Association of type 2 diabetes with prolonged hospital stay and increased rate of readmission in patients with lower limb cellulitis.

BACKGROUND/AIMS: Lower limb (LL) cellulitis-related hospitalisations are prevalent in type 2 diabetes subjects. We assess its costs and factors associated with length of stay and readmissions. METHODS: A retrospective case-control study at an urban hospital servicing a multi-ethnic population in New Zealand, where 7% of the adult population is estimated to have diabetes. Admissions with LL cellulitis in 2008-2013 were identified using coding records. Subsequent hospitalisations after 1 month with the same diagnosis were classified as readmissions. Glycaemic control was assessed by HbA1c measured within 6 months of the index admission. RESULTS: There were 4600 admissions with LL cellulitis in 3636 patients, including 719 patients (20%) with type 2 diabetes. Hospital stay was longer for type 2 diabetes patients (median 5.3 vs 3.0 days, P < 0.001), independent of age, ethnicity and HbA1c. Accompanying LL ulceration was more frequent in type 2 diabetes patients (50% vs 17%, P < 0.001); however, admissions remained longer for type 2 diabetes patients without ulceration (median 3.4 vs 2.8 days, P < 0.001). Readmission rates were also higher in type 2 diabetes patients compared to non-diabetes patients (HR 1.7, P < 0.001), even in the absence of ulceration (HR 2.2, P < 0.001). Age, HbA1c and ethnicity did not distinguish those prone to readmissions in the type 2 diabetes cohort. Type 2 diabetes patients accounted for a fifth of all admissions and one third of the estimated costs. CONCLUSIONS: A high proportion of patients with type 2 diabetes was admitted with LL cellulitis. They had significantly longer admissions and higher readmission rates. Age, HbA1c and ethnicity did not predict length of stay or recurrence.

Fulminant type 1 diabetes in pregnancy.

We report two cases of fulminant type 1 diabetes in previously well migrants from South East Asia. This entity, which is rare outside East or South-East Asia, has a high perinatal mortality. The clinical presentation differs markedly from that of typical newly recognised type 1 diabetes in pregnancy. In both our cases, the neonates required intensive care but survived.

Does exposure to hyperglycaemia in utero increase the risk of obesity and diabetes in the offspring? A critical reappraisal.

BACKGROUND: The idea that exposure to hyperglycaemia in utero is an important factor in the development of obesity and diabetes in the offspring has become entrenched as popular belief. AIM: To appraise the literature supporting this hypothesis in the light of recent studies that have clarified the main drivers of obesity in children and adolescents. METHODS: A review of published evidence from animal studies, human observational studies, systematic reviews and experimental trials that address the impact of diabetes (Types 1 and 2, genetic or gestational) on the future risk of obesity and/or glucose intolerance in the offspring. RESULTS: Some animal studies support a relationship between exposure to hyperglycaemia in utero and future development of obesity and diabetes, but the results are inconsistent. Most of the human studies claiming to show a relationship have not taken into account important known confounders, such as maternal and paternal BMI. Evidence supporting a dose-response relationship between maternal hyperglycaemia exposure and obesity and diabetes in the offspring is weak, and there is no convincing evidence that treating gestational diabetes reduces the later risk of offspring obesity or glucose intolerance. CONCLUSIONS: Exposure to hyperglycaemia in utero has minimal direct effect on the later risk of obesity and Type 2 diabetes. The increased risk of obesity in the offspring of women with Type 2 or gestational diabetes can be explained by confounding factors, such as parental obesity.

Differing perceptions of intervention thresholds for fracture risk: a survey of patients and doctors.

UNLABELLED: This survey suggests that patients are prepared to accept higher absolute fracture risk than doctors, before considering pharmacological therapy to be justified. Patients require that drug treatments confer substantial fracture risk reductions in order to consider long-term therapy. INTRODUCTION: Absolute fracture risk estimates are now incorporated into osteoporosis treatment guidelines. At present, little is known about how patients regard fracture risk and its management. We set out to describe and compare the views of patients and doctors on the level of fracture risk at which drug treatment is justified. METHODS: A cross-sectional survey was conducted on 114 patients referred for bone density measurement and 161 doctors whose practice includes management of osteoporosis. Participants were asked about fracture risk thresholds for pharmacological intervention. RESULTS: The absolute risk of both major osteoporotic fracture and hip fracture at which drug treatment was considered by patients to be justifiable was higher than that reported by doctors [major osteoporotic fracture, median (interquartile range): patients, 50% (25 to 60); doctors, 10% (10 to 20); P < 0.0001; hip fracture: patients, 50% (25 to 60); doctors, 10% (5 to 20); P < 0.0001]. Patients required that a drug provide a median 50% reduction in relative risk of fracture in order to consider taking long-term therapy, irrespective of the treatment mode or dosing schedule. Among doctors, there was an inverse relationship between the number of osteoporosis consultations conducted each month and threshold of risk for recommending drug treatment (r = -0.22 and r = -0.29 for major osteoporotic fracture and hip fracture, respectively, P < 0.01 for both) CONCLUSIONS: Patients are prepared to accept higher absolute fracture risk than doctors, before considering pharmacological therapy to be justified. Patients require that drug treatments confer substantial fracture risk reductions in order to consider long-term therapy.

Proposed new diagnostic criteria for gestational diabetes--a pause for thought?

New criteria for the diagnosis of gestational diabetes promulgated by the International Association of Diabetes and Pregnancy Study Groups (IADSPG) have been adopted by a number of groups, including the American Diabetes Association. These criteria will increase two- to three-fold the number of women diagnosed with gestational diabetes and have enormous resource implications. The recommendations are derived from observations made in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, which demonstrated continuous relationships between maternal glucose tolerance and two clinically relevant outcomes of pregnancy (caesarean section rate and neonatal hypoglycaemia) and two surrogate measures (birth weight and cord C-peptide). The recent randomized intervention studies in mild gestational diabetes indicate that the major effects of detecting and treating mild gestational diabetes are a reduction in mean birthweight of 100-140 g, and a reduction in the incidence of shoulder dystocia. However, the women included in these studies were identified using different diagnostic criteria, and it cannot be assumed that women diagnosed by the less stringent IADSPG criteria will have the same benefit. Moreover, as the majority of cases of macrosomia and shoulder dystocia occur in women with normal glucose tolerance, the real impact of diagnosing many more 'cases' of gestational diabetes is likely to be minimal. The concentration on mild degrees of hyperglycaemia may well be misplaced, as most of the outcomes usually attributed to gestational diabetes are more strongly associated with maternal obesity and weight gain in pregnancy. The new testing procedure (with diagnosis based on a single blood glucose measurement) will inevitably be imprecise. Given the many reservations about the new criteria an urgent but dispassionate debate is required on the risks, costs and benefits of their introduction.

Anterior approach retroperitoneal laparoscopic renal surgery in children.

Retroperitoneoscopic renal surgery is performed by lateral or posterior approaches. Iterative modification led to development of an alternative 'anterior' approach. The study authors' experience with this novel approach in a prospective series of 69 children that includes 17 infants is reported. Mean operating time was 225 min for reduction pyeloplasty. Peritoneal tear is not uncommon (22%) but often does not require conversion. In the study authors' early experience, the conversion rate was 17% and postoperative complications 2.9%. This approach overcomes many existing challenges with retroperitoneoscopy. Benefits of exposure, orientation, and working space achieved with a transperitoneal approach are afforded while preserving the advantages of retroperitoneoscopy.

Severe intrauterine growth retardation and atypical diabetes associated with a translocation breakpoint disrupting regulation of the insulin-like growth factor 2 gene.

CONTEXT: IGF-II is an imprinted gene (predominantly transcribed from the paternally inherited allele), which has an important role in fetal growth in mice. IGF2 gene expression is regulated by a complex system of enhancers and promoters that determine tissue-specific and development-specific transcription. In mice, enhancers of the IGF2 gene are located up to 260 kb telomeric to the gene. The role of IGF-II in humans is unclear. OBJECTIVE: A woman of short adult stature (1.46 m, -3 sd score) born with severe intrauterine growth retardation (1.25 kg at term, -5.4 SD score) and atypical diabetes diagnosed at the age of 23 yr had a balanced chromosomal translocation t(1;11) (p36.22; p15.5). We hypothesized that her phenotype resulted from disruption of her paternally derived IGF2 gene because her daughter who inherited the identical translocation had normal birth weight. DESIGN: Both chromosomal break points were identified using fluorescent in situ hybridization. Sequence, methylation, and expression of the IGF2 gene was examined. Hyperinsulinemic, euglycemic clamp with glucose tracers and magnetic resonance imaging of the thorax, abdomen, and pelvis were performed. RESULTS: The 11p15.5 break point mapped 184 kb telomeric of the IGF2 gene. Microsatellite markers confirmed paternal origin of this chromosome. IGF2 gene sequence and methylation was normal. IGF2 gene expression was reduced in lymphoblasts. Clamp studies showed marked hepatic and total insulin resistance. Massive excess sc fat was seen on magnetic resonance imaging despite slim body mass index (21.1 kg/m2). CONCLUSIONS: A break point 184 kb upstream of the paternally derived IGF2 gene, separating it from some telomeric enhancers, resulted in reduced expression in some mesoderm-derived adult tissues causing intrauterine growth retardation, short stature, lactation failure, and insulin resistance with altered fat distribution.

Severe hypomagnesaemia in long-term users of proton-pump inhibitors.

OBJECTIVE: To explore the mechanism underlying severe hypomagnesaemia in long-term users of proton-pump inhibitors (PPIs). PATIENTS: Two cases of severe hypomagnesaemia in adult long-term users of the PPI omeprazole, presenting with hypocalcaemic seizures. MEASUREMENTS: We studied renal magnesium handling during an incremental intravenous magnesium infusion, and assessed total body magnesium status by the 24-h retention of the parenteral load. We also observed the effects of oral magnesium supplements whilst continuing the PPI, and the effect of withdrawal of the PPI. RESULTS: Both patients were severely magnesium-depleted and had avid renal magnesium retention, implicating a failure of intestinal magnesium absorption. There was no evidence of generalized malabsorption. The hypomagnesaemia could be partially corrected by high dose oral magnesium supplementation, and resolved on withdrawal of PPIs. CONCLUSIONS: PPI use can inhibit active magnesium transport in the intestine, though it is not clear if this is an idiosyncratic effect. Long-term PPI users who are highly adherent to treatment can eventually deplete total body magnesium stores and present with severe complications of hypomagnesaemia.

Enhanced RANK ligand expression and responsivity of bone marrow cells in Paget's disease of bone.

Paget's disease is characterized by highly localized areas of increased osteoclast (OCL) activity. This suggests that the microenvironment in pagetic lesions is highly osteoclastogenic, or that OCL precursors in these lesions are hyperresponsive to osteoclastogenic factors (or both). To examine these possibilities, we compared RANK ligand (RANKL) mRNA expression in a marrow stromal cell line developed from a pagetic lesion (PSV10) with that in a normal stromal cell line (Saka), and expression in marrow samples from affected bones of Paget's patients with that in normal marrow. RANKL mRNA was increased in PSV10 cells and pagetic marrow compared with Saka cells and normal marrow, and was also increased in marrow from affected bones compared with uninvolved bones from Paget's patients. Furthermore, pagetic marrow cells formed OCLs at much lower RANKL concentrations than did normal marrow. Anti-IL-6 decreased the RANKL responsivity of pagetic marrow to normal levels, whereas addition of IL-6 to normal marrow enhanced RANKL responsivity. Thus, RANKL expression and responsivity is increased in pagetic lesions, in part mediated by IL-6. These data suggest that the combination of enhanced expression of RANKL in affected bones and increased RANKL sensitivity of pagetic OCL precursors may contribute to the elevated numbers of OCLs in Paget's disease.

Camurati-Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment.

Camurati-Engelmann disease (CED) is a rare autosomal dominant type of bone dysplasia. This review is based on the unpublished and detailed clinical, radiological, and molecular findings in 14 CED families, comprising 41 patients, combined with data from 10 other previously reported CED families. For all 100 cases, molecular evidence for CED was available, as a mutation was detected in TGFB1, the gene encoding transforming growth factor (TGF) beta1. Pain in the extremities was the most common clinical symptom, present in 68% of the patients. A waddling gait (48%), easy fatigability (44%), and muscle weakness (39%) were other important features. Radiological symptoms were not fully penetrant, with 94% of the patients showing the typical long bone involvement. A large percentage of the patients also showed involvement of the skull (54%) and pelvis (63%). The review provides an overview of possible treatments, diagnostic guidelines, and considerations for prenatal testing. The detailed description of such a large set of CED patients will be of value in establishing the correct diagnosis, genetic counselling, and treatment.

Measles virus nucleocapsid transcript expression is not restricted to the osteoclast lineage in patients with Paget's disease of bone.

Abundant evidence supports a viral etiology for Paget's disease of bone (PD), however, an infectious virus has not been isolated from PD patients. Thus, it is unclear how the virus is maintained for the many years that the disease persists in patients. We considered if a primitive multipotential hematopoietic stem cell (HSC), which is self-renewing, passes the virus to its differentiated progeny and serves as a reservoir for the pathogen. If a primitive stem cell harbored measles virus (MV), then other hematopoietic lineages derived from this stem cell in PD patients should also express MV transcripts. Therefore, because the human hematopoietic stem cell has not been clearly identified or isolated in large numbers, we isolated RNA from highly purified erythroid and multipotential hematopoietic progenitors that are the precursors for erythroid, granulocyte, megakaryocyte and macrophages (CFU-GEMM), and used RT-PCR to determine if MV nucleocapsid transcripts were present. MV transcripts were detected in PD patients in early erythroid (BFU-E) and more primitive multipotential myeloid progenitors (CFU-GEMM). Nonhematopoietic stromal cells from PD patients did not express MV transcripts. The expression of MV transcripts in erythroid progenitors was further confirmed by in situ hybridization using antisense riboprobes to MV nucleocapsid transcripts. Thus, our findings suggest that the pluripotent HSCs may be a potential reservoir for the virus. We propose that when HSCs, which contain MV, divide they produce a second HSC that serves as a reservoir for the virus and also transmit the virus to their more differentiated progeny in the erythroid and myeloid lineages. This mechanism would permit a defective virus to persist in HSCs of PD patients for many years, since HSCs are usually in G0 phase, and then be transmitted to more differentiated cells. This model further suggests that a mature complete virus that affects cell function could only act pathogenetically in the osteoclast lineage, which offers a permissive milieu.

Sources of interracial variation in bone mineral density.

Many studies have demonstrated significant differences in bone mineral density between various racial groups. Although it has been suggested that differences in body weight contribute to such interracial variation, the artifactual effect of the skeletal size inherent in projectional absorptiometry methods has been largely ignored. We have measured bone mineral density by dual-energy X-ray absorptiometry in the lumbar spine and at three femoral sites in 200 premenopausal women of Chinese, Indian, European, or Polynesian origin (50 of similar mean age in each group). In the Chinese and Indian women the measured bone mineral density measurements (g/cm2) were similar, but significantly less, at all sites, than those of European women (p < or = 0.005). The European women were, however, significantly taller than both the Chinese and Indian women (p < 0.0001), and when the scale artifact of absorptiometry was removed by dividing the measured bone mineral density either by the height of the subject, or by the square root of the area over which the X-ray beam was projected, then the differences in mean bone mineral density between the Chinese, Indian, and European women were almost completely eliminated. The Polynesian women were significantly more obese (as judged from mean body mass index) than all the other groups (p < 0.0001) and had significantly greater bone mineral density at all sites than all the other groups both before (p < 0.0001) and after (p < 0.0001) correcting for the scale artifact.(ABSTRACT TRUNCATED AT 250 WORDS)

1,25-Dihydroxyvitamin D3 hypersensitivity of osteoclast precursors from patients with Paget's disease.

Our previous studies suggested that increased osteoclast formation and activity in Paget's disease may be related in part to increased responsiveness of highly purified osteoclast precursors to 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. However, the basis for this enhanced sensitivity to 1,25-(OH)2D3 is unclear. To address this question, we examined 24-hydroxylase and 1,25-(OH)2D3 receptor (VDR) messenger RNA (mRNA) expression during human osteoclast differentiation from normal subjects and patients with Paget's disease in response to 1,25-(OH)2D3 as well as VDR content and affinity. Reverse-transcription polymerase chain reaction (RT-PCR) analysis of granulocyte-macrophage colony-forming unit (GM-CFU), the earliest identifiable osteoclast precursor, derived from patients with Paget's disease demonstrated 24-hydroxylase mRNA expression in response to 1,25-(OH)2D3 was induced at concentrations of 1,25-(OH)2D3 that were at least one log less than that required for normal GM-CFU. VDR mRNA and VDR protein were detected in both immature and more differentiated osteoclast precursors, as well as in osteoclast-like multinucleated cells (MNCs). However, VDR expression was lower in MNCs than the mononuclear precursor cells. Osteoclast precursors and MNCs from patients with Paget's disease had levels of VDR expression similar to those of normal subjects but showed increased VDR affinity for 1,25-(OH)2D3. Because the effects of 1,25-(OH)2D3 are in part mediated by induction of expression of RANK ligand on marrow stromal cells, which in turn stimulates osteoclast formation, we examined expression of RANK ligand mRNA by marrow stromal cell lines derived from patients with Paget's disease and normal subjects in response to 1,25-(OH)2D3. RT-PCR analysis showed no difference in sensitivity of marrow stromal cells to 1,25-(OH)2D3 from normal subjects or patients with Paget's disease although the Paget's stromal cells expressed increased basal levels of RANK ligand mRNA. These results show that VDR protein is expressed in early and more differentiated osteoclast precursors, that expression levels of VDR decline with osteoclast differentiation, and that 1,25-(OH)2D3 has direct effects on osteoclast precursors. The enhanced sensitivity to 1,25-(OH)2D3 is an intrinsic property of osteoclast precursors from patients with Paget's disease that distinguishes them from normal osteoclast precursors. Furthermore, our results suggest that an increased affinity of VDR for 1,25-(OH)2D3 may be responsible for the enhanced 1,25-(OH)2D3 sensitivity of osteoclast precursors in patients with Paget's disease compared with normal subjects.