Beneficial effects of manually assisted chiropractic adjusting instrument in a rabbit model of osteoarthritis.

Osteoarthritis (OA) is a degenerative disease characterized by injury of all joint tissues. Our previous study showed that in experimental osteoporosis, chiropractic manipulation (CM) exerts protective effects on bone. We here assessed whether CM might ameliorate OA by improving subchondral bone sclerosis, cartilage integrity and synovitis. Male New-Zealand rabbits underwent knee surgery to induce OA by anterior cruciate ligament injury. CM was performed using the chiropractic instrument ActivatorV 3 times/week for 8 weeks as follows: force 2 setting was applied to the tibial tubercle of the rabbit right hind limb (TM-OA), whereas the corresponding left hind limb received a false manipulation (FM-OA) consisting of ActivatorV firing in the air and slightly touching the tibial tubercle. After sacrifice, subchondral bone integrity was assessed in the tibiae by microCT and histology. Cartilage damage and synovitis were estimated by Mankin's and Krenn's scores, respectively, and histological techniques. Bone mineral density and content in both cortical and trabecular compartments of subchondral bone decreased in OA rabbits compared to controls, but partially reversed in the TM-OA group. Trabecular bone parameters in the latter group also showed a significant improvement compared to FM-OA group. Moreover RANKL, OPG, ALP and TRAP protein expression in subchondral bone significantly decreased in TM-OA rabbits with respect to FM-OA group. CM was associated with lower Mankin's and Krenn's scores and macrophage infiltrate together with a decreased protein expression of pro-inflammatory, fibrotic and angiogenic factors, in TM-OA rabbits with respect to FM-OA. Our results suggest that CM may mitigate OA progression by improving subchondral bone as well as cartilage and synovial membrane status.

Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy.

Platinum drugs are the frontline therapy in many carcinomas, including high-grade serous ovarian cancers. Clinically, high-grade serous carcinomas have an apparent complete response to carboplatin, but tumors invariably recur and response to platinum drugs diminishes over time. Standard of care prohibits re-administration of platinum drugs to these patients who are labeled as having platinum-resistant disease. In this stage patients are treated with non-platinum agents and outcomes are often poor. In vivo and in vitro data presented here demonstrate that this clinical dogma should be challenged. Platinum drugs can be an effective therapy even for platinum-resistant carcinomas as long as they are combined with an agent that specifically targets mechanisms of platinum resistance exploited by the therapy-resistant tumor subpopulations. High levels of cellular inhibitor of apoptosis proteins cIAP1 and 2 (cIAP) were detected in up to 50% of high-grade serous and non-high-grade serous platinum-resistant carcinomas. cIAP proteins can induce platinum resistance and they are effectively degraded with the drug birinapant. In platinum-resistant tumors with ≥22.4 ng of cIAP per 20 µg of tumor lysate, the combination of birinapant with carboplatin was effective in eliminating the cancer. Our findings provide a new personalized therapeutic option for patients with platinum-resistant carcinomas. The efficacy of birinapant in combination with carboplatin should be tested in high-grade serous carcinoma patients in a clinical trial.

Impact of Chiropractic Manipulation on Bone and Skeletal Muscle of Ovariectomized Rats.

Evidence suggests that chiropractic manipulation might exert positive effects in osteoporotic patients. The aim of this study was to evaluate the effects of chiropractic manipulation on bone structure and skeletal muscle in rats with bone loss caused by ovariectomy (OVX). The 6-month old Sprague-Dawley rats at 10 weeks following OVX or sham operation (Sh) did not suffer chiropractic manipulation (NM group) or were submitted to true chiropractic manipulation using the chiropractic adjusting instrument Activator V® three times/week for 6 weeks as follows: Force 1 setting was applied onto the tibial tubercle of the rat right hind limb (TM group), whereas the corresponding left hind limb received a false manipulation (FM group) consisting of ActivatorV® firing in the air and slightly touching the tibial tubercle. Bone mineral density (BMD) and bone mineral content (BMC) were determined in long bones and L3-L4 vertebrae in all rats. Femora and tibia were analyzed by µCT. Mechano growth factor (MGF) was detected in long bones and soleus, quadriceps and tibial muscles by immunohistochemistry and Western blot. The decrease of BMD and BMC as well as trabecular bone impairment in the long bones of OVX rats vs Sh controls was partially reversed in the TM group versus FM or NM rats. This bone improvement by chiropractic manipulation was associated with an increased MGF expression in the quadriceps and the anterior tibial muscle in OVX rats. These findings support the notion that chiropractic manipulation can ameliorate osteoporotic bone at least partly by targeting skeletal muscle.

Beta(3)-adrenergic receptor gene variant is associated with upper body obesity only in obese Japanese-American men but not in women.

We investigated gender differences in the relationships between the Trp64Arg variant of the beta(3)-adrenergic receptor (AR) gene in obesity and insulin resistance in nondiabetic subjects. In 476 nondiabetic Japanese-Americans (M/F=204/272), the Trp64Arg variant of the beta(3)-AR gene was examined. The presence or absence of the Trp64Arg mutation was examined in DNA separated from leukocytes in peripheral blood using the PCR-RFLP method. The frequency of abnormal allele of the beta(3)-AR gene was 0.18 for males and 0.17 for females, almost the same as the reported values in Japanese. There was no difference in the frequency of the beta(3)-AR gene variant between obese and non obese subjects for each gender. However, among obese males (body mass index > or =24.2 kg/m(2)), with the beta(3)-AR gene mutation, the waist-to-hip ratio, fasting insulin, 2-h insulin, total insulin, and HOMA, an index of insulin resistance, were all significantly higher than obese males without the mutation. In females, the index of obesity, insulin resistance, or lipid metabolism did not differ significantly between the subjects with or without the beta(3)-AR gene variant either in the obese and non-obese group. We suggest that the beta(3)-AR gene variant is not important as an obesity-inducing factor in Japanese. However, in males, when obesity becomes obvious, the beta(3)-AR gene variant is considered to influence the enhancement of insulin resistance, in association with visceral obesity.

Regression of both pituitary and ovarian cysts after administration of thyroid hormone in a case of primary hypothyroidism.

We report a 19-year-old woman who was diagnosed as polycystic ovary. Hypothyroidism with a markedly elevated TSH level and an enlarged pituitary gland on MRI were noted. The 123I uptake was decreased to 6.5%. After treatment with thyroid hormone, regression of the enlarged pituitary and the ovarian cysts was observed. In the present case, hypothyroidism was considered to have caused a reversible enlargement of the pituitary gland and concomitant polycystic ovary. We concluded that the polycystic ovary might have resulted from the effects of an excessive amount of TSH on immature ovaries.

Insulin resistance precedes the appearance of albuminuria in non-diabetic subjects: 6 years follow up study.

Microalbuminuria is a marker of increased risk of cardiovascular mortality in type 1 and type 2 diabetes, and in non-diabetic subjects. Little is known about the association between prospective changes of microalbuminuria and the risk factors of atherosclerosis, or gene polymorphism in non-diabetic subjects. We conducted a 6-year prospective study of risk factors for progression of albuminuria in non-diabetic subjects. The participants were 116 non-diabetic subjects who consecutively underwent medical examinations for Japanese-Americans living in Hawaii. In the baseline examination in 1992, normoalbuminuria was found in all subjects. After 6 years, 101 subjects remained normoalbuminuria (non-progressors), 15 subjects changing from normoalbuminuria to microalbuminuria or proteinuria and were defined as progressors. In progressors, compared with non-progressors, the fasting insulin level and HOMA-R were significantly higher at 3 years follow-up, and the systolic and diastolic pressure and Sigma insulin level were significantly higher at 6 years follow-up. Insulin resistance appeared earlier than the appearance of hypertension and albuminuria. In progressors, there was no significant correlation with angiotensin-converting enzyme (ACE) genotype or angiotensinogen (AGT) genotype compared with non-progressors. Therefore, the appearance of insulin resistance should be regarded as a remarkable mediator of albuminuria.

Gln27Glu variant of the beta2-adrenergic receptor gene is not associated with obesity and diabetes in Japanese-Americans.

The beta(3)-adrenergic receptor (AR) gene variant (Trp64Arg) has been reported to be associated with obesity and insulin resistance in humans. However, this association remains controversial. We investigated the relationships between the beta(2)-AR gene variant (Gln27Glu) and obesity, insulin resistance, and serum lipids in Japanese-Americans. The frequency of an abnormal Gln27Glu allele in the beta(2)-AR gene in 652 subjects was 0.092 in males, 0.077 in females, and 0.084 overall, markedly lower than the previously reported value of 0.4 in Caucasian men and women. In both males and females, there were no differences in the indices of obesity, insulin resistance, and serum lipid levels between the subjects with and without the beta(2)-AR gene (Gln27Glu) variant in patients with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or diabetes (DM). The frequency of the beta(2)-AR gene (Gln27Glu) variant tended to increase with worsening of glucose tolerance, but the differences were not statistically significant. Furthermore, there were no differences in the frequency of the beta(2)-AR gene variant in either males or females with obesity (body mass index [BMI], > or = 25.2). Even in Japanese-Americans, who have a more westernized life style than Japanese, the association of the beta(2)-AR gene (Gln27Glu) variant with the parameters of obesity, insulin resistance, and serum lipid level has yet to be clarified. We conclude that the beta(2)-AR gene (Gln27Glu) variant might not be an important factor for obesity or IGT in Japanese subjects.

DiGeorge syndrome with Graves' disease: A case report.

DiGeorge syndrome (DGS) is characterized by aplasia or hypoplasia of the thymus and parathyroid glands, cardiac defects and anomaly face. This syndrome is usually associated with hypocalcemia resulting from hypoparathyroidism. In most cases the initial symptom is tetany caused by hypocalcemia within 24-48 hours after birth, with symptoms by immune abnormality appearing later. We report a woman who passed with no symptoms before age 18 and was diagnosed DiGeorge syndrome by tetany with developing auto-immune thyroid disease (Graves' disease). She had surgery for intraventricular septal defect at age 3, hypoparathyroidism, decrease of T cells in peripheral blood and the deletion of the 22nd chromosome long arm (22q11.2). It is supposed that abnormalities of immune function of this case are not complete as indicated by complicating of Graves' disease, and contributing to her long-term survival.

Reduced prevalence of diabetes according to 1997 American Diabetes Association criteria.

AIMS/HYPOTHESIS: We examined the prevalence of diabetes and investigated the characteristics of subjects diagnosed by the American Diabetes Association and the World Health Organization criteria. METHODS: A total of 1235 Japanese-Americans living in Hawaii and Los Angeles was studied. Of the subjects 114 were classified as previously diagnosed as having diabetes. A 75-g glucose tolerance test was given to the rest of the subjects. RESULTS: When abnormal glucose tolerance was diagnosed by the American Diabetes Association criteria, it was possible to identify only 40 % of diabetic subjects who had not been previously diagnosed compared with the current World Health Organization criteria based on a glucose tolerance test. In addition, the subjects identified by the American Diabetes Association criteria had higher glucose concentrations and had less insulin secretory capacity and they were in need of intensive treatment for diabetes. On the other hand, the subjects not diagnosed by the American Diabetes Association criteria alone were those whose glucose tolerance would be more likely to improve with lifestyle modification. CONCLUSION/INTERPRETATION: It might be better to use the fasting plasma glucose criterion advocated by the American Diabetes Association in combination with a glucose tolerance test after taking a detailed medical history. To reduce the number of subjects requiring the glucose tolerance test, priority should be given to subjects with impaired fasting glucose (6.1

Bradycardia induced by irinotecan: a case report.

Irinotecan chloride (CPT-11) is a new semi-synthetic camptothecin analogue which has encouraging antitumor activity against various malignancies. The major and unique toxicity of CPT-11 is diarrhea. Cardiovascular toxicity is rare and has not been found in clinical trials performed in Japan except for a very few cases of insignificant tachycardiac arrhythmia. We report a case of a 69-year-old man with recurrent colon cancer who suffered from bradycardia induced by infusion of CPT-11. Other toxicities including hematological toxicity and diarrhea were mild. Pharmacokinetic analysis using a limited sampling model revealed that the occurrence of bradycardia did not correlate with the excess of drug exposure. Although all of the cholinergic actions reported in the literature were mild, cardiotoxicity may come to be a clinically significant problem. If the events were examined more thoroughly, the cholinergic effect may be discovered more frequently. To administer CPT-11 safely needs meticulous monitoring not only for hematological toxicity and diarrhea but also for other cholinergic actions including bradycardia.