Single nucleotide polymorphisms in C-reactive protein (CRP) predict response to adjunctive celecoxib treatment of resistant bipolar depression.

Background: Affective illness has been associated with a proinflammatory state, and it is generally accepted that the immune system plays a key role in the pathophysiology of mood disorders. Since inflammatory biomarkers are elevated in bipolar disorder, anti-inflammatory combination therapies may enhance response and reverse treatment resistance. Purpose: In the present study we investigated the possible impact of single nucleotide polymorphisms (SNPs) within the CRP gene on CRP blood levels, treatment response and level-of-stress perception in our cohort of treatment-resistant bipolar-depressed patients receiving escitalopram and celecoxib, or escitalopram and placebo, as previously reported (Halaris et al., 2020). Methods: Study design, clinical findings, and CRP blood levels have been reported previously (Halaris et al., 2020; Edberg et al., 2018). In this follow-up study we extracted DNA from blood cells collected at baseline. Genome-wide genotyping was performed for all subjects using the Infinium Multi-Ethnic Global-8 v1.0 Kit. Based on reports in the literature indicating possible associations with psychiatric conditions, ten previously reported CRP gene polymorphisms were evaluated in a preliminary analysis. We focused on rs3093059 and rs3093077 were in complete LD. Carriers were defined as those possessing at least one C allele for rs3093059, or at least one G allele for rs3093077. Additionally, we determined blood levels of the medications administered. Results: Non-carriers of rs3093059 and rs3093077 had significantly lower baseline CRP blood levels than carriers (p = 0.03). Increased rates of HAM-D17 response (p = 0.21) and remission (p = 0.13) and lower PSS-14 scores (p = 0.13) were observed in non-carriers among subjects receiving celecoxib but they did not reach statistical significance. When examining all subjects, nominally significant associations between carrier-status and remission (p = 0.04) and PSS-14 scores (p = 0.04) were observed after correcting for treatment arm. Non-carriers receiving celecoxib had the highest rates of response and remission, and the lowest stress scores. Conclusions: Carriers of the CRP SNPs may have higher baseline CRP levels, although non-carriers appear to benefit more from celecoxib co-therapy. Determination of the carrier status in conjunction with pretreatment blood CRP level measurement may contribute to personalized psychiatric practice, but replication of the present findings is needed.

Pharmacogenomic Profiling of Pediatric Patients on Psychotropic Medications in an Emergency Department.

OBJECTIVE: The aim of the study was to evaluate the ability of a combinatorial pharmacogenomic test to predict medication blood levels and relative clinical improvements in a selected pediatric population. METHODS: This study enrolled patients between ages 3 to 18 years who presented to a pediatric emergency department with acute psychiatric, behavioral, or mental health crisis and/or concerns, and had previously been prescribed psychotropic medications. Patients received combinatorial pharmacogenomic testing with medications categorized according to gene-drug interactions (GDIs); medications with a GDI were considered "incongruent," and medications without a GDI were considered "congruent." Blood levels for escitalopram, fluoxetine, aripiprazole, and clonidine were evaluated according to level of GDI. Relative clinical improvements in response to the prescribed psychotropic medications were measured using a parent-rated Clinical Global Impression of Improvement (CGI-I) assessment, where lower scores corresponded with greater improvement. RESULTS: Of the 100 patients enrolled, 73% reported taking ≥1 incongruent medication. There was no significant difference in CGI-I scores between patients prescribed congruent versus incongruent medications (3.37 vs 3.68, P = 0.343). Among patients who presented for depression or suicidal ideation, those prescribed congruent medications had significantly lower CGI-I scores compared with those taking incongruent medications ( P = 0.036 for depression, P = 0.018 for suicidal ideation). There was a significant association between medication GDI and blood levels for aripiprazole (n = 15, P = 0.01) and escitalopram (n = 10, P = 0.01). CONCLUSIONS: Our preliminary findings suggest that combinatorial pharmacogenomic testing can predict medication blood levels and relative outcomes based on medication congruency in children presenting to an emergency department with acute psychiatric/behavioral crises. Additional studies will be needed to confirm these findings.

Characterisation of seven medications approved for attention-deficit/hyperactivity disorder using in vitro models of hepatic metabolism.

The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood.In vitro studies using cryopreserved, plated human hepatocytes (cPHHs) and pooled human liver microsomes (HLMs) were performed to more thoroughly characterise the metabolism of several ADHD medications.The use of enzyme-specific chemical inhibitors indicated a role for CYP2D6 in atomoxetine (ATX) metabolism, and roles for CYP3A4/5 in guanfacine (GUA) metabolism.The 4-hydroxy-atomoxetine and N-desmethyl-atomoxetine pathways represented 98.4% and 1.5% of ATX metabolism in cPHHs, respectively. The 3-OH-guanfacine pathway represented at least 2.6% of GUA metabolism in cPHHs, and 71% in HLMs.The major metabolising enzyme for methylphenidate (MPH) and dexmethylphenidate (dMPH) could not be identified using these methods because these compounds were too unstable. Hydrolysis of these medications was spontaneous and did not require the presence of protein to occur.Clonidine (CLD), amphetamine (AMPH), and dextroamphetamine (dAMPH) did not deplete substantially in cPHHs nor HLMs, suggesting that these compounds may not undergo considerable hepatic metabolism. The major circulating metabolites of AMPH and dAMPH (benzoic acid and hippuric acid) were not observed in either system, and therefore could not be characterised. Additionally, inhibition experiments suggested a very minimal role for CYP2D6 in CLD and AMPH metabolism.

Review and Meta-analysis on the Impact of the ADRA2A Variant rs1800544 on Methylphenidate Outcomes in Attention-Deficit/Hyperactivity Disorder.

Background: Methylphenidate is among the most prescribed medications for treating attention-deficit/hyperactivity disorder (ADHD). However, nearly half of pediatric patients with ADHD do not respond to methylphenidate treatment. Pharmacogenetic testing can aid in identifying patients for whom methylphenidate is unlikely to be safe or effective, leading to improved methylphenidate outcomes and increased use of alternative treatment options for ADHD. This article aimed to summarize findings from studies of the ADRA2A gene variant, rs1800544, and its association with methylphenidate outcomes in ADHD. Methods: We systematically reviewed and meta-analyzed available literature on the impact of rs1800544 on methylphenidate outcomes in ADHD. Results: Fourteen studies met inclusion criteria for review, 9 of which were eligible for meta-analysis. The included studies compared methylphenidate outcomes in patients with ADHD categorized by rs1800544 genotype. G-allele carriers experienced significantly greater improvements in ADHD symptom scores (Swanson, Nolan, and Pelham Version-IV Scale or ADHD Rating Scale-IV) relative to noncarriers (odds ratio 3.08, 95% confidence interval 1.71-5.56, p = .0002) and greater response rates as measured by a ≥50% improvement in symptom scores (odds ratio 2.68, 95% confidence interval 1.23-5.82, p = .01); no significant difference in response rate as measured by Clinical Global Impressions score ≤2 was found. Stouffer's z-score method showed significant improvement across all methylphenidate outcomes in G-allele carriers relative to noncarriers (z = 3.03, p = .002). Conclusions: These findings suggest that carriers of rs1800544 may have improved ADHD outcomes following methylphenidate treatment. However, the extent to which these improvements are clinically impactful remain unclear. Additional studies are required to determine if rs1800544 carrier status should influence clinical recommendations for treatment of ADHD symptoms.

Pharmacogenomics of Clozapine-induced agranulocytosis: a systematic review and meta-analysis.

Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20-15.80, pcorrected = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation.

Combinatorial pharmacogenomic algorithm is predictive of sertraline metabolism in patients with major depressive disorder.

Pharmacogenomic testing can be used to guide medication selection in patients with major depressive disorder (MDD). Currently, there is no consensus on which gene or genes to consider in medication management. Here, we assessed the clinical validity of the combinatorial pharmacogenomic algorithm to predict sertraline blood levels in a subset of patients enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial. Patients who reported taking sertraline within ≤2 weeks of the screening blood draw were included. All patients received combinatorial pharmacogenomic testing, which included a weighted assessment of individual phenotypes for multiple pharmacokinetic genes relevant for sertraline (CYP2C19, CYP2B6, and CYP3A4). Sertraline blood levels were compared between phenotypes based on: 1) the pharmacokinetic portion of the combinatorial pharmacogenomic algorithm, and 2) individual genes. When evaluated separately, individual genes (for CYP2C19 and CYP2B6) and the combinatorial algorithm were significant predictors of sertraline blood levels. However, in multivariate analyses that included individual genes and the combinatorial pharmacogenomic algorithm, only the combinatorial pharmacogenomic algorithm remained a significant predictor of sertraline blood levels. These findings support the clinical validity of the combinatorial pharmacogenomic algorithm, in that it is a superior predictor of sertraline blood levels compared to individual genes.

Clinical validation of combinatorial pharmacogenomic testing and single-gene guidelines in predicting psychotropic medication blood levels and clinical outcomes in patients with depression.

We evaluated the clinical validity of a combinatorial pharmacogenomic test and single-gene Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines against patient outcomes and medication blood levels to assess their ability to inform prescribing in major depressive disorder (MDD). This is a secondary analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) randomized-controlled trial, which included patients with a diagnosis of MDD, and ≥1 prior medication failure. The ability to predict increased/decreased medication metabolism was validated against blood levels at screening (adjusted for age, sex, smoking status). The ability of predicted gene-drug interactions (pharmacogenomic test) or therapeutic recommendations (single-gene guidelines) to predict patient outcomes was validated against week 8 outcomes (17-item Hamilton Depression Rating Scale; symptom improvement, response, remission). Analyses were performed for patients taking any eligible medication (outcomes N=1,022, blood levels N=1,034) and the subset taking medications with single-gene guidelines (outcomes N=584, blood levels N=372). The combinatorial pharmacogenomic test was the only significant predictor of patient outcomes. Both the combinatorial pharmacogenomic test and single-gene guidelines were significant predictors of blood levels for all medications when evaluated separately; however, only the combinatorial pharmacogenomic test remained significant when both were included in the multivariate model. There were no substantial differences when all medications were evaluated or for the subset with single-gene guidelines. Overall, this evaluation of clinical validity demonstrates that the combinatorial pharmacogenomic test was a superior predictor of patient outcomes and medication blood levels when compared with guidelines based on individual genes.

Combinatorial Pharmacogenomic Algorithm is Predictive of Citalopram and Escitalopram Metabolism in Patients with Major Depressive Disorder.

Pharmacogenomic tests used to guide clinical treatment for major depressive disorder (MDD) must be thoroughly validated. One important assessment of validity is the ability to predict medication blood levels, which reflect altered metabolism. Historically, the metabolic impact of individual genes has been evaluated; however, we now know that multiple genes are often involved in medication metabolism. Here, we evaluated the ability of individual pharmacokinetic genes (CYP2C19, CYP2D6, CYP3A4) and a combinatorial pharmacogenomic test (GeneSight Psychotropic®; weighted assessment of all three genes) to predict citalopram/escitalopram blood levels in patients with MDD. Patients from the Genomics Used to Improve DEpression Decisions (GUIDED) trial who were taking citalopram/escitalopram at screening and had available blood level data were included (N=191). In multivariate analysis of the individual genes and combinatorial pharmacogenomic test separately (adjusted for age, smoking status), the F statistic for the combinatorial pharmacogenomic test was 1.7 to 2.9-times higher than the individual genes, showing that it explained more variance in citalopram/escitalopram blood levels. In multivariate analysis of the individual genes and combinatorial pharmacogenomic test together, only the combinatorial pharmacogenomic test remained significant. Overall, this demonstrates that the combinatorial pharmacogenomic test was a superior predictor of citalopram/escitalopram blood levels compared to individual genes.

The Toll pathway inhibits tissue growth and regulates cell fitness in an infection-dependent manner.

The Toll pathway regulates the cellular response to infection via the transcriptional upregulation of antimicrobial peptides. In Drosophila, apart from its role in innate immunity, this pathway has also been reported to be important for the elimination of loser cells in a process referred to as cell competition, which can be locally triggered by secreted factors released from winner cells. In this work, we provide evidence that the inhibition of Toll signaling not only increases the fitness of loser cells, but also bestows a clonal growth advantage on wild-type cells. We further demonstrate that this growth advantage depends on basal infection levels since it is no longer present under axenic conditions but exacerbated upon intense pathogen exposure. Thus, the Toll pathway functions as a fine-tuned pro-apoptotic and anti-proliferative regulator, underlining the existence of a trade-off between innate immunity and growth during development.

The Drosophila MAST kinase Drop out is required to initiate membrane compartmentalisation during cellularisation and regulates dynein-based transport.

Cellularisation of the Drosophila syncytial blastoderm embryo into the polarised blastoderm epithelium provides an excellent model with which to determine how cortical plasma membrane asymmetry is generated during development. Many components of the molecular machinery driving cellularisation have been identified, but cell signalling events acting at the onset of membrane asymmetry are poorly understood. Here we show that mutations in drop out (dop) disturb the segregation of membrane cortical compartments and the clustering of E-cadherin into basal adherens junctions in early cellularisation. dop is required for normal furrow formation and controls the tight localisation of furrow canal proteins and the formation of F-actin foci at the incipient furrows. We show that dop encodes the single Drosophila homologue of microtubule-associated Ser/Thr (MAST) kinases. dop interacts genetically with components of the dynein/dynactin complex and promotes dynein-dependent transport in the embryo. Loss of dop function reduces phosphorylation of Dynein intermediate chain, suggesting that dop is involved in regulating cytoplasmic dynein activity through direct or indirect mechanisms. These data suggest that Dop impinges upon the initiation of furrow formation through developmental regulation of cytoplasmic dynein.

Clathrin heavy chain plays multiple roles in polarizing the Drosophila oocyte downstream of Bic-D.

Bicaudal-D (Bic-D), Egalitarian (Egl), microtubules and their motors form a transport machinery that localizes a remarkable diversity of mRNAs to specific cellular regions during oogenesis and embryogenesis. Bic-D family proteins also promote dynein-dependent transport of Golgi vesicles, lipid droplets, synaptic vesicles and nuclei. However, the transport of these different cargoes is still poorly understood. We searched for novel proteins that either mediate Bic-D-dependent transport processes or are transported by them. Clathrin heavy chain (Chc) co-immunopurifies with Bic-D in embryos and ovaries, and a fraction of Chc colocalizes with Bic-D. Both proteins control posterior patterning of the Drosophila oocyte and endocytosis. Although the role of Chc in endocytosis is well established, our results show that Bic-D is also needed for the elevated endocytic activity at the posterior of the oocyte. Apart from affecting endocytosis indirectly by its role in osk mRNA localization, Bic-D is also required to transport Chc mRNA into the oocyte and for transport and proper localization of Chc protein to the oocyte cortex, pointing to an additional, more direct role of Bic-D in the endocytic pathway. Furthermore, similar to Bic-D, Chc also contributes to proper localization of osk mRNA and to oocyte growth. However, in contrast to other endocytic components and factors of the endocytic recycling pathway, such as Rabenosyn-5 (Rbsn-5) and Rab11, Chc is needed during early stages of oogenesis (from stage 6 onwards) to localize osk mRNA correctly. Moreover, we also uncovered a novel, presumably endocytosis-independent, role of Chc in the establishment of microtubule polarity in stage 6 oocytes.

Splenic infarction: an update on William Osler's observations.

BACKGROUND: Osler taught that splenic infarction presents with left upper abdominal quadrant pain, tenderness and swelling accompanied by a peritoneal friction rub. Splenic infarction is classically associated with bacterial endocarditis and sickle cell disease. OBJECTIVES: To describe the contemporary experience of splenic infarction. METHODS: We conducted a chart review of inpatients diagnosed with splenic infarction in a Jerusalem hospital between 1990 and 2003. RESULTS: We identified 26 cases with a mean age of 52 years. Common causes were hematologic malignancy (six cases) and intracardiac thrombus (five cases). Only three cases were associated with bacterial endocarditis. In 21 cases the splenic infarction brought a previously undiagnosed underlying disease to attention. Only half the subjects complained of localized left-sided abdominal pain, 36% had left-sided abdominal tenderness; 31% had no signs or symptoms localized to the splenic area, 36% had fever, 56% had leukocytosis and 71% had elevated lactate dehydrogenase levels. One splenectomy was performed and all patients survived to discharge. A post hoc analysis demonstrated that single infarcts were more likely to be associated with fever (20% vs. 63%, p < 0.05) and leukocytosis (75% vs. 33%, P = 0.06) CONCLUSIONS: The clinical presentation of splenic infarction in the modern era differs greatly from the classical teaching, regarding etiology, signs and symptoms. In patients with unexplained splenic infarction, investigation frequently uncovers a new underlying diagnosis.

Natural variation of the amino-terminal glutamine-rich domain in Drosophila argonaute2 is not associated with developmental defects.

The Drosophila argonaute2 (ago2) gene plays a major role in siRNA mediated RNA silencing pathways. Unlike mammalian Argonaute proteins, the Drosophila protein has an unusual amino-terminal domain made up largely of multiple copies of glutamine-rich repeats (GRRs). We report here that the ago2 locus produces an alternative transcript that encodes a putative short isoform without this amino-terminal domain. Several ago2 mutations previously reported to be null alleles only abolish expression of the long, GRR-containing isoform. Analysis of drop out (dop) mutations had previously suggested that variations in GRR copy number result in defects in RNAi and embryonic development. However, we find that dop mutations genetically complement transcript-null alleles of ago2 and that ago2 alleles with variant GRR copy numbers support normal development. In addition, we show that the assembly of the central RNAi machinery, the RISC (RNA induced silencing complex), is unimpaired in embryos when GRR copy number is altered. In fact, we find that GRR copy number is highly variable in natural D. melanogaster populations as well as in laboratory strains. Finally, while many other insects share an extensive, glutamine-rich Ago2 amino-terminal domain, its primary sequence varies drastically between species. Our data indicate that GRR variation does not modulate an essential function of Ago2 and that the amino-terminal domain of Ago2 is subject to rapid evolution.

Does renal function remain stable after puberty in children with prenatal hydronephrosis and improved renal function after pyeloplasty?

PURPOSE: We evaluated whether improved renal function after pyeloplasty for prenatal ureteropelvic junction obstruction persisted through puberty. MATERIALS AND METHODS: A total of 441 males and 137 females with a prenatal diagnosis of hydronephrosis that led to the postnatal diagnosis of ureteropelvic junction obstruction were followed at our department from 1989 to 2008. Of the patients we reviewed the records of 49 who underwent surgery between 1989 and 1992, and completed puberty. Hydronephrosis was on the right side in 18 children (36.7%) and on the left side in 31 (63.3%). According to Society for Fetal Urology classification at first presentation postnatal hydronephrosis was grades 2 to 4 in 18 (36.7%), 23 (46.9%) and 8 children (16.3%), respectively. Initially relative renal function was more than 40% in 18 children (36.7%), between 30% and 40% in 24 (49%), and less than 30% in 7 (14.3%). Preoperatively mean +/- SEM relative renal function was 36.6% +/- 7.8% in all reviewed patients. RESULTS: Improvement in hydronephrosis was confirmed in all patients. This remained stable during and after puberty in all except 2 patients, who required endopyelotomy 8 and 10 years following pyeloplasty, respectively, due to deterioration in hydronephrosis without a decrease in relative renal function. They showed improvement in the washout curve pattern after the procedure. Pyeloplasty led to increased relative renal function in the short term from 36.7% +/- 1.2% before surgery to 41.2% +/- 0.91% in all patients (p <0.001). It remained stable at 43.2% +/- 0.75% after puberty in all reviewed patients. CONCLUSIONS: To our knowledge our data show for the first time that successful pyeloplasty after the prenatal diagnosis of ureteropelvic junction obstruction is associated with improved renal function throughout puberty.

Long-term follow up of antenatally diagnosed megaureters.

AIM: We have retrospectively evaluated our 17 years of experience with antenatal diagnosis of hydronephrosis that led to postnatal diagnosis of megaureter, and tried to determine criteria for surgery. PATIENTS AND METHODS: Seventy-nine children (64 boys and 15 girls) with antenatal diagnosis of hydronephrosis that led to postnatal diagnosis of megaureter were followed conservatively over a period of 18 years (1988-2006). Right ureterohydronephrosis was seen in 23 children, left in 30 and 26 had bilateral ureterohydronephrosis comprising a total of 105 renal units (RU). According to SFU (Society for Fetal Urology) classification, 8 RU were grade 1, 57 grade 2, 29 grade 3 and 11 grade 4 postnatal hydronephrosis. Mean ureteral diameter was 1.2 cm. Relative renal function was in 82 RU more than 40%, in 18 RU 30-40% and in 5 RU less than 30%. Functional deterioration of the hydronephrotic kidney of more than 5%, worsening of hydronephrosis (SFU upgrade) and a persistent obstructive curve on radionuclide scans were the main indications for surgery. RESULTS: Twenty-five (31%) children required surgical correction. Mean age at surgery was 14.3 months (range 3-60). Univariate analysis revealed that gender and side of obstruction are not significant predictive factors for surgery SFU grade 3-4 of postnatal hydronephrosis, Relative renal function less than 30% and ureteral diameter more than 1.33 cm were significant independent risk factors leading to reimplantation. CONCLUSIONS: Only 30% of children with antenatal diagnosis of megaureter required surgical correction. Renal function less than 30%, grades 3 and 4 hydronephrosis, and ureteric diameter more than 1.33 cm are statistically significant and independent predictive factors for surgery.

Preoperative lymphatic mapping does not predict the number of axillary sentinel lymph nodes identified during surgery in breast cancer patients.

Sentinel lymph node biopsy (SLNB) has become the standard of care in most centers for axillary staging in patients with early breast cancer. Multiple radioactive nodes are often identified at surgery. The finding of multiple sentinel lymph nodes (SLNs) has been shown to be associated with lower rates of false-negative results in the SLNB procedure, hence the importance of removing and examining all SLNs. Often preoperative lymphatic mapping (PLM) is performed prior to surgery. In this study we examined whether the exact number of SLNs identified during surgery can be accurately predicted by PLM. During the years 2001-2004, 155 patients underwent both PLM and a SLNB in our breast unit. During surgery, an attempt was made to remove all radioactive nodes. The number of axillary radioactive foci found on PLM was compared with the number of radioactive nodes identified during surgery. The average number of sentinel nodes harvested was 2.3 (range 1-9). The average number of radioactive foci identified on PLM was 1.8 (range 0-5). Of the 155 patients, the number of sentinel nodes retrieved in surgery was greater than that found in preoperative mapping in 65 patients (41.9%), equal to that found in preoperative mapping in 60 patients (38.7%), and less than that found in preoperative mapping in 30 patients (19.4%). Thus in most patients, the number of SLNs found on PLM did not reflect the number of SLNs found intraoperatively. Therefore, even when the number of nodes identified on PLM has been reached in surgery, a meticulous search for additional nodes should still be carried out. The number of hot spots in preoperative mapping should serve as a rough indicator of the smallest number of nodes the surgeon should attempt to resect, but not the exact number of nodes expected to be found.

Conservative treatment of ureteropelvic junction obstruction in children with antenatal diagnosis of hydronephrosis: lessons learned after 16 years of follow-up.

OBJECTIVES: We attempted to define predictive factors for surgery in children with antenatal diagnosis of hydronephrosis that led to postnatal diagnosis of ureteropelvic junction (UPJ) obstruction. METHODS: We retrospectively evaluated our 16-yr experience (1988-2003) with 343 children (260 male and 83 female) with antenatal diagnosis of hydronephrosis that led to postnatal diagnosis of UPJ obstruction and who were followed conservatively. Right-sided hydronephrosis was present in 110 and left-sided in 233 children. According to the Society for Fetal Urology (SFU) classification none had grade 0 of postnatal hydronephrosis, 20 had grade 1, 118 grade 2, 147 grade 3, and the remaining 58 children grade 4 postnatal hydronephrosis. Relative renal function (RRF) on radionuclide scans revealed 235 children with RRF>40%, 68 with RRF between 30% and 40%, and 40 patients with RRF<30%. Renal function deterioration >5% was the main indication for surgery. Commercially available software GraphPad Prism 4.0 (GraphPad prism, Prism 4 for Windows, version 4) using the Fisher exact test was used for statistical evaluation. RESULTS: Surgical correction was needed in 179 children (52.2%) during the course of conservative management. The average age at surgery was 10.6 mo (range, 1 mo to 7 yr). Of those, 50% underwent surgery during the first 2 yr of life and the majority of the remaining patients underwent surgery between the 2 and 4 yr of age; only two patients required surgery later on. Univariate analysis revealed that child sex, side of hydronephrosis, and SFU grade of prenatal hydronephrosis were not significant predictive factors for surgery. However, SFU grade 3-4 of postnatal hydronephrosis (p<0.0001; odds ratio, 0.06281) and RRF<40% (p<0.0001; odds ratio, 0.1022) were significant independent risk factors for surgery. CONCLUSION: In contrast with previous publications by others and by us these data show that >50% of children with antenatal diagnosis of UPJ obstruction in this series required surgical correction while on conservative protocol. SFU grade 3-4 of postnatal hydronephrosis and RRF<40% are significant independent predictive factors for surgery.

Clinical implications of contralateral axillary sentinel lymph nodes.

Extra-axillary sentinel lymph nodes can only be detected if radioactive tracer is used and pre-operative scans are carried out. The presence of metastatic sentinel lymph nodes in most extra-axillary sites will upstage patients if the ipsilateral axillary sentinel lymph node is normal. Paradoxically, the presence of metastatic sentinel lymph nodes in the contralateral axilla has the potential to prevent upstaging to stage IV, but only if detected as a sentinel node at the initial surgery rather than as a systemic recurrence at some later time. We describe a case of bilateral axillary sentinel lymph nodes detected by pre-operative lymphoscintigraphy in a patient with a medial quadrant breast cancer and discuss the possible implications of such a finding.