Transplantation of hepatitis C virus (HCV) antibody positive,nucleic acid test negative donor kidneys to HCV negative patients frequently results in seroconversion but not HCV viremia

Anecdotal reports have suggested that transplantation of hepatitis C virus (HCV) antibody positive (Ab+)/nucleic acid test negative (NAT?) donor kidneys into HCV negative recipients is not associated with HCV transmission. We reviewed our center's outcomes of 32 HCV negative patients who received kidney allografts from 25 donors who were HCV Ab+/NAT?. The mean recipient age was 56.9 ± 12.1 years and the mean donor age was 41.5 ± 14 years, with a median Kidney Donor Profile Index (KDPI) of 68%. Twelve donors (48%) met Public Health Service (PHS) increased risk status. All patients received antithymocyte globulin induction followed by tacrolimus, mycophenolate mofetil, and steroid maintenance immunosuppression. With a mean follow‐up posttransplant of 10 ± 2.7 months, 1‐ and 3‐ month serum creatinine levels were 1.7 ± 0.8 and 1.3 ± 0.4, respectively, and patient and graft survival rates were 100% and 97%, respectively. Fourteen patients (44%) seroconverted and became HCV Ab+ posttransplant. However, all 32 patients were HCV RNA negative at 1‐ and 3‐ months posttransplant, and 27 and 8 patients tested at 6‐ and 12‐months posttransplant, respectively, remain HCV RNA negative. In conclusion, transplantation of HCV Ab+/NAT? kidneys to HCV negative recipients frequently causes HCV Ab seroconversion but not HCV viremia.     

Transesophageal Pulsed Doppler echocardiography of pulmonary venous flow to assess left ventricular filling pressure in ventilated patients with acute respiratory distress syndrome

OBJECTIVE: To determine whether the systolic fraction (SF) of the pulmonary venous flow (PVF), measured by transesophageal echocardiography (TEE) could be used to estimate the pulmonary artery occlusion pressure (PAOP). DESIGN: Prospective clinical investigation. PATIENTS: Nineteen intubated patients with ARDS. INTERVENTIONS: Doppler examinations with measurement of the SF of the PVF (ie, the systolic velocity-time integral expressed as a fraction of the sum of systolic and early diastolic velocity-time integrals) were performed simultaneously with measurements of PAOP via a right heart catheter at 0 cmH2O PEEP (ZEEP), at PEEP = 8 cmH20 and at PEEP = 16 cmH2O. MEASUREMENTS AND MAIN RESULTS: At ZEEP, PAOP was inversely correlated with the SF of the PVF (r = -.89). The difference of SF between the group with PAOP <18 mm Hg and the group with PAOP > or = 18 mm Hg was statistically significant (P < .05). A SF > or = 55% predicted a PAOP < 15 mm Hg with a positive predictive value of 100% (95% CI = 63-100%). A SF < or = 40% predicted a PAOP > or =18 mm Hg with a positive predictive value of 100% (95% CI = 52-100%). At PEEP = 8 cm H20 (12 patients studied) and at PEEP = 16 cmH2O (10 patients studied), PAOP was inversely correlated with the SF of the PVF: r = -.84, and r = -.85, respectively. CONCLUSION: The SF of the PVF measured by Pulsed Doppler TEE seems to be a valuable index to estimate the left ventricular filling pressure in mechanically ventilated patients with ARDS.     

Surgical techniques for spinopelvic reconstruction following total sacrectomy: a systematic review

Purpose

To identify all available reconstruction methods for a total sacrectomy. Secondarily, we aimed to evaluate outcomes based on different interventions.

Methods

We searched PubMed to identify sacral resections for tumors requiring internal fixation for stabilization. Demographic information, fixation techniques and postoperative outcomes were abstracted.

Results

Twenty-three publications (43 patients) met inclusion criteria from an initial search of 856 (κ 0.93). Mean age was 37 years and follow-up was 33 months. Fixation methods included a combination of spinopelvic fixation (SPF), posterior pelvic ring fixation (PPRF), and/or anterior spinal column fixation (ASCF). For the purposes of analysis, patients were segregated based on whether they received ASCF. Postoperative complications including wound/instrument infections, GI or vascular complications were reported at a higher rate in the non-ASCF group (1.63 complications/patient vs. 0.7 complications/patient). Instrument failure was seen in 5 (16.1 %) out of the 31 patients with reported outcomes. Specifically, 1 out of 8 patients (12.5 %) with ASCF compared with 4 out of 23 patients (17.4 %) without ASCF had hardware failure. At final follow-up, 35 of 39 patients were ambulating.

Conclusion

While surgical treatment of primary sacral tumors remains a challenge, there have been advances in reconstruction techniques following total sacrectomy. SPF has shifted from intrapelvic rod and hook constructs to pedicle and iliac screw–rod systems for improved rigidity. PPRF and ASCF have adapted for deficiencies in the posterior ring and anterior column. A trend toward a lower rate of hardware failure emerged in the group utilizing anterior spinal column support. Despite a more involved reconstruction with ASCF, surgical complications such as infection rates and blood loss were lower compared to the group without ASCF. While we cannot definitively say one system is superior to the other, based on the data gleaned from this systematic review, it is our opinion that incorporation of ASCF in reconstructing the spinopelvic junction may lead to improved outcomes. However, most importantly, we recommend that the treating surgeon operate on patients requiring a total sacrectomy based on his or her level of comfort, as these cases can be extremely challenging even among experts.     

α-Glucosidase inhibition, 15-lipoxygenase inhibition,and brine shrimp toxicity of extracts and isolated compounds from Terminalia macroptera leaves

Context: Terminalia macroptera Guill. &; Perr. (Combretaceae), a tree that grows in West Africa, has been used in traditional medicine against a variety of diseases such as hepatitis, gonorrhea, skin diseases, and diabetes.

Objective: To investigate enzyme inhibitory activity against α-glucosidase and 15-lipoxygenase (15-LO) and toxicity against brine shrimp of extracts and compounds from T. macroptera leaves.

Materials and methods: Methanol extract, ethyl acetate, and butanol extracts obtained from the methanol extract, six isolated polyphenols (chebulagic acid, chebulic acid trimethyl ester, corilagin, methyl gallate, narcissin, and rutin), and shikimic acid were evaluated for enzyme inhibition and toxicity.

Results: In enzyme inhibition assays, all extracts showed high or very high activity. Chebulagic acid showed an IC₅₀ value of 0.05?µM towards α-glucosidase and 24.9?±?0.4?µM towards 15-LO, in contrast to positive controls (acarbose: IC₅₀?201?±?28?µM towards α-glucosidase, quercetin: 93?±?3?µM towards 15-LO). Corilagin and narcissin were good 15-LO and α-glucosidase inhibitors, as well, while shikimic acid, methyl gallate, and chebulic acid trimethyl ester were less active or inactive. Rutin was a good α-glucosidase inhibitor (IC₅₀ ca. 3?µM), but less active towards 15-LO. None of the extracts or the isolated compounds seemed to be very toxic in the brine shrimp assay compared with the positive control podophyllotoxin.

Conclusion: Inhibition of α-glucosidase in the gastrointestinal tract may be a rationale for the medicinal use of T. macroptera leaves against diabetes in traditional medicine in Mali. The plant extracts and its constituents show strong inhibition of the peroxidative enzyme 15-LO.     

Cyclic Penta- and Hexaleucine Peptides without N-Methylation Are Orally Absorbed

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The prothrombotic paradox of severe obesity after cardiac surgery under cardiopulmonary bypass

Background

Obesity is suggested to reduce postoperative bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) but perioperative hemostasis variations have not been studied. Therefore, we investigated the effects of severe obesity (body mass index [BMI] ≥ 35 kg/m²) on chest tube output (CTO) and hemostasis in patients undergoing cardiac surgery with CPB.

Materials and Methods

We prospectively investigated 2799 consecutive patients who underwent coronary and/or valve surgery using CPB between 2008 and 2012. 204 patients (7.3%) presented a severe obesity.

Results

In the severe obesity group, the 6-h and 24-h CTO were significantly reduced by -21.8% and -14.8% respectively (P < 0.0001) compared with the control group. A significant reduction of the mean number of red blood cell units transfused at 24 h was observed in the severe obesity groups (P = 0.01). On admission to the intensive care unit, a significant increase of platelet count (+ 9.2%; P < 0.0001), fibrinogen level (+ 12.2%; P < 0.0001) and prothrombin time (+ 4.1%; P < 0.01) and a significant decrease of the activated partial thromboplastin time (-4.2%; P < 0.01) were observed in the severe obesity group compared with the control group.In multivariate analysis, severe obesity was significantly associated to a decreased risk of excessive bleeding (24-h CTO > 90th percentile; Odds ratio: 0.37, 95% CI: 0.17 to 0.82). No significant differences were observed regarding postoperative thromboembolic events between the two groups.

Conclusions

Severe obesity is associated with a prothrombotic postoperative state that leads to a reduction of postoperative blood loss in patients undergoing cardiac surgery with CPB.     

Imaging-Detected Incidental Thyroid Nodules that Undergo Surgery: A Single-Center Experience Over 1 Year

BACKGROUND AND PURPOSE:Incidental thyroid nodules are commonly seen on imaging, and their work-up can ultimately lead to surgery. We describe characteristics and pathology results of imaging-detected incidental thyroid nodules that underwent surgery.MATERIALS AND METHODS:A retrospective review was performed of 303 patients who underwent thyroid surgery over a 1-year period to identify patients who presented with incidental thyroid nodules on imaging. Medical records were reviewed for the types of imaging studies that led to detection, nodule characteristics, and surgical pathology.RESULTS:Of 303 patients, 208 patients (69%) had surgery for thyroid nodules. Forty-seven of 208 patients (23%) had incidental thyroid nodules detected on imaging. The most common technique leading to detection was CT (47%). All patients underwent biopsy before surgery. The cytology results were nondiagnostic (6%), benign (4%), atypia of undetermined significance or follicular neoplasm of undetermined significance (23%), follicular neoplasm or suspicious for follicular neoplasm (19%), suspicious for malignancy (17%), and diagnostic of malignancy (30%). Surgical pathology was benign in 24 of 47 (51%) cases of incidental thyroid nodules. In the 23 incidental cancers, the most common histologic type was papillary (87%), the mean size was 1.4 cm, and nodal metastases were present in 7 of 23 cases (30%). No incidental cancers on imaging had distant metastases.CONCLUSIONS:Imaging-detected incidental thyroid nodules led to nearly one-fourth of surgeries for thyroid nodules, and almost half were initially detected on CT. Despite indeterminate or suspicious cytology results that lead to surgery, more than half were benign on final pathology. Guidelines for work-up of incidental thyroid nodules detected on CT could help reduce unnecessary investigations and surgery.

Incidental thyroid nodules (ITNs) are commonly encountered on imaging studies, being seen in 50% of ultrasonographic studies and 16%–18% of CT and MR imaging studies that include the thyroid gland.^1–3 While ITNs are associated with a low rate of malignancy, and subclinical thyroid cancers have an excellent prognosis,^2–6 ITNs pose a management dilemma for radiologists and other clinicians whose concern for missing malignancies may lead to further evaluation for small nonspecific thyroid nodules.The reporting practice of ITNs seen on imaging is highly variable among radiologists.⁷ Radiologists must exercise their judgment when reporting and issuing recommendations regarding incidental thyroid nodules. The reporting of ITN on imaging can lead to further investigation, such as follow-up sonography examinations, fine needle aspiration biopsy (FNAB), or, in some cases, diagnostic thyroid lobectomy or thyroidectomy.^8,9 Of patients who undergo FNAB, 22%–51% proceed to surgery.^10–12 These surgical patients represent an important group to study because they have higher costs and morbidity associated with the work-up of their ITNs. Thus, it is important to consider the costs and benefits of work-up in patients with ITN who fall into this surgical group.A substantial number of patients who undergo surgery do not have cancer.¹⁰ When the preoperative cytology result from FNAB is malignant, the sensitivity of cytology is high (99%).¹³ However, it is recommended that patients with cytology of “follicular neoplasm,” “suspicion for follicular neoplasm,” and “suspicion for malignancy” also proceed to surgery. With these other categories, the false-positive rate of cytology can be as high as 44%.¹³ In addition, thyroid surgery can result in such complications as recurrent laryngeal nerve injury, hypoparathyroidism, and bleeding. Therefore, radiologists should understand the downstream sequelae of a clinical pathway that begins with an imaging-detected ITN and ends with surgery.The purpose of this study was to describe characteristics and pathology results of ITNs that undergo surgery. We hypothesize that imaging-detected ITN comprise a substantial proportion of surgeries for thyroid nodules, and that many thyroid nodules are in the end benign on final surgical pathology.     

Transient Neonatal Diabetes,ZFP57, and Hypomethylation of Multiple Imprinted Loci: A detailed follow-up

OBJECTIVE

Transient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5% of the cases are due to recessive ZFP57 mutations, causing hypomethylation at the TNDM locus and other imprinted loci (HIL). This has consequences for patient care because it has impact on the phenotype and recurrence risk for families. We have determined the genotype, phenotype, and epigenotype of the first 10 families to alert health professionals to this newly described genetic subgroup of diabetes.

RESEARCH DESIGN AND METHODS

The 10 families (14 homozygous/compound heterozygous individuals) with ZFP57 mutations were ascertained through TNDM1 diagnostic testing. ZFP57 was sequenced in probands and their relatives, and the methylation levels at multiple maternally and paternally imprinted loci were determined. Medical and family histories were obtained, and clinical examination was performed.

RESULTS

The key clinical features in probands were transient neonatal diabetes, intrauterine growth retardation, macroglossia, heart defects, and developmental delay. However, the finding of two homozygous relatives without diabetes and normal intelligence showed that the phenotype could be very variable. The epigenotype always included total loss of methylation at the TNDM1 locus and reproducible combinations of differential hypomethylation at other maternally imprinted loci, including tissue mosaicism.

CONCLUSIONS

There is yet no clear genotype–epigenotype–phenotype correlation to explain the variable clinical presentation, and this results in difficulties predicting the prognosis of affected individuals. However, many cases have a more severe phenotype than seen in other causes of TNDM1. Further cases and global epigenetic testing are needed to clarify this.Imprinted genes are characterized by a parent of origin expression pattern controlled by epigenetic modifications, including DNA methylation within differentially methylated regions (DMRs). The normal methylation pattern of DMRs is established in the germlines and maintained during embryogenesis. Imprinted genes are crucial in normal growth and development. Currently, 73 human imprinted genes are known (http://igc.otago.ac.nz). Aberrant methylation of these DMRs results in imprinting disorders such as transient neonatal diabetes mellitus 1 (TNDM1; MIM 601410), Prader-Willi syndrome (MIM 176270), Angelman syndrome (MIM 105830), Beckwith-Wiedemann syndrome (BWS; MIM 130650), and Silver-Russell syndrome (SRS; MIM 180860). However, the complex mechanisms underpinning establishment and maintenance of primary DMRs are not fully understood.Until very recently, our knowledge was limited to imprinting disorders in which a single locus was exposed to abnormal methylation. It is now clear that some patients have methylation aberrations affecting multiple imprinted loci, which we termed hypomethylation of multiple imprinted loci (HIL) (1–3). This phenomenon is heterogeneous, and there are likely genetic and environmental causes.We described the first heritable global imprinting disorder compatible with life in patients presenting with TNDM1 due to HIL. The patients have total loss of methylation (LOM) at the maternally methylated TNDM1 DMR (6q24) (4). In addition, they have a mosaic pattern of hypomethylation affecting other maternally methylated loci, primarily PEG3/ZIM2 (19q13.4) and GRB10 (7p12.2). Homozygous or compound heterozygous DNA sequence mutations in the ZFP57 were identified in more than half of these patients (5). The probands with ZFP57 mutations have a more complex TNDM1 phenotype compared with patients with TNDM due to other causes. The finding of heritable mosaic epigenetic aberrations associated with ZFP57 mutations indicates that the gene may be involved in maintenance of DNA methylation at imprinted regions during the early multicellular stages of human development. In mouse, zfp57 has a clear role in methylation maintenance at imprinted loci in both the germline and postfertilization but is also implicated in methylation establishment in the developing oocyte (6).ZFP57 is localized at chromosome 6p22.1 spanning an 8.6-kb genomic region. The gene is organized in six exons encoding the ZFP57 protein consisting of 516 amino acids (Fig. 1). The ZFP57 protein is a Krüppel-associated box domain (KRAB) zinc finger protein with a KRAB A and KRAB B domain encoded by exons 4 and 5, respectively. The seven zinc fingers of the C2H2 type are encoded by exon 6.Open in a separate windowFigure 1A: Structure of the ZFP57 gene. The gray boxes represent the six exons of ZFP57. The thin black lines between the exons represent the ZFP57 introns. B: Known sequence alterations in ZFP57 are shown as predicted protein alterations. The amino acid numbers are indicated above, and each alteration is indicated below. ZF, zinc finger.In mice, expression of zfp57 has been demonstrated in embryonic stem cells (expression levels declining with cell differentiation), testes, and ovary and in rat in the nervous system (7–9). Recent studies indicate that zfp57, via interaction with its cofactor KRAB-associated protein 1, recruits DNA methyltransferases and is required for the maintenance of methylation of DNA imprints, as well as of histones in embryonic stem cells (10,11).HIL also occurs in some patients with BWS associated with hypomethylation of KCNQ1OT1 DMR (11p15.5) (12–15) and SRS due to hypomethylation of H19 DMR (11p15.5) (14,16). In some of these patients, the hypomethylation can involve paternally or maternally methylated DMRs, in contrast to ZFP57-related TNDM1 HIL patients, in whom the hypomethylation occurs only at maternally imprinted loci. However, no underlying genetic defect for BWS or SRS HIL cases is so far known, except for a single case with a homozygous sequence mutation in the NLRP2 gene in the mother of two siblings with BWS and hypomethylation at KCNQ1OT1 DMR, in which one of the patients also had hypomethylation at PEG1/MEST DMR (7q32) (17). We and others (18,19) have sequenced ZFP57 in 27 BWS patients with hypomethylation of KCNQ1OT1 DMR and 30 SRS patients with hypomethylation at H19 DMR, respectively, and could not find disease-associated alterations, but these studies did not necessarily include cases with HIL.In this study, we present the detailed genotype, phenotype, and epigenotype of the first 10 families with ZFP57-related TNDM1 HIL and discuss these findings in the context of the current knowledge of the molecular mechanisms involved.     

Safety of performing fiberoptic bronchoscopy in critically ill hypoxemic patients with acute respiratory failure

Background

The safety of fiberoptic bronchoscopy (FOB) in nonintubated critically ill patients with acute respiratory failure has not been extensively evaluated. We aimed to measure the incidence of intubation and the need to increase ventilatory support following FOB and to identify predictive factors for this event.

Methods

A prospective multicenter observational study was carried out in eight French adult intensive care units. The study included 169 FOB performed in patients with a PaO₂/FiO₂ ratio ??300. The main end-point was intubation rate. The secondary end-point was rate of increased ventilatory support defined as an increase in oxygen requirement >50?%, the need to start noninvasive positive pressure ventilation (NI-PPV) or increase NI-PPV support.

Results

Within 24?h, an increase in ventilatory support was required following 59 bronchoscopies (35?%), of which 25 (15?%) led to endotracheal intubation. The existence of chronic obstructive pulmonary disease (COPD; OR 5.2, 95?% CI 1.6?C17.8; p?=?0.007) or immunosuppression (OR 5.4, 95?% CI 1.7?C17.2; p?=?0.004] were significantly associated with the need for intubation in the multivariable analysis. None of the baseline physiological parameters including the PaO₂/FiO₂ ratio was associated with intubation.

Conclusions

Bronchoscopy is often followed by an increase in ventilatory support in hypoxemic critically ill patients, but less frequently by the need for intubation. COPD and immunosuppression are associated with the need for invasive ventilation in the 24?h following bronchoscopy.     

Rapid Microwave Synthesis,Characterization and Reactivity of Lithium Nitride Hydride,Li4NH

Lithium nitride hydride, Li₄NH, was synthesised from lithium nitride and lithium hydride over minute timescales, using microwave synthesis methods in the solid state for the first time. The structure of the microwave-synthesised powders was confirmed by powder X-ray diffraction [tetragonal space group I4₁/a; a = 4.8864(1) Å, c = 9.9183(2) Å] and the nitride hydride reacts with moist air under ambient conditions to produce lithium hydroxide and subsequently lithium carbonate. Li₄NH undergoes no dehydrogenation or decomposition [under Ar_(g)] below 773 K. A tetragonal–cubic phase transition, however, occurs for the compound at ca. 770 K. The new high temperature (HT) phase adopts an anti-fluorite structure (space group Fm3¯m; a = 4.9462(3) Å) with N³⁻ and H⁻ ions disordered on the 4a sites. Thermal treatment of Li₄NH under nitrogen yields a stoichiometric mixture of lithium nitride and lithium imide (Li₃N and Li₂NH respectively).