Imiquimod and lentigo maligna: a search for prognostic features in a clinicopathological study with long-term follow-up.

BACKGROUND: Melanoma in situ/lentigo maligna (LM) is a potential precursor of LM melanoma. It occurs most commonly in elderly individuals on sun-exposed skin of the head and neck. Although surgical excision is the treatment of choice, this may not be desirable or feasible for large lesions at functionally or cosmetically important sites. Imiquimod is a topical immunomodulator which can generate a local cytotoxic response with potentially antiviral and antitumour effects. OBJECTIVES: To present our experience of LM treated with imiquimod. METHODS: A retrospective review was performed of all patients with facial LM treated in our unit with topical imiquimod between January 2001 and December 2006. Pretreatment diagnostic biopsies were also reviewed and histologically graded. RESULTS: Forty-eight patients were treated with imiquimod. There were 37 responders and 11 treatment failures (of whom two were 'partial responders'). Of the 37 responders, 31 showed a clinical inflammatory response to imiquimod. One patient in whom treatment failed subsequently developed invasive disease. The mean follow-up duration was 49 months. We could not identify histological features of prognostic significance. However, the ability to develop an inflammatory reaction to imiquimod was a strong predictor of therapeutic benefit. CONCLUSIONS: We consider imiquimod to have a role in the treatment of LM in patients in whom surgery may be contraindicated or for those in whom the cosmetic or functional consequences may be considerable. Until better characterized, its use should probably be confined to centres with experience in the detection and treatment of LM and melanoma.

On the mechanism of the splay in the glucose titration curve in advanced experimental renal disease in the rat.

Glucose titration studies were performed in rats with unilateral chronic pyelonephritis before and after removal of the contralateral control kidneys. Identical studies were performed in animals with unilateral partial renal infarction in which the experimental kidneys had a marked reduction in nephron population but no anatomic deformation in the surviving nephrons. In the initial studies, both groups of animals were free of clinical and chemical abnormalities of uremia. In the follow-up studies uremic abnormalities were present. Minimal splay was observed in the titration curves in the initial studies; marked splay was present in the group data from the same kidneys in the subsequent studies. Thus a marked reduction in the nephron population was associated with the evolution of splay in both groups of animals. In association with the increase in splay, the mean values for maximal glucose transport increased; thus a defect in glucose transport can be excluded as the basis of the splay. Glomerular filtration rate increased proportionately more than the maximal transport of glucose; hence the ratios of glomerular filtration rate to maximal glucose transport increased consistently. The possibility of asymmetric hypertrophy of glomerular and tubular functions among the nephron population imposed by scar tissue or other anatomic deformities was considered, but the results in the animals with partially infarcted kidneys militate against this explanation. The splay also could reflect an asymmetric alteration in the distribution of glomerulotubular balance among the residual units initiated by functional adaptations. Finally, the splay could relate to an alteration in the kinetics of glucose transport without any change in the level of functional homogeneity. The possible nature of these has been considered in the text.

The influence of saline loading on renal glucose reabsorption in the rat.

Glucose titration studies were performed in normal rats under control conditions and during expansion of the extracellular fluid volume. In association with expansion, the maximal rate of glucose transport (Tm(glucose)) decreased while glomerular filtration rate (GFR) typically increased; thus there was a consistent increase in the GFR/Tm(glucose) ratio. In previous studies, marked reduction of the nephron population was associated with an alteration in the kinetics of glucose transport and GFR/Tm(glucose) ratios were observed to increase. In both volume-expanded rats and in animals and human beings with uremia, the splay in the titration curve is increased. Finally in both volume-expanded animals and uremic animals fractional reabsorption of sodium is depressed. One interpretation of the present data is that the natriuretic "third factor" may influence a key rate-limiting step in glucose transport; and it is possible that this step is shared by or coupled to a rate-limiting step in sodium transport.

Control of phosphate excretion in uremic man.

The present studies were performed in an effort to examine the characteristics of the control system governing phosphate excretion in uremic man. In a group of patients with glomerular filtration rates (GFR) ranging from normal to 2 ml/min, it was found that the lower the GFR the lower the fraction of filtered phosphate reabsorbed (TRP). On a fixed phosphate intake, phosphate excretion rate was the same in patients with GFRs ranging from 60 to 3 ml/min. When plasma phosphate concentrations were diminished to subnormal levels in hyperphosphatemic, hypocalcemic uremic patients, TRP values increased but did not return to normal. TRP failed to rise substantially when GFR, as well as plasma phosphate concentrations, were diminished. In patients with unilateral renal disease, TRP values were equal bilaterally, and values were substantially higher in the diseased kidneys than in patients with bilateral involvement. When plasma calcium concentrations were raised to normal for 2-3 wk in uremic patients in whom plasma phosphate concentrations had previously been lowered to subnormal levels, TRP values rose to an average value of 86%. Values remained in the normal range when phosphate concentrations were allowed to increase while normocalcemia was maintained. The data are interpreted to indicate that in advancing renal disease, the changing patterns of phosphate excretion are mediated by a control system in which parathyroid hormone serves as a major effector element. An increase in GFR per nephron, hyperphosphatemia, and intrinsic inability of the surviving nephrons to transport phosphate do not appear to be of primary importance in the progressive reduction in TRP.

The effects of polycations on vascular permeability in the rat. A proposed role for charge sites.

This study investigated whether charge sites in the walls of the microvasculature may play a role in maintaining the impermeability of the nonrenal capillaries to albumin. All experiments were performed in nephrectomized rats, studied in the awake state. The intravenous injection of protamine sulfate (4 mg/100 g body wt dissolved in 0.9% saline) was followed by a mean increase of 29.1% in hematocrit and a decrease of 28.4% in plasma albumin concentration over a 10-min period, indicating a significant 50-60% loss of albumin from the vascular space; a finding confirmed by studies using exogenous 125I-labeled albumin. Changes persisted for the remaining 80 min of observation, and could be reproduced by the injection of two other polycations, hexadimethrine and poly-l-lysine. These effects were not prevented by the antihistamine diphenhydramine hydrochloride. In contrast to 125I-labeled albumin, 14C-labeled neutral dextran of comparable size was not confined to the vascular space; its apparent volume of distribution progressively increased during the 90 min of observation. Intravenous injection of protamine sulfate was followed by a significantly smaller loss of 14C-dextran (36.5%) than albumin (59.1%) from the vascular space (P less than 0.01). Protamine sulfate could not be demonstrated to result in any changes in the physicochemical characteristics of albumin. These observations suggest that the negative charge sites present in nonglomerular capillary walls have functions similar to equivalent sites present in the glomerular capillaries. Thus, charge sites could contribute to the low permeability of the microvasculature to negatively charged macromolecules such as albumin. This may be an important mechanism for retaining albumin in the vascular space and preventing edema formation in health.

Normal glomerular permeability and its modification by minimal change nephrotic syndrmone.

It has been suggested that the glomerular basement membrane restricts the passage of large molecules only, the barrier to filtration of smaller molecules being at the level of the epithelial slit pore. This hypothesis was investigated by measuring glomerular permeability to (125)I-labeled polydisperse polyvinyl pyrrolidone (PVP) in 16 children with idiopathic nephrotic syndrome (INS) and in 6 children of comparable age who had no evidence of renal disease. Studies were performed in the patients with INS before, during, and after treatment with steroids. PVP in blood and urine samples was separated according to molecular size by solumn chromatography, to permit the calculation of permeability to inert macromolecules of sizes ranging from 8,000 mol wt. In untreated INS, glomerular permeability to molecules > 40 A was normal; permeability to smaller molecules was markedly reduced, frequently to 20% or less of normal. There was an average decrease in inulin clearance (C(in)) of 24%. Glomerular permeability and C(in) returned to normal in INS treated with steroids only when proteinuria disappeared. The results support the concept, derived from studies with ultrastructural tracers, that the final barrier to filtration may be at the level of the epithelial slit pore. Thus fusion of the epithelial foot processed with obliteration of the slit pores was associated with impaired passage of smaller molecules of PVP into the urine. Reversal of the pathologic abnormality resulted in return of permeability to normal. The decreased C(in) seen in INS may not reflect true glomerular filtration rate, but may result from restricted passage of inulin molecules (mol wt 5,000) through the epithelial slit pore.

Nutrient intake and blood pressure in the Dietary Intervention Study in Children.

Delineating the role that diet plays in blood pressure levels in children is important for guiding dietary recommendations for the prevention of hypertension. The purpose of this study was to investigate relationships between dietary nutrients and blood pressure in children. Data were analyzed from 662 participants in the Dietary Intervention Study in Children who had elevated low-density lipoprotein cholesterol and were aged 8 to 11 years at baseline. Three 24-hour dietary recalls, systolic pressure, diastolic pressure, height, and weight were obtained at baseline, 1 year, and 3 years. Nutrients analyzed were the micronutrients calcium, magnesium, and potassium; the macronutrients protein, carbohydrates, total fat, saturated fat, polyunsaturated fat, and monounsaturated fat; dietary cholesterol; and total dietary fiber. Baseline and 3-year longitudinal relationships were examined through multivariate models on diastolic and systolic pressures separately, controlling for height, weight, sex, and total caloric intake. The following associations were found in longitudinal analyses: analyzing each nutrient separately, for systolic pressure, inverse associations with calcium (P < .05); magnesium, potassium, and protein (all P < .01); and fiber (P < .05), and direct associations with total fat and monounsaturated fat (both P < .05); for diastolic pressure, inverse associations with calcium (P < .01); magnesium and potassium (both P < .05), protein (P < .01); and carbohydrates and fiber (both P < .05), and direct associations with polyunsaturated fat (P < .01) and monounsaturated fat (P < .05). Analyzing all nutrients simultaneously, for systolic pressure, direct association with total fat (P < .01); for diastolic pressure, inverse associations with calcium (P < .01) and fiber (P < .05), and direct association with total and monounsaturated fats (both P < .05). Results from this sample of children with elevated low-density lipoprotein cholesterol indicate that dietary calcium, fiber, and fat may be important determinants of blood pressure level in children.

Diagnosis of depression in patients with end-stage renal disease. Comparative analysis.

To evaluate the variability in the diagnosis of depression in patients receiving maintenance therapy for end-stage renal disease, a study of 60 randomly selected patients was conducted. Three representative depression assessment methods were employed concurrently in the evaluation of each patient: (1) a structured psychiatric interview based on the diagnostic criteria of the American Psychiatric Association (DSM-III); (2) the Beck Depression Inventory; and (3) the Multiple Affect Adjective Check List. Among the 60 patients, 47 percent were classified as depressed by the Beck Depression Inventory, whereas 17 percent and 5 percent were determined to be depressed according to the Multiple Affect Adjective Check List and DSM-III criteria, respectively. The data demonstrated these differences to be dependent on the overlap between the symptoms of uremia and depression, as well as on the duration of those symptoms. This study also suggests that death wish, suicidal intention, and other psychologic symptoms should receive particular attention in the clinical assessment of depression in patients with end-stage renal disease.

In vivo release of endogenous dopamine from rat caudate nucleus by phenylethylamine.

The in vivo release of endogenous dopamine (DA) from the rat caudate nucleus has been measured in the presence and absence of beta-phenylethylamine. A push-pull cannula was implanted into the brain and the tissue was perfused with artificial cerebrospinal fluid (CSF) containing phenylethylamine in concentrations ranging from 5 X 10(-3) to 5 X 10(-7) M. The DA released into the perfusate was determined radioenzymatically. Dopamine was released at rates significantly greater than its resting rate by concentrations of phenylethylamine of 5 X 10(-3) to 5 X 10(-5)M; 5 X 10(-6)M phenylethylamine caused a slight increase in release, but the difference from the resting rate was not significant. The absence of calcium in the perfusing medium did not significantly alter either the unstimulated release rate of DA or the release rate stimulated by 5 X 10(-5)M phenylethylamine. The concentrations of phenylethylamine required to increase release of DA in vivo are discussed briefly in relation to the doses required to elicit behavioural effects.

Renal injury in sick newborn infants: a prospective evaluation using urinary beta 2-microglobulin concentrations.

Urinary concentrations of beta 2-microglobulin and creatinine were measured serially in 140 sick infants, of whom 109 were asphyxiated, and in 35 healthy preterm and term infants. First voided urines and samples from days 3 and 7 postpartum were studied. Urinary beta 2-microglobulin concentrations in healthy infants averaged 1.34 +/- 1.34 mg/L (mean +/- SD) in first voided specimens and 1.32 +/- 0.98 mg/L in day 3 samples; the calculated upper limit of normal (95% confidence limit) was 4.00 mg/L. Elevated values (those exceeding the 95% confidence limit) occurred most often in the sick asphyxiated patients (56%); the first voided sample value in these patients was 10.0 +/- 10.4 mg/L. The equivalent value in the sick nonasphyxiated infants was 8.32 +/- 7.27 mg/L. Values were significantly and persistently elevated in the sick infants on days 3 and 7. Factoring beta 2-microglobulin levels by urinary creatinine concentration did not affect the significance of the findings. The increased urinary beta 2-microglobulin levels were not (1) related to gestational age; low beta 2-microglobulin values occurred at all gestational ages for both healthy and sick infants; (2) a consequence of urine flow rate; urinary beta 2-microglobulin did not correlate with urinary creatinine concentration or with urine to plasma creatinine ratio; and (3) a consequence of increased production of beta 2-microglobulin; urinary and serum beta 2-microglobulin values did not correlate (r = .03). Thus, we propose that the elevated levels of urinary beta 2-microglobulin in the sick infants were the consequence of tubular injury. This was associated with hematuria but not with a high incidence of azotemia or oliguria.(ABSTRACT TRUNCATED AT 250 WORDS)

Severe immobilization hypercalcemia, renal insufficiency, and calcification.

Severe hypercalcemia with decreased renal function, hypertension, and renal calcifications developed in a 14-year-old boy who required prolonged immobilization for multiple fractures. Parathyroid hormone was not detectable in the serum. Urinary calcium excretion was high. Initially, mobilization was impossible and the patient was treated with a high fluid intake, low calcium intake, acidification of the urine, furosemide, and a passive exercise program. Renal function improved and renal calcifications resolved but hypercalcemia did not resolve. After mobilization the serum calcium concentration became normal rapidly. This treatment regimen is suggested for use in patients with immobilization hypercalcemia when mobilization is impossible.

Urinary beta 2-microglobulin in full-term newborns: evidence for proximal tubular dysfunction in infants with meconium-stained amniotic fluid.

Urinary concentrations of beta 2-microglobulin (beta 2M) and creatinine were measured in normal term infants and in those born with meconium-stained amniotic fluid. None of the infants or their mothers had conditions known to modify beta 2M excretion. Measurements of beta 2M were made on urines collected by bagging; urines obtained from diapers were not satisfactory. Urinary beta 2M concentrations increased significantly (P less than .02) in the normal infants from the first day (0.36 +/- 0.29 mg/L: n = 29) to the third day (0.60 +/- 0.43 mg/L: n = 21) postpartum. Compared with the normal infants, values for the infants with meconium-stained amniotic fluid were increased significantly on days 1 (1.64 +/- 2.16 mg/L: n = 25: P less than .005) and 3 (2.12 +/- 2.04 mg/L: n = 23: P less than .005). Levels exceeded two standard deviations above the normal mean in 12 of the 26 infants with meconium-stained amniotic fluid on postpartum day 1, and 12 of the 23 infants with meconium-stained amniotic fluid on day 3. Urinary creatinine levels were similar in both the normal infants and those with meconium-stained amniotic fluid. All infants with meconium-stained amniotic fluid with a one-minute Apgar score of 6 or less had an elevated urinary beta 2M concentration. The elevated levels of urinary beta 2M in infants with meconium-stained amniotic fluid indicate the existence of tubular dysfunction, probably mild acute tubular necrosis secondary to hypoxia.

Inhibitory factors of lymphocyte transformation in sera from patients with minimal change nephrotic syndrome.

This study was undertaken to establish the specificity and relation to disease activity of serum inhibitors of lymphocyte function in minimal change nephrotic syndrome (MCNS). Sera from 21 children with MCNS were evaluated for their effect on blast transformation of normal human lymphocytes after stimulation with E-PHA, ConA, PWM or allogeneic cell surface antigens (mixed lymphocyte cultures;MLC). Sera from patients in relapse on no medication (n = 12), in relapse on steroids (n = 5), and in remission on steroids (n = 7) were significantly more inhibitory than sera from patients in late remission off steroids (n = 14 both in mitogen induced blast transformation and in MLC. Sera from eight children with other forms of nephrotic syndrome exhibited the same degree of inhibition of E-PHA, ConA, and PWM induced mitogenesis but significantly less inhibition of MLC when compared to 12 MCNS patients in untreated relapse. Thus serum inhibition of mitogen induced blast transformation is not specific for MCNS but occurs in other forms of nephrotic syndrome as well. Conversely, sera from MCNS patients does selectively inhibit MLC. Finally, the inhibitory activity of MCNS sera for both mitogen and cell surface antigen stimulation correlates with the course of the disease.

The quality of maintenance therapy for end-stage renal disease. A review of social adjustment and rehabilitation.

Prior to 1972, ESRD patients selected for maintenance dialysis or renal transplantation were generally young, emotionally and socially well-adjusted, and physically healthy except for their renal disease. Following the enactment of Public Law 92-603 (1972), which extended Medicare coverage to virtually all ESRD patients, the criteria for the selection of patients were substantially liberalized. During the past decade, maintenance therapy has increasingly been provided for severely debilitated ESRD patients whose reported levels of rehabilitation have been less than desired. While the majority of the current ESRD patient population have not been restored to their premorbid levels of individual and social functioning, recent studies suggest this may be the result of initiating rehabilitation efforts too late in the disease process. For optimal social functioning to be achieved by ESRD patients, it is concluded that psychosocial intervention and support must be initiated at the time ESRD is diagnosed and be focused on the maintenance, rather than rehabilitation, of the patient's functioning.

Nasal mucociliary function: comparison of saccharin clearance with ciliary beat frequency.

Mucociliary clearance as measured by saccharin clearance time is in part dependent on the physiological characteristics of mucus and is partly dependent on ciliary function. This study compared the relationship between saccharin clearance time and ciliary beat frequency in 44 patients attending a rhinology clinic. Whilst saccharin clearance time may be used as a screening test for ciliary function there was no clear linear relationship between mucociliary clearance and ciliary beat frequency.