an inhibitory effect on the nephrotoxicity of DCDFE. The N-acetylcysteine conjugate of DCDFE was identified as a major urinary metabolite of DCDFE. When administered as such, this conjugate appeared to be a potent nephrotoxin, without any effect on the liver, indicating that glutathione conjugation of DCDFE is most likely a bioactivation step for nephrotoxicity. The appearance of traces of chlorodifluoroacetic acid in urine of rats treated with higher doses of DCDFE indicates the existence of an oxidative pathway of metabolism of DCDFE, probably involving epoxidation by hepatic mixed-function oxidases. It is speculated that the latter route might account for the hepatotoxicity at higher doses of DCDFE. The nephro- and hepatotoxicity of DCDFE, therefore, most likely are the result of two different mechanisms of bioactivation.     

Early SARS-CoV-2 Reinfections within 60 Days and Implications for Retesting Policies

Illustrated by a clinical case supplemented by epidemiologic data, early reinfections with SARS-CoV-2 Omicron BA.1 after infection with Delta variant, and reinfection with Omicron BA.2 after Omicron BA.1 infection, can occur within 60 days, especially in young, unvaccinated persons. The case definition of reinfection, which influences retesting policies, should be reconsidered.     

Plant cytokinin analogues with inhibitory activity on cyclin-dependent kinases exert their antiproliferative effect through induction of apoptosis initiated by the mitochondrial pathway: determination by a multiparametric flow cytometric analysis

OBJECTIVE: Regulation of the cell cycle by cyclin-dependent kinase (CDK) activity occurs at multiple levels and is often altered in human cancers. Therefore, CDK activity has been targeted for drug discovery, and a number of small molecules have now been identified as CDK inhibitors. Plant cytokinin analogues with CDK inhibitory activity and antiproliferative effects were studied to characterize the cellular basis of the cytotoxic effect. METHODS: The IC(50) value (concentration at which 50% of the cell proliferation is inhibited) and AC(50) value (concentration at which 50% of the cell population is apoptotic) were determined by flow cytometry and microscopy, respectively. A new multiparametric flow cytometric analysis was used to study the sequence of different apoptotic events. In this assay, analysis of phosphatidylserine exposure, mitochondrial membrane depolarization, activation of caspases and DNA condensation were combined. RESULTS: Treatment of Jurkat and KG1 cells with the CDK inhibitors results in a decrease of viable cells and a parallel increase in percentage of apoptotic cells. Apoptosis was accompanied by a rapid decrease of mitochondrial membrane potential, which precedes DNA condensation, exposure of phosphatidylserine and activation of caspases. CONCLUSIONS: The main cellular mechanism of the antiproliferative effect of plant cytokinin analogues with CDK inhibitory activity is the induction of apoptosis. The multiparametric flow cytometric technique allowed to follow the kinetics of various aspects of apoptotic cell changes and demonstrated that cytokinin analogue-induced apoptosis starts through the mitochondrial pathway. This technique could also become of value for the rapid screening of pro-apoptotic properties of chemotherapeutic compounds.     

Isolated rupture of the left atrial appendage after blunt chest trauma

Traumatic cardiac damage is caused by penetrating or blunt injury.The majority of disruptures in blunt trauma are the result of deceleration traumas.We present the case of an 8-year-old boy who fell off his horse. Afterwards the horse stepped on his chest. He was successfully treated for pericardial tamponade due to an isolated left appendage rupture. The lesion was probably caused by a sudden elevated intra-atrial blood pressure during chest compression.