Stiripentol fails to lower plasma oxalate in a dialysis-dependent PH1 patient

Background: Primary hyperoxaluria type 1 (PH1) is a multisystemic metabolic disorder caused by an excessive production of oxalate by the liver. The majority of patients presenting in early infancy have end-stage renal disease (ESRD). While awaiting the results of sRNAi trials, the current standard treatment is combined liver-kidney transplantation. Recently, Stiripentol has been reported as a promising drug in the treatment of primary hyperoxaluria by reducing urinary oxalate (UOx). Stiripentol is an anti-convulsive drug used in the treatment of children suffering from Dravet syndrome. It causes blockage of the last step in oxalate production by inhibition of hepatic lactate dehydrogenase 5 (LDH5). Case: We administered Stiripentol as compassionate use in an anuric infant with dialysis-dependent PH1 over a period of 4 months. Although achieving plasma concentrations of Stiripentol that were recently reported to lower UOx excretion, we did not observe significant reduction to plasma oxalate concentrations (POx). Conclusion: We conclude that Stiripentol may not be useful to reduce POx in PH patients with advanced chronic kidney disease (CKD), but larger studies are needed to confirm this finding

Implementation of Patient-Centered Education for Chronic-Disease Management in Uganda: An Effectiveness Study.

BACKGROUND: The majority of non-communicable disease related deaths occur in low- and middle-income countries. Patient-centered care is an essential component of chronic disease management in high income settings. OBJECTIVE: To examine feasibility of implementation of a validated patient-centered education tool among patients with heart failure in Uganda. DESIGN: Mixed-methods, prospective cohort. SETTINGS: A private and public cardiology clinic in Mulago National Referral and Teaching Hospital, Kampala, Uganda. PARTICIPANTS: Adults with a primary diagnosis of heart failure. INTERVENTIONS: PocketDoktor Educational Booklets with patient-centered health education. MAIN MEASURES: The primary outcomes were the change in Patient Activation Measure (PAM-13), as well as the acceptability of the PocketDoktor intervention, and feasibility of implementing patient-centered education in outpatient clinical settings. Secondary outcomes included the change in satisfaction with overall clinical care and doctor-patient communication. KEY RESULTS: A total of 105 participants were enrolled at two different clinics: the Mulago Outpatient Department (public) and the Uganda Heart Institute (private). 93 participants completed follow up at 3 months and were included in analysis. The primary analysis showed improved patient activation measure scores regarding disease-specific knowledge, treatment options and prevention of exacerbations among both groups (mean change 0.94 [SD = 1.01], 1.02 [SD = 1.15], and 0.92 [SD = 0.89] among private paying patients and 1.98 [SD = 0.98], 1.93 [SD = 1.02], and 1.45 [SD = 1.02] among public paying patients, p<0.001 for all values) after exposure to the intervention; this effect was significantly larger among indigent patients. Participants reported that materials were easy to read, that they had improved knowledge of disease, and stated improved communication with physicians. CONCLUSIONS: Patient-centered medical education can improve confidence in self-management as well as satisfaction with doctor-patient communication and overall care in Uganda. Our results show that printed booklets are locally appropriate, highly acceptable and feasible to implement in an LMIC outpatient setting across socioeconomic groups

Multiplex Mediator Displacement Loop-Mediated Isothermal Amplification for Detection of Treponema pallidum and Haemophilus ducreyi.

Yaws, a neglected tropical disease caused by the bacterium Treponema pallidum subspecies pertenue, manifests as ulcerative skin lesions. Nucleic acid amplification tests, like loop-mediated isothermal amplification (LAMP), are versatile tools to distinguish yaws from infections that cause similar skin lesions, primarily Haemophilus ducreyi. We developed a novel molecular test to simultaneously detect T. pallidum and H. ducreyi based on mediator displacement LAMP. We validated the T. pallidum and H. ducreyi LAMP (TPHD-LAMP) by testing 293 clinical samples from patients with yaws-like lesions. Compared with quantitative PCR, the TPHD-LAMP demonstrated high sensitivity and specificity for T. pallidum (84.7% sensitivity, 95.7% specificity) and H. ducreyi (91.6% sensitivity, 84.8% specificity). This novel assay provided rapid molecular confirmation of T. pallidum and H. ducreyi DNA and might be suitable for use at the point of care. TPHD-LAMP could support yaws eradication by improving access to molecular diagnostic tests at the district hospital level

Differential Response of Pentanal and Hexanal Exhalation to Supplemental Oxygen and Mechanical Ventilation in Rats

High inspired oxygen during mechanical ventilation may influence the exhalation of the previously proposed breath biomarkers pentanal and hexanal, and additionally induce systemic inflammation. We therefore investigated the effect of various concentrations of inspired oxygen on pentanal and hexanal exhalation and serum interleukin concentrations in 30 Sprague Dawley rats mechanically ventilated with 30, 60, or 93% inspired oxygen for 12 h. Pentanal exhalation did not differ as a function of inspired oxygen but increased by an average of 0.4 (95%CI: 0.3; 0.5) ppb per hour, with concentrations doubling from 3.8 (IQR: 2.8; 5.1) ppb at baseline to 7.3 (IQR: 5.0; 10.8) ppb after 12 h. Hexanal exhalation was slightly higher at 93% of inspired oxygen with an average difference of 0.09 (95%CI: 0.002; 0.172) ppb compared to 30%. Serum IL-6 did not differ by inspired oxygen, whereas IL-10 at 60% and 93% of inspired oxygen was greater than with 30%. Both interleukins increased over 12 h of mechanical ventilation at all oxygen concentrations. Mechanical ventilation at high inspired oxygen promotes pulmonary lipid peroxidation and systemic inflammation. However, the response of pentanal and hexanal exhalation varies, with pentanal increasing by mechanical ventilation, whereas hexanal increases by high inspired oxygen concentrations

Challenges to hypertension and diabetes management in rural Uganda: a qualitative study with patients, village health team members, and health care professionals.

BACKGROUND: The prevalence of hypertension and diabetes are expected to increase in sub-Saharan Africa over the next decade. Some studies have documented that lifestyle factors and lack of awareness are directly influencing the control of these diseases. Yet, few studies have attempted to understand the barriers to control of these conditions in rural settings. The main objective of this study was to understand the challenges to hypertension and diabetes care in rural Uganda. METHODS: We conducted semi-structured interviews with 24 patients with hypertension and/or diabetes, 11 health care professionals (HCPs), and 12 community health workers (known as village health team members [VHTs]) in Nakaseke District, Uganda. Data were coded using NVivo software and analyzed using a thematic approach. RESULTS: The results replicated several findings from other settings, and identified some previously undocumented challenges including patients' knowledge gaps regarding the preventable aspects of HTN and DM, patients' mistrust in the Ugandan health care system rather than in individual HCPs, and skepticism from both HCPs and patients regarding a potential role for VHTs in HTN and DM management. CONCLUSIONS: In order to improve hypertension and diabetes management in this setting, we recommend taking actions to help patients to understand NCDs as preventable, for HCPs and patients to advocate together for health system reform regarding medication accessibility, and for promoting education, screening, and monitoring activities to be conducted on a community level in collaboration with village health team members

A Successful Approach to Kidney Transplantation in Patients With Enteric (Secondary) Hyperoxaluria

Background. Enteric hyperoxaluria due to malabsorption may cause chronic oxalate nephropathy and lead to end-stage renal disease. Kidney transplantation is challenging given the risk of recurrent calcium-oxalate deposition and nephrolithiasis. Methods. We established a protocol to reduce plasma oxalic acid levels peritransplantation based on reduced intake and increased removal of oxalate. The outcomes of 10 kidney transplantation patients using this protocol are reported. Results. Five patients received a living donor kidney and had immediate graft function. Five received a deceased donor kidney and had immediate (n = 1) or delayed graft function (n = 4). In patients with delayed graft function, the protocol was prolonged after transplantation. In 3 patients, our protocol was reinstituted because of late complications affecting graft function. One patient with high-output stoma and relatively low oxalate levels had lost her first kidney transplant because of recurrent oxalate depositions but now receives intravenous fluid at home on a routine basis 3 times per week to prevent dehydration. Patients are currently between 3 and 32 months after transplantation and all have a stable estimated glomerular filtration rate (mean, 51 +/- 21 mL/min per 1.73 m(2)). In 4 of 8 patients who underwent for cause biopsies after transplantation oxalate depositions were found. Conclusions. This is the first systematic description of kidney transplantation in a cohort of patients with enteric hyperoxaluria. Common complications after kidney transplantation impact long-term transplant function in these patients. With our protocol, kidney transplantation outcomes were favorable in this population with unfavorable transplantation prospects and even previous unsuccessful transplants

Verbleib von Soziologie-AbsolventInnen der Philipps-Universität Marburg

Soziologie ist an der Philipps-Universität in den 1960er Jahren als akademisches Studienfach entstanden und ab 1972 ausgebaut worden. Neben den beiden Kernbereichen 'Soziologische Theorien' und 'Methoden empirischer Sozialforschung' konnten Studierende Ende der 1990er Jahre zwischen sechs speziellen Soziologien ihre Schwerpunktsetzung wählen. Nach 30 Jahren Soziologie-Studium in Marburg erschien es sinnvoll, Daten und Informationen über den Verbleib der bisherigen Absolventinnen und Absolventen zusammenzutragen. Dieser Aufgabe stellte sich eine Gruppe von Soziologiestudierenden im Grundstudium (2./3. bzw. 3./4. Fachsemester) zusammen mit ihrem Tutor und ihrer Dozentin im Rahmen eines über zwei Semester laufenden Empirischen Praktikums (Oktober 2003 bis Juli 2004). In Anlehnung an Verbleibs- und Studienabbruchs-Studien anderer Hochschulen wurden Fragestellungen für verschiedene Teiluntersuchungen und Erhebungsinstrumente entwickelt, Interviewtechniken trainiert, Daten erhoben und quantitativ bzw. qualitativ ausgewertet sowie der abschließende Forschungsbericht geschrieben. Die Grundgesamtheit wurde (wegen der schwierigen Adressrecherche) auf die Abschlussjahrgänge 1990 bis 2003 beschränkt. Durchgeführt wurden: eine postalische Fragebogenuntersuchung aller erreichbaren AbsolventInnen (realisiert 88 Befragungen); drei berufsbiografische Interviews mit AbsolventInnenen der Jahre 1991-1996-2001; vier perspektivische Leitfadeninterviews (problemzentriert) mit AbsolventInnen des Jahres 2003; zwei Leitfadeninterviews mit einem Abbrecher bzw. einem Studienfachwechsler; Experteninterviews mit potenziellen ArbeitgebervertreterInnen. Für die Analysen wurden je nach Datenstandard statistische Verfahren, qualitative Inhaltsanalyse oder sequenzielle Analyse eingesetzt. Die Befunde ermöglichen Einschätzungen hinsichtlich der damaligen Diplom- und Magisterstudiengänge in Marburg - hinsichtlich Bachelor- und Master-Studiengängen oder für andere Hochschulen müsste eine Studie entsprechend modifiziert werden

Identifikation eines Chlorid-Format-Austauschers, expremiert in der Bürstensaummembran proximaler Tubuluszellen

A key function of the proximal tubule is retrieval of most of the vast quantities of NaCl and water filtered by the kidney. Physiological studies using brush border vesicles and perfused tubules have indicated that a major fraction of Cl-reabsorption across the apical membrane of proximal tubule cells occurs via Cl--formate exchange. The molecular identity of the transporter responsible for renal brush border Cl--formate exchange has yet to be elucidated. As a strategy to identify one or more anion exchangers responsible for mediating Cl- reabsorption in the proximal tubule, the EST database was screened for homologs of pendrin, a transporter previously shown to mediate Cl--formate exchange. This work reports the cDNA cloning of CFEX, a mouse pendrin homolog with expression in the kidney by Northern analysis. Sequence analysis indicated that CFEX very likely represents the mouse ortholog of human SLC26A6. Immunolocalization studies detected expression of CFEX but not pendrin on the brush border membrane of proximal tubule cells. Functional expression studies in Xenopus oocytes demonstrated that CFEX mediates Cl--formate exchange. Taken together, these observations identify CFEX as a prime candidate to mediate Cl--formate exchange in the proximal tubule and thereby to contribute importantly to renal NaCl reabsorption. However, a more detailed functional characterization of CFEX will be necessary in order to clarify its main transport function under physiological conditions. Given its wide tissue distribution, CFEX may also contribute to transcellular Cl- transport in additional epithelia such as the pancreas, and contribute to transmembrane Cl- transport in non-epithelial tissues such as the heart.Der proximale Tubulus der Niere besitzt eine Schlüsselfunktion bei der Wiedergewinnung fast der gesamten Menge des von der Niere filtrierten Kochsalzes und Wassers. Frühere physiologische Untersuchungen an Vesikeln von Bürstensaummembranen des proximalen Tubulus sowie perfundierten Nierentubuli haben gezeigt, daß ein großer Anteil der aktiven Chlorid-Reabsorption durch die apikale Membran proximaler Tubuluszellen über einen Chlorid-Format-Austausch erfolgt. Die molekulare Identität des hierfür verantwortlichen Transportsystems ist bislang noch nicht geklärt. Um einen oder mehrere Anionen-Austauscher zu identifizieren, die die Chlorid-Reabsorption im proximalen Tubulus vermitteln, wurde die EST-Datenbank (Expressed Sequence Tag) nach Homologen von Pendrin durchsucht. Die funktionelle Charakterisierung von Pendrin hatte zuvor gezeigt, dass dieses unter anderem als Chlorid-Format Austauscher operieren kann. Die vorliegende Arbeit beschreibt die cDNA-Klonierung von CFEX (für „Chloride-Formate Exchanger“), einem Homologen des Mäusependrin. Die Sequenzanalyse zeigt, das CFEX offenbar das Mäuseortholog des menschlichen SLC26A6 Gens darstellt. Durch Immunolokalisationsstudien ließ sich zeigen, dass CFEX, jedoch nicht Pendrin, in den Bürstensaummembranen proximaler Tubuluszellen expremiert ist. Funktionsanalysen in Xenopus Eizellen haben gezeigt, daß CFEX sowohl Chlorid als auch Format transportiert und darüberhinaus den Austausch dieser Anionen vermitteln kann. Die Ergebnisse erlauben somit die Schlußfolgerung, dass CFEX als primärer Kandidat für den Chlorid-Format-Austausch im proximalen Tubulus anzusehen ist und daß ihm daher eine Hauptrolle bei der renalen Kochsalzreabsorption zukommen könnte. Allerdings ist eine weiterreichende funktionelle Charakterisierung von CFEX nötig, um seine Transporteigenschaften unter physiologischen Bedingungen zu charakterisieren. Bedenkt man seine weitreichende Verteilung in den Geweben, so ist anzunehmen, dass CFEX auch zum transzellulären Chloridtransport in weiteren Epithelien wie der Bauchspeicheldrüse sowie zum transmembranären Chloridtransport in nichtepithelialen Strukturen wie dem Herzen wesentlich beitragen kann

Sat1 is dispensable for active oxalate secretion in mouse duodenum

Mice deficient for the apical membrane oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium oxalate stones due to a defect in intestinal oxalate secretion. However, the nature of the basolateral membrane oxalate transport process that operates in series with SLC26A6 to mediate active oxalate secretion in the intestine remains unknown. Sulfate anion transporter-1 (Sat1 or SLC26A1) is a basolateral membrane anion exchanger that mediates intestinal oxalate transport. Moreover, Sat1-deficient mice also have a phenotype of hyperoxalemia, hyperoxaluria, and calcium oxalate stones. We, therefore, tested the role of Sat1 in mouse duodenum, a tissue with Sat1 expression and SLC26A6-dependent oxalate secretion. Although the active secretory flux of oxalate across mouse duodenum was strongly inhibited (>90%) by addition of the disulfonic stilbene DIDS to the basolateral solution, secretion was unaffected by changes in medium concentrations of sulfate and bicarbonate, key substrates for Sat1-mediated anion exchange. Inhibition of intracellular bicarbonate production by acetazolamide and complete removal of bicarbonate from the buffer also produced no change in oxalate secretion. Finally, active oxalate secretion was not reduced in Sat1-null mice. We conclude that a DIDS-sensitive basolateral transporter is involved in mediating oxalate secretion across mouse duodenum, but Sat1 itself is dispensable for this process