Using timeliness metrics for household contact tracing and TB preventive therapy in the private sector, India.

Although screening of household contacts (HHCs) of TB patients and provision of TB preventive therapy (TPT) is a key intervention to end the TB epidemic, their implementation globally is dismal. We assessed whether introducing a '7-1-7' timeliness metric was workable for implementing HHC screening among index patients with pulmonary TB diagnosed by private providers in Chennai, India, between November 2022 and March 2023.This was an explanatory mixed-methods study (quantitative-cohort and qualitative-descriptive).There were 263 index patients with 556 HHCs. In 90% of index patients, HHCs were line-listed within 7 days of anti-TB treatment initiation. Screening outcomes were ascertained in 48% of HHCs within 1 day of line-listing. Start of anti-TB treatment, TPT or a decision to receive neither was achieved in 57% of HHC within 7 days of screening. Overall, 24% of screened HHCs in the '7-1-7' period started TPT compared with 16% in a historical control (P < 0.01). Barriers to achieving '7-1-7' included HHC reluctance for evaluation or TPT, refusal of private providers to prescribe TPT and reliance on facility-based screening of HHCs instead of home visits by health workers for screening.Introduction of a timeliness metric is a workable intervention that adds structure to HHC screening and timely management..

The relationship of peritubular capillary density with glomerular volume and kidney function in living kidney donors.

BACKGROUND: Peritubular capillary rarefaction plays an important role in the progression of chronic kidney disease. Little is known about the relation between peritubular capillary density, glomerular volume and filtration rate in the healthy kidney. METHODS: In this single-center study, we included 69 living kidney donors who donated between 2005 and 2008 and had representative renal biopsies available. In all donors, glomerular filtration rate was measured using 125I-Iothalamate before donation and at five years after donation. Before donation, the increase in glomerular filtration rate after dopamine stimulation was measured. Glomerular volume and peritubular capillary density were determined in biopsies taken at the time of transplantation. Pearson's correlation coefficient and linear regression were used to assess relations between parameters. RESULTS: Mean donor age was 52 ± 11 years and mean measured glomerular filtration rate was 119 ± 22 mL/min before donation and 82 ± 15 mL/min at five years after donation. While peritubular capillary density (measured by either number of peritubular capillaries/50,000 µm2 or number of peritubular capillaries/tubule) was not associated with measured glomerular filtration rate before or after donation, number of peritubular capillaries/tubule was associated with the increase in measured glomerular filtration rate after dopamine stimulation (St.ß = 0.33, p = 0.004), and correlated positively with glomerular volume (R = 0.24, p = 0.047). Glomerular volume was associated with unstimulated measured glomerular filtration rate before donation (St.ß = 0.31, p = 0.01) and at five years (St.ß = 0.30, p = 0.01) after donation, independent of age. CONCLUSIONS: In summary, peritubular capillary density was not related to unstimulated kidney function before or after kidney donation, in contrast to glomerular volume. However, number of peritubular capillaries/tubule correlated with the increase in glomerular filtration rate after dopamine stimulation in healthy kidneys, and with glomerular volume. These findings suggest that peritubular capillary density and glomerular volume differentially affect kidney function in healthy living kidney donors.

Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients.

BACKGROUND: In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. METHODS: This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is 'successful transplantation', defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. CONCLUSIONS: The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03797196 , registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

Rituximab in routine care of severe active rheumatoid arthritis : A prospective, non-interventional study in Germany.

OBJECTIVE: To assess safety, effectiveness and onset of effect of rituximab (RTX) in routine clinical treatment of severe, active rheumatoid arthritis (RA). METHODS: Prospective, multi-centre, non-interventional study in rheumatological outpatient clinics or private practices in Germany. RTX-naïve adult patients were to receive RTX according to marketing authorisation and at their physician's discretion. Also according to their physician's discretion, patients could receive a second cycle of RTX (re-treatment = treatment continuation). Major outcome was the change in Disease Activity Score based on 28-joints count and erythrocyte sedimentation rate (DAS28-ESR) over 24 weeks and during 6 months of re-treatment. RESULTS: Overall, 1653 patients received at least one cycle RTX; 99.2% of these had received disease-modifying antirheumatic drugs (DMARD) pre-treatment and 75.5% anti-tumor necrosis factor(TNF)­α pre-treatment. After a mean interval of 8.0 months, 820 patients received RTX re-treatment. Mean DAS28-ESR decreased from 5.3 at baseline to 3.8 after 24 weeks (-1.5 [95% confidence interval, CI: -1.6; -1.4]), and from 4.1 at start of cycle 2 to 3.5 at study end (change from baseline: -1.8 [95% CI: -2.0; -1.7]). Improvements in DAS28-ESR and Health Assessment Questionnaire (HAQ) score occurred mainly during the first 12 weeks of RTX treatment, with further DAS28-ESR improvement until week 24 or month 6 of re-treatment. Improvements in DAS28-ESR and EULAR responses were more pronounced in seropositive patients. RF was a predictor of DAS28-ESR change to study end. Safety analysis showed the established profile of RTX. CONCLUSION: RTX was safe and effective in a real-life setting with rapid and sustained improvement in RA signs and symptoms.

Molecular features of Hepatitis E Virus circulation in environmental and human samples.

BACKGROUND AND OBJECTIVES: Hepatitis E virus (HEV) is emerging but its circulation between humans and the environment remains misunderstood. HEV ORF2 gene encodes the capsid playing a key role in viral interactions with surfaces, ORF3 products are involved in the viral cycle. Our aim was to study the molecular characteristics of ORF2 and ORF3 which could favor HEV fitness in patients and the environment. STUDY DESIGN: Samples from 69 patients with hepatitis (blood/stools), 20 urban wastewaters, 20 effluents of a pig slaughterhouse, 22 farm pigs (stools), 20 wild boars (liver/stools) were collected in North-Eastern France. HEV strains were analyzed by direct sequencing within the ORF2 M region, of ORF2/ORF3, for phylogeny and physicochemical prediction and for ORF2 by ultra-deep sequencing. RESULTS: The results showed frequent HEV-positive samples: 9.1% of the patient bloods, 23.1% of their stools; 25.0% of wastewaters, 75.0% for the slaughterhouse, 10.0% of the boar livers, 5.3% of their stools. The strains were classified as HEV genotype 3. In ORF2, HEV highlighted one homogeneous major viral variant within quasispecies and a decrease in predicted antigenicity for two minor mutations (D442G, V402A). A cysteine signature at position 81 in ORF3 was observed in the boars. CONCLUSIONS: HEV RNA genotype 3 was detected in patients and in animals, in a slaughterhouse effluent and in wastewater. Moreover, the low variability of amino acids in the ORF2 M region and molecular features in ORF2 and ORF3 suggested that HEV strains could be advantageous for key properties.

Renal scintigraphy for post-transplant monitoring after kidney transplantation.

BACKGROUND: Clinicians use several diagnostic modalities to recognize post-transplant complications, such as acute tubular necrosis, acute rejection, urologic and vascular complications. Currently, there is no consensus about the best procedural approach to evaluate post-transplant renal dysfunction. Renal needle-biopsy is often required, however, this is invasive and may lead to sample errors and complications, and most clinicians prefer using one of the noninvasive diagnostic modalities. METHODS: A systematic literature search was performed using PubMed, EMBASE, the Cochrane Library, MEDLINE (OvidSP), Web of Science, and Google Scholar to identify relevant articles. This review provides a literature overview of the technical aspects, new developments and clinical value of renal scintigraphy (RS), after kidney transplantation. Additionally, the advantages and limitations of RS in comparison to other diagnostic modalities are addressed. The study protocol is registered with PROSPERO, protocol number CRD42017078391. RESULTS: A total of 32 studies were included. Studies were categorized in the following groups: tracer pharmacokinetics; acute rejection and acute tubular necrosis; vascular complications; urological complications; postoperative fluid collections; early transplant outcomes; one-year transplant outcomes. CONCLUSIONS: Several studies have described the use of RS for the diagnosis of acute rejection, however, differentiating between rejection and acute tubular necrosis remains difficult. For the diagnosis of vascular complications, RS has been described as an alternative for invasive procedures. For urologic complications, studies support the use of RS in combination with routine ultrasonography (US) surveillance. For the diagnosis of postoperative fluid collections, RS provides information to differentiate lymphoceles and urinomas. Altogether, RS should be considered in case of non-acute complications, and if US provides insufficient results.

Lipodystrophy and obesity are associated with decreased number of T cells with regulatory function and pro-inflammatory macrophage phenotype.

BACKGROUND/OBJECTIVES: In lipodystrophy (LD) adipose tissue function to store lipids is impaired, leading to metabolic syndrome, similar to that found in obesity. Emerging evidence links dysmetabolism with disorders of the immune system. Our aim is to investigate whether T-cell populations with regulatory function and monocyte-derived macrophages (MDMs) are affected by LD and obesity. SUBJECTS/METHODS: Blood was collected from 16 LD, 16 obese (OB, BMI>30 kg m-2) and 16 healthy normal-weight women (CNT). Physical parameters, plasma lipid profile, glucose, HbA1c, leptin levels were determined. Flow cytometry was employed to assess the number of circulating CD4+/CD25hi regulatory T cells (Tregs) and invariant natural killer T (iNKT) cells. Characterization of MDMs included: 1. morphological/oil-Red-O staining analyses to define two morphotypes: lipid laden (LL) and spindle-like (sp) MDM; 2. gene expression studies; 3. use of conditioned medium from MDMs (MDMs CM) on human SGBS cells. RESULTS: As compared to CNT, LD and, to a lesser extent, obesity were associated with reduced Tregs and iNKTs (P<0.001 and P<0.01 for LD and OB, respectively), higher number of LL-MDMs (P<0.001 and P<0.01 for LD and OB, respectively), lower number of sp-MDMs (P<0.001 for both LD and OB), which correlated with increased paracrine stimulation of lipid accumulation in cells (P<0.001 and P<0.01 for LD and OB, respectively). LD MDMs showed decreased and increased expression for anti-inflammatory (IL10 and CD163) and pro-inflammatory (CD68 and CCL20) marker genes, respectively. Analysis of correlation indicated that Tregs are directly related with HDL (P<0.01) and inversely related with LL-MDM (P<0.001) and that LL-MDM are directly related with triglycerides (P<0.01) and oxidized LDL (P<0.01). CONCLUSIONS: LD and obesity are associated with changes in the immune system: a significant reduction in the number of T cells with regulatory function and a shift of MDM towards lipid accumulation. Lipid profile of the patients correlates with these changes.

Propofol-based anaesthesia versus sevoflurane-based anaesthesia for living donor kidney transplantation: results of the VAPOR-1 randomized controlled trial.

BACKGROUND: Kidney transplantation is associated with harmful processes affecting the viability of the graft. One of these processes is associated with the phenomenon of ischaemia-reperfusion injury. Anaesthetic conditioning is a widely described strategy to attenuate ischaemia-reperfusion injury. We therefore conducted the Volatile Anaesthetic Protection of Renal Transplants-1 trial, a pilot project evaluating the influence of two anaesthetic regimens, propofol- vs sevoflurane-based anaesthesia, on biochemical and clinical outcomes in living donor kidney transplantation. METHODS: Sixty couples were randomly assigned to the following three groups: PROP (donor and recipient propofol), SEVO (donor and recipient sevoflurane), and PROSE (donor propofol and recipient sevoflurane). The primary outcome was renal injury reflected by urinary biomarkers. The follow-up period was 2 yr. RESULTS: Three couples were excluded, leaving 57 couples for analysis. Concentrations of kidney injury molecule-1 (KIM-1), N -acetyl-ß- d -glucosaminidase (NAG), and heart-type fatty acid binding protein (H-FABP) in the first urine upon reperfusion showed no differences. On day 2, KIM-1 concentrations were higher in SEVO [952.8 (interquartile range 311.8-1893.0) pg mmol -1 ] compared with PROP [301.2 (202.0-504.7) pg mmol -1 ]. This was the same for NAG: SEVO, 1.835 (1.162-2.457) IU mmol -1 vs PROP, 1.078 (0.819-1.713) IU mmol -1 . Concentrations of H-FABP showed no differences. Measured glomerular filtration rate at 3, 6, and 12 months showed no difference. After 2 yr, there was a difference in the acute rejection rate ( P =0.039). Post hoc testing revealed a difference between PROP (35%) and PROSE (5%; P =0.020). The difference between PROP and SEVO (11%) was not significant ( P =0.110). CONCLUSIONS: The SEVO group showed higher urinary KIM-1 and NAG concentrations in living donor kidney transplantation on the second day after transplantation. This was not reflected in inferior graft outcome. CLINICAL TRIAL REGISTRATION: NCT01248871.

Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized-Controlled MECANO Trial.

In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.

Exploring the Dynamic Relationship Between Cellular Metabolism and Chromatin Structure Using SILAC-Mass Spec and ChIP-Sequencing.

Metabolic state and chromatin structure are tightly linked, enabling adaptation of gene expression to changing environment and metabolism. The bioenergetic pathways and enzymes that provide metabolic cofactors for histone modification have recently emerged as central regulators of chromatin. Current research therefore focuses on the dynamic interface of cellular metabolism and chromatin structure. Here, we provide an adaptable approach to examine broadly in changing physiological states, how chromatin structure is dynamically modulated by metabolic activity. We employ two complementary methods: high-throughput sequencing to establish the location of epigenetic changes, and stable isotope tracing using mass spectrometry to evaluate chromatin modification dynamics. Our two-pronged approach is of particular advantage when interrogating how metabolic and oncogenic mutations influence the dynamic relationship between metabolism, nutritional environment, and chromatin regulation.

mTORC1 directly phosphorylates and activates ERα upon estrogen stimulation.

Breast cancer is the leading cause of cancer-related deaths among women. Approximately 75% of breast cancers are estrogen receptor-α (ERα) positive, underscoring the dependence of cancer cells on estrogen for growth and survival. Patients treated with endocrine therapy often develop resistance, either de novo or acquired, which in some cases is caused by aberrations within the growth factor signaling pathways. The mechanistic target of rapamycin complex 1 (mTORC1) has emerged as a critical node in estrogenic signaling. We have previously shown that mTORC1 can phosphorylate and activate ERα on S167 via its effector-the 40S ribosomal S6 kinase 1 (S6K1). Presently, we have uncovered a direct link between mTORC1 and ERα. We found that ERα binds to regulatory-associated protein of mTOR (Raptor) and causes it to translocate to the nucleus upon estrogen stimulation. In addition, we identified mTOR as the kinase that phosphorylates ERα on S104/106 and activates transcription of ER target genes. Our findings show a direct link between mTORC1 and ERα, which further implicates mTORC1 signaling in the pathogenesis of ER-positive breast cancer and provides rationale for FDA-approved use of mTORC1 inhibitors in combination with endocrine agents for treatment of this disease.

Inducible Nitric Oxide Inhibitors Block NMDA Antagonist-Stimulated Motoric Behaviors and Medial Prefrontal Cortical Glutamate Efflux.

Nitric oxide (NO) plays a critical role in the motoric and glutamate releasing action of N-methyl-D-aspartate (NMDA)-antagonist stimulants. Earlier studies utilized neuronal nitric oxide synthase inhibitors (nNOS) for studying the neurobehavioral effects of non-competitive NMDA-antagonist stimulants such as dizocilpine (MK-801) and phencyclidine (PCP). This study explores the role of the inducible nitric oxide synthase inhibitors (iNOS) aminoguanidine (AG) and (-)-epigallocatechin-3-gallate (EGCG) in NMDA-antagonist induced motoric behavior and prefrontal cortical glutamate efflux. Adult male rats were administered a dose range of AG, EGCG, or vehicle prior to receiving NMDA antagonists MK-801, PCP, or a conventional psychostimulant (cocaine) and tested for motoric behavior in an open arena. Glutamate in the medial prefrontal cortex (mPFC) was measured using in vivo microdialysis after a combination of AG or EGCG prior to MK-801. Acute administration of AG or EGCG dose-dependently attenuated the locomotor and ataxic properties of MK-801 and PCP. Both AG and EGCG were unable to block the motoric effects of cocaine, indicating the acute pharmacologic action of AG and EGCG is specific to NMDA antagonism and not generalizable to all stimulant class drugs. AG and EGCG normalized MK-801-stimulated mPFC glutamate efflux. These data demonstrate that AG and EGCG attenuates NMDA antagonist-stimulated motoric behavior and cortical glutamate efflux. Our results suggest that EGCG-like polyphenol nutraceuticals (contained in "green tea" and chocolate) may be clinically useful in protecting against the adverse behavioral dissociative and cortical glutamate stimulating effects of NMDA antagonists. Medications that interfere with NMDA antagonists such as MK-801 and PCP have been proposed as treatments for schizophrenia.

Immunosuppressive therapy in patients with IgA nephropathy.

BACKGROUND: There is limited evidence to support cytotoxic therapy in patients with IgA nephropathy and renal insufficiency. We studied the effect of cytotoxic therapy in patients with IgA nephropathy and renal insufficiency, and evaluated possible predictors of response. METHODS: Retrospective analysis of patients with IgA nephropathy who received immunosuppressive therapy. The primary outcome measure was progression of renal disease, defined as an increase in serum creatinine levels of ≥ 50% or development of end-stage renal disease. RESULTS: From 1996 to 2008, 19 patients with biopsy-proven IgA nephropathy were treated with cytotoxic agents and prednisone because of renal insufficiency and÷ or severe proteinuria. Characteristics of patients at the start of therapy: age 42±11 years, serum creatinine 208 (96-490) µmol÷l, estimated glomerular filtration rate (eGFR) 33 (12-65) ml÷min÷1.73 m2, and protein- creatinine ratio 3.8 (0.6-18.2) g÷10 mmol. Follow-up after initiation of therapy was 35 (7-133) months. Ten patients had progressive renal disease, whereas eGFR was stable in nine. Serum creatinine levels and proteinuria at the start of treatment were not significantly different between responders and non- responders. Proteinuria response at six months after start of therapy proved a good predictor: proteinuria decreased by ≥ 50% and÷or reached levels below 1 g÷day in 8÷9 responders. In contrast, proteinuria decreased by more than 50% and reached levels < 1 g÷day in only 3÷10 non-responders (p < 0.01). CONCLUSION: Prolonged immunosuppressive therapy with cytotoxic agents and prednisone may benefit a subgroup of patients with progressive IgA nephropathy. A reduction of proteinuria ≥ 50% to levels below 1 g÷day within six months predicts a favourable long-term response.

Impact of metabolic disorders on the relation between overweight/obesity and incident myocardial infarction and ischaemic stroke in fertile women: a nationwide cohort study.

AIMS: Whether overweight is a risk factor for cardiovascular disease in the absence of metabolic disorders remains under debate and is largely unexamined in young women. We evaluated the risk of myocardial infarction and ischaemic stroke in fertile women conditional on time-dependent presence of metabolic disorders. MATERIALS AND METHODS: From nationwide registers we identified all normal weight (body mass index [BMI] ≥ 18.5 to <25 kg m(-2) and overweight (BMI ≥ 25 kg m(-2)) Danish women giving birth from 2004 to 2009. Using multivariable Poisson regression models adjusted for age, calendar year and smoking, the risk of the composite outcome of myocardial infarction and ischaemic stroke was assessed with metabolic disorders (i.e. hypertensive conditions, abnormal glucose metabolism and/or dyslipidaemia) included as time-dependent variables. RESULTS: The population comprised 261,489 women with median age of 30.5 years (interquartile range = [27.3, 33.8]). Median follow-up was 5.6 years (interquartile range = [4.0, 6.8]). Compared with normal weight women without metabolic disorders (with an incidence rate [IR] of 17.0 [95% confidence interval {CI} = 14.5-20.0] events per 100,000 person-years), overweight women without metabolic disorders had no significantly increased risk, IR 22.6 (CI = 18.3-27.8), adjusted incidence rate ratio (IRR), 1.26 (CI = 0.97-1.65). For women with metabolic disorders, IR was 30.2 (CI = 18.8-48.6) and adjusted IRR 1.77 (CI = 1.07-2.93) in normal weight, while IR was 87.1 (CI = 67.6-112.2) and IRR 4.24 (CI = 5 3.11-5.79) in overweight. CONCLUSIONS: The risk of myocardial infarction and ischaemic stroke was more strongly associated with the presence of metabolic disorders than with overweight per se in fertile women. Targeting prevention of metabolic disorders might be beneficial to reduce cardiovascular disease in overweight/obese young women.

Pancreatitis recurrente por disquinesia hipertónica del esfínter de oddi: tratamiento endoscópico y seguimiento a largo plazo en un caso clínico / Recurrent pancreatitis caused by oddi sphincter’s hypertonic dyskinesia: case report of endoscopic treatment and long-term follow-up

It is frequently difficult to determine the exact cause of recurrent acute pancreatitis (RAP), which can be life threatening in several cases. Not detected biliary microlithiasis is the most frequent etiology, buthypertonic dyskinesis of Oddi’s sphincter also can cause RAP. Non-invasive diagnosis of this functional disorder is difficult, endoscopic manometry of Oddi’s sphincter allows measuring pressure in the choledochus,in the pancreatic duct and specifically in the sphincter region. Once hypertonic dyskinesis is demonstrated, the treatment option is the partial or total ablation of the sphincter, via endoscopic or surgical methods. This intervention results in an improvement or complete resolution in about 70 percent of the patients, preventing new bouts of acute pancreatitis and eventual progression to chronic disease. In this paper, we describe the history of one of our patients, who consulted more than ten years after cholecystectomy for recurrent abdominal pain and presented three episodes of acute pancreatitis. Endoscopic manometry of Oddi’s sphincter was performed in 1997, with the detection of very high pressure in biliary and pancreatic segments of the sphincter, demonstrating hypertonic dyskinesis involving both segments. A dual endoscopic sphincterotomy was performed, followed by marked reduction in the pressure of biliopancreatic ducts and Oddi’s sphincter and in abolition of choledocho-duodenal and pancreatic-duodenal gradient. She was asymptomatic till 2002, later on, she required endoscopic pneumatic dilatation of the sphincterotomy. She had no more acute pancreatitis episodes and CT scan in 2014 showed a normal pancreas.

Con frecuencia resulta difícil determinar la etiología de la pancreatitis aguda recurrente (PAR), que puede amenazar hasta la vida del paciente. Aparte de la patología litiásica biliar no diagnosticada, la disquinesia hipertónica del esfínter de Oddi (EO) causa con cierta frecuencia PAR. Su diagnóstico no invasivo es difícil, la manometría del esfínter de Oddi permite medir los valores de la presión en la vía biliar, en el conducto pancreático y en la región del esfínter. Una vez que la disquinesia hipertónica se demuestra, su tratamiento es la ablación parcial o total del esfínter, con método endoscópico o quirúrgico, con resolución del cuadro clínico en aproximadamente 70 por ciento de los pacientes, logrando evitar los nuevos brotes de pancreatitis aguda (PA) y la eventual progresión hacia pancreatitis crónica. En este trabajo describimos la historia de una paciente colecistectomizada, quien después de varios años de dolor abdominal recurrente, presentó tres brotes de PA. Manometría de EO fue realizada en 1997, detectando presiones muy elevadas, comprobando disquinesia hipertónica de los segmentos biliar y pancreático del esfínter. Se realizó esfinterotomía endoscópica doble, seguida por gran disminución de los valores de presión, abolición del gradiente colédoco-duodenal y pancreático-duodenal. Estuvo asintomática hasta el 2002, y posteriormente requirió dilatación neumática de los orificios de esfinterotomías. No ha tenido más recaídas de pancreatitis, la tomografía computada de control en noviembre de 2014 mostró un páncreas normal.

Induction therapy with short-term high-dose intravenous cyclophosphamide followed by mycophenolate mofetil in proliferative lupus nephritis.

BACKGROUND: For decades, high-dose intravenous cyclophosphamide (ivCY) given for 24-30 months was regarded as the standard therapy for proliferative lupus nephritis, despite serious side effects. Our aim was to evaluate the effect of induction therapy with short-term high-dose ivCY followed by mycophenolate mofetil (MMF) on disease parameters, mortality and health-related quality of life (HRQoL) in patients with proliferative lupus nephritis. METHODS: Between January 2003 and November 2006, 71 patients with biopsy-proven proliferative lupus nephritis were included in the second Dutch Lupus Nephritis Study. All patients were treated with ivCY (750 mg÷m2, six monthly pulses) plus oral prednisone, followed by MMF (2000 mg÷day) plus oral prednisone for 18 months, and then azathioprine (2 mg÷kg÷day) plus oral prednisone. Study endpoints included the occurrence of renal relapse, end-stage renal disease (ESRD) and mortality. RESULTS: After a median follow-up of 3.8 years (range 0.1-4.5), four (5.6%) of the 71 patients had a renal relapse, one (1.4%) failed treatment, one (1.4%) reached ESRD, and two (2.8%) died. Systemic lupus erythematosus (SLE) Disease Activity Index, serum creatinine, proteinuria and antibodies against anti-dsDNA decreased significantly during treatment and serum levels of complement factor 3 and 4 increased significantly. Furthermore, six of eight domains of the Short Form-36 as well as the number of symptoms and total distress level according to the SLE Symptom Checklist improved significantly over time. CONCLUSIONS: This open-label study shows that induction therapy with short-term (six monthly pulses) high-dose ivCY followed by MMF is effective in preventing renal relapses, ESRD and mortality and improving HRQoL in patients with proliferative lupus nephritis.

[Patient satisfaction in oncological aftercare--differential results of gender aspects in doctor-patient dyads]. / Patientenzufriedenheit in der onkologischen Nachsorge--differentielle Befunde zur Geschlechtsspezifik in Arzt-Patient-Dyaden.

OBJECTIVE: The aim of this study was to explore the role of gender of the physician and gender of the patient in explaining differences in patient satisfaction. MATERIAL AND METHODS: Overall, 1,130 patients were assigned to one of 4 possible physician-patient sex dyads and were interviewed with a questionnaire about their patient satisfaction. RESULTS: Female patients in a dyad with a female physician were most satisfied with the overall judgment of practice visit and the inclusion of life situation in comparison to all other dyads. Male patients in a dyad with a male physician were least satisfied. CONCLUSION: In the future, the specific role of patient-physician dyads has to be considered more in the assessment of subdimensions of patient satisfaction.

Cathepsin proteases promote angiogenic sprouting and laser-induced choroidal neovascularisation in mice.

Cysteine cathepsins are a family of proteases involved in intracellular protein turnover and extracellular matrix degradation. Cathepsin B (Ctsb) and cathepsin Z (Ctsz) promote tumorigenesis and Ctsb is a known modulator of tumor angiogenesis. We therefore investigated the angiomodulatory function of these cathepsins in vitro as well as in a mouse model of laser-induced choroidal neovascularization (laser-CNV). Ctsb(-/-), Ctsz(-/-), Ctsb/Ctsz double-knockout (Ctsb/z DKO), and wild type (WT) mice underwent argon laser treatment to induce choroidal neovascularization (CNV). The neovascularized area was quantified individually for each lesion at 14 days after laser coagulation. In vitro the effects of cathepsin inhibitors on angiogenesis were analysed by endothelial cell (EC) spheroid sprouting and EC invadosome assays. Retinas from cathepsin KO mice did not show gross morphological abnormalities. In the laser CNV model, however, Ctsb/z DKO mice displayed a significantly reduced neovascularized area compared to WT (0.027 mm(2) vs. 0.052 mm(2); p = 0.012), while single knockouts did not differ significantly from WT. In line, VEGF-induced EC spheroid sprouting and invadosome formation were not significantly altered by a specific cathepsin B inhibitor alone, but significantly suppressed when more than one cathepsin was inhibited. Our results demonstrate that laser-CNV formation is significantly reduced in Ctsb/z DKO mice. In line, EC sprouting and invadosome formation are blunted when more than one cathepsin is inhibited in vitro. These results reveal an angiomodulatory potential of cathepsins with partial functional redundancies between different cathepsin family members.

Patient participation in the medical decision-making process in haemato-oncology--a qualitative study.

Cancer patients are showing increased interest in shared decision-making. Patients with haematological illnesses, however, express considerably less desire for shared decision-making as compared with other oncological patient groups. The goal of the current project was to identify the reasons for the lower desire for shared decision-making among patients with haematological illness. We conducted qualitative, semi-structured interviews with 11 haematological patients (39-70 years old) after the beginning of therapy concerning the course and evaluation of medical shared decision-making. The patients were often overwhelmed by the complexity of the illness and the therapy and did not want to assume any responsibility in medical decision-making. They reported a great deal of distress and very traditional paternalistic role expectations with regards to their health care providers, which limited the patients' ability to partake in the decision-making process. In contrast to the socio-cultural support for many other oncological diseases, haematological diseases are not as well supported, e.g. there is a lack of self-help materials, systematic provision of information and support groups for patients, which may be related to a lower empowerment of this patient population. Results show the limits of patient participation in the context of highly complicated medical conditions. In addition to already researched preferences of the physicians and patients for shared decision-making, future research should pay greater attention to the process and other variables relevant to this aspect of the doctor-patient relationship.

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model.

Despite the prominent pro-apoptotic role of p53, this protein has also been shown to promote cell survival in response to metabolic stress. However, the specific mechanism by which p53 protects cells from metabolic stress-induced death is unknown. Earlier we reported that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific member of a family of mitochondria-associated enzymes that have a central role in fatty acid metabolism promotes cell survival and tumor growth. Unlike other members of the CPT family, the subcellular localization of CPT1C and its cellular function remains elusive. Here, we report that CPT1C is a novel p53-target gene with a bona fide p53-responsive element within the first intron. CPT1C is upregulated in vitro and in vivo in a p53-dependent manner. Interestingly, expression of CPT1C is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53 and AMP activated kinase-dependent manner. Furthermore, in a murine tumor model, depletion of Cpt1c leads to delayed tumor development and a striking increase in survival. Taken together, our results indicate that p53 protects cells from metabolic stress via induction of CPT1C and that CPT1C may have a crucial role in carcinogenesis. CPT1C may therefore represent an exciting new therapeutic target for the treatment of hypoxic and otherwise treatment-resistant tumors.