The 2021 Bo Lindell Lecture: Inclusive, accountable, transparent: the direction we should take for the benefit of present and future generations.

The International Commission on Radiological Protection (ICRP) is recognised as the de-facto world authority in the field of radiological protection. The ICRP Recommendations have been used as a basis for regulations and policy in almost every country, and with the current review and revision of the System of Radiological Protection, it will continue to make significant contributions in radiation safety for patients, workers, the public, and the environment. In a society undergoing significant change, it is necessary to give careful thought to which groups will be perceived as authoritative organisations by the constituents of the future. The ideal form of an authoritative organisation in the new society of the future is to continue to show how it came to make such recommendations, how it reflected the opinions of interested parties in the process, and how it discloses its records with as much transparency as possible. The question now is what we must do to ensure that decision-making advances in a way that not only makes sense to the present generation, but will be easily consumed by future generations. The path that ICRP is taking to formulate the next set of General Recommendations is doing just that, in line with the key procedural values of INCLUSIVE, ACCOUNTABLE, AND TRANSPARENT.

Quantitative assessment of provability of radiation-related cancers considering unavoidable existence of unadjusted risk factors.

The attribution of stochastic effects to exposure to ionizing radiation has been qualitatively discussed by introducing two distinct concepts of provability and probability. This study aims to develop a method of quantitatively assessing the provability of radiation-related cancers. To this end, the 'minimum provable dose' (MPD) was developed and applied to actual cancer mortality in Japan. The background lifetime risk of cancer mortality was calculated for the esophagus, stomach, colon, liver, lungs, skin, breasts, ovaries, bladder, and bone marrow as well as the age-specific risk coefficients reproducing those given in the 2007 Recommendations of the International Commission on Radiological Protection (ICRP). Comparing the relative ratio of MPDs, which was defined herein as the 'provability index' (PI), we quantitatively ranked radiation-related cancers for different tissues and organs predicated on provability for ages of 10, 30, 50, and 0-85+ years at exposure. We discuss the radiological protection of male emergency workers focusing on cancers highly prioritized according to the ranking (i.e. colon, bone marrow, and bladder). The present study proposed the system to quantitatively evaluate the level of radiological protection taking into account the variations of the background cancer risk on the provability of radiation-related cancers.

Discordance and accordance between patient's and physician's assessments in rheumatoid arthritis.

OBJECTIVES: The American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria for rheumatoid arthritis (RA) are more stringent than index-based criteria, making it more difficult to achieve a patient's global assessment (PGA) than an evaluator's global assessment (EGA). We investigated the reason for the discrepancy between the PGA and the EGA in a Japanese clinical cohort. METHOD: We assessed clinical and laboratory variables in our clinical cohort. The frequency of remission achievement according to the ACR/EULAR remission criteria and predictors of the discrepancy between the PGA and EGA were analysed. RESULTS: Of 370 patients with RA, 89 fulfilled PGA criteria and 167 patients fulfilled EGA criteria. The PGA was highly correlated with the visual analogue scale (VAS) pain score and non-inflammatory variables including Steinbrocker class and the Health Assessment Questionnaire Disability Index (HAQ-DI). Conversely, inflammatory variables, including swollen joint count (SJC), tender joint count (TJC), and C-reactive protein (CRP) levels, were significantly associated with the EGA. The main predictors of the discrepancy between the PGA and the EGA were patient's VAS pain score, SJC, and functional disability. CONCLUSIONS: Increased pain and functional disability led to a discrepancy towards a worse PGA than EGA, whereas increased SJC led to an accordance towards a worse EGA.

Fractionated stereotactic radiotherapy using CyberKnife for the treatment of large brain metastases: a dose escalation study.

AIMS: To evaluate the toxicity and efficacy of fractionated stereotactic radiotherapy (FSRT) with doses of 18-30 Gy in three fractions and 21-35 Gy in five fractions against large brain metastases. MATERIALS AND METHODS: Between 2005 and 2012, 61 large brain metastases (≥ 2.5 cm in maximum diameter) of a total of 102 in 54 patients were treated with FSRT as a first-line therapy. Neurological symptoms were observed in 47 of the 54 patients before FSRT. Three fractions were applied to tumours with a maximum diameter ≥ 2.5 cm and <4 cm, and five fractions were used for brain metastases ≥ 4 cm. After ensuring that the toxicities were acceptable (≤ grade 2), doses were escalated in steps. Doses to the large brain metastases were as follows: level I, 18-22 Gy/three fractions or 21-25 Gy/five fractions; level II, 22-27 Gy/three fractions or 25-31 Gy/five fractions; level III, 27-30 Gy/three fractions or 31-35 Gy/five fractions. Level III was the target dose level. RESULTS: Overall survival rates were 52 and 31% at 6 and 12 months, respectively. Local tumour control rates of the 102 total brain metastases were 84 and 78% at 6 and 12 months, respectively. Local tumour control rates of the 61 large brain metastases were 77 and 69% at 6 and 12 months, respectively. Grade 3 or higher toxicities were not observed. CONCLUSIONS: The highest dose levels of 27-30 Gy/three fractions and 31-35 Gy/five fractions seemed to be tolerable and effective in controlling large brain metastases. These doses can be used in future studies on FSRT for large brain metastases.

PARG dysfunction enhances DNA double strand break formation in S-phase after alkylation DNA damage and augments different cell death pathways.

Poly(ADP-ribose) glycohydrolase (PARG) is the primary enzyme responsible for the degradation of poly(ADP-ribose). PARG dysfunction sensitizes cells to alkylating agents and induces cell death; however, the details of this effect have not been fully elucidated. Here, we investigated the mechanism by which PARG deficiency leads to cell death in different cell types using methylmethanesulfonate (MMS), an alkylating agent, and Parg(-/-) mouse ES cells and human cancer cell lines. Parg(-/-) mouse ES cells showed increased levels of γ-H2AX, a marker of DNA double strand breaks (DSBs), accumulation of poly(ADP-ribose), p53 network activation, and S-phase arrest. Early apoptosis was enhanced in Parg(-/-) mouse ES cells. Parg(-/-) ES cells predominantly underwent caspase-dependent apoptosis. PARG was then knocked down in a p53-defective cell line, MIAPaCa2 cells, a human pancreatic cancer cell line. MIAPaCa2 cells were sensitized to MMS by PARG knockdown. Enhanced necrotic cell death was induced in MIAPaCa2 cells after augmenting γ-H2AX levels and S-phase arrest. Taken together, these data suggest that DSB repair defect causing S-phase arrest, but p53 status was not important for sensitization to alkylation DNA damage by PARG dysfunction, whereas the cell death pathway is dependent on the cell type. This study demonstrates that functional inhibition of PARG may be useful for sensitizing at least particular cancer cells to alkylating agents.

[Aortic dissection with ischemia of the abdominal organs].

Abdominal organ ischemia associated with aortic dissection is a serious problem, although its incidence is not so high. In particular, the prognosis of bowel ischemia is extremely poor, especially, in cases with the diagnosis delayed and with extensive bowel ischemia. Consequently, 1st it should be suspected, in cases with abdominal pain or distension associated with acute or chronic aortic dissection. Then, its pathology should be assessed quickly with enhanced computed tomography (CT) or ultrasound examination to clarify the mechanism of critical organ ischemia including dynamic obstruction or static obstruction of the visceral arteries. According to the mechanism of abdominal organ ischemia, the best treatment of catheter interventions such as catheter fenestration, endovascular aortic repair, and branch-stenting, or of conventional open surgery such as surgical abdominal aortic fenestration, graft replacement, and branch-bypass should be appropriately chosen without delay.

Mesenteric phlebosclerosis associated with long-term oral intake of geniposide, an ingredient of herbal medicine.

BACKGROUND: Idiopathic mesenteric phlebosclerosis (IMP) is a rare disease, characterised by thickening of the wall of the right hemicolon with calcification of mesenteric veins. However, the aetiology remains unknown. AIM: To investigate the possible association of herbal medicines with IMP. METHOD: The clinical data of four of our own patients were collected. Furthermore, we searched for previous reports about similar patients with detailed descriptions of herbal prescriptions that they had taken. We compared herbal ingredients to identify the toxic agent as a possible aetiological factor. RESULTS: Clinical data on a total of 25 patients were summarised. Mean age was 61.8 years and there was female predominance (6 men and 19 women). The used Kampo prescription, the number of cases, and the mean duration of use were as follows: kamisyoyosan in 12 cases for 12.8 years, inshin-iseihaito in 5 cases for 13.4 years, orengedokuto in 4 cases for 14.3 years, inchinkoto in 1 case for 20 years, kamikihitou in 1 case for 19 years, seijobofuto in 1 case for 10 years and gorinsan in 1 case for an unknown duration. Only one ingredient, sansisi, was common to the herbal medicines of all 25 patients. This crude drug called geniposide in English is a major constituent of the Gardenia fruits. CONCLUSION: The long-term use of geniposide in herbal medicines appears to be associated with mesenteric phlebosclerosis.

Improvement in organic solvent tolerance by double disruptions of proV and marR genes in Escherichia coli.

AIMS: To investigate the involvement of osmoprotectant transporters in organic solvent tolerance in Escherichia coli and to construct an E. coli strain with high organic solvent tolerance. METHODS AND RESULTS: The organic solvent tolerance of ΔbetT, ΔproV, ΔproP or ΔputP single-gene knockout mutants of E. coli K-12 strain was examined. Among these mutants, the organic solvent tolerance of the ΔproV mutant remarkably increased compared with that of the parent strain. It has been known that a marR mutation confers tolerance on E. coli to organic solvents. A ΔproV and ΔmarR double-gene mutant was more tolerant to organic solvents than the ΔproV or ΔmarR single-gene mutant. The n-hexane amount accumulated in E. coli cells was examined after incubation in an n-hexane-aqueous medium two-phase system. The intracellular n-hexane level in the ΔproV and ΔmarR double-gene mutant was kept lower than those of the parent strain, ΔproV mutant and ΔmarR mutant. CONCLUSIONS: The organic solvent tolerance level in E. coli highly increased by dual disruption of proV and marR. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggests a new strategy for increasing the organic solvent tolerance level in E. coli to improve the usability of the whole-cell biocatalysts in two-phase systems employing organic solvents.

Use of the triaxial microcatheter method in super-selective transcatheter arterial chemoembolisation for hepatocellular carcinoma.

OBJECTIVES: Transcatheter arterial chemoembolisation (TACE) has been widely used for inoperable hepatocellular carcinoma (HCC). Super-selective TACE is preferable to non-selective therapy, because it maximises the impact of treatment on the tumour while minimising damage to tumour-free liver parenchyma. It is therefore important to advance the catheter tip as close as possible in the feeding artery. There is now a new microcatheter with a 1.9-Fr tip with no taper, which can be inserted into a 2.7-Fr microcatheter. In this study we describe the new technique of using the two microcatheters called the triaxial microcatheter method. METHODS: We evaluated 30 TACE procedures to investigate whether or not the catheter tip could be advanced closer to HCC with the triaxial microcatheter method than with previous TACE using a conventional microcatheter. RESULTS: With conventional microcatheters, the level of embolisation was a lobar artery in 4 cases, segmental in 8 cases, subsegmental in 15 cases and sub-subsegmental in only 1 case. TACE could not be performed in two cases. When using the triaxial microcatheter method the level of embolisation was subsegmental in 8 cases, including 2 in which the level was the same as that with a conventional microcatheter, sub-subsegmental in 13 cases and more distal in 7 cases. In the two cases in which TACE could not be performed with the conventional microcatheter, it could be performed sufficiently using the new method. As a whole, in 28 of the 30 procedures (93%) we could successfully advance a catheter tip closer than with the previous TACE. CONCLUSION: The triaxial microcatheter method appears to be useful.

Multiple ulcers in the small and large intestines occurred during tocilizumab therapy for rheumatoid arthritis.

Tocilizumab is a monoclonal antibody against human interleukin-6 receptor which blocks the binding of interleukin-6 to its receptor. Tocilizumab is effective for the treatment of inflammatory disorders including rheumatoid arthritis. We report a case of multiple ulcers in the small and large intestines, which occurred during tocilizumab therapy. A 57-year-old woman started to use tocilizumab for rheumatoid arthritis. Three months later, she complained of hematochezia. Double-balloon endoscopy revealed multiple small aphthoid ulcers in the small and large intestines. One month after the woman had recovered, she was given tocilizumab again. The woman had hematochezia and abdominal pain again 2 weeks later. Colonoscopy revealed multiple round, discrete punched-out ulcers in the terminal ileum, and vast deep ulcers from the cecum to the descending colon. Bioptic histopathology and cultivation showed non-specific findings. Six weeks after discontinuation of tocilizumab, ulcers in the small and large intestine dramatically improved, leaving ulcer scars. This disease course and the results of examination made us strongly suspect that tocilizumab induced multiple ulcers in the small and large intestines. Interleukin-6 is a pleiotropic cytokine and involved in intestinal mucosal wound healing as well as in inflammatory processes. It is possible that tocilizumab inhibited tissue repair of the intestine and caused intestinal ulcers.

Postpuncture CSF leakage: a potential pitfall of radionuclide cisternography.

OBJECTIVE: We sought to evaluate radioisotope cisternography (RICG)-related postpuncture CSF leakage by MRI. METHODS: We conducted a prospective 3-day imaging study. Ten patients with orthostatic headache and other symptoms underwent pre-RICG brain and spinal MRI, magnetic resonance myelography (MRM), RICG, and post-RICG spinal MRI and MRM. For RICG, we used a 25-gauge pencil point spinal needle at the L3/4 or L4/5 level after which subjects took bed rest for 2.5 hours. RESULTS: On pre-RICG MRI and MRM, none of the 10 patients showed CSF leakage. However, 5 subjects (50%) showed epidural abnormalities suggesting CSF leakage on MRI after lumbar puncture for RICG. On RICG and subsequent MRM, 4 of the subjects showed definite findings of CSF leakage and 1 showed minimal leakage. CONCLUSIONS: RICG carries a risk of iatrogenic CSF leakage even with careful puncturing using a fine needle. This leakage produces abnormal RICG and MRM findings at the lumbosacral level. Therefore, abnormal RICG findings restricted to the lumbosacral level should be carefully interpreted when diagnosing SIH.

Persistent gut motor dysfunction in a murine model of T-cell-induced enteropathy.

BACKGROUND: Inflammatory bowel disease (IBD) patients in remission often experience irritable bowel syndrome (IBS)-like symptoms. We investigated the mechanism for intestinal muscle hypercontractility seen in T-cell-induced enteropathy in recovery phase. METHODS: BALB/c mice were treated with an anti-CD3 antibody (100 microg per mouse) and euthanized at varying days post-treatment to investigate the histological changes, longitudinal smooth muscle cell contraction, cytokines (Th1, Th2 cytokines, TNF-alpha) and serotonin (5-HT)-expressing enterochromaffin cell numbers in the small intestine. The role of 5-HT in anti-CD3 antibody-induced intestinal muscle function in recovery phase was assessed by inhibiting 5-HT synthesis using 4-chloro-DL-phenylalanine (PCPA). KEY RESULTS: Small intestinal tissue damage was observed from 24 h after the anti-CD3 antibody injection, but had resolved by day 5. Carbachol-induced smooth muscle cell contractility was significantly increased from 4 h after injection, and this muscle hypercontractility was evident in recovery phase (at day 7). Th2 cytokines (IL-4, IL-13) were significantly increased from 4 h to day 7. 5-HT-expressing cells in the intestine were increased from day 1 to day 7. The 5-HT synthesis inhibitor PCPA decreased the anti-CD3 antibody-induced muscle hypercontractility in recovery phase. CONCLUSIONS & INFERENCES: Intestinal muscle hypercontractility in remission is maintained at the smooth muscle cell level. Th2 cytokines and 5-HT in the small intestine contribute to the maintenance of the altered muscle function in recovery phase.

Spinal cord injury is not negligible after TEVAR for lower descending aorta.

OBJECTIVES: To clarify the incidence of spinal cord injury (SCI) after thoracic endovascular aneurysm repair (TEVAR), we investigate the intercostal/lumbar arteries that supply the Adamkiewicz artery (ICA-AKA). PATIENTS: Among 81 patients subjected to TEVAR, we retrospectively reviewed the clinical records of 50 patients (range: 57-86 (median age: 77) years, 41 males) who underwent TEVAR for part of or the whole distal descending aorta (T7 to L2) after identification of ICA-AKA by magnetic resonance angiography (MRA) or computed tomography angiography (CTA). RESULTS: The 50 patients were classified into group A: 17 patients whose patent ICA-AKA was not covered, group B: 24 patients whose ICA-AKA was covered and group C: nine patients in whom no patent ICA-AKA was identified. Only three patients in group B suffered paraplegia and of them two recovered full ambulation. The estimated incidence of permanent and transient paraplegia was 3.7% in all TEVAR patients, 6.0% when part of or the entire distal aorta was covered and 12.5% when the patent ICA-AKA was covered. The length of aortic coverage in patients with paraplegia was >300 mm. CONCLUSIONS: Paraplegia after TEVAR occurred in one of eight patients in whom the stent graft covered ICA-AKA. Long coverage of the aorta including the ICA-AKA was critical. To prevent this serious complication, identification of the ICA-AKA is crucial.

Poly(ADP-ribose) Glycohydrolase deficiency sensitizes mouse ES cells to DNA damaging agents.

Poly(ADP-ribose) glycohydrolase (Parg) is the main enzyme for degradation of poly(ADP-ribose) by splitting ribose-ribose bonds. Parg-deficient (Parg(+/-) and Parg(-/-)) mouse ES cell lines have been established by disrupting both alleles of Parg exon 1 through gene-targeting. A transcript encoding a full length isoform of Parg was eliminated and only low amounts of Parg isoforms were detected in Parg(-/-) embryonic stem (ES) cells. Poly(ADP-ribose) degradation activity was decreased to one-tenth of that in Parg(+/+) ES cells. Parg(-/-) ES cells exhibited the same growth rate as Parg(+/+) ES cells in culture. Sensitivity of Parg(-/-) ES cells to various DNA damaging agents, including an alkylating agent dimethyl sulfate, cisplatin, gemcitabine, 5-fluorouracil, camptothecin, and gamma-irradiation was examined by clonogenic survival assay. Parg(-/-) ES cells showed enhanced lethality after treatment with dimethyl sulfate, cisplatin and gamma-irradiation compared with wild-type (Parg(+/+)) ES cells (p<0.05, respectively). In contrast, a sensitization effect by Parg-deficiency was not observed with gemcitabine and camptothecin. These results suggest the possibility that functional inhibition of Parg leads to sensitization of tumor cells to some chemo- and radiation therapies.

[Long-term outcome of aortic valve sparing procedures in connective tissue disorders].

OBJECTIVES: The aim of this study is to determine the long-term outcome of aortic valve sparing procedures for patients having connective tissue disorder. METHODS: Between 1993 and 2008, the aortic valve sparing surgery was performed in 94 patients having aortic root dilatation. Eighty patients of them (37.2 +/- 13.4 years, 50 male) had cystic medial necrosis in the aortic wall, which was confirmed the pathological examination. We reviewed these patients. Sixty percent (48/80) had Marfan syndrome, 5% (4/80) had Loeyz-Dietz syndrome, 2% (2/80) had bicuspid aortic valve, and 11% (9/80) had aortic dissection. Our reimplantation procedure has been refined as followed: with a tube graft in 41, a tube graft with creation of neo-sinuses in 11, and a Valsalva graft in 14. Fourteen patients underwent the remodeling procedure. The follow-up rate was 100% with the duration of 3.7+/- 3.4 years. RESULTS: There were no operative death but six late deaths. Seventeen (21.3%) patients required aortic valve replacement, for recurrent aortic insufficiency in 13 and infection in 4. Freedom from reoperation was 80%, 43%, and freedom from moderate or severe aortic insufficiency was 80%, 54%, at 5 and 10 years, respectively. Pathological findings of the aortic valve obtained in the reoperations showed elongation and prolapse of the aortic valve due to myxomatous degeneration and fibrous thickening caused by aortic insufficiency. CONCLUSIONS: Even in connective tissue disorders, aortic valve sparing operation is associated with acceptable long-term durability, although cusp degeneration resulting in recurrent aortic insufficiency might be progressive.

Involvement of tazarotene-induced gene 1 in proliferation and differentiation of human adipose tissue-derived mesenchymal stem cells.

OBJECTIVE: Mesenchymal stem cells (MSC) have both self-renewal and multilineage differentiation potential, and bone marrow-derived MSC have been applied for tissue regeneration and repair. Although adipose tissue-derived MSC (ASC) have emerged as an alternative cell source, little information is available regarding the biologic difference between ASC derived from visceral and subcutaneous fat. Therefore, we aimed to compare the proliferation and gene expression profile of cultured human visceral ASC (VASC) and subcutaneous ASC (SASC), and to identify a novel gene involved in proliferation and differentiation of ASC. MATERIALS AND METHODS: We performed microarray analysis of cultured VASC and SASC, and investigated the role of tazarotene-induced gene 1 (TIG1), a most differentially expressed gene, in the proliferation and differentiation of ASC. RESULTS: SASC proliferated faster than VASC for over 10 passages, and TIG1 expression was consistently up-regulated in VASC of humans, rats and mice. Overexpression of the TIG1 gene in human SASC inhibited cell proliferation, whereas knockdown of TIG1 expression by siRNA promoted cell proliferation. In addition, overexpression of the TIG1 gene in SASC enhanced their differentiation into adipocytes, and promoted up-regulation of peroxisome proliferators-activated receptor gamma and CCAAT/enhancer binding protein alpha. On the other hand, TIG1 overexpression in SASC inhibited their differentiation into osteocytes and the expression of osteocalcin. CONCLUSION: TIG1 plays an important role in regulating proliferation and differentiation of ASC.

Impact of double-balloon endoscopy on the diagnosis of jejunoileal involvement in primary intestinal follicular lymphomas: a case series.

In recent years, primary gastrointestinal follicular lymphoma has been increasingly detected in the duodenum on esophagogastroduodenoscopy (EGD). Primary gastrointestinal follicular lymphomas are frequently distributed to multiple sites in the gastrointestinal tract. Therefore, investigation into the spread of follicular lymphomas in the small bowel is important in order to determine the most appropriate treatment strategy. The performance of double-balloon endoscopy (DBE) in the diagnosis of jejunoileal follicular lymphoma lesions has not been fully evaluated. We aimed to investigate the value of DBE in addition to computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) in the diagnosis of jejunoileal follicular lymphoma. DBE with biopsy was performed in seven patients with primary duodenal follicular lymphoma diagnosed by EGD, in order to investigate jejunoileal involvement. Jejunoileal follicular lymphoma lesions were detected by DBE in six out of the seven patients (three in the jejunum and three in the jejunum and ileum), whereas CT and (18)F-FDG-PET failed to detect the existence of these lesions. Endoscopic findings of the jejunoileal lesions revealed multiple white nodules and white villi, which were similar to those of duodenal lesions. DBE was more useful for the diagnosis of jejunoileal involvement in primary intestinal follicular lymphoma than CT and (18)F-FDG-PET. The use of DBE will become important for determining the most appropriate treatment for gastrointestinal follicular lymphoma.

Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight gain and improves lipid profiles in rats.

Cetilistat is a novel inhibitor of pancreatic lipase. The aim of this report is to evaluate the anti-obesity action of cetilistat in diet-induced obesity (DIO) rats. Cetilistat inhibited rat and human pancreatic lipase activity with an IC (50) of 54.8 nmol/l, and 5.95 nmol/l, respectively, meaning that it is 9.2 times more potent for human pancreatic lipase than for that of rat. Cetilistat was orally administered simultaneously with fat emulsion to Sprague-Dawley rats. Plasma triglyceride (TG) concentrations were measured before and after oral fat loading. The elevation in plasma triglyceride concentration by oral fat loading was reduced by cetilistat in a dose-dependent manner at 3, 10, 30, and 100 mg/kg, indicating that cetilistat reduces intestinal fat absorption in rats. Cetilistat was administered to DIO F344 rats as food admixture in a high-fat diet at 4.9, 14.9, or 50.7 mg/kg/day for three weeks. Both triglyceride and nonesterified fatty acid content in the feces were dose-dependently and drastically increased, suggesting the intestinal breakdown of fat and excretion. Body weight (BW) gain and white adipose tissue (WAT) weight were reduced in a dose-dependent manner. In addition, leptin, TG, and total cholesterol (TC) in plasma were reduced and there were no reports of oily stools. These results suggest that cetilistat ameliorates obesity and hyperlipidemia in DIO rats, a plausible animal model of the most common type of human obesity.