Gene therapy of metastatic colon carcinoma: regression of multiple hepatic metastases by adenoviral expression of bacterial cytosine deaminase

Colon carcinoma accounts for 20% of deaths due to malignancies in the Western world. Once metastases occur, therapeutic options are limited, with an approximate 5-year survival of only 5%. To investigate the potential of new gene therapeutic approaches, a hepatic micrometastasis model of colon carcinoma in BALB/c mice was established. Inoculation of syngeneic MCA26 colon carcinoma cells into the spleens of 18- to 20-week-old mice resulted in the formation of multiple hepatic metastases. Selective transduction of developing hepatic metastases was demonstrated using a beta-galactosidase-expressing recombinant adenovirus. Cytosine deaminase (CD) can metabolize 5-fluorocytosine into the chemotherapeutic reagent 5-fluorouracil (5FU). The antitumoral potential of this suicide gene therapy approach was explored by systemic application of a recombinant replication-deficient adenovirus encoding for the bacterial CD gene under the control of the cytomegalovirus promoter (Ad.CMV-CD). Injection into the tail vein of tumor-bearing mice resulted in delayed tumor growth with significant reduction in hepatic metastases. The potential of this experimental approach for possible future clinical applications was evaluated by investigating adenoviral transduction efficiency, 5FU sensitivity, and 5-fluorocytosine-dependent Ad.CMV-CD toxicity in a variety of human colon cancer cell lines. Although the murine cell lines MCA26 and CC36 were highly sensitive to 5FU, the human colon cancer cell lines showed a 1-100 times higher resistance to 5FU. Specific Ad.CMV-CD toxicity correlates with 5FU toxicity. Transduction efficiency in human colon carcinoma cell lines was shown to be 10-1700 times higher compared with murine cell lines, thus compensating for 5FU resistance. In conclusion, suicide gene therapy using CD may be promising as an adjuvant treatment regimen for hepatic micrometastases of human colon carcinoma.     

Outplacement service for the nurse executive

Outplacement service (OPS) is a human resource service provided by organizations to terminated executives. In addition to assisting organizations with the mechanics of the termination process, OPS helps terminated executives cope with the trauma of job loss and find new employment. Given the frequent involvement of nurse executives in termination decisions and the risk of termination inherent in their own positions, nurse executives have a vested interest in OPS policies and programs.     

Isolated dislocation of the tarsal navicular

An unusual case of isolated dorsal dislocation of the tarsal navicular bone due to hyperextension of the foot is presented. The treatment was closed reduction with percutaneous fixation with a Kirschner wire and immobilization for 8 weeks. The end result was satisfactory. To prevent redislocation leading to arthritis, the Kirschner wire should be left in place for at least 6 months.     

Zur Klinik und Pathophysiologie der Vincristinwirkungen am Nervensystem

Zusammenfassung Es wurden 22 Patienten während einer Vincristin-Behandlung mehrfach neurologisch und elektromyographisch untersucht. Die Ergebnisse zeigen eine charakteristische, dosisabhängige Schädigung des Nervensystems. Im Vordergrund stehen bei relativ niedriger Dosierung (weniger als 15 mg) distale Paraesthesien, ein Erlöschen der Eigenreflexe und elektromyographisch eine zunehmende Schwellenerhöhung des H-Reflexes im Vergleich zur Schwelle des direkten Muskelaktionspotentials. Motorische Störungen treten erst bei Dosierungen über 21 mg auf und äußern sich durch starke Atrophie mit relative geringer Parese und muskulärer Hypotonie. Sensible Ausfälle sind auch nach hohen Dosen selten und betreffen dann isoltiert das Berührungs- und Vibrationsempfinden. Die motorische Nervenleitgeschwindigkeit zeigte keine eindeutige Beeinflussung durch die Vincristinbehandlung, während Muskelaktionspotentiale und Nervenaktionspotentiale bei Dosen über 15 mg eine Amplitudenreduktion zeigten.Der bei Gesamtdosen unter 15 mg Vincristin auftretende Verlust der Eigenreflexe und die Schwellenerhöhung des H-Reflexes ohne motorische oder sensible Ausfälle spricht für eine Erregbarkeitsminderung der Motoneurone. Diese Hypothese wird durch morphologische Befunde von Moress gestützt, der bei 2 Patienten nach Vincristin-Behandlung eine Vorderhornzellschädigung fand. Der günstige Effekt des Vincristins bei vermehrter Erregbarkeit der Motoneurone (Spastik) spricht ebenfalls für diese Annahme.Nach unseren Ergebnissen und den morphologischen Befunden der Literatur kommt es erst bei höheren Dosen (>15 mg) zu einer zusätzlichen Schädigung von Axon und Markscheide des peripheren Nerven i. S. einer toxischen Polyneuropathie, allerdings atypisch, d. h. ohne Schmerzen und typische Sensibilitätsstörung.Eine Besserung der Spastik bei Patienten nach Vincristin (12–15 mg) wird durch Erregungsminderung der Motoneurone erklärt. Eine zusätzliche motorische Axonschädigung ist erst bei mehr als 15 mg Vincristin zu erwarten.

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Clinical and pathophysiological aspects of the effects of vincristine on the central nervous system

Summary Neurological and electromyographical examinations were performed in 22 patients treated with vincristine sulphate. The results show a characteristic development of neurological symptoms in relation to the drug dosage, however, the symptoms are not consistent with a pure neuropathy. With lower doses (15 mg) paresthesia and loss of tendon reflexes are the prominent features. Electromyography reveals increasingly higher thresholds of the H-reflex only as compared to normal persons. Stimulation of mixed nerves after vincristine medication shows higher thresholds for the afferent fibers of the H-reflex than for efferent fibers of the muscle potential.With higher doses (21 mg) lower motor neuron disturbances appear rather suddenly associated with marked atrophy and relatively slight pareses and hypotonia. Cutaneous and deep sensibility remains normal in most cases. In a few cases responses to touch and vibration are diminished. There was no slowing of motor nerve conduction velocity, but with doses exceeding 15 mg a decrease in amplitude of both the muscle action potential and sensory nerve action potential occurred.The loss of tendon reflexes and the increase in threshold of the H-reflex in patients receiving less than 15 mg indicate a diminished excitability of motoneurons. This is in agreement with Moress' findings on autopsy of motoneuron lesions in 2 patients after vincristine treatment. An improved spasticity following the administration of vincristine in 3 patients is explained by the influence of this drug on the excitability of motoneurons. An additional lesion of the axon develops if doses exceed 15 mg.

     

Pap smear rates among Haitian immigrant women in eastern Massachusetts

OBJECTIVE: Given limited prior evidence of high rates of cervical cancer in Haitian immigrant women in the U.S., this study was designed to examine self-reported Pap smear screening rates for Haitian immigrant women and compare them to rates for women of other ethnicities. METHODS: Multi-ethnic women at least 40 years of age living in neighborhoods with large Haitian immigrant populations in eastern Massachusetts were surveyed in 2000-2002. Multivariate logistic regression analyses were used to examine the effect of demographic and health care characteristics on Pap smear rates. RESULTS: Overall, 81% (95% confidence interval 79%, 84%) of women in the study sample reported having had a Pap smear within three years. In unadjusted analyses, Pap smear rates differed by ethnicity (p=0.003), with women identified as Haitian having a lower crude Pap smear rate (78%) than women identified as African American (87%), English-speaking Caribbean (88%), or Latina (92%). Women identified as Haitian had a higher rate than women identified as non-Hispanic white (74%). Adjustment for differences in demographic factors known to predict Pap smear acquisition (age, marital status, education level, and household income) only partially accounted for the observed difference in Pap smear rates. However, adjustment for these variables as well as those related to health care access (single site for primary care, health insurance status, and physician gender) eliminated the ethnic difference in Pap smear rates. CONCLUSIONS: The lower crude Pap smear rate for Haitian immigrants relative to other women of color was in part due to differences in (1) utilization of a single source for primary care, (2) health insurance, and (3) care provided by female physicians. Public health programs, such as the cancer prevention programs currently utilized in eastern Massachusetts, may influence these factors. Thus, the relatively high Pap rate among women in this study may reflect the success of these programs. Public health and elected officials will need to consider closely how implementing or withdrawing these programs may impact immigrant and minority communities.     

Luminal preservation of rat small intestine with University of Wisconsin or Celsior solution

AIMS: Luminal administration of a preservation solution that prevents mucosal injury may decrease posttransplant complications. However, luminal administration of University of Wisconsin solution (UW) is controversial. In this study, we examined the potential of Celsior as a luminal small bowel preservation solution in comparison to UW or UW enriched with glutamine. METHODS: Small bowels of six normal WagRij rats were excised and divided into six equal segments. Each segment was luminally flushed with 10 mL ice-cold UW, UW with glutamine (20 g/L) or Celsior, and stored for 0, 2.5, and 24 hours at 4 degrees C. LDH, glucose, and lactate concentrations were determined in the preservation solutions. Histologic changes were determined using the Park score. RESULTS: Lactate dehydrogenase (LDH) was increased in all solutions after 2.5- and after 24-hour preservation. However, LDH was lower in Celsior than UW and UW with glutamine. Furthermore, higher glucose and lactate levels were found after 2.5- and 24-hour preservation in UW and UW with glutamine compared to Celsior. Histologically, jejunal segments were more susceptible to preservation than ileal segments, irrespective of the preservation solution used. Mucosal injury was evident after 2.5 hours (Park Scale 0-3) and increased significantly after 24 hours (park scale 3-6). CONCLUSIONS: Based on the lower glucose, lactate, and LDH levels in small intestines stored in Celsior, this study suggests that Celsior is a better luminal preservation solution than UW. Unfortunately, histological evaluations still show severe mucosal injury, indicating that there is a need for better luminal preservation solutions or for concomittant intravascular delivery of a preservation solution.