Active versus latent pulmonary tuberculosis: which one is the appropriate distinguishing biomarker?

This study tried to assess the possibility of using the estimated levels of plasma expression of microRNAs (miR-) for distinguishing healthy subjects with latent pulmonary tuberculosis (LTB) from healthy controls (HC) and patients with active tuberculosis (ATB). Study participants included 30 newly diagnosed ATB patients, 30 of the households of ATB patients who were free of clinical manifestations, had normal chest radiography but had positive results on the whole-blood QuantiFERON tuberculosis (TB) Gold In-Tube (QFT-GIT) test (LTB patients), and 30 HC who were free of clinical symptoms and showed normal chest X-rays and negative QFT-GIT tests. All participants gave blood samples for quantitation of the plasma expression levels of miR- using the reverse transcription-quantitative polymerase chain reaction. Plasma levels of miR-150-5p were significantly downregulated in ATB samples than in other samples. However, miR-155-5p and miR-378-5p were significantly overexpressed in patients' samples compared to HC's samples and in ATB samples compared to LTB samples. On the contrary, plasma miR-4523-5p showed significant upregulation in LTB samples compared to ATB and HC samples, indicating insignificant in-between differences. The receiver operating characteristic curve analysis showed the ability of the estimated levels of the four miR- to differentiate TB patients from HC. Multivariate regression analysis defined expression levels of miR-155-5p and miR-378-5p as the significant biomarkers for distinguishing TB patients and levels of miR-378-5p and miR-4523-5p for identification of LTB patients. Pulmonary TB induces deregulated expression of miR-, according to the infection severity. An estimation of the expression levels of miR-378-5p and miR-4523-5p might be a reliable combination for identifying LTB patients.

Circulating long non-coding RNAs HOTAIR, Linc-p21, GAS5 and XIST expression profiles in diffuse large B-cell lymphoma: association with R-CHOP responsiveness.

The reliable identification of diffuse large B-cell lymphoma (DLBCL)-specific targets owns huge implications for its diagnosis and treatment. Long non-coding RNAs (lncRNAs) are implicated in DLBCL pathogenesis; however, circulating DLBCL-related lncRNAs are barely investigated. We investigated plasma lncRNAs; HOTAIR, Linc-p21, GAS5 and XIST as biomarkers for DLBCL diagnosis and responsiveness to R-CHOP therapy. Eighty-four DLBCL patients and thirty-three healthy controls were included. Only plasma HOTAIR, XIST and GAS5 were differentially expressed in DLBCL patients compared to controls. Pretreatment plasma HOTAIR was higher, whereas GAS5 was lower in non-responders than responders to R-CHOP. Plasma GAS5 demonstrated superior diagnostic accuracy (AUC = 0.97) whereas a panel of HOTAIR + GAS5 superiorly discriminated responders from non-responders by ROC analysis. In multivariate analysis, HOTAIR was an independent predictor of non-response. Among patients, plasma HOTAIR, Linc-p21 and XIST were correlated. Plasma GAS5 negatively correlated with International Prognostic Index, whereas HOTAIR positively correlated with performance status, denoting their prognostic potential. We constructed the lncRNAs-related protein-protein interaction networks linked to drug response via bioinformatics analysis. In conclusion, we introduce plasma HOTAIR, GAS5 and XIST as potential non-invasive diagnostic tools for DLBCL, and pretreatment HOTAIR and GAS5 as candidates for evaluating therapy response, with HOTAIR as a predictor of R-CHOP failure. We provide novel surrogates for future predictive studies in personalized medicine.

The Emerging Treatment Options of Plasmablastic Lymphoma: Analysis of 173 Individual Patient Outcomes.

Plasmablastic lymphoma (PBL) is a newly recognized aggressive subtype of non-Hodgkin lymphoma. Its rarity hinders testing effective treatment options in clinical trials. We conducted a systematic review of PubMed and our internal records to retrieve patients with a PBL diagnosis with evaluable treatment outcomes. Aggressive chemotherapy was defined as more intense regimens than CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). We compiled a meta-dataset of 173 patients. The median age at diagnosis was 48.5 years, 75% of patients were male, and stages III/IV accounted for 47% of the cohort. Of 138 patients with known response status after first-line chemotherapy, 63 (45%) achieved a complete response with a 2-year relapse-free survival of 71.6%. Sixty-nine (50%) patients received first-line CHOP. There was no significant difference in the objective response rate among the 2 most commonly used regimens, CHOP and DA-EPOCH (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) (69% vs. 79%; P = .4). The median follow-up was 9 months, and the 2-year overall survival (OS) was 47.4%. A univariate analysis identified factors associated with worse OS, including stage III/IV (hazard ratio [HR], 2.82; P < .001), human herpes virus-8-positive (HR, 3.30; P = .01), bone marrow (HR, 1.07; P = .035), and cardiorespiratory involvement (HR, 2.26; P = .015). Meanwhile, Epstein-Varr virus-encoded small RNA-positivity (HR, 0.31; P < .001) and involvement of head and neck (HR, 0.44; P = .009) were associated with better OS. Multivariate analysis showed that aggressive chemotherapy was significantly associated with better OS (HR, 0.22; P = .016). Patients with PBL with high-risk features, such as advanced stage, human herpes virus-8-positivity, bone marrow, and cardiorespiratory involvement, require more aggressive chemotherapy. Bortezomib and lenalidomide are promising add-on agents.

Safety issues with the ALK inhibitors in the treatment of NSCLC: A systematic review.

INTRODUCTION: Oral tyrosine kinase inhibitors targeting the chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) in non-small cell lung cancer (NSCLC) were associated with superior clinical outcome. Tyrosine Kinase inhibitors (TKIs) are known to have peculiar toxicity profile, hence, increasing awareness to the safety profile of ALK inhibitors is essential. METHODS: A comprehensive systematic review of literature has been conducted to include prospective trials that used the ALK inhibitors Crizotinib, Ceritinib, Alectinib, Brigatinib and Lorlatinib in patients with advanced NSCLC and have available efficacy and toxicity results. RESULTS: A total of 14 studies including 2793 patients were considered eligible for our review and included two phase IB, seven phase II and five phase III studies. The most common adverse events (AEs) observed with ALK inhibitors were gastrointestinal (GI) toxicities as nausea (up to 83%), vomiting (up to 67%) and diarrhea (up to 86%), elevation of liver enzymes occurred in up to 60% and fatigue (up to 43%). There were differences in the toxicity patterns between the different ALK inhibitors with more GI and hepatic toxicities with Ceritinib, more visual disorders with Crizotinib, more dysgeusia with crizotinib and Alectinib and possibly more respiratory complications with Brigatinib. Most of the AEs were low grade and treatment-related deaths were associated with ALK inhibitors in 0-1% of patients. CONCLUSION: Most of adverse effects of ALKi can be managed efficiently via dose modifications or interruptions. Timely identification of each ALKi pattern of toxicity can prevent treatment-related morbidity and mortality in this palliative setting.

Biomolecular Changes and Cortical Neurodegenerative Lesions in Trichinella Spiralis Infected BALB/c Mice: A Preliminary Study Elucidating a Potential Relationship Between Systemic Helminthic Infections and Idiopathic Parkinson's.

Idiopathic Parkinson's (IP) is a neurodegenerative disease that is suspected to be due to exposure to infections during early life. Toxoplasmosishas been the only suspected parasitic infection in IP (Celik et al., 2010). Recently, some non-central nervous system bacterial and viral infections have been incriminated in IP (Çamci & Oguz, 2016). So in the current study, we tried to explore if the systemic inflammatory reactions triggered by some helminths like Trichinella spiralis can induce Parkinsonian lesions in the brain, especially that the cerebral complications have been reported in 10-20% of Trichinella spiralis infected patients . An experimental study was designed to assess the neurodegenerative and biomolecular changes that may occur in Trichinella spiralis infected BALB/C mice in comparison to rotenone induced PD model and apparently healthy ones. The motor affection was significantly lesser in the Trichinella infected mice than the Parkinson's model, but when the catalepsy score was calculated (through the grid and bar tests) it was found to be significantly higher in the infected mice than in the healthy ones. A significant increase in the blood advanced oxidative protein products (AOPP), IFN-γ, TGF-ß, and brain DNA fragmentation was also detected in the Trichinella spiralis infected mice. After histopathological examination, a significant increase in the cortical apoptotic neurons and Lewy's body were observed in the Trichinella infected and the rotenone induced Parkinson's model sections. A significant decrease in the immunohistochemical expression of the tyrosine hydroxylase expression in the brain sections and the ELISA measured dopamine level in the brain homogenate was also reported in the infected mice group. This study findings may collectively suggest that the systemic inflammatory reactions and the oxidative stresses associated with some systemic helminthic infections like trichinellosis are possible to precipitate neurodegenerative lesions and biomolecular changes in the brain , and manifest with IPD later in life.

3-D flexible nano-textured high-density microelectrode arrays for high-performance neuro-monitoring and neuro-stimulation.

We introduce a new 3-D flexible microelectrode array for high performance electrographic neural signal recording and stimulation. The microelectrode architecture maximizes the number of channels on each shank and minimizes its footprint. The electrode was implemented on flexible polyimide substrate using microfabrication and thin-film processing. The electrode has a planar layout and comprises multiple shanks. Each shank is three mm in length and carries six gold pads representing the neuro-interfacing channels. The channels are used in recording important precursors with potential clinical relevance and consequent electrical stimulation to perturb the clinical condition. The polyimide structure satisfied the mechanical characteristics required for the proper electrode implantation and operation. Pad postprocessing technique was developed to improve the electrode electrical performance. The planar electrodes were used for creating 3-D "Waterloo Array" microelectrode with controlled gaps using custom designed stackers. Electrode characterization and benchmarking against commercial equivalents demonstrated the superiority of the Flex electrodes. The Flex and commercial electrodes were associated with low-power implantable responsive neuro-stimulation system. The electrodes performance in recording and stimulation application was quantified through in vitro and in vivo acute and chronic experiments on human brain slices and freely-moving rodents. The Flex electrodes exhibited remarkable drop in the electric impedance (100 times at 100 Hz), improved electrode-electrolyte interface noise (dropped by four times) and higher signal-to-noise ratio (3.3 times).

Massively-parallel neuromonitoring and neurostimulation rodent headset with nanotextured flexible microelectrodes.

We present a compact wireless headset for simultaneous multi-site neuromonitoring and neurostimulation in the rodent brain. The system comprises flexible-shaft microelectrodes, neural amplifiers, neurostimulators, a digital time-division multiplexer (TDM), a micro-controller and a ZigBee wireless transceiver. The system is built by parallelizing up to four 0.35 µm CMOS integrated circuits (each having 256 neural amplifiers and 64 neurostimulators) to provide a total maximum of 1024 neural amplifiers and 256 neurostimulators. Each bipolar neural amplifier features 54 dB-72 dB adjustable gain, 1 Hz-5 kHz adjustable bandwidth with an input-referred noise of 7.99 µVrms and dissipates 12.9 µW. Each current-mode bipolar neurostimulator generates programmable arbitrary-waveform biphasic current in the range of 20-250 µA and dissipates 2.6 µW in the stand-by mode. Reconfigurability is provided by stacking a set of dedicated mini-PCBs that share a common signaling bus within as small as 22 × 30 × 15 mm³ volume. The system features flexible polyimide-based microelectrode array design that is not brittle and increases pad packing density. Pad nanotexturing by electrodeposition reduces the electrode-tissue interface impedance from an average of 2 MΩ to 30 kΩ at 100 Hz. The rodent headset and the microelectrode array have been experimentally validated in vivo in freely moving rats for two months. We demonstrate 92.8 percent seizure rate reduction by responsive neurostimulation in an acute epilepsy rat model.

High-density intracortical microelectrode arrays with multiple metallization layers for fine-resolution neuromonitoring and neurostimulation.

Intracortical microelectrodes play a prominent role in the operation of neural interfacing systems. They provide an interface for recording neural activities and modulating their behavior through electric stimulation. The performance of such systems is thus directly meliorated by advances in electrode technology. We present a new architecture for intracortical electrodes designed to increase the number of recording/stimulation channels for a given set of shank dimensions. The architecture was implemented on silicon using microfabrication process and fabricated 3-mm-long electrode shanks with six relatively large (110 µm ×110 µm) pads in each shank for electrographic signal recording to detect important precursors with potential clinical relevance and electrical stimulation to correct neural behavior with low-power dissipation in an implantable device. Moreover, an electrode mechanical design was developed to increase its stiffness and reduce shank deflection to improve spatial accuracy during an electrode implantation. Furthermore, the pads were post-processed using pulsated low current electroplating and reduced their impedances by ≈ 30 times compared to the traditionally fabricated pads. The paper also presents microfabrication process, electrodes characterization, comparison to the commercial equivalents, and in vitro and in vivo validations.

Reproducibility of liver stiffness measurements in hepatitis C virus (HCV)-infected patients in Egypt.

Elastometry has demonstrated good accuracy, but little is known about its reproducibility. The aim of this study was to assess the intra- and inter-operator reproducibility of liver stiffness measurement among hepatitis C virus (HCV)-infected patients in Egypt. The study was conducted among HCV-infected patients referred for treatment evaluation in two hepatitis treatment centres of Cairo. Two operators took liver stiffness measurement two times per patient the same day. Intra- and inter-reproducibility were estimated by different methods: Bland and Altman graphics, variation coefficient, intraclass correlation coefficient and Kappa coefficient; 7.1 kPa was used as the threshold of significant (≥F2) fibrosis whenever needed. Fifty-eight patients were included in the study, and 216 measurements were taken. Failure rate was 7% and associated with overweight. For a value of 7.1 kPa, the inter-operator 95% limits of agreement were estimated at ±2.88 kPa. Intra- and inter-operator coefficients of variation ranged between 11% and 15%, intraclass correlation coefficients [95% confidence interval] between 0.94 [0.86-0.97] and 0.97 [0.95-0.99], and Kappa coefficients between 0.65 [0.44-0.88] and 0.92 [0.81-1.00]. The reliability of liver stiffness measurement is questionable when considering the decision to initiate antiviral therapy because of the percentage of discordance between measurements is notable, especially in the intermediate fibrosis stages.

3D microprobes for deep brain stimulation and recording.

A new generation of three dimensional (3D) multi channel microprobes is reported for deep brain stimulation (DBS) applications offering both stimulation and recording capabilities. The devices are comprised of planar flexible microprobes assembled or folded over cylindrical polyurethane shafts with radiuses as low as 350 microm. As a direct benefit of this approach, the dimensions and density of the electrode sites are precisely defined by the sub-micrometer resolution of the lithography processes employed for fabrication of planar devices. This work presents a microprobe with 16 stimulating and 16 recording channels. The stimulation sites are 100 microm × 1.5 mm while the recording sites are 20 microm × 20 microm.

Unusual appearance of a cerebral hydatid cyst as a hemorrhagic infarct.

We herein present a 32-year-old Lebanese woman with a history of cardiac hydatid cyst presenting with headache, confusion, and right arm clumsiness. A CT of the head showed hemorrhagic infarct of the left fronto-parietal lobe. Eleven months later, the subsequent development of hydatid cysts within the necrotic area of the infracted hemisphere suggested a cerebral hydatid embolism of cardiac origin. In patients with a positive history of hydatid disease, hydatid embolism should be considered in the differential diagnosis of stroke in young patients.

Enterocutaneous fistula. Causes and management.

OBJECTIVE: To study the main causes of fistula, and to determine the factors related to a successful treatment. METHODS: From November 2002 to October 2005, a total of 70 consecutive patients with enterocutaneous fistula in Gastroenterology and Hepatology Teaching Hospital, Baghdad, Iraq, were studied prospectively. Fifty-two patients received total parenteral nutrition. Internal gastrointestinal fistula, and pure pancreatic and biliary fistula were excluded from this study. RESULTS: In 68 patients, the fistula developed postoperatively, the most common primary cause was missile injury (42%), and 2 patients have fistula that developed spontaneously. The fistula was healed by conservative treatment in 34 patients, and by surgical intervention in 10. Twenty-five patients died, and in one patient the fistula failed to heal by conservative as well as by surgical treatment. The mean duration of hospital stay for all patients was 25.9 days. CONCLUSION: The most common cause of enterocutaneous fistula found in this study was missile injury. Duodenal fistula and, to a lesser extent, ileal fistula, respond more to conservative treatment. High output and jejunal fistula were associated with poorer outcome. Octreotide administration did not significantly improve the output of the fistula or the outcomes.

Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome.

We investigated the phenotypic expression of factor H mutations in two patients with atypical hemolytic uremic syndrome (HUS). Factor H in serum was assayed by rocket immunoelectrophoresis, immunoblotting, and double immunodiffusion and in tissue by immunohistochemistry. Functional activity was analyzed by hemolysis of sheep erythrocytes and binding to endothelial cells. A homozygous mutation in complement control protein (CCP) domain 10 of factor H was identified in an adult man who first developed membranoproliferative glomerulonephritis and later HUS. C3 levels were very low. The patient had undetectable factor H levels in serum and a weak factor H 150 kDa band. Double immunodiffusion showed partial antigenic identity with factor H in normal serum owing to the presence of factor H-like protein 1. Strong specific labeling for factor H was detected in glomerular endothelium, mesangium and in glomerular and tubular epithelium as well as in bone marrow cells. A heterozygous mutation in CCP 20 of factor H was found in a girl with HUS. C3 levels were moderately decreased at onset. Factor H levels were normal and a normal 150 kDa band was present. Double immunodiffusion showed antigenic identity with normal factor H. Factor H labeling was minimal in the renal cortex. Factor H dysfunction was demonstrated by increased sheep erythrocyte hemolysis and decreased binding to endothelial cells. In summary, two different factor H mutations associated with HUS were examined: in one, factor H accumulated in cells, and in the other, membrane binding was reduced.

Children and television tipovers: a significant and preventable cause of long-term neurological deficits.

OBJECT: Television tipover has recently been recognized as a significant cause of injury in children, and head injury accounts for most of the associated deaths. The authors reviewed their experience with children who sustained head injury from falling televisions. METHODS: Children admitted with the diagnosis of head injury related to falling televisions since 1992 were identified from the authors' trauma database, and a retrospective review of the medical records was performed. Eighteen patients were identified: 13 boys and five girls whose ages ranged from 12 months to 10 years (mean 44 months). The admission Glasgow Coma Scale (GCS) score was 15 in 10 patients. Only three patients had a GCS score of 8 or less (one patient had a score of 4). Neurological examinations were normal in 10 patients; three had cranial nerve deficits and three had otorrhea, otorrhagia, or hemotympanum. Radiological abnormalities included 16 skull fractures, three epidural hematomas, three small subdural hematomas, one intracranial hemorrhage, and three venous obstructions of the transverse-sigmoid sinus. The mean hospital stay was 8.9 days (range 2-39 days). Follow up at 0.2 to 68 months (mean 13.4 months) revealed severe neurological deficits in one patient and cranial nerve deficits of cranial nerves six, seven, or eight in six patients. CONCLUSIONS: Falling televisions result in significant head injuries in children, with substantial short- and long-term sequelae. This injury is easily preventable through simple measures taken by both the manufacturers and caregivers.

Role of transplant induction therapy on recurrence rate of focal segmental glomerulosclerosis.

Individuals with focal segmental glomerulosclerosis (FSGS) are at risk for recurrence of disease following renal transplantation. The rate of recurrence has been estimated to range from 20% to 30%. The factors associated with an increased probability of recurrence are not known, although the rapidity of progression of disease, age at onset, and the presence of diffuse mesangial proliferation in the native kidney have all been implicated. We analyzed the data from 35 patients with FSGS who received 37 renal transplants at this institution between October 1968 and December 1997. Recurrence was diagnosed by the development of nephrotic-range proteinuria and a transplant biopsy compatible with the diagnosis. Sixteen recurrences were noted, with an overall recurrence rate of 43%. The risk of recurrence was associated with the use of antilymphocytic serum (ALS) for initial induction therapy; being 11% in those who received no induction therapy versus 53% in those who received ALS. Furthermore, in the latter group, the rate of recurrence was 88% in those who received antithymocyte globulin (ATGAM) versus 40% in those who received Minnesota antilymphocytic globulin. Factors such as race, sex, age at time of diagnosis, rapidity of progression to end-stage renal disease (ESRD), response to alkylating agents and/or cyclosporin therapy prior to ESRD, age at time of transplant, donor source, and triple or double immunosuppressive therapy did not appear to have an effect on the rate of recurrence. We conclude that induction therapy with ALS at time of transplantation increases the risk of recurrence of FSGS following renal transplantation.