Delusional infestation: an Australian multicentre study of 23 consecutive cases.

Delusional infestation remains a debilitating condition that is therapeutically challenging for clinicians. This case series identifies 23 patients with delusional infestation in an Australian setting. The majority of patients are women and unlikely to have a psychiatric comorbid background. The use of unnecessary anti-parasitic medication is prevalent.

ATP-induced beta-glucuronidase release from undifferentiated HL-60 cells is dependent on Ca2+ ions.

Extracellular ATP (0.1-100 microM) evoked a biphasic increase in cytosolic free Ca2+ ion concentration ([Ca2+]i) in fura-2 loaded undifferentiated HL-60 cells and activated the release of the lysosomal enzyme beta-glucuronidase. The EC50 for the elevation of [Ca2+]i was about 0.2 microM. However, the EC50 for the activation of beta-glucuronidase release was two orders of magnitude higher (about 20 microM). These data imply that the ATP-induced elevation in [Ca2+]i is not sufficient to provoke beta-glucuronidase release. The role of [Ca2+]i in ATP-induced beta-glucuronidase release was further investigated using Ca(2+)-free solutions and by loading HL-60 cells with the non-fluorescent Ca(2+)-chelator BAPTA-AM. Ca2+ ions from both intracellular and extracellular sources were necessary for the activation of beta-glucuronidase secretion by extracellular ATP. However, the internal store is the major source of Ca2+ ions for the response.

Phase I clinical trial of the chimeric monoclonal antibody (c30.6) in patients with metastatic colorectal cancer.

The murine antibody 30.6 recognizes an antigen that is expressed on a high proportion of colorectal carcinomas and their metastases. We report the results of single-dose escalation studies of the chimeric 30.6 (c30.6) monoclonal antibody in metastatic colorectal cancer, to evaluate its safety, pharmacokinetics, and biodistribution. Recombinant c30.6 (IgG1kappa) antibody was secreted from Chinese hamster ovary cells and purified by a multistep chromatography process. Seventeen patients with metastatic colorectal cancer were enrolled in this dose escalation study. The first four patients were treated with 3 mg of 123I-labeled c30.6, whereas the next 13 received a single dose of unlabeled antibody (maximum dose, 50 mg/m2). The most frequent side effect was a novel syndrome of severe burning and erythema of the face, chest, neck, ears, palms, soles, and genitalia. The frequency of this syndrome was markedly reduced in those patients premedicated with high doses of histamine receptor 1 and histamine receptor 2 blockers. Other side effects were mild and predictable. Biodistribution studies showed a rapid and intensive hepatic uptake. At the 50 mg/m2 level the half-life and maximum serum concentration were 81 +/- 15 h and 7.9 microg/ml, respectively. One patient developed a low-level human anti-c30.6 response. Tumor response was assessed by computed tomography, positron emission tomography scanning, and serial carcinoembryonic antigen measurements. There were no partial responses, although positron emission tomography scanning demonstrated some reduction in tumor activity in three individuals. The chimerized c30.6 antibody is not immunogenic in humans and appears worthy of further study. It does, however, produce a unique profile of side effects that can be well controlled with premedication.

Arachidonate and other fatty acids mobilize Ca2+ ions and stimulate beta-glucuronidase release in a Ca(2+)-dependent fashion from undifferentiated HL-60 cells.

Arachidonate (1-300 microM) mobilized Ca2+ ions from an intracellular store and stimulated the entry of Ca2+ ions from the extracellular fluid in undifferentiated HL-60 cells that had been loaded with Fura-2. The integrated response was biphasic in form: arachidonate liberated Ca2+ ions from the intracellular store first, resulting in a transient increase in cytosolic free Ca2+ concentration ([Ca2+]i). Ca2+ entry from the extracellular fluid was not evident for a further 1-2 min. At baseline, [Ca2+]i was 48.1 +/- 14.0 nM (SEM, n = 5). Upon addition of arachidonate (100 microM), [Ca2+]i rose to a transient peak level of 217 +/- 38.6 nM (SEM, n = 5) and a later plateau level of 427 +/- 118 nM (SEM, n = 5). Removal of added Ca2+ ions from the extracellular fluid in the presence of EGTA (1.0 mM) had no effect on the initial transient response but abolished the second phase of the response. In HL-60 cells that had been loaded with BAPTA/AM, the initial transient phase of the response was abolished but the elevation in [Ca2+]i due to Ca2+ entry from the extracellular fluid was unaffected. Undifferentiated HL-60 cells also responded to arachidonate (100 microM) with an increase in the release of the lysosomal enzyme beta-glucuronidase. Arachidonate-induced beta-glucuronidase release from BAPTA-loaded cells or in control cells exposed to Ca(2+)-free solutions was inhibited by about 50%. In BAPTA-loaded cells that were incubated with Ca(2+)-free solutions, arachidonate-induced beta-glucuronidase release was inhibited by about 90%. Leukotriene B4 failed to elevate [Ca2+]i in the concentration range 0.01-1 microM and failed to activate beta-glucuronidase release in concentrations up to 10 microM. Furthermore, the cyclo-oxygenase/lipoxygenase inhibitor ETYA (100 microM) was without effect on secretion. Consistent with this finding, we found that a large number of unsaturated fatty acids could reproduce the effect of arachidonate on [Ca2+]i and beta-glucuronidase release. Fatty acids belonging to the omega-3, omega-6 and omega-7 unsaturated fatty acid families were effective in elevating [Ca2+]i and stimulating beta-glucuronidase release. However, three unsaturated fatty acids, all belonging to the omega-9 fatty acid family, were ineffective.

In vitro HIV-specific CTL activity from HIV-seropositive individuals is augmented by interleukin-12 (IL-12).

IL-12 production is reduced in HIV infection, and recombinant human IL-12 (rhIL-12) augments in vitro HIV-specific proliferative responses in PBMC from HIV-seropositive individuals. To determine whether rhIL12 could also augment HIV-specific CTL responses we studied 41 HIV-seropositive individuals. Recombinant hIL-12 increased the detectable in vitro HIV-specific CD8 CTL activity of PBMC taken from HIV-seropositive individuals with CD4 counts >500 cells/microl and from some individuals with lower CD4 counts. IL-12 increased cell recovery in cultures of PBMC from HIV-seropositive individuals with CD4 counts >500 cells/microl and also increased the precursor CTL frequency. However, the increase in HIV-specific CTL activity was not due to IL-2 or IFN-gamma production or an increase in the number of cells with surface markers characteristic of CTL effector cells. This study demonstrates that rhIL-12 augments in vitro HIV-specific CTL activity and provides evidence to justify further investigation within clinical trials of this cytokine in HIV infection.

Lambda light chain induced nephropathy: a rare cause of the Fanconi syndrome and severe osteomalacia.

The Fanconi syndrome is a generalized disorder of proximal renal tubular transport characterized by wasting of phosphate, amino acids, glucose, bicarbonate, and uric acid. The association of the acquired Fanconi syndrome with lambda light-chain proteinuria is rare. We report the third case in the English language literature. A 65-year-old man presented with severe pelvic pain. Investigations showed an elevated serum creatinine level, and a 24-hour urine collection contained 2.56 g protein. The Fanconi syndrome was diagnosed, with findings of phosphaturia, glycosuria, and aminoaciduria. Bence Jones protein (lambda sub-type) was present in the urine at a concentration of 0.58 g/L. Monocytic cells in the bone marrow and proximal tubular cells in the kidney contained cytoplasmic crystalline inclusions. Undecalcified bone sections confirmed the clinical diagnosis of osteomalacia. The patient was treated with phosphate, calcium, and ergocalciferol and experienced significant symptomatic improvement. The Fanconi syndrome caused by light-chain deposition in proximal tubular cells is well described in the literature. However, it is rare for the light chains to be of the lambda subtype. This may reflect differences in the physicochemical properties of kappa and lambda light chains.

Time trends in HIV incidence among homosexually active men seen at sexual health clinics in Australia, 1993-1999.

BACKGROUND: Increases in sexual risk behaviour have recently been reported among homosexually active men in Australia and in other industrialised countries, potentially facilitating an increase in HIV incidence. OBJECTIVE: To monitor HIV incidence among homosexually active men seen through a network of sexual health clinics in Australia. STUDY DESIGN: Selected metropolitan public sexual health clinics provided counts of the number of people seen at the clinics during a calendar year, the number voluntarily tested for HIV antibody and the number newly diagnosed with HIV infection, broken down by sex, age group, HIV exposure category and HIV antibody testing history. HIV incidence was estimated among homosexually active men with a history of a negative test in the 12 months prior to last being seen in a calendar year. RESULTS: Of 23924 men seen at the clinics in 1993-1999 with a reported history of male homosexual contact, 7440 (31.1%) had a negative test in the 12 months prior to last being seen in a calendar year. The percentage of men with a recent negative test declined significantly over time, from more than 33% in 1994-1996 to 29% in 1999 (P=0.003), and with increasing age, from 34.3% among men aged 25-29 years to 27.4% among men aged 40 years or older (P<0.0005). A total of 5346 (71.9%) men were retested for HIV antibody within 12 months of the last negative test. The percentage of men retested declined significantly over time, from 77.8% in 1994 to 67.2% in 1999 (P=0.021) but did not change by age group (P=0.132). Overall, 56 men were newly diagnosed with HIV infection. Estimated HIV incidence was 2.1% in 1993-1999; incidence did not change significantly by year (P=0.498) or age group (P=0.757). CONCLUSION: HIV incidence has remained stable among homosexually active men seen through a network of sexual health clinics in Australia.

Glomerulosclerosis and hyalinosis in rabbits.

Histological appearances of remnant kidney in female New Zealand white rabbits undergoing left nephrectomy at 6 mths were studied. All 20 rabbits had evidence of previous Encephalitozoon cuniculi (E. cuniculi) infection. Half of the 10 uninephrectomized and 10 control animals completed 3 pregnancies before sacrifice (15 mths). Twelve of 30 kidneys at sacrifice showed focal and segmental hyalinosis and sclerosis (FSHS), a lesion not previously reported in rabbits. Four of 5 kidneys in both uninephrectomized pregnant and uninephrectomized virgin animals showed FSHS compared with 2 of 10 in both control pregnant and non-pregnant rabbits (p = 0.0026). More glomeruli were sclerosed in control pregnant (median 3.5%) than non pregnant animals (median 0.4%) (p < 0.005). Median right kidney weights per kilogram body weight were greater in previously nephrectomized animals (3.9 gm/kg) than controls (2.6 gm/kg), (p < 0.001). Absolute glomerular area was increased in hypertrophied kidneys, however, after correction for kidney weight, glomerular area was smaller in previously uninephrectomized animals than controls (p < 0.0001).

Histological features of IgA glomerulonephritis as predictors of pregnancy outcome.

116 pregnancies undertaken by 70 women with IgA glomerulonephritis and their diagnostic renal biopsies have been reviewed. An IgA diffuse mesangial proliferative lesion with superimposed focal and segmental proliferative lesions (IgA FSP) on diagnostic renal biopsy was associated with a greater incidence of maternal complications than IgA diffuse mesangial proliferative glomerulonephritis with no superimposed lesions (IgA DMP) and IgA diffuse mesangial proliferative glomerulonephritis with superimposed focal and segmental hyalinosis and sclerosis (IgA FSHS) (p less than 0.025). Patients with severe vessel lesions had a significantly greater incidence of fetal loss than those with only mild to moderate lesions (p less than 0.025).

IgA glomerulonephritis and pregnancy.

One hundred and sixteen pregnancies in 70 women with a biopsy-proven diagnosis of IgA glomerulonephritis have been analysed. Thirty percent (35) of the fetuses died, 22% (26) were premature and 44% (52) were full term. Maternal renal function declined during pregnancy in 26% (30) and in 2% (2) this was irreversible post-partum. Hypertension developed in 52% (61) of the pregnancies and in 13% (15) this was irreversible. Increased proteinuria was recorded in 62% (74) of the pregnancies. Fetal loss in pregnancies taking place after biopsy diagnosis was lower (16%) than those in which biopsy was performed either during or following the pregnancy (36%).

Membranous glomerulonephritis and pregnancy.

The clinical courses of 33 pregnancies in 24 patients with biopsy proven membranous glomerulonephritis have been analyzed. Twenty-four percent (8) of pregnancies resulted in fetal loss, 43% (14) in premature delivery and 33% (11) in a live birth after 36 weeks gestation. Maternal renal function declined during pregnancy in 9% (3) of the pregnancies and in 46% (15) hypertension developed. In 55% (18) proteinuria increased significantly during pregnancy. In 30% (10) nephrotic range proteinuria was recorded in the first trimester. Presence of nephrotic range proteinuria during the first trimester correlated with both poor fetal and poor maternal outcome (p less than 0.0004 and p less than 0.0002, respectively). It is concluded that pregnancy in patients with membranous glomerulonephritis is associated with increased fetal loss and, in some instances, a worsening in maternal renal function. The literature on this topic is reviewed in relation to these findings.

Large, rapid skeletal changes after parathyroidectomy.

We report dramatic increases in spine and hip bone mineral density six weeks following parathyroidectomy in renal patients. We have previously reported a cross-sectional association between parathyroidectomy and higher axial bone mineral density in dialysis patients. Large axial increases in bone mineral density after surgery for primary hyperparathyroidism have been recorded by others at one year postoperatively. Bone mineral density was recorded before and six weeks after parathyroidectomy. Scans were performed at the lumbar spine, hip and non-dominant radius. Values were expressed as Z-scores (standard deviations from the mean of an age- and gender-matched reference population). Large increases in lumbar were spine and femoral neck bone mineral density seen at six weeks post parathyroidectomy. Median increases were 0.57 (p = 0.006) and 0.26 (p = 0.039) Z-score units for these sites, respectively. Individual six-week increases were as large as 1.3 Z-score units at the spine and 1.0 Z-score units at the femoral neck. No significant cohort change was detected at the forearm but individual forearm changes were highly variable. Several mechanisms to explain these large rapid increases can be postulated. These include: mineralization of osteoid and/or contraction of the remodeling space. The changes illustrate the extent to which the skeleton is capable of rapid and profound change in mineral content. Our findings emphasize that the skeleton is a heterogeneous organ and that bone density should be measured at multiple skeletal sites.

Response to parathyroidectomy at the axial and appendicular skeleton in renal patients.

AIM AND METHODS: We report increases in axial and appendicular bone density after parathyroidectomy in renal patients. Bone density was recorded pre-operatively and at 6 weeks, 6 months and 1 year post-operatively. We have previously reported that axial bone density increased dramatically at 6 weeks but that there were no early cohort increases at the appendicular skeleton [Stein et al. 1997]. RESULTS: We now report that at six months, bone density had continued to increase at the lumbar spine and femoral neck, with median respective 6 months increases over baseline of 1.3 (p < 0.01) and 0.7 (p < 0.01 ) Z-scores. Bone density then appeared to stabilize at the axial skeleton. At the appendicular skeleton increases were significant at the one year time point with median respective increases at the ultradistal radius and one third radius of 0.46 (p < 0.05) and 0.49 (p < 0.05) Z-scores. The different pattern of responses to parathyroidectomy between the axial and appendicular sites supports the concept that appendicular bone turnover is slower than axial bone turnover. Furthermore, at the appendicular skeleton, bone turnover appears similar between cortical and trabecular bone. CONCLUSION: In renal patients, bone density increases after parathyroidectomy at both the axial and appendicular skeleton. Axial increases are large and occur early. Appendicular increases occur at both cortical and trabecular sites but are slower than the axial changes.

Pregnancy-related complications in women with reflux nephropathy.

Three hundred and forty-five pregnancies in 137 women with reflux nephropathy have been studied. All pregnancies took place after 1971. Overall foetal loss was 48 (14%) of which only 6 (2%) were therapeutic abortions. Maternal complications (urine infection, hypertension, proteinuria, oedema, deterioration in renal function, hematuria or renal stones) occurred alone or in combination in 39% of pregnancies. Fifty-two pregnancies took place in women with plasma creatinine (P.Cr > 0.11 mmol/l) prior to conception. Foetal loss after 12 weeks gestation (excluding therapeutic abortions) was 18% compared with 8% in the 104 pregnancies where maternal P.Cr was known to be < or = o.11 per/l at conception (p < 0.05). Maternal complications were also more common in the impaired renal function group (p < 0.001). Comparison of pregnancies in women with unilateral versus bilateral renal scarring revealed no significant difference in foetal loss but an increased incidence of over 50% maternal complications in the bilateral renal scar group (p < 0.01). The incidence of pre-eclampsia was higher in women with bilateral renal scars, 50 (24%) than in women with unilateral scars 8 (7%) (p < 0.001). Persistent vesicoureteric reflux was not associated with increased foetal loss or maternal risk. Impaired renal function prior to conception is associated with increased foetal and maternal complications in pregnancy. Bilateral renal scarring is associated with increased maternal complications during pregnancy.

Pregnancy in women with diffuse mesangial proliferative glomerulonephritis.

The clinical course of 168 pregnancies in 91 women with non-IgA diffuse mesangial proliferative glomerulonephritis has been analyzed. Twenty percent (33) of pregnancies resulted in fetal loss, 18% (31) in premature delivery and 62% (105) in a term infant. Maternal renal function declined, reversibly, in 3% (5) of pregnancies and in 48% (80) hypertension developed. In 53% (89) a significant increase in proteinuria occurred in pregnancy. Fetal and maternal complications of pregnancy occurred more frequently in patients with pre-existing hypertension although differences failed to reach statistical significance (p greater than 0.01). The presence of severe vessel lesions on the diagnostic renal biopsy was associated with a significantly higher fetal loss and prematurity rate (p less than 0.0005 and p less than 0.005, respectively).

Pregnancy in women with primary focal and segmental hyalinosis and sclerosis.

Thirty-one pregnancies and post partum clinical course of 21 women with a diagnosis of primary focal and segmental hyalinosis and sclerosis have been analyzed. Forty-five percent (14) of pregnancies resulted in fetal loss, 39% (12) in premature delivery and 16% (5) in a term infant. Of 17 fetuses for whom birthweight was recorded, 29% (5) were small for gestational age. Maternal renal function deteriorated in 49% (15) of pregnancies, in 13% (4) irreversibly. Three of these patients (15%) subsequently progressed to end-stage renal failure, and one to progressive chronic renal impairment, by the end of follow-up (median 4 years, range 1-25 years). In 74% (23) of pregnancies hypertension was recorded and this frequently developed early (61%) and was severe (45%). Nephrotic range proteinuria developed in 42% (13) of pregnancies. Increased proteinuria was recorded in 22 (17%) pregnancies. It is concluded that pregnancy in women with primary focal and segmental hyalinosis and sclerosis is associated with increased fetal loss and maternal complications.

The significance of focal and segmental hyalinosis and sclerosis (FSHS) and nephrotic range proteinuria in IgA nephropathy.

Between 1971 and 1991, 845 patients were diagnosed as having IgA glomerulonephritis on renal biopsy performed. These patients were followed for a mean period of 53 months post biopsy (range 0-336 months). By the end of follow up 147 (17%) of patients have developed chronic renal failure (Cr > 0.2 mmol/l) or end-stage renal failure. Presenting creatinine > 0.12 mmol/l, hypertension, nephrotic range, age > 40 years and male gender, all correlated strongly on univariate analysis with the development of chronic renal failure or kidney disease (all p < 0.0001). However, a number of patients developing chronic renal failure or end-stage renal failure already had renal impairment (creatinine > 0.12 mmol/l at presentation). A separate comparison was performed of patients presenting with creatinine < 0.12 mmol/l and either developing chronic failure or end-stage renal failure within 5 years of biopsy (n = 18) and those with creatinine still < 0.12 mmol/l after 5 years follow up (n = 186). Of the 18 patients who deteriorated 6 (35%) were nephrotic at presentation and 9 (56%) had focal hyalinosis and sclerosis on renal biopsy. This compared with 5 (3%) patients with nephrotic range proteinuria and 16 (10%) patients with focal hyalinosis and sclerosis among the 186 patients who did not deteriorate (p < 0.0001). The sensitivity and specificity of the presence of either or both factors in predicting deterioration was calculated at 65% and 87% respectively. Thus in patients with normal renal function at presentation the presence of nephrotic range or focal hyalinosis and sclerosis are strong predictors of adverse clinical outcome.