Tc-99m Radiolabeled Peptide p5 + 14 is an Effective Probe for SPECT Imaging of Systemic Amyloidosis

Purpose

Systemic peripheral amyloidosis is a rare disease in which misfolded proteins deposit in various organs. We have previously developed I-124 labeled peptide p5?+?14 as a tracer for positron emission tomography imaging of amyloid in patients. In this report, we now document the labeling efficiency, bioactivity, and stability of Tc-99m labeled p5?+?14 for single-photon emission computed tomography (SPECT) imaging of amyloidosis, validated in a mouse model of systemic amyloidosis.

Procedures

Radiochemical yield, purity, and biological activity of [^99mTc]p5?+?14 were documented by instant thin-layer chromatography (ITLC), SDS-PAGE and a quantitative amyloid fibril pulldown assay. The efficacy and stability were documented in serum amyloid protein A (AA) amyloid-bearing or wild-type (WT) control mice imaged with SPECT/X-ray computed tomography (CT) at two time points. The uptake and retention of [^99mTc]p5?+?14 in hepatosplenic amyloid was evaluated using region of interest (ROI) and tissue counting measurements.

Results

Tc-99m p5?+?14 was produced with a radiochemical yield of 75 % with greater than 90 % purity and biological activity comparable to that of radioiodinated peptide. AA amyloid was visualized by SPECT/CT imaging with specific uptake seen in amyloid-laden organs at levels ～5 folds higher than in healthy mice. ROI analyses of decay-corrected SPECT/CT images showed <20 % loss of radiolabel from the 1 to 4 h imaging time points. Biodistribution data confirmed the specificity of the probe accumulation by amyloid-laden organs as compared to non-diseased tissues.

Conclusion

[^99mTc]p5?+?14 is a specific and stable radiotracer for systemic amyloid in mice and may provide a convenient and inexpensive alternative to imaging of peripheral amyloidosis in patients.

     

Predictive role of PI-RADSv2 and ADC parameters in differentiating Gleason pattern 3 + 4 and 4 + 3 prostate cancer

Purpose

To compare the predictive roles of qualitative (PI-RADSv2) and quantitative assessment (ADC metrics), in differentiating Gleason pattern (GP) 3 + 4 from the more aggressive GP 4 + 3 prostate cancer (PCa) using radical prostatectomy (RP) specimen as the reference standard.

Methods

We retrospectively identified treatment-naïve peripheral (PZ) and transitional zone (TZ) Gleason Score 7 PCa patients who underwent multiparametric 3T prostate MRI (DWI with b value of 0,1400 and where unavailable, 0,500) and subsequent RP from 2011 to 2015. For each lesion identified on MRI, a PI-RADSv2 score was assigned by a radiologist blinded to pathology data. A PI-RADSv2 score ≤ 3 was defined as “low risk,” a PI-RADSv2 score ≥ 4 as “high risk” for clinically significant PCa. Mean tumor ADC (ADC_T), ADC of adjacent normal tissue (ADC_N), and ADC_ratio (ADC_T/ADC_N) were calculated. Stepwise regression analysis using tumor location, ADC_T and ADC_ratio, b value, low vs. high PI-RADSv2 score was performed to differentiate GP 3 + 4 from 4 + 3.

Results

119 out of 645 cases initially identified met eligibility requirements. 76 lesions were GP 3 + 4, 43 were 4 + 3. ADC_ratio was significantly different between the two GP groups (p = 0.001). PI-RADSv2 score (“low” vs. “high”) was not significantly different between the two GP groups (p = 0.17). Regression analysis selected ADC_T (p = 0.03) and ADC_ratio (p = 0.0007) as best predictors to differentiate GP 4 + 3 from 3 + 4. Estimated sensitivity, specificity, and accuracy of the predictive model in differentiating GP 4 + 3 from 3 + 4 were 37, 82, and 66%, respectively.

Conclusions

ADC metrics could differentiate GP 3 + 4 from 4 + 3 PCa with high specificity and moderate accuracy while PI-RADSv2, did not differentiate between these patterns.

     

A comprehensive psychometric evaluation of the UK FIM + FAM

Abstract

Purpose: To evaluate the psychometric properties of the UK FIM?+?FAM. Methods: (a) A systematic literature review integrating the evidence for psychometric qualities of both the original and UK versions, and (b) exploratory and confirmatory factor analysis of admission/discharge data from an inpatient general neuro-rehabilitation cohort using parametric and non-parametric techniques. A prospective cohort of 459 patients with a male:female ratio of 57:43 and mean age of 44.5 (SD 14.3) years participated in this study. Results: Seven published articles together demonstrated acceptable utility, concurrent validity, inter-rater reliability and responsiveness of the UK FIM?+?FAM. Factor analysis demonstrated that all items loaded high (>0.58) on the first principal component and distinct motor and cognitive factors emerged after rotation. A four-factor solution also demonstrated four distinct, interpretable dimensions (Physical, Psychosocial, Communication and Extended Activities of Everyday Living (EADL)). Mokken analysis of the second data set confirmed these dimensions. Cronbach’s αs were 0.97 and 0.96 for the motor and cognitive domains and 0.90–0.97 for the subscales. Analysis of responsiveness demonstrated “large” effect sizes (0.86–1.29). Conclusions: The UK FIM?+?FAM, including the newer EADL module, is a valid, reliable scale of functional independence. It has high internal consistency in two domains and four subscales and is responsive to changes occurring in a general inpatient neuro-rehabilitation population.

• Implications for Rehabilitation

• The UK FIM?+?FAM is a valid, reliable scale of functional independence, which is responsive to changes occurring in a general inpatient neuro-rehabilitation population.

• It can be used to derive a reliable, single score of overall independence and also yields specific information in two main domains and four separate subscales of independence: Physical, Psychosocial, Communication and Extended Activities of Daily Living (EADL).

• The newer EADL item module provides added value, measuring functional independence for community-based activities.

     

Myeloid growth factor therapy in malignant lymphomas��a 5-year retrospective study from Hungary

Myeloid growth factors help to prevent and cure neutropenic events in malignant lymphoma patients treated by chemotherapeutical regimens. Administering either filgrastim or pegfilgrastim, treatment schedule can be kept well and less dose reductions are needed, which results in better survival rates. The aim of this study was to examine the indications and the outcome of myeloid precursor therapy among our malignant lymphoma patients. Between 2003 and 2007, 249 malignant lymphoma patients received 1,655 cycles of different polychemotherapies. Myeloid growth factor therapy was administered in 138 cases by 65 patients, which meant 8.33% of all treatment cycles and 26.1% of all patients, respectively. As for the indications, prevention was more common than intervention (71.7% vs. 28.3%). By preventive usage of growths factors, two-thirds of threatening neutropenic events could be avoided. Side effects were uncommon and mild: grades I–II toxicity was observed in 31% of all treatments. Analyzing the risk factors for febrile neutropenia among patients who received myeloid growth factor therapy compared to those who did not, we found the incidence of comorbidities, hypoalbuminemia, advanced stage disease, and aggressive chemotherapies significantly different in the two groups. Interestingly, there was no significant difference regarding the median age and the incidence of low body surface area. Our observations support that myeloid precursor therapy is an effective and safe implement to prevent or treat neutropenia in high-risk malignant lymphoma patients.     

Regulatory T CD4 + CD25+ lymphocytes increase in symptomatic carotid artery stenosis

Background: Atherosclerosis is a multifactorial disease characterized by an immune-inflammatory remodeling of the arterial wall. Treg and Th17 subpopulations are detectable inside atherosclerotic plaque; however, their behavior in symptomatic carotid artery stenosis (CAS) is not fully elucidated. The aim of this study was to evaluate Th17 and Treg subsets and their ratio in patients affected by symptomatic and asymptomatic CAS.

Methods: 14 patients with symptomatic CAS (CAS-S group), 41 patients with asymptomatic CAS (CAS-A group), 32 subjects with traditional cardiovascular risk factors (RF group), and 10 healthy subjects (HS group) were enrolled. Th17 and Treg frequency was determined by flow cytometry and by histology and immunohistochemistry. Interleukin (IL)-10, IL-17, and metalloproteinase (MMP)-12 levels were measured by ELISA.

Results: Th17 were significantly increased in CAS-A versus RF and versus HS. Tregs were significantly increased in CAS-S versus CAS-A. Tregs/Th17 ratio was significantly reduced in CAS-A versus RF and versus HS, whereas it was significantly increased in CAS-S versus CAS-A.

Conclusions: The results of this study suggest that Th17 are related to the late stages of CAS but not to plaque instability. Moreover, Treg expansion seems to represent a specific cellular pattern displayed by patients with symptomatic CAS and associated with brain injury.

• KEY MESSAGES

• Tregs expansion seems to represent a specific cellular pattern displayed by patients with symptomatic CAS and associated with CD4+ effector depletion and brain ischemic injury.

• Th17 lymphocytes are related to the late stages of CAS but not to plaque instability.

     

Guillian-Barré syndrome--a case study

'Acute Guillian-Barré Syndrome is an acute inflammatory demyelinating disease of the peripheral nerves' (Pfister & Bullas 1990) which affects the normal transmission of electrical impulses along these nerves and consequently the function of the organs and tissues which they innervate (Springhouse 1998, Waldock 1995). This disorder can rapidly replace an individual's busy and active lifestyle with one of total dependence, often lasting months (Waldock 1995). It is important, therefore, that nurses understand the pathophysiology of the disease and its effect on the organs and tissue within the body, to enable them to provide a high standard of care for patients suffering from this condition. This discussion of Guillian-Barré Syndrome (GBS) will be in relation to patient (who shall be called Jane Smith for the purpose of this discussion) who was admitted to the Accident and Emergency (A&E) department and diagnosed with GBS (see Box 1 for patient history). Within this discussion GBS will be defined and its pathophysiology explained. The epidemiology and aetiology of the disease will also be highlighted. The majority of the discussion will focus on the physiological effects of GBS on the components of the peripheral nervous system and the appropriate assessment and treatment measures. Finally, the outcomes of the disease will be highlighted. The focus will be on the management of this condition within the A&E department.     

Intra-aortal therapy with 5-fluorouracil- polyethylene glycol stealth liposomes: does the metabolism of 5-fluorouracil into 5-fluoro-2'-deoxyuridine depend on ph value?. An animal study in VX-2 liver tumor-bearing rabbits

BACKGROUND: The application of liposome-encapsulated cytostatics results in higher concentrations in tumor tissue. This effect can be further increased by blood flow retardation with longer retention time in the tumor and by arterial administration realized in abdominal stop-flow therapy, a separate partial circulation with a defined flow under hypoxic conditions. The pH changes under stop-flow therapy may affect the further metabolism of 5-fluorouracil (5-FU), used here. METHODS: The in vitro 5-fluoro-2'-deoxyuridine (5-FUrd) concentrations at increasing pH values were measured using liposomal encapsulated and free 5-FU. Subsequently, 20 chinchilla rabbits were treated intra-aortally with 5-FU or 5-FU-polyethylene glycol (PEG) liposomes. The pH value was maintained in the physiological range by continuous NaHCO3 application. After 20 min, concentrations of 5-FU and its metabolite 5-FUrd were determined in different organs, the perfusate, serum and the VX-2 tumor by HPLC. RESULTS: The in vitro 5-FUrd concentrations, which occur only in the physiological pH range, were doubled by the use of 5-FU-PEG liposomes. In the animal trial, NaHCO(3) titration doubled the 5-FUrd concentrations found in our preliminary studies. Compared to free 5-FU, 5-FU-PEG liposomes significantly increased the concentrations in the VX-2 liver tumor by 6.6-fold and in the para-aortal lymph nodes by 8.76-fold. CONCLUSION: The metabolism of 5-FU into its active metabolite 5-FUrd depends on the pH value and can be modulated. 5-FUrd concentrations can be approximately doubled with the intra-aortal application of 5-FU-PEG liposomes compared to free 5-FU.     

Association study of CCR5 delta 32 polymorphism among the HLA-DRB1 Caucasian population in Northern Paraná, Brazil

Chemokines are important determinants of early inflammatory response. The CC chemokine receptor 5 (CCR5) delta 32 variant results in a nonfunctional form of the chemokine receptor and has been implicated in a variety of immune-mediated diseases. In the present study, polymerase chain reaction (PCR) for genomic deoxyribonucleic acid (DNA) samples, using specific CCR5 oligonucleotide primers surrounding the breakpoint deletion, detected a 225-basepair (bp) product from the normal CCR5 allele and a 193-bp product from the 32 bp deletion allele. Human leukocyte antigen (HLA) class II (DRB1) typing was performed by PCR-sequence-specific primer (PCR-SSP). The aim of this study was to evaluate the association of HLA-DRB1 and CCR5 genetic polymorphisms. To evaluate the frequency distributions of CCR5 delta 32 polymorphisms in a Brazilian population and their association with allelic distribution of HLA genes, DRB1; a total of 120 Caucasian individuals from northern Paraná, Brazil, were tested. The CCR5/CCR5 genotype was found in 108 individuals (90%) and only one carried the CCR5 delta 32 allele homozygous genotype (0.0238), while 12 (10%) carried the CCR5 delta 32 allele heterozygous genotype. The observed frequency for the CCR5 delta 32 allele was 0.05 in the population studied. The results revealed a CCR5 delta 32 allele occurrence with HLA-DRB1(*)01 and DRB1(*)04 (P<0.05). It is possible that HLA-DRB1(*)01 and DRB1(*)04 alleles could be associated with the delta 32-bp deletion of CCR5.     

Red blood cell transfusions—are we narrowing the evidence-practice gap? An observational study in 5 Israeli intensive care units

Purpose

The aim of the study was to document transfusion practices in a cross section of general intensive care units (ICUs) in Israel and to determine whether current guidelines are being applied.

Materials and Methods

This prospective study was performed in 5 general ICUs in Israel over a 3-month period. Red cell transfusion data collected on consecutive patients included the trigger, units transfused per transfusion event, and indications, categorized either to treat a specified condition for which transfusions may be beneficial (acute hemorrhage, acute myocardial ischemia, or severe sepsis) or to treat a low hemoglobin concentration.

Results

Of the 238 patients studied, 50% received at least one red blood cell transfusion. The main indication for transfusion (43.7%, or 162/368 U transfused) was to treat a low hemoglobin concentration, in the absence of one of the specified conditions. Total red cell use was 3.0 ± 2.9 U per admission, and patients received a mean of 1.2 ± 0.4 U per transfusion event. The transfusion trigger for the whole group was 7.9 ± 1.1 g/dL. This did not differ significantly between the indications apart from a significantly higher trigger for patients with acute myocardial ischemia (8.8 ± 0.9 g/dL). In addition, patients with a history of heart disease had a higher trigger irrespective of the primary indication for transfusion and received significantly more units per transfusion event. Patients receiving a transfusion had significantly longer ICU stay and hospital mortality.

Conclusions

Our study showed that evidence-practice gaps continue to exist, and it appears that physician behavior is mainly driven by the absolute level of hemoglobin. Educational interventions focused on these factors are required to limit the widespread and often unnecessary use of this scarce and potentially harmful resource.     

The Functional MR study of motor cortex

By certain functional stimulates, the brain cortex becomes active. The MR scan has been proven to image these cortex activities by comparing the images with and without functional stimulates. The signal differences between the image with and without functional stimulates is related with the hemodynamic and metabolic changes induced by functional activities. This signal difference is very small, but detectable by MR system, and is the functional MR signal. The MR scan displaying the functio…     

How many subjects constitute a study?

In fMRI there are two classes of inference: one aims to make a comment about the "typical" characteristics of a population, and the other about "average" characteristics. The first pertains to studies of normal subjects that try to identify some qualitative aspect of normal functional anatomy. The second class necessarily applies to clinical neuroscience studies that want to make an inference about quantitative differences of a regionally specific nature. The first class of inferences is adequately serviced by conjunction analyses and fixed-effects models with relatively small numbers of subjects. The second requires random-effect analyses and larger cohorts.     

Ultrasonic study of homœopathic solutions

Ultrasonic velocity and absorption measurements have been performed in homœopathic solutions and in corresponding placebo solutions. The possibility of microstructural differences between ‘normal water’ and ‘homœopathic’ water solutions was investigated by propagation of ultrasonic waves in diluted water-ethanol mixtures. Our spectroscopic results do not display any difference between the two liquid systems.