An easy approach to ultrasonographic volumetry of the thyroid.

To establish an easy way to perform volumetry of the thyroid gland using ultrasonography, we evaluated the accuracy of the products of the depth and width of the right thyroid lobe as indices of thyroid volume. The depth and width of both thyroid lobes were measured using ultrasonography before surgery in 193 patients with Graves' disease. The products were compared with the weight of the thyroid obtained from operative records. We also evaluated the depth and width of the right thyroid lobe in 312 subjects who presented without any thyroid disease. The products of depth and width of the right and left lobes of patients with Graves' disease correlated similarly well with the weight of the thyroid obtained from operative records (ρ = 0.896 for right, ρ = 0.886 for left, p < 0.0001). Because the right lobes were larger than the left lobes, the products of the depth and width of the right lobe were adopted as novel parameters for an easy volumetric approach. The relationship between the weight and the measurements of the right lobe was described using the following regression equation: weight (g) = [11.8 × depth (cm) × width (cm)] - 16.0. The products of the subjects without any thyroid diseases were distributed between 0.6 cm2 and 4.4 cm2, with a median of 2.0 cm2. The upper limit of these values in these subjects was estimated to be 3.8 cm2. This easy ultrasonographic volumetric technique makes it possible to perform a semi-quantitative assessment of thyroid volume and to differentiate diffuse goiter from normal-sized thyroids.

A case report of anaplastic thyroid carcinoma transformed from small papillary carcinoma successfully detected by ultrasonography in its early stage with review of literature.

An 82-year-old woman was referred to our hospital because of a suspicious thyroid nodule. She was diagnosed with papillary microcarcinoma with a maximum diameter of 9 mm based on ultrasonography and fine-needle aspiration (FNA) cytology. She preferred observation without surgery. Her papillary carcinoma grew gradually and reached a maximum diameter of 19 mm after 23 months. At that time, ultrasonography showed an apparent change in the shape of the nodule as well as in its diameter. At the initial ultrasound examination, papillary microcarcinoma was demonstrated as a hypoechoic solid nodule with an irregular shape. No punctuate microcalcifications were shown. After 23 months, the preexisting nodule had expanded toward the common carotid artery. The expanded portion was round and well demarcated. FNA revealed that the expanded portion consisted of anaplastic thyroid carcinoma. She underwent hemithyroidectomy and lymph node dissection of the central compartment. She remained in good health for 18 months after surgery. Anaplastic thyroid carcinoma is generally found as an aggressive large tumor, and the ultrasound appearance of small anaplastic thyroid carcinoma is poorly understood at present. We successfully detected anaplastic transformation in the early period by ultrasonography and FNA. When observation is indicated for small papillary thyroid carcinoma, the change in the shape of the nodule as well as in its diameter should be carefully monitored by ultrasonography. FNA should be performed at a proper site on the nodule to avoid overlooking anaplastic transformation, as resection following the early detection of anaplastic transformation might bring a favorable prognosis.

The Safety and Efficacy of Weekly Paclitaxel Administration for Anaplastic Thyroid Cancer Patients: A Nationwide Prospective Study.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare and extremely aggressive malignancy, with a median survival of less than 6 months due to rapid progression and resistance to multimodal therapies. Effective treatment strategies have not been identified. A prospective clinical study was performed to objectively evaluate outcomes of treatment with paclitaxel. METHODS: An investigator-initiated, multicenter, nonrandomized, open-label, single-arm study to evaluate the feasibility and efficacy of weekly paclitaxel (80 mg/m(2)) administration for patients with pathologically confirmed ATC was conducted in a nationwide organization. RESULTS: Feasibility was analyzed in 56 patients. More than one course of treatment was performed in 52 (93%) patients retaining sufficient dose intensity (>84%). No patient had to terminate the treatment because of an adverse event. The median overall survival was 6.7 months [confidence interval 4.4-9.0]. The 6-month survival was 54%. Among the 42 patients with an evaluable lesion, none demonstrated complete remission, 9 (21%) showed partial remission, 22 (52%) achieved stable disease, and 8 (19%) exhibited progressive disease; 3 did not complete the initial treatment course. The objective response rate was 21%, and the clinical benefit rate was 73%. The median time to progression was 1.6 months. Statistically, no additional effect of concomitant radiation was demonstrated in 6 patients receiving combined therapy. Eight patients, in whom a complete post-treatment surgical removal of the tumor was feasible, survived significantly longer (median 7.6 months [CI 8.1-23.0]) than the other 34 patients in whom the tumor could not be completely removed after chemotherapy (5.4 months [CI 3.0-7.8], p = 0.018). SUMMARY: The study demonstrates objective and accurate information concerning the feasibility and efficacy of a standardized treatment with weekly paclitaxel administration for ATC patients. CONCLUSIONS: Weekly paclitaxel administration for ATC patients can be of clinical benefit in a neo-adjuvant setting.

Development of Primary Thyroid Lymphoma during an Ultrasonographic Follow-up of Hashimoto's Thyroiditis: A Report of 9 Cases.

We herein experienced 9 patients with primary thyroid lymphoma that developed during 3-18 years of ultrasonographic follow-up of Hashimoto's thyroiditis. All nine patients had localized mucosa-associated lymphoid tissue (MALT) lymphoma. Two patients had diffuse type, one had mixed type, and six had nodular type according to the ultrasonographic classification. A clearly enlarging goiter was observed before the diagnosis of lymphoma in 3 patients. An enlarging goiter was not apparent in the remaining 6 patients with nodular type lymphoma, however, the emergence or enlargement of a hypoechoic nodular lesion was observed. Thyroid MALT lymphoma may be diagnosed early by an ultrasonographic follow-up of Hashimoto's thyroiditis.

A clinical approach to brown adipose tissue in the para-aortic area of the human thorax.

BACKGROUND: Human thoracic brown adipose tissue (BAT), composed of several subdivisions, is a well-known target organ of many clinical studies; however, the functional contribution of each part of human thoracic BAT remains unknown. The present study analyzed the significance of each part of human thoracic BAT in the association between regional distribution, cellularity, and factors involved in the functional regulation of thoracic BAT. METHODS: We analyzed 1550 healthy adults who underwent medical check-ups by positron-emission tomography and computed tomography (PET-CT) imaging, 8 cadavers, and 78 autopsy cases in an observational study. We first characterized the difference between the mediastinum and the supraclavicular areas using counts of BAT detection and conditions based on PET-CT outcomes. The measurable important area was then subjected to systematic anatomical and immunohistochemical analyses using anti-uncoupling protein 1 (UCP1) antibody to characterize the cellularity in association with age and sex. RESULTS: In PET-CT scanning, the main site of thoracic BAT was the mediastinum rather than the supraclavicular area (P < 0.05). Systemic macroanatomy revealed that the thumb-sized BAT in the posterior mediastinal descending para-aortic area (paBAT) had feeding vessels from the posterior intercostal arteries and veins and sympathetic/parasympathetic innervation from trunks of the sympathetic and vagus nerves, respectively. Immunohistochemical analysis indicated that the paBAT exhibited immunoreactivity for tyrosine hydroxylase and vesicular acetylcholine transporter located in the pericellular nervous fibers and intracellular UCP1. The brown adipose cells of paBAT showed age-dependent decreases in UCP1 expression (P < 0.05), accompanied by a significant increase in vacuole formation, indicating fat accumulation (P < 0.05), from 10 to 37 years of age (P < 0.01). CONCLUSIONS: paBAT may be one of the essential sites for clinical application in BAT study because of its visible anatomy with feeding vessels and sympathetic/parasympathetic innervation functionally affected by outer condition and senescence.

Value of thyroid specific peroxidase and Ki-67 stains in preoperative cytology for thyroid follicular tumors.

BACKGROUND: The aim of this study was to elucidate immunocytochemically whether thyroid specific peroxidase (TPO) and Ki-67 can complement fine-needle aspiration (FNA) cytology as useful markers in order to distinguish between follicular adenoma (FA) and follicular carcinoma (FC). METHODS: We studied 40 FAs and 68 FCs obtained by surgical resection. FNA cytology smears were divided into two groups: Cytology-A (Cy-A) (94 cases) with typical benign cytology and Cytology-B (Cy-B) (14 cases) with atypical cytology. FCs were divided into two groups: FC-I (42 cases) without any poorly differentiated structures and FC-II (26 cases) with some poorly differentiated structures. Cytology smears and histology from FAs and FCs were studied immunocytochemically for thyroid specific peroxidase (TPO) and Ki-67. RESULTS: TPO expression was negative in 12.5% FAs, 21.4% FC-I, and 46.2% FC-II. In 68 FC cases, Cy-B were more frequently observed in TPO-negative cases (38.1%) than in TPO-positive cases (12.8%). The mean Ki-67 LI was 0.46 in FAs, 0.53 in FC-I, and 1.13 in FC-II. The high Ki-67 LI was correlated with Cy-B. Moreover, higher Ki-67 LI showed a close relationship with distant metastasis. In 94 Cy-A cases, 54 cases were FCs. When 38 cases with negative TPO or Ki-67 LI over 0.62 were extracted from them, as many as 28 cases were FCs, the rate of FCs were significantly higher than the rest. CONCLUSION: Therefore, addition of TPO stain and Ki-67 stain to routine Papanicolaou stain could improve the diagnostic reliability of FNA cytology for FC with high degree of malignancy.

A Novel Surgical Technique for Thyroid Cancer with Intra-Cricotracheal Invasion: Windmill Resection and Tetris Reconstruction.

The most effective treatment for thyroid cancer (TC) invading into the larynx and trachea is a complete surgical resection of the tumor, but currently employed techniques are less than ideal. We report a novel surgical technique, which we named Windmill resection and Tetris reconstruction, for patients with TC invading into the laryngeal lumen. We treated eight cases of TC with invasion into the laryngeal lumen by Windmill resection and Tetris reconstruction. We analyzed complications, clinical data, and pathological findings for all patients. Patients included one man and seven women (mean age 69 ± 10 years). Histopathology of TC indicated papillary cancer in five patients, poorly differentiated cancer in one patient, anaplastic cancer in one patient, and squamous cell carcinoma in one patient. Unilateral recurrent laryngeal nerve (RLN) palsy was confirmed preoperatively by laryngoscope in four patients, and none had bilateral RLN palsy. All patients underwent Windmill resection and Tetris reconstruction along with total thyroidectomy (three patients), subtotal thyroidectomy (three patients), and lobectomy (two patients). Neck dissection was performed in all patients. The average resected length of the larynx and trachea was 29 ± 6 mm. Air leakage at the suture line occurred in three patients; two required further surgery, while the third was closed by insertion of a Penrose drain. Postoperative RLN palsy occurred in five patients. Aspiration was observed in two patients and resolved within 4 weeks. Pneumonia, atelectasis, and pleural effusion occurred in some patients. No other complications, including hemorrhage, wound infection, or airway stenosis, occurred. There was no postoperative mortality and no recurrence at the anastomotic site. Two patients underwent permanent tracheostomy due to permanent bilateral RLN palsy. Two patients, one with anaplastic cancer and the other with poorly differentiated cancer, recurred 13 and 21 months after surgery, while patients with papillary thyroid cancer had no local recurrence. Importantly, laryngeal functions such as phonation and swallowing were preserved in all patients. This novel surgical technique may be as effective as window resection of the larynx for local control of TC and contributes to the quality of life of patients by resulting in a less unsightly surgical wound.

Revisiting the guidelines issued by the Japanese Society of Thyroid Surgeons and Japan Association of Endocrine Surgeons: a gradual move towards consensus between Japanese and western practice in the management of thyroid carcinoma.

BACKGROUND: In 2010, the Japanese Society of Thyroid Surgeons (JSTS) and Japanese Association of Endocrine Surgeons (JAES) established new guidelines entitled "Treatment of Thyroid Tumors." Since then, several new studies, including those that address the treatment of differentiated thyroid carcinoma (DTC) have been published, and the DTC treatment policy not only of Japanese physicians but those in Western countries has continued to evolve. METHODS: We selected six clinical questions regarding the treatment of DTC and revisited them based on newly published data from Western countries and Japan. RESULTS: More data have accumulated about treatment of low-risk papillary microcarcinoma. It has become clear that conservative treatment (observation) of low-risk papillary microcarcinoma in elderly patients is an acceptable alternative to immediate surgery. Total thyroidectomy versus hemithyroidectomy for low-risk papillary thyroid carcinoma (PTC) has become an important issue, and some publications after 2010 indicated that hemithyroidectomy is adequate for these low-risk patients. Unfortunately, no published manuscripts on prophylactic central node dissection offered good evidence regarding its indications or included a large number of patients. Also, it was not evident that prophylactic lateral node dissection improves cause-specific survival, although it might reduce lymph node recurrence especially in PTC patients with large tumors, distant metastases, or clinical central node metastases. Although completion total thyroidectomy was not recommended for minimally invasive follicular thyroid carcinoma in our guidelines, it may be better to perform it in elderly patients and those with a large tumor or extensive vascular invasion. Radioactive iodine (RAI) ablation after total thyroidectomy is still performed almost routinely in many Western institutions, although recent studies showed that ablation is not beneficial in low-risk patients. In Japan, because of legal restrictions, most patients did not undergo RAI ablation, and their prognoses are excellent. CONCLUSIONS: Recently, policy for treating DTCs has changed not only in Western countries but also in Japan, resulting in a gradual move toward consensus between Western practice and ours. We will continue to present the best treatments for patients with thyroid carcinoma each time we revise our guidelines.

Biomechanical study of healing of patellar tendon after resection of the central one-third in an adult-mature rabbit model.

The present study was performed to investigate effects of ageing on biomechanical properties of healing tissues of the patellar tendon (PT) after the removal of its central portion. An entire one-third defect was made in the PT of 0.5 year- (0.5 yr) and 2 year-old rabbits (2 yr). After 6 or 12 weeks, the tissue regenerated in the defect and the remaining, residual tissue was examined biomechanically and histologically. Age-related difference in the PT length was only observed in operated tendons at 6 weeks, and in the cross-sectional area such difference was observed only in unoperated, normal tendons. At 12 weeks, tensile strength and tangent modulus of regenerated tissues in 0.5 yr were significantly higher than those in 2 yr. By contrast, these properties of residual tissues in 2 yr were significantly higher than those of 0.5 yr at 6 weeks. The histology of each of regenerated and residual tissues was essentially similar between the two age groups. Accordingly, ageing exhibited adverse effects on the mechanical properties of tissues regenerated in the central third defect of the PT. This may be due to high tangent modulus of normal and residual PT tissues in aged animals, which reduces the amount of mechanical stimulation applied to regenerated tissues during healing.

Remission of anorexia nervosa after thyroidectomy: A report of two cases with Graves' disease and anorexia nervosa.

We report two patients with anorexia nervosa and Graves' disease who received subtotal thyroidectomy for Graves' disease and concomitantly experienced remission from anorexia nervosa. Both were young women (aged 20 and 26) at the time of surgery. Both had well controlled thyroid function and eating behavior at the time of surgery. Both were followed for over five years without relapse of anorexia nervosa or hyperthyroidism. These cases suggest the existence of an endocrine factor originating from the thyroid gland that is involved in the pathogenesis of anorexia nervosa. Since patients of thyroidectomy can remain in good health with supplement of thyroxine alone, it can be hypothesized that this anorexigenic endocrine factor is an evolutionary relic not necessary for the normal function of humans and does not have physiological effects unless secreted beyond normal levels. Given that, it implies the existence of a creature in the animal kingdom for which such an anorexigenic hormone is essential for survival. Migrating birds eat beyond their caloric expenditure before migration and become anorexic for the duration of their flight. It is also known that their thyroid function is elevated during migration. The normal physiology of migration is a complex mechanism involving the hypothalamic, pituitary, thyroid, adrenal and reproductive hormones. The mechanism of disease, however, can be simpler. A review of the literature is presented that suggest a heretofore unreported thyroid hormone, which is involved in the regulation of migration behavior, may be the responsible factor behind anorexia nervosa.

Ghrelin in small intestine, its contribution to regulation of food intake and body weight in cross-intestinal parabiotic rats.

Ghrelin has been shown to be associated with feeding behavior in humans and rodents. It has been suggested that ghrelin may play a role behind the effect of bariatric surgery. Inbred rats were made into parabiotic pairs so that they shared a single abdominal cavity. A further operation is performed later in which the small intestines are transected and re-connected so that one rat continually lost nutrition to its partner. Changes in food intake and body weight were recorded. Seven weeks later, content of ghrelin in the plasma, stomach and upper intestines were measured in the paired rats. Rats which lost nutrients to its counterpart (Loss rats) ingested significantly more food than sham control rats (p<0.001). Rats which gained nutrient (Gain rats) ingested less than controls (p<0.001). There was no significant difference in body weight, blood glucose, insulin, free fatty acids and triglycerides between the paired rats. There was significantly higher levels of ghrelin in the plasma (p<0.008) and the intestine of the Loss rats (p<0.02). There were no difference in ghrelin in the stomach between parabiotic rats and sham operated controls. The ghrelin content of the plasma and intestines were significantly higher in the Loss rats, which ate more, and normal in the Gain rats, which ate less than controls. Because no remarkable changes in the ghrelin content were observed in the stomach, difference in the quality of the chime may affect the local synthesis and release of ghrelin.

Orbital magnetic resonance imaging combined with clinical activity score can improve the sensitivity of detection of disease activity and prediction of response to immunosuppressive therapy for Graves' ophthalmopathy.

The aim of this study was to demonstrate that the addition of orbital magnetic resonance (MR) imaging can provide improvement in sensitivity of detection of active disease and the prediction of the response to intravenous glucocorticoid therapy (ivGC), over clinical activity score (CAS) alone. A prospective case series was studied at our institution. Forty eight patients were examined by CAS and orbital MR imaging. The maximum of T2 relaxation times of extraocular muscles (maxT2RT) and other parameters were evaluated by MR imaging. Thirty five of 48 patients underwent ivGC. Twenty of 35 patients, whose CAS was 2 points or less, were evaluated for the response to ivGC. The correlation between CAS and maxT2RT was evaluated. Differentiation of active and inactive GO was performed by CAS and orbital MR imaging. The response to ivGC was evaluated by CAS, orbital MR imaging and ophthalmic parameters. As a result, CAS and maxT2RT showed significant positive correlation (r=0.58, p<0.0001), and 15 patients were positive by CAS and orbital MR imaging. However, 20 patients were positive by only MR imaging. In those 20 patients, there was significant improvement after ivGC. We concluded that orbital MR imaging combined with CAS could improve the sensitivity of detection of active disease and the prediction of the response to ivGC. In addition, even if only one parameter of CAS is positive, further examination with orbital MR imaging is advised.

Effects of maturation on the mechanical properties of regenerated and residual tissues in the rabbit patellar tendon after resection of its central one-third.

BACKGROUND: The central one-third portion of the patellar tendon is commonly used as a graft for the reconstruction of the anterior cruciate ligament. Although several studies have been carried out on mechanical properties of healing tendons in mature animals, there have been no studies on regenerated and residual tissues in the immature patellar tendon after the removal of its central portion. METHODS: An entire one-third defect was made in the patellar tendon of 2-, 3- and 6-month-old rabbits. After 3 weeks, the tissue regenerated in the defect and the residual tissue were biomechanically and histologically evaluated. FINDINGS: The length of patellar tendons in 6-month-old animals after the resection of its central one-third was significantly longer than that in age-matched controls. The cross-sectional area of all operated tendons was significantly larger compared to age-matched controls. There were no significant effects of maturation on the mechanical properties of regenerated and residual tissues in operated tendons, although tensile strength and tangent modulus of normal tendons were significantly greater in 6-month rabbits than in immature ones. The histology of each of regenerated and residual tissues was similar in the three groups. INTERPRETATION: There were no remarkable effects of maturation on regenerated and residual tissues after the removal of the central one-third tendon. However, the strength and the modulus of normal tendons are significantly lower in immature patients than in mature ones. Therefore, surgeons should take account of the inferior mechanical properties of the tendon in skeletally immature patients at the time of surgeries for the reconstruction of the anterior cruciate ligament.

Effects of stress shielding and subsequent restressing on mechanical properties of regenerated and residual tissues in rabbit patellar tendon after resection of its central one-third.

Central third of patellar tendon (PT) is used as an autograft for anterior cruciate ligament (ACL) reconstruction. Previous studies investigated temporal changes in material properties of healing tissues in PT after resection of the central third. However, no study has been performed on effects of stress shielding (SS) and restressing (RS) on the properties of healing tissues. The present study hypothesised that SS adversely affects the mechanical integrity of healing tissues, which is recovered by subsequent RS. An entire rectangular defect was created in the central third of rabbit PT. Operated PTs were subjected to either SS or no stress shielding (NSS). A subgroup of stress-shielded PTs was followed by the resumption of normal loading, namely RS. Tensile properties of tissues regenerated in the defect and residual tendons were evaluated. Regenerated tissues of SS for 3 weeks resulted in significantly lower strength than NSS, which was recovered to NSS level by 3 weeks of RS. Strength of residual tissues in RS reversed SS effects, leading to the strength at NSS level after 12 weeks. However, tangent modulus of residual tissues in RS was still significantly lower than that of NSS at 12 weeks. Therefore, SS induces detrimental effects on the mechanical integrity of healing PTs, and the response to RS was different between regenerate and residual tissues, the latter of which took longer period to reach NSS level.

Successful treatment of anaplastic thyroid carcinoma with a combination of oral valproic acid, chemotherapy, radiation and surgery.

Anaplastic thyroid carcinoma (ATC) is the most aggressive of thyroid cancers whose treatment is not yet established and mortality is extremely high. Recent in vitro studies have shown that valproic acid (VA), a newly identified histone deacetilase (HDAC) inhibitor, induces apoptosis, modulates differentiation gene expression of thyroid tumors and enhances the sensitivity of anaplastic cancer cell lines to doxorubicin. We report a case of successful treatment of anaplastic thyroid carcinoma with a combination of oral valproic acid, chemotherapy consisting of cisplatin and doxorubicin, external and intra-operative radiation and surgery. Tumor volume decreased by 50.7% under CT measurement and 44.6% under sonogram measurement over the course of the treatment. No significant rebound of tumor size was observed between each cycle of chemotherapy. Serial cytology performed via fine needle aspiration (FNA) presented a rapidly changing profile of cell types, starting with anaplastic and proceeding through increasingly well differentiated presentations. Only microscopic remnants of ATC cells were found in the histological examination of the resected thyroid. Ga scintigraphy and whole body PET scan six months after surgery revealed no evidence of recurrence or metastasis. As of Nov. 22, 2008, the patient is alive and disease free two years after diagnosis.

Hypothalamic neuronal histamine mediates the thyrotropin-releasing hormone-induced suppression of food intake.

We examined the involvement of thyrotropin-releasing hormone (TRH) and TRH type 1 and 2 receptors (TRH-R1 and TRH-R2, respectively) in the regulation of hypothalamic neuronal histamine. Infusion of 100 nmol TRH into the rat third cerebroventricle (3vt) significantly decreased food intake (p < 0.05) compared to controls infused with phosphate- buffered saline. This TRH-induced suppression of food intake was attenuated partially in histamine-depleted rats pre-treated with alpha-fluoromethylhistidine (a specific suicide inhibitor of histidine decarboxylase) and in mice with targeted disruption of histamine H1 receptors. Infusion of TRH into the 3vt increased histamine turnover as assessed by pargyline-induced accumulation of tele-methylhistamine (t-MH, a major metabolite of neuronal histamine in the brain) in the tuberomammillary nucleus (TMN), the paraventricular nucleus, and the ventromedial hypothalamic nucleus in rats. In addition, TRH-induced decrease of food intake and increase of histamine turnover were in a dose-dependent manner. Microinfusion of TRH into the TMN increased t-MH content, histidine decarboxylase (HDC) activity and expression of HDC mRNA in the TMN. Immunohistochemical analysis revealed that TRH-R2, but not TRH-R1, was expressed within the cell bodies of histaminergic neurons in the TMN of rats. These results indicate that hypothalamic neuronal histamine mediates the TRH-induced suppression of feeding behavior.

Framework analysis for the carcinogenic mode of action of nitrobenzene.

Nitrobenzene (CASRN: 98-95-3) has been shown to induce cancers in many tissues including kidney, liver, and thyroid, following chronic inhalation in animals. However, with a few exceptions, genotoxicity assays using nitrobenzene have given negative results. Some DNA binding/adduct studies have brought forth questionable results and, considering the available weight of evidence, it does not appear that nitrobenzene causes cancer via a genotoxic mode of action. Nitrobenzene produces a number of free radicals during its reductive metabolism, in the gut as well as at the cellular level, and generates superoxide anion as a by-product during oxidative melabolism. The reactive species generated during nitrobenzene metabolism are considered candidates for carcinogenicity. Furthermore, several lines of evidence suggest that nitrobenzene exerts its carcinogenicity through a non-DNA reactive (epigenetic) fashion, such as a strong temporal relationship between non-, pre-, and neoplastic lesions leading to carcinogenesis. In this report, we first describe the absorption, distribution, metabolism, and excretion of nitrobenzene followed by a summary of the available genotoxicity studies and the only available cancer bioassay. We subsequently refer to the mode of action framework of the U.S. Environmental Protection Agency's 2005 Guidelines for Carcinogen Risk Assessment as a basis for presenting possible modes of action for nitrobenzene-induced cancers of the liver, thyroid, and kidney, as supported by the available experimental data. The rationale(s) regarding human relevance of each mode of action is also presented. Finally, we hypothesize that the carcinogenic mode of action for nitrobenzene is multifactorial in nature and reflective of free radicals, inflammation, and/or altered methylation.

The tensile properties of collagen fascicles harvested from regenerated and residual tissues in the patellar tendon after removal of the central third.

The central one-third portion of the patellar tendon (PT) is commonly used for the reconstruction of the anterior cruciate ligament. For better understanding of the healing mechanisms of the PT, tensile properties of collagen fascicles harvested from the healing PT were studied. A rectangular defect was made at the central third portion in each right PT in the skeletally mature rabbit. At 6 and 12 weeks, tensile tests were performed on fascicles from the tissue regenerated in the defect and the non-resected, residual tissue. The elastic modulus and tensile strength of fascicles from the regenerated tissue gradually increased in a fashion similar to the bulk regenerated tissue. The properties of fascicles from the residual tissue were similar to those from normal tendons, which was very much different from those of the bulk residual tissue that were greatly deteriorated by the removal of the central portion.

Prepro-TRH 178-199 inhibits histamine- or restraint stress-induced activation of corticotropin releasing hormone production in rat hypothalamus.

Under restraint stress conditions, prepro-thyrotropin releasing hormone (TRH) 178-199 suppresses adrenocorticotropic hormone (ACTH) secretion from the rat pituitary, which indicates that prepro-TRH 178-199 is a candidate endogenous corticotropin releasing inhibitory factor (CRIF). Restraint stress also activates the release of hypothalamic neuronal histamine, which increases both the expression of CRH mRNA in the paraventricular nucleus (PVN) and plasma concentrations of ACTH. The aim of this study was to determine whether prepro-TRH 178-199 modulates histamine- or restraint stress-induced activation of corticotropin releasing hormone (CRH) in the rat hypothalamus. Infusion of prepro-TRH 178-199 into the third cerebroventricle (i3vt) at a dose of 6 µg/kg significantly decreased the amount of CRH in the PVN, as compared to vehicle-treated controls (p < 0.05), but did not affect the CRH amount in other hypothalamic regions. Restraint stress increased the amount of CRH in the PVN and ventromedial hypothalamic nucleus (VMH), as compared to non-restrained controls (p < 0.05); this was attenuated by pretreatment with i3vt infusion of prepro-TRH 178-199 (p < 0.05). I3vt infusion of histamine (270 nmol/rat) suppressed cumulative food consumption over 24 h, increased plasma ACTH concentrations, and increased the content of CRH in the PVN, as compared to vehicle-treated controls (p < 0.05 for each); these effects were attenuated by pretreatment with prepro-TRH 178-199 (p < 0.05). These results suggest that prepro-TRH 178-199 may regulate ACTH secretion by affecting basal and histamine- or stress-induced synthesis and/or secretion of CRH and ACTH by modulating histaminergic input to the PVN and VMH.:

The role of histamine H1 receptor and H2 receptor in LPS-induced liver injury.

To examine the role of histamine H1 and H2 receptors in the regulation of lipopolysaccharide (LPS)-induced liver injury, a combination of D-galactosamine and LPS (GalN/LPS) was administered to histamine H1 receptor knockout (H1-R KO) and H2 receptor knockout (H2-R KO) mice. The numbers of necrotic and apoptotic hepatocytes in the liver, as well as the levels of serum aspartate transaminase (AST) and alanine transaminase (ALT), were increased significantly by GalN/LPS treatment compared to the appropriate controls. Pretreatment with histamine ameliorated the GalN/LPS-induced necrotic and apoptotic changes in the hepatocytes and inhibited the elevation of serum AST and ALT levels. Histamine attenuated the GalN/LPS-induced increases in the levels of TNF-alpha, but augmented those of IL-10 both in the liver and serum. Histamine inhibited the GalN/LPS-induced caspase-3 activity in the liver. Furthermore, these effects of histamine were completely or partially attenuated in H2-R KO mice, but not in H1-R KO mice. Peritoneal macrophages from H2-R KO mice exhibited blunted changes in the effects of histamine on LPS-induced TNF-alpha and IL-10 production in vitro compared to the wild-type (WT) controls. In summary, the present findings suggest that the histamine H2-R-TNF-alpha and -IL-10 pathways play protective roles in endotoxin-induced hepatic injury.