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A new respiratory fluoroquinolone, oral gemifloxacin: a safety profile in context.

Gemifloxacin is a broad-spectrum quinolone antibacterial with enhanced potency against Gram-positive bacteria, including multi-drug resistant Streptococcus pneumoniae, and retained potency against Gram-negative bacilli and bacterial strains resistant to other antibiotics. It has proven particularly effective in respiratory and urinary tract infection. This review presents safety data from 6775 patients included in clinical trials, receiving either the recommended 320 mg once daily oral dose of gemifloxacin, or standard dose of other quinolones, macrolides or beta-lactams (n = 5248). Studies in healthy volunteer and special populations are also reported. Adverse experiences (AEs) were observed in 44.7% of gemifloxacin-treated patients and 47.5% of those who received comparator drugs. Mild gastro-intestinal adverse drug reactions (ADRs) (diarrhoea 5.1%, nausea 3.9%) predominated. Rash, usually maculo-papular and in no case proceeding to more severe eruptions, was observed in 3.6% of those receiving gemifloxacin. A higher incidence of rash (>20%) was observed in young women and was the subject of further study. Adverse drug reactions suspected or probably related to treatment occurred in 17.4% of patients receiving gemifloxacin and in 20% of those receiving comparator antibiotics. Diarrhoea and nausea were experienced by 3.6 and 2.7%, respectively, of gemifloxacin-treated patients (4.6 and 3.2% of comparators), rash by 2.8% (0.6% of comparators) and headache by 1.2% (1.5% of comparators). Gemifloxacin-related vomiting (0.9%), dizziness (0.8%) and taste perversion (0.3%) were uncommon. Treatment discontinuation followed one or more adverse drug reactions in 2.2% of gemifloxacin-treated patients (0.9% due to rash) and 2.1% of comparator-treated patients. A total of 63 deaths (33 receiving gemifloxacin) occurred in the trial population: none were considered related to treatment. A slight prolongation in QT interval (2.56 ms (S.D. +/-24.5)) was observed in gemifloxacin-treated patients: no cardiac arrhythmias were reported. There was a low incidence of liver function tests (LFTs) classified as of potential clinical concern: gemifloxacin (0.4-1.2%), comparators (0.2-1.3%). Serious adverse events (SAEs), occurring during but not necessarily related to therapy, occurred in 3.6% of gemifloxacin-treated patients (4.3% of comparators). SAEs related to treatment agents were rare (0.4% in each group) and included rash (0.1%) and elevated liver enzymes (<0.1%). Gemifloxacin was well tolerated by the elderly, those with renal or hepatic impairment and when co-administered with omeprazole, digoxin, theophylline, warfarin (with which there were no significant interactions) and Maalox. In conclusion, gemifloxacin 320 mg once daily demonstrated a favourable safety and tolerability profile similar to that of comparator antibiotics, including other quinolones.

Administration, Oral↗

Realistic population dynamics in epidemiological models: the impact of population decline on the dynamics of childhood infectious diseases. Measles in Italy as an example.

Most contributions in the field of mathematical modelling of childhood infectious diseases transmission dynamics have focused on stationary or exponentially growing populations. In this paper an epidemiological model with realistic demography is used to investigate the impact of the non-equilibrium conditions typical of the transition to sustained below replacement fertility (BRF) recently observed in a number of western countries, upon the transmission dynamics of measles. The results depend on the manner we model the relation between the (changing) age distribution of the population and contacts. Under some circumstances the transitional ageing phase typical of BRF populations might complexly interact with epidemiological variables leading to (i) a substantial reduction in the amount of vaccination effort required for eliminating the disease; (ii) a significant magnification of the perverse impact of vaccination in terms of the burden of severe age related morbidity.

Adolescent↗

Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry?

Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory. Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, nitric oxide, endogenous opioids and insulin, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault, promotion of neural development and the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection, significant physical exercise or de novo. It is proposed that release of these substances is accompanied by a loss of tolerance either to them or their receptor binding sites in CFS. Such an occurrence would have predictably serious consequences resulting from compromised function of the key roles these substances perform. All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation. Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition. The novel status of these substances together with their extremely small concentrations in blood and tissues means that clinical research into them is still in its infancy. A biologically plausible theory of CFS causation associated with vasoactive neuropeptide dysfunction would promote a coherent and systematic approach to research into this and other possibly associated disabling conditions.

Autoimmune Diseases↗

Towards a unified and interdisciplinary model of ageing.

Researchers currently disagree about the appropriate biomarkers to monitor when measuring the ageing process. The major problem is identifying symptoms that are an end in and of themselves, from symptoms that are tied directly to the root cause, or causes, of ageing. This is most likely the reason that numerous, diverse and plausible theories for ageing co-exist. When young and old nuclei are exchanged between cells, the age of the resulting cell correlated with the nucleus. This suggests a large role of the nucleus as the target of ageing, although the sources of ageing may originate externally. There are three processes that occur when eukaryotes age. They are: (1) a progressive and patterned alteration of the structure of chromosomes after young adulthood has been reached, (2) a progressive and patterned malfunction of the degradation systems, and (3) age-altered post-translational modifications of proteins. A change in any one of these processes often causes a ripple effect that affects the other two processes. This paper begins by stating that the above three processes are the appropriate biomarkers of ageing. These three processes are coordinated with one another under normal physiological conditions. For example, proteasomes and their subunits have been found to regulate excision repair, transcription, and the turnover of nuclear/cytoplasmic receptors. The degradation system is also responsible for the removal of oxidized histones and other factors, which influence chromosome structure. Regulatory post-translational modifications at the histone level include methylation, phosphorylation, and acetylation. In addition, the above three processes undergo age related changes. Some of these modifications represent valid responses by the cell, but many do not. The effect of these age-altered macromolecules is perverse and unpredictable. For example, the cell's age-compromised degradation allows the accumulation of signaling complexes, which no longer match the needs of the cell. Age related histone and non-histone post-translational modifications alter both chromosome structure and expression. Nuclear pores have been found to slowly decrease in number in an age dependent manner. These pores have been found associated with the nuclear lamin. Several types of mutations in the lamin A gene cause progeria like symptoms. There is a diverse set of mechanisms that cause age related post-translational modifications. Previous attempts to find a commonality among those modifications have been disappointing. This paper will present a possible explanation that involves conformational changes caused by ionic and other perturbations in the nucleoplasm.

Adaptation, Physiological↗

Psychiatry and political-institutional abuse from the historical perspective: the ethical lessons of the Nuremberg Trial on their 60th anniversary.

Sixty years ago at the Nuremberg Trials, 23 Nazi leaders were tried as war criminals, in what was known as "The Doctors' Trial". This trial exposed a perverse system of the criminal use of medicine in the fields of public health and human research. These practices, in which racial hygiene constituted one of the fundamental principles and euthanasia programmes were the most obvious consequence, violated the majority of known bioethical principles. Psychiatry played a central role in these programmes, and the mentally ill were the principal victims. The aim of the present work is to review, from the historical perspective, the antecedents of the shameful euthanasia programmes for the mentally ill, the procedures involved in their implementation and the use of mentally ill people as research material. The Nuremberg Code, a direct consequence of the Doctors' Trial, is considered to be the first international code of ethics for research with human beings, and represented an attempt to prevent any repeat of the tragedy that occurred under Nazism. Nevertheless, the last 60 years have seen continued government-endorsed psychiatric abuse and illegitimate use of psychoactive drugs in countries such as the Soviet Union or China, and even in some with a long democratic tradition, such as the United States. Even today, the improper use of psychiatry on behalf of governments is seen to be occurring in numerous parts of the globe: religious repression in China, enforced hospitalization in Russia, administration of psychoactive drugs in immigrant detention centres in Australia, and the application of the death penalty by lethal injection and psychiatric participation in coercive interrogation at military prisons, in relation to the USA. The Declaration of Madrid in 1996 constituted the most recent attempt to eradicate, from the ethical point of view, these horrendous practices. Various strategies can be used to combat such abuses, though it is uncertain how effective they are in preventing them.

Ethics, Medical↗

Investing in sustainable catchments.

Catchments constitute logical units for management of the water cycle. Patterns of development uninformed by sustainability concerns have degraded catchment integrity and associated ecosystem functions, imposing largely unquantified costs. Ecosystem functions are central to sustainable social and economic progress; their protection or restoration may be the only sustainable form of investment in catchments. Despite growing use of catchment functions in some policy areas, a shortfall in awareness and pragmatic tools limits progress with policies and practical tools to support sustainable development in catchments, perpetuating damaging practices. This paper reviews methods of economic valuation of riverine systems. Valuation of ecosystem functions is revealed as particularly pertinent to sustainable development, as an indicator of the benefits of ecological processes to social and economic progress. A range of practical projects, targeted at restoration of riverine habitat in the UK with the intent of improving both river ecology and the social and economic advantages that flow from it, is also reviewed. Emerging principles and themes are discussed in terms of their potential contribution to policies and practices that promote sustainability. Review of these projects highlights the importance of planning at adequately broad scales--spatial, temporal and disciplinary--to identify integrated solutions, and to maximise community "buy-in" and total benefits. In several cases, economic analyses demonstrate strongly positive benefit-cost ratios stemming from habitat improvement. However, major reform of regulatory and economic instruments is needed to promote sustainable catchment development, since prevalent "perverse" incentives continue to degrade ecosystem functions. Measures to recognise and reward ecosystem service as legitimate outputs from agricultural land use constitute a particular priority. There is a need simultaneously to address both "big picture" structural adjustments and locally-appropriate solutions, from which clear local benefits flow. Pragmatic measures that contribute to systemic outcomes must also be attractive to local decision-makers and land managers, and yield benefits that ensure they are sustained once intervention ceases. Cost need not be a barrier, as current environmentally-damaging subsidies may instead be redirected towards sensitive land use and/or measures to protect biodiversity and ecosystem functioning, particularly where targeted upon habitat of disproportionate importance to functioning of catchments as whole systems. Internalisation of the costs of damage to ecosystem functioning will promote valuation of the natural capital of catchments as a primary resource for social and economic progress.

Conservation of Natural Resources↗

The market shaping of charges, trust and abuse: health care transactions in Tanzania.

Effective health care is a relational activity, that is, it requires social relationships of trust and mutual understanding between providers and those needing and seeking care. The breakdown of these relationships is therefore impoverishing, cutting people off from a basic human capability, that of accessing of decent health care in time of need. In Tanzania as in much of Africa, health care relationships are generally also market transactions requiring out-of-pocket payment. This paper analyses the active constitution and destruction of trust within Tanzanian health care transactions, demonstrating systematic patterns both of exclusion and abuse and also of inclusion and merited trust. We triangulate evidence on charges paid and payment methods with perceptions of the trustworthiness of providers and with the socio-economic status of patients and household interviewees, distinguishing calculative, value based and personalised forms of trust. We draw on this interpretative analysis to argue that policy can support the construction of decent inclusive health care by constraining perverse market incentives that users understand to be a source of merited distrust; by assisting reputation-building and enlarging professional, managerial and public scrutiny; and by reinforcing value-based sources of trust.

Delivery of Health Care↗

The antilock braking system anomaly: a drinking driver problem?

Antilock braking systems (ABS) have held promise for reducing the incidence of accidents because they reduce stopping times on slippery surfaces and allow drivers to maintain steering control during emergency braking. Farmer et al. (Accident Anal. Prevent. 29 (1997) 745) provide evidence that antilock brakes are beneficial to nonoccupants: a set of 1992 model General Motors vehicles equipped with antilock brakes were involved in significantly fewer fatal crashes in which occupants of other vehicles, pedestrians, or bicyclists were killed. But, perversely, the risk of death for occupants of vehicles equipped with antilock brakes increased significantly after adoption. Farmer (Accident Anal. Prevent. 33 (2001) 361) updates the analysis for 1996- 1998 and finds a significant attenuation in the ABS anomaly. Researchers have put forward two hypotheses to explain this antilock brake anomaly: risk compensation and improper operation of antilock brake-equipped vehicles. We provide strong evidence for the improper operation hypothesis by showing that the antilock brake anomaly is confined largely to drinking drivers. Further, we show that the attenuation phenomenon occurs consistently after the first three to four years of vehicle service.

Accidents, Traffic↗

[Consensus, hedonism: the characteristics of new family and their consequences for the development of children].

Over the last three decades, the marital family model described by Durkheim at the end of the nineteenth century has undergone numerous changes, e.g. questioning about the principle of authority, women emancipation, occurrence of the "new fathers", the growing influence of the media on the daily life of families, the less frequent and most precious child (due to the reduced number of children per family),... Through clinical, psychoanalytical and developmental models we, here, analyze these changes together with their impact on child. Historical and sociological approaches also allowed us to examine some of the effects induced by consensus and hedonism, the new familial parameters, on the child's life and development. The modern family being classically founded upon duty (central value) and the principle of authority to settle relationships between individuals, its main features are opposed to those of the contemporary family. The latter, which started to emerge over the sixties, is characterized by both the prevalence of parent-child relationships symmetrization and the emergence of the search for immediate pleasure. The change from parental authority to consensus as a principle ruling the relationships within families leads to many consequences later noticed through changes in the construction of the child's psyche along his development and in the relationships dynamics. Authority imposes on child to submit to the parents-mediatized requirements of the society and implies a change in impulses through the setting of Superego agencies and Ego Ideal, which (both ?) represent taboos and social ideals in the psyche. When consensus is at the center of the family, and according to concrete meetings with the other offered by the thousand and one situations met in the daily life, the aims and satisfaction modalities of the child's impulses will evolve into a relation often based on either strength or seduction. As a result, the settlement of classical instances will be affected. It will result in. Considering hedonism as the central value in child education leads one to support the pleasure principle and contributes to making more difficult the switching to the reality principle. The couple " I want, I don't want" is at the origin of most behaviors, and then further leads to the development of the assertive agency, "I do what I want, and thus I am". The libidinal excitation is, therefore, little restricted and reinforced by the media-based environment. The child's Superego is built on the concrete practices of his parents, but not on their Superego, whereas the Ideal of Ego is poorly socialized and driven towards the ideal Ego, early narcissist formation with the signs of child megalomania. Due to these early years of life throughout which the pleasure principle has been favored by their environment, the children are not prepared for life with its restrictions and unavoidable frustrations possibly experienced as persecutions. In the same way, when they have to meet the requirements of life in community, eg the discipline imposed within a college, these rules are more and more often felt by a pupil as unfair, arbitrary persecutions sometimes related to his own personality, "the teacher doesn't like me" of course, it is all the more legitimate to rebel against them as the charter of the pupils' rights, posted up in the school, has been read through very quickly by the teenagers. This mechanism takes one back to the archaically perception of environment by the very young child and to the projection developed by S. Freud in his description of the building "Ego-pure pleasure", (moi-plaisir purifie) (The Ego and the id, 1920). The opposed mechanism is expressed through an experience of shame felt by the subject when he is unable to satisfy, not the requests of his own impulses, but the social group's requirements. From the libidinal point of view, advertisements stimulate one's desires, incite one to consume and are at the origin of consumer needs. As a consequence, there is a resonance between the individual pleasure principle and the promotion of hedonism suggested by the society. The modern children have their mastery of impulse motions hampered by this phenomenon. The temporality of , new children " in new families sounds centered on the present, which is made of moments of eternity, always restarted (cyclic time of the first ages of life) ; it overrides historical time with a start, an end and references to intergeneration difference and filiations. This prevalence of present offers few support to neurotic defenses, with predictable problems in social interactions due to an inability to manage the tensions issued from the time discrepancies between one and his alter ego. Tran cultural studies have shown that to any social and cultural organization corresponds one or several basic personalities; among them, modem society has exuded the standard neurotic personality characterized by an ample mental space, a strict modulation of behaviors governed by the representations play and spreading out in Le théâtre du Je (The I theatre, Mac Dougall, 1982), a conflict between desire and internalized taboo, and the problematic of transgression and guilt. The modern family produces different personality structures. This led us to assume new basic personalities as follows, and to envision some psychopathological consequences: The passive dependent personality with an extreme narcissist fragility and at high risks of depressive disorders; The perverse-anarchistic personality characterized by subjects unable to feel guilty, taking at the best advantage of others to achieve his own ends thanks to his grasping of social situations and to his own seduction, lacking of true empathy; The slightly-psychopathic personality: these subjects can integrate well, but for a short time, in a social structure. They need to frequently find a new job, move in another place or country. Their relationships with others are always disrupted and changing for they can be involved in only short commitments. They are very susceptible to immediate gratifications.

Adult↗

[Preliminary reports from a psychometric fixation-regression study using the McGill Object Relations Scale].

INTRODUCTION: Psychosexual development is generally assessed clinically, that is to say, in a qualitative manner (Piper and Duncan, 1999). Dymetryszyn, Bouchard, Bienvenu, De Carufel, and Gaston (1997) recently proposed a more quantitative approach based on the overall maturity of the subject's object relations. BACKGROUND: Object-relation maturity is quantified using a profile that defines a score for each stage of an individual's psychosexual development: oral-narcissistic, oral-objectal, anal, phallic pre-oedipal, oedipal, and genital. The McGill Object Relations Scale (MORS) (Dymetryszyn et al., 1997) was adapted (Combalbert, Vautier, Bourdet-Loubère, Favard, & Bouchard, 2002) and then used to obtain the quantitative scores. The relationship between overall object-relation maturity and psychosexual development is complex. Psychosexual development is considered here to be a constant latent dimension. Accordingly, the higher the level of development, the greater the individual's possibility of establishing the object relations that correspond to more evolved stages. Inversely, the lower the level of development, the more the individual is forced to rely on object relations corresponding to earlier stages of development. However, the connection between the object-relation maturity profile and psychosexual development is made even more complex by the existence of the well-known phenomenon of fixation-regression. OBJECTIVES: This article attempts to determine how fixation-regression is reflected in the structure of the profiles of a sample of individuals whose clinical diagnosis suggests probable regression to the anal stage. METHODS: The subjects chosen had borderline personality disorder coupled with either perversion or psychopathy. The data were modelled using an unfolding model. MORS was used on 60 criminal subjects who had been charged with, or convicted of, crimes against persons. The nosographic diagnosis was based on the psychiatric assessment of the prisoners. DSM IV diagnostic criteria were used as a reference to confirm or refute the pronounced diagnosis. Only subjects who met at least five criteria for borderline personality disorder were included in the sample. To assess the reliability of the individual scores, two expert judges blindly scored the 60 protocols. RESULTS: The results obtained with an unfolding model support the hypothesis that the observed ordinates for the oral-narcissistic, oral-objectal, phallic pre-oedipal, oedipal, and genital stages obey a law of synchrony that complies with the postulate of a continuum in psychosexual development. The second main result was the fact that the observed ordinates for the level corresponding to the anal stage could not be described by the model. Furthermore, this finding did not come from a possible scoring error, since inter-judge reliability was 0.93 for that level. DISCUSSION: These results are encouraging for the utilization of MORS as a technique for quantifying object relations. This study on a sample of individuals with a high probability of anal stage fixation-regression suggests that this type of phenomenon can be objectified by means of MORS profiles. However, the present study has some limitations of its own. The main methodological drawback pertains to the subjective aspect of the protocol scoring. The two judges had a great deal of joint experience in scoring other protocols on the MORS grid. This could explain the particularly high inter-judge correlations, compared to the within-class correlations published by Dymetryszyn et al. (1997). CONCLUSION: One cannot rule out the possibility that our analyses would have had different outcomes had other independent judges scored the 60 protocols. Moreover, our results cannot be generalized without replication. A critical test would be to replicate our analyses on similar data, and to examine the unfolding model's behavior on data from a sample of ordinary adults diagnosed as not having strong fixation-regression tendencies. If the synchrony laws defined by the unfolding model are correct, the anal stage should be included in the arc formed by projecting the six stages on the factorial plane of the principal component analysis. Fundamental research based on the psychosexual theory of the libido and supported by statistical data can objectify the vicissitudes of psychosexual development (such as fixation-regression) or developmental differences across groups of individuals. This makes a strong case for pursuing MORS-based investigations.

Adult↗

Psychological features of obesity.

The study of obesity from a variety of psychological perspectives has been exciting and inventive, although we still do not understand fully the role of psychological variables in the etiology of obesity. Many of the factors thought to be of etiologic significance--field dependence, lack of impulse control, inability to delay gratification, or a maladaptive eating style--have not been supported by experimental evidence. Other factors once thought to be of importance as causes of obesity, depression and dysphoria, for example, appear, instead, to be consequences of being obese and may serve to maintain and intensify weight-related problems. Dieting behavior in response to weight concerns appears, perversely, to be implicated in increasing overweight and adiposity. Finally, arousability in response to food cues in the environment may play a causal role in some obesities.

Eating↗

Vaginal clindamycin and oral metronidazole for bacterial vaginosis: a randomized trial.

OBJECTIVE: To compare the efficacy and safety of clindamycin vaginal ovules with oral metronidazole for treatment of bacterial vaginosis. METHODS: Women with bacterial vaginosis received either 100-mg ovules of clindamycin (intravaginally for 3 consecutive days) plus placebo capsules (orally twice daily for 7 days) or metronidazole 500 mg (two 250-mg capsules orally twice daily for 7 days) plus placebo ovules (intravaginally for 3 consecutive days). The sample was determined prospectively to provide a probability of.84 of correctly concluding that the rate of success for clindamycin is not more than 15% less than the expected 75% success rate for metronidazole. Clinical outcome was determined on the basis of vaginal fluid amine odor and clue cells. RESULTS: Of the 399 patients enrolled, 233 could be evaluated for efficacy. Of those, 77 (68.1%) of 113 patients were cured with clindamycin, compared with 80 (66. 7%) of 120 who were cured with metronidazole (95% confidence interval -10.6%, 13.4%; P =.810). Treatment-related adverse events were reported more frequently in the metronidazole treatment group. Systemic symptoms, such as nausea and taste perversion, accounted for most of the difference between groups. CONCLUSION: A 3-day regimen of clindamycin, given as intravaginal ovules, was as effective as and better tolerated than a 7-day regimen of oral metronidazole 500 mg, given twice daily, for treatment of bacterial vaginosis.

Administration, Intravaginal↗

Lanterns in the jungle: is the NHS driven by the wrong kind of efficiency?

The performance of the National Health Service is assessed in part by an Efficiency Index (EI) which is applied to the service as a whole as well as to individual health authorities. The EI relates increases in the amount of patient care activity to increases in total expenditure. The index can give a misleading impression of performance, creates perverse incentives and is at odds with the overall strategy of the health service which is to place greater emphasis on the promotion of health and to provide more care in primary and community-based settings. The philosophy, validity and appropriateness of the EI are discussed.

Community Health Services↗

Paying for health services: a public health view.

Several factors are shaping the need and demand for health care; these include demographic change, the differential improvement in the survival of those with chronic conditions, and the mismatch between personal income and health. Also, medical uncertainty results in vast variations in medical practice and costs. The scope for increasing the supply of medical care, selectively to the rich or across the board, is already vast and growing. It is argued that efficient financing systems can operate only at a level at which the health benefits of interventions are measurable, i.e. the population level. Systems of individual payment are based on inevitable ignorance about expected benefits and must therefore introduce perverse (and necessarily inefficient) incentives. Population based monitoring of outcome, with coupled incentives to efficient producers, would appear to be the only method of encouraging the production of maximum social benefit from the resources used for health.

Delivery of Health Care↗

The efficacy and safety of brinzolamide 1% ophthalmic suspension (Azopt) as a primary therapy in patients with open-angle glaucoma or ocular hypertension. Brinzolamide Primary Therapy Study Group.

A randomized, multicenter, double-masked, prospective, parallel study was designed to establish the intraocular pressure (IOP)-lowering efficacy, safety, and tolerability of brinzolamide 1.0% (Azopt) as a primary therapy compared with dorzolamide 2.0% (Trusopt) and placebo in patients diagnosed with open-angle glaucoma (with or without a pseudoexfoliative or a pigmentary dispersion component) or ocular hypertension. Brinzolamide 1.0%, dosed two times (b.i.d.) and three times (t.i.d.) a day, dorzolamide 2.0% (t.i.d.), and placebo (t.i.d) were administered to patients during a 3-month treatment period. Diurnally corrected IOP reduction from baseline, including peak and trough times, was the primary end point. Sample sizes were chosen to establish statistical equivalence between treatments. Mean IOP changes observed on treatment were as follows: -3.4 mm Hg (-13.2%) to -4.1 mm Hg (-16.7%) with brinzolamide 1.0% b.i.d.; -4.1 mm Hg (-16.6%) to -4.8 mm Hg (-19.1%) with brinzolamide 1% t.i.d.; and -4.3 mm Hg (-16.9%) to -4.9 mm Hg (-20.1%) with dorzolamide 2.0%. IOP reductions after administration of brinzolamide 1.0% b.i.d. and t.i.d. were equivalent to each other and also clinically and statistically equivalent to those with dorzolamide 2.0% t.i.d. The incidence of ocular discomfort (burning and stinging) upon instillation was significantly higher for dorzolamide (10.7%) than brinzolamide (b.i.d. or t.i.d., 3.0% each). The most frequent non-ocular event reported was taste perversion, which was less (3.7%) with brinzolamide 1.0% b.i.d., but brinzolamide t.i.d. was similar to dorzolamide t.i.d. (6.8% vs. 5.3%). Brinzolamide 1.0% b.i.d., brinzolamide 1.0% t.i.d., and dorzolamide 2.0% t.i.d. equaled each other in IOP-lowering efficacy, and brinzolamide was significantly more comfortable than dorzolamide upon instillation.

Adult↗

Suicide of the nephron.

There are various causes of renal disease. However, progressive renal disease is closely linked to the degree and duration of proteinuria. At first sight, this seems a perverse response in which a compromised organ unleashes a coordinated series of reactions that exacerbate the damage already done. Although the nephron has mechanisms whereby it can compensate for damage both by hypertrophy and hyperfunction after renal injury or ablation, these changes seem to provide only a temporary compensation. I and my colleagues found altered renal telomere shortening in the male rat linked to increased or decreased proteinuria and longevity, which suggests a mechanism whereby this compensatory process may be limited. I hypothesise that when the damaging or hypertrophic processes shorten renal telomeres to a critical length, the cells senesce with loss of function. I also suggest that the complex series of responses triggered in a protein-leaking nephron is normally a beneficial and limited process. It leads to the replacement by fibrosis of a malfunctioning unit in an otherwise healthy organ that has substantial spare capacity. The response only becomes life threatening when there is widespread nephron damage, the acceleration of which results in the ablation of all nephron function.

Animals↗

Health financing to promote access in low income settings-how much do we know?

In this article we outline research since 1995 on the impact of various financing strategies on access to health services or health outcomes in low income countries. The limited evidence available suggests, in general, that user fees deterred utilisation. Prepayment or insurance schemes offered potential for improving access, but are very limited in scope. Conditional cash payments showed promise for improving uptake of interventions, but could also create a perverse incentive. The largely African origin of the reports of user fees, and the evidence from Latin America on conditional cash transfers, demonstrate the importance of the context in which studies are done. There is a need for improved quality of research in this area. Larger scale, upfront funding for evaluation of health financing initiatives is necessary to ensure an evidence base that corresponds to the importance of this issue for achieving development goals.

Africa↗

Gestational carcinoma of the female breast.

Few neoplastic diseases can equal the amazing complexity and sheer perversity of carcinoma of the breast. No doubt as many decades of research lie ahead in its study as already have passed. Clinicians have long appreciated the special relationship of the disease to gestation. Diagnosis and treatment of breast cancer during pregnancy represent only a small part of this fascinating relationship. Although indispensable as research tools, animal models pertain to the human disease only in limited, ill-defined ways. The etiology of human breast cancer remains unclear; chemical, viral, hormonal, genetic, and immunologic theories have all been put forward as possibilities. Although gestation clearly alters both the initiation and growth of mammary tumors, its exact role in the various theoretical considerations remains a mystery. The obstetrician-gynecologist holds an important front-line position in the war against breast cancer, as does any provider of primary care to women, and, indeed, as do women themselves. Rather than decrease vigilance during pregnancy, the physician should pursue with extra vigor any breast mass discovered in the gravid patient, when the clinical examination is even less reliable than usual. The finding of a breast mass usually necessitates biopsy. Except for the inclusion of specific pregnancy-related problems, such as galactocele, the diagnostic spectrum of breast masses removed during pregnancy does not differ from that in nonpregnant women. The discovery of a highly suspicious breast mass, or the confirmed biopsy diagnosis of malignancy, in a pregnant patient should indicate the need for referral to a surgical oncologist versed in this unusual problem. The best approach to gestational breast cancer continues to be the team approach, with consultation from specialists in obstetrics, surgical oncology, anesthesiology, nuclear medicine, radiology, radiation oncology, pathology, and medical oncology. The age and general condition of the patient, the extent of the tumor, the stage of gestation, and the informed opinions of the patient and her spouse help to determine the therapeutic strategy. Careful staging not only guides present therapy but also the therapy of future victims through continued investigation. Most surgeons favor operation without delay if cure seems within reach. Mastectomy, with or without cesarean section, can be accomplished without detriment in the hands of a knowledgeable surgeon-anesthesiologist team. By following certain guidelines, the search for metastasis can be conducted safely and appropriately. The clinical situation occasionally may require the initiation of adjuvant radiotherapy or chemotherapy during pregnancy, by experienced consultants. Ongoing studies of tissue hormone receptors and cell kinetics will continue to give insight into the effects of gestational hormones on breast cancer and can aid in the selection of treatment options for the individual patient...

Abortion, Therapeutic↗