Radiotherapy and concomitant weekly 1-hour infusion of paclitaxel in the treatment of head and neck cancer--results from a Phase I trial

PURPOSE: To define the maximum tolerated dose (MTD) by describing the dose-limiting toxicity (DLT) of weekly paclitaxel (PAC) given as a 1-h I.V. infusion in patients with head and neck cancer concomitant to irradiation. METHODS AND MATERIALS: Patients with unresectable or incompletely resected head and neck cancer were enrolled into a prospective, dose-escalating Phase I study. Toxicity was graded according to the WHO toxicity score. MTD dose was defined when two out of six patients developed DLT. The starting dose of PAC was 20 mg/m2 once weekly I.V. over 60 min, with a subsequent dose escalation of 10 mg/m2 in cohorts of three new patients. Radiation therapy was administered in three field technique over 6-7 weeks in 2.0 Gy/daily fractions for 5 consecutive days/week up to total doses of 60-70 Gy. RESULTS: From 1994-1996, 18 patients completing three dose levels were included into the study. Altogether, 101 courses of chemotherapy were evaluable for toxicity. On the second dose level (30 mg/m2) one of three patients experienced DLT with Grade IV mucositis. On the next dose level with 40 mg/m2 PAC weekly one patient experienced DLT being prolonged Grade III mucositis. From the following three patients required, two patients showed no DLT. The third patient showed mucositis of WHO Grade 4 and died from hemorrhage caused by a rupture of the a pharyngeal wall. Dose level 2 (30 mg/m2) was repeated and one of the three newly treated patients again suffered from mucositis WHO Grade 4. CONCLUSION: When PAC is given weekly as a 1-h infusion concomitant to radiotherapy, MTD is 30 mg/m2 with mucositis being DLT; hematological and further nonhematological toxicity is mild.     

Factors associated with self-reported, pesticide-related visits to health care providers in the agricultural health study

To investigate factors associated with pesticide-related visits to health care providers (i.e., doctor or hospital visits), responses to self-administered questionnaires received from 35,879 licensed restricted-use pesticide applicators participating in the Agricultural Health Study were analyzed. (In Iowa, applicators are actually certified, whereas in North Carolina they are licensed; for ease of reference, the term license will be used for both states in this paper.) The cohort reported a total of more than 10.9 million pesticide-application days. These applications were associated with one or more pesticide-related health care visits by 2,214 applicators (7.0% of the applicator cohort for whom health care visit data were available). The odds of a pesticide-related health care visit were increased for commercial applicators compared to private applicators [odds ratio (OR = 1.77; 95% confidence interval (CI), 1.52-2.06) and for applicators who used insecticides 70 times or more in their lifetime compared to those who used insecticides less frequently (OR = 1.43; CI, 1.26-1.63). After adjusting for the number of applications in a logistic regression model, significantly higher odds of health care visits were observed among North Carolina applicators compared to Iowa applicators (OR = 1.35; CI, 1.17-1.52), among applicators who mixed their own pesticides (OR = 1.65; CI, 1. 22-2.23), and among applicators who personally repaired their pesticide application equipment at least once per year (OR = 1.12; CI, 1.06-1.25). Significantly lower odds were found among female versus male applicators (OR = 0.68; CI, 0.46-0.99) and among applicators who graduated from high school versus those who did not (OR = 0.82; CI, 0.71-0.94 for high school graduates and OR = 0.79; CI, 0.68-0.91 for those with at least some college). Several methods of pesticide application to crops, seed, or stored grain were also associated with significantly elevated odds ratios of health care visits. These observations suggest that several steps can be taken to reduce the number of health care visits resulting from occupational exposure to pesticides. The implications of this pattern of pesticide-related health care visits may have etiologic implications for cancer and other chronic diseases.     

Selective inhibition of human glial inducible nitric oxide synthase by interferon-beta: implications for multiple sclerosis

Nitric oxide generated from the inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of multiple sclerosis. Because significant species- and cell-specific differences exist in the expression of iNOS, we used primary human glial cell cultures to screen for an inhibitor of iNOS expression. Remarkably, among numerous soluble factors tested, interferon-beta (IFN-beta) alone showed a selective and potent inhibition of interleukin-1beta/interferon-gamma (IL-1beta/IFN-gamma)-induced iNOS expression in astrocytes. Inhibition of iNOS may provide a mechanism by which IFN-beta can ameliorate inflammation and cytotoxicity in the central nervous system of patients with multiple sclerosis.     

N-substituted octahydro-4a-(3-hydroxyphenyl)-10a-methyl-benzo[g]isoquinolines are opioid receptor pure antagonists

N-Methyl- and N-phenylethyl-(+/-)-1,2,3,4,4a,5,10,10a- octahydro-4a-(3-hydroxyphenyl)-10a-methyl-benzo[g]isoquinolines (4 and 5, respectively) were found to be pure opioid antagonists. These compounds were shown to share many of the characteristics identified with the N-methyl- and N-phenylethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (1 and 2, respectively) including N-substituent mediated potency and a lack of N-substituent mediated antagonism. These data suggest that compounds 4 and 5 and the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (1 and 2) may interact with opioid receptors similarly.     

Fermentation studies of rustmicin production by a Micromonospora sp

The antifungal antibiotic rustmicin was detected in the fermentation broth of the actinomycete MA 7094 as a specific inhibitor of sphingolipid biosynthesis in Candida albicans and as a potent fungicidal agent against Cryptococcus neoformans. Taxonomic characterization by both classical means and PCR fingerprinting supported the assignment of the producing culture to the genus Micromonospora. Fermentation medium optimization studies showed that the concentration of tomato paste in the medium was critical to increased production of rustmicin by MA 7094. The stimulatory effect of tomato paste in the medium on rustmicin production appeared to be related to the maintenance of pH at or below a value of 6.0. Addition of the antifoam agent P-2000 to the fermentation was found to dramatically reduce the rustmicin titer, while substitution of another antifoam agent, UCON-LB625, resulted in a 100% increase in the amount of rustmicin detected. After fermentation optimization studies and the generation of a non-sporulating mutant of MA 7094, the rustmicin titer was increased from an initial titer of 10mg/liter to 145 mg/liter.     

MRI: incidence and evaluation of size and form criteria in hypophysis-healthy probands and in patients with detectable microadenomas

Magnetic resonance imaging (MRI) was performed in 42 patients with proven microadenomas and in 42 patients with normal pituitary hormone analysis. The normal MRI--anatomy of the pituitary gland and its possible variations with measurement of the volume and comparison of the anatomy with that of the gland after changes caused by microadenomas has to our knowledge not yet described. In this study we measured the height, coronary and sagittal diameter of the pituitary gland in both groups as well as other indirect signs of microadenomas (asymmetry of the gland, sella turcica, and the stalk). The pituitary volume indicates the expansion of microadenomas much better than the gland height (and the other diameters). Normal pituitary glands showed a significant lower volume (525 +/- 137 mm3 [R = 225-800 mm3]) than patients with proven microadenomas (734 +/- 393 mm3 [R = 335-2800 mm3], p < 0.001). The normal pituitary gland and sella turcica show a large variety of anatomic variations. These variations are less frequent in healthy subjects (10-21%) than in patients with microadenomas (48-71%). The described criteria are of some value in diagnosis of a suspected gland hypertrophy or microadenoma. In 75% of the patients with normal pituitary parameters and in 12% of the patients with microadenomas no indirect adenoma criteria was found in our study.     

Development of an ELISA to assess the potency of horse therapeutic polyvalent antibothropic antivenom

The objective of this study was the search for a suitable venom antigen to be used in an in vitro alternative immunoassay, to the standard antivenom neutralization assay using mice. Bothrops jararaca venom was fractionated in DEAE-Sephacel columns and the fractions were tested for a correlation between antibody capture enzyme linked immunosorbent assay (ELISA) absorbance values and the 'in vivo' antivenom potency. Individual antivenoms from 14 horses and 15 separate FUNED polyspecific Bothrops ampouled antivenoms (final product) were used. Fractions showing the higher correlations were further chromatographed in a Sephadex G-75 column and again tested for the correlation. Two fractions with haemorrhagic activity displayed a correlation of r = 0.77 and r = 0.8 against the individual horse antivenom sera and of r = 0.79 and r = 0.8 for the ampouled antivenom. For all results p < 0.001. Two other fractions with phospholipase A2 activity showed a correlation of r = 0.66 (p < 0.01) and r = 0.56 (p < 0.03) against the individual horse antivenom sera. Electrophoresis results show a similar composition for both antigens with haemorrhagic activity. Results indicate that the fractions purified would be suitable for the desired objective of this study.     

Multiple sclerosis: altered expression of 70- and 27-kDa heat shock proteins in lesions and myelin

Recent studies have implicated heat shock proteins (HSP) in the pathogenesis of the multiple sclerosis (MS) lesion. Expression of the 73 kDa constitutive HSP (HSC70), the 72 kDa stress-inducible HSP (HSP70), and the 27 kDa small HSP (HSP27) was analyzed in white matter and myelin from central nervous system (CNS) tissue of MS and normal subjects using a combination of immunocytochemistry and quantitative immunoblotting. Plaques of all types were sharply defined by reduced immunostaining for HSC70, and shown by immunoblotting to contain 30 to 50% less HSC70 than surrounding white matter or normal tissue. In contrast, HSP27 was markedly enhanced 2.5- to 4-fold in plaque regions, especially in fibrous astrocytes and in hyperplastic interfascicular oligodendrocytes at the lesion edge. HSP70 was less abundant than HSC70, and no significant differences in HSP70 levels were noted between MS and normal white matter. Myelin isolated from active plaques contained 3- to 4-fold more HSC70 than normal myelin. Pronounced expression of HSP70 and HSP27 was also found in MS myelin, although neither protein was detected in normal myelin. Thus, white matter undergoing immune-mediated destruction in MS was associated with altered distribution and expression of HSC70 and HSP27. These changes may initially serve to protect myelin from further destruction and facilitate repair; however, enhanced expression of HSC70, HSP70, and HSP27 in myelin may subsequently present as additional immune targets involved in the progression of disease.     

Clinical factors contributing to the differential diagnosis of primary insomnia and insomnia related to mental disorders

OBJECTIVE: Primary insomnia and insomnia related to mental disorders are the two most common DSM-IV insomnia diagnoses, but distinguishing between them is difficult in clinical practice. This analysis was performed to identify clinical factors used by sleep specialists to distinguish primary insomnia from insomnia related to mental disorders. METHOD: Clinicians evaluated 216 patients referred for insomnia at five clinical sites, rated a list of clinical factors judged to contribute to each patient's presentation, and assigned diagnoses. Analysis of variance was performed, with contributing factors as the dependent variable and diagnostic group and clinic location as independent variables. RESULTS: Sleep specialists rated a psychiatric disorder as a stronger factor for insomnia related to mental disorders and rated negative conditioning and sleep hygiene as stronger factors for primary insomnia. However, a psychiatric disorder was rated as a contributing factor for 77% of patients who received a first diagnosis of primary insomnia. CONCLUSIONS: While neither sleep hygiene nor negative conditioning is a diagnostic criterion in DSM-IV, these results support the face validity of these clinical factors distinguishing between primary insomnia and insomnia related to mental disorders. The use of a psychiatric disorder as an inclusion criterion for insomnia related to mental disorders and an exclusion criterion for primary insomnia reinforces a categorical distinction between the two diagnoses, but the contribution of psychiatric symptoms in primary insomnia appears to be a clinically relevant one. These findings suggest the need for studies on the validity of negative conditioning and sleep hygiene in the etiology of primary insomnia, as well as on the significance of psychiatric disorders, especially depression, in primary insomnia.