Heterogeneity of toxicant response: sources of human variability.

While risk assessment models attempt to predict human risk to toxicant exposure, in many cases these models cannot account for the wide variety of human responses. This review addresses several primary sources of heterogeneity that may affect individual responses to drug or toxicant exposure. Consideration was given to genetic polymorphisms, age-related factors during development and senescence, gender differences associated with hormonal function, and preexisting diseases influenced by toxicant exposure. These selected examples demonstrate the need for additional steps in risk assessment that are needed to more accurately predict human responses to toxicants and drugs.     

TGFbeta-mediated activation of Smad1 in B-cell non-Hodgkin's lymphoma and effect on cell proliferation.

We have previously reported an overexpression of Smad1 in follicular lymphoma (FL) cells, which are characterized by the t(14;18) bcl2/IgH translocation. Smad1 is commonly involved in bone morphogenetic protein but not in tumor-transforming growth factor beta (TGFbeta) signaling pathways. This study focuses on Smad1 signaling pathway in non-Hodgkin lymphoma cells including follicular or large-cell lymphoma cells. Our results support the notion that phosphorylation of Smad1 is mediated by TGFbeta present in the microenvironment and occurs in FL in vivo. Using an in vitro coculture system mimicking interactions between stroma cells and FL cells, we found that both the cell partners release TGFbeta at a sufficient concentration to activate Smad pathways in the malignant cells. This Smad1 activation involves TGFbetaRII but not ALK-1 receptors, and does not compete with the Smad2 pathway. Moreover, proliferation assays performed on lymphoma cells expressing wild-type or mutated Smad1, or in which endogenous Smad1 level was decreased by gene silencing, strongly supported that overexpression and activation of Smad1 modifies the biological response of lymphoma B cells to TGFbeta family members. This work opens new insights into aberrant Smad pathways and their pathophysiological role in FL and in other non-Hodgkin lymphomas.     

A novel method in predicting immediate postoperative facial nerve function post acoustic neuroma excision.

To determine whether the percentage calculated by dividing the amplitude of postexcision direct facial nerve stimulus responses (at pontomedullary junction) by the amplitude of distal ipsilateral transcutaneous (stylomastoid region) maximal stimulus responses and response amplitude progression by increasing stimulus intensities have predictive value for determining normal or near-normal (House-Brackmann Grade 1 or 2) immediate postoperative facial nerve function. STUDY DESIGN: Intraoperative recordings of three muscle groups: 1) frontalis, 2) orbicularis oculi, and 3) orbicularis oris. Postexcision direct facial nerve stimulation at the pontomedullary junction and transcutaneous maximal facial nerve stimulation at the ipsilateral stylomastoid region and their associated response amplitudes were recorded. SETTING: Tertiary referral center. PATIENTS AND METHODS: Patients who underwent acoustic neuroma surgery from January 2004 to March 2006 with intraoperative facial nerve monitoring and an intact facial nerve after tumor excision were included. Recordings were available for 38 patients. RESULTS: With a stimulus intensity of 0.3 mA at the root exit zone, there was an 81% positive predictive value in patients that exhibited a compound action potential of greater than 20% of maximum (sensitivity, 81%). This increased to 93% when the compound action potential was greater than 50% of maximum. When the amplitude increase was greater than 5 microV, there was a 77% positive predictive value (sensitivity, 87%). CONCLUSION: The percentage of the response amplitude of direct facial nerve stimulation at the pontomedullary junction when compared with the maximum response amplitude of ipsilateral transcutaneous stimulation at the stylomastoid foramen is a good predictor of normal to near-normal immediate postoperative facial nerve function. Progression of amplitude response also seems to be a good predictor of normal to near-normal immediate postoperative facial nerve function.     

Laparoscopic liver resections: a feasibility study in 30 patients

OBJECTIVE: To assess the feasibility and safety of laparoscopic liver resections. SUMMARY BACKGROUND DATA: The use of the laparoscopic approach for liver resections has remained limited for technical reasons. Progress in laparoscopic procedures and the development of dedicated technology have made it possible to consider laparoscopic resection in selected patients. METHODS: A prospective study of laparoscopic liver resections was undertaken in patients with preoperative diagnoses including benign lesion, hepatocellular carcinoma with compensated cirrhosis, and metastasis of noncolorectal origin. Hepatic involvement had to be limited and located in the left or peripheral right segments (segments 2-6), and the tumor had to be 5 cm or smaller. Surgical technique included CO2 pneumoperitoneum and liver transection with a harmonic scalpel, with or without portal triad clamping or hepatic vein control. Portal pedicles and large hepatic veins were stapled. Resected specimens were placed in a bag and removed through a separate incision, without fragmentation. RESULTS: From May 1996 to December 1999, 30 of 159 (19%) liver resections were included. There were 18 benign lesions and 12 malignant tumors, including 8 hepatocellular carcinomas in cirrhotic patients. Mean tumor size was 4.25 cm. There were two conversions to laparotomy (6.6%). The resections included 1 left hepatectomy, 8 bisegmentectomies (2 and 3), 9 segmentectomies, and 11 atypical resections. Mean blood loss was 300 mL. Mean surgical time was 214 minutes. There were no deaths. Complications occurred in six patients (20%). Only one cirrhotic patient developed postoperative ascites. No port-site metastases were observed in patients with malignant disease. CONCLUSION: Laparoscopic resections are feasible and safe in selected patients with left-sided and right-peripheral lesions requiring limited resection. Young patients with benign disease clearly benefit from avoiding a major abdominal incision, and cirrhotic patients may have a reduced complication rate.     

MR Spectroscopic Evidence of Brain Injury in the Non-Diagnosed Collision Sport Athlete

With growing evidence of long-term neurological damage in individuals enduring repetitive head trauma, it is critical to detect lower-level damage accumulation for the early diagnosis of injury in at-risk populations. Proton magnetic resonance spectroscopic scans of the dorsolateral prefrontal cortex and primary motor cortex were collected from high school American (gridiron) football athletes, prior to and during their competition seasons. Although no concussions were diagnosed, significant metabolic deviations from baseline and non-collision sport controls were revealed. Overall the findings indicate underlying biochemical changes, consequential to repetitive hits, which have previously gone unnoticed due to a lack of traditional neurological symptoms.     

Transition in the Cause of Fever from Malaria to Dengue,Northwestern Ecuador, 1990–2011

In tropical areas, the predominant cause of fever has historically been malaria. However by 2011, among febrile patients in northwestern Ecuador, dengue was identified in 42% and malaria in none. This finding suggests a transition in the cause of fever from malaria to other illnesses, such as dengue.     

Aspirin Therapy in Venous Malformation: A Retrospective Cohort Study of Benefits,Side Effects,and Patient Experiences

Venous malformations (VMs) are often painful and may enlarge over time. Chronic coagulopathy is common in VMs and may contribute to phleboliths and potentially to disease progression. Few studies have examined the effects of anticoagulation on VMs and to our knowledge none have examined the use of aspirin therapy. A survey was administered to patients and parents of patients with VMs who attended the University of California at San Francisco Vascular Anomalies Center over a 4‐year period (2008–2012) to whom aspirin had been recommended. They were surveyed regarding whether they were taking aspirin and, if yes, whether aspirin had resulted in any appreciable benefit. Sixty‐five letters were sent to potential subjects: 38 participated and 27 declined to participate or could not be contacted. Twenty‐eight of the 38 had begun aspirin and 22 reported current use. Seventeen reported some benefit, including less aching (n = 2), less shooting pain (n = 15), less fullness and swelling (n = 13), and shrinking of the VM (n = 1). Discontinuation of aspirin was associated with worsening VM symptoms in five of six patients. Side effects were reported in 6 of 28 patients, including five episodes of minor bleeding or excessive bruising and one of nausea and vomiting. This study suggests that aspirin may be a beneficial treatment for VM, with a reduction in pain and soft tissue swelling and an acceptable side‐effect profile, but the retrospective nature of the study and the small size of the cohort limited our conclusions. Larger prospective studies of aspirin for VM using clinical and laboratory outcome measures are needed to confirm these observations.