Intravenous bisphosphonate therapy in children with spinal muscular atrophy.

This is the first report on safety and efficacy of intravenous bisphosphonates (IV BP) for treatment of disuse osteoporosis and low bone mineral density (BMD) in children with spinal muscular atrophy (SMA). IV BP appears to be safe and effective in fracture rate reduction. However, caution is necessary given the occurrence of an atypical femur fracture. INTRODUCTION: Children with SMA are at high risk for fragility fractures and low BMD. IV BP have been used for treatment of disuse osteoporosis in pediatrics. However, safety and efficacy of IV BP in the SMA population has not been reported. METHODS: Retrospective chart review of IV BP for treatment of disuse osteoporosis and low BMD in children with SMA at a tertiary pediatric center from 2010 to 2018 RESULTS: Eight patients (50% female; 75% SMA type 1; median age at first infusion 6.7 years) receiving a total of 39 infusions (54% pamidronate, 46% zoledronic acid) were included in this report. Acute phase reactions occurred following 38% and 3% of initial and subsequent infusions, respectively. BMD trended toward improvement at 1 year post-treatment. Among six patients who had > 2 years of follow-up, fracture rate decreased from 1.4 to 0.1 fracture/year. An atypical femur fracture was observed in one patient. CONCLUSION: These findings suggest that in children with SMA, IV BP therapy appears to be safe with minimal acute side effects and effective to reduce fracture rate. Caution is still needed given the occurrence of an atypical femur fracture in SMA population.

Elevated levels of plasma C-reactive protein are associated with decreased graft survival in cardiac transplant recipients.

BACKGROUND: Inflammation may be involved in the origin of transplant coronary artery disease. We hypothesized that plasma levels of C-reactive protein (CRP) and interleukin-6 (IL-6), markers for systemic inflammation, would correlate with cardiac transplant graft survival. METHODS AND RESULTS: We studied 99 consecutive cardiac transplant recipients who were referred for routine endomyocardial biopsy and/or surveillance coronary angiography. Plasma levels of CRP and IL-6 were measured by their respective ELISAs. Patients were divided into 2 groups: those who died or required retransplantation and those who survived without the need for retransplantation. During the follow-up period of 5.0+/-2.7 years (range, 0.2 to 15.1 years) after transplant, 20 patients died and 9 required retransplantation. There was no significant difference in age, race, sex, cause of native myopathy, presence of diabetes, or use of aspirin, statins, or calcium channel blockers between the 2 groups. Although IL-6 did not relate to graft failure, CRP level was predictive of allograft failure (P:=0.003). The risk of allograft failure increased 36% for every 2-fold increase in CRP level. Moreover, CRP levels also correlated significantly with the frequency of grade 3 rejection (P:=0.02). In multivariate analysis, when combined with other significant predictors such as donor age and sex mismatching of the graft, CRP still significantly predicted graft failure (P:=0.025) with a 32% increase in the risk of graft failure for every 2-fold increase in CRP level. CONCLUSIONS: These findings suggest that elevated plasma levels of CRP are associated with subsequent allograft failure in cardiac transplant recipients.

Biodistribution of 131I-radiolabelled plasma low density lipoprotein in hyperlipidaemic vervet monkeys.

Low density lipoprotein (LDL) labelled with 131I has been administered to 6 Vervets 2 of which were high responders to an atherogenic Western diet in terms of plasma cholesterol, 2 were low responders and 2 were fed a high carbohydrate control diet. The ratio of hepatic to cardiac activity was recorded for up to 10 days after administration of the labelled LDL. Liver activity had a longer biological half life in the high-responders and this can be interpreted in terms of a variation of hepatic metabolism of LDL, with direct relevance to the human situation.

Plasma levels of tissue plasminogen activator and plasminogen activator inhibitor-1 are correlated with the presence of transplant coronary artery disease in cardiac transplant recipients.

Hemostatic factors are involved in the pathogenesis of native coronary artery disease. However, their role in transplant coronary artery disease is less established. To assess the role of hemostatic factors in transplant coronary artery disease we studied 52 consecutive cardiac transplant patients. The presence of transplant coronary artery disease was determined by angiography. Plasma levels of tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), von Willebrand Factor (vWF), and fibrin D-dimer were determined by enzyme-linked immunosorbent assays. Serum lipids were measured by enzymatic methods. Patients with transplant coronary artery disease had higher circulating t-PA (8.6 +/- 0.8 vs. 5.4 +/- 0.6 ng/ml, p = 0.021) and PAI-1 antigen concentrations (38.0 +/- 3.4 vs 25.8 +/- 2.2 ng/ml, p = 0.037). t-PA and PAI-1 antigen concentrations correlated with the severity of angiographic disease (R = 0.34; p = 0.014 for t-PA, and R = 0.45; p = 0.001 for PAI-1). Serum cholesterol levels were higher in patients with transplant coronary artery disease (221 +/- 7.6 vs 191 +/- 9.2 mg/dl, p = 0.039). Serum triglycerides were also higher in patients with transplant coronary artery disease by angiography (246 +/- 38.3 vs 139 +/- 20.8 mg/dl, p = 0.050). Multivariate analysis identified t-PA antigen (p = 0.003) and triglyceride levels (p = 0.038) as independent predictors for the presence of transplant coronary artery disease. We conclude that cardiac transplant patients with evidence of transplant coronary artery disease on coronary angiography have altered hemostatic function which is reflected by elevated levels of circulating t-PA and PAI-1 antigens. The interaction of the hemostatic system and serum lipids in the development of transplant coronary artery disease warrants further study.

Elevated plasma tissue plasminogen activator and anti-THP-1 antibodies are independently associated with decreased graft survival in cardiac transplant recipients.

Hemostatic and immunologic factors have been implicated in future cardiac events in patients with coronary artery disease. The role of these factors and their interaction is less established in cardiac transplant recipients. We sought to characterize the role of these factors in these patients. Cardiac transplant patients who presented for surveillance coronary angiography and/or endomyocardial biopsy were eligible for enrollment. Ninety-nine consecutive patients were enrolled. Plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1, von Willebrand factor, fibrin D-dimer, and anti-t-PA antibody were determined by enzyme-linked immunosorbent assays. Anti-THP-1 cell antibodies directed against a monocytic leukemia cell line were detected by incubating patient plasma with THP-1 cells. Bound antibody was detected using goat peroxidase-labeled immunoglobulin G directed against human immunoglobulins. Lipids were measured by enzymatic methods. Multivariate analysis identified the presence of anti-THP-1 cell antibodies (risk ratio 4.41, p = 0.002), t-PA antigen (risk ratio 1.10, p = 0.033), donor age 20 to 26 years (risk ratio 8.83, p = 0.042), and donor age >36 years (risk ratio 15.53, p = 0.009) as predictors of allograft failure. Altered hemostatic function, as demonstrated by elevated plasma t-PA antigen levels, is predictive of subsequent allograft failure in cardiac transplant recipients. In addition, the presence of anti-THP-1 cell antibodies in these patients is predictive of allograft failure.

Reversible and potent uncoupling of hog gastric (H(+)+K(+))-ATPase by prodigiosins.

Prodigiosin, prodigiosin 25-C, and metacycloprodigiosin all strongly inhibited the acidification activity of (H(+)+K(+))-ATPase on membrane vesicles from hog gastric mucosa (IC(50) = 32 to 103 pmol/mg protein). But, the prodigiosins, unlike omeprazole, showed little inhibitory effect on K(+)-dependent ATPase (K(+)-ATPase) activity, although at higher concentrations they inhibited K(+)-ATPase activity with an IC(50) of 1.5 to 3.0 microM. Furthermore, the inhibitory effect of the prodigiosins was rapid and completely reversible unlike that of omeprazole, and the mode of inhibition was non-competitive with respect to ATP. Hog gastric (H(+)+K(+))-ATPase itself showed an absolute requirement of halide (effectively, chloride) for acidification activity. Prodigiosins also showed a chloride requirement for inhibition of vesicular acidification, and quickly reversed the acidification of vesicular pH to neutrality even in the presence of N, N'-dicyclohexylcarbodiimide (DCCD), showing their ionophoric nature of acidification inhibitory activity. In fact, tributyltin chloride (TBT, an OH(-)/Cl(-) exchange ionophore) also inhibited vesicular acidification, but it inhibited K(+)-ATPase activity too. Finally, the prodigiosins inhibited the acid secretion from parietal cells isolated from rabbit gastric mucosa. These results suggest that prodigiosins are potent reversible uncouplers of (H(+)+K(+))-ATPase that inhibit gastric acid secretion.

Disseminated Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome.

Pneumocystis carinii, a frequent cause of pneumonia in immunocompromised patients, rarely disseminates to involve other organs. This report describes a patient with acquired immunodeficiency syndrome and pneumocystis pneumonia in whom extrapulmonary P. carinii infection was diagnosed on duodenal and esophageal endoscopic biopsy specimens. Autopsy revealed dissemination to multiple organs.

Prodigiosins uncouple mitochondrial and bacterial F-ATPases: evidence for their H+/Cl- symport activity.

Prodigiosin, metacycloprodigiosin, and prodigiosin 25-C all inhibited the acidification activity of submitochondrial and bacterial (Escherichia coli) F-ATPases (FoF1-ATPases) strongly (IC50 = 20-30 and 24-30 pmol/mg protein, respectively), without affecting significantly the ATP hydrolysis activity. Their effect on the acidification activity was rapid and reversible, showing non-competitive apparent Ki values of the order of nM to sub-nM. However, unlike FCCP (an ordinary uncoupler of oxidative phosphorylation), they showed no protonophoric activity, as demonstrated by the absence of acceleration of ATP hydrolysis. Prodigiosins also inhibited the acidification of proteoliposomes reconstituted from phospholipids and purified F-ATPase of E. coli, suggesting that their acidification-inhibitory effect is not due to the inhibition of anion channels. They did not, however, inhibit the ATP-dependent formation of membrane potential of F-ATPase vesicles. Furthermore, they inhibited and quickly reversed acidification by F-ATPase only in the presence of chloride, and not in the presence of gluconate anion. Finally, they induced swelling of liposomes and submitochondrial particles in isotonic solution of ammonium chloride but not ammonium gluconate, suggesting that intravesicular entry of Cl- is promoted by prodigiosins. These results suggest that prodigiosins uncouple F-ATPases through promotion of H+/Cl- symport (or OH-/Cl- exchange) across vesicular membranes.

Single photon emission computed tomography of the brain with Tc-99m HMPAO during sumatriptan challenge in obsessive-compulsive disorder: investigating the functional role of the serotonin auto-receptor.

1. Symptoms of obsessive-compulsive disorder (OCD) may be acutely exacerbated by administration of certain serotonin agonists Exacerbation of OCD symptoms by sumatriptan, a 5HT1D agonist (Zohar, 1993), is consistent with pre-clinical data suggesting that the serotonin auto-receptor plays an important role in this disorder (El Mansari et al, 1995). 2. In order to investigate the functional role of the serotonin auto-receptor in OCD, the authors undertook single photon emission computed tomography in OCD patients after administration of sumatriptan and placebo. The authors hypothesized that, as in the case of m-chlorophenylpiperazine (mCPP) challenge (Hollander et al, 1995), exacerbation of OCD symptoms would be accompanied by increased cortical metabolism and thus blood flow, and more specifically by increased activity in the orbitofrontal-striatal circuit. They also expected, that as in the case of mCPP challenge (Hollander et al, 1993), exacerbation of OCD symptoms would be associated with a relatively poor response to subsequent treatment with serotonin specific reuptake inhibitors. 3. Sumatriptan (100 mg orally) and placebo were administered on separate days to 14 patients who met DSM-IV diagnostic criteria for OCD, using a randomized double-blind design. After 90 minutes, patients were injected with Tc-99m HMPAO and underwent single photon emission computed tomography (SPECT) of the brain. Activity in regions of interest was calculated, and compared using repeated measures analysis of variance. Patients were subsequently treated with a serotonin specific reuptake inhibitor (SSRI). 4. Behavioral response to sumatriptan was heterogenous, with 4 patients showing acute exacerbation, and 4 patients demonstrating a decrease in symptoms. On sumatriptan challenge, there was a significant association between symptom exacerbation and decreased activity in frontal areas. There was an association between decreased activity in an inferior frontal area with worse response to treatment, and also patients with symptom exacerbation after sumatriptan had poorer response to SSRI treatment. 5. Heterogeneity of behavioral response to sumatriptan in OCD is consistent with previous studies demonstrating conflicting and heterogenous behavioral responses to serotonergic challenges (Hollander et al, 1992), and with underlying heterogeneity in the neurobiology of this disorder. 6. It may be hypothesized that increased frontal activity in some patients with OCD is itself a compensatory mechanism. In patients with such compensatory hyperactivity, administration of a serotonin auto-receptor agonist results in decreased frontal activity and exacerbation of OCD symptoms. These patients may also be less likely to respond to treatment with a SSRI. 7. Further work combining pharmacological challenge paradigms and functional imaging techniques in OCD may be helpful in elucidating the neurobiology of this complex disorder.

Temperature distributions obtained with diathermy electrodes implanted into a phantom.

Uniform patterns of heating in a homogeneous phantom were obtained by implanting shortwave diathermy electrodes in a particular configuration. The methods of heating and measurement are described. The technique can be considered for applying localized hyperthermia in the treatment of cancer.

Optimisation of density and contrast yielded by multiformat photographic imagers used for scintigraphy.

The maximum optical density (MOD) and contrast (characterised by an effective gamma, gamma eff) yielded by multiformat photographic imagers used for scintigraphy, was determined by densitometry of a computer image, which consisted of a pattern of uniform squares containing known counts. A series of clinical scintigrams were photographed using various MOD and gamma eff values, and were graded by three experienced clinicians. It was found that a MOD of 1.6 and a gamma eff of 2.9 yielded optimal images for general use if bone scintigrams are also to be photographed. Lesion detectability in phantom images using extreme MOD and gamma eff values that were still clinically acceptable was determined. At very low false-positive rates (less than or equal to 1%) the higher gamma eff yielded a significantly greater lesion detectability (p = 0.02) at an information density of 2200 counts cm-2 in accordance with White-head's theory. It is concluded that quantification and optimisation of density and contrast factors are important and that the technique described enables quality control of multiformat imagers with respect to these factors.

Clinical trial of plasma exchange with a membrane filter in treatment of crescentic glomerulonephritis.

Four patients with rapidly progressive crescentic glomerulonephritis were treated with repeated plasma exchanges, using a disposable plasma filter (PLASMAFLO), combined with immunosuppression and anticoagulation. A definite improvement of renal function was observed in two patients and complete recovery of the severe lung changes of Goodpasture's syndrome was seen in one of them. In another patient rapid progression of renal insufficiency was arrested. One patient with anuria at the start of treatment remained anuric. The filter was capable of removing as large a molecule as IgM, and the plasma concentrations of immunoglobulins and complement factors declined successively after each treatment. Plasma exchange with the filter technique is readily accessible and safe in hands of the hemodialysis staff. Easy availability and simplicity are important advantages over the centrifuge methods, considering that prompt commencement of the treatment is a key issue in success.

An improved technique for interstitial radiotherapy of the tongue.

An improvement of the plastic tube afterloading technique for interstitial radiotherapy of the tongue is described. This modification allows most of the work to be done outside the patient's mouth. The anchorage for the intra-oral ends of the polythene tubes is produced by transfixing then with a silk thread. This obvioates the need to form loops and simplifies afterloading. It provides a method for crossing the entire lingual end of the implant. All areas and volumes of lower jaw structures are accessible to this form of treatment. Removal of the implant, irrespective of position, is simple and rapid.

Determination of the partition coefficient of 133xenon between oral tissues and blood in the dog.

Ostwald solubility coefficients for 133Xe in plasma (Sp), red blood cells (Sc), and selected oral tissue homogenates (St) obtained from the dog were determined at 4, 20, 27 and 37 degrees C by counting the 133Xe activity of the air phase and the sample (liquid, red cells or tissue) in the same tube following equilibration. The partition coefficient for xenon (lambda, in ml/g) between red cells and plasma (lambda cp) and that between tissues and plasma (lambda tp) were calculated from the measured Sp, Sc and St. The tissue-blood partition coefficients (lambda tb) of oral tissues for 133Xe were then calculated using lambda cp, lambda tp and the haematocrit value. The calculated values of lambda tb at 37 degrees C and 50 per cent haematocrit were 0.650 for the pulp, 0.674 for the tongue, 0.828 for the submandibular gland and 0.881 for the gingiva of the dog. lambda cp increased and lambda tp decreased as the temperature was reduced from 37 to 4 degrees C.

Quantification of gamma camera spatial resolution by means of bar phantom images.

A method that has previously been described for rapid objective measurement of intrinsic gamma camera spatial resolution using statistical moments has been applied to images of a four-quadrant bar phantom acquired with various collimators. The full-width at half-maximum (FWHM) of the line spread function (LSF) and modulation transfer functions determined by the moments method was compared with those obtained directly from line spread functions. It was found that, for highest accuracy, the formulae originally described for intrinsic measurements have to be modified to take account of a more accurate description of the Fourier components of the input from a bar phantom. When this modification was applied, FWHM measurements agreed to within 4.0% with the LSF measurements in the range 4.5-7.2 mm if well-resolved images of bars wider than 3.0 mm were used. The method is simple to apply and since the coefficient of variation of these measurements was < 2.2%, it is well-suited for rapid objective routine monitoring of gamma camera spatial resolution. For modulation transfer functions > 0.2, bar sizes of 4.0 and 4.5 mm gave values within 4% of the LSF measurements, when the modified formula was applied, with coefficients of variation less than 4%.

Uniformity testing of a dual-head gamma camera with a nearby point source.

Limitations to head movement of dual-head gamma cameras may prevent proper geometry being attained for testing of intrinsic uniformity with a point source. When a point source is placed too near to the uncollimated crystal, the detected flood image will be non-uniform due to the inverse square law effect, oblique incidence, and increased path length traversed through the crystal by oblique rays. A formula has been deduced for constructing a map to correct for these effects. The general formula has been applied to a particular dual-head camera in which a point source has been placed on the face of one head, at 65.5 cm from the opposite uncollimated crystal. It is shown that division of the non-uniform image, acquired with this geometry, by the correction map yields a uniform image which may be used for routine investigation of the uniformity characteristics of the camera.

Analysis of radiation doses received by the public from 131I treatment of thyrotoxic outpatients.

Radiation doses to the family and general public from 131I therapy of outpatients were assessed for comparison with the 1990 International Commission on Radiation Protection (ICRP) dose limits. Doses to family members of such patients, measured by previous workers, were converted to show that on average 5.6 +/- 3.7 microSv MBq-1 is received by the spouse and 1.5 +/- 0.87 microSv MBq-1 by other family members. It was deduced that the average dose to the spouse (D microSv MBq-1) when couples sleep apart for T days after administration is given by: D = 2.528 + 3.072e-0.11T if an effective half-life, T(eff), of 6.35 days is used. The cumulative effect of repeated treatments should be considered and in view of ALARA it is recommended that couples sleep apart for at least 14 days after each administration, even if this is below limits permitted by authorities. The dose to a pregnant colleague or family member other than the wife should be below 2 mSv if the total administered activity is not more than 600 MBq. If the wife is pregnant, couples should sleep apart for at least 30 days after administration.

Imaging infection and inflammation in an African environment: comparison of 99Tcm-HMPAO-labelled leukocytes and 67Ga-citrate.

A considerable segment of the population of South Africa has a disease spectrum similar to those of the industrialized countries. However, a much larger proportion of its inhabitants comes from historically disadvantaged communities and is plagued by diseases typical of the developing world. Infectious diseases head the list as a cause of mortality in certain age groups. We have studied 108 patients presenting with a wide array of infections. Fifty-eight patients were examined with 67Ga-citrate and with 99Tcm-HMPAO-labelled leukocytes, 40 with leukocytes alone and 10 who had a high pre-test probability of tuberculosis with 67Ga only. The sensitivity and specificity of 99Tcm-labelled leukocyte scintigraphy in the 58 patients who had both studies were 89 and 84%, respectively, while the corresponding values for 67Ga scintigraphy were 81 and 74%, respectively. The overall sensitivity and specificity for 99Tcm-labelled leukocytes for detecting inflammatory sites in all 98 cases were 92 and 89%, respectively. Although labelled leukocytes were the better of the two agents for the early diagnosis of infections with a high probability of neutrophil infiltration, 67Ga remains an excellent alternative. It is the first choice in patients in whom tuberculosis or a neoplastic process is suspected as a cause of fever. It is also safer to use in areas where labelling of leukocytes is inadvisable because of inadequate sterility or where the risk is high of infecting other patients or staff with HIV.

The role of kidney uptake of Tc-99m pertechnetate during quantitation of gastric scintigraphy.

It is shown that during quantitative gastric scintigraphy with Tc-99m pertechnetate significant errors may occur if kidney uptake is ignored. The magnitude of the error was assessed in 12 patients, and could lead to an over-estimation of gastric uptake by up to 20%.