Familial neuroblastoma: report of a kindred with later age at diagnosis

The first reported effective adjuvant combination regimen for patients with operable breast cancer comprised oral cyclophosphamide (C) days 1-14 with intravenous methotrexate (M) and fluorouracil (F) on days 1 and 8, repeated every 28 days ('classical' CMF). These drugs have since been extensively used with or without endocrine therapies and/or other cytotoxics, as well as with radiation therapy to the chest wall yielding conflicting results. Although doses and schedules have varied widely, the combination of these three drugs has been generically referred to as CMF. Evidence exists that reducing the dose and/or altering the schedule of CMF ('modified' CMF) have compromised its efficacy in metastatic breast cancer. Reduction below standard dose of a similar regimen also gave inferior results in the adjuvant setting. In fact, the recently reported improved outcome of adding radiation therapy to CMF was only demonstrated in comparisons with a 'modified' CMF. Furthermore, trials in women with estrogen receptor-positive breast cancer, which did not demonstrate any significant benefit for the addition of adjuvant CMF to tamoxifen compared with tamoxifen alone, also used 'modified' CMF. Therefore, adherence to the 'classical' dose and schedule is recommended when CMF is used in adjuvant therapy.     

Basilar membrane vibration in the gerbil hemicochlea

Excised gerbil cochleae were cut along the mid-modiolar plane (hemicochlea). Along one-half turn of this preparation, fluorescent microbeads were placed on the basilar membrane (BM). The BM was vibrated with click stimuli (50 micros) produced mechanically by a piezo pusher. The stimulus delivery probe could be positioned either more apical or more basal from the beads. Vibration patterns were measured with a wide bandwidth photomultiplier from the movements of the beads. When the probe was positioned more basal, the responses to click stimuli were brief, damped sinusoids. According to the fast Fourier transforms (FFTs) of the averaged time wave forms, the best frequency between successive beads decreased toward the apex (0.8 octave/mm). Sharpness of tuning of the normalized FFT spectra (NQ10dB) on average was 1.5. Response amplitude at a fixed input level, measured at different beads away from the stimulation site, dropped exponentially (58 dB/mm). In addition, for each individual bead, amplitude dropped linearly with decreasing stimulus intensity. In experiments where the stimulating probe was placed more apical, two major properties were observed: first, beads revealed only the spectral components present in the motion of the probe. Second, magnitude reduction of the displacement of the cochlear partition was greater, on average 155 dB/mm, indicating a lack of significant propagation in the reverse direction.     

2-Fluoro-4-pyridinylmethyl analogues of linopirdine as orally active acetylcholine release-enhancing agents with good efficacy and duration of action

In an effort to improve the pharmacokinetic and pharmacodynamic properties of the cognition-enhancer linopirdine (DuP 996), a number of core structure analogues were prepared in which the 4-pyridyl pendant group was systematically replaced with 2-fluoro-4-pyridyl. This strategy resulted in the discovery of several compounds with improved activity in acetylcholine (ACh) release-enhancing assays, in vitro and in vivo. The most effective compound resulting from these studies, 10, 10-bis[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (9), is between 10 and 20 times more potent than linopirdine in increasing extracellular hippocampal ACh levels in the rat with a minimum effective dose of 1 mg/kg. In addition to superior potency, 9 possesses an improved pharmacokinetic profile compared to that of linopirdine. The half-life of 9 (2 h) in rats is 4-fold greater than that of linopirdine (0.5 h), and it showed a 6-fold improvement in brain-plasma distribution over linopirdine. On the basis of its pharmacologic, pharmacokinetic, absorption, and distribution properties, 9 (DMP543) has been advanced for clinical evaluation as a potential palliative therapeutic for treatment of Alzheimer's disease.     

The HIV-epidemic among drug addicts in Norway

Up to 1996, 368 persons in Norway (population 4.3 million) had been reported as being HIV-infected because of intravenous drug use. 72 of these had developed AIDS and 59 had died from AIDS. HIV-testing is very common among drug users in Norway and new cases are rarely detected at treatment centres or at autopsy. Some 15-30 cases may still be undiagnosed. HIV spread very rapidly among drug users in Norway in 1984 and 1985, by around 100 new cases per year. Since then, the annual incidence has decreased from 30-40 cases in 1986 to 10-15 in 1995. Although the drug users seldom shared syringes even before the advent of the HIV epidemic, we believe that the public rehabilitation programmes, needle exchange programmes and health information have contributed to control HIV in this group. We expect an annual incidence of 10-15 cases the next five years.     

Post-tonsillectomy bacteraemia in children

It has been postulated that the bacteraemia rate following guillotine tonsillectomy is lower than that following dissection tonsillectomy due to intra-operative compression of tonsillar blood vessels by the guillotine. The aim of this study was to evaluate the incidence of bacteraemia following dissection and guillotine tonsillectomy. Sixty-four patients undergoing elective tonsillectomy for recurrent acute tonsillitis were randomly selected, 32 underwent dissection tonsillectomy and 32 guillotine tonsillectomy. Positive intra-operative blood cultures were obtained in 16 patients (25 per cent), nine (28.1 per cent) of the dissection group and seven (21.8 per cent) of the guillotine group. There was no significant difference between the two methods (Chi-squared test, p = 0.77).     

A humanized form of a CD4-specific monoclonal antibody exhibits decreased antigenicity and prolonged plasma half-life in rhesus monkeys while retaining its unique biological and antiviral properties

Certain monoclonal antibodies (MAbs) directed against CD4 can efficiently block HIV-1 replication in vitro. To explore CD4-directed passive immunotherapy for prevention or treatment of AIDS virus infection, we previously examined the biological activity of a nondepleting CD4-specific murine MAb, mu5A8. This MAb, specific for domain 2 of CD4, blocks HIV-1 replication at a post-gp120-CD4 binding step. When administered to normal rhesus monkeys, all CD4+ target cells were coated with antibody, yet no cell clearance or measurable immunosuppression occurred. However, strong anti-mouse Ig responses rapidly developed in all monkeys. In the present study, we report a successfully humanized form of mu5A8 (hu5A8) that retains binding to both human and monkey CD4 and anti-AIDS virus activity. When administered intravenously to normal rhesus monkeys, hu5A8 bound to all target CD4+ cells without depletion and showed a significantly longer plasma half-life than mu5A8. Nevertheless, an anti-hu5A8 response directed predominantly against V region determinants did eventually appear within 2 to 4 weeks in most animals. However, when hu5A8 was administered to rhesus monkeys chronically infected with the simian immunodeficiency virus of macaques, anti-hu5A8 antibodies were not detected. Repeated administration of hu5A8 in these animals resulted in sustained plasma levels and CD4+ cell coating with humanized antibody for 6 weeks. These studies demonstrate the feasibility of chronic administration of CD4-specific MAb as a potential means of treating or preventing HIV-1 infection.     

Men and women in optometry. II. Attitudes toward career and family

BACKGROUND: Optometry has experienced a dramatic upward shift in the percentage of women entering the profession during the past 20 years. Our survey assessed the mechanisms for sustaining balance in professional and personal roles used by women optometrists and how these mechanisms may differ from those of their male colleagues. METHODS: A survey questionnaire was mailed to a large nationwide random sample of optometrists, composed of equal numbers of men and women. RESULTS: Data were analyzed from 353 men and 358 women; margin of error was +4%. Most of the respondents indicated they derived personal satisfaction from their career. A majority of both groups did not indicate that lack of time for their career was a source of frustration. However, significantly more women than men indicated some frustration in pursuing those activities that lead to career advancement. There were significant differences in response patterns of men and women about the effect of family, child care, and household work on their careers. CONCLUSIONS: Both men and women optometrists are satisfied with their careers and neither group feels compelled to choose between career and family. Optometrists do not fit into one pattern, but instead make individualized career choices on the basis of needs.     

The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family

A physiological role for paraoxonase (PON1) is still uncertain, but it catalyzes the hydrolysis of toxic organophosphates. Evidence that the human genome contains two PON1-like genes, designated PON2 and PON3, is presented here. Human PON1 and PON2 each have nine exons, and the exon/intron junctions occur at equivalent positions. PON1 and PON2 genes are both on chromosome 7 in human and on chromosome 6 in the mouse. Turkey and chicken, like most birds, lack paraoxonase activity and are very susceptible to organophosphates. However, they have a PON-like gene with approximately 70% identity with human PON1, PON2, and PON3. Another unexpected finding is that the deduced amino acid sequences of PON2 in human, mouse, dog, turkey, and chicken and of human PON3 are all missing the amino acid residue 105, which is lysine in human PON1. The expanded number of PON genes will have important implications for future experiments designed to discover the individual functions, catalytic properties, and physiological roles of the paraoxonases.