Differences in prevalence of hepatitis B virus infection and genotypes between ethnic populations in Suriname, South America.

Epidemiological data on hepatitis B virus (HBV) are needed to benchmark HBV elimination goals. We recently assessed prevalence of HBV infection and determinants in participants attending the Emergency Department in Paramaribo, Suriname, South America. Overall, 24.5% (95%CI = 22.7-26.4%) of participants had anti-Hepatitis B core antibodies, which was associated with older age (per year, adjusted Odds Ratio [aOR] = 1.03, 95%CI = 1.02-1.04), Afro-Surinamese (aOR = 1.84, 95%CI = 1.52-2.19) and Javanese ethnicity (aOR = 1.63, 95%CI = 1.28-2.07, compared to the grand mean). 3.2% of participants were Hepatitis B surface Ag-positive, which was also associated with older age (per year, aOR = 1.02, 95%CI = 1.00-1.04), Javanese (aOR = 4.3, 95%CI = 2.66-6.95) and Afro-Surinamese ethnicity (aOR = 2.36, 95%CI = 1.51-3.71). Sex, nosocomial or culturally-related HBV transmission risk-factors were not associated with infection. Phylogenetic analysis revealed strong ethnic clustering: Indonesian subgenotype HBV/B3 among Javanese and African subgenotypes HBV/A1, HBV/QS-A3 and HBV/E among Afro-Surinamese. Testing for HBV during adulthood should be considered for individuals living in Suriname, specifically with Javanese and Afro-Surinamese ancestry.

Microscopic localization of PEG-liposomes in a rat model of focal infection.

In the present study the microscopic localization of polyethylene glycol (PEG) liposomes in infected tissues was studied with both light microscopy (LM) and transmission electron microscopy (TEM) in rats with focal intramuscular Staphylococcus aureus infection. PEG-liposomes containing colloidal gold were prepared and injected intravenously in rats with focal S. aureus infection and tissues were dissected at 24 h post injection. Sections were cut and liposomes were visualized for microscopic evaluation using silver enhancement. Uptake of PEG-liposomes was visualized by both scintigraphy and LM in the abscess, liver and spleen. In the infected area, the liposomes were mainly found in the vicinity of blood vessels. TEM showed that the liposomes were localized in the macrophages and to a lesser extent in endothelial cells in the infectious tissue. In the liver, the liposomes appeared mainly localized in Kupffer cells. In the spleen, uptake was only seen in cells of the red pulp and in cells around the central arteries. Our microscopic observations indicate that uptake and retention of PEG-liposomes in the infectious focus is a result of enhanced extravasation due to increased vascular permeability and subsequent phagocytosis of PEG-liposomes by macrophages in the infected tissue.

Factors affecting the accelerated blood clearance of polyethylene glycol-liposomes upon repeated injection.

Previously, we showed that long-circulating polyethylene glycol (PEG)-liposomes are cleared rapidly from the circulation when injected repeatedly in the same animal. In this article, we describe the effects of PEG-coating, the circulation time, the lipid dose, and the presence of encapsulated doxorubicin on the pharmacokinetics upon repeated injection in rats. Furthermore, the role of liver and splenic macrophages was investigated. Liposomes without PEG-coating also showed the so-called "enhanced clearance effect": blood levels at 4 h post injection decreased from 62.8 +/- 13.7% of injected dose (%ID) after the first injection to 0.54 +/- 0.21%ID after the second injection. This decrease was independent of the circulation time of the first dose. Decreasing the first lipid dose of PEG-liposomes to 0.05 micromol/kg still led to enhanced clearance of a second dose of 5 micromol/kg. No changes in pharmacokinetics were observed when the second dose was 50 micromol/kg. When hepatosplenic macrophages were depleted, no enhanced clearance of repeated liposome injections was observed. A dose of doxorubicin containing PEG-liposomes (Doxil), injected 1 week after injection of empty PEG-liposomes, was cleared rapidly from the circulation in rats. Our results indicate that hepatosplenic macrophages play an essential role in the enhanced clearance effect and that the change in pharmacokinetic behavior upon repeated injection is a general characteristic of liposomes, unrelated to the presence of PEG. Therefore, these findings may have a considerable impact on the clinical application of liposomal formulations that are administered repeatedly.

Radiopharmaceuticals for scintigraphic imaging of infection and inflammation.

Scintigraphic imaging of infection and inflammation is a powerful diagnostic tool in the management of patients with infectious or inflammatory diseases. Most infectious and inflammatory foci can be visualized accurately with radiolabeled autologous leukocytes. However, preparation of this radiopharmaceutical is laborious and requires the handling of potentially contaminated blood. Nowadays, a few radiopharmaceuticals are available that could replace radiolabeled leukocytes, such as: 67Ga-citrate, 99mTc-IgG and 99mTc-labeled antigranulocyte antibody preparations. Furthermore, various agents labeled with 99mTc are currently developed for this application: chemotactic peptides, cytokines and liposomes. Here, the characteristics and the diagnostic potential of established and experimental radiopharmaceuticals for infection and inflammation imaging are reviewed.

Preclinical and clinical evidence for disappearance of long-circulating characteristics of polyethylene glycol liposomes at low lipid dose.

This study describes the effect of the lipid dose of (99m)Tc-polyethylene glycol (PEG) liposomes in the low-dose range (0. 02-1.0 micromol/kg) on the pharmacokinetics and biodistribution in rats, rabbits, and humans. The biodistribution and pharmacokinetics of (99m)Tc-PEG liposomes at various dose levels were studied in rats and rabbits with a focal Escherichia coli infection. Scintigraphic images were recorded on a gamma camera. In addition, the role of macrophages in the biodistribution of a low-dose PEG liposome injection was studied. Finally, the pharmacokinetics of (99m)Tc-PEG liposomes at two lipid dose levels was studied in four patients. At a dose level of 0.03 micromol/kg, the blood level in rats at 4 h postinjection was significantly lower than at the highest dose level (1.1 micromol/kg). The same effect was observed in rabbits where enhanced clearance was observed at a dose level of 0.02 micromol/kg. The circulatory half-life decreased from 10.4 to 3.5 h (at 1.0 and 0. 02 micromol/kg, respectively). At the lowest dose level, liposomes were mainly taken up by the liver and to a lesser extent by the spleen. Injection of a low dose of PEG liposomes in macrophage-depleted rabbits resulted in normal pharmacokinetics, suggesting involvement of macrophages in the effectuation of the rapid elimination of the liposomes from the circulation. Most importantly, the rapid clearance of low-dose PEG liposomes was also observed in humans when relatively low lipid doses were administered. This study showed that at very low lipid doses the biodistribution of PEG liposomes is dramatically altered.

Scintigraphic evaluation of experimental chronic osteomyelitis.

UNLABELLED: Assessment of disease activity and disease extent in chronic osteomyelitis remains a difficult diagnostic problem. Radiography is not particularly sensitive. Scintigraphic techniques can be more helpful, but the routinely available agents lack specificity (99mTc-methylene diphosphonate [MDP], 67Ga-citrate) or are laborious to prepare (111In-leukocytes). We evaluated the performance of 2 new radiopharmaceuticals, 99mTc-polyethyleneglycol (PEG) liposomes and 99mTc-hydrazinonicotinamide (HYNIC)-immunoglobulin G (IgG), in an experimental model of chronic osteomyelitis. METHODS: Chronic osteomyelitis was induced in rabbits by inserting S. aureus into the right reamed and washed femoral canal. The canal was closed with cement. A sham operation was performed on the left femur. Routine radiographs were obtained immediately after surgery and before scintigraphy. Four weeks after surgery, each rabbit was injected with 37 MBq 99mTc-PEG liposomes, 99mTc-HYNIC-IgG, and 99mTc-MDP on 3 consecutive days and imaged up to 4 (MDP) or 22 (liposomes and IgG) h after injection. On day 4, rabbits received either 18 MBq 111In-granulocytes or 67Ga-citrate and were imaged up to 44 h after injection. Uptake in the infected femur was determined by drawing regions of interest. Ratios of infected-to-sham-operated femur were calculated. After the last image, the rabbits were killed, and the left and right femur were scored for microbiologic and histopathologic evidence of osteomyelitis. RESULTS: 99mTc-PEG liposomes and 99mTc-HYNIC-IgG correctly identified all 6 rabbits with osteomyelitis. 11In-granulocytes and 67Ga-citrate gave equivocal results in 1 infected rabbit. 99mTc-MDP missed 1 case of osteomyelitis. The uptake in the affected region did not differ significantly between the agents, although 99mTc-MDP tended to have higher values (MDP, 4.75 +/- 1.23 percentage injected dose per gram [%ID/g]; 67Ga, 2.05 +/- 0.54 %ID/g; granulocytes, 1.56 +/- 0.83 %ID/g; liposomes, 1.75 +/- 0.76 %ID/g, and IgG, 1.96 +/- 0.27 %ID/g). The ratios of infected-to-normal femur were also not significantly different for the respective radiopharmaceuticals. Radiography visualized only severe osteomyelitis. CONCLUSION: In this rabbit model, 99mTc-PEG liposomes and 99mTc-HYNIC-IgG performed at least as well as 111In-granulocytes and 67Ga-citrate in the localization of chronic osteomyelitis. The ease of preparation, the better image quality, and the lower radiation dose suggest that 99mTc-PEG liposomes and 99mTc-HYNIC-IgG might be suitable alternatives for 67Ga-citrate and 111In-granulocytes in the scintigraphic evaluation of osteomyelitis.

Improved imaging of infections by avidin-induced clearance of 99mTc-biotin-PEG liposomes.

UNLABELLED: This article describes the preparation and optimization of biotin-polyethyleneglycol (PEG) liposomes and their application in experimental infection models to improve the scintigraphic imaging of infection and inflammation. METHODS: Biotin was coupled to PEG-distearoylphosphatidylethanolamine (DSPE) and subsequently incorporated in the PEG liposomes. Biotinylated liposomes were radiolabeled with 99mTc-hydrazinonicotinamide. In vitro binding studies were performed to find the optimal biotin concentration in the liposomes. In rats the biodistribution of the 99mTc-biotin-PEG liposomes was compared with the biodistribution of normal (nonbiotinylated) 99mTc-PEG liposomes. Furthermore, in vivo studies in rats were performed to study both the effect of the biotin content and the optimal avidin dose for efficient clearance of the liposomes. Liposomes containing 0.5 or 1.0 mol% biotin-PEG-DSPE were compared in rats with a Staphylococcus aureus infection in the left calf muscle. Avidin was injected 4 h after injection of the liposomes. RESULTS: Biotinylation of the liposomes did not affect their in vivo behavior. All biotin-PEG liposome formulations tested showed good in vitro avidin binding with 50% inhibitory concentrations ranging from 36 to 8 micromol/L. With avidin doses higher than 100 microg, both preparations rapidly cleared from the circulation. As a result, abscess-to-blood ratios increased 5-fold. To illustrate the potential of the avidin-induced clearance of radiolabeled PEG liposomes, we also studied the 99mTc-biotin-PEG liposomes in rabbits with a subcutaneous S. aureus abscess. The infection was visualized only after injection of 100 microg avidin. CONCLUSION: This study shows that biotin-coated 99mTc-PEG liposomes in combination with the injection of avidin can lead to improved imaging of infection or inflammation localized especially in regions with high blood-pool activity.

99mTc-PEG liposomes for the scintigraphic detection of infection and inflammation: clinical evaluation.

UNLABELLED: Polyethyleneglycol (PEG) liposomes have been shown to be excellent vehicles for scintigraphic imaging of infection and inflammation in various experimental models. In this article we report on a series of patients with possible infectious and inflammatory disease in whom the performance of 99mTc-PEG liposomes was evaluated. The results of 99mTc-PEG liposome scintigraphy were directly compared with those of 111In-immunoglobulin G (IgG) scintigraphy. METHODS: Thirty-five patients (22 men, 13 women; mean age, 51 y; range, 20-76 y), suspected of having infectious or inflammatory disease, received 740 MBq 99mTc-PEG liposomes intravenously. Imaging was performed at 4 and 24 h after injection. Patients received 75 MBq 111In-IgG 24 h after administration of the liposomes. The scintigraphic results were compared and verified by culture, biopsy, surgery, and follow-up of at least 6 mo. RESULTS: Of the 16 proven infections and inflammations, 15 were detected by 99mTc-PEG liposome scintigraphy: soft-tissue infection (n = 3), septic arthritis (n = 3), autoimmune polyarthritis (n = 2), infected hip prosthesis (n = 1), infected osteosynthesis (n = 1), spondylodiscitis (n = 1), infected aortic prosthesis (n = 1), colitis (n = 1), abdominal abscess (n = 1), and pneumonia (n = 1). 99mTc-PEG liposome and 111In-IgG scintigraphy both missed 1 case of endocarditis. In addition, an 111In-IgG scan of a patient with mild soft-tissue infection was false-negative. Concordantly false-positive scans were recorded from 2 patients, both with uninfected pseudarthrosis and focal signs of sterile inflammation. During liposomal administration, 1 patient experienced flushing and chest tightness, which rapidly disappeared after lowering the infusion rate. No other adverse events were observed. CONCLUSION: This clinical evaluation of 99mTc-PEG liposomes shows that focal infection and inflammation can be adequately imaged with this new agent. The performance of 99mTc-PEG liposomes is at least as effective as that of 111In-IgG. With the simple and safe preparation and the physical and logistic advantages of a 99mTc label, 99mTc-PEG liposomes could be an attractive agent for infection or inflammation imaging.

Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes.

Sterically stabilized liposomes are considered promising carriers of therapeutic agents because they can facilitate controlled release of the drugs, thereby reducing drug-related toxicity and/or targeted delivery of drugs. Herein, we studied the pharmacokinetics and biodistribution of repeated injections of radiolabeled polyethyleneglycol (PEG) liposomes. Weekly injections of (99m)Tc-PEG liposomes dramatically influenced the circulatory half-life in rats. Biodistribution 4 h after the second dose showed a significantly reduced blood content (from 52.6 +/- 3.7 to 0.6 +/- 0.1% injected dose (ID), P <.01) accompanied by a highly increased uptake in the liver (from 8.1 +/- 0.8 to 46.2 +/- 9.8%ID, P <.01) and in the spleen (from 2.2 +/- 0.2 to 5.3 +/- 0.7%ID, P <.01). At subsequent injections the effect was less pronounced: after the fourth dose, the pharmacokinetics of the radiolabel had almost returned to normal. The same phenomenon was observed in a rhesus monkey, but not in mice. The enhanced blood clearance of the PEG liposomes also was observed in rats after transfusion of serum from rats that had received PEG liposomes 1 week earlier, indicating that the enhanced blood clearance was caused by a soluble serum factor. This serum factor was a heat-labile molecule that coeluted on a size exclusion column with a 150-kDa protein. In summary, i.v. administration of sterically stabilized PEG liposomes significantly altered the pharmacokinetic behavior of subsequently injected PEG liposomes in a time- and frequency-dependent manner. The observed phenomenon may have important implications for the repeated administration of sterically stabilized liposomes for targeted drug delivery.

Tc-99m-PEG-Liposomes for the evaluation of colitis in Crohn's disease.

In the present study, the potential role of 99mTc-PEG-liposome to determine the extent and severity of active disease of Crohn's colitis was investigated. Patients suspected of having an exacerbation of Crohn's disease underwent a 99mTc-PEG-liposome scan (740 MBq, imaging at 4 and 24 h p.i.). A barium enema or endoscopy was performed as the standard verification procedure. Disease activity indices (Clinical Disease Activity Index and Van Hees Activity Index) were calculated. In seven patients positive images of colon segments affected by Crohn's colitis were obtained using 99mTc-PEG-liposomes. Only a moderate relation between 99mTc-liposome scan grading and verification procedures was found (Spearman rank r = 0.22). In accordance with previous studies, no significant correlation was found between the clinical disease activity indices and the verification procedures. This study was prematurely terminated because of unacceptable side-effects in 3 out of 9 patients, which occured almost immediately after starting the infusion. The complaints consisted of dyspnea and facial erythema. The symptoms were self-limiting when the infusion was stopped. In conclusion, the extent of Crohn's colitis can be established non-invasively with 99mTc-PEG-liposome scintigraphy. However, in view of the encountered side-effects, the PEG-liposomal preparation may have to be modified.

Imaging experimental intraabdominal abscesses with 99mTc-PEG liposomes and 99mTc-HYNIC IgG.

OBJECTIVE: To evaluate the accuracy of technetium-99m-labeled polyethylene glycol-coated liposomes (99mTc-PEG liposomes) and technetium-99m-labeled nonspecific human immunoglobulin G (99mTc-HYNIC IgG) for the scintigraphic detection of experimental intraabdominal abscesses in comparison with that of a standard agent, gallium-67 citrate. BACKGROUND: Scintigraphic imaging techniques can be very useful for the rapid and accurate localization of intraabdominal abscesses. Two newly developed radiolabeled agents, 99mTc-PEG liposomes and 99mTc-HYNIC IgG, have shown to be excellent agents for imaging experimental focal infection, but have not yet been studied in the detection of abdominal abscesses. METHODS: Intraabdominal abscesses were induced in 42 rats using the cecal ligation and puncture technique. Seven days later, randomized groups of rats received 99mTc-PEG liposomes, 99mTc-HYNIC IgG, or 67Ga citrate intravenously. The rats were imaged up to 24 hours after the injection. The biodistribution of the radiolabel was determined by counting dissected tissues ex vivo. Macroscopic intraabdominal abnormalities and focal uptake on the images were independently scored on a semiquantitative scale. RESULTS: 99mTc-PEG liposomes provided the earliest scintigraphic visualization of the abscess (as soon as 2 hours after the injection vs. 4 hours for the other two agents). Liposomes, IgG, and gallium all showed similarly high absolute uptake in the abscess. Focal uptake of liposomes and gallium correlated best with the extent of the macroscopic abnormalities. CONCLUSIONS: 99mTc-PEG liposomes and 99mTc-HYNIC IgG performed at least as well as the standard agent, 67Ga citrate, in the detection of experimental intraabdominal abscesses, with obvious advantages such as lower radiation exposure and more favorable physical properties. Of the two technetium agents, the liposomes seemed to be superior, providing the earliest diagnostic image and the best correlation with the inflammatory abnormalities. In addition, the preferential localization of radiolabeled PEG liposomes holds promise for targeted delivery of liposome-encapsulated drugs.

A novel method to label liposomes with 99mTc by the hydrazino nicotinyl derivative.

UNLABELLED: In this study a new 99mTc labeling method for polyethyleneglycol (PEG)-coated liposomes is described. The in vitro and in vivo characteristics were compared with the conventional 99mTc-HMPAO-labeled PEG-coated liposomes. METHODS: PEG-coated liposomes were labeled with 99mTc by the hydrazino nicotinyl (HYNIC) derivative of distearoylphosphatidyl-ethanolamine (DSPE) and compared with PEG-coated liposomes labeled with 99mTc-HMPAO. In vitro stability tests were performed. Biodistribution and imaging characteristics of both liposomal preparations were determined in rats with Staphylococcus aureus infection in the left calf muscle. RESULTS: Per liposome, 230 hydrazine groups were incorporated. The labeling efficiency of the 99mTc-HYNIC liposomes was greater than 95%, so no postlabeling purification was required, in contrast to the 99mTc-HMPAO liposomes. The 99mTc-HYNIC liposomes showed greater in vitro stability than the conventional 99mTc-HMPAO liposomes. Abscess uptake of the 99mTc-HYNIC liposomes was significantly greater (1.74+/-0.38%ID/g versus 1.26+/-0.29%ID/g, 24 h postinjection, P < 0.03). Furthermore, kidney uptake of the 99mTc-HYNIC liposomes was one third of the uptake of the 99mTc-HMPAO liposomes (0.79+/-0.07%ID/g versus 2.47+/-0.35%ID/g, 24 h postinjection, P < 0.0001). CONCLUSION: This new 99mTc-HYNIC-based labeling method for liposomes is rapid, efficient and easy to perform. Most importantly, the 99mTc-labeled liposomes have an improved stability and in vivo characteristics. The new labeling method is a major step forward toward a radiopharmaceutical for infection imaging that can be prepared in a one-step procedure within 15 min at room temperature and thus can be applied in every routine clinical practice.

Scintigraphic imaging of bacterial and fungal infection in granulocytopenic rats.

UNLABELLED: Scintigraphic imaging in granulocytopenic patients can be very useful to detect and localize infections, which often do not show localizing signs and symptoms. We studied the potential of 99mTc-labeled polyethylene glycol (PEG)-coated liposomes and 99mTc-labeled IgG to image bacterial and fungal infection in a granulocytopenic rat model. 67Ga-citrate was used as a reference agent. METHODS: 99mTc-PEG-liposomes, 99mTc-hydrazinonicotinate (HYNIC)-IgG or 67Ga-citrate was administered to granulocytopenic rats with a Staphylococcus aureus abscess or with unilateral invasive pulmonary aspergillosis. Imaging and biodistribution studies were performed. RESULTS: All agents visualized the S. aureus infection from 1 h after injection onward. However, only with 99mTc-PEG-liposomes and with 99mTc-HYNIC-IgG did activity in the infectious foci increase with time up to 24 h. 99mTc-PEG-liposomes and 99mTc-HYNIC-IgG showed significantly higher accumulation in the infectious focus compared with 67Ga-citrate (1.33+/-0.31 and 1.40+/-0.16 percentage injected dose per gram [%ID/g], respectively, versus 0.31+/-0.04 %ID/g 24 h after injection; P<0.05). At 24 h after injection, abscess-to-muscle ratios were highest for 99mTc-liposomes (72.1+/-19.1), followed by 99mTc-HYNIC-IgG (18.3+/-3.3) and 67Ga-citrate (4.4+/-0.7). In pulmonary aspergillosis, both 99mTc-PEG-liposomes and 99mTC-HYNIC-IgG showed significantly higher uptake in the infected lung than did 67Ga-citrate (3.6+/-0.4 and 8.3+/-0.8 %ID/g, respectively, versus 1.3 %ID/g at 24 h after injection; P<0.05). CONCLUSION: 99mTc-PEG-liposomes and 99mTc-HYNIC-IgG performed better than did 67Ga-citrate in the localization of peripheral bacterial infection and fungal infection in the lung in granulocytopenic rats. The high focal uptake and high target-to-nontarget ratios of 99mTc-PEG-liposomes and 99mTc-HYNIC-IgG indicate that both radiopharmaceuticals may become valuable agents to image infection in granulocytopenic patients.

Technetium-99m-labeled liposomes to image experimental colitis in rabbits: comparison with technetium-99m-HMPAO-granulocytes and technetium-99m-HYNIC-IgG.

UNLABELLED: Scintigraphic techniques are routinely used for the evaluation of the extent and severity of inflammatory bowel disease. Currently, the radiopharmaceutical of choice is 99mTc-hexamethyl propyleneamine oxime (HMPAO)-leukocytes. We studied the imaging potential of two recently developed 99mTc-labeled agents, polyethylene glycol (PEG)-coated liposomes and hydrazinonicotinate (HYNIC) IgG, in a rabbit model of acute colitis, and compared them with that of 99mTc-labeled, granulocyte-enriched (>90%), white blood cells. METHODS: Acute colitis was induced in rabbits by retrograde instillation of trinitrobenzene sulfonic acid. After 48 hr, 37 MBq of each radiopharmaceutical was administered intravenously. Gamma camera images were taken at 0, 1, 2, 4, 10 and 24 hr. At 4 and 24 hr postinjection, groups of rabbits were killed, and the uptake of the radiolabel in the dissected tissues was determined. For each affected 5-cm segment, the colitis index (CI, affected-to-normal-colon-uptake ratio) was calculated and correlated to the macroscopically scored severity of inflammation. RESULTS: All three agents visualized the colitis lesions within 1 hr postinjection. The CI correlated with the severity of the abnormalities. With increasing severity, the CI at 4 hr postinjection for liposomes was 3.89+/-0.73, 4.41+/-0.47 and 5.76+/-0.65; for IgG 1.67+/-0.08, 3.92+/-0.44 and 6.14+/-0.65; and for granulocytes 2.90+/-0.09, 6.15+/-0.96 and 9.36+/-3.35. For liposomes, the CI further increased during 24-hr postinjection to 6.56+/-0.84, 8.50+/-0.53 and 10.61+/-1.34, respectively. The CI for the other two agents did not change significantly with time. CONCLUSION: In this rabbit model, 99mTc-labeled granulocytes, IgG and liposomes all rapidly visualized colonic inflammation. Granulocytes and liposomes showed the highest CI. Technetium-99m-labeled PEG-liposomes may be an attractive alternative for labeled leukocytes to image inflammatory bowel disease, because they can be prepared off the shelf and no handling of blood is required.

Dynamic distribution and dosimetric evaluation of human non-specific immunoglobulin G labelled with 111In or 99Tcm.

This study presents data on the dynamic distribution and dosimetry of 111In- and 99Tcm-labelled human non-specific immunoglobulin G (IgG), two recently developed radiopharmaceuticals for the detection of infection and inflammation. Five healthy volunteers were injected with 20-75 MBq 111In-IgG and seven patients were injected with 740 MBq 99Tcm-hydrazinonicotinamide derivative (HYNIC)-IgG. Blood samples, urine and feces were collected. Whole-body gamma camera imaging studies were performed. The activity in source organs was quantified using the conjugate view counting method and a partial background subtraction technique. Dosimetric calculations were performed using the MIRD technique. For 111In-IgG, the mean biological half-times in the blood were 0.90 and 46 h for the a- and b-phase, respectively. For 99Tcm-HYNIC-IgG, these half times were 0.46 and 45 h. For 111In-IgG, the mean cumulative urinary excretion in the first 48 h was 18% of the injected dose, while excretion in the feces was less than 2% of the injected dose. For 99Tcm-HYNIC-IgG, the whole-body retention was always 100% up to 24 h. The mean absorbed doses in the liver, spleen, kidneys, red marrow and testes from 111In-IgG were 0.8, 0.7, 1.2, 0.3 and 0.4 mGy MBq-1 respectively. The mean absorbed doses for 99Tcm-HYNIC-IgG to these organs were 16, 24, 15, 10 and 22 mu Gy MBq-1 respectively. The mean effective dose was 0.25 mSv MBq-1 and 8.4 mu Sv MBq-1 for 111In-IgG and 99Tcm-HYNIC-IgG respectively. In conclusion, the radiation absorbed doses for both 111In-IgG and 99Tcm-HYNIC-IgG are low and, therefore, these radiopharmaceuticals can be administered safely from a radiation risk perspective.

Technetium-99m labeled to human immunoglobulin G through the nicotinyl hydrazine derivative: a clinical study.

UNLABELLED: A novel method to label polyclonal human immunoglobulin G (IgG) with 99mTc through the nicotinyl hydrazine derivative (HYNIC) has shown promising results in the detection of experimental infection. In this study, 99mTc-labeled HYNIC-IgG was directly compared to (111)In-labeled diethylenetriaminepentaacetic acid (DTPA)-IgG in patients suspected of infectious or inflammatory disease. METHODS: Thirty-seven patients (22 women and 15 men; mean age = 54 yr, range = 17-78 yr) with 39 suspected infectious or inflammatory foci were prospectively studied. After administration of 740 MBq 99mTc-HYNIC-IgG, imaging was performed at 4 and 24 hr postinjection. To avoid cross-over activity, (111)In-DTPA-IgG was injected 24 hr after 99mTc-HYNIC-IgG and imaged at 4, 24 and 48 hr postinjection. The scintigraphic results were confirmed by microbiological, histological, radiological and clinical methods. RESULTS: Technetium-99m-HYNIC-IgG and (111)In-DTPA-IgG scintigraphy showed 100% concordancy. All 17 patients with proven infection or inflammation (19 foci, mainly localized in the locomotor system) had positive scintigraphic findings. No false-negative scintigrams were recorded. In three patients, the scintigrams were concordantly false-positive. As a result, the sensitivity and specificity of imaging infectious or inflammatory foci with 99mTc-HYNIC-IgG and (111)In-DTPA-IgG in these patients were 100% and 85%, respectively. CONCLUSION: Technetium-99m-HYNIC-IgG scintigraphy is equally as effective as (111)In-IgG scintigraphy for the detection of infection and inflammation. The apparent physical and logistic advantages of 99mTc over (111)In make 99mTc-HYNIC-IgG a promising new radiopharmaceutical for imaging infection and inflammation.

An unusual case of severe combined immunodeficiency with hypereosinophilia.

Investigation of the cytokine profile in a 26-year-old man, suffering from combined immunodeficiency with hypereosinophilia, revealed high levels of interleukin-4 and interleukin-5 and relatively low levels of interleukin-2 and interferon gamma, consistent with a T-helper type 2 pattern, as has been reported in Omenn's syndrome. However, some distinct clinical and immunological features suggest that this case may represent a unique disease with specific pathogenesis.

Scintigraphic evaluation of experimental colitis in rabbits.

UNLABELLED: Scintigraphic techniques are frequently used for evaluation of inflammatory bowel disease. The radiopharmaceutical of choice is labeled leukocytes. In this study, two new agents, 111In-labeled polyethylene glycol-coated liposomes and 111In-labeled human nonspecific gamma globulin (immunoglobulin G; IgG), were compared with 111In-leukocytes in a rabbit model of colitis. METHODS: In rabbits, acute colitis was induced by colonic instillation of trinitrobenzene sulfonic acid at 25 cm from the anal sphincter. After 24 hr, 15 MBq of the radiopharmaceuticals was injected intravenously in groups of four rabbits. Twenty-four hours after injection, the animals were killed and macroscopic abnormalities were scored in seven consecutive affected colonic segments of 5 cm each (0 = normal, 1 = inflammation, 2 = ulcers). The ex vivo uptake was measured in the normal ascending colon and the affected colonic segments. The colitis index (CI, affected-to-normal colon-uptake ratio) was calculated. RESULTS: Histologically, an acute, patchy, transmural colitis was observed at the site of instillation and the distal colon. The CI of all agents in colitis lesions correlated with the severity of the abnormalities. With increasing severity, the CI for liposomes was 1.86 +/- 0.24, 4.88 +/- 0.42 and 7.42 +/- 0.54 (r2 = 0.68, p < 0.001); for leukocytes 1.77 +/- 0.32, 3.10 +/- 0.58 and 5.54 +/- 0.83 (r2 = 0.31, p < 0.01); for IgG 1.60 +/- 0.29, 2.81 +/- 0.21 and 2.65 +/- 0.21 (r2 = 0.29, p < 0.02). CONCLUSION: Indium-111-labeled-leukocytes, -IgG and -liposomes all show increased uptake in inflamed colonic tissue. Indium-111-liposomes showed the highest CI, which correlates best with the morphological abnormalities. Indium-111-leukocytes and 111In-liposomes are superior to 111In-IgG for this indication.

X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase.

X-linked liver glycogenosis type II (XLG II) is a recently described X-linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.