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BACKGROUND To date, plastic surgeons do not have an objective method of measuring facial symmetry for zygomatic bone fracture management. Based on clinical practice, the authors utilized a 3-dimensional (3D) model to propose the symmetry index from the anterior view (SIAV) and the symmetry index from inferior view (SIIV). This study aimed to assess the application of these 2 indices. METHODS The SIAV is defined as the distance between the superior and lower orbital rims (DSLOR) of the defective side divided by that of the healthy side in the anterior view. The SIIV is defined as the area within the region of interest (AROI) of the defective side divided by that of the healthy side in the inferior view. We retrospectively reviewed 95 patients who underwent zygomatic fracture surgery at our medical center from January 2017 to September 2020. The Patients who had bilateral zygomatic fractures and did not have both pre- and postoperative computed tomography (CT) images were excluded. RESULTS Five out of the 95 patients were enrolled in this study. The difference between pre- and postoperative mean AROI and DSLOR on the healthy side was not significant. The insignificant difference indicates the repeatability of the measurement of the 3D skull model and different CT machines would not affect the calculation of AROI and DSLOR. The mean values of postoperative SIAV (1.06 ± 0.07) and SIIV (1.02 ± 0.08) were closer to 1 than the preoperative values (0.97 ± 0.09 and 1.10 ± 0.12). Although the difference was not statistically significant, the SIIV and SIAV would numerically present the changes in malar bone fracture postoperatively. CONCLUSION The SIAV and SIIV based on clinical practice could numerically assess the symmetry of the malar mound.

BACKGROUND Static progressive orthosis is used for the treatment of severe joint contracture after trauma and/or surgery. However, a custom-fabricated static progressive splint would be expensive and labor intensive. Especially, owing to very limited payment under the current Taiwanese National Health Insurance, the incentives to fabricate a patient-specific splint are insufficient for a therapist. To ease splint construction, we introduced three-dimensional (3D)-printed "shark fin"-shaped device works as a static progressive orthosis for the hand rehabilitation. The aim of this study was to describe and demonstrate the newly designed device. METHODS This study included a 46-year male suffered from a left distal radius fracture and underwent open reduction internal fixation and a 23-year male with the right thumb flexor pollicis longus rupture, requiring tendon repair. Both subjects used this "shark fin"-shaped device to stretch for increasing range of motion (ROM) of wrist extension and the thumb. RESULTS The patient receiving ulnar shortening surgery used this device to stretch for increasing ROM of wrist extension. The active ROM of wrist extension improved from 30° to 50°. The other patient with the right thumb flexor pollicis longus rupture suffered from thumb contracture; the ROMs of the metacarpophalangeal (MCP) joint and interphalangeal (IP) joint were 40°-55° and 20°-25°, respectively. After tenolysis surgery, his ROMs of the MCP and IP joints were improved to 10°-35° and 40°-65°, respectively. Following physical therapy by applying the device, his ROMs of the MCP and IP joints were further increased to 0°-40° and 25°-70°, respectively. CONCLUSION Incorporating the "shark fin"-shaped orthosis into hand rehabilitation increased the ROM of wrist extension for a patient with distal radius fracture and improved the ROM of the MCP and IP joints in another patient after tenolysis surgery.

Background To surgically remove osteoma and to keep an optimal cosmetic profile would be very challenging. To solve the difficulty, we utilized the three-dimensional (3D) printing technologies in generating a patient-specific instrument guide (PSIG) for the safe removal of a skull bone tumor. Methods The preoperational brain computed tomography (CT) provided the digital imaging with thin slices, and then images were reconstructed into a 3D skull model. Based on the model, we designed a PSIG to make landmarks on the osteoma to avoid excessive removal of the skull bone. During the operation, the surgeons could remove the osteoma piece by piece by using the landmark as a reference point. Results The PSIG was successfully applied to remove an osteoma that measured 60 × 48 × 40 mm over the left frontoparietal skull of a female patient. The 3D CT reconstruction taken both before and 4 months after surgery showed a significant change in the appearance of the osteoma. Conclusion The PSIG was able to guide the surgeon in the safe removal of the skull osteoma, as well as in maintaining the cosmetic skull profile.

Application of 3-dimensional (3D) printing technology has grown in the medical field over the past 2 decades. In managing orbital blowout fractures, 3D printed models can be used as intraoperative navigators and could shorten the operational time by facilitating prebending or shaping of the mesh preoperatively. However, a comparison of the accuracy of computed tomography (CT) images and printed 3D models is lacking.This is a single-center retrospective study. Patients with unilateral orbital blowout fracture and signed up for customized 3D printing model were included. Reference points for the 2D distance were defined (intersupraorbital notch distance, transverse horizontal, sagittal vertical, and anteroposterior axes for orbital cavity) and measured directly on 3D printing models and on corresponding CT images. The difference and correlation analysis were conducted.In total, 9 patients were reviewed from June 2017 to December 2020. The mean difference in the intersupraorbital notch measurement between the 2 modules was -0.14 mm (P = 0.67). The mean difference in the distance measured from the modules in the horizontal, vertical, and anteroposterior axes of the traumatic orbits was 0.06 mm (P = 0.85), -0.23 mm (P = 0.47), and 0.51 mm (P = 0.32), whereas that of the unaffected orbits was 0.16 mm (P = 0.44), 0.34 mm (P = 0.24), and 0.1 mm (P = 0.88), respectively. Although 2D parameter differences (1 mm) between 3D printing models and CT images were discovered, they were not statistically significant.Three-dimensional printing models showed high identity and correlation to CT image. Therefore, personalized models might be a reliable tool of virtual surgery or as a guide in realistic surgical scenarios for orbital blowout fractures.

Key words Coronavirus disease 2019; COVID-19; 3D printing; door handle

Thyroidectomy transoral endoscopic thyroidectomy vestibular approach (TOETVA) is a safe and cosmetically appealing alternative for well-selected patients undergoing thyroidectomy. However, during TOETVA, placement of the two lateral trocars and/or manipulation of the surgical instruments through the trocars may potentially injure and/or compress the mental nerve (MN) because the actual location of the nerve foramen may vary among individuals. The MN injury rate was reported to be as high as 75% in the initial period of robotic-assisted TOETVA. To reduce the potential risk of MN injury, we implemented a three-dimensional printing technology to develop a safety device for TOETVA. The patient-specific safety device (PSSD) was a brace with an exact fit to the lower teeth and two safety markers on each side to indicate the location of the mental foramen. For patient in whom the brace would not be applicable, a 3D mandibular model was printed as a PSSD instead. We analyzed 66 patients undergoing TOETVA at our institution from March 2017 to March 2019. The preoperative details and complication profiles were also analyzed. With incorporation of the PSSD into our TOETVA procedure, there have been no cases of MN injury. Our own TOETVA series has demonstrated that the implementation of the PSSD has been successful in preoperatively identifying and preventing the potential risk of MN injury. Although the additional requirements of preoperative CT and time for fabricating the device impose limitations, the influence of the PSSD in TOETVA is positive.

The whole picture of the BNCT facility at Tsing Hua Open-pool Reactor will be presented which consists of the following aspects: the construction project, the beam quality, routine operations including the QA program for the beam delivery, determination of boron-10 concentration in blood, T/N ratio, and the clinical affairs including the patient recruit procedure and the patient irradiation procedure. The facility is positioned to serve for conducting clinical trials, emergent (compassionate) treatments, and R&D works.

Background Liposomes are drug nano-carriers that are capable of targeting therapeutics to tumor sites because of enhanced permeability retention (EPR). In several preclinical studies with various tumor-bearing mice models, 188Re-liposome that has been developed by the Institute of Nuclear Energy Research (INER) demonstrates favorable in vivo tumor targeting, biodistribution, pharmacokinetics, and dosimetry. It inhibits the growth of tumors, increased survival, demonstrates good synergistic combination, and was safe to use. This study conducts a phase 0 low-radioactivity clinical trial of nano-targeted radiotherapeutics 188Re-liposome to evaluate the effectiveness with which it targets tumors and the pharmacokinetics, biodistribution, dosimetry, and its safety in use. Twelve patients with metastatic cancers are studied in this trial. Serial whole-body scans and SPECT/CT are taken at 1, 4, 8, 24, 48, and 72 h after intravenous injection of 111 MBq of 188Re-liposome. The effectiveness with which tumors are targeted, the pharmacokinetics, biodistribution, dosimetry, and safety are evaluated using the VelocityAI and OLINDA/EXM software. Blood samples are collected at different time points for a pharmacokinetics study and a safety evaluation that involves monitoring changes in liver, renal, and hematological functions. Results The T½z for 188Re-liposome in blood and plasma are 36.73 ± 14.00 h and 52.02 ± 45.21 h, respectively. The doses of radiation that are absorbed to vital organs such as the liver, spleen, lung, kidney, and bone marrow are 0.92 ± 0.35, 1.38 ± 1.81, 0.58 ± 0.28, 0.32 ± 0.09, and 0.06 ± 0.01 mGy/MBq, respectively, which is far less than the reference maximum tolerance dose after injection of 188Re-liposome. 188Re-liposome is absorbed by metastatic tumor lesions and the normal reticuloendothelial (RES) system. Certain patients exhibit a therapeutic response. Conclusion This phase 0 exploratory IND study shows that nanocarrier 188Re-liposome achieves favorable tumor accumulation and tumor to normal organ uptake ratios for a subset of cancer patients. The clinical pharmacokinetic, biodistribution, and dosimetry results justify a further dose-escalating phase 1 clinical trial. Trial registration Taiwan FDA MA1101G0 (Jan 31, 2012).

Background: S1P has been shown to improve the endothelialization of decellularized vascular grafts in vitro. Here, we evaluated the potential of tissue-engineered vascular grafts (TEVGs) constructed by ECs and S1P on decellularized vascular scaffolds in a rat model. Methods: Rat aorta was decellularized mainly by 0.1% SDS and characterized by histology. Rat ECs, were seeded onto decellularized scaffolds, and the viability of the ECs was evaluated by biochemical assays. Then, we investigated the in vivo patency rate and endothelialization for five groups of decellularized vascular grafts (each n = 6) in a rat abdominal aorta model for 14 days. The five groups included (1) rat allogenic aorta (RAA), (2) decellularized RAA (DRAA), (3) DRAA with S1P (DRAA/S1P), (4) DRAA with EC recellularization (DRAA/EC), and (5) DRAA with S1P and EC recellularization (DRAA/EC/S1P). Results: In vitro, ECs were identified by the uptake of Dil-Ac-LDL. S1P enhanced the expression of syndecan-1 on ECs and supported the proliferation of ECs on decellularized vascular grafts. In vivo, RAA and DRAA/EC/S1P both had 100% patency without thrombus formation within 14 days. Better endothelialization, more wall structure maintenance and less inflammation were noted in the DRAA/EC/S1P group. In contrast, there was thrombus formation in the DRAA, DRAA/S1P and DRAA/EC groups. Conclusion: S1P could inhibit thrombus formation to improve the patency rate of EC-covered decellularized vascular grafts in vivo and may play an important role in the construction of TEVGs.

Purpose To investigate the efficacy and safety of fractionated boron neutron capture therapy (BNCT) for recurrent head and neck (H&N) cancer after photon radiation therapy. Methods and Materials In this prospective phase 1/2 trial, 2-fraction BNCT with intravenous L-boronophenylalanine (L-BPA, 400 mg/kg) was administered at a 28-day interval. Before each fraction, fluorine-18-labeled-BPA–positron emission tomography was conducted to determine the tumor/normal tissue ratio of an individual tumor. The prescription dose (D80) of 20 Gy-Eq per fraction was selected to cover 80% of the gross tumor volume by using a dose volume histogram, while minimizing the volume of oral mucosa receiving >10 Gy-Eq. Tumor responses and adverse effects were assessed using the Response Evaluation Criteria in Solid Tumors v1.1 and the Common Terminology Criteria for Adverse Events v3.0, respectively. Results Seventeen patients with a previous cumulative radiation dose of 63-165 Gy were enrolled. All but 2 participants received 2 fractions of BNCT. The median tumor/normal tissue ratio was 3.4 for the first fraction and 2.5 for the second, whereas the median D80 for the first and second fraction was 19.8 and 14.6 Gy-Eq, respectively. After a median follow-up period of 19.7 months (range, 5.2-52 mo), 6 participants exhibited a complete response and 6 exhibited a partial response. Regarding acute toxicity, 5 participants showed grade 3 mucositis and 1 participant showed grade 4 laryngeal edema and carotid hemorrhage. Regarding late toxicity, 2 participants exhibited grade 3 cranial neuropathy. Four of six participants (67%) receiving total D80 > 40 Gy-Eq had a complete response. Two-year overall survival was 47%. Two-year locoregional control was 28%. Conclusions Our results suggested that 2-fraction BNCT with adaptive dose prescription was effective and safe in locally recurrent H&N cancer. Modifications to our protocol may yield more satisfactory results in the future.

Background Reduced brain serotonin transporter (SERT) has been demonstrated in bipolar disorder (BD). The aim of this study was to explore the potential role of cytokines on reduced SERT in BD. Methods Twenty-eight BD type I patients and 28 age- and gender-matched healthy controls (HCs) were recruited. Single photon emission computed tomography with the radiotracer 123I ADAM was used for SERT imaging. Regions of interest included the midbrain, thalamus, putamen and caudate. Seven cytokines, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1α (IL-1α), IL-1β, IL-4, IL-6 and IL-10, were measured using an enzyme linked immune-sorbent assay. Results: SERT availability in the midbrain and caudate was significantly lower in BD compared to HCs. IL-1β was significantly lower, whereas IL-10 was significantly higher in BD compared to HCs. Multiple linear regression analyses revealed that there were associations between cytokines, IL-1α, IL-1β, IL-6 and SERT availability in the midbrain but not in the thalamus, putamen and caudate. Furthermore, linear mixed effect analyses demonstrated that these associations were not different between HCs and BD. Conclusion While many cytokines have been proposed to be important in the pathophysiology of BD, our results demonstrated that significant associations between cytokines and SERT availability may explain the role of cytokines in mood regulation. However, these associations were not different between HCs and BD, which imply the role of these cytokines is not specific for BD.

Background Liposomes are drug nano-carriers that are capable of targeting therapeutics to tumor sites because of enhanced permeability retention (EPR). In several preclinical studies with various tumor-bearing mice models, 188Re-liposome that has been developed by the Institute of Nuclear Energy Research (INER) demonstrates favorable in vivo tumor targeting, biodistribution, pharmacokinetics, and dosimetry. It inhibits the growth of tumors, increased survival, demonstrates good synergistic combination, and was safe to use. This study conducts a phase 0 low-radioactivity clinical trial of nano-targeted radiotherapeutics 188Re-liposome to evaluate the effectiveness with which it targets tumors and the pharmacokinetics, biodistribution, dosimetry, and its safety in use. Twelve patients with metastatic cancers are studied in this trial. Serial whole-body scans and SPECT/CT are taken at 1, 4, 8, 24, 48, and 72 h after intravenous injection of 111 MBq of 188Re-liposome. The effectiveness with which tumors are targeted, the pharmacokinetics, biodistribution, dosimetry, and safety are evaluated using the VelocityAI and OLINDA/EXM software. Blood samples are collected at different time points for a pharmacokinetics study and a safety evaluation that involves monitoring changes in liver, renal, and hematological functions. Results The T½z for 188Re-liposome in blood and plasma are 36.73 ± 14.00 h and 52.02 ± 45.21 h, respectively. The doses of radiation that are absorbed to vital organs such as the liver, spleen, lung, kidney, and bone marrow are 0.92 ± 0.35, 1.38 ± 1.81, 0.58 ± 0.28, 0.32 ± 0.09, and 0.06 ± 0.01 mGy/MBq, respectively, which is far less than the reference maximum tolerance dose after injection of 188Re-liposome. 188Re-liposome is absorbed by metastatic tumor lesions and the normal reticuloendothelial (RES) system. Certain patients exhibit a therapeutic response. Conclusion This phase 0 exploratory IND study shows that nanocarrier 188Re-liposome achieves favorable tumor accumulation and tumor to normal organ uptake ratios for a subset of cancer patients. The clinical pharmacokinetic, biodistribution, and dosimetry results justify a further dose-escalating phase 1 clinical trial. Trial registration Taiwan FDA MA1101G0 (Jan 31, 2012).

Three-dimensional (3D) printing technology can generate objects in almost any shape and geometry. This technique also has clinical applications, such as the fabrication of specific devices based on a patient's anatomy. A demonstration study is presented of a 54-year-old man who needed a thermoplastic splint to limit arm movement while a dehisced left shoulder wound healed. The patient's upper extremity was scanned using the appropriate noncontact scanner and 3D technology software, and the polylactic acid splint was printed over the course of 66 hours. This patient-specific splint was worn during the day, and after 2 weeks the wound was healed sufficiently to permit hospital discharge. Creation of an individualized splint is one of many potential medical uses of 3D technology. Although the lengthy printing time imposes limitations, the implications for practice are positive.

Bipolar disorder (BD) is highly heritable and associated with dysregulation of brain glucose utilizations (GU). The mitochondrial DNA (mtDNA) 10398A polymorphism, as a reported BD risk factor, leads to deficient glycolytic energy production by affecting mitochondrial matrix pH and intracellular calcium levels. However, whether mtDNA-10398A has functional effects on the brain and how our body responds remain elusive. We compared peripheral and central glucose-utilizing patterns between mtDNA A10398G polymorphisms in BD and their unaffected siblings (BDsib). Since siblings carry identical mtDNA, we hypothesized that certain characteristics co-segregate in BD families. We recruited twenty-seven pairs of non-diabetic BD patients and their BDsib and 30 well-matched healthy control subjects (HC). The following were investigated: mtDNA, fasting plasma glucose/insulin, cognitive functions including Montreal Cognitive Assessment (MoCA), and brain GU at rest. Insulin resistance was rechecked in sixty-one subjects (19-BD, 18-BDsibib, and 24-HC) six months later. We found that BD-pairs (BD+BDsib) carried more mtDNA-10398A and had higher fasting glucose, even after controlling for many covariates. BD-pairs had abnormally lower dorso-prefrontal-GU and higher cerebellar-GU, but only BD demonstrated lower medio-prefrontal-GU and MoCA. Subjects carrying mtDNA-10398A had significantly lower prefrontal-GU (FWE-corrected p

BackgroundMedication-resistant depression (MRD) is associated with poorer attentional performance and immense socioeconomic costs.AimsWe aimed to investigate the central pathophysiology of MRD, previously linked to impaired prefrontal cortex function.MethodA total of 54 participants (22 with MRD, 16 with non-resistant depression, 16 healthy controls) were recruited. Non-MRD status was confirmed by a prospective 6-week antidepressant trial. All medication-free participants underwent a go/no-go task to study prefrontal cortical function (attention) and positron emission tomography scans to study regional cerebral glucose metabolism (rCMglu) at rest.ResultsThe MRD group had worse attentional ratings and decreased rCMglu compared with the non-MRD and control groups. Attentional performance was positively associated with prefrontal cortex rCMglu. The prefrontal cortex differences between MRD and non-MRD groups remained after adjusting for past depressive episodes (F(1,35) = 4.154, P = 0.043).ConclusionsPronounced hypofrontality, with the associated attentional deficits, has a key role in the neuropathology of medication-resistant depression.

Introduction The purpose of this study was to investigate the feasibility of using low-dose computed tomography (CT) in coronary artery calcium scoring and PET attenuation correction for patients in different weight categories undergoing cardiac PET/CT examinations. Materials and methods Calcium scoring computed tomography (CSCT) scans and PET scans of anthropomorphic cardiac phantoms simulating normal-weight, mildly obese, and severely obese patients were acquired with a hybrid PET/CT scanner. CSCT images were acquired at 120 kVp, with tube current ranging from 10 to 550 mA. PET scans were performed in three-dimensional mode, with acquisition time of 3 min/bed position. The image quality of cardiac PET/CT was evaluated by assessing the signal-to-noise ratio. CT-based coronary artery calcium quantification was performed using the Agatston scoring system. Results On the basis of our results, the CSCT protocols using tube currents of 50 and 150 mA should be able to achieve the lowest possible radiation dose while maintaining the desired image quality for normal-weight and mildly obese patients undergoing cardiac PET/CT examinations, respectively. When the proposed low-dose CSCT protocols were performed, radiation dose could be reduced by 83.34 and 50% compared with those from CSCT scans acquired with standard tube current settings for normal-weight and mildly obese patients, respectively. In the scanning of severely obese patients, an increase in tube voltage or current would help improve the reliability of image information provided by cardiac PET/CT. Conclusion Our study demonstrated the feasibility of low-dose CT protocols for coronary artery calcium scoring and PET attenuation correction in cardiac PET/CT to examine patients in different weight categories. The calculations performed in this work should be able to provide practical information to achieve necessary diagnostic information while keeping radiation dose as low as reasonably achievable.

US common law recites a natural law, natural phenomenon or abstract idea as exceptions to the 4 statutory patentable categories to guard against the wholesale preemption of fundamental principles. The very recent evolutions of patent exceptions in the US may increase the difficulty of patenting and may create uncertainty in determining patent eligibility. To solve the thorny problem of eligibility, this study presents a flow chart based on the courts’ decisions that can serve as a set of guidelines for determining patent eligibility. A case related to prostate cancer immune therapy is presented for discussion.

Suicide with charcoal burning, which results in carbon monoxide (CO) poisoning, is common in Asia. This study was designed to elucidate associations between changes in the dopamine transporter (DAT) and cognitive function in patients following CO poisoning during a follow-up period of 6 months. Participants comprised 31 healthy controls (HCs) and 21 CO poisoning patients. Each subject underwent single photon emission computed tomography with [(99m)Tc] TRODAT-1 to measure DAT availability and completed a cognitive battery assessing attention, memory, and executive function. For CO poisoning patients, a second DAT measurement and repeated cognitive evaluations were performed 6 months later. At baseline, DAT availability over bilateral striatum in CO poisoning subjects was significantly lower than in HCs. After 6 months, there was no significant change of DAT availability in CO poisoning patients. CO poisoning patients also had worse cognitive performance in all domains compared with HCs at baseline. After 6 months, most cognitive functions were significantly improved, except for the Wisconsin Card Sorting Test (WCST), a measure of executive function. Interestingly, changes in the WCST were significantly correlated with changes in DAT availability during the 6-month follow-up period. The persistence of reduced DAT availability and its association with impaired performance on the WCST indicate a crucial role of DAT in the recovery of executive function following CO poisoning.

A product-by-process claim was initially developed when the invention could not otherwise be adequately defined. In the US, a patent applicant can use a product-by-process claim for a new product, no matter whether the product can also be defined by using structure features. However, the applicant mainly bears the burden to establish the novelty between the claimed product and the prior art product. Moreover, in terms of infringement, the very recent CAFC cases indicate that the product must be made by a process recited in the claim to infringe a product-by-process claim. Thus, an assignee almost can not take advantage from product-by-process claims during the patent enforcement by comparing with process claims. From the points of the burden during patent prosecution and confined scope in determining infringement, the benefit of using a product-by-process claim would be very limited.

Inequitable conduct regarding any single claim can render the entire patent unenforceable and further damage other related patents and applications in the assignee's patent portfolio. The adverse impact of inequitable conduct significantly became a litigation strategy. The US Federal Circuit (CAFC) observed that inequitable conduct as a patent litigation strategy had become a plague and thus tightened the standard for finding inequitable conduct in a case with full court judges. However, under the shadow of previous adverse impact of inequitable conduct, patent applicants may still submit many marginal related references. This study demonstrates that an applicant even prepared an information disclosure statement (IDS) as many as 50 pages. Actually, under the new standard, inequitable conduct would not further produce significant impact in the US patent system. Thus, a patent applicant need not submit marginal references but should distinguish the prior art from the current application, especially for those listed in the IDS, to avoid the novelty rejection.

To introduce our experience of treating locally and regionally recurrent head and neck cancer patients with BNCT at Tsing Hua Open-Pool Reactor in Taiwan, 12 patients (M/F=10/2, median age 55.5 Y/O) were enrolled and 11 received two fractions of treatment. Fractionated BNCT at 30-day interval with adaptive planning according to changed T/N ratios was feasible, effective and safe for selected recurrent head and neck cancer in this trial.

Objectives The serotonin hypothesis plays a critical role in the etiology of bipolar disorder (BD). Although many studies have demonstrated reciprocal relationships between serotonin metabolism and immune-inflammatory pathways that occur in depression, studies linking serotonergic function and cytokines are still limited concerning BD. The aim of this study was to investigate the interaction of brain serotonin transporter (SERT) and cytokines in BD. Methods Twenty patients with euthymic BD and 20 age- and sex-matched healthy controls (HC) were recruited. Single photon emission computed tomography with the radiotracer 123I-ADAM was used for the SERT imaging. The specific uptake ratio, which represents SERT availability, was the primary measured outcome. Cytokines included the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and the anti-inflammatory cytokine interleukin-10 (IL-10). Cytokine concentration was measured using an enzyme-linked immunosorbent assay. Results SERT availability was significantly lower in the midbrain and caudate of patients with BD compared with HC, but not in the thalamus and putamen. IL-10 was significantly higher, whereas TNF-α was not different in euthymic patients with BD compared with HC. There was a significant association of SERT availability and IL-10 in the thalamus, but not in the midbrain, caudate, or putamen. Conclusions Our results demonstrate the interaction of SERT availability and IL-10 in euthymic BD. This result may further explain the role of SERT and cytokines in the etiology of BD.

Two galactose derivatives, a monovalent (99m)Tc-MAMA-MGal galactoside and a divalent (99m)Tc-MAMA-DGal galactoside, were synthesized and radiolabeled in high radiochemical purity (>98%). Dynamic microSPECT imaging and biodistribution study of two traces in normal and liver fibrosis mice showed that the (99m)Tc-MAMA-DGal revealed higher specific binding to asialoglycoprotein receptors in liver and then rapidly excreted via both hepatobiliary system and renal clearance. The results suggest that (99m)Tc-MAMA-DGal may be used as SPECT probes for noninvasive evaluation of asialoglycoprotein receptor-related liver dysfunction.

To demonstrate the influence of the US Supreme Court's KSR case, our analysis has shown that the ratio of obvious ruling increased from 0.42 to 0.62 after this case, whereas the ratio of non-obvious ruling decreased from 0.47 to 0.28. Therefore, without the rigid application of a "teaching, suggestion or motivation" test, the trends of obvious and non-obvious CAFC rulings significantly increased and decreased, respectively. Based on this analysis, biotech inventors should contemplate the factors that have resulted in ruling of obviousness, which include claims that are too broad, the lack of secondary considerations, the reasonable expectation of success, and the reason or motivation to create a structure based on structural similarity. The presence of these factors most likely would result in the rejection of the claim during patent prosecution or the invalidation of the claim in patent litigation. Two immunotherapy and vaccine cases have applied these factors to overcome the obvious rejections.

Background Aggression is frequently observed in patients diagnosed with bipolar disorder (BD). Previous studies found a negative association between aggression and serotoninergic function in patients with BD, as well as in healthy subjects. The objective of this study was to determine whether there is an association between aggression and the availability of the serotonin transporter (SERT) in euthymic BD II patients. Methods Thirty-eight age-matched healthy controls (HCs) and 24 BD II patients were recruited. BD II patients were under stable treatment in the euthymic state. The Overt Aggression Scale (OAS) was used for the assessment of aggression. Single photon emission computed tomography with 123I-ADAM was used for SERT imaging. A specific uptake ratio, which represents availability, was the primary measured outcome. Results The total OAS scores, as well as the scores on all of the sub-items, were significantly higher in BD II patients than in the HCs group. There was no significant difference in SERT availability between BD II and HCs subjects in different brain regions. The Pearson’s correlation between the total OAS scores and the sub-item aggression and SERT availability was significant. Limitation The OAS was used for the assessment of the past week of the patients’ condition and thus did not reflect their trait status. Conclusions The higher total scores of OAS in euthymic BD II patients than in HCs support the idea that aggression might be a trait marker for BD. Although SERT availability in euthymic BD II patients and in HCs did not differ significantly, the correlation of SERT availability and total OAS provides the possible explanation of aggression in BD II.

To study the impact of video game playing on the human brain, the effects of two video games playing on cerebral blood flow (CBF) in young adults were determined. Thirty healthy subjects comprising 18 males and 12 females who were familiar with video game playing were recruited. Each subject underwent three sessions of single photon emission computed tomography (SPECT) with a bolus injection of 20 mCi (99m)Tc ECD IV to measure their CBF. The first measurement was performed as baseline, the second and third measurements were performed after playing two different video games for 30 min, respectively. Statistic parametric mapping (SPM2) with Matlab 6.5 implemented on a personal computer was used for image analysis. CBF was significantly decreased in the prefrontal cortex and significantly increased in the temporal and occipital cortices after both video games playing. Furthermore, decreased CBF in the anterior cingulate cortex (ACC) which was significantly correlated with the number of killed characters was found after the violent game playing. The major finding of hypo-perfusion in prefrontal regions after video game playing is consistent with a previous study showing reduced or abnormal prefrontal cortex functions after video game playing. The second finding of decreased CBF in the ACC after playing the violent video game provides support for a previous hypothesis that the ACC might play a role in regulating violent behavior.

Background Studies have proposed that cognitive deficits are present in a variety of mood states in bipolar disorder (BD). The goal of this study was to find the cognitive deficits in euthymic BD patients and to further explore possible underlying mechanisms of the deficits. Methods Thirty-three healthy controls (HCs) and twenty-three euthymic BD type I patients were recruited. Single photon emission computed tomography (SPECT) with 123 I-ADAM was used to image the serotonin transporter (SERT). Ten milliliters of venous blood was drawn for the measurement of brain derived neurotrophic factor (BDNF). Cognitive functions were tested included attention, memory, and executive function. Results We found that the SERT availability in both the midbrain and striatal regions was decreased in the BD patients compared with the HCs; however, the BDNF were not different between the two groups. There was no correlation between the SERT availability and the BDNF. Interestingly, there were statistically significant differences in sub-items of the facial memory test and the Wisconsin Card Sorting Test between the BD patients and the HCs, which showed that there was a cognitive deficit in the BD patients. However, the overall deficits in cognition were not significantly correlated with the SERT availability or the BDNF. Limitation The effect of medications on cognitive function and BDNF should be considered. Conclusions We replicated previous findings that showed cognitive deficits in euthymic BD patients. However, the underlying mechanism of cognitive deficits in euthymic BD patients cannot be entirely explained by SERT and BDNF.

Li C-T, Hsieh J-C, Wang S-J, Yang B-H, Bai Y-M, Lin W-C, Lan C-C, Su T-P. Differential relations between fronto-limbic metabolism and executive function in patients with remitted bipolar I and bipolar II disorder. Bipolar Disord 2012: 14: 831–842. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd. Objectives: The aim of this study was to investigate the relationship between resting brain glucose metabolism and cognitive profiles in patients with remitted bipolar I disorder (BD-I) and bipolar II disorder (BD-II). We hypothesized that BD-I patients (compared to BD-II patients) would perform worse on tests of cognitive function because of abnormal metabolism in the prefrontal cortex and other mood-related brain areas. Methods: Thirty-four patients with remitted bipolar disorder (BD) (BD-I = 17, BD-II = 17) under treatment and 17 well-matched healthy controls received both fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and neuropsychological tests of attention, memory, and executive function. Results: Clinical features in patients with BD-I and BD-II were comparable. Executive function, as indicated by performance on the Wisconsin Card Sorting Test, was significantly worse (i.e., higher percentage of errors, lower percentage of conceptual level responses, and fewer categories completed) in BD-I patients than in BD-II patients and healthy subjects. No difference in attention and memory tests was found among these three groups. Brain PET analysis showed that BD-I patients (compared to BD-II patients) had significantly lower glucose uptake in the bilateral anterior cingulum, insula, striatum, and part of the prefrontal cortex, and higher glucose uptake in the left parahippocampus. Further analyses revealed significant correlations between poor executive function and abnormal glucose uptake in other brain areas in BD-I patients. Conclusions: There are neurobiological differences between subtypes of BD. BD-I is associated with more impaired fronto-limbic circuitry, which might account for reduced executive function in BD-I patients during remission.

Introduction 99m Tc-labeled macroaggregated albumin ( 99m Tc-MAA) scintigraphy scan is routinely performed for lung perfusion imaging and for the assessment of in vivo distribution of 90 Y-labeled SIR-Spheres prior to selective internal radiation treatment for hepatocellular carcinoma. Positron emission tomography (PET) imaging is superior to gamma scintigraphy in terms of sensitivity, spatial resolution and accuracy of quantification. This study reported that 18 F-labeled macroaggregated albumin ( 18 F-MAA) is an ideal PET imaging surrogate for 99m Tc-MAA. Methods 18 F-MAA was prepared from the commercial MAA kit via a one-step conjugation with N -succinimidyl 4- 18 F-fluorobenzoate ( 18 F-SFB). The biodistribution study and microPET/microSPECT imaging were conducted in normal SD rats after intravenous injection of 18 F-MAA/ 99m Tc-MAA. A comparison study of these two radiotracers was performed after co-injection via the intrahepatic arterial in a N1S1 hepatoma-bearing SD rat model. Results The optimal condition for 18 F-MAA preparation is coupling MAA (0.5mg) with 18 F-SFB at 45°C for 5min in a phosphate buffer of pH 8.5. 18 F-MAA was prepared in 60min with high radiochemical yield (30%–35%) and high radiochemical purity (>95%). The in vivo distribution of 18 F-MAA after intravenous injection meets the specifications of MAA depicted in European Pharmacopeia. Our study demonstrated excellent correlation between 18 F-MAA and 99m Tc-MAA in the regional distribution of tumor, liver and lungs (R 2 =0.965, 0.886 and 0.991, respectively), and also in the tumor-to-liver and tumor-to-lungs ratio (R 2 =0.965 and 0.987, respectively) in a N1S1 hepatoma-bearing SD rat model. The organ uptakes derived from animal PET/CT and SPECT/CT imaging after administration of these two tracers were in accordance with those obtained in the distribution studies. Conclusions Starting from commercial MAA kit, an efficient preparation of 18 F-MAA was successfully established. Highly correlated, almost parallel, regional distribution of 18 F-MAA and 99m Tc-MAA in both normal rats and hepatoma-bearing rats was observed. The findings, taken together, demonstrate that 18 F-MAA is an ideal surrogate for 99m Tc-MAA for clinical PET applications.

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Previous brain imaging studies have demonstrated a seasonal difference of serotonin transporter (SERT) binding in the human brain. However, the results were somewhat contradictory. We conducted test–retest study with single photon emission computed tomography (SPECT) with 123 I-ADAM as ligand in 28 healthy subjects. Ten of the subjects were studied within 1month, whereas 18 were randomly assigned to be studied over a period of up to 1year. The primary measure was the specific uptake ratio (SUR). Regions of interest included the midbrain, thalamus, putamen and caudate. The intra-class correlation coefficient (ICC) was 0.52–0.94 across different brain regions over 1month, whereas the ICC was -0.24–0.63 over a 1-year period. The 1-month variability ranged from 6.5±5.1% to 12.5±10.6% across different brain regions, and the 1-year variability ranged from 16.5±9.6% to 41.9±35.5%. The Kruskal–Wallis test revealed a significant difference of variability across months. The Wilcoxon Signed Ranks Test showed the SUR between test-retest scans was of borderline significance. Curve fitting, using a 4th degree polynomial model, revealed a significant circadian correlation between the variability and interval of test-retest measurements. Our findings demonstrate the test–retest reproducibility of 123 I-ADAM in different time periods and suggest that circadian variation of SERT levels in the human brain might exist.

Carbon monoxide poisoning (COP) after charcoal burning results in delayed neuropsychological sequelae (DNS), which show clinical resemblance to Parkinson's disease, without adequate predictors at present. This study examined the role of dopamine transporter (DAT) binding for the prediction of DNS. Twenty-seven suicide attempters with COP were recruited. Seven of them developed DNS, while the remainder did not. The striatal DAT binding was measured by single photon emission computed tomography with (99m)Tc-TRODAT. The specific uptake ratio was derived based on a ratio equilibrium model. Using a logistic regression model, multiple clinical variables were examined as potential predictors for DNS. COP patients with DNS had a lower binding on left striatal DAT binding than patients without DNS. Logistic regression analysis showed that a combination of initial loss of consciousness and lower left striatal DAT binding predicted the development of DNS. Our data indicate that the left striatal DAT binding could help to predict the development of DNS. This finding not only demonstrates the feasibility of brain imaging techniques for predicting the development of DNS but will also help clinicians to improve the quality of care for COP patients.

This study attempted to increase the boron uptake of human head and neck carcinoma SAS cells for BNCT by using a gamma dose of 0.1 Gy for combined treatment. Intracellular boron concentrations in 25 μgB/mL medium of BPA treated and BPA combined gamma-irradiation treated SAS cells were 73.8±1.73 and 95.15±1.36 ppm, respectively. After neutron irradiation, the G2/M-phase cell populations of untreated, BPA treated and BPA combined gamma-irradiation treated SAS cells were 19.31±1.71%, 52.47±2.25% and 59.19±2.63%, respectively. Experimental results indicate that the low dose gamma radiation with combination BPA treatment has the highest killing rate after neutron irradiation. Capable of significantly increasing the G2/M arrest after neutron irradiation, the combined treatment of a low dose of gamma irradiation with 25 μg B/mL medium of BPA also provided a higher killing effect for BNCT.

Background Our aim was to investigate CT dose reduction strategies on a hybrid PET/CT scanner for cardiac applications. Materials Image quality and dose estimation of different CT scanning protocols for CT coronary angiography (CTCA), and CT-based attenuation correction for PET imaging were investigated. Fifteen patients underwent CTCA, perfusion PET imaging at rest and under stress, and FDG PET for myocardial viability. These patients were divided into three groups based on the CTCA technique performed: retrospectively gated helical (RGH), ECG tube current modulation (ETCM), and prospective gated axial (PGA) acquisitions. All emission images were corrected for photon attenuation using CT images obtained by default setting and an ultra-low dose CT (ULDCT) scan. Results Radiation dose in RGH technique was 22.2±4.0 mSv. It was reduced to 10.95±0.82 and 4.13±0.31 mSv using ETCM and PGA techniques, respectively. Radiation dose in CT transmission scan was reduced by 96.5% (from 4.53±0.5 to 0.16±0.01 mSv) when applying ULDCT as compared to the default CT. No significant difference in terms of image quality was found among various protocols. Conclusion The proposed CT scanning strategies, i.e. ETCM or PGA for CTCA and ULDCT for PET attenuation correction, could reduce radiation dose up to 47% without degrading imaging quality in an integrated cardiac PET/CT coronary artery examination.

Biotech firms always pursue broad claims to secure new discoveries, new technologies and even as yet undiscovered results of future research. However, expansive claims without sufficient description violate the principal of granting the patentee the right to exclude others from using the technical development for a certain amount of time in return for disclosing the innovation. Based on this investigation, a written description can be a barrier to biotech patents with broad claims. To avoid a written description rejection during patent prosecution or invalidation in litigation, the patent applicant or assignee should demonstrate possession of the claimed invention by describing the claimed invention with all of its limitations using descriptive means such as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Although the court cases analyzed in this study were not directly related to vaccines, the guideline indeed is applicable to patents of vaccine. Furthermore, a vaccine patent application is also demonstrated.