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.

Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the Dietary Intervention Study in Children (DISC).

OBJECTIVE: Diets reduced in fat and cholesterol are recommended for children over 2 years of age, yet long-term safety and efficacy are unknown. This study tests the long-term efficacy and safety of a cholesterol-lowering dietary intervention in children. METHODS: Six hundred sixty-three children 8 to 10 years of age with elevated low-density lipoprotein cholesterol (LDL-C) were randomized to a dietary intervention or usual care group, with a mean of 7.4 years' follow-up. The dietary behavioral intervention promoted adherence to a diet with 28% of energy from total fat, <8% from saturated fat, up to 9% from polyunsaturated fat, and <75 mg/1000 kcal cholesterol per day. Serum LDL-C, height, and serum ferritin were primary efficacy and safety outcomes. RESULTS: Reductions in dietary total fat, saturated fat, and cholesterol were greater in the intervention than in the usual care group throughout the intervention period. At 1 year, 3 years, and at the last visit, the intervention compared with the usual care group had 4.8 mg/dL (.13 mmol/L), 3.3 mg/dL (.09 mmol/L), and 2.0 mg/dL (.05 mmol/L) lower LDL-C, respectively. There were no differences at any data collection point in height or serum ferritin or any differences in an adverse direction in red blood cell folate, serum retinol and zinc, sexual maturation, or body mass index. CONCLUSION: Dietary fat modification can be achieved and safely sustained in actively growing children with elevated LDL-C, and elevated LDL-C levels can be improved significantly up to 3 years. Changes in the usual care group's diet suggest that pediatric practices and societal and environmental forces are having positive public health effects on dietary behavior during adolescence.

Cutaneous perineurioma: a poorly recognized tumour often misdiagnosed as epithelioid histiocytoma.

AIMS: Eleven cases of cutaneous perineurioma were studied to further characterize the histological features of this entity. METHODS AND RESULTS: The histological and immunocytochemical features of 11 cases of cutaneous perineurioma were studied and detailed by two pathologists. Clinical data were obtained from the referring clinician. Seven patients were female and four were male with ages ranging from 19 to 67 years (median 41 years). Six lesions arose on the leg. Macroscopically lesions ranged from 4 mm to 14 mm in maximum diameter (median 7 mm). Diagnostic histological features included a nonencapsulated but sharply demarcated tumour with a dumbbell architecture. The tumour cells were spindle-shaped with delicate inconspicuous cytoplasm and arranged in sheets, whorls or with a vague fascicular pattern. Epithelioid cells with moderate amounts of eosinophilic cytoplasm were frequently admixed with the spindle cells. One tumour had trabeculae of cells embedded within a dense collagenous stroma as described in sclerosing perineurioma. One case displayed a prominent myxoid stroma. Three further cases contained small foci of fibrosis or myxoid change suggesting a morphological spectrum exists in cutaneous perineurioma. Mitoses were exceptionally rare and necrosis and significant cytonuclear pleomorphism was not found. All tumours were epithelial membrane antigen (EMA) positive. Six cases showed focal positivity for factor XIIIa. Follow-up ranged from 5 months to 6 years (median 1 years). No tumour recurred or metastasized. CONCLUSIONS: The histological appearance of this tumour is broader than hitherto realized. Several cases in this series were misdiagnosed histologically and cutaneous perineuriomas may be more common than currently appreciated.

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.

Cyclin/proliferation cell nuclear antigen immunohistochemistry does not improve the prognostic power of Dukes' or Jass' classifications for colorectal cancer.

Immunohistochemistry of cyclin/proliferation cell nuclear antigen (PCNA) is an attractive alternative to tumour cell proliferation activity determined by flow cytometry which has been shown to be independently predictive of survival in patients with colorectal carcinoma and to enhance Dukes' classification. Dukes' and Jass' histopathological classifications were determined in 91 patients who had undergone curative resection for cancer of the colon (n = 51) or rectum (n = 40) and followed up for a minimum of 10 years. PCNA immunohistochemistry was possible in 79 tumours. Univariate analysis revealed that Jass' (P < 0.0001) and Dukes' classifications (P < 0.0002) were powerful predictors of survival but that the PCNA index had little prognostic power (P = 0.4). Multivariate analysis of both classifications showed similar predictive power and the PCNA index improved the prediction of survival when used with either classification for patients with colon cancer (chi 2 = 5.3, 1 d.f., P = 0.02 for each combination). The PCNA index, however, was not predictive for rectal cancer. Patients with the lowest PCNA index had the worst prognosis.

Curvularia urinary tract infection: a case report.

A healthy 5-year-old child had recurrent symptomatic urinary tract infections, the last of which was accompanied by black specks in her urine. These specks were identified as Curvularia species, a dermatiaceous mold. Symptoms resolved and fungi disappeared with long-term hydration, without specific antifungal treatment.

Ciliary ultrastructure in nasal brushings.

Normal ciliary ultrastructure is thought to be necessary for effective function. There has been little or no attempt to quantify ultrastructural abnormalities in nasal disease and assess their significance. In this study we measured nasal ciliary function and examined ciliary ultrastructure in nasal brushings from 35 patients with perennial nasal symptoms refractory to treatment. Ultrastructural defects included microtubular abnormalities, compound cilia and ciliary 'blebs'. The incidence of abnormal cilia was 16.7%, compared with 9% in controls, but there was only a poor correlation between ultrastructural defects and ciliary beat frequency. One patient had primary ciliary dyskinesia (PCD) with a typical clinical history and immotile cilia. However, only secondary ultrastructural abnormalities were seen. We have been unable to show that ciliary ultrastructural defects form the basis of impaired function. In patients with suspected PCD, nasal brushings should be taken for functional and ultrastructural studies; ideally, a further sample should be obtained for examination of possible primary ultrastructural abnormalities.

Factors affecting ciliary function in vitro: a preliminary study.

Nasal ciliary function forms an important defence mechanism within the upper respiratory tract which has largely been ignored in recent years. The effects of various drugs used extensively in the treatment of diseases of the nose have not been fully established. Furthermore, the physiological control of ciliary activity is unclear. The aim of this study was therefore to investigate the effects of drugs on ciliary beat frequency in vitro using a photometric technique. A dose-dependent response to alpha and beta receptor drugs was found, cocaine hydrochloride achieved ciliostasis even at 40-fold dilution, and potassium ions, except at the limits of tolerance for excitable tissue, did not affect ciliary function. In conclusion, we suggest that alpha and beta receptors may be present on ciliated epithelium and be involved in the control of ciliary function in vivo. Ion fluxes across the ciliary cell membrane may also be important in ciliary activity akin to nervous tissue.

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.

HLA extended haplotypes in steroid-sensitive nephrotic syndrome of childhood.

Idiopathic nephrotic syndrome has been postulated to have an immunopathogenic basis. To determine whether steroid-sensitive nephrotic syndrome is associated with greater than expected frequencies of specific extended haplotypes of the major histocompatibility complex, we studied genetic markers (Class I, II, III HLA alleles and glyoxalase I) in 173 subjects in 42 families of patients with nephrotic syndrome of childhood. The single allele, DQW2, was found in 72% of steroid sensitive patients compared with only 35% of the controls (P = 0.003). In half of 32 steroid sensitive, but not 10 steroid resistant, patients, one or both of two specific extended haplotypes (alleles that segregate together) were identified. The first, [HLA-A1, B8, DR3, DRW52, SCO1], occurred in 11 of 64 haplotypes, or 17%, compared to 5% of controls (P = 0.017). The other, [HLA-B44, DR7, DRW53, FC31], occurred in 10 of 64 haplotypes, 16% compared to 3.8% of controls (P = 0.014). Five patients had both haplotypes. Patients with these specific extended haplotypes had a greater frequency of relapses than did those with other haplotypes. These data provide additional support for the hypothesis that steroid-sensitive nephrotic syndrome has an immunogenetic basis.

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)

Course and resolution of the coagulopathy in nephrotic children.

Blood coagulation function was serially studied in 84 children with nephrotic syndrome. Fifty-eight had minimal change disease, six had focal glomerulosclerosis and 20 had other forms of renal disease associated with the nephrotic syndrome. Qualitatively similar abnormalities in fibrinogen metabolism were present in all groups with clinically overt nephrotic syndrome; plasma fibrinogen concentration and high molecular weight fibrin(ogen) complexes (HMWFC) were grossly elevated (P less than 0.001 in most groups). With disease remission fibrinogen and HMWFC concentrations decreased to the normal range, usually with concomitant transient increase in plasma fibrinolytic activity (P less than 0.02). Alterations in concentrations of other proteins involved in coagulation and fibrinolysis differed depending on the underlying cause for the nephrotic syndrome. Antithrombin III concentration was normal except in the focal glomerulosclerosis group. The results demonstrate that a coagulopathy characterized by pathological degree of thrombin action on fibrinogen complicates the nephrotic state and may be initiated by different mechanisms. It is suggested that this coagulopathy, which remits with clinical improvement, is consequent upon local intrarenal activation of the blood coagulation system.

Depressive symptomatology and treatment in patients with end-stage renal disease.

A sample of 60 patients selected at random from an adult population of 419 patients with end-stage renal disease was assessed for major depression. Diagnoses were based on a structured interview using DSM-III criteria. Eighteen patients (30%) met criteria for a major depression on a lifetime basis. In addition, depressive symptoms and treatment for each depressed patient are reported.

Living-related kidney donors: a multicenter study of donor education, socioeconomic adjustment, and rehabilitation.

To determine the consequences of living-related kidney donation, a study was conducted of 536 donors whose nephrectomies had been performed at nine geographically dispersed centers during the past 12 years. The data demonstrated that greater than 84.0% of the donors thought they had been adequately informed regarding all aspects of donation, and less than 15.0% reported being pressured in their decision. Only two serious medical complications were directly attributable to the surgery, greater than 92.0% of the donors believed their health had not been adversely affected by donation, and 96.8% reaffirmed their decision regardless of the graft's success or the financial distress they experienced (P greater than .05). However, greater than 14.0% experienced direct pressure, particularly not to donate. Donation also appeared to stress previously troubled marriages, especially among donors without a religious affiliation, who were pressured to donate by their families, or who borrowed from family members (P less than .05). Substantial unreimbursed expenses (greater than or equal to $1,000) were incurred by 43 donors, and 23.2% of all donors reported that donation caused a financial hardship.

Use of beta 2 microglobulin to diagnose tubulo-interstitial renal lesions in children.

Fractional excretion (FE) of beta 2 microglobulin (beta 2M) was studied in children with glomerular (N = 114), tubular (N = 50) or other (N = 18) renal diseases. FE-beta 2M (normal less than 0.36%) was significantly (P less than 0.001) lower in glomerular diseases (mean 0.104%) than in tubular lesions (mean 4.27%). Unexpectedly, several patients with glomerular disease were found to have increased values for FE-beta 2M. To determine whether this was due to a tubular component in a primary glomerular disease process, FE-beta 2M was measured in 30 children with various glomerulopathies who underwent renal biopsy. Thirteen of these patients had tubulo-interstitial lesions in addition to their glomerular disease. FE-beta 2M in these patients averaged 3.76% (range 0.14 to 44.6%); only two results were normal. Mean FE-beta 2M in the 17 patients without biopsy evidence of tubulo-interstitial disease was 0.063% (range 0.02 to 0.34%); all values were in the normal range. The types of glomerular diseases in the two groups of patients were similar. Patients with a glomerular lesion complicated by tubulo-interstitial lesions had a poorer prognosis than did those with a pure glomerular disease. The high incidence of tubulo-interstitial lesions in patients with glomerular diseases was unexpected. Our data demonstrates that FE-beta 2M represents a reliable non-invasive method to diagnose such involvement. Measurements of beta 2M also provide a convenient method to follow the course and response to treatment of renal tubular injury.

Sodium-lithium countertransport in erythrocytes of children and adolescents with hypertension.

We have investigated the sodium-lithium countertransport system as a screening test for hypertensive disease in children and adolescents using the method of Canessa et al. [New Engl. J. Med. 302: 772-776, 1980]. The sodium-lithium countertransport in erythrocytes was measured in patients, ages 4-18 years, having essential hypertension or secondary hypertension and compared with age-, weight-, sex- and race-matched normotensive controls. Children and adolescents with essential hypertension possessed a significantly higher erythrocyte sodium-lithium countertransport rate than the normotensive control group (0.39 +/- 0.18, n = 28, vs. 0.22 +/- 0.14 mmol Li/l red cells/h, n = 20, respectively; p less than 0.001). Children with secondary hypertension had intermediate values (0.31 +/- 0.15 mmol Li/l red cells/h; n = 17) which did not differ significantly from values of subjects with essential hypertension or normotensive controls. There was no correlation of counter-transport values with age, sex, or body weight in either hypertensive or normotensive groups. However, white normotensive children had significantly higher countertransport levels compared with black normotensives (0.32 +/- 0.14, n = 10, vs. 0.13 +/- 0.07 mmol Li/l red cells/h, n = 10, respectively; p less than 0.005). Similarly, white children and adolescents with essential hypertension had higher mean countertransport measurements than did black hypertensives (0.42 +/- 0.20, n = 21, vs. 0.27 +/- 0.05 mmol Li/l red cells/h, n = 7, respectively) although this difference did not reach statistical significance (p less than 0.1). Although children and adolescents with essential hypertension had a significant elevation of sodium-lithium countertransport when compared to normotensives, the large degree of overlap of countertransport values in these two groups, as well as the intermediate values of children with secondary hypertension, limits the usefulness of the sodium-lithium countertransport as a screening test for essential hypertension in this population. Taking into account the influence of racial differences on the countertransport assay does not sufficiently improve the discriminatory value of the test to render it clinically useful.

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.