Mobilan: a recombinant adenovirus carrying Toll-like receptor 5 self-activating cassette for cancer immunotherapy.

Toll-like receptor 5 (TLR5) is considered an attractive target for anticancer immunotherapy. TLR5 agonists, bacterial flagellin and engineered flagellin derivatives, have been shown to have potent antitumor and metastasis-suppressive effects in multiple animal models and to be safe in both animals and humans. Anticancer efficacy of TLR5 agonists stems from TLR5-dependent activation of nuclear factor-κB (NF-κB) that mediates innate and adaptive antitumor immune responses. To extend application of TLR5-targeted anticancer immunotherapy to tumors that do not naturally express TLR5, we created an adenovirus-based vector for intratumor delivery, named Mobilan that drives expression of self-activating TLR5 signaling cassette comprising of human TLR5 and a secreted derivative of Salmonella flagellin structurally analogous to a clinical stage TLR5 agonist, entolimod. Co-expression of TLR5 receptor and agonist in Mobilan-infected cells established an autocrine/paracrine TLR5 signaling loop resulting in constitutive activation of NF-κB both in vitro and in vivo. Injection of Mobilan into primary tumors of the prostate cancer-prone transgenic adenocarcinoma of the mouse prostate (TRAMP) mice resulted in a strong induction of multiple genes involved in inflammatory responses and mobilization of innate immune cells into the tumors including neutrophils and NK cells and suppressed tumor progression. Intratumoral injection of Mobilan into subcutaneously growing syngeneic prostate tumors in immunocompetent hosts improved animal survival after surgical resection of the tumors, by suppression of tumor metastasis. In addition, vaccination of mice with irradiated Mobilan-transduced prostate tumor cells protected mice against subsequent tumor challenge. These results provide proof-of-concept for Mobilan as a tool for antitumor vaccination that directs TLR5-mediated immune response toward cancer cells and does not require identification of tumor antigens.

Phenytoin as a possible cause of acetaminophen hepatotoxicity: case report and review of the literature.

A 55-year-old woman was hospitalized for treatment of community-acquired pneumonia. Unexplained, moderate elevations in hepatic transaminase and enzyme levels prompted review of her drug regimen. She had taken acetaminophen 1,300-6,200 mg/day during the hospitalization. She also received phenytoin for posttraumatic seizures. Acetaminophen was discontinued, and the patient's liver chemistries returned to normal within 2 weeks of discharge. Acetaminophen is metabolized in part by cytochrome P450 (CYP) 2E1, and inducers of CYP2E1 are known to predispose patients to acetaminophen-related hepatotoxicity. Phenytoin induces CYP2C and CYP3A4 isoforms, but not CYP2E1. The literature suggests, however, that CYP3A4 may participate in acetaminophen metabolism to a greater extent than previously realized, and induction of this isoform may predispose patients to acetaminophen-induced hepatotoxicity.

Defining and achieving optimum therapeutic goals in critically ill patients.

Patients who are critically ill with sepsis, shock, respiratory failure, trauma, or major surgical procedures may have reduced morbidity and mortality when hemodynamic and oxygen transport variables are augmented to values higher than those traditionally considered normal. Lactate production and suboptimum oxygen transport values are associated with anaerobic metabolism and insufficient tissue oxygenation. Since lactate can be a marker of inadequate tissue oxygenation, serial lactate measurements may be useful in individualizing therapy to reverse tissue hypoxia. Optimum hemodynamic and oxygen transport values are highly individual, and no accepted method has been established for guiding therapy. These values, together with plasma lactate concentrations, may assist in individualizing therapy in critically ill patients. No consensus can be reached at this time as to which specific therapeutic end points are optimal, how to achieve these end points, and which subset of patients will benefit from this therapy.

Use of transdermal nicotine systems in a possible suicide attempt.

BACKGROUND: Transdermal drug delivery systems, a relatively recent development, are well accepted by physicians and patients because of reliability and ease of administration. The patch reservoirs, however, contain large quantities of drug, and the potential for considerable toxicity exists if they are used incorrectly. A case is presented of an apparent suicide attempt that involved the use of nicotine transdermal patches. METHODS: This case report involved a patient seen in the emergency department by one of the authors. Data were obtained from the patient's medical record while maintaining confidentiality. RESULTS: The drug overdose was a potentially serious one. The patient recovered fully after an uneventful hospital course. CONCLUSIONS: Transdermal drug delivery systems now deliver many drugs, several of which are quite potent. Intentional or unintentional misuse of the systems can result in toxicity. The physician and pharmacist should carefully instruct each patient in the appropriate use and handling of transdermal drug delivery systems.

Psychosocial and physiological predictors of sudden cardiac death after healing of acute myocardial infarction.

Several major prospective studies that have examined the relation between type A behavior and cardiac mortality have failed to find an association. Since psychosocial factors have been implicated in the etiology of sudden cardiac death, it is possible that this association may emerge if sudden cardiac death is distinguished as an outcome distinct from other cardiac mortality. Predictors of sudden death and other cardiac outcomes were examined using data from the Recurrent Coronary Prevention Project, a 4.5-year prospective clinical trial of 1,012 postinfarction patients begun in San Francisco in 1978. A unique set of risk factors was found for the differing outcomes: sudden cardiac death had predominantly psychosocial predictors while nonsudden cardiac death and nonfatal recurrences were predominantly predicted by biologic factors. Type A behavior was an independent predictor of sudden, but not nonsudden, cardiac death in this population (p = 0.04). These results are the first demonstration of a direct relation between stress and sudden cardiac death in a large prospective clinical study, and provide insight into the failure of past prospective studies to find an association between type A behavior and cardiac mortality.

Facial nerve schwannoma in a 16-year-old girl.

A 16-year-old girl with unilateral facial nerve schwannoma in the cerebellopontine angle is presented in this report. The characteristic computerized tomography (CT) findings described in schwannomas and the patient's clinical findings established the preoperative diagnosis of a rare but benign tumor in the pediatric age group. The value of early diagnosis of potentially resectable benign tumors is emphasized.

Suprascapular entrapment neuropathy: a clinical, anatomical, and comparative study. Part 3: comparative study.

The suprascapular ligament seems to serve no defined function in the human. A comparative study was undertaken to elucidate its function. The suprascapular region was dissected in species representing seven existing primate families and six subprimate families. A striking dichotomy of pattern was observed. In the New World primates, the suprascapular ligament appeared to be continuous with the coracoclavicular ligament; the former merely served to increase the area of bony attachment of the coracoclavicular ligament. In the Old World monkeys and subprimate mammals, the suprascapular ligament was entirely absent. The human anatomy was comparable to that found in the New World primates. This dichotomy of pattern seems to be related to the function of the upper extremity in the different classes of mammals.

Pathogenesis of intracranial arachnoid cysts.

The pathogenesis of intracranial arachnoid cysts is reviewed. Light and electron microscopic features of arachnoid cysts are presented in support of the hypothesis of Starkman et al, that these cysts are truly intraarachnoid in location and are formed by splitting or duplication of the arachnoid membrane. Documentary evidence is provided to prove that Richard Bright's original description in 1831 contains these concepts, which have passed unnoticed for nearly a century and a half. A brief description of the meninges and the subarachnoid spaces is given.

A prospective study of tracheobronchial bacterial flora in acutely brain-injured patients with and without antibiotic prophylaxis.

The authors observed prospectively 28 brain-injured patients, who required respiratory tract intubation, to determine the effect of antibiotic prophylaxis on bacterial flora, the rate of flora change, and the appearance of infection. Antibiotics not only failed to alter the rate of abnormal colonization but were associated with an earlier appearance of Gram-negative bacilli, the organisms that produced the most severe infections. Although more infections occurred in patients initially untreated with antibiotics, these infections were usually mild and caused by organisms susceptible to highly effective and relatively safe drugs. Although highly reproducible as a laboratory determination, the nitroblue tetrazolium dye test score showed no consistent relationship with the presence or absence of bacterial infection. Regular and extensive clinical and laboratory observations, including cultures of the respiratory tract helped to make the antibiotic administration in these patients specific, appropriate, and reasonable. Broad spectrum antibiotic prophylaxis does not prevent and may enhance the development of severe pulmonary infection in these patients.

Hypothermic total body washout and intracranial pressure monitoring in Stage IV Reye syndrome.

The number of children in this report treated with either TBW or exchange transfusions is small. Case mortality rates among children with Reye syndrome in Stage IV coma tends to be exceedingly high, varying from 50 to 100%. Intracranial pressure monitoring with the subarachnoid screw may have been an additional factor in increasing our survival data in three patients in the TBW group, since it provided continuous monitoring of ICP and allowed judicious administration of mannitol intravenously. Survival of five of six patients without neurologic sequelae in the present series has encouraged us to coninue utilization of TBW in children with Stage IV Reye syndrome.

Gliomas (astrocytomas) of the brain-stem with spinal intra- and extradural metastases: report of three cases.

Astrocytomas of the pons and medulla oblongata ('brain-stem gliomas') while often invasive locally, do not as a rule seed and metastasize along the spinal meninges. Three cases are here reported (two adults, one child) in whom astrocytoma of the brain-stem metastasized along the spinal cord. The dura mater itself and the spinal epidural space were invaded in two cases. The child and one adult had a pontine astrocytoma, the other adult's tumour originated in the medulla oblongata. In the two cases that came to necropsy the tumour of the brain-stem was much better differentiated than the meningeal deposits. These three cases suggest that the possibility of spinal spread of brain-stem gliomas should be considered when dealing with diagnostic and therapeutic problems of such patients.