A qualitative investigation of recovery after femoral fracture in Rett syndrome.

BACKGROUND: Children with severe disability often develop osteoporosis and have an increased risk of fracture. In Rett syndrome, the prevalence of fracture is four times greater than in the general population, and the femur is commonly affected. This study used qualitative methods to investigate the regaining of mobility within 12 months following femoral fracture in Rett syndrome and parent caregiver experiences. METHODS: Caregivers (n = 14) of cases registered with the Australian Rett Syndrome Database with a daughter with Rett syndrome were recruited if their daughter sustained a femoral fracture between 2009 and 2014. Median (interquartile range) age at fracture was 11 years and 4 months (8 years and 8 months to 22 years and 3 months). Qualitative methods were used to investigate parent/caregiver experiences and their daughter's recovery following fracture. Themes in the interview data were identified with thematic analysis. RESULTS: Operative management was chosen for those walking independently and non-operative management for most of the remaining. All who walked independently and one of the four who required assistance recovered pre-operative walking skills within 6 months. Themes identified by caregivers related to the complexities of pain recognition, the caregiver emotional journey and later rebuilding of relationships with service providers. CONCLUSIONS: Those who walked with assistance were vulnerable to loss of this skill. Difficulties in pain recognition increased time to diagnose fracture, and the acute episode was associated with heightened caregiver stress. Service providers can use family-centred practice models to support the strengthening of family functioning following this acute event that is surprisingly common in those with severe disability.

Fungal respiration: a fusion of standard and alternative components.

In animals, electron transfer from NADH to molecular oxygen proceeds via large respiratory complexes in a linear respiratory chain. In contrast, most fungi utilise branched respiratory chains. These consist of alternative NADH dehydrogenases, which catalyse rotenone insensitive oxidation of matrix NADH or enable cytoplasmic NADH to be used directly. Many also contain an alternative oxidase that probably accepts electrons directly from ubiquinol. A few fungi lack Complex I. Although the alternative components are non-energy conserving, their organisation within the fungal electron transfer chain ensures that the transfer of electrons from NADH to molecular oxygen is generally coupled to proton translocation through at least one site. The alternative oxidase enables respiration to continue in the presence of inhibitors for ubiquinol:cytochrome c oxidoreductase and cytochrome c oxidase. This may be particularly important for fungal pathogens, since host defence mechanisms often involve nitric oxide, which, whilst being a potent inhibitor of cytochrome c oxidase, has no inhibitory effect on alternative oxidase. Alternative NADH dehydrogenases may avoid the active oxygen production associated with Complex I. The expression and activity regulation of alternative components responds to factors ranging from oxidative stress to the stage of fungal development.

The effect of sildenafil on gastric emptying in patients with end-stage renal failure and symptoms of gastroparesis.

BACKGROUND: Delayed gastric emptying is a common disorder among patients with end-stage renal failure (ESRF). Pyloric relaxation, a major determinant of gastric emptying, is a nitric oxide (NO)-mediated process. NO-induced smooth muscle relaxation is mediated through its second messenger cyclic guanosine monophosphate, which is broken by tissue phosphodiesterases (PDEs). Thus the inhibition of cyclic guanosine monophosphate breakdown by PDE inhibitors can potentiate NO-mediated responses and facilitate pyloric relaxation. In an animal model of diabetes mellitus, treatment with sildenafil (a PDE-5 inhibitor) restored NO-mediated pyloric relaxation and improved gastric emptying. The aim of our study was to examine the hypothesis that sildenafil may improve gastric emptying in patients with ESRF and symptoms of gastric paresis. METHODS: We studied 12 patients with ESRF (6 men; age range, 54-80 years; 5 with diabetic nephropathy; 4 +/- 1 years receiving long-term renal replacement therapy) after either placebo or a 25-mg tablet of sildenafil (Viagra; Pfizer Inc). Gastric emptying of a solid meal (one medium-sized fried egg mixed with 37 MBq [1 mCi] technetium Tc 99m phytate plus 1 slice of bread and 150 mL of water at the end of the meal) was assessed 1 hour after dosing by use of a single-headed camera. Images were acquired every 30 seconds for 90 minutes immediately after patients ate. RESULTS: The gastric emptying rate was decreased at baseline (after placebo), to 33% +/- 6% (normal, > or =50%). Treatment with sildenafil had no effect on gastric emptying rates after 90 minutes (from 33% +/- 6% after placebo to 30% +/- 6% after sildenafil, P =.9). CONCLUSIONS: Sildenafil did not improve gastric emptying in patients with ESRF and gastric paresis. Sildenafil may have opposing effects on gastric peristalsis (causing gastric relaxation) compared with its effects on pyloric relaxation. Studies combining sildenafil with prokinetic drugs are of interest.

Altered P450 activity associated with direct selection for fungal azole resistance.

Azole antifungals inhibit CYP51A1-mediated sterol 14 alpha-demethylation and the mechanism(s) of resistance to such compounds in Ustilago maydis were examined. The inhibition of growth was correlated with the accumulation of the substrate, 24-methylene-24,25-dihydrolanosterol (eburicol), and depletion of ergosterol. Mutants overcoming the effect of azole antifungal treatment exhibited a unique phenotype with leaky CYP51A1 activity which was resistant to inhibition. The results demonstrate that alterations at the level of inhibitor binding to the target site can produce azole resistance. Similar changes may account for fungal azole resistance phenomena in agriculture, and also in medicine where resistance has become a problem in immunocompromised patients suffering from AIDS.

New sequence data enable modelling of the fungal alternative oxidase and explain an absence of regulation by pyruvate.

Respiratory rates involving the alternative oxidase (AO) were studied in mitochondria from Tapesia acuformis. There was no evidence for regulation by pyruvate, in contrast with plant AO. The site of interaction of pyruvate with the plant AO is a conserved cysteine. The primary sequence was obtained for AO from Magnaporthe grisea and compared with four published sequences for fungal AO. In all cases this cysteine was absent. Sequence data were obtained for the C-terminal domain of a further five fungal AOs. In this region the fungal sequences were all consistent with a four-helix, di-iron binding structure as in the ferritin-fold family. A molecular model of this domain was deduced from the structure of Delta-9 desaturase. This is in general agreement with that developed for plant AOs, despite very low sequence identity between the two kingdoms. Further modelling indicated an appropriate active site for binding of ubiquinol, required in the AO redox reaction.

Uptake of iodine-123 MIBG by pheochromocytomas, paragangliomas, and neuroblastomas: a histopathological comparison.

The percentage uptake of [123I]metaiodobenzylguanidine (MIBG) by tumors of the paraganglion system is compared with the number of neurosecretory granules (assessed by both light and electron microscopy) in the subsequently resected tumors in six patients. Iodine-123 MIBG was injected intravenously; the tumor uptake of [123I]MIBG varied between 0.001% and 0.14% of the injected dose per gram of tumor tissue at 22 hr. The number of neurosecretory granules in tissue sections was scored on a scale of I-III. A direct proportional correlation was found between the percentage uptake of [123I]MIBG by the tumor and the number of neurosecretory granules in the tissue sections but not with plasma or urinary catecholamines. This technique for imaging reflects the storage status of the tumor better than plasma and urinary catecholamine measurements.

Quantitation of iodine-123 MIBG uptake by normal adrenal medulla in hypertensive patients.

Eighteen hypertensive patients with a clinical suspicion of pheochromocytoma and raised or borderline raised plasma catecholamine and urinary vanillyl mandelic acid (VMA) levels were studied by scintigraphy using 123I-labeled metaiodobenzylguanidine (MIBG). None of these patients had any scintigraphic evidence of pheochromocytoma at the time of study or on subsequent clinical follow-up. A quantitative approach was taken to calculate the adrenal medullary uptake of [123I]MIBG in these patients. Three different methods of quantitation were evaluated using data acquired from an anthropomorphic phantom and analysed by three independent observers. In the patient studies 34 out of 35 adrenal medullas were visualized with uptake in the range of 0.01-0.22% of the administered dose 22 hr postinjection which was calculated using the preferred quantitation method. This is an appropriate control group range for comparison with patients who have proven norepinephrine and epinephrine secreting tumors. A quantitative approach to [123I]MIBG imaging provides an important tool for studying adrenomedullary pathophysiology.

Maternal effort and male quality in the bank vole, Clethrionomys glareolus.

Parental investment in reproduction is adjusted according to potential benefits in terms of offspring survival and/or mating success. If male quality affects the reproductive success of a female, then females mating with high-quality males should invest more in reproduction. Although the subject has been of general interest, further experimental verification of the hypothesis is needed. We studied whether female bank voles (Clethrionomys glareolus) adjusted their maternal effort according to male quality, measured as mating success. To enable the measurement of maternal effort during nursing separately from male genetic effects the litters were cross-fostered. Further, the genetic background of male quality was examined. Male quality did not correlate with litter size or offspring size at birth. Offspring growth was positively related to food consumption and milk production of mothers. However, these direct measurements of maternal effort were independent of male quality. Male mating success appeared to be significantly heritable indicating that there are genetic benefits. Still, females did not adjust maternal effort according to the genetic quality of their offspring. We suggest that female bank voles gain significant genetic benefits from mating with high-quality males whereas they cannot improve their reproductive success by increasing maternal effort.

Molecular mechanisms of azole resistance in fungi.

This paper reviews the current status of our understanding of azole antifungal resistance mechanisms at the molecular level and explores their implications. Extensive biochemical studies have highlighted a significant diversity in mechanisms conferring resistance to azoles, which include alterations in sterol biosynthesis, target site, uptake and efflux. In stark contrast, few examples document the molecular basis of azole resistance. Those that do refer almost exclusively to mechanisms in laboratory mutants, with the exception of the role of multi-drug resistance proteins in clinical isolates of Candida albicans. It is clear that the technologies required to examine and define azole resistance mechanisms at the molecular level exist, but research appears distinctly lacking in this most important area.

Defective sterol delta 5(6) desaturase as a cause of azole resistance in Ustilago maydis.

Resistance to azole antifungals in Ustilago maydis was associated with a leaky defect in sterol delta 5(6)desaturase. This defect resulted in reduced accumulation of 14 alpha-methylergosta-24(28)-diene-3 beta,6 alpha-diol and an increase in the proportion of 14 alpha-methylfecosterol in treated cells when compared to the parent strain. The results demonstrate the importance of this mechanism in pathogenic fungi.

Nonsterol related resistance in Ustilago maydis to the polyene antifungals, amphotericin B and nystatin.

Two amphotericin B resistant mutants of Ustilago maydis were isolated following direct selection from a wild-type population. Each mutant was demonstrated to be cross-resistant to nystatin yet remained sensitive to azoles. Sterol analysis indicated a sterol profile similar to the parent strain, precluding the involvement of an alteration in ergosterol biosynthesis as the cause of polyene resistance.

Lateral neck imaging for spatial localization of parathyroid tissue.

Two patients with an ectopic parathyroid adenoma are described. In both cases the lesions were clearly demonstrated in an anterior view on T1-201/Tc-99m scintigraphy, but were not identified during the first surgical exploration. Failure to identify the ectopic adenoma at surgery in the second patient led to oblique and lateral views being obtained. These views permitted correct depth localization. We, therefore, believe that lateral and oblique views can be of assistance in improving preoperative localization of an ectopic parathyroid adenoma.

Coma due to hypercalcemia in a patient with Paget's disease and multiple parathyroid adenomata.

A patient with histologically proven coexistent Paget's disease of the bone and parathyroid adenomatosis is described. She developed coma associated with hypercalcemia and underwent successfully surgical removal of two parathyroid adenomata. The differential diagnosis of hypercalcemia in patients with this rare association is discussed and the importance of early surgical treatment is stressed. A review of similar reported case is presented.

Cerebral blood flow in hypertensive patients with cerebrovascular disease: technique for measurement and effect of captopril.

Nineteen patients with unilateral cerebrovascular disease underwent cerebral blood flow (CBF) measurements; ten had been receiving conventional therapy and then were studied after treatment with captopril without or with a diuretic and nine on conventional therapy were studied twice as a control group. CBF (ml min-1) was measured after an intravenous injection of 99Tcm-labelled patient's red cells with a computer linked gamma camera over the vertex and a probe over the aorta. With deconvolution analysis regional CBF is given by regional cerebral volume divided by regional mean transit time. Results in the captopril group showed on average a 10% fall in mean blood pressure and a 10% rise in blood flow to the affected hemisphere. In the control group there was on average a 4% fall in pressure, together with an 11% fall in CBF to the affected hemisphere. Captopril appears to maintain autoregulation in cerebrovascular disease.

99Tc(m)-tetrofosmin scintimammography for detecting breast cancer: a comparative study with 99Tc(m)-MIBI.

Scintimammography using 99Tc(m)-MIBI (99Tc(m)-sestamibi) has demonstrated promising results in the detection of breast cancer. Recently scintimammography using 99Tc(m)-tetrofosmin has been suggested as a better diagnostic tool and a more convenient agent to use in this condition. In this study we compared both agents in 35 consecutive women with abnormal mammographic or physical findings. Thirty-four of them underwent MIBI scan, followed by tetrofosmin scan 2 days later (performed on all 35 women). Within 2 weeks, a pathological diagnosis was obtained either by needle or open biopsy. In both scans the uptake ratio between the lesion and the background uptake was calculated. Twenty patients who underwent tetrofosmin scan and 19 patients with MIBI scan had malignant breast tumours, while 15 women had benign lesions. The sensitivity, specificity, positive and negative predictive values and total accuracy of the MIBI scan were 89.4%, 80%, 85%, 85.7% and 85.3%, respectively; almost identical values were obtained with tetrofosmin (90%, 80%, 85.6%, 85.7% and 85.7%, respectively). The uptake ratios in the MIBI and tetrofosmin scans were 1.68 +/- 0.52 and 1.7 +/- 0.47, respectively. No differences were found between the two scintimammographies in all the parameters examined. In conclusion, MIBI and tetrofosmin breast scans are accurate and equally efficient for the detection of breast malignancies.

99Tcm-MIBI scintimammography for the detection of breast malignancies: the contribution of the count ratio to specificity.

We evaluated the efficacy of 99Tcm-sestamibi (MIBI) scintimammography for the detection of breast cancer in 332 patients. Two hundred and seven scans were confirmed by histological or cytological results; the other patients were examined because they belonged to high-risk groups or had dense fibroglandular breasts. Of 207 patients with histological confirmation, 112 positive studies were obtained: 86 true-positive and 26 false-positive. Scintimammography was negative in 95 patients: 88 true-negative and seven false-negative. Six of seven false-negative results were obtained in patients with impalpable tumours. The sensitivity, specificity, positive and negative predictive values were 92.5%, 77.2%, 76.8% and 92.6% respectively. The overall accuracy was 84.1%. To identify false-positive results, the count ratio of the target lesion to the contralateral normal area on 38 true-positive scans and in 26 false-positive examinations was calculated from the region of interest drawn on the 99Tcm-MIBI scan (L/N ratio). A significantly higher ratio was found for the true-positive scans (1.583 +/- 0.501 vs 1.246 +/- 0.213; P = 0.0002). In conclusion, 99Tcm-MIBI scintimammography is a sensitive and accurate method for the detection of breast malignancies.

Imaging of phaeochromocytoma and adrenal medulla with 123I-meta-iodobenzyl guanidine.

A method for preparing meta-iodobenzyl guanidine (MIBG) labelled with 123I is described. This compound clearly imaged the normal adrenal medulla in seven out of eight patients with hypertension. The sites of metastases were demonstrated in two patients with malignant phaeochromocytoma.

Hyperostosis corticalis generalisata: surgical management and long-term follow-up of one patient.

A 24-year-old woman presented for treatment of her distorted facial appearance. She showed marked widening of the face and skull, which had first become noticeable in childhood. Significant thickening of the cortical bone was seen radiographically throughout the skeleton. Routine laboratory and endocrinological tests showed normal results. These findings, together with a family history of bone disorder, led to the diagnosis of hyperostosis corticalis generalisata. The lower border of the mandible was resected, resulting in improved facial appearance. During the 8-year follow-up, no changes were seen with regard to the mandible.

Predictors of physical activity intentions and behaviour for rural homemakers.

This research combined social psychological theory testing with the practical concern of gathering information useful for the social marketing of active living. The study examined variables related to the intentions and behaviour of rural homemakers with respect to moderate physical activity, using the theory of planned behaviour as a framework. Rural homemakers (n = 630) in four Alberta communities were surveyed by telephone concerning their attitudes, self-efficacy, perceived social support, intentions, and present activity behaviour. Intentions, self-efficacy, and various beliefs related to barriers and social support discriminated active from inactive homemakers. For active homemakers (n = 473), attitude, perceived social support, and self-efficacy predicted future intentions. For inactive homemakers (n = 157), only attitude and self-efficacy predicted intentions. The practical implications of the findings are discussed, in terms of fostering enjoyable experiences, reducing barriers, and providing supportive environments.

The role of morphine-augmented cholescintigraphy and real-time ultrasound in detecting gallbladder disease.

OBJECTIVE: Rapid diagnosis of acute cholecystitis is essential to minimize morbidity and mortality. The purpose of this study was to assess the diagnostic utility of cholescintigraphy using morphine augmentation compared with ultrasound, in acute and chronic gallbladder disease. METHODS: Cholescintigrams were performed on 103 patients suspected of having acute cholecystitis. In 79 patients (Group A) morphine sulfate was administered to reduce the scintigraphic imaging time if the gallbladder was not visualized during the first hour. In 24 control patients (Group B) no morphine was administered. All patients were evaluated clinically and 93 patients had concurrent ultrasound examination. RESULTS: The clinical presentation was nonspecific. The ultrasound findings were sensitive in detecting gallbladder disease (100%), but had low specificity (24%). Only findings of sediments and pericholecystic fluid were specific for cystic duct obstruction. Morphine augmentation reduced the imaging time by 126 min in patients with chronic cholecystitis. CONCLUSION: Real-time ultrasound has low specificity for gallbladder disease. In the presence of an abnormal ultrasound, it is essential to perform a hepatobiliary scan, either to exclude gallbladder disease or distinguish acute from chronic cholecystitis. Low-dose morphine administration is a safe and useful adjunct to standard cholescintigraphy by substantially reducing the time required to obtain a diagnostic study.