Management of pregnancy for a patient with the new syndromic macrothrombocytopenia,DIAPH1-related disease

The number of genes involved in the identification of macrothrombocytopenia (MTP) is growing but the clinical consequences for the affected patients are not well determined. Here, we report the management of the bleeding risk for a patient with the newly reported and rare DIAPH1-related disease during surgery for infertility and then during her subsequent pregnancy. The R1213* DIAPH1 variant responsible for a mild bleeding syndrome in six families was considered a potential risk factor for our patient. Preliminary laparoscopic surgery was followed by neosalpingostomy to open the obstructed fallopian tube that was followed by an ectopic pregnancy requiring further surgery, tranexamic acid was used on each occasion and no bleeding complications were observed. A second pregnancy proceeded to term; the mother’s platelet count was controlled throughout the gestation period and remained close to her basal values. No bleeding occurred at delivery or during the postpartum period. In conclusion, with strict repeated assessments of blood parameters and maintenance of the platelet count, the bleeding risk in pregnancy in DIAPH1-related disease can be successfully controlled.     

Painful Hip Arthroplasty: What Should We Find? Diagnostic Approach and Results

IntroductionIdentifying the source of pain is paramount for determining appropriate treatment and ensuring successful outcome in terms of management and relief of pain. The difficulty is that each surgeon has his or her own way of seeing the problem, and there is no consensus for the evaluation of these patients. The study hypothesis was that it is possible to find the cause of the pain in most cases.Patients and methodsAll patients consulting for unexplained painful hip arthroplasty were included and followed a decision tree to assess the cause of the pain. The primary endpoint was the final diagnosis. Secondary endpoints were subgroup comparison between main causes and assessment of risk factors.ResultsTwo hundred one hips of 194 patients were included as unexplained painful hip arthroplasty 6 months postoperatively. Final diagnoses comprised periarticular pain in 53 cases (26.4%): 40 cases of trochanteric bursitis, 5 of iliopsoas tendinitis, 5 of abductor deficiency, 1 of ischial tuberosity tendinitis, and 2 of heterotopic ossification; projected pain in 49 (24.4%): 45 cases of back pain with or without neuropathy, 3 of knee osteoarthritis, and 1 of metabolic neuropathy; wear in 40 (19.9%), in the polyethylene liner; loosening in 20 (10.0%): loosening of the femoral component in 8 and that of the cup in 12; material problems in 17 (8.5%): trunnionosis in 13 and metallosis in metal-on-metal implants in 4; no diagnosis in 7 hips (3.5%); infection in 6 (3.0%), all chronic; instability without real dislocation in 3 (1.5%); misplacement in 3 (1.5%), all for leg-length discrepancy; fracture in 2 (1.0%): 1 of greater trochanter and 1 of ilio-ischiopubic ramus; complex regional pain syndrome in 1 (0.5%).DiscussionTo our knowledge, this is the first study on the causes of painful hip arthroplasty in clinical practice, whether leading to revision or not. A systematic approach, including physical examination, radiographic assessment and laboratory studies, is needed to find the cause of the pain. It is important to understand the pain so that it can be treated appropriately. Revision surgery can sometimes help—but the worst thing is to make the patient worse.Level of Evidencelevel 4, retrospective study.     

Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients

AIM:To assess,in a routine practice setting,the sus-tained virologic response(SVR) to telaprevir(TPV) or boceprevir(BOC) in hepatitis C virus(HCV) nullresponders or relapsers with severe liver fibrosis.METHODS:One hundred twenty-five patients were treated prospectively for 48 wk with TPV or BOC + pegylated-interferon(peg-INF) α2a + ribavirin(PR) according to standard treatment schedules without randomization.These patients were treated in routine practice settings in 10 public or private health care centers,and the data were prospectively collected.Only patients with severe liver fibrosis(Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography),genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study.RESULTS:The Metavir fibrosis scores were F3 in 35(28%) and F4 in 90(72%) of the patients.In total,62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy.The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%.The SVR was 65.9% in the TPV group and 44.1% in the BOC group.Independent predictive factors of an SVR included a response to previous treatment,relapsers vs null-responders [OR = 3.9;(1.4,10.6),P = 0.0084],a rapid virological response(RVR) [OR 6.9(2.6,18.2),P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2(2.3,29.5),P = 0.001].During treatment,63 patients(50.8%) had at least one severe adverse event(SAE) of grade 3 or 4.A multivariate analysis identified two factors associated with SAEs:female gender [OR = 2.4(1.1,5.6),P = 0.037] and a platelet count below 150 × 103/ mm3 [OR = 5.3(2.3,12.4),P ≤ 0.001].CONCLUSION:More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting.The SVR rate was influenced by the response to previous PR treatment,the RVR and liver stiffness.     

Fatal hemorrhage due to an isolated dissection of the superior mesenteric artery

Intensive Care Medicine -     

Discrepancy between simultaneous digital skin microvascular and brachial artery macrovascular post-occlusive hyperemia in systemic sclerosis

OBJECTIVE: Vascular impairment, a main feature of the pathogenesis of systemic sclerosis (SSc), involves both the macro- and the microvasculature. We compared and correlated simultaneously measured skin microvascular and brachial artery macrovascular post-occlusive hyperemia in 3 groups: patients with SSc, patients with primary Raynaud's phenomenon (RP), and healthy volunteers. METHODS: Thirty-three healthy volunteers, 36 patients with primary RP, and 42 patients with SSc were enrolled. For each subject, brachial artery flow-mediated dilation (FMD) and cutaneous post-occlusive reactive hyperemia (PORH) were simultaneously recorded after 5-minute occlusion of the brachial artery. Local thermal hyperemia, nitroglycerin-mediated dilation (NMD), intima-media thickness (IMT), and pulse wave velocity (PWV) were also assessed. RESULTS: Digital cutaneous peak PORH was altered in patients with primary RP and SSc compared to healthy controls, whereas FMD was not significantly different among all groups. We observed a correlation between digital peak cutaneous vascular conductance and brachial FMD in healthy controls (r = 0.49; p = 0.004), but not in patients with primary RP or SSc. Thermal hyperemia was altered only in patients with SSc. Brachial NMD, IMT, and PWV were not different among all groups. CONCLUSION: We observed a loss of the correlation between brachial FMD and digital cutaneous PORH in patients with SSc and primary RP. Microvascular function is impaired in SSc, whereas brachial artery endothelial function is normal.     

Beta cyclodextrins bind,stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium

Accumulation of lipofuscin bisretinoids (LBs) in the retinal pigment epithelium (RPE) is the alleged cause of retinal degeneration in genetic blinding diseases (e.g., Stargardt) and a possible etiological agent for age-related macular degeneration. Currently, there are no approved treatments for these diseases; hence, agents that efficiently remove LBs from RPE would be valuable therapeutic candidates. Here, we show that beta cyclodextrins (β-CDs) bind LBs and protect them against oxidation. Computer modeling and biochemical data are consistent with the encapsulation of the retinoid arms of LBs within the hydrophobic cavity of β-CD. Importantly, β-CD treatment reduced by 73% and 48% the LB content of RPE cell cultures and of eyecups obtained from Abca4-Rdh8 double knock-out (DKO) mice, respectively. Furthermore, intravitreal administration of β-CDs reduced significantly the content of bisretinoids in the RPE of DKO animals. Thus, our results demonstrate the effectiveness of β-CDs to complex and remove LB deposits from RPE cells and provide crucial data to develop novel prophylactic approaches for retinal disorders elicited by LBs.The retinal pigment epithelium (RPE), strategically situated between the neural retina and the choroid blood vessels, is essential for photoreceptor (PR) function. It recycles vitamin A, which is required for the visual cycle and clears debris generated by the circadian shedding of PR outer segments (1, 2). Each RPE cell phagocytoses and digests the material produced by 30–50 overlying PRs, which shed 10% of their mass daily. The intense and continual phagocytic activity of RPE cells results in the progressive accumulation of indigestible products or “lipofuscin” in their lysosomal compartment (3, 4). Unlike lipofuscins found in other body tissues, which are composed mainly of protein, RPE lipofuscin consists predominantly of lipid-bisretinoids and only 2% protein (5). Lipofuscin bisretinoids (LBs) are vitamin A-derived side products of the visual cycle. Light converts 11-cis-retinal (11CR), the visual pigment chromophore, into all-trans-retinal (ATR), which is immediately flipped by the ATP-binding cassette transporter 4 (Abca4) transporter from the lumen of the outer segment discs to the cytoplasm, where it is reduced to inert all-trans-retinol by retinol dehydrogenase 8 (Rdh8), in mice (6, 7). Small fractions of 11CR and ATR are converted into N-retinylidine-N-ethanolamine (A2E) and other less abundant bisretinoids, which once accumulated in the lysosomes of RPE cells are refractory to all known lysosomal hydrolases (8, 9). The concept that LB accumulation causes retinal degeneration is supported by in vitro and in vivo data that show that excessive LBs are toxic for cultured RPE cells (10, 11), that photoreceptors overlying A2E-laden RPE are more prone to degeneration (12) and that excessive accumulation of LBs in Stargardt’s disease precedes macular degeneration (13). Mice carrying null mutations in Abca4 and Rdh8 develop blindness, basal laminar deposits, and focal accumulations of extracellular debris between the RPE and the Bruch membrane (drusen) (6).Here we report that a family of modified cyclic oligosaccharides, beta cyclodextrins (β-CDs), formed by seven d-glucose units, can encapsulate the hydrophobic arms of A2E within their nonpolar cavity, protect A2E from oxidation, and remove A2E from RPE cells. Our data demonstrate a direct correlation between the ability of β-CDs to perform these protective functions and their affinity for A2E.     

Vulnerability for apoptosis in the limbic system after myocardial infarction in rats: a possible model for human postinfarct major depression

OBJECTIVE: Major depressive disorder occurs in 15%-30% of patients who have had a myocardial infarction (MI), but the neurobiological mechanisms involved are not well understood. Previously, we found early intracellular signalling changes in the limbic system after acute MI in rats. The aim of the present study was to test the presence of behavioural deficits compatible with animal models of depression after acute MI in rats and to verify whether this is associated with apoptosis vulnerability markers. METHODS: Occlusion of the left-anterior descending artery was induced for 40 minutes under anesthesia in adult male Sprague-Dawley rats. Control sham rats underwent the same surgical procedure without occlusion. After surgery, subgroups of MI and sham rats were treated with desipramine, 10 mg/kg, intraperitoneally for 14 days. All rats were tested on measures of behavioural depression 14 days after surgery with a sucrose preference test, a forced swimming test, and a memory test (Morris water maze [MWM]). The rats were sacrificed, and the MI size was determined; apoptosis was estimated in the prefrontal cortex, hypothalamus, amygdala and hippocampus by measuring Bax:Bcl-2 ratio and caspase-3 activity. RESULTS: Untreated MI rats drank significantly less sucrose and swam significantly less than sham rats. No difference was found on the MWM. Behavioural depression was prevented by desipramine. Bax:Bcl-2 ratio was significantly increased in the prefrontal cortex and hypothalamus of MI rats, compared with sham rats; caspase-3 activity showed no difference between the 2 groups. Bax:Bcl-2 ratio in the prefrontal cortex was correlated with swim time in the forced swim test. CONCLUSION: Behavioural impairment and limbic apoptotic events observed after a myocardial infarct are consistent with a model of human post-MI depression.     

Plasma neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in adult critically ill patients: A prospective study

Purpose

The aim of the study was to assess the ability of plasma neutrophil gelatinase-associated lipocalin (pNGAL) to predict acute kidney injury (AKI) in adult intensive care unit (ICU) patients.

Methods

All consecutives patients admitted to 3 ICUs were enrolled in this prospective-observational study. Plasma neutrophil gelatinase-associated lipocalin was analyzed at ICU admission. Risk, injury, failure, loss, and end-stage kidney (RIFLE) criteria were calculated at admission and for each day during the first week. Patients were classified according to whether they met the threshold for RIFLE criteria (RIFLE 0 or 1) at admission and during the first week. Four groups were identified: RIFLE (0-0), (1-1), (1-0), and (0-1).

Results

During this 1-month period, 88 patients were included in the study. Thirty-six patients met the criteria for RIFLE 0-0 with a mean pNGAL of 98 ± 60 nmol/L, 22 for RIFLE 1-1 with a mean pNGAL of 516 ± 221 nmol/L, and 20 patients had no AKI at admission but develop AKI at 48 hours (24-96 hours) (RIFLE 0-1) with a pNGAL of 342 ± 183 nmol/L. Ten patients met the criteria for RIFLE 1-0 and had a mean pNGAL of 169 ± 100 nmol/L. Using a cutoff of 155 nmol/L, sensitivity and specificity to predict AKI were 82% and 97%, respectively (area under the curve [AUC] = 0.92 [0.852-0.972]; P = .001). Looking at the patients without AKI at admission (n = 56) and who developed (n = 20) or did not develop (n = 36) AKI, receiver operating characteristic curve analysis was as follows: AUC = 0.956 (0.864-0.992). Sensitivity was 85% and specificity was 97%. Of the 7 patients who required renal replacement therapy, all of them had pNGAL of more than 303 nmol/L (AUC = 0.788 [0.687-0.868]).

Conclusion

Plasma neutrophil gelatinase-associated lipocalin at ICU admission is an early biomarker of AKI in adult ICU patients. Plasma neutrophil gelatinase-associated lipocalin increased 48 hours before RIFLE criteria.