Biomedical subjects

K Taylor

Publications and source records attributed to K Taylor.

At least 19 recordsLinked to original sources

PubMed2025

Identification and Validation of Novel Combinatorial Genetic Risk Factors for Endometriosis across Multiple UK and US Patient Cohorts.

BACKGROUND: Endometriosis affects about 10% of women usually of reproductive age. It often has severe negative impacts on patients' quality of life, but the average time to a definitive diagnosis remains 7-9 years, and there are few effective therapeutic options. Relatively little is known about the genetic drivers of the disease even though its heritability is fairly high. A recent large genome wide association study (GWAS) meta-analysis identified 42 genomic loci associated with risk of endometriosis, but together these explain only 5% of disease variance. METHODS: We used the PrecisionLife® combinatorial analytics platform to identify multi-SNP disease signatures significantly associated with endometriosis in a white European UK Biobank (UKB) cohort. We assessed the reproducibility of these multi-SNP disease signatures as well as 35 of the 42 meta-GWAS SNPs in a multi-ancestry American endometriosis cohort from All of Us (AoU) after controlling for population structure. RESULTS: We identified 1,709 disease signatures, comprising 2,957 unique SNPs in combinations of 2-5 SNPs, that were associated with increased prevalence of endometriosis in UKB. Pathways enriched in the disease signatures included cell adhesion, proliferation and migration, cytoskeleton remodeling, angiogenesis as well as biological processes involved in fibrosis and neuropathic pain.We observed a significant enrichment of these signatures (58-88%, p<0.04) that are also positively associated with endometriosis in the AoU cohort, including one 2-SNP signature that is individually significant. Reproducibility rates were greatest for higher frequency signatures, ranging from 80-88% for signatures with greater than 9% frequency (p<0.01) in AoU. Encouragingly, the disease signatures also show high reproducibility rates in non-white European AoU sub-cohorts (66-76%, p<0.04 for signatures with greater than 4% frequency).A total of 195 unique SNPs mapping to 98 genes were identified in the high frequency reproducing signatures (>9%). Of these, 7 genes were previously identified in the endometriosis meta-GWAS study and 16 genes have a previous association with endometriosis. 75 novel genes were identified in this study.We characterized 9 novel genes that occur at the highest frequency in reproducing signatures and that do not contain any SNPs linked to known GWAS genes, providing new evidence for links between endometriosis and autophagy and macrophage biology. Reproducibility rates, ranging between 73% to 85%. are especially strong for the signatures that contain these 9 genes independently of any SNPs mapping to the meta-GWAS genes. CONCLUSION: Although using much smaller, less well-characterized datasets than the previous whole genome meta-GWAS study, combinatorial analysis has provided important new insights into the genetics and biology of endometriosis including reproducible biologically relevant genes that are overlooked by GWAS approaches.The 75 novel gene associations provide new insights and routes for study of the disease and potential new therapies. Several of the novel genes identified are credible targets for drug discovery, repurposing and/or repositioning. Using the disease signatures identified as genetic biomarkers in trials of candidates drugs targeting specific mechanisms will enable precision medicine-based approaches. We hope this will encourage new targeted therapy discovery efforts.

Endometriosis↗

PubMed2025

Reproducibility of genetic risk factors identified for long COVID using combinatorial analysis across US and UK patient cohorts with diverse ancestries.

BACKGROUND: Long COVID is a major public health burden causing a diverse array of debilitating symptoms in tens of millions of patients globally. In spite of this overwhelming disease prevalence, staggering cost, severe impact on patients' lives and intense global research efforts, study of the disease has proved challenging due to its complexity. Genome-wide association studies (GWAS) have identified only four loci potentially associated with the disease, although these results did not statistically replicate between studies. A previous combinatorial analysis study identified a total of 73 genes that were highly associated with two long COVID cohorts in the predominantly (> 91%) white European ancestry Sano GOLD population, and we sought to reproduce these findings in the independent and ancestrally more diverse All of Us (AoU) population. METHODS: We assessed the reproducibility of the 5343 long COVID disease signatures from the original study in the AoU population. Because the very small population sizes provide very limited power to replicate findings, we initially tested whether we observed a statistically significant enrichment of the Sano GOLD disease signatures that are also positively correlated with long COVID in the AoU cohort after controlling for population substructure. RESULTS: For the Sano GOLD disease signatures that have a case frequency greater than 5% in AoU, we consistently observed a significant enrichment (77-83%, p < 0.01) of signatures that are also positively associated with long COVID in the AoU cohort. These encompassed 92% of the genes identified in the original study. At least five of the disease signatures found in Sano GOLD were also shown to be individually significantly associated with increased long COVID prevalence in the AoU population. Rates of signature reproducibility are strongest among self-identified white patients, but we also observe significant enrichment of reproducing disease associations in self-identified black/African-American and Hispanic/Latino cohorts. Signatures associated with 11 out of the 13 drug repurposing candidates identified in the original Sano GOLD study were reproduced in this study. CONCLUSION: These results demonstrate the reproducibility of long COVID disease signal found by combinatorial analysis, broadly validating the results of the original analysis. They provide compelling evidence for a much broader array of genetic associations with long COVID than previously identified through traditional GWAS studies. This strongly supports the hypothesis that genetic factors play a critical role in determining an individual's susceptibility to long COVID following recovery from acute SARS-CoV-2 infection. It also lends weight to the drug repurposing candidates identified in the original analysis. Together these results may help to stimulate much needed new precision medicine approaches to more effectively diagnose and treat the disease. This is also the first reproduction of long COVID genetic associations across multiple populations with substantially different ancestry distributions. Given the high reproducibility rate across diverse populations, these findings may have broader clinical application and promote better health equity. We hope that this will provide confidence to explore some of these mechanisms and drug targets and help advance research into novel ways to diagnose the disease and accelerate the discovery and selection of better therapeutic options, both in the form of newly discovered drugs and/or the immediate prioritization of coordinated investigations into the efficacy of repurposed drug candidates.

Humans↗

PubMed2006

Beta-defensin evolution: selection complexity and clues for residues of functional importance.

We have examined the evolution of the genes at the major human beta-defensin locus and the orthologous loci in a range of other primates and mammals. For the first time, these data allow us to examine selective episodes in the more recent evolutionary history of this locus as well as in the ancient past. We have used a combination of maximum-likelihood-based tests and a maximum-parsimony-based sliding window approach to give a detailed view of the varying modes of selection operating at this locus. We provide evidence for strong positive selection soon after the duplication of these genes within an ancestral mammalian genome. During the divergence of primates, however, variable selective pressures have acted on beta-defensin genes in different evolutionary lineages, with episodes of both negative and, more rarely, positive selection. Positive selection appears to have been more common in the rodent lineage, accompanying the birth of novel rodent-specific beta-defensin gene clades. Sites in the second exon have been subject to positive selection and, by implication, are important in functional diversity. A small number of sites in the mature human peptides were found to have undergone repeated episodes of selection in different primate lineages. Particular sites were consistently implicated by multiple methods at positions throughout the mature peptides. These sites are clustered at positions that are predicted to be important for the function of beta-defensins.

Animals↗

PubMed2006

Circulating levels and clinical significance of soluble CD86 in myeloma patients.

Circulating soluble CD86 (sCD86) levels are elevated in a number of leukaemias and are an independent prognostic factor in acute myeloid leukaemia. We investigated the clinical significance of circulating sCD86 in 299 patients from the UK Medical Research Council myeloma VIth trial, where patients received ABCM [adriamycin, carmustine (BCNU), cyclophosphamide, melphalan] either alone or with prednisolone (ABCM + P). Serum levels of sCD86 were significantly elevated (P = 0.0001) in myeloma patients and using the median normal donor level (0.621 ng/ml) as a cut-off point, 70% of patients had elevated levels (range = 0.015-15.87 ng/ml, median = 1.1 ng/ml). In univariate analysis elevated sCD86 levels were associated with significantly shorter (P < 0.001) survival (median = 22 vs. 51 months) and event-free survival (median = 14 vs. 31 months) in ABCM + P but not ABCM patients. Multivariate analysis demonstrated that sCD86 was a significant, independent prognostic marker of both overall [risk ratio (RR) = 2.04, P = 0.0006] and event-free (RR = 1.95, P = 0.0004) survival in ABCM + P patients. In conclusion, this study demonstrated that sCD86 levels are a significant independent prognostic marker in at least some myeloma treatment groups and its biological role and prognostic value should be further investigated.

Adult↗

PubMed2006

Levels of the soluble forms of CD80, CD86, and CD83 are elevated in the synovial fluid of rheumatoid arthritis patients.

The release of soluble forms of CD80 (sCD80), CD86 (sCD86), and CD83 (sCD83) provide a potentially powerful immunoregulatory mechanism. We therefore investigated the potential presence and relative levels of these molecules in the synovial fluid (SF) and serum of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum and SF levels were measured by enzyme-linked immunosorbent assay. Serum levels of sCD80, sCD86, and sCD83 in RA and OA patients were similar to those present in normal donor serum (NDS) and the SF of OA patients. In contrast, when compared with NDS and OA SF levels, almost all RA SF samples had elevated sCD83 levels (32/35, >0.63 ng/ml) and a substantial proportion had elevated sCD80 (13/29, >0.22 ng/ml) or sCD86 (16/33, >2.31 ng/ml) levels. Analysis of matched pairs of serum and SF from RA patients demonstrated that the SF/serum ratio for sCD80 (95% CI = 1.7-3), sCD86 (95% CI = 1.5-3.1), and sCD83 (95% CI = 3.6-7.8) levels was >1 in almost all patients. In conclusion, this study shows that the SF from almost all RA patients contain elevated levels of sCD83 and the majority of these samples also contain elevated levels of sCD80 and/or sCD86. These molecules may play a role in modulating immune responses within the rheumatoid joint.

Adolescent↗

PubMed2005

Coherent oscillatory activity in monkey area v4 predicts successful allocation of attention.

Attention serves to select objects from often complex scenes for enhanced processing and perception. In particular, the perception of shape depends critically on attention for integrating the various parts of the selected object into a coherent representation of object shape. To study whether oscillatory neuronal synchrony may serve as a mechanism of attention in shape perception, we introduced a novel shape-tracking task requiring sustained attention to a morphing shape. Attention was found to strongly increase oscillatory currents underlying the recorded field potentials in the gamma-frequency range, thus indicating enhanced neuronal synchrony within the population of V4 neurons representing the attended stimulus. Errors indicating a misdirection of attention to the distracter instead of the target were preceded by a corresponding shift of oscillatory activity from the target's neuronal representation to that of the distracter. No such effect was observed for errors unrelated to attention. Modulations of the attention-dependent enhancement of oscillatory activity occurred in correspondence with changing attentional demands during the course of a trial. The specificity of the effect of attentional errors together with the close coupling between attentional demand and oscillatory activity support the hypothesis that oscillatory neuronal synchrony serves as a mechanism of attention.

Algorithms↗

PubMed2005

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation.

In this prospective multicentre trial, 90 patients undergoing autologous stem cell transplantation (ASCT) were randomised to receive (n=43) or not receive (n=47) amifostine 910 mg/m(2) prior to melphalan 200 mg/m(2). Patients were monitored for regimen-related toxicity, engraftment, supportive care, response and survival. Both groups underwent ASCT at a median of 8 months from diagnosis and were matched for disease characteristics, prior therapy and pre-ASCT disease responsiveness. Amifostine infusional side-effects were frequent, occurring in 65% of patients, but of mild severity. Amifostine use was associated with a reduction in the median grade of oral mucositis (1 vs 2, P=0.01) and the frequency of severe (WHO grades 3 or 4) mucositis (12 vs 33%, P=0.02), but no reduction in the requirement for parenteral nutrition or analgesic use. Conversion to complete remission post-ASCT occurred in 30 and 14% of the amifostine and control groups, respectively (P=0.09). With a median follow-up of 35 months, there was no statistically significant difference between the median progression-free or overall survival times for the two groups. We conclude that amifostine can be safely administered prior to high-dose melphalan and significantly reduces the frequency and severity of therapy-induced oral mucositis.

Adult↗

PubMed2005

Day-long subcutaneous infusion of exenatide lowers glycemia in patients with type 2 diabetes.

Exenatide (exendin-4) is an incretin mimetic with potential antidiabetic activity. This study examined the effects of a continuous subcutaneous (SC) infusion of exenatide (0.2, 0.4, 0.6, or 0.8 microg/kg/day) or placebo (PBO) on glycemic control over 23 h intervals. Twelve subjects with type 2 diabetes treated with metformin and/or diet received 10 infusions (4 exenatide, 6 PBO) on consecutive days. Exenatide was given in a dose-increasing design with at least one placebo infusion between each exenatide infusion, and with meals and a snack provided during the first 14 h of infusion. Plasma exenatide concentrations were dose-proportional. Plasma glucose (4-23 h) was lower in all exenatide arms compared to placebo (p<0.0001). The change in insulin/glucagon ratio and amylin concentrations from pre-infusion to post-infusion was increased (p<0.005, p<0.05, respectively) in the combined exenatide arms, but remained unchanged in the placebo groups. Nausea and vomiting were the most common treatment emergent adverse events. Exenatide infusion also appeared to have positive effects on beta-cell and alpha-cell function as measured by proinsulin/insulin ratios and mean glucagon concentrations. In summary, exenatide lowered plasma glucose during both prandial and fasting states when delivered as a continuous SC infusion over twenty-three hours, suggesting that exenatide can provide day-long glycemic control in patients with type 2 diabetes.

Adult↗

PubMed2005

Patients at high risk for upper tract urothelial cancer: evaluation of hydronephrosis using high resolution magnetic resonance urography.

PURPOSE: We assessed the potential of magnetic resonance urography (MRU) in the evaluation of hydronephrosis not explained by standard investigation in patients at high risk for upper tract urothelial cancer. MATERIALS AND METHODS: A total of 23 consecutive patients in a specialist urological unit with unexplained hydronephrosis prospectively underwent MRU which comprised overview heavily T2-weighted MR urographic images followed by focused high resolution turbo spin echo T2-weighted sequences obtained in an axial and coronal oblique plane through the level of urinary obstruction. All were at high risk for urothelial cancer and had either contraindications to or problems with standard investigations including poor contrast excretion due to obstruction or renal failure, failed ureteral cannulation or contrast allergy. Clinical events and imaging followup, subsequent endoscopic/surgical findings and histopathology validated MR findings. RESULTS: In 23 patients with a high clinical suspicion of upper tract transitional cell tumors (TCC), 8 ureteral and 5 renal pelvic TCCs (2 bilateral) were diagnosed by MR, and confirmed histologically. In a further 5 patients benign causes for the hydronephrosis were found. No intrinsic or extrinsic pathology was demonstrable in 5 patients whose imaging findings were stable during 1 year of followup. CONCLUSIONS: MRU is a valuable noninvasive investigation for evaluating hydronephrosis in this group of patients with suspected urothelial cancer in which routine investigation had failed to provide clinically important information. Focused high resolution T2-weighted images were reliable in the diagnosis of ureteral and renal pelvic TCCs, and were valuable in excluding these and other mass lesions as the cause of hydronephrosis.

Aged↗

PubMed2005

Managing passively acquired autoimmune neonatal neutropenia: a case study.

Pregnant women with autoimmune neutropenia (AIN) and circulating neutrophil-specific autoantibodies can deliver neutropenic neonates at risk of sepsis. We report the case of a woman who had two such pregnancies. The woman had been on prophylactic granulocyte colony-stimulating factor (G-CSF) treatment, but this was ceased prior to conception in both pregnancies. In the first pregnancy, there was no monitoring or interventions, and the neonate was neutropenic and required intensive care treatment. In the second pregnancy, the maternal neutrophil autoantibody level was monitored, and G-CSF treatment was introduced in the third trimester. The second infant had no neutropenia at delivery and an excellent Apgar score. We discuss the management strategy in the second pregnancy that included monitoring of serial titres of the maternal autoantibody and the introduction of G-CSF in the third trimester, which may have contributed to a more favourable clinical outcome. This may assist other clinicians faced with similar dilemmas in the future.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed2005

Eletriptan treatment of migraine in patients switching from barbiturate-containing analgesics: results from a multiple-attack study.

The aim of this study was to examine efficacy and tolerability of eletriptan in patients switched from barbiturate-containing combinations (Fiorinal), Fioricet. Migraineurs (n = 160) meeting IHS criteria, with unsatisfactory response in the past year to butalbital-containing combinations, treated up to 16 attacks over 3 months with eletriptan 40 mg. Assessments included headache response and pain-free rates and functional impairment at baseline and 2 h postdose, and global ratings of treatment satisfaction at 24 h. At 2 h postdose, average headache response and pain-free rates were 71% (95% CI, 69-74%) and 37% (95% CI, 35-40%), respectively; 68.5% of patients (95% CI, 65-72%) reported functional response. Within-patient analysis found no efficacy diminution over time (no tolerance). Average headache recurrence rate was 20% (95% CI, 18-23%). Eletriptan was well-tolerated; 6 (3.7%) patients discontinued due to adverse events. There were no serious treatment-related adverse events. We conclude that in poor responders to butalbital-caffeine combinations, switching to eletriptan 40 mg was well-tolerated and efficacious.

Acetaminophen↗

PubMed2005

Antimicrobial activity of murine lung cells against Staphylococcus aureus is increased in vitro and in vivo after elafin gene transfer.

Staphylococcus aureus is a pathogen often found in pneumonia and sepsis. In the context of the resistance of this organism to conventional antibiotics, an understanding of the regulation of natural endogenous antimicrobial molecules is of paramount importance. Previous studies have shown that both human and mouse airways express a variety of these molecules, including defensins, cathelicidins, and the four-disulfide core protein secretory leukocyte protease inhibitor. We demonstrate here by culturing mouse tracheal epithelial cells at an air-liquid interface that, despite the production of Defb1, Defb14, and Defr1 in this system, these cells are unable to clear S. aureus when exposed to this respiratory pathogen. Using an adenovirus (Ad)-mediated gene transfer strategy, we show that overexpression of elafin, an anti-elastase/antimicrobial molecule (also a member of the four-disulfide core protein family), dramatically improves the clearance of S. aureus. In addition, we also demonstrate that this overexpression is efficient in vivo and that intratracheal instillation of Ad-elafin significantly reduced the lung bacterial load and demonstrates concomitant anti-inflammatory activity by reducing neutrophil numbers and markers of lung inflammation, such as bronchoalveolar lavage levels of tumor necrosis factor and myeloperoxidase. These findings show that an increased antimicrobial activity phenotype is provided by the elafin molecule and have implications for its use in S. aureus-associated local and systemic infections.

Adenoviridae↗

PubMed2004

The effect of vaccination and sea water entry on immunocompetence and susceptibility to Kudoa thyrsites in Atlantic salmon (Salmo salar L.).

The effect of intraperitoneal (IP) vaccination and sea water entry (SWE) on the immunocompetence of Cascade Atlantic salmon was investigated. Smolts were IP injected with Aqua Health's Forte trade mark vaccine (Listonella (Vibrio) anguillarum, Listonella ordalii, Vibrio salmonicida and Aeromonas salmonicida) at four times (42, 238, 433 and 630 degree days, DD) prior to SWE and were examined for immunocompetence. Immune response measurements included mitogen-driven proliferation of peripheral blood leukocytes (PBL), head kidney leukocyte respiratory burst activity and alternative complement hemolytic titres and were measured 24h prior to SWE, 72 h post-SWE and again 3.5 weeks post-SWE. A 50% reduction in the number of PBL was observed 3 days post-vaccination. At this time LPS-driven proliferation was low (stimulation index, SI, 1.5-2.9) in all groups prior to SWE compared with that of PBL from freshwater-reared Atlantic salmon parr (6.7). By 72 h and 3.5 weeks post-SWE, the LPS-driven SI from unvaccinated salmon and those vaccinated 630 and 433 DD prior to SWE increased 3-fold. In contrast, SI from salmon vaccinated 42 and 238 DD prior to SWE remained low. A similar pattern was observed for cultured PBL stimulated with PHA, although unlike LPS-stimulated PBL, the SI of cells from parr and unvaccinated control smolts remained low following SWE but increased in fish vaccinated 433 and 630 DD prior to SWE. The respiratory burst activity of head kidney leukocytes was not affected by SWE but showed a transient 50% depression 3 days post-vaccination. The alternative complement activity (ACH50) was similar for all treatment groups prior to and at 72h post-SWE. By 3.5 weeks post-SWE, ACH50 values in salmon vaccinated 42 and 238 DD prior to SWE doubled to 874 and 860 U/ml, respectively. The prevalence and severity of Kudoa thyrsites infections, detected in all treatment groups approximately 2400 DD following SWE, were not significantly different among groups. Atlantic salmon parr should be IP vaccinated no earlier than 433 DD before SWE to avoid an enhanced risk of acquiring pathogens because of transient depression in some immune mechanisms.

Animals↗

PubMed2004

Monitoring dendritic cells in clinical practice using a new whole blood single-platform TruCOUNT assay.

Dendritic cells (DC) from distinct DC subsets are essential contributors to normal human immune responses. Despite this, reliable assays that enable DC to be counted precisely have been slow to evolve. We have now developed a new single-platform flow cytometric assay based on TruCOUNT beads and the whole blood "Lyse/No-Wash" protocol that allows precise counting of the CD14(-) blood DC subsets: CD11c(+)CD16(-) DC, CD11c(+)CD16(+) DC, CD123(hi) DC, CD1c(+) DC and BDCA-3(+) DC. This assay requires 50 microl of whole blood; does not rely on a hematology blood analyser for the absolute DC counts; allows DC counting in EDTA samples 24 h after collection; and is suitable for cord blood and peripheral blood. The data is highly reproducible with intra-assay and inter-assay coefficients of variation less than 3% and 11%, respectively. This assay does not produce the DC-T lymphocyte conjugates that result in DC counting abnormalities in conventional gradient-density separation procedures. Using the TruCOUNT assay, we established that absolute blood DC counts reduce with age in healthy individuals. In preliminary studies, we found a significantly lower absolute blood CD11c(+)CD16(+) DC count in stage III/IV versus stage I/II breast carcinoma patients and a lower absolute blood CD123(hi) DC count in multiple myeloma patients, compared to age-matched controls. These data indicate that scientific progress in DC counting technology will lead to the global standardization of DC counting and allow clinically meaningful data to be obtained.

Adult↗

PubMed2004

DNM1DN: a new class of paralogous genomic segments (duplicons) with highly conserved copies on chromosomes Y and 15.

Screening a testis cDNA selection library for Y-linked genes yielded 79 cDNAs. Of these, 9 matched the 3' region of the dynamin 1 gene (DNM1) on chromosome 9q34 with >90% identity. Fluoresence in situ hybridisation and PCR amplification were used to localise a large number of DNM1-like sequences to human chromosomes 15 and Y. PCR amplification of overlapping Y-linked YACs allowed a more accurate mapping of the Y-linked DNM1-like cDNAs to a euchromatic locus in close proximity to heterochromatin at Yq11.23. A search of the genome database identified 64 highly homologous copies of the DNM1 fragment. Most of these copies were localised to chromosomes 15 and Y, but others mapped to chromosomes 5, 8, 10, 12, 19 and 22. These sequences exhibit all the major features of a duplicon and have been designated DNM1DN (DNM1 duplicon). Evolutionary studies using fluorescence in situ hybridisation indicate that transposition of the DNM1DN sequence to chromosome 15 took place earlier in primate evolution than the transposition to the Y chromosome. The translocation to the Y took place at a time following the divergence of a common ancestor from gorilla, approximately 4-7 million years ago.

Animals↗

PubMed2004

Evaluation of painful hydronephrosis in pregnancy: magnetic resonance urographic patterns in physiological dilatation versus calculous obstruction.

PURPOSE: We evaluated magnetic resonance urography (MRU) appearances in symptomatic hydronephrosis in pregnancy and compared urographic patterns in physiological and calculous disease. MATERIALS AND METHODS: A total of 24 consecutive pregnant women with symptomatic hydronephrosis underwent MRU, comprising an overview fast T2-weighted examination of the abdomen and pelvis, and thick slab, heavily T2-weighted MRU images, followed by focused, high resolution T2-weighted sequences obtained in an axial and coronal oblique plane through the level of ureteral caliber change. RESULTS: Of these 24 pregnant women 15 were found to have physiological hydronephrosis, 7 had calculous disease and 2 had preexisting urinary anomalies. MRU findings in physiological hydronephrosis cases were extrinsic compression of the middle third of the ureter, no filling defect and a collapsed ureter below it. Obstruction by ureteral calculi was seen at points of ureteral narrowing in the ureter, that is at the vesicoureteral junction in 2 cases, in the compressed mid ureter in 3 and at the pelviureteral junction in 1. Nonobstructive renal calculi were seen in another patient. Calculi presented throughout pregnancy but physiological hydronephrosis presented only in the late second and third trimesters. With distal calculi the MRU appearance was the double kink sign with constriction at the pelvic brim and the vesicoureteral junction with a standing column of urine in the pelvic ureter. There was renal edema and perirenal extravasation. Small calculi were only identified using high resolution T2-weighted magnetic resonance imaging. CONCLUSIONS: MRU is a valuable and well tolerated investigation for evaluating painful hydronephrosis in pregnancy. There are characteristic and differing urographic appearances in physiological and calculous obstruction.

Adolescent↗

PubMed2004

Androgen excess in women: experience with over 1000 consecutive patients.

The objective of the present study was to estimate the prevalence of the different pathological conditions causing clinically evident androgen excess and to document the degree of long-term success of suppressive and/or antiandrogen hormonal therapy in a large consecutive population of patients. All patients presenting for evaluation of symptoms potentially related to androgen excess between October 1987 and June 2002 were evaluated, and the data were maintained prospectively in a computerized database. For the assessment of therapeutic response, a retrospective review of the medical chart was performed, after the exclusion of those patients seeking fertility therapy only, or with inadequate follow-up or poor compliance. A total of 1281 consecutive patients were seen during the study period. Excluded from analysis were 408 patients in whom we were unable to evaluate hormonal status, determine ovulatory status, or find any evidence of androgen excess. In the remaining population of 873 patients, the unbiased prevalence of androgen-secreting neoplasms was 0.2%, 21-hydroxylase-deficient classic adrenal hyperplasia (CAH) was 0.6%, 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) was 1.6%, hyperandrogenic insulin-resistant acanthosis nigricans (HAIRAN) syndrome was 3.1%, idiopathic hirsutism was 4.7%, and polycystic ovary syndrome (PCOS) was 82.0%. Fifty-nine (6.75%) patients had elevated androgen levels and hirsutism but normal ovulation. A total of 257 patients were included in the assessment of the response to hormonal therapy. The mean duration of follow-up was 33.5 months (range, 6-155). Hirsutism improved in 86%, menstrual dysfunction in 80%, acne in 81%, and hair loss in 33% of patients. The major side effects noted were irregular vaginal bleeding (16.1%), nausea (13.0%), and headaches (12.6%); only 36.6% of patients never complained of side effects. In this large study of consecutive patients presenting with clinically evident androgen excess, specific identifiable disorders (NCAH, CAH, HAIRAN syndrome, and androgen-secreting neoplasms) were observed in approximately 7% of subjects, whereas functional androgen excess, principally PCOS, was observed in the remainder. Hirsutism, menstrual dysfunction, or acne, but not alopecia, improved in the majority of patients treated with a combination suppressive therapy; although more than 60% experienced side effects.

Acanthosis Nigricans↗

PubMed2003

Prior and concurrent administration of recombinant human megakaryocyte growth and development factor in patients receiving consolidation chemotherapy for de novo acute myeloid leukemia--a randomized, placebo-controlled, double-blind safety and efficacy study.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) administered after acute myeloid leukemia (AML) chemotherapy (CT) failed to shorten the time of transfusion-dependent thrombocytopenia in a previous study. In this multicenter, randomized, placebo-controlled, double-blind study we determined the effect of administration of PEG-rHuMGDF prior to CT and of administration prior, concurrent, and 1 day post CT on platelet recovery and transfusion requirements in patients receiving consolidation CT for de novo AML. Patients were randomized to receive either 30 microk/kg PEG-rHuMGDF as a single dose on day -6 ( n=37), placebo as a single dose on day -6 ( n=9), 30 microk/kg PEG-rHuMGDF administered on day -6 followed by 10 microg/kg on days -5 to day 6 (through CT and including the day after CT, n=35), or placebo administered on day -6 to day 6 ( n=9). The median times to transfusion-independent platelet recovery to >20x10(9)/l were 24.5 and 24.0 days in the PEG-rHuMGDF day -6 group and PEG-rHuMGDF day -6 to 6, respectively, compared to 21.0 days in the placebo group. There were no significant differences in the number of days of platelet transfusions between either PEG-rHuMGDF schedule or placebo. The PEG-rHuMGDF day -6 to 6 group had a delayed absolute neutrophil count (ANC) recovery compared to either placebo or PEG-rHuMGDF day -6 treated patients. Thus, alteration of the scheduling of PEG-rHuMGDF in terms of earlier dosing before and during chemotherapy did not improve platelet recovery but rather delayed hematopoietic reconstitution. Although unexpected, these observations may be of major relevance for the design of future clinical trials with recombinant thrombopoietins.

Adult↗