Toward global advancement of medicine: the International Society of Nephrology experience

BACKGROUND: Since its foundation in 1960, the International Society of Nephrology (ISN) has pursued the worldwide advancement of education, science and patient care in nephrology. This goal was achieved by means of the Society's journal and the organization of international congresses and symposia. In order to better reach its colleagues and patients in economically less developed countries, the ISN expanded its activities as of 1980 by a large number of specific programs aimed at these regions. METHODS: The first phase of activities included teaching programs, fellowship and visiting scholar programs, and the provision of travel grants to enhance accessibility to the ISN congresses. A second phase consisted of the creation of a library enhancement program, a commission on acute renal failure and--to improve the organization and efficiency--a central commission on global advancement of nephrology (COMGAN). Currently, a third phase has been entered in which all activities have been intensified: (1) under the guidance of COMGAN, supported by a large number of teaching programs and fact finding missions; (2) by establishing a renal sister program; and (3) by initiating commissions on informatics and on clinical trials. RESULTS: As a result, the ISN has reached most parts of the world, previously deprived of contact with renal science and renal patient care. The fellowship program now counts 160 fellows, who spend one or two years in training. The library enhancement program reaches 218 institutions worldwide. ISN membership has soared over the past two years with over 2,500 new members, mostly in the developing countries. They receive Kidney International and other relevant forms of information. Thus far, 135 pairs of renal units in developing and developed countries have been linked for support on a more continuous basis. ISN-sponsored congresses, symposia, and courses are being held in increasing numbers in the developing world. In many of its activities, the ISN closely collaborates with sister organizations, which also contribute financially. In total, the ISN spends annually over $1 million US from its own budget on the programs described above. CONCLUSION: The various programs and initiatives are proving helpful in advancing renal medicine in areas in need. Expansion into supporting similar programs within other medical subspecialties is being explored.     

Dexamethasone perfusion of the labyrinth plus intravenous dexamethasone for Ménière's disease

Recent clinical and laboratory evidence indicates that Meniere's disease is an immune-mediated disease. Dexamethasone perfusion of the inner ear through the round window plus intravenous dexamethasone often will stop the dizzy spells, reduce the fullness and low-frequency tinnitus, and sometimes improve the hearing in patients with Meniere's disease. The dexamethasone must act mostly on the endolymphatic sac and, to a lesser extent, on the stria vascularis and spiral ligament, the known targets of immune response in the inner ear, to reduce the endolymphatic hydrops and restore the fluid dynamics of the endolymph. Despite the good results with streptomycin perfusion, the number of patients with further hearing loss is large, so dexamethasone perfusion with intravenous dexamethasone should be tried first. The initial response to dexamethasone perfusion plus intravenous dexamethasone has been very good, with very little risk of further hearing loss, and it holds great promise for the future.     

Solution structure of the superactive monomeric des-[Phe(B25)] human insulin mutant: elucidation of the structural basis for the monomerization of des-[Phe(B25)] insulin and the dimerization of native insulin

The three-dimensional solution structure of des-[Phe(B25)] human insulin has been determined by nuclear magnetic resonance spectroscopy and restrained molecular dynamics calculations. Thirty-five structures were calculated by distance geometry from 581 nuclear Overhauser enhancement-derived distance constraints, ten phi torsional angle restraints, the restraints from 16 helical hydrogen bonds, and three disulfide bridges. The distance geometry structures were optimized using simulated annealing and restrained energy minimization. The average root-mean-square (r.m.s.) deviation for the best 20 refined structures is 1.07 angstroms for the backbone and 1.92 angstroms for all atoms if the less well-defined N and C-terminal residues are excluded. The helical regions are more well defined, with r.m.s. deviations of 0.64 angstroms for the backbone and 1.51 angstroms for all atoms. It is found that the des-[Phe(B25)] insulin is a monomer under the applied conditions (4.6 to 4.7 mM, pH 3.0, 310 K), that the overall secondary and tertiary structures of the monomers in the 2Zn crystal hexamer of native insulin are preserved, and that the conformation-averaged NMR solution structure is close to the structure of molecule 1 in the hexamer. The structure reveals that the lost ability of des-[Phe(B25)] insulin to self-associate is caused by a conformational change of the C-terminal region of the B-chain, which results in an intra-molecular hydrophobic interaction between Pro(B28) and the hydrophobic region Leu(B11)-Leu(B15) of the B-chain alpha-helix. This interaction interferes with the inter-molecular hydrophobic interactions responsible for the dimerization of native insulin, depriving the mutant of the ability to dimerize. Further, the structure displays a series of features that may explain the high potency of the mutant on the basis of the current model for the insulin-receptor interaction. These features are: a change in conformation of the C-terminal region of the B-chain, the absence of strong hydrogen bonds between this region and the rest of the molecule, and a relatively easy accessibility to the Val(A3) residue.     

The US market for SO2 permits: Policy implications of the low price and trading volume

The price of SO₂ permits and the volume of trading under the US Acid Rain Program have been lower than expected. This can be explained by the creation and distribution of more permits than were initially authorized, by the sale of permits by high cost abaters who are subject to more stringent local emission constraints or who have irreversibly invested in high cost abatement technologies and by the deregulation of the natural gas and railroad industries which, in combination with incentives for cost-cutting under the new market approach to SO₂ control, has lowered marginal costs of abatement curves and made them more uniform across powerplants. The low price of permits and low trading volume are evidence that market approaches to pollution control can be more cost-effective than command and control regulations. The effect of public policies and technological changes on the allowance market are usefully examined in the context of an ideal market, in which the equilibrium price of allowances equals the marginal cost of abatement of individual powerplants. Using recent data from Coggins and Swinton (1996), we are able to explain the current price of permits with some accuracy.     

Abnormal behavioral responses to fenfluramine in patients with affective and personality disorders. Correlation with increased serotonergic responsivity

Serotonergic responsivity was assessed in 20 psychiatric patients by the prolactin response to a fenfluramine challenge test. During the fenfluramine challenge 6 of 20 patients (30%) spontaneously reported psychopathologic reactions that included: increased anxiety/agitation, psychotic symptoms, illusions, mood elevation, and anergia. The time of peak behavioral symptoms (2.5 +/- 0.8 hrs) corresponded closely to the time of peak increase in prolactin levels (3.0 +/- 1.1 hr). Abnormal behavioral responders had statistically significant greater increases in prolactin 1 to 4 hr after fenfluramine when compared to normal responders. Patients who developed an abnormal psychopathologic response to fenfluramine were characterized by higher levels of anxiety and agitation at the time of admission to the hospital but otherwise were not distinguishable on the basis of severity of other psychiatric symptoms. This study suggests that increased serotonergic transmission may trigger anxiety, psychosis, and mood elevation in specific vulnerable individuals, whereas other patients with similar psychiatric illnesses are not affected.     

Prenatal diagnosis: update addresses technological advances

This is the second in a series of articles provided to the readers of PENNSYLVANIA MEDICINE as an update from researchers and clinicians in this cutting-edge medical field. The series is partially sponsored through a grant from the Pennsylvania Department of Health to the University of Pittsburgh Department of Human Genetics.     

Combination calculi for uncertainty reasoning: representing uncertainty using distributions

There are many different methods for incorporating notions of uncertainty in evidential reasoning. A common component to these methods is the use of additional values, other than conditional probabilities, to assert current degrees of belief and certainties in propositions. Beginning with the viewpoint that these values can be associated with statistics of multiple opinions in an evidential reasoning system, we categorize the choices that are available in updating and tracking these multiple opinions. In this way, we develop a matrix of different uncertainty calculi, some of which are standard, and others are new. The main contribution is to formalize a framework under which different methods for reasoning with uncertainty can be evaluated. As examples, we see that both the “Kalman filtering” approach and the “Dempster–Shafer” approach to reasoning with uncertainty can be interpreted within this framework of representing uncertainty by the statistics of multiple opinions. This revised version was published online in June 2006 with corrections to the Cover Date.     

Polarization control in a vertical cavity surface emitting laser submitted to optical feedback

We study experimentally and theoretically two polarization effects in a vertical cavity surface emitting laser submitted to optical feedback. In a first experiment, we obtain flips between two linearly polarized laser modes up to a frequency of 50 MHz using an external cavity with a polarizer. In a second experiment, polarization self modulation is demonstrated up to a frequency of 2.6 GHz, using a quarter wave plate instead. Numerical calculations, based on a four levels model for the active medium, show a good agreement with the experiments.     

Postoperative radiotherapy with concurrent cisplatin appears to improve locoregional control of advanced, resectable head and neck cancers: RTOG 88-24

PURPOSE: Despite aggressive surgery and postoperative radiation therapy, only 30% of patients who have advanced, potentially resectable carcinomas of the head and neck survive for 5 years. In the hope of improving this situation we studied the effect of postoperative radiotherapy delivered concurrently with cisplatin. METHODS AND MATERIALS: Patients who had Stage IV tumors and/or involved surgical margins received 60 Gy in 30 fractions over 6 weeks plus 100 mg/m2 of cisplatin on radiotherapy days 1, 23 and 43. Fifty-two patients participated in this trial and 51 were evaluated. Forty-three (84%) patients had pathologic T3 or T4 disease, 43 (84%) had Stage IV disease, and 27 (53%) had histologically involved surgical margins. RESULTS: Severe and life-threatening toxicities occurred in 20% and 12% of patients, respectively; the most common drug-related toxicities were leukopenia, anemia, nausea, and vomiting. Seventeen patients (43%) remain alive with no evidence of disease. Four patients (8%) died with no evidence of neoplastic disease, and one patient has died of a second independent malignancy. By actuarial analysis at 3 years, 48% of patients are alive, 81% have locoregional control of disease, and 57% are free of distant metastases. CONCLUSIONS: Based on comparison with similar patients treated in a prior Radiation Therapy Oncology Group/Intergroup trial (RTOG), we conclude that postoperative radiotherapy with concurrent cisplatin may improve locoregional control rates and should be prospectively tested.