Does positron emission tomography data acquisition impact simultaneous diffusion-weighted imaging in a whole-body PET/MRI system?

Objectives

The purpose of this study was to test whether the acquisition of positron emission tomography (PET) does interfere with simultaneous diffusion weighted imaging (DWI) in an integrated whole-body PET/MRI system.

Material and methods

Fourteen consecutive oncological patients (9 men, 5 women; age 54 ± 13 years ([mean ± standard deviation]) scheduled for routine [¹⁸F]-FDG PET/CT were prospectively enrolled. For DWI, an echo planar imaging (EPI) sequence (b = 0–500–1000 s/mm²) was acquired twice on an integrated whole-body 3 T PET/MRI system in each patient; first with simultaneous PET acquisition and a second time with the PET component switched off. The apparent diffusion coefficient (ADC) and the signal-to-noise ratio at b = 1000 s/mm² (SNR) of the myocardium, paraspinal muscle, liver, spleen, renal cortex and tumor tissue (if present) were measured. In addition, the coefficient of variation (CV) of ADC values was calculated. Student's t-test for paired samples was performed to test for differences of the mean ADC, ADC CV and SNR between DWI with and without simultaneous PET acquisition.

Results

There were no significant differences of the ADC [(mean ± standard deviation)] between the DWI acquisitions with and without simultaneous PET acquisition for the myocardium (2572 ± 441 × 10⁻⁶ mm²/s and 2586 ± 376 × 10⁻⁶ mm²/s, respectively) (P = 0.817), paraspinal muscle (1279 ± 254 × 10⁻⁶ mm²/s vs. 1219 ± 181 × 10⁻⁶ mm²/s) (P = 0.318), liver (1245 ± 158 × 10⁻⁶ mm²/s vs. 1254 ± 171 × 10⁻⁶ mm²/s) (P = 0.848), spleen (980 ± 122 × 10⁻⁶ mm²/s vs. 1000 ± 187 × 10⁻⁶ mm²/s) (P = 0.676) and renal cortex (1951 ± 226 × 10⁻⁶ mm²/s vs. 1930 ± 273 × 10⁻⁶ mm²/s) (P = 0.730). Mean ADC of lymph node metastases (n = 6) did not differ between with PET acquisition (853 ± 174 × 10⁻⁶ mm²/s) and without simultaneous PET (865 ± 170 × 10⁻⁶ mm²/s) (P = 0.675). There were no significant differences between the CV of ADC values or the SNR values measured in DWI datasets that were acquired with or without simultaneous PET for any evaluated organ site.

Conclusion

The simultaneous acquisition of DWI and PET on an integrated PET/MRI system does not impact ADC quantification of normal and tumor tissue and does not alter SNR. This knowledge provides a basis for the use of simultaneous multiparametric PET/MRI comprising DWI in diagnostic imaging and quantitative tumor therapy monitoring using repeated ADC measurements.     

Hybrid [F]-FDG PET/MRI including non-Gaussian diffusion-weighted imaging (DWI): Preliminary results in non-small cell lung cancer (NSCLC)

Purpose

To assess the feasibility of non-Gaussian DWI as part of a FDG-PET/MRI protocol in patients with histologically proven non-small cell lung cancer.

Material and methods

15 consecutive patients with histologically proven NSCLC (mean age 61 ± 11 years) were included in this study and underwent whole-body FDG-PET/MRI following whole-body FDG-PET/CT. As part of the whole-body FDG-PET/MRI protocol, an EPI-sequence with 5 b-values (0, 100, 500, 1000 and 2000 s/mm²) was acquired for DWI of the thorax during free-breathing. Volume of interest (VOI) measurements were performed to determine the maximum and mean standardized uptake value (SUV_max; SUV_mean). A region of interest (ROI) was manually drawn around the tumor on b = 0 images and then transferred to the corresponding parameter maps to assess ADC_mono, D_app and K_app. To assess the goodness of the mathematical fit R² was calculated for monoexponential and non-Gaussian analysis. Spearman's correlation coefficients were calculated to compare SUV values and diffusion coefficients. A Student's t-test was performed to compare the monoexponential and non-Gaussian diffusion fitting (R²).

Results

T staging was equal between FDG-PET/CT and FDG-PET/MRI in 12 of 15 patients. For NSCLC, mean ADC_mono was 2.11 ± 1.24 × 10⁻³ mm²/s, D_app was 2.46 ± 1.29 × 10⁻³ mm²/s and mean K_app was 0.70 ± 0.21. The non-Gaussian diffusion analysis (R² = 0.98) provided a significantly better mathematical fitting to the DWI signal decay than the monoexponetial analysis (R² = 0.96) (p < 0.001). SUV_max and SUV_mean of NSCLC was 13.5 ± 7.6 and 7.9 ± 4.3 for FDG-PET/MRI. ADC_mono as well as D_app exhibited a significant inverse correlation with the SUV_max (ADC_mono: R = −0.67; p < 0.01; D_app: R = −0.69; p < 0.01) as well as with SUV_mean assessed by FDG-PET/MRI (ADC_mono: R = −0.66; p < 0.01; D_app: R = −0.69; p < 0.01). Furthermore, K_app exhibited a significant correlation with SUV_max (R = 0.72; p < 0.05) and SUV_mean as assessed by FDG-PET/MRI (R = 0.71; p < 0.005).

Conclusion

Simultaneous PET and non-Gaussian diffusion acquisitions are feasible. Non-Gaussian diffusion parameters show a good correlation with SUV and might provide additional information beyond monoexponential ADC, especially as non-Gaussian diffusion exhibits better mathematical fitting to the decay of the diffusion signal than monoexponential DWI.     

Antibacterial Properties and Mode of Action of a Short Acyl-Lysyl Oligomer

We investigated the potency, selectivity, and mode of action of the oligo-acyl-lysine (OAK) NC₁₂-2β₁₂, which was recently suggested to represent the shortest OAK sequence that retains nonhemolytic antibacterial properties. A growth inhibition assay against a panel of 48 bacterial strains confirmed that NC₁₂-2β₁₂ exerted potent activity against gram-positive bacteria while exhibiting negligible hemolysis up to at least 100 times the MIC. Interestingly, NC₁₂-2β₁₂ demonstrated a bacteriostatic mode of action, unlike previously described OAKs that were bactericidal and essentially active against gram-negative bacteria only. The results of various experiments with binding to model phospholipid membranes correlated well with those of the cytotoxicity experiments and provided a plausible explanation for the observed activity profile. Thus, surface plasmon resonance experiments performed with model bilayers revealed high binding affinity to a membrane composition that mimicked the plasma membrane of staphylococci (global affinity constant [K_app], 3.7 × 10⁶ M⁻¹) and significantly lower affinities to mimics of Escherichia coli or red blood cell cytoplasmic membranes. Additional insertion isotherms and epifluorescence microscopy experiments performed with model Langmuir monolayers mimicking the outer leaflet of plasma membranes demonstrated the preferential insertion of NC₁₂-2β₁₂ into highly anionic membranes. Finally, we provide mechanistic studies in support of the view that the bacteriostatic effect resulted from a relatively slow process of plasma membrane permeabilization involving discrete leakage of small solutes, such as intracellular ATP. Collectively, the data point to short OAKs as a potential source for new antibacterial compounds that can selectively affect the growth of gram-positive bacteria while circumventing potential adverse effects linked to lytic compounds.The widespread resistance of bacteria to conventional antibiotics continues to stimulate the search for alternative antimicrobials, such as the host defense antimicrobial peptides (AMPs). AMPs can demonstrate a broad spectrum of activities, including antibiotic activity against both gram-positive and gram-negative bacteria and antiviral and antifungal activities, as well as chemotactic activity and the ability to stimulate chemokine production (23). While the precise mechanism of action needs to be better understood, a multitude of observations suggest more than one mode of action (8, 60). These include abrupt disruption of the cell membrane, which is often concomitant with rapid depolarization of the transmembrane potential (30, 58), as well as intracellular targets, including inhibition of enzymatic activities (2, 10, 37) and biosynthesis (6, 27, 41, 53). Such a multitarget mode of action might significantly overcome various drug resistance mechanisms, which renders AMPs attractive in a variety of antimicrobial applications (21). Nevertheless, various drawbacks, including high susceptibility to proteolysis, toxicity, and high manufacturing costs, complicate the application of AMPs in systemic routes of administration and encourage de novo and rational design of novel compounds with improved properties.The peptidomimetic approach has emerged in recent years as a powerful means for overcoming the inherent limitations of peptide physical characteristics, where the therapeutic potential can be improved by increasing selectivity and bioavailability (9, 40, 45, 49, 52). Peptidomimetic strategies consisting of peptide backbone modifications and incorporation of unnatural amino acids, aromatic rings (25), and amino fatty acids (43, 44) have been proposed as novel building blocks to improve potency by enhancing binding affinity to membranes and to reduce susceptibility to inactivation by serum proteases (39). Oligo-acyl-lysines (OAKs) are among the simpler AMP-mimetic designs, in which the two most important characteristics for AMP activity, hydrophobicity and charge, are represented as tandem repeats of amide-linked fatty acids and lysines (15, 42-44, 46, 48). This design was shown to overcome the limitations of conventional AMPs with respect to in vivo efficacy and toxicity (43-45). Two types of OAKs have been presented so far, each composed of acyl-lysyl (α_n) or lysyl-acyl-lysyl (β_n) subunits, where n defines the acyl length (43). In previous studies, the α-OAKs C₁₂K-7α₈ (44) and C₁₂K-5α₈ (46) showed potent antibacterial activity against most gram-negative strains tested, both in vitro and in vivo. Furthermore, the OAKs were shown to induce bacterial death by damaging the cytoplasmic membrane or by inhibiting DNA expression, respectively. Shorter OAK sequences also displayed potent antiplasmodial activity (42) but were too hemolytic to be considered for systemic applications.To study the structure-activity relationships in OAKs, we recently used a rapid screening assay to test >100 OAK sequences for their hemolytic activities against human red blood cells (RBCs) and antibacterial activities against Escherichia coli and Staphylococcus aureus as representatives of gram-negative and gram-positive bacteria, respectively. The structure-activity relationships that emerged indicated that the self-assembly properties of excessively hydrophobic OAKs are responsible for poor antibacterial properties and for high hemolytic activity (43). Moreover, the study suggested that the minimal requirements for potent and selective antibacterial activity are embedded in the sequence aminolauryl-[lysyl-aminolauryl-lysyl]₂ (designated NC₁₂-2β₁₂), the structure of which is depicted in Fig. ​Fig.1a.1a. Here, we tested this premise and further characterized the antimicrobial properties of NC₁₂-2β₁₂ to shed new light on the mechanism of action.Open in a separate windowFIG. 1.Biophysical characteristics of NC₁₂-2β₁₂. (a) OAK molecular structure (mass, 1,121.7 g/mol). (b and c) Effects of ionic strength and pH on antimicrobial activity, as assessed against two strains of S. aureus: ATCC 29213 (squares) and ATCC 25923 (triangles). (d) Dose-dependent hemolytic activity of NC₁₂-2β₁₂ (stars) and C₁₆-K-β₁₂ (circles) as determined by measuring the absorbances of the supernatants (at 470 nm) after 1 h of incubation with RBCs (10%; 37°C) in PBS. (e) Dose-dependent light-scattering intensities of PBS solutions of NC₁₂-2β₁₂ (stars) and C₁₆-K-β₁₂ (circles). The error bars indicate standard deviations calculated from at least three independent experiments performed in duplicate. Lack of standard deviations indicates consistency.     

Pregnancy outcome after gestational exposure to the new macrolides: a prospective multi-center observational study

Objectives

To determine whether the use of the new macrolides (azithromycin, clarithromycin, roxithromycin) during the first trimester of pregnancy is associated with an increased risk of major malformations.

Study design

In a prospective multi-center study, pregnancy outcome was compared between pregnant women exposed to one of the new macrolides during the first trimester of pregnancy and two comparison groups one exposed to other antibiotics and the other to other non-teratogenic medications. All women enrolled in the study called one of the three participating teratogen information services (TIS). Group 1 macrolides (n = 161), group 2 other antibiotics (n = 213) and group 3 non-teratogens (n = 740).

Results

A total of 161 women exposed to the new macrolides (118 were exposed in the first trimester of pregnancy) and 953 from a comparison groups were followed up. The rate of major malformations in the study group was 4.1% compared to 2.1% in the other antibiotics exposed group (OR = 1.41, 95% CI 0.47–4.23) and 3.0% in the non-teratogens exposed group. The rate of elective terminations of pregnancy was significantly higher in the exposed group in compare to both comparison groups.

Conclusion

Our study, although relatively small sized, suggests that the use of the new macrolides during the first trimester of pregnancy does not represent an increased risk for congenital malformations strong enough for an induced abortion after such an exposure. Elective terminations of pregnancy because of early exposure to these medications should be reconsidered.     

Pigmented epithelial tumours of the conjunctiva.

Two out of 60 conjunctival epithelial tumours reviewed between 1973 and 1989 were found to be pigmented. One tumour was a pigmented papilloma and the other a pigmented squamous cell carcinoma. The melanin pigment was found in epithelial tumour cells as well as in macrophages, dendritic melanocytes, and Langerhans cells. The distinction between the latter two types of cells was possible in one of the tumours only. Both tumours were found in dark-skinned white patients without any evidence of conjunctival acquired melanosis.     

Vacuum extraction delivery at first vaginal birth following cesarean: maternal and neonatal outcome

Archives of Gynecology and Obstetrics - To evaluate the maternal and neonatal morbidity outcome associated with vacuum assisted (VA) vaginal delivery at first vaginal birth following a previous...     

Development of the nasopharynx: A radiological study of children

The relation between pharyngeal tonsil and the bony nasopharynx determines the nasopharyngeal airway patency. Despite its importance, an anatomical study utilizing advanced imaging has not been conducted. The aim of the study was to evaluate the pharyngeal tonsil and bony nasopharynx depth and their ratio (adenoid-nasopharyngeal ratio [ANR]) with relation to sex and age in the general pediatric population. After excluding reported history of adenoidectomy, acute upper airway illness, allergy, and poor quality, 200 randomly selected head computed tomographies (CTs) of children were evaluated. CTs were divided into five age groups (0–5, 5.1–8, 8.1–11, 11.1–14, and 14.1–17 years). For each CT scan, the pharyngeal tonsil, bony nasopharynx and ANR values were calculated. A significant difference was found in the bony nasopharynx and pharyngeal tonsil depth between the five age subgroups (P < 0.001). Both bony nasopharynx and pharyngeal tonsil depth significantly increased between the age groups of 0–5 years to 5.1–8 years (4.17 mm increase, P < 0.001 and 3.47 mm increase, P < 0.009, respectively). The pharyngeal tonsil depth gradually decreases following the age of 8 years. No difference was found between age groups beyond age of eight for both the pharyngeal tonsil tissue and the bony nasopharynx. The ANR has an upward trend in the age group of 5.1–8 years. No sexual predilection was found. The bony nasopharynx and the pharyngeal tonsil tissue both grow during childhood. Different growth rates result in the narrowest airway in the age group of 5.1–8 years (ANR peak). These growth curves should be taken under consideration when treating pediatric pharyngeal tonsil hypertrophy. Clin. Anat., 33:1019–1024, 2020. © 2019 Wiley Periodicals, Inc.     

Local anaesthesia for first carpometacarpal joint arthroplasty

Summary A simple method of local subcutaneous anaesthesia for the surgical treatment of the first carpometacarpal joint (CMC-1) osteoarthritis is described. The first carpometacarpal joint arthroplasty is performed under local anaesthesia. The choice of the procedure depends upon each individual case. The method has been used for five years in 181 consecutive patients undergoing CMC-1 arthroplasty with great satisfaction. The procedure is described. Its advantages are: total low dose anaesthetic agents, simplicity, and safety. Its value in high risk patients is emphasized.     

Use of buried skin implants after recurrent failure of conventional skin grafting in a massive burn: the renewal of an old technique

The technique of burying small pieces of skin under old granulation tissue after recurrent failure of conventional skin grafting is described in a patient with 95 per cent full skin thickness burns. This method of treatment, which was described in the past and neglected, is of value for massive burns or grafting in difficult areas. The technique is described again and the relevant literature reviewed.     

Cellular immune functions in patients with primary hyperparathyroidism: effects of histamine and cimetidine

The possibility of a link between parathyroid hyperfunction and cellular immune functions was studied in primary hyperparathyroid (1 degree HP) patients. The effect of cimetidine on lymphocyte functions in 1 degree HP patients and control subjects was also investigated. Histamine-induced suppressor activity of lymphocytes from 1 degree HP patients was significantly greater than that of controls. Cimetidine addition to both normal and 1 degree HP lymphocyte cultures abolished histamine-induced suppression. In vivo administration of cimetidine, while ineffective towards normal lymphocytes, depressed phytohemagglutinin stimulation of 1 degree HP lymphocytes, indicating possible immunological damage caused by this drug, which is frequently used in the treatment of patients with 1 degree HP.