Effects of short-term sitagliptin treatment on immune parameters in healthy individuals, a randomized placebo-controlled study.

Sitagliptin, a dipeptidyl-peptidase 4 (DPP-4) inhibitor, improves blood glucose control in patients with type 2 diabetes by blocking cleavage of glucagon-like peptide 1 (GLP-1). In type 2 diabetes patients sitagliptin use is associated with an increase in minor infections, and in new-onset type 1 diabetes patients the ability of sitagliptin to dampen autoimmunity is currently being tested. DPP-4, also known as CD26, is expressed on leucocytes and can inactivate many chemokines important for leucocyte migration, as well as act as a co-stimulatory molecule on T cells. Therefore, this study was conducted to test whether sitagliptin is immunomodulatory. In this randomized, placebo-controlled trial, healthy volunteers were given sitagliptin or placebo daily for 28 days, and blood was drawn for immune assays. No significant differences were observed in the percentage of leucocyte subsets within peripheral blood mononuclear cells (PBMCs), plasma chemokine/cytokine levels or cytokines released by stimulation of PBMCs with either lipopolysaccharide (LPS) or anti-CD3. Individuals taking sitagliptin displayed increases in the percentage of cells expressing higher levels of CD26 at early time-points compared to placebo controls, but these differences resolved by day 28 of treatment. Therefore, in healthy volunteers, treatment with sitagliptin daily for 28 days does not overtly alter systemic immune function.

Pasireotide: successful treatment of a sparsely granulated tumour in a resistant case of acromegaly.

The granulation pattern of somatotroph adenomas is well known to be associated with differing clinical and biochemical characteristics, and it has been shown that sparsely granulated tumours respond poorly to commonly used somatostatin receptor ligands (SRLs). We report a challenging case of acromegaly with a sparsely granulated tumour resistant to multiple modalities of treatment, ultimately achieving biochemical control with pasireotide. A 26-year-old lady presented with classical features of acromegaly, which was confirmed by an oral glucose tolerance test. Insulin-like growth factor 1 (IGF1) was 1710 µg/L (103-310 µg/L) and mean growth hormone (GH) was >600 U/L. MRI scan showed a 4 cm pituitary macroadenoma with suprasellar extension and right-sided cavernous sinus invasion. She underwent trans-sphenoidal pituitary surgery. Histology displayed moderate amounts of sparsely granular eosinophilic cytoplasm, staining only for GH. Postoperative investigations showed uncontrolled disease (IGF1:1474 µg/L, mean GH:228 U/L) and residual tumour in the cavernous sinus. She received external beam fractionated radiation. Over the years, she received octreotide LAR (up to 30 mg), lanreotide (up to 120 mg) two weekly, cabergoline, pegvisomant and stereotactic radiosurgery to no avail. Only pegvisomant resulted in an element of disease control; however, this had to be stopped due to abnormal liver function tests. Fifteen years after the diagnosis, she was started on pasireotide 40 mg monthly. Within a month, her IGF1 dropped and has remained within the normal range (103-310 µg/L). Pasireotide has been well tolerated, and there has been significant clinical improvement. Somatostatin receptor subtyping revealed a positivity score of two for both sst5 and sst2a subtypes. LEARNING POINTS: Age, size of the tumour, GH levels on presentation, histopathological type and the somatostatin receptor status of the tumour in acromegaly should be reviewed in patients who poorly respond to first-generation somatostatin receptor ligands.Tumours that respond poorly to first-generation somatostatin receptor ligands, especially sparsely granulated somatotroph adenomas, can respond to pasireotide and treatment should be considered early in the management of resistant tumours.Patients with membranous expression of sst5 are likely to be more responsive to pasireotide.

Deep wound infection after proximal femoral fracture: consequences and costs.

The purpose of this study was to assess the impact of deep wound infection after surgery for proximal femoral fracture (PFF) on the patient in terms of mortality and social consequences, and on the National Health Service in terms of financial burden. Sixty-one cases of PFF over a six-year period were complicated with deep surgical wound infection. These cases were compared with a matched control group of 122 patients without infection. Infected cases had greatly increased hospital stay (P<0.001), were 4.5 times less likely to survive to discharge (P=0.002), and if they survived, were three times less likely to return to their original residence (P=0.05). The total cost of treatment per infected case was 24,410 pound sterling compared with 7210 pound sterling for controls (P<0.001). Meticillin-resistant Staphylococcus aureus (MRSA) infection increased admission length and cost compared with non-MRSA infection (P=0.02). Deep wound infection after PFF is a devastating and costly complication for both the patient and the healthcare services. The cost consequences should be considered when allocating resources to trauma services to ensure adequate provision to minimize infection risks and to accommodate treatment costs in this vulnerable group.

Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels.

Menstrual irregularity is a common complaint at presentation in women with Cushing's syndrome, although the etiology has been little studied. We have assessed 45 female patients (median age, 32 yr; range, 16-41 yr) with newly diagnosed pituitary-dependent Cushing's syndrome. Patients were subdivided into 4 groups according to the duration of their menstrual cycle: normal cycles (NC; 26-30 days), oligomenorrhea (OL; 31-120 days), amenorrhea (AM; > 120 days), and polymenorrhea (PM; < 26 days). Blood was taken at 0900 h for measurement of LH, FSH, PRL, testosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol (E2), sex hormone-binding globulin (SHBG), and ACTH; cortisol was sampled at 0900, 1800, and 2400 h. The LH and FSH responses to 100 micrograms GnRH were analyzed in 23 patients. Statistical analysis was performed using the nonparametric Mann-Whitney U and Spearman tests. Only 9 patients had NC (20%), 14 had OL (31.1%), 15 had AM (33.3%), and 4 had PM (8.8%), whereas 3 had variable cycles (6.7%). By group, AM patients had lower serum E2 levels (median, 110 pmol/L) than OL patients (225 pmol/L; P < 0.05) or NC patients (279 pmol/L; P < 0.05), and higher serum cortisol levels at 0900 h (800 vs. 602 and 580 nmol/L, respectively; P < 0.05) and 1800 h (816 vs. 557 and 523 nmol/L, respectively; P < 0.05) and higher mean values from 6 samples obtained through the day (753 vs. 491 and 459 nmol/L, respectively; P < 0.05). For the whole group of patients there was a negative correlation between serum E2 and cortisol at 0900 h (r = -0.50; P < 0.01) and 1800 h (r = -0.56; P < 0.01) and with mean cortisol (r = -0.46; P < 0.05). No significant correlation was found between any serum androgen and E2 or cortisol. The LH response to GnRH was normal in 43.5% of the patients, exaggerated in 52.1%, and decreased in 4.4%, but there were no significant differences among the menstrual groups. No differences were found in any other parameter. In summary, in our study 80% of patients with Cushing's syndrome had menstrual irregularity, and this was most closely related to serum cortisol rather than to circulating androgens. Patients with AM had higher levels of cortisol and lower levels of E2, while the GnRH response was either normal or exaggerated. Our data suggest that the menstrual irregularity in Cushing's disease appears to be the result of hypercortisolemic inhibition of gonadotropin release acting at a hypothalamic level, rather than raised circulating androgen levels.

A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing's disease and the occult ectopic adrenocorticotropin syndrome.

The clinical, biochemical, and radiological features of pituitary ACTH-dependent Cushing's syndrome (CS) [Cushing's disease (CD)] are often indistinguishable from those of occult ectopic ACTH-dependent CS (oEAS). We have evaluated, retrospectively, the results of simultaneous bilateral inferior petrosal sinus (IPS) ACTH sampling before and after CRH stimulation in 128 patients with ACTH-dependent CS: 107 patients with CD, 6 with oEAS, 1 with an adrenal adenoma, 1 with a pituitary gangliocytoma, and 1 with Nelson's syndrome; while, in the remaining 12, the source remains unclear. One hundred seven patients received human-sequence CRH (hCRH), and 11 received ovine CRH; another 6 patients underwent stimulation with desmopressin and hCRH, and 4 with desmopressin alone. A successful bilateral IPS catheterization and sampling (IPSCS) rate of 87.5% was obtained only after considerable experience had been gained. Sixty-nine patients with CD underwent successful bilateral IPSCS: the IPS-to-peripheral ratio of plasma ACTH value (IPS/P) rose from 9.5 +/- 1.4 to a maximum ratio of 55.8 +/- 7.5 in 67 patients, after CRH stimulation. The maximum ratio was obtained at 5 min in 60 of the 69 patients with CD; however, all 69 patients obtained a ratio of more than 2, at that time. In contrast, the 6 patients with occult ACTH-secreting neoplasms had a maximal IPS/P ratio of 1.3 +/- 0.16, and this did not change after CRH stimulation. A bilateral IPS/P ratio more than 2, obtained 5 min after CRH stimulation, had a sensitivity of 97% and a specificity of 100% in diagnosing CD. Two patients with proven active CD had an IPS/P ratio of less than 2. After successful bilateral IPSCS, the gradients between the IPS ACTH concentrations [IPS ACTH gradient (IPSG)] of more than 1.4, at 5 min after CRH stimulation, had a sensitivity of 83% in correctly lateralizing the pituitary microadenoma, compared with 72% sensitivity for magnetic resonance imaging (MRI) scanning. Furthermore, when IPSG and MRI findings were contradictory, IPSG was more often correct than MRI scanning. Although oEAS is a relatively uncommon cause of ACTH-dependent hypercortisolism (5.5% in our series), the accurate diagnosis of ACTH-dependent CS and localization of an intrapituitary microadenoma requires bilateral IPSCS with CRH stimulation, provided that the appropriate technical experience is available. hCRH is as effective a secretagogue as ovine CRH, and either may be used. The value of the combination of CRH and desmopressin stimulation requires more detailed investigation.

Brain gamma-aminobutyric acid deficiency in dialysis encephalopathy.

We measured levels of gamma-aminobutyric acid (GABA) in the CSF and in the autopsied brain of patients with dialysis encephalopathy. GABA concentrations were low in the CSF of three of five living patients. Mean GABA content was reduced by 30 to 50% in five brain regions (frontal, occipital, and cerebellar cortex, caudate nucleus, and medial dorsal thalamus) in five fatal cases. GABA content was normal in brain regions where GABA is characteristically reduced in Huntington's disease. Choline acetyltransferase activity was diminished (by 25 to 35%) in cerebral cortex of the dialysis encephalopathy patients.

Experience with 1,25-dihydroxycholecalciferol therapy in undergoing hemodialysis patients with progressive vitamin D2-treated osteodystrophy.

Six long-term hemodialysis patients with progressive skeletal deterioration during long-term pharmacologic vitamin D2 therapy were treated for six to 12 months with oral 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) to determine its therapeutic effectiveness in vitamin D2-unresponsive osteodystrophy. On bone biopsy, three of the patients had severe osteomalacia and three showed predominant osteitis fibrosa. Previous therapies, including phosphate binders and dialysis schedules, were maintained. The three patients with osteomalacia and the two with osteitis fibrosa showed clinical deterioration. There was no significant change in serum calcium, phosphate, alkaline phosphatase, bone densitometry, immunoreactive parathyroid hormone levels or bone histology. Roentgenograms showed multiple new fractures of ribs and femoral necks in the patients with osteomalacia and increased bone resorption in two of three patients with osteitis fibrosa. 1,25-(OH)2D3 dosage had to be decreased in all patients because of hypercalcemia with a mean tolerated dose of 0.22 microgram/day. In these patients, 1,25-(OH)2D3 was not effective therapy for progressive osteodystrophy unresponsive to pharmacologic vitamin D2.

Spurious hypocalcemia in hemodialysis patients after heparinization. In-vitro formation of calcium soaps.

Patients on long-term hemodialysis via arteriovenous fistula received heparin when the fistula needle was inserted, before a sample of blood was obtained for chemical analysis. The resultant release of lipoprotein lipase activity in vivo and continued lipolytic activity in vitro sometimes produced sufficient free fatty acid to precipitate calcium soaps. The consequent spurious hypocalcemia was most frequently observed when the patients had chylomicronemia. This cause of apparent hypocalcemia was eliminated either by immediate analyses of the blood samples or by obtaining samples before systemic heparinization.

Flucloxacillin in the treatment of infectious conditions in children.

A multi-centre study was carried out in 107 children with skin and soft-tissue infections (46) or upper respiratory tract infections (61) to assess the effectivness of flucloxacillin (125 mg. q.d.s. for 5 days). Swabs were taken from the lesion sites before and after treatment for bacteriological assessment and sensitivity of the isolated organisms. The clinical success rate achieved was 93% in skin and soft-tissue infections and 94% in upper respiratory tract infections and these results correlate closely with the bacteriological findings. The main causative organism in the skin and soft-tissue infections was Staph. aureus which was resistant to benzyl penicillin and to ampicillin in all but 2 cases. All strains proved sensitive to flucloxacillin. Minimal side-effects were reported and the syrup presentation was well accepted.

Machiavellianism in patients and their children.

The role of the family in the development of Machiavellianism was examined in this study. High- and low-Machiavellian sixth graders played a bluffing game. Their parents completed Machiavellian belief measures. The Machiavellianism of fathers and mothers was positively related to their children's success at deceiving others but not at seeing through others' attempts at deception. In addition, fathers' Machiavellianism was positively related to their children's Machiavellian beliefs. These data support a modeling hypothesis for the development of Machiavellianism. Unexpectedly, the children's own behaviors and beliefs were unrelated. This pattern of results suggests that a child's manipulative behaviors and beliefs are learned separately and only become consistent over time.

Nonlinear bioavailability of metoclopramide in the rat: evidence for saturable first-pass metabolism.

In vivo and in vitro experiments were conducted in rats to examine the possibility of either extrahepatic metabolism or saturable first-pass effect as an explanation for the unusual presystemic clearance of metoclopramide (I) previously reported. In vivo studies involved two-thirds hepatectomized rats and animals pretreated with carbon tetrachloride to induce hepatic necrosis, whereas in vitro studies involved incubation of equal amounts of I (5.0 mumol/mL) with various tissue homogenates (viz., liver, kidney, and lung) or their 9000 X g supernatant fractions. Results suggest that the metabolism of I principally occurs in the rat liver, and there was no evidence suggesting the involvement of kidney or lung tissue in the metabolism of I. Forty-eight-hour cumulative urinary excretion studies following oral and intravenous administration of less than or equal to 5.0 mg/kg of metoclopramide hydrochloride were conducted. The bioavailability (F) values of I at dosage levels 0.1, 0.5, 1.0, and 5.0 mg/kg were 0.49, 0.75, 0.77, and 0.83, respectively. It is concluded that the liver is the primary organ for the metabolism of I in the rat and that the drug exhibits dose-dependent hepatic first-pass metabolism.

Ion-exchange resins as potential phosphate-binding agents for renal failure patients: effect of the physicochemical properties of resins on phosphate and bile salt binding.

The effect of resin type, degree of cross-linking, bead size, and surface area on the phosphate and bile salt binding characteristics of five strongly basic Dowex anion-exchange resins in the chloride form was studied. The maximum uptake of phosphate (expressed as uptake of phosphorus) from sodium phosphate solutions was 137, 82, 86, 138, and 76 mg of phosphorus per gram of dry Dowex resins XF 43311, XY 40013, XF 43254, XY 40011, and XY 40012, respectively. The presence of simulated gastric or intestinal fluids resulted in small but insignificant alterations in phosphorus uptake by the resins. The resins all bound similar amounts of phosphorus and taurocholate (80-100% of the total phosphorus and taurocholate in solution) at physiological concentrations of phosphate and bile salt. Dowex resins XY 40013 and XF 43254, with identical physicochemical properties, but different bead sizes and surface areas, bound similar amounts of the bile salt sodium taurocholate at all taurocholate concentrations, indicating that binding was not restricted to the surface sites on the resin bead. The 2% cross-linked resins bound 3-4 times more taurocholate than the 8% cross-linked resins (at high taurocholate concentrations); the smaller pore size of the latter resins probably presents a greater mechanical exclusion barrier than the larger pore size of the 2% cross-linked resins.

Membranoproliferative glomerulonephritis type 1: comparison of natural history in children and adults.

Clinical, laboratory and pathological data on 46 patients (29 children and 17 adult) with Type 1 membranoproliferative glomerulonephritis (MPGN) were reviewed in order to compare the natural history of the disease in two age groups. The nephrotic syndrome was the most common presenting clinical feature in both age groups. Established renal failure at time of biopsy was seen in adult males only. All the adults males, but none of the women, were either dead or in renal failure after a mean duration of diseases of 17.7 months. In contrast 43% of the children (both sexes) were in renal failure after a mean duration of disease of 51.6 months. Statistical analysis disclosed that only up to 48 months was there a significant difference in survival between the two age groups (P less than .01). Beyond this time the difference was not statistically significant. The difference in behaviour of MPGN in the two age groups is similar to that observed in other glomerulonephropathies.

Subjective barriers to prevent wandering of cognitively impaired people.

BACKGROUND: People with dementia often wander, at times putting themselves at risk and presenting challenges to carers and institutional staff. Traditional interventions to prevent wandering include restraint, drugs and locked doors. Cognitively impaired people may respond to environmental stimuli (sounds, images, smells) in ways distinct from healthy people. This has led to trials of visual and other selective barriers (such as mirrors, camouflage, grids/stripes of tape) that may reduce wandering. OBJECTIVES: We assess the effect of subjective exit modifications on the wandering behaviour of cognitively impaired people. The second objective is to inform the direction and methods of future research. SEARCH STRATEGY: The search strategy includes electronic searches of relevant bibliographic and trials databases, citation indices and relevant medical journals. SELECTION CRITERIA: Randomized controlled trials and controlled trials provide the highest quality evidence, but interrupted time series are also considered as they may contribute useful information. Participants are people with dementia or cognitive impairment who wander, of any age, and in any care environment - hospital, other institution, or their own home. Interventions comprise exit modifications that aim to function as subjective barriers to prevent the wandering of cognitively impaired people. Locks, physical restraints, electronic tagging and other types of barrier are not included. DATA COLLECTION AND ANALYSIS: The criteria for inclusion or exclusion of studies are applied independently by two reviewers. All outcomes that are meaningful to people making decisions about the care of wanderers are recorded. These include the number of exits or carer interventions, resource use, acceptability of the intervention and the effects on carer and wanderer anxiety or distress. heterogeneity of clinical area, of study design and of intervention was substantial. MAIN RESULTS: No randomized controlled or controlled trials were found. The other experimental studies that we identified were unsatisfactory. Most were vulnerable to bias, particularly performance bias; most did not classify patients according to type or severity of dementia; in all studies, outcomes were measured only in terms of wandering frequency rather than more broadly in terms of quality of life, resource use, anxiety and distress; no studies included patients with delirium; no studies were based in patients' homes. REVIEWER'S CONCLUSIONS: There is no evidence that subjective barriers prevent wandering in cognitively impaired people.

Perioperative fluid volume optimization following proximal femoral fracture.

BACKGROUND: Proximal Femoral Fracture (PFF) or 'hip fracture' is a frequent injury, and adverse outcomes are common. Several factors suggest the importance of developing techniques to optimize intravascular fluid volume. These may include protocols that enhance the efficacy of clinicians' assessments, invasive techniques such as oesophageal Doppler or central venous pressure monitoring, or advanced non-invasive techniques such as plethysmographic pulse volume determination. OBJECTIVES: To determine the optimal method of fluid volume optimization for adult patients undergoing surgical repair of PFF. Comparisons of fluid types, of blood transfusion strategies or of pharmacological interventions are not considered in this review. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library, issue 4, 2003), MEDLINE (1985 to 2003), EMBASE (1985 to 2003), and bibliographies of retrieved articles. Relevant journals and conference proceedings were handsearched. SELECTION CRITERIA: Randomized controlled studies comparing a fluid optimization intervention with normal practice or with another fluid optimization intervention, in patients following PFF undergoing surgery of any type under anaesthesia of any type. DATA COLLECTION AND ANALYSIS: Searches and exclusion of clearly irrelevant articles were performed by one reviewer. Two reviewers examined independently the remaining studies, extracting study quality and results data. A wide range of short- and long-term outcome data were sought. Studies were excluded if they did not meet selection criteria or if results were likely to be biased. Due to inconsistent data reporting, combination of data was not generally possible. MAIN RESULTS: Searches identified four trials, of which two studies, randomizing a total of 130 patients, were of adequate quality and addressed the review question. Both studies were of invasive advanced haemodynamic monitoring, either oesophageal Doppler ultrasonography or central venous pressure monitoring, during the intraoperative period only. In both, invasive monitoring led to significant increases in fluid volumes infused and reductions in length of hospital stay. The pooled Peto odds ratio for in-hospital fatality was 1.44 (95% confidence interval 0.45-4.62). Neither study followed patients beyond hospital discharge or assessed functional outcomes. No serious complications were directly attributable to the interventions. There were no studies of protocol-guided fluid optimization or of advanced non-invasive techniques. REVIEWER'S CONCLUSIONS: Invasive methods of fluid optimization during surgery may shorten hospital stay, but their effects on other important, patient-centred, longer-term outcomes are uncertain. Adverse effects on fatality cannot be excluded. Other fluid optimization techniques have not been evaluated. The lack of randomized studies of adequate quality addressing this important question is disappointing. More research is needed.

Complications of surgery for oral malignancy.

The post-operative complications on 100 patients who had surgery for oral malignancy were studied. Sixty-five per cent developed one or more complications, wound breakdown being the most common. Complications increased with the clinical staging of the tumour and the extent of the surgery, but were not significantly related to age (if under 80 years), site or whether radiotherapy had been previously employed.

Candida glabrata (syn. Torulopsis glabrata) associated with a chronic hyperplastic lesion of the palate.

A case initially presenting as chronic hyperplastic candidosis is described. After treatment with nystatin on three separate occasions over a seven-year period, a lesion similar to that diagnosed originally occurred in the same site. Further examination of this later occurrence showed it to be associated with the imperfect fungus Candida glabrata which had a high minimum inhibitory concentration for nystatin (greater than 30 micrograms/ml). The lesion eventually resolved following treatment with miconazole gel and surgical excision of the hyperplastic tissue. The patient has remained symptomless for a two-year follow-up period.