Scabies outbreaks in residential care homes: factors associated with late recognition, burden and impact. A mixed methods study in England.

Scabies is an important public health problem in residential care homes. Delayed diagnosis contributes to outbreaks, which may be prolonged and difficult to control. We investigated factors influencing outbreak recognition, diagnosis and treatment, and staff experiences of outbreak control, identifying areas for intervention. We carried out a semi-structured survey of managers, affected residents and staff of seven care homes reporting suspected scabies outbreaks in southern England over a 6-month period. Attack rates ranged from 2% to 50%, and most cases had dementia (37/39, 95%). Cases were diagnosed clinically by GPs (59%) or home staff (41%), none by dermatologists. Most outbreaks were attributable to avoidably late diagnosis of the index case. Participants reported considerable challenges in managing scabies outbreaks, including late diagnosis and recognition of outbreaks; logistically difficult mass treatment; distressing treatment processes and high costs. This study demonstrates the need for improved support for care homes in detecting and managing these outbreaks.

Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance.

AIMS/HYPOTHESIS: Inflammation in obesity increases the levels of the suppressor of cytokine signalling-3 (SOCS3) protein in adipose tissue, but the physiological importance of this protein in regulating whole-body insulin sensitivity in obesity is not known. METHODS: We generated Socs3 floxed (wild-type, WT) and Socs3 aP2 (also known as Fabp4)-Cre null (Socs3 AKO) mice. Mice were maintained on either a regular chow or a high-fat diet (HFD) for 16 weeks during which time body mass, adiposity, glucose homeostasis and insulin sensitivity were assessed. RESULTS: The HFD increased SOCS3 levels in adipose tissue of WT but not Socs3 AKO mice. WT and Socs3 AKO mice had similar body mass and adiposity, assessed using computed tomography (CT) imaging, irrespective of diet or sex. On a control chow diet there were no differences in insulin sensitivity or glucose tolerance. When fed a HFD, female but not male Socs3 AKO mice had improved glucose tolerance as well as lower fasting glucose and insulin levels compared with WT littermates. Hyperinsulinaemic-euglycaemic clamps and positron emission tomography (PET) imaging demonstrated that improved insulin sensitivity was due to elevated adipose tissue glucose uptake. Increased insulin-stimulated glucose uptake in adipose tissue was associated with enhanced levels and activating phosphorylation of insulin receptor substrate-1 (IRS1). CONCLUSIONS/INTERPRETATION: These data demonstrate that inhibiting SOCS3 production in adipose tissue of female mice is effective for improving whole-body insulin sensitivity in obesity.

MRI and PET studies of manganese-intoxicated monkeys.

Using MRI and PET, we investigated the consequences of manganese intoxication in a primate model of parkinsonism and dystonia. Three rhesus monkeys were injected intravenously with doses of 10 to 14 mg/kg of MnCl2 on seven occasions, each a week apart. Two animals became hypoactive with abnormal extended posturing in the hind limbs. These motor disturbances did not improve with administration of levodopa. In all three monkeys, T1-weighted MRI demonstrated high signal intensities in the regions of the striatum, globus pallidus, and substantia nigra. No significant changes were found on [18F]6-fluoro-L-dopa, [11C]raclopride, or [18F]fluorodeoxyglucose PET. These results are consistent with the pathologic findings, which were primarily confined to the globus pallidus, and indicate that manganese intoxication is associated with preservation of the nigrostriatal dopaminergic pathway, despite clinical evidence of parkinsonian deficits. Chronic manganese intoxication may cause parkinsonism by damaging output pathways downstream to the nigrostriatal dopaminergic pathway. This is consistent with the demonstrated lack of therapeutic response to levodopa.

Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study.

We gave three adult rhesus monkeys seven IV injections of manganese chloride at approximately 1-week intervals. We evaluated neurologic status by serial clinical examinations and performed a levodopa test if the animal developed features of basal ganglia dysfunction. After the animals were killed, we performed neuropathologic, neurochemical, and laser microprobe mass analysis (LAMMA) studies. Two of three animals developed a parkinsonian syndrome characterized by bradykinesia, rigidity, and facial grimacing suggestive of dystonia but not tremor. Neither animal responded to levodopa. Autopsy demonstrated gliosis primarily confined to the globus pallidus (GP) and the substantia nigra pars reticularis (SNr). We detected focal mineral deposits throughout the GP and SNr, particularly in a perivascular distribution. LAMMA studies noted that mineral deposits were primarily comprised of iron and aluminum. The severity of pathologic change correlated with the degree of clinical dysfunction. These studies demonstrate that, in contrast to Parkinson's disease (PD) and MPTP-induced parkinsonism, manganese primarily damages the GP and SNr and relatively spares the nigrostriatal dopaminergic system. Further, the results suggest that Mn-induced parkinsonism can be differentiated from PD and MPTP-induced parkinsonism by the clinical syndrome and response to levodopa. The accumulation of iron and aluminum suggests that iron/aluminum-induced oxidant stress may contribute to the damage associated with Mn toxicity.

The reproducibility of striatal uptake data obtained with positron emission tomography and fluorine-18-L-6-fluorodopa tracer in non-human primates.

Cynomolgus and rhesus monkeys have been studied via PET with [18F]-L-6 fluorodopa tracer. Striatal fluorodopa uptake rate constants have been derived by graphical analysis of transaxial slice images centered on the striata. The differences between pairs of values of the rate constant, obtained from two scans on the same monkey separated by two weeks or more, exhibited a relative standard deviation of 34.4%. If the two scans were conducted one immediately after the other, with the position of the monkey undisturbed, the standard deviation was reduced to 14.0%. The utility of this technique was demonstrated by comparing the effects on the scans of halothane and pentobarbital anesthesia and by the administration of NSD 1015, a peripheral and central inhibitor of L-aromatic amino-acid decarboxylase, between back-to-back scans. With NSD 1015, the fluorodopa uptake constant was reduced by an average of 76.0%.

Routes of administration and effect of carbidopa pretreatment on 6-[18F]fluoro-L-dopa/PET scans in non-human primates.

In 6-[18F]fluoro-L-dopa (Fdopa)/positron emission tomography (PET) studies, carbidopa pretreatment increases the Fdopa bioavailability to the brain and enhances the intensity of striatal PET images. Different PET research teams have used various carbidopa doses and routes of administration in non-human primate studies. The purpose of this study was to examine the plasma profiles of carbidopa and the effect of the route of administration of carbidopa on a Fdopa/PET scan. Cynomolgus monkeys were given carbidopa either orally (5 mg/kg), intraperitoneally (2.5 and 5 mg/kg) or intravenously (5 mg/kg) 60-90 min prior to the Fdopa injection. Carbidopa-treated monkeys were compared to monkeys without carbidopa treatment. No carbidopa was detected in the plasma samples when it was given orally, possibly due to poor absorption in the gastrointestinal tract. In addition, the striatal and cortical activities were not statistically different from those of the untreated monkeys, indicating that little or no inhibition of the peripheral decarboxylation of Fdopa by carbidopa had taken place. When carbidopa was given intraperitoneally at a dose of 2.5 and 5 mg/kg and intravenously at 5 mg/kg, plasma carbidopa concentrations at the time of Fdopa injection were 0.95 +/- 0.26, 2.22 +/- 0.23 and 2.79 +/- 0.26 micrograms/ml, respectively. Because of inhibition of peripheral decarboxylation of Fdopa by carbidopa, more Fdopa was available for transport into the brain and as a result, both the striatal and cortical activities were significantly higher than those of the untreated monkeys. Carbidopa administration had no effect on either the striatal-to-cortical activity ratio or the striatum uptake value.

Routine determination of [18F]-L-6-fluorodopa and its metabolites in blood plasma is essential for accurate positron emission tomography studies.

A batch-contact alumina-extraction method has been used to separate [18F]-L-6-fluorodopa (FD) from its principal metabolite, 3-O-methyl-[18F]-6-fluorodopa (3-OMe-FD), in arterial blood plasma samples collected from subjects pretreated with carbidopa during positron emission tomography (PET) scans. The time course of the metabolite-corrected blood plasma activity is then used as an input function for kinetic analysis of striatal FD uptake. Results obtained from using the batch-contact alumina-extraction method were compared with those from high performance liquid chromatography, and also with those from a chromatographic alumina cartridge technique developed in this laboratory. In 60 human subjects including normal healthy volunteers and patients diagnosed as having a movement disorder, arterial blood plasma samples were collected after FD injection during a two-hour PET scan and analyzed by the batch-contact alumina-extraction method. The activity ratio (metabolites/FD) increased linearly with time for all subjects. However, there was a wide variation in the slope of the plot of the activity ratio (metabolites/FD) versus time among the subjects. No significant linear or curved relationship was observed between the slope and the age of the subject. Separation of FD from its metabolites is therefore necessary for each PET-FD study conducted.

The transport of L-6-fluorodopa and its metabolites from blood to cerebrospinal fluid and brain.

The transport of L-6-fluorodopa and its major metabolites from the blood to the brain, cerebrospinal fluid (CSF), and muscle was studied in carbidopa-pretreated cynomolgus monkeys. A bolus intravenous injection of 18F-L-6-fluorodopa was followed by serial positron emission tomography scans and sampling of cisternal CSF and arterial blood. The relative concentrations of L-6-fluorodopa and its metabolites were determined in blood plasma and CSF by high-performance liquid chromatography. Raising the blood concentration of phenylalanine by intraperitoneal injection markedly reduced the accumulation of tracer in the brain. This indicates that L-6-fluorodopa and 3-O-methylfluorodopa, like native L-dopa and its O-methylated derivative, are transported at the brain capillary by the large neutral amino acid carrier-mediated system, which is subject to saturation and competition by other large neutral amino acids (such as phenylalanine) at physiological plasma concentrations. In contrast, administration of phenylalanine had no effect on the accumulation of tracer either in muscle, or as L-6-fluorodopa and 3-O-methylfluorodopa, in CSF. This suggests that the transport of L-dopa and its derivatives at the blood-CSF barrier differs from the transport at the blood-brain barrier and also that measurement of CSF L-dopa is not a good index of the transport and pharmacokinetics of L-dopa in the brain. However, the effect of phenylalanine administration in reducing the concentration of fluorohomovanillic acid in the CSF suggests that the concentration of homovanillic acid in the CSF is an accurate reflection of dopamine turnover in the brain.

Correlation of striatal fluorodopa uptake in the MPTP monkey with dopaminergic indices.

Striatal 18F-6-fluorodopa (FD) uptake constants were measured by positron emission tomography in (1) normal cynomolgus monkeys and (2) a series of cynomolgus and rhesus monkeys that had received intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After the animals were killed, the number and average size of dopaminergic neurons in the substantia nigra pars compacta were measured. Striatal levels of dopamine and its metabolites, and the striatal activities of the dopaminergic synthetic enzymes, were also determined. The striatal FD uptake constants showed highly significant positive correlations with both number and size of dopaminergic neurons, indicating atrophy of surviving neurons in MPTP-treated animals. The uptake constants also showed significant positive correlations with striatal levels of dopamine, total catecholamines, and the activities of the synthetic enzymes. Both histochemical and biochemical data on tyrosine hydroxylase suggested some contralateral enzyme loss in these MPTP-treated monkeys, as well as decreased enzyme activity in surviving neurons on the lesioned side. However, residual enzyme activities were apparently not rate limiting to striatal FD uptake. It is concluded that PET-FD measurements by positron emission tomography provide a good index of the integrity of the nigrostriatal pathway.