Morphometrics of the human thumb metacarpal bone: interest for developing an osseointegrated prosthesis.

INTRODUCTION: Amputation of the thumb presents a serious insult to the hand and diminished quality of life for a patient physically, vocationally, and possibly psychologically. The aim of this study was to define the geometry of the thumb metacarpal in order to help create a standardized set of transcutaneous osseointegrated prostheses to treat patients who have suffered amputation of the thumb at the level of the metacarpophalangeal joint. MATERIALS AND METHODS: A total of 80 metacarpals from 46 cadavers were studied. All soft tissues were removed and the thumb metacarpals were imaged using computed tomography. Three-dimensional models were constructed using images from the coronal, sagittal, and axial planes. Using HyperMesh™ CAD software, the bones were analyzed for overall length, radius of curvature, medullary canal diameter, cortical thickness, and distance to the isthmus, defined as the narrowest portion of the intramedullary canal. RESULTS: The average length of the first metacarpal was 47.6 mm (±3.3 mm, 39.2-56.9 mm). The average radius of curvature was 55.5 mm (±10.7 mm, 33-78.9 mm). Inner bone diameter, measured in two axes, was 10.5 mm (±1.3 mm, 5.4-18.7 mm) for the major axis and 7.7 mm (±0.9 mm, 4.3-17.8 mm) for the minor axis. The average cortical thickness was 1.4 mm (±0.3 mm, 0.7-3.1 mm). The distance to the center of the isthmus from the distal end had an average length of 21.3 mm (±1.9 mm, 17-25 mm). CONCLUSIONS: Using these findings a standardized set of intramedullary stems can be developed as a base for a transcutaneous osseointegrated prosthesis, helping to create a reliable method for treating patients with amputated thumbs.

Invited review: An evaluation of the likely effects of individualized feeding of concentrate supplements to pasture-based dairy cows.

In pasture-based dairy systems, supplementary feeds are used to increase dry matter intake and milk production. Historically, supplementation involved the provision of the same amount of feed (usually a grain-based concentrate feed) to each cow in the herd during milking (i.e., flat-rate feeding). The increasing availability of computerized feeding and milk monitoring technology in milking parlors, however, has led to increased interest in the potential benefits of feeding individual cows (i.e., individualized or differential feeding) different amounts and types of supplements according to one or more parameters (e.g., breeding value for milk yield, current milk yield, days in milk, body condition score, reproduction status, parity). In this review, we consider the likely benefits of individualized supplementary feeding strategies for pasture-based dairy cows fed supplements in the bail during milking. A unique feature of our review compared with earlier publications is the focus on individualized feeding strategies under practical grazing management. Previous reviews focused primarily on research undertaken in situations where cows were offered ad libitum forage, whereas we consider the likely benefits of individualized supplementary feeding strategies under rotational grazing management, wherein pasture is often restricted to all or part of a herd. The review provides compelling evidence that between-cow differences in response to concentrate supplements support the concept of individualized supplementary feeding.

Mother knows best, even when stressed? Effects of maternal exposure to a stressor on offspring performance at different life stages in a wild semelparous fish.

The environment mothers are exposed to has resonating effects on offspring performance. In iteroparous species, maternal exposure to stressors generally results in offspring ill-equipped for survival. Still, opportunities for future fecundity can offset low quality offspring. Little is known, however, as to how intergenerational effects of stress manifest in semelparous species with only a single breeding episode. Such mothers would suffer a total loss of fitness if offspring cannot survive past multiple life stages. We evaluated whether chronic exposure of female sockeye salmon (Oncorhynchus nerka) to a chase stressor impaired offspring performance traits. Egg size and early offspring survival were not influenced by maternal exposure to the repeated acute stressor. Later in development, fry reared from stressed mothers swam for shorter periods of time but possessed a superior capacity to re-initiate bouts of burst swimming. In contrast to iteroparous species, the mechanisms driving the observed effects do not appear to be related to cortisol, as egg hormone concentrations did not vary between stressed and undisturbed mothers. Sockeye salmon appear to possess buffering strategies that protect offspring from deleterious effects of maternal stress that would otherwise compromise progeny during highly vulnerable stages of development. Whether stressed sockeye salmon mothers endow offspring with traits that are matched or mismatched for survival in the unpredictable environment they encountered is discussed. This study highlights the importance of examining intergenerational effects among species-specific reproductive strategies, and across offspring life history to fully determine the scope of impact of maternal stress.

Diagnosis of antiphospholipid syndrome in routine clinical practice.

The updated international consensus criteria for definite antiphospholipid syndrome (APS) are useful for scientific clinical studies. However, there remains a need for diagnostic criteria for routine clinical use. We audited the results of routine antiphospholipid antibodies (aPLs) in a cohort of 193 consecutive patients with aPL positivity-based testing for lupus anticoagulant (LA), IgG and IgM anticardiolipin (aCL) and anti-ß(2)glycoprotein-1 antibodies (aß(2)GPI). Medium/high-titre aCL/aß(2)GPI was defined as >99th percentile. Low-titre aCL/aß(2)GPI positivity (>95(th )< 99(th) percentile) was considered positive for obstetric but not for thrombotic APS. One hundred of the 145 patients fulfilled both clinical and laboratory criteria for definite APS. Twenty-six women with purely obstetric APS had persistent low-titre aCL and/or aß(2)GPI. With the inclusion of these patients, 126 of the 145 patients were considered to have APS. Sixty-seven out of 126 patients were LA-negative, of whom 12 had aCL only, 37 had aß(2)GPI only and 18 positive were for both. The omission of aCL or aß(2)GPI testing from investigation of APS would have led to a failure to diagnose APS in 9.5% and 29.4% of patients, respectively. Our data suggest that LA, aCL and aß(2)GPI testing are all required for the accurate diagnosis of APS and that low-titre antibodies should be included in the diagnosis of obstetric APS.

The clinical significance of differences between point-of-care and laboratory INR methods in over-anticoagulated patients.

INTRODUCTION: Patients receiving warfarin are at increased risk of bleeding when their International Normalised Ratio (INR) >4.5. Although not standardised above 4.5 the INR is measured in over-anticoagulated patients, consequently we have examined the reliability of INR results ≥4.5. We assessed: the relationship between different prothrombin time systems for INRs >4.5; the relationships between the INR and levels of vitamin K-dependent coagulation factors (VKD-CF) and thrombin generation test (TGT) parameters; and the impact that variation in results would have on warfarin dosing. METHODS: INRs were performed using a CoaguChek XS Plus point-of-care (POC) device (measuring range 0.6-8.0). For POC INRs ≥4.5, laboratory INRs were also measured using a recombinant tissue factor (rTF) and a rabbit brain (RBT) thromboplastin. RESULTS: There was good correlation between POC (INR ≥4.5, <8.0) and Lab INRs (rTF n=154, rs=0.87, p<0.0001; RBT n=102, rs=0.76, p<0.0001); and significant correlations between each of the VKD-CF and the INR, the strongest being with FVII (POC INR rs=-0.53 p<0.0001; Lab rTF-INR rs=-0.70 p<0.0001). TGT peak thrombin and ETP also showed good correlations with INR values (R(2)>0.71). Using POC and Lab rTF-INR, 109/154 (71%), or POC and Lab RBT-INR 75/102 (74%) results exhibited dosage concordance and/or were within 0.5 INR units. In the remaining patients variation in warfarin dosing was generally slight. CONCLUSIONS: Our data suggest that CoaguChek XS Plus INRs >4.5 and <8.0 are comparable to laboratory INRs (both methods) and it is probably unnecessary to perform laboratory INRs for clinical management of patients with INRs >4.5 including those >8.0.

Physiological and molecular endocrine changes in maturing wild sockeye salmon, Oncorhynchus nerka, during ocean and river migration.

Maturing adult sockeye salmon Oncorhynchus nerka were intercepted while migrating in the ocean and upstream in freshwater over a combined distance of more than 1,300 km to determine physiological and endocrine changes associated with ionoregulation. Sockeye migrating through seawater and freshwater showed consistent declines in gill Na+/K+ -ATPase (NKA) activity, plasma osmolality and plasma chloride concentration. In contrast, plasma sodium concentration became elevated in seawater as fish approached the river mouth and was then restored after sockeye entered the river. Accompanying the movement from seawater to freshwater was a significant increase in mRNA for the NKA α1a subunit in the gill, with little change in the α1b subunit. Potential endocrine signals stimulating the physiological changes during migration were assessed by measuring plasma cortisol and prolactin (Prl) concentrations and quantifying mRNA extracted from the gill for glucocorticoid receptors 1 and 2 (GR1 and GR2), mineralocorticoid receptor (MR), growth hormone 1 receptor (GH1R), and prolactin receptor (PrlR). Plasma cortisol and prolactin concentrations were high in seawater suggesting a preparatory endocrine signal before freshwater entry. Generally, the mRNA expression for GR1, GR2 and MR declined during migration, most notably after fish entered freshwater. In contrast, PrlR mRNA increased throughout migration, particularly as sockeye approached the spawning grounds. A highly significant association existed between gill PrlR mRNA and gill NKA α1a mRNA. GH1R mRNA also increased significantly, but only after sockeye had migrated beyond tidal influence in the river and then again just before the fish reached the spawning grounds. These findings suggest that cortisol and prolactin stimulate ionoregulation in the gill as sockeye salmon adapt to freshwater.

The efficacy of field techniques for obtaining and storing blood samples from fishes.

Prompted by the dramatic increase in the use of blood analyses in fisheries research and monitoring, this study investigated the efficacy of common field techniques for sampling and storing blood from fishes. Three questions were addressed: (1) Do blood samples taken via rapid caudal puncture (the 'grab-and-stab' technique) yield similar results for live v. sacrificed groups of fishes? (2) Do rapidly obtained caudal blood samples accurately represent blood properties of fishes prior to capture? (3) Does storage of whole blood in an ice slurry for a working day (8·5 h) modify the properties of the plasma? It was shown that haematocrit, plasma ions, metabolites, stress hormones and sex hormones of caudal blood samples were statistically similar when taken from live v. recently sacrificed groups of adult coho salmon Oncorhynchus kisutch. Moreover, this study confirmed by using paired blood samples from cannulated O. kisutch that blood acquired through the caudal puncture technique (mean ±s.e. 142 ± 26 s after capture) was representative of fish prior to capture. Long-term (8·5 h) cold storage of sockeye salmon Oncorhynchus nerka whole blood caused significant decreases in plasma potassium and chloride, and a significant increase in plasma glucose. Previous research has suggested that these changes largely result from net movements of ions and molecules between the plasma and erythrocytes, movements that can occur within minutes of storage. Thus, blood samples from fishes should be centrifuged as quickly as practicable in the field for separation of plasma and erythrocytes to prevent potentially misleading data.

Physiological condition differentially affects the behavior and survival of two populations of sockeye salmon during their freshwater spawning migration.

Recently, a segment of the Adams-Shuswap sockeye salmon (Oncorhynchus nerka) population initiated freshwater migration several weeks earlier than historically recorded, resulting in high mortality rates. The comigrating Chilko population maintained their historic river entry timing and did not experience elevated mortality. To test the hypothesis that population-specific differences in physiological condition would differentially influence behavior and survival when exposed to fisheries capture stress, we physiologically sampled individuals from both populations at the onset of the freshwater phase of their reproductive migration and tracked the remainder of their migrations using radio telemetry. Adams-Shuswap individuals had slower migration rates and were less likely to reach natal subwatersheds relative to Chilko individuals. Metabolic and osmoregulatory impairment was related to mortality for Adams-Shuswap individuals but not for Chilko individuals. Similarly, physiological condition correlated with migration rate for Adams-Shuswap but not Chilko fish. Survival to natal subwatersheds was 1.9 times higher for Chilko relative to Adams-Shuswap, a result that did not emerge until individuals approached natal subwatersheds several days after the stressor was applied. We conclude that physiological condition differentially affects the behavior and survival of these two populations, which may be a consequence of the early-entry phenomenon by a segment of the Adams-Shuswap population.

Self-monitoring of oral anticoagulation: does it work outside trial conditions?

BACKGROUND: Patient self-monitoring (PSM) of oral anticoagulation therapy (OAT) can improve anticoagulant control, but poor uptake and high dropout rates have prompted suggestions that PSM is suitable for only a minority of patients in the UK. AIMS: To determine whether PSM could be a viable alternative to regular hospital anticoagulant clinic attendance, if offered from the start of treatment. METHODS: 318 consecutive patients referred, for the first time, to an anticoagulation clinic were assessed for eligibility using established criteria. Patients electing for PSM attended training and, following successful assessment, performed a capillary blood INR every two weeks or more frequently if directed to do so by the anticoagulation clinic. Primary outcome measures were uptake of PSM and the percentage time in target therapeutic INR range (TIR) compared to patients electing for routine clinic care. RESULTS: Of 318 patients referred for OAT, 188 were eligible for PSM. 84 (26%) elected to self-monitor, of whom 72 (23%) remained self-monitoring or had completed their course of treatment at the end of the audit. Self-monitoring patients had significantly better anticoagulant control than those receiving routine hospital anticoagulation clinic care (TIR 71% vs 60%, p = 0.003) and significantly less time outside critical limits, ie, INR <1.5 or >5.0 (0.45% vs 2.04%, p = 0.008). CONCLUSIONS: Patients offered PSM from the start of treatment show increased uptake compared to previous UK studies and a level of oral anticoagulation control comparable to that reported in previous clinical trials.

Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.

The authors report five elderly men with the fragile X premutation who had a progressive action tremor associated with executive function deficits and generalized brain atrophy. These individuals had elevated fragile X mental retardation 1 gene (FMR1) messenger RNA and normal or borderline levels of FMR1 protein. The authors propose that elevations of FMR1 messenger RNA may be causative for a neurodegenerative syndrome in a subgroup of elderly men with the FMR1 premutation.

Short-term satiety in preschool children: a comparison between high protein meal and a high complex carbohydrate meal.

The aim of this study was to investigate whether a high protein meal has a different effect on short-term satiety in preschool children than a high carbohydrate meal by measuring their intake of a subsequent meal. Subjects were 35 normal preschool children of both genders aged 5 to 6 years. All children were healthy and randomly chosen from those who were attending to a day-care center where they received feeding at three meal times: breakfast, lunch and teatime. Children were weighed with light clothes following standard recommendations. They were normal according to the weight for height index, using the NCHS standards. Two meals with different levels of protein and carbohydrate and equal energy contents were assayed at lunch. The lunches were cooked dishes made from common ingredients. The high carbohydrate meal was consumed in greater amount than the high protein meal (P < 0.01) and a significantly greater energy intake was observed (P < 0.01). Food and energy intakes at teatime were greater with the high carbohydrate meal, but only the energy intake was significant (P < 0.05). When subjects consumed the high protein meal during lunch, they ate a significantly lower amount of protein in the subsequent meal, but the carbohydrate intake was similar. The long-term effects of a high protein diet remain to be investigated before recommending of a high protein for obese children.

Characterisation of SB-221420-A - a neuronal Ca(2+) and Na(+) channel antagonist in experimental models of stroke.

For progression to clinical trials in stroke, putative neuroprotective compounds should show robust efficacy post-ischaemia in several experimental models of stroke. This paper describes the characterisation of (+)(1S, 2R)-cis-1-[4-(1-methyl-1-phenylethyl)phenoxy]-2-methylamino indane hydrochloride (SB-221420-A), a Ca(2+) and Na(+) channel antagonist. SB-221420-A inhibited (IC(50)=2.2 microM) N-type voltage-operated Ca(2+) channel currents in cultured superior cervical ganglion neurons, which were pretreated with 10 microM nimodipine to block L-type voltage-operated Ca(2+) channel currents. In dorsal root ganglion neurons pretreated with 1 microM omega-conotoxin GVIA to block N-type voltage-operated Ca(2+) channel currents, SB-221420-A inhibited the residual Ca(2+) current with an IC(50) of 7 microM. SB-221420-A also inhibited Na(+) currents in dorsal root ganglion neurons with an IC(50) of 8 microM. In rats, the pharmacokinetic profile of SB-221420-A shows that it has a half-life of 6.4 h, a high volume of distribution, is highly brain penetrating, and has no persistent metabolites. Following bilateral carotid artery occlusion in gerbils, SB-221420-A significantly reduced the level of ischaemia-induced hyperlocomotor activity and the extent of hippocampal CA1 cell loss compared to the ischaemic vehicle-treated group. SB-221420-A was also effective in focal models of ischaemia. In the mouse permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously, post-ischaemia significantly (P<0.05) reduced lesion volume compared to the ischaemic vehicle-treated group. In the normotensive rat permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously over 1 h, beginning 30 min postmiddle cerebral artery occlusion, significantly (P<0.05) reduced lesion volume from 291+/-16 to 153+/-30 mm(3), compared to ischaemic vehicle-treated controls when measured 24 h postmiddle cerebral artery occlusion. Efficacy was maintained when the same total dose of SB-221420-A was infused over a 6-h period, beginning 30 min postmiddle cerebral artery occlusion. SB-221420-A also significantly (P<0.05) reduced lesion volume following transient middle cerebral artery occlusion in normotensive rats and permanent middle cerebral artery occlusion in spontaneously hypertensive rats (SHR). Investigation of the side effect profile using the Irwin screen in mice revealed that, at neuroprotective doses, there were no overt behavioural or cardiovascular changes. These data demonstrate that robust neuroprotection can be seen post-ischaemia with SB-221420-A in both global and focal ischaemia with no adverse effects at neuroprotective doses, and indicate the potential utility of a mixed cation blocker to improve outcome in cerebral ischaemia.

Prompt Optical Observations of Gamma-Ray Bursts.

The Robotic Optical Transient Search Experiment (ROTSE) seeks to measure simultaneous and early afterglow optical emission from gamma-ray bursts (GRBs). A search for optical counterparts to six GRBs with localization errors of 1 deg2 or better produced no detections. The earliest limiting sensitivity is mROTSE>13.1 at 10.85 s (5 s exposure) after the gamma-ray rise, and the best limit is mROTSE>16.0 at 62 minutes (897 s exposure). These are the most stringent limits obtained for the GRB optical counterpart brightness in the first hour after the burst. Consideration of the gamma-ray fluence and peak flux for these bursts and for GRB 990123 indicates that there is not a strong positive correlation between optical flux and gamma-ray emission.

Fragile X syndrome and an isodicentric X chromosome in a woman with multiple anomalies, developmental delay, and normal pubertal development.

We report on an individual with developmental delays, short stature, skeletal abnormalities, normal pubertal development, expansion of the fragile X triplet repeat, as well as an isodicentric X chromosome. S is a 19-year-old woman who presented for evaluation of developmental delay. Pregnancy was complicated by a threatened miscarriage. She was a healthy child with intellectual impairment noted in infancy. Although she had global delays, speech was noted to be disproportionately delayed with few words until age 3.5 years. Facial appearance was consistent with fragile X syndrome. Age of onset of menses was 11 years with normal breast development. A maternal male second cousin had been identified with fragile X syndrome based on DNA studies. The mother of this child (S's maternal first cousin) and the grandfather (S's maternal uncle) were both intellectually normal but were identified as carrying triplet expansions in the premutation range. S's mother had some school difficulties but was not identified as having global delays. Molecular analysis of S's fragile X alleles noted an expansion of more than 400 CGG repeats in one allele. Routine cytogenetic studies of peripheral blood noted the presence of an isodicentric X in 81of 86 cells scored. Five of 86 cells were noted to be 45,X. Cytogenetic fra(X) studies from peripheral blood showed that the structurally normal chromosome had the fragile site in approximately 16% of the cells. Analysis of maternal fragile X alleles identified an allele with an expansion to approximately 110 repeats. FMRP studies detected the expression of the protein in 24% of cells studied. To our knowledge, this is the first patient reported with an isodicentric X and fragile X syndrome. Whereas her clinical phenotype is suggestive of fragile X syndrome, her skeletal abnormalities may represent the presence of the isodicentric X. Treatment of S with 20 mg/day of Prozac improved her behavior. In the climate of cost con trol, this individual reinforces the recommendation of obtaining chromosomes on individuals with developmental delay even with a family history of fragile X syndrome.

Fragile X syndrome and selective mutism.

This is the first report that details an association between fragile X syndrome (FXS) and selective mutism (SM). This 12-year-old girl with heterozygous full mutation at FMR1 has a long history of social anxiety and shyness in addition to SM. Her sister also has the full mutation and a history of SM that resolved in adolescence. A beneficial response to fluoxetine and psychotherapy is described. The FMR1 mutation appears to be the first gene mutation associated with SM and further studies are recommended to assess what percentage of patients with SM have the FMR1 mutation.

Compound heterozygous female with fragile X syndrome.

We report on a 15-year-old compound heterozygous young woman with fragile X syndrome who has a full mutation of 363 repeats on one X chromosome and a premutation of 103 repeats on the other X chromosome. As predicted, subsequent testing demonstrated that her father carries a premutation (98 repeats) as does her mother (146 repeats). There is only one previous report of a compound heterozygous female with fragile X syndrome. By quantitation of Southern blot signals, the activation ratio for the premutation (the proportion of the premutation on the active X chromosome) was determined to be 0.78. Immunocytochemistry of blood smears showed fragile X mental retardation-1 protein (FMRP) expression in 63.5% of lymphocytes. Cognitively, this woman is functioning in the mid-range of involvement for fragile X females. She attends regular classes and receives supplemental assistance for her learning disabilities. She experiences behavior characteristics typical of females with fragile X syndrome including severe shyness, anxiety, panic episodes, mood swings, and attention deficits. She has responded very well to appropriate treatment including fluoxetine for anxiety, methylphenidate for attentional problems, and educational therapy.

Sonographic incidence of deep venous thrombosis contralateral to hip or knee replacement surgery.

PURPOSE: This study assesses the sonographic incidence of deep venous thrombosis (DVT) contralateral to and the venographic incidence ipsilateral to hip or knee replacement surgery and the role of sonography in routine surveillance. METHODS: We prospectively evaluated 178 consecutive patients with sonography of the femoropopliteal venous systems of the contralateral lower extremity and venography of the ipsilateral lower extremity on days 3 and 4, respectively, after total hip or knee replacement surgery. RESULTS: No cases of acute DVT and only 1 case of chronic DVT isolated to the popliteal system were identified by sonography in the contralateral extremity. In the ipsilateral extremity, venography identified 26 patients with acute DVT (3 femoropopliteal, 21 calf, and 2 concurrent femoropopliteal and calf). CONCLUSIONS: Routine sonographic evaluation of the lower extremity contralateral to hip or knee replacement surgery is not cost-effective because of the extremely low incidence of detectable acute thrombus.

The optimization of helical thoracic CT.

PURPOSE: Our purpose was to determine the optimal helical thoracic CT scanning protocol. METHOD: Three adult Suffolk sheep under general anesthesia were repeatedly scanned by a variety of variable thickness helical and conventional plus thin section high resolution (lung gold standard) CT sequences, reconstructed for mediastinal (standard interpolator and algorithm) and lung parenchymal (extrasharp interpolator, bone algorithm) detail. The images were evaluated in a random order by five separate blinded, experienced imagers utilizing a predetermined grading scale. RESULTS: At equivalent slice thicknesses, the mediastinal images showed no statistically significant differences between conventional and helical CT using pitches of 1.0, 1.5, and 2.0. However, the 5-mm-thick sections, regardless of technique, performed better than did either the 2- or the 10-mm-thick section images. For the lung interstitium, there was an obvious and marked advantage to reconstructing the lung images separately from the mediastinal images with edge-enhancing algorithms and interpolators. With 1-mm-high mA thin section, high resolution lung CT as the gold standard, 2 mm conventional and helical pitch 1.0, 1.5, and 2.0 images were all graded equivalent. Of the 5 mm images, the helical pitches of 1.0 and 1.5 were graded equivalent to the gold standard. All of the 10 mm lung sections using both conventional and helical CT were graded statistically worse than the gold standard (p < 0.05). CONCLUSION: The use of helical CT with a 5 mm beam collimation and a pitch of 1.0 or 1.5 reconstructed twice to maximize both the mediastinal and the lung parenchymal detail provides the optimal way to routinely evaluate the chest.

Effect of potent urease inhibitor, fluorofamide, on Helicobacter sp. in vivo and in vitro.

The therapeutic potential of urease inhibition of Helicobacter pylori has been studied by examining the effect of the potent urease inhibitor, fluorofamide (N-(diaminophosphinyl)-4-fluorobenzenamide), on urease activity and bacterial survival in vivo and in vitro. In culture, acid protection in H. pylori was shown to be due to changes in the pH of the medium brought about by the release of ammonia. Both the acid protection and the ammonia release were completely blocked by fluorofamide at low doses (ED50 = approximately 100 nM). However, fluorofamide was unstable under acidic conditions (T1/2 = 5.7 min at pH 2). Despite this, fluorofamide was the best available compound to test in vivo. In ferrets naturally infected with H. mustelae, a single dose (50 mg/kg, per os) of fluorofamide completely inhibited bacterial urease. In repeat dosing studies, fluorofamide (50 mg/kg per os, three times a day) was compared with the Helicobacter triple therapy regime (amoxycillin, metronidazole, and bismuth subcitrate). Fluorofamide failed to eradicate the H. mustelae infection, compared to 80% eradication with triple therapy. However, histological samples showed a profound reduction in bacterial numbers following fluorofamide treatment. A combination of fluorofamide and amoxycillin was dosed to ferrets (seven days of treatment with 50 mg/kg fluorofamide plus 10 mg/kg amoxycillin per os twice a day); however, this failed to eradicate the infection, despite there being a reduction in bacterial numbers in 3/5 ferrets after 21 days after dosing stopped. It was concluded that urease inhibitors (either alone or in combination with antibiotics) are unlikely to have therapeutic potential for Helicobacter pylori infections. This is probably because, in vivo, some bacteria (perhaps dormant forms) are not entirely dependent upon urease for survival. However, given the acid instability of fluorofamide, the possibility that more stable urease inhibitors might have therapeutic potential, cannot be excluded.