Defining the decision problem: a scoping review of economic evaluations for Clostridioides difficile interventions.

BACKGROUND: Clostridioides difficile infection is the leading cause of healthcare-associated infectious diarrhoea. Several preventative and treatment interventions exist; however, decisions for their use are typically made independent of other interventions along the care pathway. AIM: To assess how the scope of the decision problem is defined in economic evaluations of C. difficile interventions. METHODS: A scoping review was conducted following the Joanna Briggs Institute framework using a comprehensive literature search with C. difficile and economic evaluation as key search concepts. Study selection and extraction were performed independently by two reviewers. An in-depth analysis of all cost-utility and cost-effectiveness analyses was conducted. Care pathway domains (i.e. infection prevention and control, antimicrobial stewardship programmes, prevention, diagnostics, treatment) were defined iteratively, and each study was classified according to the scope of the decision problem: (i) one intervention, one domain; (ii) one intervention, multiple domains; (iii) multiple interventions, one domain; and (iv) multiple interventions, multiple domains. RESULTS: In total, 3886 studies were identified. Of these, 116 studies were included in the descriptive overview, and 46 were included in the in-depth analysis. Most studies limited the scope of the decision problem to one intervention (43/46; 93%). Only three studies (3/46; 7%) assessed multiple interventions - either as bundled vs standalone interventions for prevention (i.e. a single domain), or as sequences of treatments for initial and recurrent infection (i.e. multiple domains). No study assessed multiple interventions across prevention and treatment domains. CONCLUSIONS: Economic evaluations for C. difficile infection assess narrowly defined decision problems which may have implications for optimal healthcare resource allocation.

Estimating chronic hepatitis C prognosis using transient elastography-based liver stiffness: A systematic review and meta-analysis.

Chronic hepatitis C (CHC) is a leading cause of hepatic fibrosis and cirrhosis. The level of fibrosis is traditionally established by histology, and prognosis is estimated using fibrosis progression rates (FPRs; annual probability of progressing across histological stages). However, newer noninvasive alternatives are quickly replacing biopsy. One alternative, transient elastography (TE), quantifies fibrosis by measuring liver stiffness (LSM). Given these developments, the purpose of this study was (i) to estimate prognosis in treatment-naïve CHC patients using TE-based liver stiffness progression rates (LSPR) as an alternative to FPRs and (ii) to compare consistency between LSPRs and FPRs. A systematic literature search was performed using multiple databases (January 1990 to February 2016). LSPRs were calculated using either a direct method (given the difference in serial LSMs and time elapsed) or an indirect method given a single LSM and the estimated duration of infection and pooled using random-effects meta-analyses. For validation purposes, FPRs were also estimated. Heterogeneity was explored by random-effects meta-regression. Twenty-seven studies reporting on 39 groups of patients (N = 5874) were identified with 35 groups allowing for indirect and 8 for direct estimation of LSPR. The majority (~58%) of patients were HIV/HCV-coinfected. The estimated time-to-cirrhosis based on TE vs biopsy was 39 and 38 years, respectively. In univariate meta-regressions, male sex and HIV were positively and age at assessment, negatively associated with LSPRs. Noninvasive prognosis of HCV is consistent with FPRs in predicting time-to-cirrhosis, but more longitudinal studies of liver stiffness are needed to obtain refined estimates.

Human growth hormone receptor (GHR) expression in obesity: II. Regulation of the human GHR gene by obesity-related factors.

BACKGROUND AND METHODS: In our previous analyses, we found significantly lower levels of growth hormone receptor (GHR) mRNA in adipose tissues of obese than in those of lean individuals, suggesting that idiopathic obesity involves GH resistance due to decreased GHR availability. To understand the mechanism(s) behind this downregulation, we performed an in silico analysis of the three most relevant GHR gene promoters, which revealed putative response elements (REs) for a number of obesity adipose-associated factors, including tumor necrosis factor-alpha (TNFα), hypoxia-inducible factor-1-alpha (HIF-1α) and glucocorticoids. We then characterized the dose-dependent effects of these factors on GHR expression in HEK293 cells and in mature human SGBS (Simpson-Golabi-Behmel syndrome) adipocytes using quantitative reverse transcriptase-PCR and assessed the function of their putative REs by luciferase-reporter assays, site-directed mutagenesis and chromatin immunoprecipitation (ChIP) assays. RESULTS: TNFα treatments significantly reduced GHR mRNA levels and GHR promoter activities at doses ≥ 10 ng ml(-1) in both cell lines. Transient overexpression of HIF-1α or exposure to the hypoxia mimetic CoCl(2) significantly increased GHR mRNA levels and promoter activities. Dexamethasone had biphasic effects: there was a significant increase in GHR mRNA levels at 10(-10) M and in promoter activities at 10(-10) and 10(-8) M, whereas a significant decrease in both mRNA levels and promoter activities occurred at 10(-6) M. Site-directed mutagenesis of the putative nuclear factor-κB, HIF-1α and glucocorticoid REs resulted in the loss of these effects, whereas ChIP analysis confirmed specific transcription factor-promoter interactions. CONCLUSIONS: Our results suggest that the increased activity of TNFα, HIF-1α and glucocorticoids in obese adipose tissues could alter GHR gene transcription through specific REs and that TNFα may be involved in the development of GH resistance.

Human growth hormone receptor (GHR) expression in obesity: I. GHR mRNA expression in omental and subcutaneous adipose tissues of obese women.

OBJECTIVES: Growth hormone (GH)-deficient individuals display increased adiposity that can be effectively reduced by GH therapy because of GH's lipolytic effects. However, similar GH treatments of individuals with idiopathic obesity (not associated with an endocrinopathy/syndrome) have had little success. We hypothesized that this form of obesity may be associated with GH resistance at the level of the adipocyte because of reduced GH receptor (GHR) expression. SUBJECTS AND METHODS: We studied GHR expression in omental and subcutaneous fat tissues from a cohort of 55 women ranging from lean to obese by various adiposity parameters. mRNA levels of total GHR and the dominant-negative truncated GHR(1-279) (trGHR) form were assayed by quantitative reverse transcriptase-PCR. Associations between adiposity measures and GHR levels as well as trGHR/GHR ratios were analyzed. RESULTS: Total GHR mRNA expression was 2-3-fold lower in omental as well as subcutaneous adipose tissues of obese compared with lean women (P ≤ 0.05-0.001). Lean individuals expressed higher GHR mRNA levels in omental fat compared with subcutaneous (P ≤ 0.01); in obese women, this depot-specific difference was lost. Omental and subcutaneous adipose GHR mRNA levels displayed significant negative correlations with a spectrum of indicators of obesity while, in subcutaneous fat, there was a significantly higher trGHR/GHR ratio with increasing adiposity (P ≤ 0.05). CONCLUSION: These results support our hypothesis that, with obesity, there is lower GHR expression in the adipocyte, and suggest one possible explanation why GH supplementation is not an effective treatment for individuals with idiopathic obesity.

Superficial cell differentiation during embryonic and postnatal development of mouse urothelium.

After drastic urothelial destruction around birth and around postnatal day 6, mouse urothelial renewal starts each time de novo. The differentiation of superficial cells during urothelial restoration was followed for the first time from embryonic day 15 to postnatal day 6 by the detection of differentiation markers: cytokeratins, uroplakins and apical membrane specialization. The differentiation markers of short-lived superficial cells were studied before and after urothelial destruction. Three distinctive types of superficial cells, typical for certain developmental period, were characterised: cells at low differentiation stage with microvilli and cilia, expressing CK7 and CK18, detected on embryonic day 15; cells at advanced differentiation stage with star-like arrangement of prominent membrane ridges, expressing CK7 and CK20, present between the two urothelial destruction events; highly differentiated cells with typically jagged apical surface, expressing CK7 and CK20, found twice during development. This cell type appears for the first time on embryonic day 18 as the terminal stage of embryonic differentiation. It was found again on postnatal day 6 as an initial stage of differentiation, leading toward terminally differentiated cells of the adult urothelium. Our work proves that apical membrane specialization is the most valuable differentiation marker of superficial cells.

[Recurrent meningiomas with progressive aggressiveness and posterior extracranial extension]. / Meningiomas recidivantes con agresivisad progresiva y posterior extensión extracraneana. Análisis de 2 casos.

Meningiomas are in most cases benign tumors. They represent about 15% of primitive intracranial tumors. Complete surgical resection achieves healing in the majority of patients. Recurrences occur in 9 to 12% in spite of that kind of surgical resection in the initial approach. This percentage rises to 40% when removing was not complete. Recurrences sometimes show histological changes into aggressiveness, and even malignization. Two cases of originally benign meningiomas with several recurrences and progressive aggressive behaviour are presented. Both cases led to extracranial extension of the lesions, even passing through synthetic dural grafts (De Bakey's Dacron Fabric-Elastic) and the Titanium mesh covering the craniectomy.

[Names-Lab : a model for the standardization of biology message exchanges]. / Names-Lab: un modèle de normalisation des messages de biologie.

The growing requirements of communication between health partners urges to standardize the language used in laboratories data management systems. Names-Lab is the only semantic reference system allowing to describe synchronously the body of prescription and result messages. Its hierarchical structure allows a simple coding, easily accessible to all biologists without imposing or even requiring a language. Other internationally proposed systems as Loinc and Euclides are similar to Names-Lab in their purposes but are completely different by their content and structure. This prompts the medical and biologic community for a comparison of these tools before setting the choice of an international referencing system.

Beta2-microglobulin and hypertensive complications in pregnant women at risk.

BACKGROUND AND AIM: Beta2-microglobulin (beta2-m) is a polypeptide, which is freely filtered through the glomerular basement membrane and absorbed almost entirely by the proximal tubular cells. Preeclampsia, a common complication of pregnancy, is characterized by pathological renal changes, mainly glomerular lesions. The aim of the present study was to investigate whether serum beta2-m measured in the early stages of pregnancy could be used as a marker to predict hypertensive complications in women at increased risk. PATIENTS AND METHODS: Serum beta2-m concentrations were prospectively measured in 75 pregnant women with history of chronic hypertension, chronic renal disease, chronic vascular disease or preeclampsia and compared with those in 16 healthy pregnant women. RESULTS: Of the 75 women in the study group, 10 (13%) developed preeclampsia and 20 (26%) had other complications, such as intrauterine growth restriction (n = 8), fetal or neonatal loss (n = 9) and delivery before 30 weeks of gestation (n = 8). Gestational age at delivery, birth weight and cesarean section rate were significantly worse in the patients with complications than in those without and in the healthy controls. No significant difference was detected in early serum beta2-m concentrations between the women who later developed preeclampsia or other complications and those who did not. There was a significant positive correlation of beta2-m concentrations with serum creatinine level (R2 = 0.394, p < 0.001), but not with gestational week at blood collection. CONCLUSION: Serum beta2-m concentrations are not predictive of the development of preeclampsia or other complications in woman at risk.

Postnatal restoration of the mouse urinary bladder urothelium.

Mouse urothelium is disrupted just before birth, followed by a postnatal restoration process which includes cell proliferation, death and differentiation. We assessed urothelial proliferation by the expression of proliferating cell nuclear antigen (PCNA), desquamation by electron microscopy, and apoptosis by TUNEL staining and urothelial differentiation by the expression of uroplakins and cytokeratin 20 (CK20) as well as the apical plasma membrane maturation. Our results indicated that urothelial proliferation was high from birth until about the 14th postnatal day. A majority of basal cells and even occasional superficial cells were PCNA positive during the first 5 postnatal days. Cell death occurred during the first 9 postnatal days. Between birth and day 5, single cells underwent apoptosis, whereas between days 6 and 9 cells mainly desquamated. CK20 and uroplakins were expressed in all superficial cells in postnatal urothelium. Their subcellular distribution characteristically changed in accordance with the progressive differentiation of superficial cells. During the urothelial postnatal development, proliferation activity slowly decreases to the proliferatively quiescent urothelium of the adult animal. Apoptosis is present in the first 9 postnatal days and within a few days of this period it appears simultaneously with desquamation. Superficial urothelial cells gradually differentiate, which is reflected in the changeable morphology of the apical plasma membrane.

Increased serum angiotensin-converting enzyme activity and plasma angiotensin II levels during pregnancy and postpartum in the diabetic rat.

OBJECTIVE: The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, electrolyte balance and renal function in normal human pregnancy. The present study was designed to assess various components of the RAS and renal function during pregnancy and immediately after pregnancy in the streptozotocin (STZ)-diabetic rat. METHODS: Pregnant Wistar rats were allocated to three groups: I-control, non-diabetic rats (n=24), II-STZ-diabetic rats (STZ 55 mg/kg body weight, i.v. on day 10 of pregnancy, n=24), III-diabetic rats, as above, treated with insulin (4 units/day, s.c. n=21). On days 17-18 of pregnancy, or within 24 hours after delivery, the rats were sacrificed and the various components of the RAS were determined. RESULTS: Urinary protein excretion (UP) and creatinine clearance(CCr) were greater in group II, four days after STZ, than in group I (UP: I-7.6+/-2.8, II-18.6+/-6.3 mg/24-hour, p<0.001, CCr: I-1.04+/-0.33, II-2.38+/-0.7 ml/minute, p<0.001). Mean (+/-SD) serum angiotensin-converting enzyme (ACE) activity and plasma angiotensin II(Ang II) levels at days 17-18 of pregnancy were greater in the untreated diabetic rats than in control pregnant rats (ACE: 163+/-18 vs. 111+/-21 nmol/ml/minute, p<0.001, Ang II: 115+/-45 vs. 43+/-10 pg/ml, p<0.005). Postpartum serum ACE activity and plasma Ang II levels were greater in group II (ACE: I-123+/-14, II-142+/-24, III-108+/-21 nmol/ml/minute, p<0.01, Ang II: I-56+/-38, II-148+/-62, III-38+/-17 pg/mI, p<0.001). ACE activity in the lung was greater, whereas the activity in the renal cortex was less, in group II than in group I. Kidney weight in untreated diabetic rats was greater than in the other two groups. CONCLUSION: Increased serum ACE activity during pregnancy and postpartum in the untreated diabetic rat is associated with enhanced serum Ang II levels, which may contribute to increased protein excretion and renal hypertrophy.

Effects of vasoactive substances released from ischemic reperfused liver on the isolated rat heart.

BACKGROUND: Cardiovascular dysfunction frequently occurs after major vascular surgery or liver transplantation. OBJECTIVE: To evaluate the effects on myocardial activity of vasoactive agents released from ischemic-reperfused liver. ANIMALS AND METHODS: Isolated rat livers were perfused with Krebs-Henseleit solution (KH), propranolol 10(-5) M, losartan 2x10(-5) M and indomethacin 10(-5) M, then made globally ischemic for 120 min (37 degrees C) and reperfused. Isolated hearts from other rats were stabilized with KH and reperfused for 15 min with the perfusate exiting the livers. Livers were disconnected, and the hearts continued to be recirculated with the accumulated liver and heart effluent for an additional 50 min. Enzyme leakage, different vasoactive substances, left ventricular developed pressure (LVP) and coronary flow were measured during the experimental protocol. RESULTS: Hepatic release of adrenaline, noradrenaline, angiotensin II, prostaglandin E(2) and thromboxane B(2) was significantly increased in the liver effluent following ischemia. When this effluent was directed to the heart, LVP was significantly raised in the first 10 min of reperfusion (137+/-5%) followed by marked decreased (46+/-6%) during the following 65 min of myocardial reperfusion. In the ischemic-reperfused drug-treated groups, the initial positive effect on LVP was milder than in controls (propranolol 112+/-12%, losartan 111+/-11%, indomethacin 113+/-9%) and the final LVP was lower (propranolol 29+/-6%, losartan 27+/-7% [P<0.05 versus ischemic control], indomethacin 46 +/-12%). CONCLUSION: During the initial phase of reperfusion, vasoactive substances released in the hepatic effluent potentiated LVP of the hearts exposed to this effluent. When the three inhibitory drugs were added to KH, this initial augmentation was not sustained. Propranolol and losartan, but not indomethacin, further depressed LVP. Vasoactive substances released from ischemic reperfused livers directly influenced heart function.

Mouse urothelial cells in early postnatal development--proliferation and apical plasma membrane specialization.

The purpose of this work was to investigate proliferation and differentiation of the mouse urothelial cells from the day of birth until the 5th postnatal day. The expression of proliferating cell nuclear antigen (PCNA) was studied immunocytochemically and the differentiation of apical plasma membrane of superficial cells was analysed by scanning microscopy. It was established that proliferation activity is very high during all five days since PCNA positive cells are seen in the superficial and in basal cell layer of the urothelium. Results of scanning microscopy show that the differentiation of superficial urothelial cells is a nonsynchronous process, which gradually progresses from the day of birth and leads into homogeneous population of terminally differentiated superficial cells on the 5th postnatal day.

[Exploration of the uterine cavity in the gynecologic preoperative diagnosis]. / L'esplorazione cavitaria uterina nella diagnostica preoperatoria ginecologica.

BACKGROUND: The diagnostic accuracy of dilatation and curettage (D & C) was studied comparing retrospectively the results of histologic findings of D & C with the correspondent specimen from hysterectomy. METHODS: During five years, at the Institute of Gynecology and Obstetrics, II University of Studies in Naples, 260 women underwent hysterectomy, 160 of which underwent D & C prior to hysterectomy. The histologic findings were classified in: a) physiological endometrium; b) hyperplasia; c) polyps; d) atrophia; e) adenomatous hyperplasia; f) adenocarcinoma. During the period January 1989-October 1993, 260 patients underwent hysterectomy. The age was between 32 and 65 years. The indications to the intervention were: menometrorrhagia, hypogastric pains, dysmenorrhea, metrorrhagia, genital prolapse, urinary incontinence, anemia. Two hundred-sixty patients underwent hysterectomy, 160 of which underwent D & C prior to hysterectomy. Curettage was performed using a right size curette after dilatation of the uterine cervix using Hegar's metallic dilatator. Patients were submitted to general anesthesia. Histologic tissues were fixed with formalin and were sent to the Institute of Anatomopathology for examinations. RESULTS: The histologic results obtained by cavitary exploration have been compared with those reached by the analysis of the surgical samples. The results obtained confirm the reliability of D & C for the identification of endometrial lesions. CONCLUSIONS: Therefore, the diagnostic utility of cavitary exploration before hysterectomy is confirmed, particularly in selected cases.

Should the use of short acting angiotensin-converting enzyme inhibitors be abandoned?

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACE-I) have different modes of action and different durations of inhibition. The effects of ACE-I on the various components of the renin-angiotensin system (RAS) at trough hours were studied in patients with diabetes mellitus receiving long-term ACE-I treatment. METHODS: Out of 86 Type 1 and 2 diabetic patients, 49 were untreated, 25 received captopril and 12 received enalapril as chronic treatment. Blood for the determination of plasma renin activity (PRA), serum ACE activity and plasma angiotensin II (Ang II) was drawn in the morning (0700-0900 hours) after an overnight fast, about 12 hours after the last dose. PRA and Ang II were measured by RIA and serum ACE activity was assayed by a radiometric assay using (3)H-hippuryl-glycyl-glycine as a substrate. RESULTS: Mean age was significantly greater in the enalapril-treated patients. Systolic and diastolic blood pressures were not different between the captopril-treated and untreated groups. Serum ACE activity in the captopril-treated diabetic patients was 101.5+/-42.5 nmol/mL/min, values obtained in untreated diabetic patients (101.4+/-25.2 nmol/mL/min). In contrast, ACE activity in the enalapril-treated patients was significantly reduced (5.5+/-7.5 nmol/mL/min) compared with untreated and captopril-treated patients (p<0.00001). PRA values in the ACE-I treated patients were significantly increased. Plasma Ang II levels were significantly increased in the captopril-treated vs. untreated patients (65.1+/-50.2 vs. 36.2+/-31.7 pg/mL, p=0.006), whereas the values in the enalapril-treated patient were slightly, but not significantly, reduced (23.8+/-21.4 pg/mL). CONCLUSIONS Trough serum ACE activity is not suppressed in diabetic patients receiving captopril, compared with those receiving enalapril and we thus question the use of short acting ACE-I in these patients.

Microalbuminuria after pregnancy complicated by pre-eclampsia.

BACKGROUND: Microalbuminuria is an important risk factor for underlying vascular disease. Its detection after pregnancy complicated by pre-eclampsia may have predictive value for the later development of chronic hypertension or renal disease. METHOD: The study group consisted of 48 women in whom pregnancy had been complicated by pre-eclampsia. Urinary albumin excretion rate, blood pressure, and renal function parameters were assessed 2-4 months and 3-5 years after the pregnancy. Results were compared with those in 44 women after normal pregnancy. RESULTS: Mean urinary albumin excretion rate was significantly higher in the study group than in the controls both at 2-4 months after delivery (27.0 +/- 33 vs 6.1 +/- 3.3 mg/24 h) and at 3-5 years after delivery (23.5 +/- 26.8 vs 6.7 +/- 2.8 mg/24 h) (P = 0.001). The rate of occurrence of microalbuminuria was not significantly different between the early (58%) and late (42%) time-points within the study group or between the nulliparous and the multiparous women. CONCLUSIONS: A history of pregnancy complicated by pre-eclampsia is associated with a high occurrence of microalbuminuria. Whether the presence of microalbuminuria reflects a possible underlying vascular disease in affected patients needs to be further investigated in large-scale studies.

Acute and chronic effects of spirapril, alone or in combination with isradipine on kidney function and blood pressure in patients with reduced kidney function and hypertension.

In the present study we investigated the effect of a single dose, and 3 months of treatment with spirapril on kidney function, renin-angiotensin system, renal handling of sodium and blood pressure, in patients with reduced kidney function (serum creatinine 1.5-3 mg%) and hypertension. A single dose of 6 mg spirapril given at the beginning of the study did not affect glomerular filtration rate (GFR), renal plasma flow (RPF), angiotensin converting enzyme (ACE) activity, plasma renin activity (PRA) or renal handling of sodium. When the single dose of spirapril was given after 3 months of treatment with this agent, renal hemodynamics and PRA did not change. ACE activity, which was depressed by the previous spirapril treatment, decreased further (from 9.5 +/- 3.1 to 1.4 +/- 1.0 nmol/ml/min), (p < 0.05). Administration of 6 mg spirapril o.d. for 3 months did not have any effect on GFR or RPF. Serum ACE activity decreased from 92.1 +/- 8.0 to 5.1 +/- 2.6 nmol/ml/min (p < 0.05) and PRA increased from 1.4 +/- 1.2 to 4.1 +/- 3.6 ng/ml/min (p < 0.05). Plasma aldosterone did not change. Similar results were obtained when spirapril was combined with 5 mg isradipine in the initial and final single dose, or in the 3 months' treatment (5 mg o.d.). Blood pressure was normalized in 38% of the patients who received spirapril and in 71% of the patients who received spirapril and isradipine. Thus, (a) treatment with spirapril in patients with mild to moderate chronic renal insufficiency was not associated with deleterious effects on kidney function; (b) spirapril in a dose of 6 mg alone or in combination with 5 mg isradipine is effective in reducing blood pressure in hypertensive patients with reduced kidney function.

DNA polymorphisms in the ACE gene, serum ACE activity and the risk of nephropathy in insulin-dependent diabetes mellitus.

BACKGROUND: To determine the relationship between DNA polymorphisms in the angiotensin I converting enzyme (ACE) gene, serum ACE activity and the risk of diabetic nephropathy. METHODS: A case-control study was carried out in a population of Jewish insulin-dependent diabetes mellitus (IDDM) patients. Cases (77 IDDM patients with diabetic nephropathy) and controls (89 IDDM patients with normoalbuminuria) were genotyped with PCR protocols for detecting two DNA polymorphisms in the ACE gene: one in intron 7 detected with the restriction enzyme PstI and the other in intron 16 identified as an insertion/deletion (I/D). RESULTS: The risk of nephropathy was increased only in patients homozygous for the allele with the PstI site. These homozygotes had a nephropathy risk that was 2.3 times (95% C.I.: 1.2-4.5) that of the other genotypes. Furthermore, these individuals did not have elevated serum ACE activity. CONCLUSIONS: The results of this study are evidence that the risk of diabetic nephropathy in IDDM is influenced by genetic variability at the ACE locus, but the responsible variant is not the I/D polymorphism in intron 16. Our findings require further studies in other populations.