Nazareth Hospital EMMS

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.

BACKGROUND: Lymphomatoid papulosis is a benign cutaneous eruption that in 10 to 20 percent of patients is associated with the development of lymphoma. The atypical cells of lymphomatoid papulosis histologically resemble the malignant cells of cutaneous T-cell lymphoma or the Reed-Sternberg cells of Hodgkin's disease. We studied a patient in whom lymphomatoid papulosis developed in 1971, Hodgkin's disease in 1975, and cutaneous T-cell lymphoma in 1985, to determine whether these diseases are clonally related. METHODS: The T-cell-receptor alpha-chain gene was cloned and sequenced from a cell line derived from the advanced-stage cutaneous T-cell lymphoma, and the polymerase chain reaction was used to search for this rearrangement of the alpha-chain gene in tissues obtained earlier that were affected by Hodgkin's disease or lymphomatoid papulosis. RESULTS: The tumor-specific rearrangement of the alpha-chain gene was detected in the patient's earlier tissues affected by lymphomatoid papulosis and Hodgkin's disease, but not in control tissue, including uninvolved tissues from the staging laparotomy for Hodgkin's disease. Cytogenetic studies revealed a translocation, t(8;9)(p22;p24), in cutaneous T-cell lymphoma lines and in a dermatopathic lymph node removed two years before the clinical onset of the cutaneous T-cell lymphoma. Immunohistochemical findings were consistent with an activated T-cell phenotype for the atypical cells of lymphomatoid papulosis, the Reed-Sternberg cells of Hodgkin's disease, and the malignant cells of the T-cell lymphoma. CONCLUSIONS: Lymphomatoid papulosis, Hodgkin's disease, and cutaneous T-cell lymphoma can be derived from a single T-cell clone. A t(8;9) genetic translocation may be involved in the pathogenesis of lymphomatoid papulosis or its progression to malignant disease.

Much progress has been made in elucidating early events in signal transduction by growth factor receptors with intrinsic tyrosine kinase activity. Upon ligand addition, these receptors dimerize and activate, becoming phosphorylated at a number of tyrosyl residues. These phosphorylation sites serve as docking points for proteins containing src homology-2 (SH2) domains. However, little is known about how phosphotyrosine phosphatases (PTPs), participate in these events. Recently, we and others molecularly cloned a ubiquitously expressed SH2 domain-containing PTP, SH-PTP2 (Syp, PTP1D, PTP2C), and found that it interacts directly with several activated growth factor receptors via its SH2 domains. Using a peptide competition assay, we now demonstrate that the major binding site for SH-PTP2 on the platelet-derived growth factor receptor is phosphotyrosine 1009. Immunoprecipitation studies indicate that SH-PTP2 is the previously unidentified "64-kDa" protein known to bind at this site. Addition of a phosphotyrosyl peptide comprising the region around Tyr-1009 stimulates SH-PTP2 activity 5-10-fold, whereas other phosphotyrosyl peptides from the platelet-derived growth factor receptor have no stimulatory effect. Our data suggest that binding of SH-PTP2 to the activated receptor in vivo should result in stimulation of SH-PTP2 activity.

RECOGNITION of the magnitude of the problem of pulmonary embolism in man requires reliable data concerning its incidence. Unfortunately, most of the available statistics on incidence are based on routine post-mortem examinations in which the pulmonary arteries are rarely inspected adequately.We were stimulated to examine the frequency of human pulmonary embolism found at autopsy as a result of observations in an experimental investigation of pulmonary embolism in dogs.1 , 2 While studying the fate of experimentally induced autologous peripheral venous thrombi released to the pulmonary circulation, we repeatedly noted that some of the residua observed weeks to months after the embolic . . .

Neural circuits linking activity in anatomically segregated populations of neurons in subcortical structures and the neocortex throughout the human brain regulate complex behaviors such as walking, talking, language comprehension, and other cognitive functions associated with frontal lobes. The basal ganglia, which regulate motor control, are also crucial elements in the circuits that confer human reasoning and adaptive function. The basal ganglia are key elements in the control of reward-based learning, sequencing, discrete elements that constitute a complete motor act, and cognitive function. Imaging studies of intact human subjects and electrophysiologic and tracer studies of the brains and behavior of other species confirm these findings. We know that the relation between the basal ganglia and the cerebral cortical region allows for connections organized into discrete circuits. Rather than serving as a means for widespread cortical areas to gain access to the motor system, these loops reciprocally interconnect a large and diverse set of cerebral cortical areas with the basal ganglia. Neuronal activity within the basal ganglia associated with motor areas of the cerebral cortex is highly correlated with parameters of movement. Neuronal activity within the basal ganglia and cerebellar loops associated with the prefrontal cortex is related to the aspects of cognitive function. Thus, individual loops appear to be involved in distinct behavioral functions. Damage to the basal ganglia of circuits with motor areas of the cortex leads to motor symptoms, whereas damage to the subcortical components of circuits with non-motor areas of the cortex causes higher-order deficits. In this report, we review some of the anatomic, physiologic, and behavioral findings that have contributed to a reappraisal of function concerning the basal ganglia and cerebellar loops with the cerebral cortex and apply it in clinical applications to attention deficit/hyperactivity disorder (ADHD) with biomechanics and a discussion of retention of primitive reflexes being highly associated with the condition.

Muscle weakness in the elderly is prevalent and morbid, closely linked to the frailty, functional decline, immobility, falls, and injuries in this population. The marked decrease in skeletal muscle strength and size with aging is a multifactorial syndrome which may be attributable in part to: (a) biological changes of aging itself; (b) the accumulation of acute and chronic diseases; (c) the assumption of a sedentary life style, and (d) selective or generalized nutritional inadequacies. Inactivity and undernutrition are potentially at least partially reversible with appropriate interventions, and therefore the delineation of the attributable risk of these two factors to the muscle weakness of aging is a critical research goal. Similarly, identification of appropriate modalities of physical activity and nutrition which have positive effects on muscle physiology in the aged is the focus of major investigations currently.

A MOST important complication of erythroblastosis fetalis is brain damage, commonly known as kernicterus,1 which has in the past affected about 15 per cent of liveborn infants with erythroblastosis. About 70 per cent of babies with kernicterus die within seven days of birth, and many of the remainder succumb during the first year to infectious diseases. Kernicterus is thus the most important cause of post-natal death in erythroblastosis fetalis. Babies with kernicterus who do not die have permanent neurologic sequelae, and constitute perhaps 10 per cent of all cases of cerebral palsy. Kernicterus has been proved to be preventable by . . .

BACKGROUND: Omadacycline, a new once-daily aminomethylcycline antibiotic agent that can be administered intravenously or orally, reaches high concentrations in pulmonary tissues and is active against common pathogens that cause community-acquired bacterial pneumonia. METHODS: In a double-blind trial, we randomly assigned (in a 1:1 ratio) adults with community-acquired bacterial pneumonia (Pneumonia Severity Index risk class II, III, or IV) to receive omadacycline (100 mg intravenously every 12 hours for two doses, then 100 mg intravenously every 24 hours), or moxifloxacin (400 mg intravenously every 24 hours). A transition to oral omadacycline (300 mg every 24 hours) or moxifloxacin (400 mg every 24 hours), respectively, was allowed after 3 days; the total treatment duration was 7 to 14 days. The primary end point was early clinical response, defined as survival with improvement in at least two of four symptoms (cough, sputum production, pleuritic chest pain, and dyspnea) and no worsening of symptoms at 72 to 120 hours, without receipt of rescue antibacterial therapy. A secondary end point was investigator-assessed clinical response at a post-treatment evaluation 5 to 10 days after the last dose, with clinical response defined as resolution or improvement in signs or symptoms to the extent that further antibacterial therapy was unnecessary. A noninferiority margin of 10 percentage points was used. RESULTS: The intention-to-treat population included 386 patients in the omadacycline group and 388 patients in the moxifloxacin group. Omadacycline was noninferior to moxifloxacin for early clinical response (81.1% and 82.7%, respectively; difference, -1.6 percentage points; 95% confidence interval [CI], -7.1 to 3.8), and the rates of investigator-assessed clinical response at the post-treatment evaluation were 87.6% and 85.1%, respectively (difference, 2.5 percentage points; 95% CI, -2.4 to 7.4). Adverse events that emerged after treatment initiation were reported in 41.1% of the patients in the omadacycline group and 48.5% of the patients in the moxifloxacin group; the most frequent events were gastrointestinal (10.2% and 18.0%, respectively), and the largest difference was for diarrhea (1.0% and 8.0%). Twelve deaths (8 in the omadacycline group and 4 in the moxifloxacin group) occurred during the trial. CONCLUSIONS: Omadacycline was noninferior to moxifloxacin for the treatment of community-acquired bacterial pneumonia in adults. (Funded by Paratek Pharmaceuticals; OPTIC ClinicalTrials.gov number, NCT02531438 .).

BACKGROUND: Disulfiram, an alcohol aversion agent, has been in use for >50 years. Numerous authors have reported an anticancer effect of this drug in vitro and in mouse models. More recently, several reports have claimed that disulfiram also possesses anti-stem cell activity. We set out to obtain initial data regarding the safety of combining this drug with chemotherapy and the possible effectiveness of disulfiram in a combination regimen in non-small cell lung cancer (NSCLC). METHODS: This phase II, multicenter, randomized, double-blinded study assessed the safety and efficacy of adding of disulfiram to cisplatin and vinorelbine for six cycles. Newly diagnosed NSCLC patients were recruited. Patients with either stage IV or what was considered at the time "wet IIIb" (since 2009, these patients have been considered stage IV) were recruited. The patients were treated with only chemotherapy, and none were treated with either surgery or chemoradiation. Disulfiram was administered at a dose of 40 mg three times daily. RESULTS: Forty patients were treated for more than two cycles, half with and half without disulfiram, which was well tolerated. An increase in survival was noted for the experimental group (10 vs. 7.1 months). Interestingly, there were only two long-term survivors, both in the disulfiram group. CONCLUSION: The addition of disulfiram to a combination regimen of cisplatin and vinorelbine was well tolerated and appeared to prolong survival in patients with newly diagnosed non-small cell lung cancer. The results from this small study seem encouraging enough for assessment in larger trials. Disulfiram is an inexpensive and safe drug; if its addition to chemotherapy could be shown to prolong survival, an effective regimen could be established and used widely, even in resource-poor countries.

Preeclampsia is a serious complication of pregnancy where it affects 5-8% of all pregnancies. It increases the morbidity and mortality of both the fetus and pregnant woman, especially in developing countries. It deleteriously affects several vital organs, including the kidneys, liver, brain, and lung. Although, the pathogenesis of preeclampsia has not yet been fully understood, growing evidence suggests that aberrations in the angiogenic factors levels and coagulopathy are responsible for the clinical manifestations of the disease. The common nominator of tissue damage of all these target organs is endothelial injury, which impedes their normal function. At the renal level, glomerular endothelial injury leads to the development of maternal proteinuria. Actually, peripheral vasoconstriction secondary to maternal systemic inflammation and endothelial cell activation is sufficient for the development of preeclampsia-induced hypertension. Similarly, preeclampsia can cause hepatic and neurologic dysfunction due to vascular damage and/or hypertension. Obviously, preeclampsia adversely affects various organs, however it is not yet clear whether pre-eclampsia per se adversely affects various organs or whether it exposes underlying genetic predispositions to cardiovascular disease that manifest in later life. The current review summarizes recent development in the pathogenesis of preeclampsia with special focus on novel diagnostic biomarkers and their relevance to potential therapeutic options for this disease state. Specifically, the review highlights the renal manifestations of the disease with emphasis on the involvement of angiogenic factors in vascular injury and on how restoration of the angiogenic balance affects renal and cardiovascular outcome of Preeclamptic women.

Regulating immunity is a leading target for cancer therapy. Here, we show that the anti-tumor immune response can be modulated by the brain's reward system, a key circuitry in emotional processes. Activation of the reward system in tumor-bearing mice (Lewis lung carcinoma (LLC) and B16 melanoma) using chemogenetics (DREADDs), resulted in reduced tumor weight. This effect was mediated via the sympathetic nervous system (SNS), manifested by an attenuated noradrenergic input to a major immunological site, the bone marrow. Myeloid derived suppressor cells (MDSCs), which develop in the bone marrow, became less immunosuppressive following reward system activation. By depleting or adoptively transferring the MDSCs, we demonstrated that these cells are both necessary and sufficient to mediate reward system effects on tumor growth. Given the central role of the reward system in positive emotions, these findings introduce a physiological mechanism whereby the patient's psychological state can impact anti-tumor immunity and cancer progression.

Nonalcoholic fatty liver disease (NAFLD) has become one of the most common causes of liver disease worldwide and has been recognized as a major health burden. The prevalence of NAFLD has grown proportionally with the rise in obesity, sedentary lifestyle, unhealthy dietary pattern, and metabolic syndrome. Currently, there is no drug therapy that can be formulated for treating NAFLD. A combination of dietary modifications and increased physical activity remains the mainstay of NAFLD management. It is hard to maintain this mode of management; however, it seems to have significant long-term benefits. Furthermore, NAFLD patients, whether obese or not, should be educated that a healthy diet and physical activity have benefits beyond weight reduction. Further large controlled randomized trials are needed in order to identify the best dietary regimen and physical activity in the management of NAFLD patients. This review highlights the role of diet and lifestyle modifications in the management of NAFLD, and focuses on human studies regarding dietary modifications and physical activity.

We have studied the effects of thyrotropin (TSH) on the growth and on the levels of the mRNAs of the cellular proto-oncogenes, c-myc, and c-fos, in the specific target of TSH action, the thyroid follicular cell. FRTL5 cells, a cloned line from normal rat thyroid gland that depends upon TSH for its replication, were maintained in a quiescent state for 5 days by keeping them in a medium devoid of serum or TSH. The addition of bovine TSH (bTSH, 1 nM) increased DNA synthesis and stimulated cell proliferation after a lag period of 24 h. This growth response was anteceded by prompt, but transient, increases in the levels of c-myc and c-fos mRNAs, with peak responses at 60 and 30 min, respectively. The minimally and maximally effective concentrations of bTSH were 0.01 mM and 1.0 nM, respectively. Dibutyryl cAMP (Bt2cAMP) stimulated cell growth and increased the level of c-myc mRNA in a concentration-dependent manner, with maximum effects at a Bt2cAMP concentration of 1 mM. At the single concentration tested (1 mM), Bt2cAMP also increased the level of c-fos mRNA. Hence, bTSH-stimulated mitogenesis in quiescent FRTL5 cells is associated with rapid, but short-lived, increases in the levels of the mRNAs of the proto-oncogenes, c-myc and c-fos. Since bTSH is known to stimulate adenylate cyclase in these cells, and since the effect of TSH on c-myc and c-fos mRNAs is mimicked by Bt2cAMP, it is possible that these responses to bTSH are mediated, at least in part, by cAMP.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder caused by several distinct defects in genes responsible for ciliary beating, leading to defective mucociliary clearance often associated with randomization of left/right body asymmetry. Individuals with PCD caused by defective radial spoke (RS) heads are difficult to diagnose owing to lack of gross ultrastructural defects and absence of situs inversus. Thus far, most mutations identified in human radial spoke genes (RSPH) are loss-of-function mutations, and missense variants have been rarely described. We studied the consequences of different RSPH9, RSPH4A, and RSPH1 mutations on the assembly of the RS complex to improve diagnostics in PCD. We report 21 individuals with PCD (16 families) with biallelic mutations in RSPH9, RSPH4A, and RSPH1, including seven novel mutations comprising missense variants, and performed high-resolution immunofluorescence analysis of human respiratory cilia. Missense variants are frequent genetic defects in PCD with RS defects. Absence of RSPH4A due to mutations in RSPH4A results in deficient axonemal assembly of the RS head components RSPH1 and RSPH9. RSPH1 mutant cilia, lacking RSPH1, fail to assemble RSPH9, whereas RSPH9 mutations result in axonemal absence of RSPH9, but do not affect the assembly of the other head proteins, RSPH1 and RSPH4A. Interestingly, our results were identical in individuals carrying loss-of-function mutations, missense variants, or one amino acid deletion. Immunofluorescence analysis can improve diagnosis of PCD in patients with loss-of-function mutations as well as missense variants. RSPH4A is the core protein of the RS head.

LEUCINE aminopeptidase is a proteolytic enzyme that is capable of hydrolyzing L-leucyl peptides. It is widely distributed in bacteria, plants and animals and has been demonstrated in all human tissues assayed, with high activity in the duodenum, kidney and liver.1 2 3 The intracellular function of this enzyme is not known but probably involves hydrolysis of a peptide bond near an L-leucine residue or the transfer of L-leucine from one peptide molecule to another. In the small intestine this peptidase is active in the terminal phases of protein digestion. We have demonstrated it regularly in gastric juice, bile and duodenal secretion, in . . .

UNLABELLED: Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the "brain reward cascade," a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). METHODOLOGY: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. RESULTS: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. CONCLUSIONS: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific "reward" phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.

CARDIAC arrest may occur unexpectedly during various diagnostic and therapeutic procedures, particularly under anesthesia. Though infrequent (1 in every 500 to 5000 operations1 , 2), each accident is a catastrophe. Despite the wide, active interest in this problem current therapy is too often unsuccessful.The commonly recognized mechanisms of cardiac arrest are ventricular standstill and ventricular fibrillation; standstill is the usual cause. In a compilation of 1200 cases of cardiac arrest, Stephenson et al.3 placed the occurrence of standstill at 88 per cent. Of 141 cases4 5 6 7 8 in which the mechanisms were specifically diagnosed by electrocardiograms or direct observations of the heart, . . .

Human cord blood mononuclear cells were cultured for 35 days in media containing recombinant human interleukin 5 (rhIL-5) supplemented with a fraction of the culture supernatant of phytohemagglutinin (PHA)-stimulated human T lymphocytes from which interleukin 2 (IL-2) was eliminated. Cultured cells were studied by electron microscopy and an immunogold procedure to detect subcellular site(s) of Charcot-Leyden crystal (CLC) protein. The majority of cells (greater than 70%) developing in this system were mature eosinophils, with descending frequency of other cells, including macrophages, mature basophils, eosinophilic myelocytes, and mature neutrophils. Mature eosinophils were characterized by increased numbers of primary granules, small granules, tubulovesicular structures, and decreased secondary granules. These eosinophils showed extensive piecemeal degranulation (PMD) characterized by partially empty and empty secondary granule chambers in the cytoplasm. Small, smooth vesicles were evident within empty granule chambers as well as adjacent to them. Eosinophils formed close associations with phagocytic macrophages that contained both standard-shaped and irregularly shaped CLC within phagolysosomes. Subcellular sites of CLC protein were demonstrated by immunogold in eosinophils and macrophages arising in these cultures. Charcot-Leyden crystal protein was present in the nuclear matrix and extraorganellar cytoplasm of eosinophils. Primary granules and some cytoplasmic vesicles were labeled for CLC protein, but full and empty secondary granules and the extensive network of tubulovesicles were not. Charcot-Leyden crystals were absent from eosinophils, nor were they present in the extracellular space. Charcot-Leyden crystals were absent from eosinophils, nor were they present in the extracellular space. Charcot-Leyden crystals within phagosomes of macrophages were labeled by the immunogold procedure for CLC protein. These results demonstrate that rhIL-5-supplemented, PHA-stimulated, T-cell-conditioned media induced the development of mature human eosinophils from cord blood cells. These eosinophils underwent PMD of secondary granule contents. Immunogold analysis showed eosinophil CLC protein in the cytoplasm, nucleus, and primary granules of eosinophils. Macrophages also were present in these cultures. They contained CLC protein-containing crystals in their phagosomes, suggesting active sequestration of eosinophil CLC protein by macrophages in vitro.

PULMONARY angiography is potentially the most positive means for diagnosing thromboembolism of the lung. The importance of such a procedure can hardly be overstated when one is dealing with a diagnosis that is missed more often than it is made1 and in which recurrences may subsequently prove to be fatal. Since current therapy has been shown to improve prognosis significantly2 early diagnosis becomes especially important.The present report was prompted by the successful use of pulmonary angiography in 8 of 11 patients in whom the diagnosis of thromboembolic disease was suspected. Five cases of the group studied are presented in . . .