Combined vitamin D and magnesium supplementation does not influence markers of bone turnover or glycemic control: A randomized controlled clinical trial.

High-dose vitamin D supplementation can increase total osteocalcin concentrations that may reduce insulin resistance in individuals at risk for prediabetes or diabetes mellitus. Magnesium is a cofactor in vitamin D metabolism and activation. The purpose of this study was to determine the combined effect of vitamin D and magnesium supplementation on total osteocalcin concentrations, glycemic indices, and other bone turnover markers after a 12-week intervention in individuals who were overweight and obese, but otherwise healthy. We hypothesized that combined supplementation would improve serum total osteocalcin concentrations and glycemic indices more than vitamin D supplementation alone or a placebo. A total of 78 women and men completed this intervention in 3 groups: a vitamin D and magnesium group (1000 IU vitamin D3 and 360 mg magnesium glycinate), a vitamin D group (1000 IU vitamin D3), and a placebo group. Despite a significant increase in serum 25-hydroxyvitamin D concentrations in the vitamin D and magnesium group compared with the placebo group (difference = 5.63; CI, -10.0 to -1.21; P = .001) post-intervention, there were no differences in serum concentrations of total osteocalcin, glucose, insulin, and adiponectin or the homeostatic model assessment of insulin resistance (HOMA-IR) among groups (P > .05 for all). Additionally, total osteocalcin (ß = -0.310, P = .081), bone-specific alkaline phosphatase (ß = 0.004, P = .986), and C-terminal cross-linked telopeptide (ß = 0.426, P = .057), were not significant predictors of HOMA-IR after the intervention. Combined supplementation was not associated with short-term improvements in glycemic indices or bone turnover markers in participants who were overweight and obese in our study. This trial was registered at clinicaltrials.gov (NCT03134417).

The effect of combined magnesium and vitamin D supplementation on vitamin D status, systemic inflammation, and blood pressure: A randomized double-blinded controlled trial.

OBJECTIVE: Poor vitamin D and magnesium status is observed in individuals who are overweight and obese (Owt/Ob) and is often associated with a heightened risk of cardiovascular disease. Magnesium is a cofactor that assists vitamin D metabolism. We aimed to determine the efficacy of a combined magnesium and vitamin D regimen compared with vitamin D only on increasing serum 25-hydroxyvitamin D (25OHD) concentrations and the effects of these supplements on cardiometabolic outcomes. METHODS: This 12-week double-blinded randomized controlled trial had three treatment arms: magnesium + vitamin D (MagD; 360 mg magnesium glycinate + 1000 IU vitamin D 3 × daily), vitamin D only (VitD; 1000 IU vitamin D 3 × daily), and placebo. A total of 95 Owt/Ob participants were randomized into one of these three study arms. Anthropometry, dietary intake, concentrations of serum 25OHD, serum parathyroid hormone (PTH), serum inflammatory markers, and blood pressure were obtained at baseline and week 12. RESULTS: The MagD group experienced the greatest increase in serum 25OHD concentrations (6.3 ± 8.36 ng/mL; P < 0.05). There was a decrease in systolic blood pressure (7.5 ± 8.26 mmHg; P < 0.05) for individuals who had a baseline systolic blood pressure of >132 mmHg in the MagD group. There were no statistically significant treatment effects on serum PTH concentrations and markers of inflammation. CONCLUSIONS: A combined MagD treatment may be more effective in increasing serum 25OHD concentrations compared with VitD supplementation alone in Owt/Ob individuals.

Role of Glutathione in Buffering Excess Intracellular Copper in Streptococcus pyogenes.

Copper (Cu) is an essential metal for bacterial physiology but in excess it is bacteriotoxic. To limit Cu levels in the cytoplasm, most bacteria possess a transcriptionally responsive system for Cu export. In the Gram-positive human pathogen Streptococcus pyogenes (group A Streptococcus [GAS]), this system is encoded by the copYAZ operon. This study demonstrates that although the site of GAS infection represents a Cu-rich environment, inactivation of the copA Cu efflux gene does not reduce virulence in a mouse model of invasive disease. In vitro, Cu treatment leads to multiple observable phenotypes, including defects in growth and viability, decreased fermentation, inhibition of glyceraldehyde-3-phosphate dehydrogenase (GapA) activity, and misregulation of metal homeostasis, likely as a consequence of mismetalation of noncognate metal-binding sites by Cu. Surprisingly, the onset of these effects is delayed by ∼4 h even though expression of copZ is upregulated immediately upon exposure to Cu. Further biochemical investigations show that the onset of all phenotypes coincides with depletion of intracellular glutathione (GSH). Supplementation with extracellular GSH replenishes the intracellular pool of this thiol and suppresses all the observable effects of Cu treatment. These results indicate that GSH buffers excess intracellular Cu when the transcriptionally responsive Cu export system is overwhelmed. Thus, while the copYAZ operon is responsible for Cu homeostasis, GSH has a role in Cu tolerance and allows bacteria to maintain metabolism even in the presence of an excess of this metal ion.IMPORTANCE The control of intracellular metal availability is fundamental to bacterial physiology. In the case of copper (Cu), it has been established that rising intracellular Cu levels eventually fill the metal-sensing site of the endogenous Cu-sensing transcriptional regulator, which in turn induces transcription of a copper export pump. This response caps intracellular Cu availability below a well-defined threshold and prevents Cu toxicity. Glutathione, abundant in many bacteria, is known to bind Cu and has long been assumed to contribute to bacterial Cu handling. However, there is some ambiguity since neither its biosynthesis nor uptake is Cu-regulated. Furthermore, there is little experimental support for this physiological role of glutathione beyond measuring growth of glutathione-deficient mutants in the presence of Cu. Our work with group A Streptococcus provides new evidence that glutathione increases the threshold of intracellular Cu availability that can be tolerated by bacteria and thus advances fundamental understanding of bacterial Cu handling.

[A standard data set for the evaluation of venous leg ulcers in selective contracts : National consensus]. / Standarddatensatz für die Evaluation bei Selektivverträgen bei Ulcus cruris : Nationaler Konsensus.

BACKGROUND: Selective agreements are becoming increasingly important in health care management. To date, no standard recommendations for the evaluation of selective contracts are available. OBJECTIVES: Against this background, a recommendation on the evaluation of selective contracts in patients with leg ulcers (LU) was developed and approved by the nationwide consensus conference. MATERIALS AND METHODS: Based on a systematic literature review and followed by a manual search through other possible evaluation indicators in the care of patients with LU, a Delphi-based consensus process was performed by various scientific societies, professional associations, insurances and supply networks. RESULTS: For the evaluation of efficiency and quality of care, a recommendation on the evaluation of selective agreements with patients with LU was consented in six meetings and in five multistage online surveys. In total, 44 evaluation indicators were identified in the quality subareas structure, process, and outcome. The outcome indicators are divided into clinical, patient-related, and cost-related indicators. CONCLUSIONS: The developed evaluation indicators represent the quality of care in patients with LU. The indicators can be applied individually, depending on the agreed contract-specific supply target. After implementation of this national standard, the comparability of selective agreements in the management of patients with LU can be ensured and consolidated.

Garlic (Allium sativum) feeding impairs Sertoli cell junctional proteins in male Wistar rat testis: microscopy study.

Sertoli cell junctions, such as adhesion junction (AJ), gap junction (GJ) and tight junction (TJ), are important for maintaining spermatogenesis. In previous studies, we showed the inhibitory effect of crude garlic (Allium sativum, As) on spermatogenesis and steroidogenesis. The aim of this work was to complete our investigation on the impact of this plant, especially on Sertoli cell junctional proteins (SCJPs). During 1 month, 24 male rats were divided into groups: group control (0% of As) and treated groups fed 5%, 10% and 15% of As. Light and electron microscopy observations were performed to localise junctional proteins: connexin-43, Zona Occluding-1 and N-cadherin (immunohistochemistry) and to describe junctions. We showed that the specific cells involved in the localisation of the SCJP were similar in both control and treated groups, but with different immunoreactivity intensity between them. The electron microscopy observation focused on TJs between Sertoli cells, constituting the blood-testis barrier, showed ultrastructural changes such as fragmentation of TJs between adjacent Sertoli cell membranes and dilatation of rough endoplasmic reticulum saccules giving an aspect of scale to these junctions. We concluded that crude garlic consumption during 1 month induces perturbations on Sertoli cell junctions. These alterations can explain apoptosis in testicular germ cells previously showed.

[The diagnostic and therapeutic challenges of bilateral renal oncocytosis : Illustrative case presentations and a review of the literature]. / Die bilaterale renale Onkozytose als diagnostische und therapeutische Herausforderung : Falldarstellung und Literaturreview.

Bilateral oncocytosis along with multiple tumours in both kidneys represents a very rare pathology that is accompanied by diagnostic and therapeutic challenges. We report the case of a 60-year old male patient who underwent computer tomography with incidental detection of multiple bilateral and contrast enhancing renal tumours of different size. Subsequently the patient underwent nephron-sparing tumor resection, first on the right side and 4 weeks later on the left side. The histology of all removed tumors showed evidence of pure oncocytoma. There were no postoperative complications and renal function reached a stable state within 6 months follow-up. The major challenge regarding diagnostic process and therapy of this pathology is to distinguish benign oncocytoma from chromophobe renal cell carcinoma and hybrid tumours, which can all be associated with renal oncocytosis. Because of limitations concerning imaging processes and biopsy, all patients should undergo nephron-sparing surgery as far as possible. On the other hand alternative therapies should - regarding to therapy-associated morbidity and the basically benign prognosis of oncocytoma - be well discussed to obtain informed consent. In this case report different therapy options and the international literature concerning renal oncocytosis will be discussed.

Perinatal xenohormone exposure impacts sweet preference and submandibular development in male rats.

OBJECTIVE: To determine the effect of perinatal exposure to low doses of genistein and/or vinclozolin on submandibular salivary gland (SSG) development in juvenile and adult male rats and to establish a link with sweet preference. MATERIAL AND METHODS: Female rats received orally (1 mg kg(-1) body weight/day) genistein and vinclozolin, alone or in combination, from the first gestational day up to weaning. Sweet preference was assessed at weaning and in adulthood in male offspring; submandibular glands were then collected to study the morphogenesis and mRNA expression of steroid receptors, growth factors and taste related proteins. RESULTS: Exposure to genistein and/or vinclozolin resulted in a higher saccharin intake on postnatal day 25 (P < 0.05) linked to a higher number of pro-acinar cells (P < 0.01) and mRNA expression of progesterone receptor, growth factors and gustine (P < 0.01). These increases disappeared in adulthood, but mRNA expressions of sex hormone receptors and growth factors were strongly repressed in all treated groups (P < 0.01). CONCLUSION: Our findings confirm that the SSG are target for xenohormones and provide evidence that perinatal exposure to low doses of genistein and/or vinclozolin could simultaneously disrupt not only the salivary gland prepubertal development and sweet intake but also endocrine gene mRNA expression later in life.

Impact of garlic feeding (Allium sativum) on male fertility.

Many medicinal plants are designed to improve health but their mechanism of action remains not clear. Among these plants, garlic (Allium sativum) has attracted particular attention of modern medicine because of its widespread use for the prevention and treatment of some human diseases such as cardiovascular diseases and cancer. However, the impact of garlic on the male reproductive system has not been clearly defined. Some studies have reported that garlic improves male sexual function and has beneficial effect in the recovery of testicular functions. However, other authors have shown that this plant impairs testicular functions (such as inhibition of testosterone production) and has spermicidal effect on spermatozoa. In this review, we attempt to clarify the current ambiguity regarding the effects of garlic and its preparations on the male reproductive system.

Development of an electronic medical record based intervention to improve medical care of osteoporosis.

UNLABELLED: Osteoporosis is infrequently addressed during hospitalization for osteoporotic fractures. An EMR-based intervention (osteoporosis order set) was developed with physician and patient input. There was a trend toward greater calcium supplementation from July 2008 to April 2009 (s = 0.058); however, use of antiresorptives (13%) or discharge instructions for BMD testing and osteoporosis treatment (10%) remained low. INTRODUCTION: Osteoporosis is infrequently addressed during hospitalization for osteoporotic fractures. The study population consisted of patients over 50 years of age. METHODS: Northwestern Memorial Hospital is a tertiary care academic hospital in Chicago. This study was conducted from September 1, 2007 through June 30, 2009. RESULTS: Physicians reported that barriers to care comprised nonacute nature of osteoporosis, belief that osteoporosis should be addressed by the PCP, low awareness of recurrent fractures, and radiographs with terms such as "compression deformity", "wedge deformity", or "vertebral height loss" which in their opinion were not clearly indicative of vertebral fractures. An EMR-based intervention was developed with physician and patient input. Over the evaluation period, 295 fracture cases in individuals over the age of 50 years in the medicine floors were analyzed. Mean age was 72 ± 11 years; 74% were female. Sites of fracture included hip n = 78 (27%), vertebral n = 87 (30%), lower extremity n = 61 (21%), upper extremity n = 43 (15%) and pelvis n = 26 (9%). There was no increase in documentation of osteoporosis in the medical record from pre- to post-EMR implementation (p = 0.89). There was a trend toward greater calcium supplementation from July 2008 to April 2009 (p = 0.058); however, use of antiresorptives (13%) or discharge instructions for BMD testing and osteoporosis treatment (10%) remained low. CONCLUSION: An electronic medical record intervention without electronic reminders created with physician input achieves an increase in calcium supplementation but fails to increase diagnosis or treatment for osteoporosis at the time of hospitalization for a fragility fracture.

Mitigation of indirect environmental effects of GM crops.

Currently, the UK has no procedure for the approval of novel agricultural practices that is based on environmental risk management principles. Here, we make a first application of the 'bow-tie' risk management approach in agriculture, for assessment of land use changes, in a case study of the introduction of genetically modified herbicide tolerant (GMHT) sugar beet. There are agronomic and economic benefits, but indirect environmental harm from increased weed control is a hazard. The Farm Scale Evaluation (FSE) trials demonstrated reduced broad-leaved weed biomass and seed production at the field scale. The simplest mitigation measure is to leave a proportion of rows unsprayed in each GMHT crop field. Our calculations, based on FSE data, show that a maximum of 2% of field area left unsprayed is required to mitigate weed seed production and 4% to mitigate weed biomass production. Tilled margin effects could simply be mitigated by increasing the margin width from 0.5 to 1.5 m. Such changes are cheap and simple to implement in farming practices. This case study demonstrates the usefulness of the bow-tie risk management approach and the transparency with which hazards can be addressed. If adopted generally, it would help to enable agriculture to adopt new practices with due environmental precaution.

Effects of genetically modified herbicide-tolerant cropping systems on weed seedbanks in two years of following crops.

The Farm Scale Evaluations (FSEs) showed that genetically modified herbicide-tolerant (GMHT) cropping systems could influence farmland biodiversity because of their effects on weed biomass and seed production. Recently published results for winter oilseed rape showed that a switch to GMHT crops significantly affected weed seedbanks for at least 2 years after the crops were sown, potentially causing longer-term effects on other taxa. Here, we seek evidence for similar medium-term effects on weed seedbanks following spring-sown GMHT crops, using newly available data from the FSEs. Weed seedbanks following GMHT maize were significantly higher than following conventional varieties for both the first and second years, while by contrast, seedbanks following GMHT spring oilseed rape were significantly lower over this period. Seedbanks following GMHT beet were smaller than following conventional crops in the first year after the crops had been sown, but this difference was much reduced by the second year for reasons that are not clear. These new data provide important empirical evidence for longer-term effects of GMHT cropping on farmland biodiversity.

Effects of chondroitin and glucosamine sulfate in a dietary bar formulation on inflammation, interleukin-1beta, matrix metalloprotease-9, and cartilage damage in arthritis.

This study examined the effects of chondroitin sulfate (CS) alone and CS plus glucosamine sulfate (GS) in a dietary bar formulation on inflammatory parameters of adjuvant-induced arthritis and on the synthesis of interleukin-1beta (IL-1beta) and matrix metalloprotease-9 (MMP-9). Following 25 days pretreatment with dietary bars containing either CS alone, CS plus GS, or neither CS nor GS, rats were either sham injected or injected with Freund's complete adjuvant into the tail vein. Rats were fed their respective bars for another 17 days after inoculation. Parameters of disease examined included clinical score (combination of joint temperature, edema, hyperalgesia, and standing and walking limb function), incidence of disease, levels of IL-1beta in the serum and paw joints, levels of MMP-9 in the paw joints, paw joint histology, and joint cartilage thickness. Treatment with CS plus GS, but not CS alone, significantly reduced clinical scores, incidences of disease, joint temperatures, and joint and serum IL-1beta levels. Treatment with CS alone and CS plus GS inhibited the production of edema and prevented raised levels of joint MMP-9 associated with arthritis. Similarly, CS alone and CS plus GS treatment also prevented the development of cartilage damage associated with arthritis. Combination CS plus GS treatment in a dietary bar formulation ameliorates clinical, inflammatory, and histologic parameters of adjuvant-induced arthritis. The benefits of CS and GS in combination are more pronounced than those of CS alone. The reduction of arthritic disease by CS plus GS is associated with a reduction of IL-1beta and MMP-9 synthesis.

A tyrosine-based sorting signal regulates intracellular trafficking of protease-activated receptor-1: multiple regulatory mechanisms for agonist-induced G protein-coupled receptor internalization.

Protease-activated receptor-1 (PAR1), a G protein-coupled receptor (GPCR) for thrombin, is irreversibly proteolytically activated, internalized, and then sorted to lysosomes and degraded. Internalization and lysosomal sorting of activated PAR1 is critical for termination of receptor signaling. We previously demonstrated that activated PAR1 is rapidly phosphorylated and internalized via a clathrin- and dynamin-dependent pathway that is independent of arrestins. Toward understanding the mechanisms responsible for activated PAR1 internalization through clathrin-coated pits we examined the function of a highly conserved tyrosine-based motif, YXXL, localized in the cytoplasmic carboxyl tail of the receptor. A mutant PAR1 in which tyrosine 383 and leucine 386 were replaced with alanines (Y383A/L386A) was significantly impaired in agonist-triggered internalization and degradation compared with wild-type receptor. In contrast, constitutive internalization, and recycling of unactivated PAR1 Y383A/L386A mutant was not affected, suggesting that tonic cycling of the mutant receptor remained intact. Strikingly, a PAR1 C387Z truncation mutant in which the YXXL motif was exposed at the C terminus constitutively internalized and degraded in an agonist-independent manner, whereas C387Z truncation mutant in which the critical tyrosine and leucine were mutated to alanine (C387Z-Y383A/L386A) failed to internalize. Inhibition of PAR1 C387Z mutant constitutive internalization with dominant-negative K44A dynamin blocked agonist-independent degradation of the mutant receptor. Together these findings strongly suggest that internalization of activated PAR1 is controlled by multiple regulatory mechanisms involving phosphorylation and a highly conserved tyrosine-based motif, YXXL. This study is the first to describe a function for a tyrosine-based motif, YXX, in GPCR internalization and reveal novel complexities in the regulation of GPCR trafficking.

On the rationale and interpretation of the Farm Scale Evaluations of genetically modified herbicide-tolerant crops.

Farmland biodiversity and food webs were compared in conventional and genetically modified herbicide-tolerant (GMHT) crops of beet (Beta vulgaris L.), maize (Zea mays L.) and both spring and winter oilseed rape (Brassica napus L.). GMHT and conventional varieties were sown in a split-field experimental design, at 60-70 sites for each crop, spread over three starting years beginning in 2000. This paper provides a background to the study and the rationale for its design and interpretation. It shows how data on environment, field management and the biota are used to assess the current state of the ecosystem, to define the typical arable field and to devise criteria for selecting, sampling and auditing experimental sites in the Farm Scale Evaluations. The main functional and taxonomic groups in the habitat are ranked according to their likely sensitivity to GMHT cropping, and the most responsive target organisms are defined. The value of the seedbank as a baseline and as an indicator of historical trends is proposed. Evidence from experiments during the twentieth century is analysed to show that large changes in field management have affected sensitive groups in the biota by ca. 50% during a year or short run of years--a figure against which to assess any positive or negative effects of GMHT cropping. The analysis leads to a summary of factors that were, and were not, examined in the first 3 years of the study and points to where modelling can be used to extrapolate the effects to the landscape and the agricultural region.

Crop management and agronomic context of the Farm Scale Evaluations of genetically modified herbicide-tolerant crops.

The Farm Scale Evaluations of genetically modified herbicide-tolerant crops (GMHT) were conducted in the UK from 2000 to 2002 on beet (sugar and fodder), spring oilseed rape and forage maize. The management of the crops studied is described and compared with current conventional commercial practice. The distribution of field sites adequately represented the areas currently growing these crops, and the sample contained sites operated at a range of management intensities, including low intensity. Herbicide inputs were audited, and the active ingredients used and the rates and the timings of applications compared well with current practice for both GMHT and conventional crops. Inputs on sugar beet were lower than, and inputs on spring oilseed rape and forage maize were consistent with, national averages. Regression analysis of herbicide-application strategies and weed emergence showed that inputs applied by farmers increased with weed densities in beet and forage maize. GMHT crops generally received only one herbicide active ingredient per crop, later and fewer herbicide sprays and less active ingredient (for beet and maize) than the conventional treatments. The audit of inputs found no evidence of bias.

[Psychological aspects and details of care of patients on hemodialysis]. / Aspects psychologiques et particularites du soin chez l'hemodialyse.

Chronic renal failure and periodic hemodialysis, by the physical reach and the therapeutic imperatives that they mislead disrupt by several ways the universe of the patient. This one is confronted to changes, or even to aggressions that undergo his body, his domestic and socio-professional life, which is accepted in general with difficulty. Indeed, our survey that concerned 109 patients on chronic hemodialysis shows that the minor psychiatric pathology is frequent and can represent a source of problems as well for the patients that for the medical and nursing staff. Besides the analysis of minor psychiatric specificities revealed by a known measure instrument (the GHQ), this work insists on the importance to take account of this aspects with the aim to enhance management and holistic care of these patients.

The effect of vitamin E and vitamin C supplementation on LDL oxidizability and neutrophil respiratory burst in young smokers.

OBJECTIVE: The purpose of this study was to determine the effect of vitamin E and/or vitamin C supplementation on low-density lipoprotein (LDL) oxidizability and neutrophil (PMN) superoxide anion production in young smokers. METHODS: Thirty smokers with a <5 pack-year history were randomly assigned to take placebo; vitamin C (1 g/day); vitamin E (400 IU/day), or both vitamins in a double-blind fashion. Subjects took the supplements for 8 weeks. At weeks 0 and 8, blood was collected for isolation of LDL and PMN, and for antioxidant vitamin analysis. LDL was oxidized with a copper (Cu) catalyst, and oxidation was measured by formation of conjugated dienes over a 5-hour time course. Lag times and maximum oxidation rates were calculated from the time course data. PMN superoxide anion release was assessed by respiratory burst after stimulation with phorbol ester and opsonized zymosan, and their ability to oxidize autologous LDL following treatment with the above stimuli was measured with the conjugated diene assay. RESULTS: Subjects who received vitamin E alone had a significant increase in the lag phase of Cu-catalyzed LDL oxidation (week 0, 118+/-31 min vs. week 8, 193+/-80 min, mean +/- SD, p < 0.05), whereas the vitamin C and placebo groups had no changes in LDL oxidation kinetics. The group receiving both vitamins E and C had a significant reduction in oxidation rate (week 0. 7.4+/-2.3 vs. week 8, 5.1+/-2.1, p < 0.05). There were no significant changes for any group in PMN superoxide anion production or PMN LDL oxidation after stimulation with either phorbol ester or opsonized zymosan. Plasma and LDL vitamin E concentrations were significantly increased in both groups that received vitamin E. The subjects who received vitamin C alone had no significant change in plasma vitamin C concentrations; however, when data were pooled from both groups who received vitamin C, the increases were significant. CONCLUSION: Vitamin E supplementation of young smokers was effective in reducing Cu-catalyzed LDL oxidizability; however, vitamin E and/or C supplementation showed few significant effects on the more physiologically relevant PMN function. This casts doubt on the ability of antioxidant supplementation to reduce oxidative stress in smokers in vivo. Therefore, smoking cessation remains the only means by which young smokers can prevent premature coronary heart disease.

Inoculating the urban poor in the late eighteenth century.

Historical accounts of the practice of smallpox inoculation in the late eighteenth century invariably made a distinction between the widespread general inoculations carried out within small rural parishes and the partial inoculations in urban centres such as London, Manchester, Newcastle and Leeds. This distinction, moreover, is generally reinforced by concluding that the rural inoculation programmes were 'highly effective' or 'successful' in contrast with the urban inoculation schemes, which are often seen as 'marginally effective' or indeed 'failing'. Success or failure tends to be judged by the impact which inoculation had upon reducing mortality from smallpox, but as a result of this demographic focus the motives behind the implementation of urban inoculation have been overlooked. My paper readjusts this balance by looking more closely at motives and by judging success in relation to aims. To achieve this I have taken a new approach towards the history of smallpox inoculation as a whole, and portray the basic idea of giving a person smallpox in order to confer subsequent immunity as being modified in the hands of different people throughout the course of the century. Hence it is possible to trace the development of inoculation from a folk practice carried out within the home with the aim of protecting individuals, to large-scale general inoculation of an entire community, which aimed to eradicate the disease altogether.