A Guide to Immunotherapy of Genital Warts

Genital warts affect at least 1% of sexually active adults. Current therapies are inadequate because they are often painful, may fail to prevent recurrence and transmission of warts, and usually require either surgery or at least application by a physician. Investigation of immunotherapy for genital warts began with interferon. It has been studied in topical, intralesional, systemic and adjuvant applications. We review the major clinical trials of interferon for genital warts, and conclude that intralesional therapy with interferon-alpha or interferon-beta, with complete response rates of 36 to 63%, is the most successful route for interferon monotherapy. In choosing patients for therapy with interferon, major considerations include immune status, pregnancy and ability to return for frequent injections. Imiquimod is a new immune response enhancer that acts through stimulating host cytokine production. Interleukins-1, -2, -6, -8 and -12, interferons alpha, beta and gamma and tumour necrosis factor alpha have all been associated with the mechanism of action of imiquimod. Recently, 3 clinical trials have reported positive results using topical imiquimod to treat genital warts. Complete response rates ranged from 37 to 54% for these controlled trials of 5% imiquimod cream. Adverse effects reported include localised pruritis, erythema, erosion, burning and pain, which were rarely severe enough to cause discontinuation of the medication. Although further trials are necessary to identify the role of imiquimod in the therapy of genital warts, it appears to be an efficacious and well tolerated patient-controlled measure for wart therapy.     

Investigation of a severity-based classification of mood and anxiety symptoms in primary care patients

BACKGROUND: Current Diagnostic and Statistical Manual of Mental Disorders (DSM) classifications describe spectrums of symptoms that define mood and anxiety disorders. These DSM classifications have been applied to primary care populations to establish the frequency of these disorders in primary care. DSM classifications, however, might not adequately describe the underlying or natural groupings of mood and anxiety symptoms in primary care. This study explores common clusters of mood and anxiety symptoms and their severity while exploring the degree of cluster congruency with current DSM classification schemes. We also evaluate how well the groupings derived from these different classifying methods explain differences in patients' health-related quality of life. METHODS: Study design was cross-sectional, using a sample of 1333 adult primary care patients attending a university-based family medicine clinic. We applied cluster analysis to responses on a 15-item instrument measuring symptoms of mood and anxiety and their severity. We used the PRIME-MD to determine the presence of DSM-III-R disorders. The SF-36 Health Survey was used to assess health-related quality of life. RESULTS: Cluster analysis produced four groups of patients different from groupings based on the DSM. These four groups differed from each other on sociodemographic indicators, health-related quality of life, and frequency of DSM disorders. Cluster membership was associated in three of four clusters with a clinically significant and progressive decrease in mental and physical health functioning as measured by the SF-36 Health Survey. This decline was independent of the presence of a DSM diagnosis. CONCLUSIONS: A primary care classification scheme for mood and anxiety symptoms that includes severity appears to provide more useful information than traditional DSM classifications of disorders.     

ATP-Dependent colchicine transport by human erythrocyte glutathione conjugate transporter

We have recently demonstrated mutually inhibitory ATP-dependent transport of dinitrophenyl-S-glutathione (DNP-SG) and doxorubicin by DNP-SG ATPase purified from human erythrocyte membranes (S. Awasthi et al., 1998a,b). Our previous studies indicate a broad substrate specificity for this transport mechanism, including some P-glycoprotein substrates. Present studies were carried out to determine whether colchicine (COL), a classical P-glycoprotein substrate, could be transported by purified human erythrocyte DNP-SG ATPase reconstituted in artificial liposomes. We also investigated whether leukotriene C4 (LTC4), an endogenous proinflammatory glutathione-conjugate derived from arachidonic acid, would inhibit colchicine transport. Uptake of COL was compared in proteoliposomes reconstituted with the purified DNP-SG ATPase as well as control liposomes in the presence or absence of ATP. Increased colchicine uptake was observed upon addition of ATP to proteoliposomes, but not control liposomes. Uptake was linear with respect to the amount of vesicle protein used. Sensitivity to osmolarity was consistent with intravesicular COL accumulation. The ATP-dependent colchicine uptake was sensitive to temperature in a manner consistent with a protein-mediated transport process with activation energy of 7.3 kcal/mol. Time-dependent COL uptake by proteoliposomes in the presence of ATP was consistent with a single compartment model with an apparent rate constant of 0.21 +/- 0.02 min-1. Kinetic studies indicated a saturable behavior with respect to ATP (Km 2.3 +/- 0.7 mM) and colchicine (Km 4.3 +/- 0.2 microM). LTC4 was found to be a competitive inhibitor of COL transport (Kis 16.4 microM). Since DNP-SG ATPase is present in many tissues, it may play an important role in determining colchicine accumulation in cells. Increased LTC4 would tend to increase cellular COL accumulation.     

RTOG Phase I study on fast neutron teletherapy for squamous cell carcinoma of the esophagus

From August, 1977, through January, 1981, the Radiation Therapy Oncology Group sponsored a Phase I study (RTOG 77-09) on the use of fast neutrons for treating inoperable squamous cell carcinomas of the esophagus. A total of 39 evaluable patients were treated with curative intent using either fast neutrons alone or in combination with low LET irradiation as part of a mixed beam fractionation scheme. Actuarial survival curves are presented for both the "neutrons alone" and the "mixed beam" treatment groups. There was no significant survival difference between these groups of patients. The projected survival at two years is less than 10%, which is comparable with megavoltage photon results for an unselected series of patients. The size of the primary lesion and the initial Karnofsky performance status were found to be the most important prognostic indications for prolonged survival. Sixteen of 39 patients were felt to have achieved local clearance of their tumor at some time during their follow-up with the median time until a local recurrence being 17 months. Treatment related complications and patterns of metastatic spread are discussed. In general, it appeared that the response of large tumors to neutron irradiation resulted in necrosis and fistula formation. In many cases this was accompanied by persistent/recurrent tumor within the high dose radiation volume.     

Infantile right hemisphere injury: a case report with MRI and 13 year follow-up

Serial neuropsychological findings were obtained in a case of infantile right parietal injury who was studied over a 13 year follow-up period. Magnetic resonance imaging at age 13 years documented extensive injury to the right hemisphere, particularly the parietal region. Serial examinations at age 7 and 13 years showed intact visual attention, normal expression and processing of affect and variable visuospatial abilities. However, intellectual development was generally depressed. Implications of these findings for recovery from early brain injury are discussed.     

Cerebral metabolic and vasopressin and oxytocin responses during osmotic stimulation in conscious rats

Intravenous infusion of hypertonic saline increased plasma [Na (+) ] and osmolality and induced a short-latency drinking response. These changes were associated with increased glucose utilization in the supraoptic and paraventricular nuclei and neural lobe, and decreases in the medial septum and nucleus ambiguus. The increases in glucose utilization were more accentuated in the supraoptic nuclei than in paraventricular nuclei, indicating that they are more sensitive to osmotic stimulation than the paraventricular nuclei. In association with enhanced activity in the hypothalamo-neurohypophysial system, plasma vasopressin and oxytocin concentrations increased, with a preferential increase of oxytocin over vasopressin. The hormonal contents in the neural lobe were not depleted by the osmotic stimulus despite the large increases of their concentrations in the plasma.     

Motion analysis in two dimensions of radial-ulnar deviation of type I versus type II lunates

The motions of 2 different types of lunate (type I, no medial hamate facet; type II, medial hamate facet) were evaluated and compared during radial-ulnar deviation of the wrist using radiography and magnetic resonance imaging. Ten right wrists (5 type I and 5 type II lunates) were studied using posteroanterior and lateral x-rays. Six of the 10 normal volunteers (3 type I and 3 type II lunates) were studied using magnetic resonance imaging in 6 positions of radial-ulnar deviation. In the radiographic study the ulnar shift ratio of the lunate (USR), the shortest distance between the proximal ulnar tip of the lunate and the distal ulnar edge of the sigmoid notch of the radius (R-L), the closest distance between the distal ulnar tip of the lunate and the proximal pole of the hamate (L-H), the radius of curvature of the proximal head of the capitate (Cr) on posteroanterior view, and the radiolunate angle on lateral view were measured in each wrist in each of the 6 positions. There were statistically significant differences between type I and II lunates with regard to average maximum ulnar deviation of USR and R-L, total change of USR, R-L distance and L-H distance, average L-H distance and Cr distance in all positions, and average radiolunate angle in neutral and 15 degrees ulnar deviation. In the magnetic resonance imaging study the wrists with a type I lunate did not have contact between the lunate and hamate in any position; the wrists with a type II lunate did have contact between the hamate and the lunate, but only in ulnar deviation. The results of this study demonstrate that the kinematics of a type I lunate are different from those of a type II lunate during radial-ulnar deviation of the wrist.     

Effects of tracheostomies on infection and airway complications in pediatric burn patients

Considerable controversy exists as to whether tracheostomy is ever indicated in burn patients. New advents in the treatment of inhalation injury have improved survival, making the use of tracheostomy more usual. The purpose of this study was to analyze the outcome of tracheostomies, and the effect of time on complications. Patients requiring ventilatory support and tracheostomies were studied. Demographic data, hospital course, ventilatory parameters and complications were analyzed. Two hundred ninety patients required ventilation and 36 tracheostomy. Mean percentage of TBSA burned was 59%+/-4. Ninety percent of these patients presented with inhalation injury. Mortality in tracheostomy patients was 25 and 16% in all ventilated patients. Thirty-five percent of the patients developed late complications. Patients who had their airway converted to tracheostomy before day 10 postinjury had a significantly lower incidence of subglottic stenosis. and patients who required airway pressures over 50 cm H2O for more than 10 days had a significantly higher incidence of tracheomalacia. Pneumonia occurred at similar incidence in ventilated and tracheostomy patients. The mortality and late complications of pediatric burn patients with tracheostomy has decreased over the last decade. They do not present with higher incidence of pneumonia. Maintenance of airway pressures below 50 cm H2O and conversion of the artificial airway to tracheostomy before day 10 postinjury may be advisable in patients requiring long term ventilation to prevent late complications.