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The authors reflect on research developments on chronic kidney disease of uncertain aetiology (CKDu), which is the impairment of kidney function with no predisposing factor for kidney disease like chronic hypertension, diabetes mellitus and obstructive nephropathy. Topics include a study published in the journal showing that subclinical kidney injury causing the disease starts prior to working life and the high risk of CKDu in children seven to 17 years old.

Chronic kidney disease (CKD) is associated with fatal cardiovascular consequences in part due to ectopic calcification of soft tissues particularly arteries, capillaries, and cardiac valves. An increasing body of evidence from experimental studies and in vivo data suggest that (I) a mineral imbalance with hyperphosphatemia and high-circulating calcium × phosphate product, (II) a deficiency of systemic or local calcification inhibitors, (III) death or ‘damage’ of vascular smooth muscle cells (VSMCs), and/or (IV) phenotypic transformation of VSMCs to osteo/chondrocytic cells may all act in concert to initiate and sustain vascular calcification. In CKD patients inhibitory systems are overwhelmed by a multitude of agents that induce VSMC damage and cell death resulting in the release of vesicles capable of nucleating basic calcium phosphate. Studies with genetically altered mice have identified both local and systemic calcification inhibitors that act to maintain VSMC differentiation or regulate vesicle properties. However, for many of these proteins the mechanisms and sites of action are still under investigation. In particular, it is unclear whether factors present in the circulation have an inhibitory role there and whether circulating levels of these proteins influence or are indicative of underlying disease processes in individual patients. A greater understanding of the origins and roles of potential circulating inhibitors may result in novel strategies aimed at the prevention or reversal of the life-limiting calcifying vasculopathies seen in CKD patients.Kidney International (2008) 73, 384–390; doi:10.1038/sj.ki.5002696; published online 28 November 2007 [ABSTRACT FROM AUTHOR]

In the 3 years leading up to March 2001, the general anaesthesia rate for emergency and elective caesarean sections at our hospital was higher than that recommended by the Royal College of Anaesthetists. There were also concerns regarding the quality of communication between surgeon and anaesthetist prior to emergency caesarean section. A multidisciplinary audit was undertaken on both the indications for obstetric general anaesthesia and quality of communication between staff members during the perioperative period between January and August 2002. The results of the audit highlighted potential serious shortfalls in communication and teamworking; however, there was insufficient information to assess the appropriateness of the indication for general anaesthesia. Following this audit recommendations were made to improve communication channels between the personnel on labour ward and this coincided with a reduction in the use of general anaesthesia. [ABSTRACT FROM AUTHOR]

Prospective Epstein-Barr virus (EBV) surveillance post transplant was undertaken by qualitative polymerase chain reaction testing for EBV DNA in plasma so as to detect EBV viremia as early as possible and thereby attempt to pre-empt post-transplant lymphoproliferative disease by reduction of immunosuppression. Forty-three children (46 transplants) were followed for a median (range) of 15.5 (3-25) months. Thirty-one children (67%) were EBV seropositive pre transplant. Twenty children (44%) developed EBV viremia; of these 9 (60%) were seronegative and 11 (36%) seropositive recipients. Primary infection developed later (median difference 14.2 weeks, P = 0.009), was more likely to be symptomatic (odds ratio 2.91, 95% confidence interval 0.95-4.88) and associated with a rise in serum creatinine (odds ratio 6.13, 95% confidence interval 4.13-8.13) than reactivation disease. There was a higher incidence of EBV disease in children receiving quadruple therapy and tacrolimus (odds ratio 13.2, 95% confidence interval 11.5-14.9) compared with those given cyclosporin-based immunosuppression. Immunosuppression was reduced when EBV infection was detected. All children became asymptomatic and renal function returned to normal by a median (range) of 17 (6-52) days, although mild relapses occurred in 3 children. Regular EBV surveillance allowed prompt reduction of immunosuppression and was associated with a good outcome in this group of children. Prospective Epstein-Barr virus (EBV) surveillance post transplant was undertaken by qualitative polymerase chain reaction testing for EBV DNA in plasma so as to detect EBV viremia as early as possible and thereby attempt to pre-empt post-transplant lymphoproliferative disease by reduction of immunosuppression. Forty-three children (46 transplants) were followed for a median (range) of 15.5 (3-25) months. Thirty-one children (67%) were EBV seropositive pre transplant. Twenty children (44%) developed EBV viremia; of these 9 (60%) were... [ABSTRACT FROM AUTHOR]

We present an unusual case of cerebellar ataxia in a 2 year old girl several days after treatment with piperazine citrate for suspected worm infestation. This is the first reported case of delayed onset neurotoxicity following the therapeutic administration of piperazine in a previously well child. [ABSTRACT FROM AUTHOR]

We describe five babies, who were exclusively breast fed, with life-threatening complications of hypernatraemic dehydration secondary to inadequate breast feeding. An increased awareness among health professionals is required so that this potentially devastating condition can be prevented. [ABSTRACT FROM AUTHOR]

Investigates the treatment dilemmas after gonadectomy in complete androgen insensitivity syndrome. Medication of daily doses of estrogen and progesterone to increase bone mineral density; Risk associated with hormone replacement therapy; Potential of selective estrogen receptor modulators to reduce breast cancer incidence in postmenopausal women with osteoporosis.

Reports on a case of cerebellar ataxia in a two-year-old girl. Occurrence of the disease several days after treatment with piperazine citrate for suspected worm infestation; Clinical presentation of the disease; Diagnosis and treatment.

Purpose Keratocytes show differential gene expression in culture media; and are extensively used to study wound healing, corneal disease biology and response to topical drugs. However, mono-layer culture cannot replicate the 3-dimensional biological environment of corneal stroma. Hence, we propose to establish corneal lenticule as an ex-vivo model to study keratocyte biology for corneal diseases, drug response studies and in wound healing experiments. Methods SMILE surgery was performed using the VisuMax femtosecond laser system (Carl Zeiss Meditec AG, Jena, Germany). After the refractive lenticule of intra-stromal corneal tissue was created using the femtosecond cutting procedure, it was dissected and separated through the side-cut opening and removed manually. SMILE lenticules from patients were obtained in MK media and were transferred to DMEM F12 with 10% FBS and 1% PSA. The media was replenished every 24 h and lenticules were harvested at 0 h, 24 h, 48 h, 78 h and 96 h. Gene Expression analysis was performed for pro-fibrotic genes (fibronectin, ɑ-sma, vimentin, TGF-β and TGF-βR2), pro-inflammatory (IL-6 and TNF-ɑ) and structural genes (Col1-A1, Col4-A1and Col5-A1). Results Our results demonstrate that lenticules remain metabolically active in culture media for long periods of time as evident from the varying expression of different pro-fibrotic, pro-inflammatory and structural genes after 0 h, 24 h, 48 h, 78 h and 96 h of culture. Furthermore, linear regression analyses show that clinical parameters like lenticule thickness do not affect the expression profile of the various genes by the keratocytes contained in the lenticule. Conclusions In conclusion, lenticule can be used as an ex-vivo model to study keratocyte biology in various corneal diseases and for drug testing. [ABSTRACT FROM AUTHOR]

Purpose Keratocytes show differential gene expression in culture media; and are extensively used to study wound healing, corneal disease biology and response to topical drugs. However, mono-layer culture cannot replicate the 3-dimensional biological environment of corneal stroma. Hence, we propose to establish corneal lenticule as an ex-vivo model to study keratocyte biology for corneal diseases, drug response studies and in wound healing experiments. Methods SMILE surgery was performed using the VisuMax femtosecond laser system (Carl Zeiss Meditec AG, Jena, Germany). After the refractive lenticule of intra-stromal corneal tissue was created using the femtosecond cutting procedure, it was dissected and separated through the side-cut opening and removed manually. SMILE lenticules from patients were obtained in MK media and were transferred to DMEM F12 with 10% FBS and 1% PSA. The media was replenished every 24 h and lenticules were harvested at 0, 24, 48, 78 and 96 h. Gene Expression analysis was performed for pro-fibrotic genes (fibronectin, α-sma, vimentin, TGF-β and TGF-βR2), pro-inflammatory ( IL-6 and TNF-α) and structural genes (Col1-A1, Col4-A1and Col5-A1). Results Our results demonstrate that lenticules remain metabolically active in culture media for long periods of time as evident from the varying expression of different pro-fibrotic, pro-inflammatory and structural genes after 0, 24, 48, 78 and 96 h of culture. Furthermore, linear regression analyses show that clinical parameters like lenticule thickness do not affect the expression profile of the various genes by the keratocytes contained in the lenticule. Conclusions In conclusion, lenticule can be used as an ex-vivo model to study keratocyte biology in various corneal diseases and for drug testing. [ABSTRACT FROM AUTHOR]

To further explore the clinical applicability of the calcium (Ca) isotope marker (CIM), we determined the 44Ca/42Ca isotope ratio in blood serum and urine. This ratio is expressed in the conventional δ-notation (as defined in the text below) specifically as CIM-serum for serum and as CIM-urine for urine. Our study tested the hypothesis that CIM values can differentiate between positive and negative bone mineral balance (BMB) across a diverse clinical population considering variables such as age, gender, and diet. The threshold values (CIM-serum: −0.85 ± 0.06 ‰ and CIM-urine: 0.23 ± 0.06 ‰) established in the OsteoGeo study (NCT02967978 , Eisenhauer et al., 2019) were evaluated in 2320 participants as part of a surveillance study referred to as Osteolabs study. The earlier study revealed women with osteoporosis had an average CIM-serum value of −0.91 ± 0.21 ‰ (N = 24) and a CIM-urine value of 0.18 ± 0.33 ‰ (N = 71) that are significantly below the threshold values (p = 0.02 for urine, one-sided Wilcoxon rank test, p < 0.001 for serum, one-sided Student's t -test). Diseases affecting BMB such as osteoporosis, acute and chronic kidney disease (CKD), hyperthyroidism, breast cancer, prostate cancer, and myeloma were associated with significantly lower average CIM values, falling below the equilibrium thresholds and indicating negative BMB. In contrast, patients receiving osteoprotective treatments such as denosumab, Romosozumab, bisphosphonates, or hormone replacement therapy for certain diseases, had CIM values above the equilibrium thresholds indicating a positive BMB. Additionally, Ca supplements taken by some of the patients ((N = 22 (serum), N = 49 (urine), median dose: 500 mg) showed a Ca isotope composition approximately 1 ‰ higher than that from a normal diet. Consequently, their CIM values need to be adjusted to account for the amount and duration of supplementation to be comparable to those with a normal diet. Participants taking vitamin D (237 women; 58 men) showed no significant difference from the average values of the study group. Counterintuitively, the possible impact of malnutrition on individual BMB was most pronounced in vegans, who exhibited the highest average CIM-urine values compared to patients on a normal diet (p < 0.001, N = 17). The results of this study were consistent with the registered OsteoGeo study (NCT02967978) and other earlier published Ca isotope-based studies on BMB. We confirm that the CIM threshold values determined in the OsteoGeo study are generally valid for this much larger and diverse surveillance study group covering a diverse population encompassing various medical conditions and therapies. • First report on the application of CIM in the serum and urine of 2320 participants • CIM correlates with all metabolic diseases affecting musculoskeletal metabolism • Diseases negatively affecting BMB fall below CIM thresholds • Osteoprotective treatment positively affecting BMB fall above the CIM thresholds [ABSTRACT FROM AUTHOR]

Mineral and bone disorder in chronic kidney disease (CKD-MBD) is a triad of biochemical imbalances of calcium, phosphate, parathyroid hormone and vitamin D, bone abnormalities and soft tissue calcification. Maintaining optimal bone health in children with CKD is important to prevent long-term complications, such as fractures, to optimise growth and possibly also to prevent extra-osseous calcification, especially vascular calcification. In this review, we discuss normal bone mineralisation, the pathophysiology of dysregulated homeostasis leading to mineralisation defects in CKD and its clinical consequences. Bone mineralisation is best assessed on bone histology and histomorphometry, but given the rarity with which this is performed, we present an overview of the tools available to clinicians to assess bone mineral density, including serum biomarkers and imaging such as dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. We discuss key studies that have used these techniques, their advantages and disadvantages in childhood CKD and their relationship to biomarkers and bone histomorphometry. Finally, we present recommendations from relevant guidelines—Kidney Disease Improving Global Outcomes and the International Society of Clinical Densitometry—on the use of imaging, biomarkers and bone biopsy in assessing bone mineral density. Given low-level evidence from most paediatric studies, bone imaging and histology remain largely research tools, and current clinical management is guided by serum calcium, phosphate, PTH, vitamin D and alkaline phosphatase levels only. [ABSTRACT FROM AUTHOR]

Background: Hypermethylation of promoter CpG islands [CpG island methylator phenotype (CIMP)] represents a unique pathway for the development of colorectal cancer (CRC), characterized by lack of chromosomal instability and a low rate of adenomatous polyposis coli (APC) mutations, which have both been correlated with taxane resistance. Similarly, small bowel adenocarcinoma (SBA), a rare tumor, also has a low rate of APC mutations. This phase II study evaluated taxane sensitivity in SBA and CIMP-high CRC. Patients and methods: The primary objective was Response Evaluation Criteria in Solid Tumors version 1.1 response rate. Eligibility included Eastern Cooperative Oncology Group performance status 0/1, refractory disease, and SBA or CIMP-high metastatic CRC. Nab-paclitaxel was initially administered at a dose of 260 mg/m² every 3 weeks but was reduced to 220 mg/m² owing to toxicity. Results: A total of 21 patients with CIMP-high CRC and 13 with SBA were enrolled from November 2012 to October 2014. The efficacy-assessable population (patients who received at least three doses of the treatment) comprised 15 CIMP-high CRC patients and 10 SBA patients. Common grade 3 or 4 toxicities were fatigue (12%), neutropenia (9%), febrile neutropenia (9%), dehydration (6%), and thrombocytopenia (6%). No responses were seen in the CIMP-high CRC cohort and two partial responses were seen in the SBA cohort. Median progression-free survival was significantly greater in the SBA cohort than in the CIMP-high CRC cohort (3.2 months compared with 2.1 months, P=0.03). Neither APC mutation status nor CHFR methylation status correlated with efficacy in the CIMP-high CRC cohort. In vivo testing of paclitaxel in an SBA patient-derived xenograft validated the activity of taxanes in this disease type. Conclusion: Although preclinical studies suggested taxane sensitivity was associated with chromosomal stability and wild-type APC, we found that nab-paclitaxel was inactive in CIMP-high metastatic CRC. Nab-paclitaxel may represent a novel therapeutic option for SBA. [ABSTRACT FROM AUTHOR]

Background: Cachexia is a frequent manifestation of pancreatic cancer, can limit a patient's ability to take chemotherapy, and is associated with shortened survival. We developed a model to predict the early onset of cachexia in advanced pancreatic cancer patients.Methods: Patients with newly diagnosed, untreated metastatic or locally advanced pancreatic cancer were included. Serum cytokines were drawn prior to therapy. Patient symptoms were recorded using the M.D. Anderson Symptom Inventory (MDASI). Our primary endpoint was either 10% weight loss or death within 60 days of the start of therapy.Results: Twenty-seven of 89 patients met the primary endpoint (either having lost 10% of body weight or having died within 60 days of the start of treatment). In a univariate analysis, smoking, history symptoms of pain and difficulty swallowing, high levels of MK, CXCL-16, IL-6, TNF-a, and low IL-1b all correlated with this endpoint. We used recursive partition to fit a regression tree model, selecting four of 26 variables (CXCL-16, IL-1b, pain, swallowing difficulty) as important in predicting cachexia. From these, a model of two cytokines (CXCL-16 > 5.135 ng/ml and IL-1b < 0.08 ng/ml) demonstrated a better sensitivity and specificity for this outcome (0.70 and 0.86, respectively) than any individual cytokine or tumor marker.Conclusions: Cachexia is frequent in pancreatic cancer; one in three patients met our endpoint of 10% weight loss or death within 60 days. Inflammatory cytokines are better than conventional tumor markers at predicting this outcome. Recursive partitioning analysis suggests that a model of CXCL-16 and IL-1B may offer a better ability than individual cytokines to predict this outcome. [ABSTRACT FROM AUTHOR]

Background: Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed. Patients and methods: Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays. Results: Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002. Conclusions: Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials. [ABSTRACT FROM AUTHOR]

Background Whether carcinomas of the ampulla of Vater should be classified with biliary tract tumors and treated in a similar manner remains unknown. We sought to compare the outcomes of similarly staged periampullary adenocarcinomas (AAs) and analyze the chemotherapy responsiveness of AAs. Patients and methods A total of 905 patients with resected periampullary adenocarcinomas were identified from a prospective surgical registry from 1988 to 2010. A second cohort of 64 metastatic AA patients from 1992 to 2009 who received either front-line fluoropyrimidine-based or gemcitabine-based chemotherapy was also identified. Results Overall survival (OS) for AAs was similar to survival with duodenal adenocarcinomas, but was significantly different from both extrahepatic biliary and pancreatic adenocarcinomas (P < 0.001 for each comparison). In multivariate analysis, AAs had a significantly improved OS in comparison with extrahepatic biliary adenocarcinomas (HR = 1.97, P = 0.006). Fluoropyrimidine-based as opposed to gemcitabine-based chemotherapy for metastatic AAs resulted in a significant improvement in time to progression (P = 0.001) but only a trend toward benefit for OS (P = 0.07) in multivariate analysis. Conclusions Differences in the natural history of ampullary and extrahepatic biliary adenocarcinomas exist. Analyses of metastatic ampullary adenocarcinomas suggest that fluoropyrimidine-based chemotherapy may represent a more appropriate front-line chemotherapy approach. [ABSTRACT FROM PUBLISHER]

Many chronic illnesses affect bone health, and commonly lead to mineralization abnormalities in young people. As cortical and trabecular bone may be differentially affected in certain diseases, an imaging technique that allows for detailed study of the bone structure is required. Peripheral quantitative computed tomography (pQCT) overcomes the limitations of dual energy X-ray absorptiometry (DXA) and is perhaps more widely available for use in research than bone biopsy. However, in contrast to DXA, where there are large reference datasets, this is not the case for pQCT. Fifty-five children and young adults aged 7 to 30 years had the non-dominant tibia scanned at the 3% & 4% sites for trabecular bone mineral density and the 38% site for cortical bone mineral density and bone mineral content. Image acquisition and analysis was undertaken according to the protocols of two of the largest reference datasets for tibial pQCT. The Z-scores generated were compared to examine the differences between protocols and the differences from the expected median of zero in a healthy population. The trabecular bone mineral density Z-scores generated by the two protocols were similar. The same was true for cortical mineral content Z-scores at the 38% site. Cortical bone mineral density was significantly different between protocols and likely affected by differences in the ethnicity of our cohort compared to the reference datasets. Only one reference dataset extended from childhood to young adulthood. Only trabecular bone mineral density, periosteal and endosteal circumference Z-scores from one methodology were not significantly biased when tested for deviation of the median from zero. pQCT is a useful tool for studying trabecular and cortical compartments separately but, there are variations in pQCT scanning protocols, analysis methodology, and a paucity of reference data. Reference datasets may not be generalizable to local study populations, even when analysed using identical analysis protocols. • pQCT is a useful tool for assessing trabecular and cortical compartments separately. • There is a marked variation in the literature in methods and scanning protocols. • There are few reference datasets to use as comparators. • Reference datasets may not be generalizable to local study populations. [ABSTRACT FROM AUTHOR]

Purpose To evaluate if the gene expression profile of corneal epithelium from the cone area in Keratoconus (KC) differs from the peripheral non-ectatic areas. Hypothesis The ectasia in Keratoconic cornea is localized to the cone while the peripheral areas are apparently normal. Hence we hypothesized that within the cone of a KC patient cornea, the structural weakness may be a function of localized gene expression differences. Methods Study group contained 54 KC patients undergoing epithelium off corneal collagen crosslinking (CXL) and 9 non-ectatic subjects undergoing photo refractive keratectomy (PRK) as controls. The cone vs periphery distinction is based on keratometry and location of the cone based on elevation map. Using a 4.5 mm trephine centered on the cone, epithelium was scraped separately for cone and rest as periphery. In non-ectatic controls, the central 4.5 mm area was taken as cone. Gene expression profiling was performed for each pair of cone and periphery samples by quantitative PCR. Results Lysyl oxidase levels were significantly reduced in the cone of KC patients (p = 0.002). Structure related genes COL1 (p = 0.01) and COL4 (p = 0.008) were also reduced significantly in KC patient cones. The cytokines IL6, TGF β and TNF α did show an increased trend; regulatory cytokine IL10 did not show significant trend. Matrix remodeler MMP9 showed an increasing trend at the cone while its inhibitor TIMP1 showed a reducing trend that was not significant(p = .09). Conclusions Ectasia in KC may be driven by local molecular factors at the cone that possibly spreads to other parts of cornea as disease progresses. [ABSTRACT FROM AUTHOR]

Purpose To evaluate if the gene expression profile of corneal epithelium from the cone area in Keratoconus (KC) differs from the peripheral non-ectatic areas. Hypothesis: The ectasia in Keratoconic cornea is localized to the cone while the peripheral areas are apparently normal. Hence we hypothesized that within the cone of a KC patient cornea, the structural weakness may be a function of localized gene expression differences Methods Study group contained 54 KC patients undergoing epithelium off corneal collagen crosslinking (CXL) and 9 non-ectatic subjects undergoing photo refractive keratectomy (PRK) as controls. The cone vs periphery distinction is based on keratometry and location of the cone based on elevation map. Using a 4.5 mm trephine centered on the cone, epithelium was scraped separately for cone and rest as periphery. In non-ectatic controls, the central 4.5 mm area was taken as cone. Gene expression profiling was performed for each pair of cone and periphery samples by quantitative PCR. Results Lysyl oxidase levels were significantly reduced in the cone of KC patients (p = 0.002). Structure related genes COL1 (p = 0.01) and COL4 (p = 0.008) were also reduced significantly in KC patient cones. The cytokines IL6, TGFβ and TNFα did show an increased trend; regulatory cytokine IL10 did not show significant trend. Matrix remodeler MMP9 showed an increasing trend at the cone while its inhibitor TIMP1 showed a reducing trend that was not significant(p = 0.09). Conclusions Ectasia in KC may be driven by local molecular factors at the cone that possibly spreads to other parts of cornea as disease progresses. [ABSTRACT FROM AUTHOR]

An abstract of the article "The Medium Term Outcome of Chronic Dialysis in Children Under Age of Two, by H. E. Jones and colleagues is presented.