Pain Management in Nursing Home Residents: Results from the INCUR Study.

OBJECTIVES: Pain is very common among older persons living in nursing home, affecting 45% to 80% of residents, interfering with daily activities and quality of life. Aims of the study are: 1) to measure the analgesics non-prescription in nursing home residents who present pain symptoms; 2) to identify the main determinants of analgesics non-prescription. DESIGN: Retrospective cross-sectional analysis. SETTING: Data from an observational study ('Incidence of pNeumonia and related ConseqUences in nursing home Residents' [INCUR] study). PARTICIPANTS: 800 older persons living in 13 French nursing homes. Measurments: Pain symptoms were definied by one of the following criteria: i) Presence of pain affecting the individual's function in the Activities of Daily Living; ii) Presence of daily pain, and/or; iii) Severe pain measured with a visual analogue scale. RESULTS: Among the patients originally included in the study, 288 (36%) reported pain symptomatology (mean age 86.9 [SD 7.2] years, 220 (76%) participants women). Amongst these, 138 (47.9%) were treated with non-opioid analgesic drugs, 52 (18.1%) with opioids, and 98 (34%) did not receive any analgesic prescription. An adjusted logistic regression analysis found that the strongest determinant of analgesics non-prescription was the number of concomitantly prescribed drugs (p<0.001). Age, education, and frailty were not associated with prescription of analgesic drugs. CONCLUSIONS: Pain undertreatment is very common among older persons living in nursing homes. The number of prescribed medications represents the most relevant risk factor for the analgesics non-prescription. Our findings document the importance of reviewing prescriptions in nursing home residents.

Risedronate and pamidronate treatment in the clinical management of patients with severe Paget's disease of bone and acquired resistance to bisphosphonates.

The aim of this study was to evaluate the efficacy and safety of risedronate and pamidronate in 30 patients (mean age = 57.86 +/- 8.90 years) with severe Paget's disease of bone (PDB), showing acquired resistance to intravenous (IV) clodronate treatment. Fifteen patients were treated with oral risedronate (30 mg/day for 8 weeks). Treatment was repeated in patients without evidence of PDB remission [total alkaline phosphatase (tALP) serum levels in the normal range] at day 120. Fifteen patients were treated with IV pamidronate (30 mg/day for 3 days). Pamidronate treatment (60 mg/day for 3 days) was repeated in patients without evidence of PDB remission at day 120. At day 60, a significant decrease in tALP serum levels was obtained in all pagetic patients. At day 360, 13 (86.6%) patients treated with risedronate achieved PDB remission, 9 patients during the initial treatment and 4 after retreatment. Two patients showed a significant decrease in tALP serum levels without clinical remission after two risedronate treatments. At the same time, 12 (80%) patients treated with pamidronate achieved PDB remission, 6 patients during the first treatment and 6 after retreatment. Three patients showed a significant decrease in tALP serum levels but no clinical remission after two pamidronate courses. Two of these patients showed a relapse during the study. The incidence of minor side effects and transient hyperparathyroidism related to bisphosphonate treatment was significantly lower after risedronate therapy. In patients with resistant PDB, oral risedronate therapy has comparable efficacy to IV pamidronate with a lower incidence of treatment-related side effects.

Biochemical markers of bone turnover, serum levels of interleukin-6/interleukin-6 soluble receptor and bisphosphonate treatment in Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare non-Langherans form of histiocytosis characterized radiologically by symmetrical sclerosis of the metaphysis and the diaphysis of long tubular bones. Macrophages are potent interleukin-6 (IL-6) producers and elevated IL-6 serum levels have been described in pathological conditions characterized by increased bone resorption. In a patient with ECD, during the acute phase of the disease we found high serum levels of IL-6 and IL-6 soluble receptor (sIL-6R) and high levels of bone turnover markers. After 5 years of combination therapy with oral prednisone and intravenous clodronate a significant reduction in the above mentioned biological parameters was seen. We suggest that the systemic disorders present in ECD could be related to the high serum levels of IL-6 and sIL-6R. We also propose the use of bisphosphonates in the clinical management of ECD.

Association between vitamin D receptor gene polymorphisms and tubular citrate handling in calcium nephrolithiasis.

OBJECTIVES: Hypocitraturia is a risk factor for calcium nephrolithiasis. 1,25(OH)2D3 influences renal citrate handling and enhances citraturia. The aim of this study was to evaluate the relationship between vitamin D receptor (VDR) allelic variant and urinary citrate excretion in recurrent stone formers (SF) patients. DESIGN: Case-control study. SUBJECTS: A total of 220 recurrent calcium oxalate SF patients and 114 healthy control (C) subjects were enrolled for this study. Subjects with urinary tract infections, hyperparathyroidism, cystinuria >70 micromol/24 h, gouty diathesis, renal tubular acidosis, renal failure, chronic diarrhoeal states, intake of thiazide diuretics, angiotensin-converting enzyme (ACE)-inhibitors, glucocorticoids or oestrogens were excluded. A standard constant diet was given for 7 days. The 24-h urinary citrate excretion and the active tubular reabsorption of filtered citrate (Rcit) were evaluated. Hypocitraturia was defined as a urinary citrate excretion lower than 1.7 mmol day-1. Stone formers patients and C were genotyped for BsmI and TaqI VDR alleles. Contingency table chi-square tests were used to compare genotype frequencies in hypocitraturic SF patients, normocitraturic SF and C. RESULTS: The prevalence of hypocitraturia in SF patients was 32.7% (72 of 200). Hypocitraturia in these patients resulted from excessive Rcit of a normal load of citrate. We found a different distribution (P < 0.05) of BsmI and TaqI VDR genotypes in hypocitraturic SF patients compared with normocitraturic SF and C. In particular, the prevalence of bb and TT VDR genotypes in hypocitraturic SF was significantly higher than in normocitraturic SF and C. CONCLUSIONS: These results point to a genetic association between BsmI and TaqI VDR polymorphisms and idiopathic hypocitraturia in calcium-oxalate recurrent SF patients.

Clodronate treatment reduces serum levels of interleukin-6 soluble receptor in Paget's disease of bone.

OBJECTIVE: Interleukin-6 (IL-6) and its soluble receptor (sIL-6R) stimulate osteoclast formation and activity. The primary cell abnormality in Paget's disease of bone (PDB) involves osteoclasts. Pagetic osteoclasts overproduce IL-6 and IL-6 receptor in vitro. In vivo, IL-6 serum levels are very high in the acute phase of PDB. The aim of this study was to evaluate the modification in the serum levels of IL-6, sIL-6R and osteotropic hormones (parathormone, 25OHD3 and 1,25(OH)2D3) as a in long-term response to clodronate treatment in patients with PDB. METHODS: 16 patients (8 females) with polyostotic PDB were studied. IL-6, sIL-6R and osteotropic hormones serum levels were evaluated in active PDB and after clodronate treatment (300 mg injected intravenously for 5 consecutive days). The sequential changes in total alkaline phosphatase (tALP) serum levels were used to assess the maximal pharmacological response to treatment. RESULTS: In untreated pagetic patients, mean serum levels of IL-6 (3.20+/-1.18 pg/ml) and sIL-6R (35.02+/-8.33 ng/ml) were significantly increased. Serum osteotropic hormone levels fell within the normal range. Eight weeks after treatment, the maximal pharmacological response to clodronate was associated with a significant reduction of sIL-6R serum levels in all patients, without a significant variation in serum IL-6 and osteotropic hormone levels. Moreover, we observed a correlation between lower sIL-6R serum levels before clodronate therapy and complete remission of PBD, defined as a decrease of tALP serum levels within the normal range. CONCLUSION: The decrease in serum sIL-6R levels could be one of the molecular mechanisms that play a role in the clinical response to clodronate treatment in PDB.

Past history of nephrolithiasis and incidence of hypertension in men: a reappraisal based on the results of the Olivetti Prospective Heart Study.

BACKGROUND: We have previously reported that in the Olivetti Prospective Heart Study cohort the incidence of nephrolithiasis was higher in hypertensive participants than in normotensive ones. As the time sequence and the mechanisms underlying the association between nephrolithiasis and hypertension remain controversial, we further tested the hypothesis that in a cohort of normotensive males a history of nephrolithiasis predicts the development of future hypertension. METHODS: The analysis was conducted in 381 male workers at Olivetti who were normotensive at the baseline examination and who were re-examined 8 years later. RESULTS: A past history of nephrolithiasis is associated with an increased risk of hypertension of 1.96 (95% CI=1.25-3.07) relative to subjects with a negative history, after adjusting for age. CONCLUSION: In this 8-year follow-up study, a history of nephrolithiasis resulted in an increased risk of developing hypertension in the future. As the reverse was also true, as previously reported, a clear-cut time sequence, as well as the mechanisms linking these two conditions, remain to be identified.

Frequent RET protooncogene mutations in multiple endocrine neoplasia type 2A.

The occurrence of mutations in the RET protooncogene has been investigated in 12 multiple endocrine neoplasia type 2A families and 18 cases of sporadic thyroid medullary carcinomas and pheochromocytomas. Ten of 12 families showed single base substitutions in the RET protooncogene exons 10 and 11, coding for the extracellular domain of the protein. Tumor tissues from 2 multiple endocrine neoplasia type 2A patients were analyzed at the DNA and ribonucleic acid levels and revealed the same heterozygous mutations found in the peripheral blood lymphocytes. This demonstrates that both the normal and mutant alleles are expressed. No mutations in these exons were detected in the 18 cases of sporadic tumors investigated. These data provided further evidence that the mutated RET protooncogene acts in a dominant fashion and is responsible for the pathogenesis of this syndrome.

Vitamin D status in Paget's bone disease. Effects of calcitonin therapy.

In 15 patients suffering from Paget's disease, the serum levels of alkaline phosphatase (ALP), 25-hydroxycholecalciferol (25OHD3), 24,25-dihydroxycholecalciferol (24,25 [OH] 2D3), 1,25-dihydroxycholecalciferol (1,25 [OH] 2D3), and parathormone (PTH) as well as urinary excretion of hydroxyproline (HP) have been determined before and after three-month calcitonin therapy. Before therapy, high concentrations of serum ALP and urinary HP excretion had been observed, whereas serum levels of 24,25 (OH) 2D3 were below the lower limit of the normal range. Calcitonin therapy caused a 31% reduction in ALP and a 50% reduction in HP, as well as a significant increase in serum levels of 24,25 (OH) 2D3; the levels of 25OHD3, 1,25 (OH) 2D3, and PTH remained unchanged after treatment. The significant negative correlation between 24,25 (OH) 2D3 and ALP and HP before and after calcitonin therapy suggests that in Paget's disease there is an uncompensated increased bone usage of 24,25 (OH) 2D3.

Characterization of the clinical features of five families with hereditary primary cutaneous lichen amyloidosis and multiple endocrine neoplasia type 2.

The hereditary conditions of primary cutaneous lichen amyloidosis and multiple endocrine neoplasia type 2 (MEN 2) are rare clinical entities. The initial reports of two families in which the two conditions coincided have led to the identification of at least eight additional families with this clinical syndrome. In this report we describe the clinical features in five of these eight families. The salient feature in these five families is the presence of unilateral (46%) or bilateral (64%) pruritic and lichenoid skin lesions located over the upper portion of the back. Family members describe these skin lesions as intermittently intensely pruritic leading to scratching and excoriation of the upper back region. The presence of MEN 2 has been documented in 97% of family members with this skin lesion, the one exception being a child who is at risk for development of MEN 2A in whom the diagnosis has not yet been made. Of family members who have MEN 2A, 27% do not have an identifiable skin lesion, although the skin lesion developed in one patient two years after a curative thyroidectomy for medullary thyroid carcinoma (MTC). Four of the five families have members with pheochromocytoma; one with five affected members has only MTC. The finding of this clinical syndrome in geographically diverse portions of the world and the lack of overlap with MEN 2A without the skin lesion suggest it is a distinct clinical variant of MEN 2A.

Recurrent kidney stones: causes and diagnostic criteria in patients from Campania (southern Italy).

A study was carried out on 180 recurrent kidney stone formers from the Campania region of southern Italy. The data showed that this hypercalciuric population was similar to that in previous studies; however, there was no difference in terms of parathyroid activity when compared with normal controls. The slightly depressed serum levels of vitamin D in hypercalciurics indicate that gut calcium absorption is not directly related to vitamin D levels. We found no difference in the prevalence of metabolic abnormalities associated with stone formation between the patients in this series and those in previous studies.

Adult Fanconi syndrome and liver cirrhosis.

A female presenting primary adult Fanconi syndrome and liver cirrhosis of obscure aetiology is described. The only other report of this association appeared over four decades ago and concerned a male patient who, however, was subsequently diagnosed as having Wilson's cirrhosis, a well-known cause of acquired Fanconi syndrome. Therefore, the present report is the first account of primary Fanconi syndrome with authentic cryptogenic liver cirrhosis. Since the chronic urinary amino acid leakage is not a pathogenetic mechanism of the cirrhotic process, we believe that this association in fortuitous.

High turnover osteoporosis in acro-osteolysis (Hajdu-Cheney syndrome).

Acro-osteolysis with diffuse osteoporosis in the absence of other associated diseases is named Hajdu-Cheney syndrome. Reduced bone formation rather than enhanced bone resorption has been indicated as the mechanism of osteoporosis. On the assumption that in this syndrome the active bone resorption which produces distal osteolysis must also predominate in generalized osteoporosis, we investigated bone histology, calcium kinetics, calciotropic hormones and bone markers in a patient suffering from sporadic Hajdu-Cheney syndrome. A radius bone biopsy taken far from the osteolytic lesions showed severe osteoporosis with a marked increase in osteoclastic bone resorption and reduced bone formation. Total body calcium clearance, performed through an analysis of the kinetics of calcium infusion, was 2.8 times higher than in normal controls, indicating the presence of active osteoclastic bone resorption. Serum parathormone, 1,25-dihydroxycholecalciferol, alkaline phosphatase and urinary hydroxiproline were in the normal range. These data indicate that in Hajdu-Cheney syndrome trabecular osteoporosis is produced by the same mechanism that induces distal osteolysis, which suggests that it may be sustained by local acting factors stimulating osteoclastic resorption.

Altered kinetics of an intravenous calcium load in idiopathic hypercalciuria.

Increased gut calcium absorption or reduced renal tubular calcium reabsorption have been alternatively reported in idiopathic hypercalciuria with kidney calculi. The present study aimed to investigate the handling of an exogenous calcium load in hypercalciuric stone formers to detect possible differences with regard to tissue calcium metabolism in vivo. A constant rate intravenous calcium infusion (0.2 mmol kg bodyweight per two hours) was carried out on six absorptives and six renals, defined according to the reported criteria, as well as on normal controls from clinical staff. Serum ionized calcium concentration were determined at regular intervals during the infusion and in the four hours after the end of calcium load. Over the same period, urinary calcium excretion was evaluated in timed urine collections. Absorptive and renal hypercalciurics had lower serum ionized calcium levels compared with normal controls at all experimental times, a finding that suggests a faster disappearance of calcium from the circulation. The total body calcium clearance calculated from the area under the curve of the serum calcium concentrations was enhanced in hypercalciuric patients (P less than .001). Although renal calcium excretion was higher in hypercalciurics, renal calcium clearance accounted for only a minor fraction of the total body clearance, suggesting that the reduced serum calcium levels found in the hypercalciurics could not be explained by the renal calcium leak. The enhanced total body calcium clearance found in hypercalciuric subjects is therefore due to an increased tissue calcium uptake. This finding provides indirect evidence of altered cell calcium handling in idiopathic hypercalciura with no difference between the so-called absorptives and renals in terms of the pathophysiologic mechanism.

Cutaneous lichen amyloidosis associated with multiple endocrine neoplasia type 2A.

We have previously described a kindred with hereditary medullary thyroid carcinoma and pheochromocytoma (multiple endocrine neoplasia type 2A [MEN 2A]) with localized pruritic cutaneous manifestations present only in affected members. Although the initial skin biopsies reported did not show amyloidosis, subsequent skin biopsy results reported here have demonstrated amyloid which stained for keratin but not for calcitonin and established that this family represents an association of a rare autosomal dominant form of lichen amyloidosis with MEN 2A.

Hereditary localized pruritus in affected members of a kindred with multiple endocrine neoplasia type 2A (Sipple's syndrome).

We describe a kindred with medullary thyroid carcinoma and phaeochromocytoma (MEN 2A or Sipple's syndrome) in which a cutaneous manifestation is only present in affected members. These members felt an intense itching in an area 5-10 cm in length and passing through the scapular region where, after long-term scratching, the skin appears hyperkeratotic and pigmented. Cutaneous biopsies proved negative for dermis nerve abnormality. This restricted itching strongly suggests dominant transmitted hereditary localized pruritus which was described many years ago in a family which was apparently free from inherited diseases. In the examined kindred this skin peculiarity was said to have appeared before the patients reached 10 years of age and, therefore, prior to the biochemical manifestation of the thyroid tumour. Three children of the last generation, aged 4 to 11 years, all of whom presented this cutaneous manifestation, were considered unaffected because of normal basal and stimulated calcitonin, but thyroid C-cell hyperplasia was recently proved in the eldest. In this MEN 2A kindred the presence of such a characteristic hereditary itch in affected members may be considered as a phenotypic marker giving advance warning of medullary thyroid carcinoma.

Altered extracellular calcium homoeostasis in essential hypertension: a consequence of abnormal cell calcium handling.

A number of abnormalities in the extracellular and intracellular handling of calcium in arterial hypertension, namely an increased urinary calcium excretion, a reduced serum ionized calcium level and an enhanced intracellular free calcium concentration, have previously been reported by this and other laboratories. The present study aimed to investigate the handling of an exogenous calcium load in hypertensive and normotensive subjects in order to detect possible differences with regard to tissue calcium metabolism in vivo. A constant rate intravenous calcium infusion (0.2 mmol 2 h-1 kg-1 body wt.) was carried out in the participants. Serum calcium concentrations were determined at regular intervals during the infusion and in the 4 h after the end of the calcium load. Over the same period, urinary calcium excretion was evaluated in timed urine collections. Hypertensive subjects had lower serum ionized calcium levels compared with normotensive subjects at all the experimental points, a finding suggestive of a faster disappearance of calcium from the circulation. The total body calcium clearance, calculated from the area under the curve of the serum calcium concentrations, was enhanced in hypertensive patients (P less than 0.03). Although the renal calcium excretion was higher in hypertension, the renal calcium clearance accounted for only a minor fraction of the total body clearance, suggesting that the reduced serum calcium levels achieved by the hypertensive patients were not explained by the renal calcium leak. The enhanced total body calcium clearance found in hypertensive subjects is therefore due to an increased tissue calcium uptake. This finding provides indirect evidence of an altered cell calcium handling in hypertension.

The effect of an intravenous calcium load on serum total and ionized calcium in normotensive and hypertensive subjects.

Altered regulation of serum calcium level was proposed to be associated with arterial hypertension and to be dependent on a renal calcium leak or an altered calcium binding to plasma proteins and cell membrane described in human and experimental hypertension. The aim of this study was to analyze the regulation of serum total and ionized calcium levels during an intravenous calcium infusion (0.25 mmol calcium/kg body weight/hr for 2 hours) in a group of untreated essential hypertensives and a comparable normotensive group. Basal serum calcium concentrations did not differ between the two groups, whereas parathyroid activity and urinary calcium were significantly increased in hypertensive subjects. During the calcium load, serum calcium rose almost linearly in all subjects but with a reduced slope in the hypertensive group, which showed serum total and ionized calcium levels significantly lower than those of the controls at the end of the infusion. Our data indicate that hypertensive patients have an altered regulation of serum calcium concentrations, probably due to a different body distribution of calcium, rather than to an altered calcium binding to plasma proteins.

Altered kinetics of an intravenous calcium load in hypertensive patients.

Essential hypertensive (EH) patients have a higher rate of urinary calcium excretion and, according to some reports, somewhat lower levels of serum ionized calcium. The aim of this study was to investigate the kinetics of an i.v. calcium load in EH patients and in normotensive controls. Fifteen EH patients and twelve sex-and weight-matched controls received a constant ionized rate i.v. calcium infusion (0.1 mmol Ca2+/kg body weight/h) for 2 h. Serum ionized calcium and urinary calcium excretion were determined at regular intervals during the infusion and, in two subgroups of seven hypertensives and seven controls, for up to 4 hours later. EH patients had significantly higher excretion rates (P less than (P less than 0.001) and slightly, but not significantly, lower serum ionized calcium compared to controls. The serum ionized calcium concentration attained at 60 and 120 min of the Ca2+ infusion was significantly lower in EH (P less than 0.01) and it remained appreciably lower for up to 220 min from the beginning of the test. The area under the curve of serum ionized calcium calculated at different time points was significantly reduced in the hypertensives. The mean renal calcium clearance of the patients during the infusion and the elimination phase was somewhat higher, but the difference from controls did not reach statistical significance. These data indicate an abnormal handling of a calcium load by patients with EH and raise the possibility that such abnormality may not be due simply to a renal defect but perhaps to an altered calcium distribution among different compartments in the body.

Multiple endocrine neoplasia type 2 (Sipple's syndrome): clinical and cytogenetic analysis of a kindred.

This report describes the clinical and cytogenetic analysis of a kindred with multiple endocrine neoplasia type 2 (MEN-2 or Sipple's syndrome) in two generations. Medullary thyroid carcinoma was present in five members either as a large or as an occult tumour. Phaeochromocytoma was demonstrated in one severely hypertensive relative and urine vanillylmandelic acid (VMA) was increased in one normotensive member. Serum parathormone (PTH) was normal in all but one normocalcaemic patient of this family who did not have a history of nephrolithiasis. Prometaphase banding failed to detect a 20p12.2 deletion or chromosome instability as observed in some MEN-2 families.