Understanding c-MET signalling in squamous cell carcinoma of the head & neck.

c-MET is a membrane spanning receptor tyrosine kinase for hepatocyte growth factor (HGF) also termed scatter factor. Transmitting signals from mesenchymal to epithelial cells, the HGF/c-MET axis mediates a range of biological processes that stimulate proliferation, motility, invasiveness, morphogenesis, apoptosis, and angiogenesis. Aberrant c-MET signal transduction favours tumorigenesis with the acquisition of invasive and metastatic phenotypes. Biological functions of c-MET may strongly vary according to microenvironmental changes, which occur at different stages of tumorigenesis and include also HGF/c-MET activation in stromal cells. In this review, we focused on abnormalities in non-nasopharyngeal squamous cell carcinoma of the head & neck. While the prevalence of c-MET mutations and amplifications ranges 0-25%, c-MET upregulation can be found in the majority of squamous head & neck carcinomas. Despite marked heterogeneity in published scoring methods, immunohistochemical overexpression of c-MET has been typically linked to advanced stages and associated with impaired survival and/or resistance to radiotherapy, chemoradiotherapy, and cetuximab. Experimental studies in cell lines and patient-derived xenografts using various c-MET antagonists (both as single-agents and in combination with cytotoxic and epidermal growth factor receptor [EGFR]-directed agents) yielded promising results, albeit benefit in clinical trials remains to be demonstrated. Consequently, selecting more active agents and integrating them effectively in studies, which incorporate predictive biomarkers such as c-MET gene mutations, amplifications, and overexpression, remains challenging. Further investigations should increase emphasis on disentangling the role of tumour-stromal interactions and analyse their potential as modifiers of drug response.

Umbilical artery histomorphometry: a link between the intrauterine environment and kidney development.

Prematurity is a risk factor for hypertension, vascular stiffness, nephron deficit and adult onset cardiorenal disease. The vascular tree and kidneys share morphogenic drivers that promote maturation in utero before 36 weeks of gestation. Vascular elastin accrual terminates after birth leaving collagen to promote vascular stiffness. Our objective was to determine if the histomorphometry of the umbilical artery, an extension of the aorta, parallels nephron mass across gestational age groups. From a cohort of 54 newborns, 32 umbilical cord specimens were adequate for evaluation. The umbilical cord was sectioned, stained with trichrome, and digitalized. Muscular and collagenous areas of the umbilical artery were measured in pixels using the Image J 1.48q software. Total kidney volume was measured by ultrasound and factored by body surface area (TKV/BSA). The umbilical artery total area was significantly greater in term v. preterm infants (9.3±1.3 v. 7.0±2.0 mm2; P<0.05) and increased with gestational age; while the percent muscular and collagen areas were independent of gestational age (R 2=0.04; P=ns). Percent muscular area correlated positively with TKV/BSA (r=0.53; P=0.002); while an increase in collagen correlated inversely with kidney mass (r=-0.53; P=0.002). In conclusion, an enhanced % muscular area and presumed vascular elasticity was associated with increased renal mass in all infants. Umbilical artery histomorphometry provides a link between the intrauterine environment, vascular and kidney development.

Hepatitis C infection in a pediatric dialysis population.

A variable prevalence of hepatitis C (HCV) infection has been reported in adult patients on hemodialysis. We have studied HCV infection and associated risk factors in a pediatric dialysis unit. Sera from all 27 patients undergoing either hemodialysis or peritoneal dialysis in our unit were tested for antibody to HCV by enzyme-linked immunosorbent assay, and seropositives were confirmed by recombinant immunoblot assay. Records were reviewed for demographic, biochemical, and risk factor data. From the total of 27 patients (12 male, mean age 20.9 years, range 7.3 to 28.1 years), five were anti-HCV(+) (18.5%). All the anti-HCV(+) patients had been on hemodialysis (69 to 194 months, mean 105 months), while of the 22 anti-HCV(-) patients, only 14 had been on hemodialysis (5 to 209 months, mean 41.4 months), P less than .005. All the anti-HCV(+) patients had received blood transfusions (10 to 124 units, mean 61.4 units) as had 12 of the anti-HCV(-) patients (1 to 54 units, mean 14 units), P less than .02. Of the 5 anti-HCV(+) patients, only one had prior hepatitis B infection; of the 22 anti-HCV(-) patients, three had hepatitis B surface antigen, and no others had evidence of hepatitis B infection. The most predictive risk factor for HCV infection was length of time on hemodialysis. Eleven of the 27 patients (40.7%) had abnormal alanine aminotransferase values, of whom four were anti-HCV(+), three were hepatitis B surface antigen(+), and one was seropositive for antibody to human immunodeficiency virus.(ABSTRACT TRUNCATED AT 250 WORDS)

Diuretic MAG3 scintigraphy (F0) in acute pyelonephritis: regional parenchymal dysfunction and comparison with DMSA.

UNLABELLED: 99mTc-DMSA late static planar imaging or SPECT is being used for the investigation of focal acute pyelonephritis (APN), especially in children with urinary tract infection (UTI). Diuretic 99mTc-mercaptoacetyltriglycine (MAG3) dynamic scintirenography has been applied in the evaluation of kidney function and structure, frequently to exclude obstruction. However, in children and adults with a clinical picture of APN, diuretic MAG3 scintigraphy with zero time injection of furosemide (MAG3-F0) was observed to display focal parenchymal abnormalities; regional dysfunction (focal parenchymal decrease in early uptake; slow filling in and prolonged late retention of activity); or, less frequently, fixed defects. This observation was further studied both retrospectively and prospectively, and its sensitivity and specificity for APN were compared with those of dimercaptosuccinic acid (DMSA). METHODS: In the retrospective study, for 36 children with UTI and regional parenchymal findings on MAG3-F(0), data were reviewed, analyzed, and compared with the results of concurrent DMSA studies. In the prospective study, for 57 children with clinical and laboratory findings suggestive of APN, the 2 radiopharmaceuticals were used for imaging sequentially and the results of the 2 studies were compared. The criteria for abnormal findings compatible with the diagnosis of APN were, for MAG3-F(0), regional parenchymal dysfunction and fixed focal defects and, for DMSA, focal defects without parenchymal loss. RESULTS: In all groups of patients, most abnormal MAG3-F(0) studies (80%) showed regional parenchymal dysfunction, but in some (20%) a fixed defect was found. Compared with DMSA and when both regional dysfunction and focal defects were considered, MAG3-F(0) was as sensitive as DMSA. Some patients had only MAG3-F(0) abnormalities, suggesting a slightly lower specificity for MAG3-F(0) compared with DMSA (86%); this finding needs further study, because it also raises questions about the sensitivity of DMSA, considering that only a small percentage of patients with clinically suggestive findings had abnormal study findings. In most patients with fixed defects on both DMSA and MAG3-F(0), follow-up studies showed no resolution, suggesting that a fixed defect on MAG3-F(0) may indicate either more severe APN or preexistent scars and that regional dysfunction may be a sign more specific for APN and prognostic of potential recovery. In addition, a pattern more specific for a scar--a fixed defect with a dilated regional calyx--was seen on follow-up MAG3-F(0). CONCLUSION: A fast (25-min) planar dynamic MAG3-F(0) study was found to be as sensitive at depicting focal parenchymal abnormalities in APN as was the 3- to 4-h DMSA routine procedure. The sensitivity and specificity of both studies need further evaluation.

Diuretic MAG3 scintirenography in children with HIV nephropathy: diffuse parenchymal dysfunction.

UNLABELLED: HIV nephropathy (HIVN) is prevalent in 15%-56% of HIV-infected children and induces mild to severe progressive nephropathy. METHODS: A total of 33 renal diuretic scintirenographic studies with 99mTc-mercaptoacetyltriglycine (MAG3) were reviewed and analyzed from 23 HIV pediatric patients, 21 of whom had HIVN with varying degrees of renal impairment. Results were compared with 10 studies of control patients of matching ages. Visual interpretation of images and renograms as well as semiquantitative analyses were performed. Variables compared were size of kidneys, time of peak and one-half peak activities, residual (or retained) cortical activity at 20 min, ratio of cortical activity at 2.5-20 min, and ratio of kidney activity to kidney plus background activity at 2 min. The results of MAG3 renal studies were also compared with laboratory data pertaining to creatinine clearance in all patients and with sonography in 17 patients. RESULTS: In most patients with HIVN (18/21), the kidneys were larger than normal, with a diffuse parenchymal dysfunction (decreased uptake, slow processing, and increased retention of activity) and flat renograms, findings similar to those observed in other diffuse parenchymal diseases. In all patients with HIVN, semiquantitative analysis (paired t test) showed statistically significant differences from control patients for all variables. On ANOVA, a statistically significant correlation was found between most scintigraphic parameters and the severity of renal impairment. Of the 17 concurrent sonographic studies in HIVN patients, 7 showed no abnormalities, whereas the results of scintigraphy were abnormal. CONCLUSION: Diuretic MAG3 scintirenography shows nonspecific diffuse parenchymal dysfunction in pediatric patients with HIVN. Such dysfunction may provide corroborative evidence of HIVN and should be recognized when the test is performed for standard indications. Further work is necessary to prove that the test has indeed the high sensitivity and good correlation with the seventy of HIVN suggested in this population; the test may be useful to follow up the progression of disease and the effect of treatment.

Massive hematuria following percutaneous biopsy of renal allograft. Successful control by selective embolization.

We report on a patient who underwent a percutaneous needle biopsy of a renal allograft for evaluation of compromised function. Gross hematuria occurred immediately and persisted for three weeks, interrupted only by long intervals of anuria due to obstruction by a clot. The bleeding was controlled successfully by selective transcatheter embolization with a coli and an absorbable gelatin sponge (Gelfoam). The techniques and complications of allograft biopsy procedures are reviewed, and the management of hematuria occurring after a percutaneous needle biopsy is discussed. A percutaneous needle biopsy is the preferred method of sampling the transplanted kidney, with an adequate specimen obtained in 96% of cases. Hematuria, that has been reported to complicate 7% of percutaneous biopsy procedures, is usually transient, and only rarely is intervention required. Angiographically directed selective embolization is an effective technique for controlling massive or prolonged urinary hemorrhage after renal allograft biopsy.

Effect of dialysate composition on the lipid response to L-carnitine supplementation.

Cumulative carnitine losses through dialysis membranes may worsen hyperlipidemia during long-term hemodialysis. However, carnitine supplementation has not shown a consistent beneficial response in hyperlipidemia. We have compared in a double-blind, cross-over study the effect of dialysate buffer composition (acetate or bicarbonate) on the serum lipid response to L-carnitine supplementation during hemodialysis. We studied nine patients (mean age, 19 years; range, 14 to 23) with hyperlipidemia undergoing maintenance hemodialysis. Plasma levels of carnitines and lipids, including total and HDL cholesterol (HDL-C) and triglycerides (TG), were measured at baseline and monthly intervals after receiving 2 grams of L-carnitine or placebo added to dialysis bath for three months. One month of carnitine supplementation in acetate hemodialysis significantly reduced plasma TG (230 +/- 95 to 136 +/- 20 mg/dl; P less than 0.05) and elevated HDL-C (50 +/- 12 to 71 +/- 26 mg/dl; P less than 0.05). However, this effect was no longer observed at the end of three months of supplementation. Bicarbonate hemodialysis had lower baseline TG values, but carnitine supplementation did not modify plasma lipids (TG:144 +/- 87 to 158 +/- 115 mg/dl; HDL-C:50 +/- 23 to 50 +/- 19 mg/dl). Both groups had a significant increase in plasma carnitine levels after carnitine supplementation. These results suggest that bicarbonate hemodialysis may add a protective effect in hyperlipidemia by reducing requirements of carnitine supplementation. On the other hand, carnitine supplementation should be considered in patients with hyperlipidemia undergoing acetate hemodialysis. The observed difference in response between acetate and bicarbonate hemodialysis may be due to enhanced formation of acetyl-CoA and fatty acid synthesis during acetate hemodialysis.

Effects of amino acid additives during hemodialysis of children.

The intradialytic losses into the dialysate of free amino acids (AA) and alpha-amino nitrogen were determined during the dialysis of three children. Variations in plasma AA were determined pre- and postdialysis. The effect of these losses with the addition of an Abbott General Amino Acid Mixture to the dialysate in concentrations of 8.5, 17, and 34 mg/100 ml was studied. The major determinant of AA losses was the plasma concentration of the AA before beginning the dialysis treatment. Dialysance of individual AA varied inversely with their molecular weights. A zero flux of alpha-amino nitrogen occurred at a derived concentration of 22 mg/100 ml of the AA additive in the dialysate. Plasma concentrations of nonessential amino acids were little affected by the dialysate additive. In contrast, total essential amino acid nitrogen which fell during baseline dialyses showed significant improvement when the AA solution was added to the dialysate. This study suggests that the addition of AA to the dialysate bath may be effective in decreasing AA nitrogen losses during dialysis.

Total parenteral nutrition in anuric children.

Six children who were anuric, intolerant of oral nutrition and depleted of body protein, were treated with total parenteral nutrition. Nitrogen utilization was studied during infusion of dextrose alone and dextrose with essential amino acids. An increase in non-protein (glucose) calories from 20 to 70 kcal/kg/day progressively reduced body protein catabolism; nitrogen balance became less negative. When essential amino nitrogen was added, net urea production decreased; protein nitrogen balance became positive. It is concluded that total parenteral nutrition with essential amino acids improves the nutritional status of severely ill, anuric children, and may influence recovery.

The effect of energy and nitrogen intake upon urea production in children with uremia and undernutrition.

Children with severe uremia who had anorexia were observed in a clinical study center where dietary energy and nitrogen intake could be compared with urea nitrogen production (UNPr). The children received a supplement of dextrose and amino acids at night, ate a self-selected diet and were encouraged to use carbohydrate supplements. Energy intake varied from 22 to 110 kcal/kg/day and nitrogen intake from 105 to 323 mg/kg/day. UNPr was reciprocally related to energy intake. Nitrogen intake minus UNPr, an index of nitrogen balance, was positively related to energy intake. UNPr was not related to nitrogen intake. Nitrogen intake (NI) and NI-UNPr were correlated and the slope of the regression was 1.15. We inferred from the data that low energy intakes (less than 60 kcal/kg/day) were associated with catabolic losses of body protein. Intakes above that level were associated with a low and stable rate of UNPr. The level of energy and nitrogen intake within the range observed limited the rate of nitrogen retention. Once maintenance requirements for energy and nitrogen were satisfied, the efficiency with which nitrogen was used for net protein synthesis was very high.

Fungal peritonitis in pediatric patients.

Fungal peritonitis (FP) is a rare complication of peritoneal dialysis (PD). Although treatment with fluconazole (FCZ) has improved catheter survival and preservation of the peritoneal membrane, FP still carries a high morbidity and mortality in pediatrics. High-risk factors for FP include previous usage of systemic antibiotics and recurrent bacterial peritonitis. A prospective experience in the treatment of FP was conducted at the University of Miami/Jackson Children's Hospital from 1992 to 1997. All patients received either oral or intravenous loading dose of FCZ (5-7 mg/kg) followed by intraperitoneal (i.p.) FCZ (75 mg/L). Amphotericin B (amp B) was added when clinical sepsis was present. A total of 6 patients had FP (all Candida sp.; mean age: 6 years). Two of these patients were neonates with Tenckhoff-catheter placement at less than 1 week of age. Five patients achieved sterilization of the peritoneal fluid. One patient required catheter removal (C. tropicalis). The 2 neonates were infection free for 29 and 41 days, respectively, but both died of superimposed bacterial sepsis. The remaining 4 patients survived and completed 6 weeks of FCZ treatment. Two have had preservation of the peritoneal membrane for more than 1 year. The other 2 were switched to hemodialysis. We conclude that FCZ is an effective treatment for fungal peritonitis in pediatric patients. Adjunct therapy with amp B is usually necessary if sepsis is present. Although eradication of the fungus is possible in a majority of cases, neonates and immunocompromised hosts remain at high risk for morbidity and mortality.

Remission of relapsing childhood nephrotic syndrome with mycophenolate mofetil.

We report a 21-year-old male with childhood-onset familial nephrotic syndrome and frequent relapses who manifested toxicity or treatment resistance to corticosteroids, cyclophosphamide, cyclosporin-A, and tacrolimus. Monotherapy with mycophenolate mofetil (MMF) resulted in maintenance of clinical remission for 14 months without noticeable toxicity, while allowing resolution of steroid-induced side effects. Our observation suggests that MMF may be useful in maintaining remission in nephrotic patients who manifest toxicity to standard immunosuppressive agents.

Optical optimization of the inversion of convolution products f = g * u when the unknown u is space-limited.

For several convolution equations such as f = g * u, the support domain of the unknown being bounded, optical resolution becomes difficult as soon as f does not decrease quickly enough at infinity. When the approximation g(x - y) asymptotically equal to g(x) is good for |x| >> |Y|, we are able to correct by interferometric means the necessary truncation of the f information. In particular, the proposed correction is interesting for the optical treatment of the primary data used in transaxial tomography.

Urea synthesis in moderate experimental uremia.

Urea synthesis rates (USR) were examined in relation to individual variations in energy and nitrogen intakes. Rats made uremic by 7/8 nephrectomy (N = 12) were pairfed with sham-operated controls (N = 11) and divided into two diet groups: diet 1 (4 kcal/g, 18% protein) and diet 2 (4 kcal/g, 42% protein). Nitrogen intake (NI) and energy intake (EI) were varied according to the quantity of feed given and the addition of a nonprotein gavage supplement. The USR was determined by 14C-urea excretion during four periods when EI ranged from 20 to 50 kcal/day and NI ranged from 150 to 675 mg/day. Although USR did not correlate directly with either dietary protein or energy, the percent of protein-derived calories allowed the prediction of USR from NI. Fractional urea synthesis was not related to NI but rather to total EI. The nonlinear regression described a critical EI of 30 kcal/day below which USR increased to 75% of the NI. USR was not different between control and uremic animals. These data suggest an advantage in maintaining an appropriate protein: energy ratio (2.5 g per 100 kcal) to minimize the fractional urea synthesis. The utilization of nitrogen at different levels of protein and energy intake was not altered by the state of experimental uremia.

Growth of uremic infants on forced feeding regimens.

Infants born with congenital renal insufficiency generally grow poorly during the first years of life and incur a height deficit that is rarely regained. Actual energy and protein requirements have not been determined for these children. In 12 infants with creatinine clearances less than 70 ml/min per 1.73 m2, growth and nutrient intakes were monitored during the first 2 years of life. Forced feeding regimens after 3 months of age, including gastrostomy in 3 patients, were necessary to maintain energy intakes near 100% of the recommended dietary allowance (RDA). Protein intakes averaged in excess of 140% RDA. Linear growth did not correlate with either energy or protein intakes, suggesting that neither was a limiting factor to growth. Length velocity standard deviation score (LV-SDS) did not correlate with degree of renal insufficiency at any age, but average LV-SDS did relate significantly and inversely to C-terminal parathyroid hormone (PTH) levels. Growth parameters, including LV-SDS and weight velocity SDS (WV-SDS) were lowest at 6 months of age. Weight and length SDS followed with a maximum decline at 12 months of age. While weight for length SDS remained normal and WV-SDS showed recovery during the 2nd year, LV-SDS remained negative. Length SDS stabilized near--2 SDS. In summary, these data suggest that the major height deficit in infants with renal insufficiency is incurred during the first 6 months of life. Ponderal indices suggested that very early nutritional deficits may have been a primary contributor to subsequent height deficits.(ABSTRACT TRUNCATED AT 250 WORDS)