Use of antibiotic and analgesic drugs during lactation.

During lactation, multiple situations can arise that require maternal pharmacological treatment. Because of the many health advantages of human milk to infants, breast feeding should be interrupted only when the needed drug might be harmful to the nursing child and exposure via the breast milk will be sufficient to pose a risk. Since the majority of drugs have not been shown to cause adverse effects when used during lactation, and even temporary interruption of breast feeding can be difficult for the nursing dyad, decisions regarding maternal medication use during breast feeding should be based on accurate and up-to-date information. This article reviews available data on the most commonly used antibiotics and analgesics. The use of most antibiotics is considered compatible with breast feeding. Penicillins, aminopenicillins, clavulanic acid, cephalosporins, macrolides and metronidazole at dosages at the low end of the recommended dosage range are considered appropriate for use for lactating women. Fluoroquinolones should not be administered as first-line treatment, but if they are indicated, breast feeding should not be interrupted because the risk of adverse effects is low and the risks are justified. Paracetamol (acetaminophen), low-dose aspirin (acetylsalicylic acid) [up to 100 mg/day] and short-term treatment with NSAIDs, codeine, morphine and propoxyphene are considered compatible with breast feeding. Safer alternatives should be considered instead of dipyrone, aspirin at a dosage >100 mg/day and pethidine (meperidine). In the light of the many safe alternatives for pain control, breast-feeding mothers should not be allowed to experience pain or be made to feel that they must choose between analgesia and breast feeding.     

Gastrointestinal stromal sarcomas

BACKGROUND: Gastrointestinal stromal sarcomas are a rare group of malignancies originating in the bowel wall. METHODS: The treatment of 12 patients with gastrointestinal stromal sarcoma who underwent operation between 1994 and 1998 was reviewed. RESULTS: Eight tumours originated in the stomach; others were in the small bowel or rectum. Five of the tumours were of myogenic origin, two were gastrointestinal autonomic nerve tumours, one was a mixed neural-myoid tumour, and four could not be differentiated. Complete resection was possible in ten patients; in two of the ten en bloc resection of adjacent organs was required to ensure adequate margins. The tumours in the remaining two patients were irresectable because of diffuse intra-abdominal metastatic disease. All patients who underwent complete resection were alive after 4-48 (median 14) months. Two of the ten patients developed recurrence, which was reresected completely. The patients with metastatic disease died less than 1 year after operation. CONCLUSION: Aggressive surgical resection, achieving complete resection, can lead to prolongation of life and may be a potential cure for patients with gastrointestinal stromal sarcoma.     

Experimental evidence of physician social preferences

Physicians’ professional ethics require that they put patients’ interests ahead of their own and that they should allocate limited medical resources efficiently. Understanding physicians’ extent of adherence to these principles requires understanding the social preferences that lie behind them. These social preferences may be divided into two qualitatively different trade-offs: the trade-off between self and other (altruism) and the trade-off between reducing differences in payoffs (equality) and increasing total payoffs (efficiency). We experimentally measure social preferences among a nationwide sample of practicing physicians in the United States. Our design allows us to distinguish empirically between altruism and equality–efficiency orientation and to accurately measure both trade-offs at the level of the individual subject. We further compare the experimentally measured social preferences of physicians with those of a representative sample of Americans, an “elite” subsample of Americans, and a nationwide sample of medical students. We find that physicians’ altruism stands out. Although most physicians place a greater weight on self than on other, the share of physicians who place a greater weight on other than on self is twice as large as for all other samples—32% as compared with 15 to 17%. Subjects in the general population are the closest to physicians in terms of altruism. The higher altruism among physicians compared with the other samples cannot be explained by income or age differences. By contrast, physicians’ preferences regarding equality–efficiency orientation are not meaningfully different from those of the general sample and elite subsample and are less efficiency oriented than medical students.

In a classic article, Kenneth Arrow (1) argued that asymmetric information pervades the health-care market. Patients rely on physicians’ expert knowledge in planning their medical care. Health insurers and government agencies (Medicare and Medicaid) largely rely on physicians to decide which treatments are appropriate for their patients. This deference to physicians’ authority may be justified given their superior expertise and informational advantages (2). However, the dual role of recommending and providing treatments creates opportunities for physicians to place their interests ahead of their patients’ interests, for example by recommending profitable tests and treatments that offer little or no health benefits. A second risk is more subtle. Physicians must trade off their individual patients’ interests in getting care, even if the benefit is likely to be small, against society’s interest in allocating limited medical resources efficiently, in order to generate the greatest benefits for the overall health of a population.The norms of physician professionalism—including, in particular, the patient-centered norms that constitute physicians’ traditional professional ethic—are intended to address the risk of selfishness. Arrow argues that due to information asymmetry, the principle of“buyer beware” that governs ordinary consumer markets should be replaced, in health care, by the physicians’ professional responsibility to put patients’ interests ahead of their own (1). Physician leaders publicly promote the importance of professionalism, while exhorting physicians to act altruistically. For example, the editors of the New England Journal of Medicine have asserted that “medicine is one of the few spheres of human activity in which the purposes are unambiguously altruistic” (3), while the American Board of Internal Medicine similarly asserts that “altruism is the essence of professionalism … the best interest of patients, not self-interest, is the rule” (4). On the other hand, empirical studies have suggested that, at least in some situations, some physicians create “supplier-induced demand,” which influences a patient’s demand for care “against the physician’s interpretation of the best interest of the patient” (5), contributing to skepticism about whether physicians do in fact behave altruistically. [Such skepticism is not limited to medicine. Legal ethics, for example, has long sought to control lawyers’ abuse of discretion through professional norms of client loyalty and care (6). But skeptics have cast these norms as self-serving, and the law governing lawyers increasingly subjects them to elaborate institutionalized mechanisms of bureaucratic control.]While the effects of professional norms on physician behavior are difficult to measure directly, a clearer understanding of physicians’ social preferences can help to illuminate whether professional norms and physicians’ individual preferences are oppositional or aligned. Our study therefore helps to evaluate the likely effectiveness of both professional norms and the turn to bureaucracy. While altruism and related professional norms are important in many other professions (7), the distinct characteristics of the market for medical care, namely information asymmetry and uncertainty in the relationship between medical treatments and patient outcomes (1), render it especially critical to study these issues among physicians.Health care systems in the US and elsewhere address the second risk—concerning efficiency—in more complex ways. Although professional ethics give physicians a responsibility to conserve scarce medical resources (8), the norm that directs individual physicians to put their patients first may render a norm-based approach inadequate to the problem of efficiency (9). Health insurers therefore use bureaucratic mechanisms and financial incentives to manage the information asymmetry between a physician who knows the specific patient’s situation and the insurer which does not (9).^*We deploy an incentivized economic experiment to investigate both altruism (the trade-off between self and other) and equality–efficiency orientation (the trade-off between reducing self–other differences in payouts and increasing payout totals) in practicing US physicians, and we compare our results with analogous experiments that measure parallel behaviors in other populations. A vast literature considers social preferences, and laboratory experiments have been very fruitful in both establishing the empirical reliability of such preferences and directing theoretical attention to them. [We will not attempt to review the enormous body of work in behavioral and experimental economics on social preferences. Camerer (10) provides a comprehensive discussion, if now somewhat dated, of the vast body of experimental and theoretical research in economics focusing on dictator, ultimatum, and trust games. Engel (11) provides the most comprehensive meta-study of dictator games.] After presenting our results, we relate them to the results from prior work that are particularly relevant to our study (Discussion). We note that the social preferences of physicians and professionals more generally remain relatively understudied, and our discussion of the relationship between our study and prior work explains the specific contributions that we make.Our sample consists of 284 physicians from 36 medical groups around the United States, including physicians in primary care (internal medicine and family medicine) and cardiology, and physicians in private practices and employed by hospitals. Our experiment gives subjects broad discretion to implement their preferences, free from bureaucratic control or even surveillance. Our results therefore inform the question whether norms are likely to affect physician choices along both dimensions of behavior. Our study measures altruism in a large multisite sample of practicing physicians and measures both dimensions of social preferences.Our experiment asked subjects to make trade-offs between their own self-interest and the interest of an anonymous other and, at the same time, between equality and efficiency. These two aspects of social preferences often operate together, but they remain conceptually distinct. [Social preferences can be weighted toward equality (reducing differences in payoffs) or weighted toward efficiency (increasing total payoffs) and range from pure utilitarian to maxmin or Rawlsianism. As the dispute between Harsanyi (12, 13) and Rawls (14) shows, fair-minded people (who are all perfectly impartial between self and other) can disagree about how to trade off equality and efficiency. The work of Harsanyi and Rawls, and of the many others who have followed them, has had broad-reaching influence across many disciplines, including philosophy, economics, and law.] To capture both of these features in our experiment, we employ a modified dictator game (15–17) in which we ask physicians to allocate real money between themselves and an anonymous other drawn from a broadly representative sample of the US population. Our experiment presents subjects with allocation decisions in which the “price of giving” varies across decision problems—sometimes the subject may need to sacrifice more than a token (the experimental currency)—to give a single token to other (the recipient); in other decisions, it may cost only a fraction of a token. These decisions are made through an intuitive “point-and-click” graphical interface in which the choices are represented as a budget line where each point represents a possible allocation. The slope of the line captures the price of giving tokens to other.^†Intuitively, this method allowed us to collect a rich dataset capable of measuring both altruism and equality–efficiency orientation at the level of the individual subject. [The importance of studying individual heterogeneity in social preferences is emphasized by Andreoni and Miller (17). Because of this heterogeneity, it is necessary to investigate behavior at an individual level. Our experimental design allows subjects to make numerous choices over a wide range of budget lines, and this yields a rich dataset that is well-suited to analysis at the individual level. It is clearly advantageous to estimate individual-level parameters and then generate individual-level distributions of the estimations rather than to pool data and then estimate population-level parameters.] The degree of altruism is reflected in the amount subjects give on average, whereas equality–efficiency orientation is captured by how subjects respond to the price of giving. Increasing the fraction of the budget spent on other as the price of giving increases indicates social preferences weighted toward equality (reducing the difference in payoffs between self and other), whereas decreasing it when the price of giving increases indicates social preferences weighted toward efficiency (increasing the total payoffs to self and other). We rely on techniques developed in our prior work (15, 16, 18) to evaluate the consistency of physicians’ choices (i.e., whether they reflect a complete and transitive preference ordering) and to explore the structure of the social utility functions that rationalize the observed data.We further compare physicians’ preferences with preferences previously measured in three other populations using equivalent experiments: 1) a broadly representative sample of US adults (18), 2) an “elite” subsample of those who hold a graduate degree and have an annual household income over $100,000 (15, 18), and 3) a sample of medical students from nine schools around the United States (19, 20). The social preferences of these populations provide important benchmarks against which physicians’ social preferences can be assessed; furthermore, the comparison with medical students may shed light on whether physicians’ distinctive social preferences reflect a “selection effect” based on who enters medicine or a “treatment effect” of practicing medicine.^‡We begin our analysis of the experimental data by using classical revealed preference theory (21–23) to test whether subjects’ choices are consistent with the essence of all traditional models of economic decision-making—utility maximization.^§ Our physician subjects exhibit a remarkably high degree of consistency when compared with other populations, including medical students and also students from Yale Law School (YLS), the population that had exhibited the highest degree of consistency in prior experiments (15). [In our subsequent analysis, we do not draw detailed comparisons between our physician sample and the sample YLS students (15). The experimental design in Fisman et al. (15) differs from the current one in that the YLS student subjects were asked to allocate money between themselves and another student, rather than an individual drawn from a sample broadly representative of the US adults.] This result reveals that our physician subjects are highly adept at implementing a consistent, well-behaved social preference ordering. This makes it natural to estimate—at the level of the individual subject—the substantive social preferences that physicians display.We then estimate social preferences at the level of the individual physician using a constant elasticity of substitution (CES) utility function commonly employed by economists in demand analysis. The CES functional form is appealing because the degree of altruism and equality–efficiency orientation are each independently represented in a precise and transparent manner through its two parameters, which we estimate separately for each subject (further details on the CES specification and estimation are provided in Empirical Framework).We find that physicians are more altruistic than any other population, while physicians’ preferences concerning the trade-off between equality and efficiency are almost indistinguishable graphically from the preferences of the American Life Panel (ALP) elites and also the broader ALP sample. These findings on physicians’ distinctive social preferences have direct and concrete implications for professionalism, incentives, and bureaucratic rules directed at physicians. Insofar as physicians are altruistic, they may be more likely to live up to the professional ideal of putting patients’ interests ahead of their own. At the same time, altruism as captured in our experiment is far from ubiquitous, even among physicians and, furthermore, physicians’ efficiency orientation is indistinguishable from than that of the general population. Taken together, our findings suggest that the ideal of physician professionalism—putting the patient first—is not merely a self-serving myth but that other mechanisms may be required to support the quality of medical care and to promote efficient allocation of medical resources.     

Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2

Permanent neonatal diabetes mellitus (PNDM) is a rare form of diabetes characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Recently, activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 were identified in 10 PNDM patients. Tolbutamide-stimulated insulin secretion, demonstrated in 3 of these patients suggested that some PNDM patients may respond to oral sulfonylurea treatment. In this report, we describe an infant with PNDM due to an arginine-to-histidine substitution at position 201 (R201H) of the gene encoding Kir6.2. After insulin pump therapy for six months, he was shifted to oral glybenclamide therapy at a daily dose of 0.8 mg/kg. Basal c-peptide level increased by two fold during glybenclamide treatment, but no further elevation was observed following intravenous glucose administration. Outpatient, continuous glucose monitoring while on a normal infant diet demonstrated a marked improvement in glycemic control. This study demonstrates the feasibility of oral sulfonylurea treatment in PNDM patients with Kir6.2 mutations even during infancy, and the superiority of this approach over insulin administration.     

The leukergy test in rheumatic diseases. New implications for an old test

In order to assess the value of the leukergy test in which leukocytes aggregate in citrated whole blood, we examined 65 patients with various rheumatic conditions. In addition, plasma samples from 40 patients were examined for neutrophil aggregation activity in vitro. Results of the leukergy test were found to be in very good correlation with disease activity (P = 0.0001), whereas no increased neutrophil aggregation activity was found in the 40 plasma samples examined. The value of the leukergy test in assessing patients with rheumatic disease and its theoretical etiopathogenic role in these diseases are discussed.     

Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by Lewy body formation and death of dopaminergic neurons. Mutations in alpha-synuclein and parkin cause familial forms of PD. Synphilin-1 was shown to interact with alpha-synuclein and to promote the formation of cytosolic inclusions. We now report that synphilin-1 interacts with the E3 ubiquitin-ligases SIAH-1 and SIAH-2. SIAH proteins ubiquitylate synphilin-1 both in vitro and in vivo, promoting its degradation by the ubiquitin-proteasome system. Inability of the proteasome to degrade synphilin-1/SIAH complex leads to a robust formation of ubiquitylated cytosolic inclusions. Ubiquitylation is required for inclusion formation, because a catalytically inactive mutant of SIAH-1, which still binds to synphilin-1, fails to promote inclusions. Like synphilin-1, alpha-synuclein associates with SIAH in intact cells, but the interaction with SIAH-2 was much stronger that with SIAH-1. In vitro experiments show that SIAH-2 monoubiquitylates alpha-synuclein. Further evidence that SIAH proteins may play a role in inclusion formation comes from the demonstration of SIAH immunoreactivity in Lewy bodies of PD patients.