Incidence and outcomes of humeral fractures in the older person.

Humeral fractures are not well understood and thus we examined the incidence and outcomes of elderly humeral fractures at a single institution over a 3-year period. We found increasing incidence in humeral fractures with increasing age and negative outcomes comparable to hip fractures. INTRODUCTION: In this study, we report the incidence of humeral fractures in the older patient and their outcomes, including new nursing homes discharges and mortality, residing in the metropolitan referral area of a Sydney tertiary referral hospital. METHODS: All admissions between 2013 and 2016, of patients aged 65 years or more, presenting to hospital with humeral fractures were reviewed. The data was explored primarily for outcomes (mortality and new admissions to residential aged care facility) and secondarily for clinical association with humeral fractures. RESULTS: Two hundred eighty-one episodes of humeral fracture were identified. Incidence peaked in the above 85-year-old group at 670 per 100,000 persons per year. Proximal fractures were accounted for 84.3% of the cohort. 12.8% received operative management. The in-hospital mortality rate was 3.6%. Gender was a significant predictor for mortality (OR = 5.8, 95% CI 1.3-28.5, p value = 0.0032) with males six times more likely to experience in-hospital mortality compared to females. 17.8% of participants were admitted to a new nursing home. Logistical regression demonstrated age (OR = 1.10, 95% CI 1.04-1.17; p value = 0.001) and Charlson comorbidity index (OR = 1.32, 95% CI 1.04-1.66; p value = 0.02) were predictors of admission to a new nursing home. CONCLUSION: Humeral fractures are common in the older population and cause a substantial amount of new nursing home admissions and mortality. Further study is required to ascertain appropriate guidelines for treatment and rehabilitation.

The effects of dietary supplementation with isoflavones from red clover on cognitive function in postmenopausal women.

OBJECTIVE: To examine the effects of dietary isoflavone supplementation with an extract from red clover on cognitive function in postmenopausal women. DESIGN: Thirty postmenopausal women aged greater than 60 years received either two tablets of an extract of aglycone isoflavones from red clover (each containing formononetin 25 mg, biochanin 2.5 mg and less than 1 mg of daidzein and genistein) for 6 months in a randomized, controlled clinical trial. Cognitive function tests were performed at baseline and at the end of isoflavone or placebo therapy. RESULTS: Isoflavone supplementation was associated with an apparent improvement in block design (a test of visual-spatial intelligence) compared to placebo (isoflavone +12%, placebo -3%; p = 0.03), no improvement in verbal memory compared to an improvement on placebo (isoflavone +1%, placebo +29%; p = 0.023) and a deterioration in digit recall compared to placebo (isoflavone -6%, placebo +12%; p = 0.029). However, these findings were not statistically significant when corrections were made for potential chance findings due to multiple comparisons. CONCLUSION: Isoflavone supplementation does not appear to have major short-term effects on cognitive function in postmenopausal women. However, further clinical trials are required to determine whether small effects or long-term effects on cognitive function occur during isoflavone supplementation.

Prevalence of malnutrition and 12-month incidence of mortality in two Sydney teaching hospitals.

AIMS: The objectives of the present study were to determine: (i) the prevalence of malnutrition in two Sydney teaching hospitals using Subjective Global Assessment (SGA), (ii) the effect of malnutrition on 12-month mortality and (iii) the proportion of patients previously identified to be at nutritional risk. METHODS: A prospective study using SGA to assess nutritional status of eligible inpatients, from April to September 1997, with a 12-month follow-up to assess mortality. A total of 819 patients was systematically selected from 2,194 eligible patients. Patients were excluded if they were under the age of 18, had dementia or communication difficulties, or were under obstetric or critical care. The main outcome measures were prevalence of malnutrition, 12-month incidence of mortality, proportion of patients identified with malnutrition, and hospital length of stay (LOS). RESULTS: The prevalence rate of malnutrition was 36%. The proportion of malnourished patients was not significantly different between the two hospitals (P = 0.4). The actuarial incidence of mortality at 12 months after assessment was 29.7% in malnourished subjects compared with 10.1% in well-nourished subjects (P < 0.0005). Malnourished subjects had a significantly longer median LOS (17 days vs 11 days, P< 0.0005) and were significantly older (median 71 years vs 63 years, P < 0.0005) than well-nourished subjects. Only 36% of the malnourished patients had been previously identified as being at nutritional risk. CONCLUSIONS: Malnutrition in Australian hospitals is a continuing health concern and is associated with increased LOS and decreased survival after 12 months. The present study revealed that malnourished patients were not regularly identified. Further studies are required to determine whether routine identification of malnutrition and subsequent nutritional intervention are effective in improving clinical outcomes in these individuals.

Predictors of bone mass in healthy older men in the community.

OBJECTIVES: To determine the predictors of bone mass (in lumbar spine and femoral neck) in healthy older men living in the community. DESIGN: Cross-sectional study. Bone mineral density (BMD) was measured and known predictors of bone mass and bone turnover were assessed. SUBJECTS AND SETTING: 113 independent, healthy men (70 years and over), not taking glucocorticoid therapy and without medical conditions known to affect bone mass and bone turnover, were recruited from recreational and sports clubs in southern Sydney in April/May 1997. MAIN OUTCOME MEASURES: BMD (measured by dual-energy x-ray absorptiometry); known predictors of bone mass (height; weight; body mass index; calcium level; serum 25-hydroxyvitamin D and free testosterone levels); and markers of bone turnover (serum bone Gla protein and procollagen-1 concentrations, and urinary deoxypyridinoline excretion rates). RESULTS: The mean age of the men was 76.6 years (range, 70-92 years). Mean (SE) BMD of the lumbar spine was 1.143 (0.019) g/cm2 and that of the femoral neck was 0.897 (0.013) g/cm2. BMD values indicating osteoporosis were found in the lumbar spine in 13 men (11.5%) and in the femoral neck in 35 men (31%). The best predictor of lumbar spine BMD was weight (R = 0.37; P = 0.001), and weight- and age-predicted femoral-neck BMD (R = 0.49; P < 0.001). The study group was analysed in two groups with BMD higher or lower than median bone mass corrected for age. Men with lower femoral-neck BMD for age had significantly lower weight, lower lean mass and higher bone Gla protein concentrations. In addition, men with lower lumbar spine BMD for age also had significantly lower fat mass. CONCLUSIONS: These data indicate that measures of body composition, such as weight and lean mass, are the main predictors of bone mass in healthy, community-dwelling older men.

Amiodarone compared with iodine exhibits a potent and persistent inhibitory effect on TSH-stimulated cAMP production in vitro: a possible mechanism to explain amiodarone-induced hypothyroidism.

Amiodarone (AMD) is a powerful anti-arrhythmic drug used for the treatment of a wide variety of cardiac arrhythmias and its most striking feature is its high iodine content. Thyroid dysfunction is a limiting side-effect of the drug and both AMD-induced hypothyroidism (AIH) and AMD-induced thyrotoxicosis (AIT) are reported. To examine the hypothesis that altered bioavailability of iodine is a contributing event in the pathogenesis of AIH, we compared the effects of AMD and inorganic iodine in vitro on events involved in the process of thyroid autoregulation. FRTL-5 cells and JP26 CHO cells (transfected with the human TSH receptor) were exposed to AMD or NaI in the presence of TSH, and cAMP production was measured as an indicator of cellular function. Forskolin and cholera toxin were also used to determine the possible target sites of AMD and iodide. Our results indicated that there was a difference between the effects of AMD versus those of physiological doses of iodide. The inhibitory effects of AMD occurred at lower concentrations of iodide than those seen in the NaI-treated cells. The effects of AMD were irreversible indicating a possible persistence of the Wolff-Chaikoff effect due to a constant high intracellular iodide level. The inhibitory effects of AMD (also seen at supraphysiological doses of iodide) were partially overcome by forskolin but not by cholera toxin indicating an effect on TSH receptor interactions with the other signal transduction elements such as G proteins and adenylate cyclase. The persistence of the Wolff-Chaikoff effect through loss of autoregulation may be a mechanism of the observed hypothyroidism in some patients taking AMD. The combined effects of the constant release of iodide together with the drug toxicity may be the mechanism for the observed effects.

Body mass and body composition after total thyroidectomy for benign goiters.

To date there are no data available as to whether postmenopausal women who undergo total thyroidectomy for benign euthyroid goiter demonstrate changes in body mass or body composition. We prospectively evaluated 8 postmenopausal women (mean age 57 +/- 7; range 48 to 70 years) who underwent total thyroidectomy for benign goiter. All patients were euthyroid preoperatively (serum free thyroxine [FT4] 12.7 +/- 0.6 pmol/L and serum thyrotropin [TSH] 0.98 +/- 0.2 mU/L) and were commenced on adequate thyroxine replacement immediately postoperatively in order to maintain a serum TSH within the normal range (0.5-4 mU/L). Body mass, body composition, and thyroid function were assessed preoperatively, and at 4 and 12 months postoperatively. Body composition was assessed by anthropometry and dual energy x-ray absorptiometry (Lunar DPX-L scanner). Eight healthy postmenopausal women without evidence of thyroid disease matched for age, weight, and estrogen therapy who were followed over the same period were used as controls. All patients were maintained in a euthyroid status throughout the study. No significant changes in body mass or any parameter of body composition were demonstrated at 4 and 12 months postoperatively. Similar findings were recorded in our control group. We conclude that total thyroidectomy in euthyroid postmenopausal women with benign goiter does not result in a significant change in either body mass or body composition if adequate thyroxine replacement is maintained.

Hip fracture in elderly men: the importance of subclinical vitamin D deficiency and hypogonadism.

OBJECTIVE: To determine the major risk factors for hip fracture in elderly men. DESIGN: Prospective recruitment, followed by analysis of clinical and biochemical variables. PATIENTS AND SETTING: Men aged 60 years and older who presented to St George Hospital (a 650-bed tertiary-care centre) in 1995, comprising all 41 men with hip fractures, as well as 41 hospital inpatient and 41 outpatient control subjects without hip fractures. MAIN OUTCOME MEASURES: Osteoporotic risk factors (including age, body weight, comorbid illnesses, alcohol intake, cigarettes smoked, and corticosteroid use) and serum concentrations of creatinine, urea, calcium, albumin, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D and free testosterone. RESULTS: There were no significant differences between the hip fracture and two control groups on any of the osteoporotic risk factors. Men with hip fracture had significantly lower mean serum 25-hydroxyvitamin D concentration (45.6 nmol/L; 95% confidence interval [CI], 36.9-52.3 nmol/L) than both inpatient (61.1 nmol/L; 95% CI, 50.0-72.2 nmol/L) and outpatient (65.9 nmol/L; 95% CI, 59.0-72.8 nmol/L) controls (P=0.007). Subclinical vitamin D deficiency (defined as <50 nmol/L serum 25-hydroxyvitamin D) was 63% in the fracture group, compared with 25% in the control groups combined (odds ratio, 3.9; 95% CI, 1.74-8.78; P=0.0007). Inpatients with and without hip fractures had significantly lower mean serum albumin, calcium and free testosterone concentrations than outpatients (P< 0.05). In a multiple regression analysis, subclinical vitamin D deficiency was the strongest predictor of hip fracture (beta [regression coefficient], 0.34+/-0.19; P=0.013). CONCLUSIONS: Subclinical vitamin D deficiency in Australian men may contribute significantly to the development of hip fracture through the effects of secondary hyperparathyroidism, resulting in increased bone loss.

Relationship between serum parathyroid hormone levels in the elderly and 24 h ambulatory blood pressures.

BACKGROUND: An association between serum parathyroid hormone (PTH) levels in normotensive elderly subjects and blood pressure values had been reported. OBJECTIVE: To examine the relationship between PTH levels and other biochemical markers of calcium metabolism in elderly subjects and 24 h ambulatory blood pressures. METHODS: We performed 24 h ambulatory blood pressure recordings for 123 independent elderly subjects aged 63-88 years using a SpaceLabs 90207 recorder. Mean night-time blood pressures were calculated from the average of readings during sleep; mean daytime blood pressures were calculated from the remaining recordings. Demographic data and details concerning the alcohol consumption and medication usage of the subjects were recorded. Serum PTH, 25-hydroxy-vitamin D, albumin, renin, aldosterone, noradrenaline, creatinine and calcium levels were measured. RESULTS: Fifty-five patients were being administered antihypertensive therapy. Serum PTH levels correlated to the nocturnal systolic blood pressure (SBP; beta = 0.29, P = 0.002), nocturnal diastolic blood pressure (DBP), daytime SBP and mean 24 h SBP on univariate and multivariate analysis. Aldosterone levels were related to nocturnal SBP in univariate analysis (beta = 0.21, P = 0.02) but the relationship was weakened when PTH levels were included in the analysis (beta = 0.16, P = 0.09). Nocturnal, daytime and mean 24 h blood pressures were not significantly related to serum calcium, 25-hydroxy-vitamin D, age, body mass index and alcohol consumption. Sex was a significant predictor of the DBP, men having higher levels than did women (daytime DBP beta = 0.29, P = 0.001). CONCLUSIONS: Serum PTH levels are related strongly to the blood pressure, particularly the nocturnal blood pressure in the elderly. It is not known whether PTH levels are a consequence or a cause of the elevation in blood pressure.

Hip fracture in elderly men: prognostic factors and outcomes.

OBJECTIVE: To examine prognostic factors and outcomes after hip fracture in men aged 60 years and older. DESIGN AND SETTING: Cohort study of all men presenting to St George Hospital (a 650-bed tertiary care centre) with hip fractures in 1995, recruited retrospectively from medical records and evaluated prospectively at six and 12 months after fracture. PATIENTS: 51 men aged 60 years or more (and, for comparison, 51 age-matched women) who presented with hip fracture not caused by high impact injuries or local bone disease. MAIN OUTCOME MEASURES: Prognostic factors (such as pre-existing illness and osteoporotic risk factors) and outcome data (such as fracture-related complications, mortality, and level of function as measured by the Barthel index of activities of daily living at six and 12 months postfracture). RESULTS: Median age of the 51 men was 80 years (interquartile range, 74-86 years); four were aged under 70 years. Outcome assessment was possible for 41 men (80%). Similar proportions of men and women came from institutions (32% v. 28%), and similar additional proportions required institutionalisation after discharge (18% v. 14%). Fracture-related complications affected similar proportions of men and women (30% v. 32%), and mean length of hospital stay was similar. Fourteen per cent of men died in hospital compared with only 6% of women (P = 0.06). Men had more risk factors for osteoporosis (P < 0.01). Physical functioning (measured by the Barthel index) deteriorated significantly in men from 14.9 at baseline to 13.4 at six months (P < 0.05) and 12.4 at 12 months (P < 0.05) after fracture. CONCLUSION: Compared with women, elderly men presenting with hip fracture have higher mortality and have more risk factors for osteoporosis. Like women with hip fracture, men are usually fragile, with pre-existing medical illness and fracture-related complications contributing to their overall poor outcomes.

Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both the BB/W rat and the Wistar rat.

Amiodarone (AMD)-induced toxicity can be a life-threatening complication which limits the use of amiodarone as an anti-arrhythmic agent. The aim of the present study was to determine the nature of AMD toxicity by comparing ultrastructural changes induced by AMD and equivalent amounts of iodide in two animal models, the Wistar and the autoimmune BB/W rat. Rats were divided into control (water), AMD- (30 mg AMD/kg) or iodide-treated (10 mg/kg) groups. Thyroids were removed at 15 weeks and processed for electron microscopy. We found that AMD induced specific ultrastructural changes of thyroid cytotoxicity in both rat models, which were distinct compared with changes induced by excess iodide alone. Specific changes included marked distortion of thyroid architecture, evidence of necrosis and apoptosis, inclusion bodies, lipofuscinogenesis and markedly dilated endoplasmic reticulum (ER). Our data indicate that AMD is directly cytotoxic to the thyroid an effect mediated by disruption of subcellular organelle function. ER dilatation is suggestive that AMD cytotoxicity may be mediated through disruption of the protein sorting pathways leading to a drug-induced form of ER storage disease. The predilection of the thyroid to AMD may be explained by the additive effects of excess iodine and AMD drug toxicity on protein sorting pathways.

The G2M arrest caused by iodide is unrelated to the effects of iodide at adenylate cyclase.

Previously, we have shown that the iodide was able to inhibit TSH induced thyrocyte proliferation by arresting the cell cycle at G0G1 and G2M, suggesting that the iodide may be exerting its effects through more than the TSH-adenylate cyclase-cAMP system. To confirm the effects of iodide on the adenylate cyclase (AC) system, forskolin- and dibutyryl-cyclic-AMP (dBcAMP)-stimulated FRTL5 thyroid cells were exposed to inhibitory concentrations of iodide and the resultant effects on the cell cycle were compared to the effects observed with TSH, using flow cytometric DNA analysis. Forskolin stimulated the proliferation of FRTL5 cells in a dose-dependent manner. Cell numbers rose from baseline by 169 +/- 4% to peak at 10 microM forskolin. Interestingly, 100 microM forskolin inhibited cell proliferation, causing cell numbers to fall by approximately 50%. Iodide inhibited forskolin-induced proliferation to baseline levels. However, the pattern of cell cycle perturbation was different to that with TSH-stimulated cells. There were no differences in the proportion of cells in G0G1 between forskolin alone and forskolin + NaI, while there was a marked fall in the proportion of cells in S phase, indicating possible partial arrest at G0G1. Furthermore, there was a marked accumulation of cells in G2M over and above that found with TSH + NaI, indicating arrest at G2M. dBcAMP maximally stimulated cell numbers to rise from baseline by 125% with 1 mM dBcAMP. Again, higher concentrations of the mitogen had an inhibitory effect on proliferation. The addition of NaI inhibited dBcAMP stimulated cell proliferation.

Evidence that the inhibitory effects of iodide on thyroid cell proliferation are due to arrest of the cell cycle at G0G1 and G2M phases.

The thyroid gland is unique in its ability to respond to ambient levels of iodine to autoregulate thyroid function and, possibly, thyroid cell proliferation. Although the inhibitory effects of iodide on thyroid cell proliferation have been previously reported, the exact mechanism and site of action of iodide on cellular proliferation events are poorly understood. Our initial experiments established the optimal cell plating density and timing to achieve exponential cell growth of FRTL5 thyroid cells, and subsequent studies using flow cytometric DNA analysis established the normal cell cycle kinetics of FRTL5 thyroid cell proliferation. FRTL5 cells were then exposed to graded concentrations of sodium iodide to establish whether the inhibitory effects of iodide are mediated through specific cell cycle events. We observed that increasing concentrations of iodide inhibited FRTL5 thyroid cell proliferation. Analysis of the cell cycle revealed two specific effects of iodide on cell cycle kinetics. The first was an arrest of cells in G0G1, evidenced by an accumulation of cells in this phase and a concomitant reduction in the percentage of cells in the S-phase. The second was an arrest of cells in the G2M phase of the cycle. G0G1 and G2M arrest occurred within 24 h and then reached a plateau. Iodide exposure did not increase the number of cells undergoing necrosis. The addition of methimazole at two concentrations (0.2 and 2 mM) to cells exposed to 100 mM NaI prevented the accumulation of cells in G2M, but did not abolish the accumulation of cells in G0G1 or the reduction in cell number. These results indicate that the inhibitory effects of iodide on FRTL5 thyroid cell proliferation are mediated by its action at two critical regulating points of the cell cycle, G0G1 and G2M. It appears that organified iodine may mediate the cell cycle arrest in the G2M phase, whereas inorganic iodide may be responsible for the inhibitory effects at G0G1.

Methimazole inhibits FRTL5 thyroid cell proliferation by inducing S-phase arrest of the cell cycle.

Previous studies, using tritiated thymidine uptake assays, had indicated a nil or stimulatory effect of methimazole (MMI) on thyroid cell proliferation. Whilst examining cell cycle kinetics of FRTL5 thyrocytes, we observed an inhibitory effect of MMI on thyroid cell proliferation. To further examine this observation, FRTL5 cells whilst in log phase proliferation were exposed to media containing either 6H or MMI in 6H. Cell number and cell cycle kinetics were examined using flow cytometric DNA analysis every 24 hrs for 96 hrs. We found that MMI inhibited cell proliferation (as assessed by cell number) throughout the experimental period. Cell cycle analysis revealed a persistent arrest of cells in S phase. Concomitantly, there was a fall in the proportion of cells in both G0G1 and G2M phases, in keeping with cell cycle arrest in S phase. Taken in isolation, the finding of a high proportion of cells in S phase would suggest stimulation of cell proliferation, consistent with the findings of previous studies which used tritiated thymidine uptake assays to assess cell proliferation. However, the absence of a concomitant increase in total cell number renders this argument invalid and argues for a specific effect of MMI on the cell cycle. This study demonstrates a hitherto unrecognised inhibitory action of MMI on FRTL5 thyroid cell proliferation which has implications in understanding the broader effects of MMI on thyroid cell physiology. Additionally, this study highlights the dangers of using tritiated thymidine uptake measures as the sole indicator of mitogenic activity.

Topical iodine-containing antiseptics and neonatal hypothyroidism in very-low-birthweight infants.

The thyroid function of very-low-birthweight (VLBW; below 1500 g) infants admitted to neonatal intensive-care units was studied at two hospitals; one routinely used topical iodinated antiseptic agents and the other used chlorhexidine-containing antiseptics. Serial monitoring of urinary iodine excretion and serum thyrotropin and thyroxine levels was undertaken from birth for the first 4 weeks of life. Urinary iodine excretion rose dramatically in the 54 iodine-exposed infants and was up to fifty times greater than in the 29 non-exposed infants. Within 14 days, 25% (9 of 36) of the infants exposed to iodine had serum thyrotropin levels above 20 mIU/l, compared with none of the control group. The mean serum thyroxine level in these 9 infants (44.1 nmol/l) was significantly lower than that in exposed infants with normal thyrotropin levels (83.1 nmol/l) and in the non-exposed control group (83.0 nmol/l); thyroxine levels fell before serum thyrotropin rose. These disturbances in thyroid function correlated positively with urinary iodine excretion and hence iodine absorption. Thyroid function had returned to normal by the time of discharge from hospital. It is concluded that iodine absorption, from topical iodine-containing antiseptics, may cause hypothyroidism during a critical period of neurological development in the newborn infant. The routine use of iodine antisepsis in VLBW infants should be avoided because of this effect.