Paraneoplastic Cushing ’ s Syndrome in a patient with multiple tumors – case report

Sepsis, severe sepsis and septic shock are some of the most serious affections which threaten the lives of the patients who come to the Emergency Department and which require fast treatment because the more severe the sepsis was, the higher the mortality, up to 50% higher in severe sepsis. That is why, at present, the 2013 Guides of Surviving Sepsis Campaign recommend that the potential source of infection should be confirmed as soon as possible, in the first 6 hours since the patient arrived in the Emergency Unit if possible, moreover the large spectrum antibiotics therapy must be administered in one hour after the severe sepsis or the septic shock were identified. That is why the identification of these patients at risk is very important and this identification can only be made using POCT type devices. This type of devices has the capacity to make precise determinations, in a short time (15-17 minutes), using minimum quantities of integral blood, without using test tubes, sepsis biomarkers and other additional material. The possibility to fast diagnose sepsis, offers the doctors from the Emergency Department, the capacity to fast initiate an antibiotic treatment, to hospitalize the patient and at the same time, it gives them the certainty that they did not miss the sepsis diagnosis, thus avoiding the situation of malpractice. A preliminary study, regarding the sepsis biomarkers, which took place in the Emergency Unit of University Central Emergency Military Hospital, is also presented within this article.


The Romanian Military Medical System transformation strategy Constantin Ștefani, Daniel Aron
Facing the Romanian military sistem changeover determined by the affiliation to international security alliances and by the necessity to adapt it to global and regional security environment in order to be able to cope with actual threats and risks, the military medical system should be adapted in order to become efficient in providing medical support in operations and in the same time to provide medical care for soldiers and their families.The military medical system transformation strategy represents the basic document which reflects the picture of desired end state showing the roads to get there.
The major challenge is represented by the harmonizing process between national and operational NATO laws and rules, because the interoperability is one of the main tasks in National Security Strategy.
Excellent trained medical personnel, establishing the standards of medical logistic support and procedures, the adapting process of the medical structures are the key points of this strategy, being in the same time the main courses of action.
Having the medical military system as a picture on the wall, it can be described as a dual functional mechanism, depending on its acting conditions: operational medicine providing medical support in operations, and stationary medicine providing medical care in peace time.In order to be efficient, the military medical system should have the following features: to be complete from the battlefield through all stage off care, to be selfsustained, to be deployable with troops, and to be able for integration in multinational operational medical system and in the national civilian medical system as well.
The two main missions of the medical military system are preservation of health and the second, treating casualties and healing ill soldiers and their families.During all the actions, in order to accomplish both previous missions, the following general principles will be applied: the best medical practice, continuity of care, the interest of patient and the importance of the mission.This complex system works with excellent trained medical personnel in military medical educational system and combat medical training centers, having a proper medical logistics.For that, beside regulation domain, a significant financial effort will be needed.Moreover, a coordinated long time term financial strategic program to provide proper medical supplies will solve logistical issues in medical military system.Medical research and standardization processes are the engines to progress of all parts of the military medicine.A dedicated and efficient command-control system, working under well defined procedures will integrate medical

Chief of Medical Directorate, Ministry of National Defence, Romania
considerations in the complex military mechanism.
The implementation plan will have the Medical Directorate in the center of the process, being involved from the highest to the smallest level of the medical support, using the military hospitals and the others subordinate structures to coordinate medical activities and to optimize the whole process.
Eventually, in the operational medicine domain every battalion level unit will be supported by a ROL 1 medical facility, every brigade level unit by a ROL 2 medical facility, all military hospitals except Central Universitary Emergency Military Hospital will fulfill the ROL 3 medical facility criteria, and Central Universitary Emergency Military Hospital will be the Romanian ROL 4 medical facility.
An important goal in the development of military hospitals will be represented by involving them in the training activities in their area of responsibility, so six military hospitals near the main ranges will have specific capabilities in order to be able to solve all medical situations with can be a result of high risk activities.
The medical military system will be fully integrated in the operations at all level by a professional and dedicated medical planning system which is the key of an effective medical support.
In the stationary medical domain, the target is to grow up the quality of the medical act from primary medicine to hospitals, in the mean time to prioritize the access of soldiers and their families to military medical system.Another important goal is to optimize the procedures for soldiers to get their legal rights regarding the payment for medical services and pharmaceutically services.
Last but not least, the military medical system should become the most available medical solution for soldiers and their families on the free medical services market.
The military medical system is a special medical system serving a special structure which is Romanian Military Force.

INTRODUCTION
Sepsis, severe sepsis and septic shock are some of the most common affections which are handled in the Emergency Departments and in the intensive therapy sections and they still represent a major cause of morbidity and mortality for critic patients despite the use of respiratory and cardiovascular support, modern antibiotics and resuscitation therapy.In compliance with the newest guides published, fast identification and the speed of implementation of an adequate treatment in the first hours after the patient came to the Emergency Department can influence radically the prognostic of septic patients, facts which determined the concentration on biomarkers for precocious diagnosis, risk stratification and the assessment of these patients' prognostic. 1 Sepsis is an exacerbated systemic reaction at REVIEW ARTICLE 1 Carol Davila Central Emergency Military Hospital, Bucharest 2 Titu Maiorescu University, Faculty of Medicine, Bucharest something which would normally be a common infection.Although it was identified from the oldest times, the sepsis is still a challenge for clinicians and it remains, most of the times, a lethal complication.
During the last 10 years, in compliance with the Protocol initiated by Surviving Sepsis Campaign for the management of patients with sepsis, the mortality was reduced from 37% to 30%, nevertheless its percentage is still unacceptably high. 2 The legal framework for the management of patients who come to the Emergency Unit is provided in the Order of the Health Ministry no.1706/2007 regarding the management and organization of the emergency receiving units and compartments.
The patients who come to the Emergency Department are taken over by the employees of the department and they are selected according to the emergency degree in compliance with the Order of the Health Ministry no.48/2009 -National Protocol for the Selection of Patients from the Emergency Receiving Structures. 33Patients' selection is defined by law as follows: the mechanism or procedure by means of which the patients who come to the Emergency Receiving Unit (ERU) or to the Emergency Receiving Department (ERD) are assessed and classified, upon arrival in ERU or ERD, by a competent person (physician or average sanitary employee), taking into consideration their clinical state and the symptoms they declare, correlated with their age and medical history, how stable their vital functions are, the potential of exacerbation of their medical state, the necessity to implement a treatment or to perform some investigations, as well as other information which are considered to be relevant, so that it can be decided which is the priority for each patient to be assisted and the level of assistance necessary for each of them. 33tients' selection within the Emergency Department represents the medical procedure used to assess and categorize the patients arrived within the ERU by a nurse/physician, in order to decide their priority for medical care and its level.The nurse responsible with the patients' selection procedure is the nurse with specific preparation and with appropriate experience and abilities.The recommendation provided by the law is that the time allowed for the patients' selection should not be longer than 2 minutes. 33e level of patients' selection refers to all patients who have the same priority degree according to the severity and/or critical state of their pathology and to the necessary resources.Priority levels are the following: 33  Level I -resuscitation (Red Code): The patient who requires an intervention to save his/her life NOW.Maximum time allowed for the patient to be taken over in the treatment area: 0 minutes.
 Level II -critical (Yellow Code): The patient who is in a situation with major risk or altered mental status (acute modification) or any intense pain or major discomfort.Maximum time allowed for the patient to be taken over in the treatment area: 10 minutes.
 Level III -urgent (Green Code): The patient with stable vital functions who requires however, two or more medical laboratory or paraclinical investigations.Maximum time allowed for the patient to be taken over in the treatment area: 30 minutes.
 Level IV -nonurgent (Blue Code): The patient with stable vital functions who requires only one laboratory or paraclinical investigation.Maximum time allowed for the patient to be taken over in the treatment area: 60 minutes.
 Level V -examination (White Code).The patient who requires neither emergency medical assistance nor laboratory or paraclinical investigations.This category includes people who come for one of the following reasons: vaccination; social case without clinical symptoms; clinical and administrative issues (medical certificates, prescriptions, etc.).Maximum time allowed for the patient to be taken over in the treatment area: 120 minutes.
The patient has the right to have his health state periodically reevaluated if he has been taken over in the treatment area after more than 30 minutes or if there are significant modifications in his/her state, which means that patients' selection procedure within the Emergency Department is periodically resumed. 33More than once, this task is a difficult task to be performed, taking into account the big number of patients, insufficient personnel and the permanent stress the personnel from the Emergency Department has to deal with.In addition to these, the risk of bad evolution for septic patients and not only for them is quite high, therefore it is necessary that the diagnosis methods in this department are fast, precise and trustworthy.
We debate the issue of septic patients in this article because this kind of patients have a rather unpredictable evolution if they are not diagnosed correctly and in due time.More than often, old patients who also suffer from diseases in different stages are neglected or superficially treated at home, fact which makes the sepsis evolve frequently up to advanced stages until patients come to the hospital.This kind of patient is brought to the hospital with the ambulances of the national system 112 (SMURD or Ambulance Service) or by his/her relatives, being already in a critical state, dehydrated, with high temperature or with neurological signs.
Diagnosis of sepsis is not easy, it involves special issues, because at present, the available methods are related to the performance of the following laboratory analyses: the number of leukocytes (WBC) in the patient's blood resulting from a complete hemogram with leukocytes formula, the number of germs, sepsis biomarkers, CRP (reactive protein C) and last but not least the performance of bacterial cultures from blood (hemocultures) and from other fluids.Moreover when the physician from the Emergency Department is under time pressure and under pressure from the patients' relatives as well as from the other patients who do not understand the patients' selection Protocol mentioned above, a fast diagnosis has an even greater importance.The main topic of discussions is the fact that some patients have higher priority than others, meaning that some have to wait longer and others, who have just arrived, are immediately taken over and treated in the Emergency Department.The duty to introduce the patients in the 5 levels of selection belongs to the nurse from the patients' selection and eventually to the physician on duty; the two decide which patients have a higher level of priority.
Therefore, the physician from the Emergency Department should have available all necessary resources in order to make a fast, correct and hard to question diagnosis in the prospect of any malpractice accusations.Sometimes, there are patients who arrive in a state of septic shock and they have a fast evolution to decease because of multisystem organ failure (MSOF), so it is difficult for the patients' relatives to understand the reason why a patient having an apparently good state during the day, dies in hospital in less than 24 hours.That is why the physician from the Emergency Department (emergency medicine physician or intensive care physician) must make the correct diagnosis: SIRS, sepsis, severe sepsis or septic shock, so that a fast, appropriate and complex treatment can be initiated.
According to the law, the physician from the Emergency Department has the possibility to require all necessary examinations from different specialties in order to make a diagnosis, the period of time allowed before the patient is examined varies between 10 and 60 minutes according to the level of emergency -10 minutes for red code and maximum 60 minutes for green code. (32) is important to have in mind that patients must be subjected to a series of laboratory and paraclinical investigations, as soon as possible upon their arrival, especially in the case of patients belonging to the first 2 levels of priority.In view of a better understanding of the phenomenon, we shall make a review of the definitions of the Systemic Inflammatory Response Syndrome (SIRS) and of the sepsis with its stages.

DEFINITIONS
Systemic Inflammatory Response Syndrome (SIRS) is the clinical syndrome which results as a consequence of an inadequate inflammatory response of the body at a noninfectious origin lesion, such as: pancreatitis, vasculitis, autoimmune affection, thrombembolism, burns or surgery interventions. (3)SIRS diagnosis is made in the presence of 2 or more of the following criteria, as follows: temperature >38,5 o C or <36°C; ventricular rate >90/min; respiratory frequency >20/min or PaCO2 <32 mmHg; leukocytes >12000/mm 3 or <4000/mm 3 ; Sepsis is the clinical syndrome which results as a consequence of an inadequate inflammatory response of the body at an infection.Sepsis can be presumed if 2 or more of the conditions mentioned above are present and the infection is identified either through germs culture or visually. 1vere sepsis: sepsis associated with the organ dysfunction/insufficiency, impercipient perfusion or hypotension. 1ptic shock: hypotension within sepsis, with all appropriate replenishment. 1 Multisystem organ dysfunction -MSOD: organ dysfunction at a patient with an acute pathological state so that homeostasis cannot be maintained without medical intervention. 1

WHY "POINT OF CARE TESTING -POCT" DEVICES FOR EMERGENCY DEPARTMENTS?
Point-of-care testing (POCT) is defined as a medical testing at or near the site of patient care. 21,22Another definition would be the following: a group of investigation, diagnosis or screening technologies, which require neither personnel nor laboratory conditions, performed on spot where medical assistance is provided, within or outside a medical unit.The purpose of POCT is to provide immediate, convenient, and easy-to-use diagnostic testing that shortens the therapeutic turnaround time when providing care for a patient.
The objective is to provide rapid diagnostic information that permits immediate clinical management decisions to be made that will improve patient safety and clinical outcomes, not to mention patient satisfaction.It is important to be noticed that these technologies do not require special spaces or additional personnel, other than those that can be found in any hospital/physician office.POCT can be found in more environments: hospital bedside, ambulatory care settings (clinics or physician offices), alternate care (skilled nursing facilities), and home settings.
In Romania, medical devices are governed by Law no.176/2000 regarding medical devices, within this law, in article 2 point a) and b) we find their definition as follows 29 : a) Medical device -any instrument, device, mechanism, material or another article used alone or in combination with others, including the necessary software for its correct use, designed by the manufacturer for human use and which does not fulfill the main action for which it was designed in/or on the human body by pharmacological, immunological or metabolic means, but which can be helped in its function by such means, with the purpose of: diagnosis, prevention, monitoring, treatment…; b) Active medical device -any medical device whose functioning is based on another source of power or of energy than the one generated by the human body or by gravity; POCT benefits are numerous, below we are presenting the most important of them  Elimination of blood collection tubes and centrifugation with fresh whole blood specimen;  Reduced blood specimen volume;  Reduced volume of reagents -POCT is a less invasive method from the clinical point of view;  Data management and connectivity -POCT systems can be connected to the informatics systems of the hospitals having as result: less transcription errors, immediate data analysis -utilization, quality control, compliance and data mining, development of disease specific algorithms;  Good cost-benefits report -although generally the tests are more expensive, they can offer large economical benefits, by reducing the number of visits in hospital, days spent in hospital and repeated hospitalizations. 21,22:  Weak analyses quality;  Lack of results interpretation;  Wrong results which are difficult to trace;  The possibility to make a battery of tests can lead to the performance of unnecessary and inadequate analyses;

Potential disadvantages
 Lack of alignment with laboratory resultsreference intervals and results can be different to those issued from the classical laboratory which makes the comparison difficult.
The current diagnostic laboratory system has been slow to change and is in need of change to a more patient-centered system.Thus, today we need personalized medicine and a patient-centered medical system.
The model of centralized lab testing was developed in the late 1960s but the new technologies and the evolution of the health system demanded more rapid testing which led to a significant increase of POCT.The development of new technologies, such as "lab on a chip" 23,24 and DNA/RNA-based molecular diagnostic tests 25,26,27,28 , will expand the menu of POCT tests and will lead to an increase in the use of this device.
Taking into consideration all the benefits mentioned above, POCT improves the diagnostic activity; the most important aspects are immediate and precise diagnostic, the use of whole blood specimen in an extremely small quantity and reduction of specimen/sample transport to the laboratory.Due to the fact that it provides information to the Emergency Department physician upon diagnosis and patient's critical state, it also offers him/her a certain safety which, at the same time, eliminates the stress related to malpractice.
The physician from the Emergency Department can ask for interdisciplinary examinations, as already mentioned, however, if he/she does not have any investigations to show to his colleagues in order to make at least a presumptive diagnosis, the physician extends patient's hospitalization time in the Emergency Department waiting for the laboratory analyses made in the central laboratory.
In addition to that, the Romanian legislation, more precisely, the Order of the Health Ministry no.1706/2007 -which regulates the activities from the Emergency Departments, in Annex 1 -stipulates a series of minimum mandatory paraclinical and laboratory investigations which should always be available for the patients from the Emergency Departments.
These investigations complexity depends on the type of the Emergency Department (I or II), as related to imaging, but if we refer to basic analyses (hemogram, blood glucose meter, electrolytes, sanguineous gases), these are mandatory and it is preferable for them to be made in the Emergency Department in order to reduce the time until a diagnosis is made.
High level Emergency Departments -type I, must also have the possibility to make toxicology analyses.All these mandatory analyses, but also other analyses which can lead to an immediate and precise diagnosis, can only be made with the help of POCT technology.

SEPSIS DIAGNOSIS Biomarkers
Biomarkers can have an important role in proving the presence, absence or stringency of sepsis and they can make the difference between fungal and viral infections, between systemic sepsis and local infection.Other potential roles of the biomarkers include prognostic, antibiotic therapy, evaluation of treatment answer and postsepsis recovery, differentiation between gram-negative and grampositive germs, the possibility to predict sepsis complications and the development of organ malfunctions (heart, kidneys, liver or multiple organ malfunctions) 4 Biomarkers definition.At present, the accepted definitions for biomarkers are in compliance with the studies made by U.S. National Institute of Health (NIH) and by European Medicines Agency.A biomarker is a "biological characteristic, objectively measured (with acceptable accuracy and reproducibility) and used as an indicator for a physiological or pathological process or for the activity of a medicine".
In compliance with NIH standards, biomarkers can be classified in two categories: prognostic markerswhich allow for the patients to be classified according to the individual risk to have a specific prognostic, regardless of the treatment (or lack of treatment) and predictive markers -which allow the forecast of the potential benefit (efficacy) and/or the risks (toxicity) of a treatment according to the status of a biomarker (absent/present) 5 .
The ideal biomarker in infectious diseases is used to identify a high risk group or predisposing factors, as a tool for disease identification or for treatment prescription and classification of patients according to their specific factors as well as/or as indicator of the therapeutic management in order to avoid reinfection.An ideal marker for infections would combine the diagnostic, prognostic and treatment follow-up characteristics and it should be easily and fast available for clinic use 6 .Biomarkers should evaluate the severity of an infection or predict an evolution excluding complications to help the clinician make a decision regarding the best therapeutic approach in the most appropriate environment (hospital or specialty ambulatory, intensive therapy or hospital section).Furthermore, it should help the clinician decide if it is necessary to introduce or to continue antibiotic therapy.
Concluding, the "ideal" biomarker for sepsis diagnosis should make different diagnosis between SIRS and sepsis, between viral infections and bacterial ones, it should also "detect" sepsis fast, reflect de severity of the disease so that therapy can be monitored, have a high predictive value, be stable in different samples and eventually be quantified fast using "Point of Care" devices.
During the last few years, more potential biomarkers for infection were suggested and their analysis is a complex task.The present tendency is to use biomarkers -especially cytokine -in correlation with multiple tests which measure simultaneously more biomarkers from only one biological sample.The main purpose is to examine if the clinical performance and utility can be transposed in every day clinical situations, taking into account the great number of patients which come to the Emergency Departments and the necessity to make a diagnosis fast.
A fast diagnosis allows physicians from the Emergency Department to implement a precocious treatment which increases the patient's survival rate and which, at the same time, offers them the certainty that they are not wrong and that they have not passed by an infectious affection with lethal potential for that patient.Thus, the malpractice risk for the physicians from the Emergency Department is lower, since it is known that they have to deal with a great number of patients every day.

Available routine biomarkers
Three biomarkers fulfill the criteria mentioned above and are available at all times: C reactive protein (CRP), procalcitonine (PCT) and presepsin (PSEP).CRP was tested in different studies but only some of these studies focused on its use for the improvement of antibiotic therapy.Further to these studiescompleted or ongoing -the use of CRP cannot be recommended at present as a criterion for the initiation or end of antibiotic therapy in adults; however, for children, CRP can be probably used as an indicator to end the antibiotic treatment although the proofs obtained up to present are limited 5 .
Procalcitonine -PCT was tested on a larger scale for the improvement of antibiotic therapy, both for adults and for children.The conclusion of more studies completed recently, which involved a significant number of patients, is that the introduction of procalcitonine values in the decision algorithms for infection management in specific infections is most likely adequate.It is however necessary to continue researches for specific infections which have not been examined enough up to the present time, for a more precise definition of procalcitonine role in the management of antibiotic therapy 5 .

Presepsin -PSEP.
In this article, we shall present a new biomarker, which is a viable option for sepsis precocious diagnosis -presepsin (sCD14-ST) and we shall present its correlation with a score (MEDS score) to supply the gaps which are related to this biomarker, in comparison with what is used in present in clinical practice.The biomarker was used for the first time in 1993 32 and then in 1994 (Durieux et al.Eur J Immunol 1994;24:2006-12).Presepsin was studied starting with 2005 and it became an important new marker for the diagnosis and prognostic of sepsis in the last years. 8,9,10,11,12.
CD14 is a glycoprotein expressed on the surface of the monocytes/macrophages membrane (mCD14) and it serves as receptor for lipopolysaccharides (LPS) and for the protein which ties the LPS (LPBP).CD14 co-locates using a receptor 4, Toll-like type (TLR4).When tying LPBP complex, CD14 activates the specific pro-inflammatory signalizing cascade TLR4, thus initiating the host inflammatory reaction against any type of infectious agents.

LPS-LPBP-CD14
complex is released in circulation, canceling CD14 from the cellular membrane, thus soluble CD14 (sCD14) is produced.Nevertheless the activity of the proteose from the plasma generates another molecule sCD14, referred to as subtype sCD14 (sCD14-ST) or presepsin -a protein of 13 kDa which is actually a part of CD14, lysated at N-terminal head (Durieux et al.Eur J Immunol 1994;24:2006-12).PSEP levels were significantly higher at septic patients than at those with SIRS or at those apparently healthy.The increase of PSEP levels was more precocious than the increase of IL-6 and D-dymers levels in a study which created a model of bacteremia on animals (cecal ligation and puncture on rabbit -CLP).The determination of presepsin concentration can be used not only for the diagnosis and prognostic of sepsis, but also to monitor disease evolution and feedback at therapeutical interventions. 8,9,10,11,12cently discovered biomarkers of potential interest in the near future At present, intensive efforts are being made in the research field of some new prognostic and diagnostic biomarkers which can be useful in antibiotics therapy management from acute infections.For adults, three of these seem promising: sTREM-1 (soluble Triggering Receptor Expressed on Myeloid cells-1), suPAR (Soluble urokinase-type Plasminogen receptor) and ProADM (proadrenomeduline).These biomarkers are accessible, they have proved sensitivity and/or specificity and they were studied on a significant number of patients so that they are worth to be taken into consideration further on.For children and babies other studies are also necessary. 5,13 EM-1 is a member of immunoglobulins big family, surface receptor which appears at mature monocites and polimorphonuclears, they contribute at native immunity.Its expression is upregulated when phagocytes are exposed to bacterial fungic pathogens but not during other noninflammatory processes.TREM-1 amplifies the inflammatory response by increasing the proinflammatory cytokines production, inhibiting the synthesis of IL10.During the upadjustment of the surface receptor TREM-1, the soluble form sTREM-1 increases in biological fluids (blood, bronchoalveolar lavage fluid, cerebrospinal fluid) and it can be determined with ELISA commercial kits.According to some recent studies, the dosage from the infection spot seems to be more significant than the measurements made from plasma. 5,13PAR (Soluble urokinase-type Plasminogen Activator Receptor) or CD87 is a receptor for inflammatory response spread on a large scale.It appears only on the surface of a few cell types, such as: endothelial cells and leukocytes (monocytes/ macrophages, polymorphonuclears).
Expression of its gene is under the control of immune and inflammatory effectors, such as bacterial products (LPS), cytokines (IFN-γ, TNF-α, IL-1β) and growth factors (FGF-2, VEGF, TGF-β, EGF).During the inflammatory and immune response, suPAR expression is upregulated by epithelial cells, white blood cells (lymphocytes), smooth muscle cells and fibroblasts.Expression is also upregulated during tumor growth and metastatic spread.The dosage may be achieved using commercial ELISA kits available on the market, but also as part of the multiplex kit with multiple cytokines.However, suPAR seems to be of limited value as a diagnostic test in specific pathologies (patients at risk, HIV patients on antiretroviral therapy, monitoring patients with nonpulmonary bacterial infection and children with malaria with Plasmodium falciparum). 5,13o-ADM Adrenomedulin is a 52 amino acid peptide, a marker of CALC gene family that works as a mediator of cell proliferation, hormonal regulation and embryogenesis.ADM is produced by the endothelial cells where it induces vasodilation and maintains homeostasis.Pro-hormonal fragments (pro-ADM) are more stable than the complete peptide and their levels in biological fluids can be measured by automated methods TRACE (Time Resolved Amplified Crypt-Emission) after the capture of immunoassays.The secretion of proADM increases during an immune response against viral or bacterial products according to the size of the stimulus.Pro-ADM is a valuable prognostic marker.As part of an evaluation score of pneumonia severity, it can identify patients in rather critical state which would require monitoring/ hospitalization in an intensive care unit. 5,13

Future Biomarkers
Micro-RNA (miR) are newly discovered potential biomarkers.miR are small molecules (approximately 20 nucleotides) present in eukaryotic cells, which act as biological regulators by modulating posttranslational regulation.They are ubiquitous and present in abundance in the lungs, liver and kidneys.After binding to the appropriate smRNA sequence, they regulate the expression of the gene by a repressor effect or by altering the target sequence.A fragment of miR can bind several smRNA.Their expression can be measured by RT-PCR and quantitative PCR.miR are potential candidates for early diagnosis and/or prognostic markers in sepsis, but other numerous studies are necessary to understand their role in biochemical and immunobiological processes before it can be used to stratify, to make prognosis or therapeutic decision in septic patients. 5,13e diagnostic and prognostic evaluation of presepsin in sepsis in the Emergency Department was studied in comparison to other available routine biomarkers, in a study involving 859 patients, conducted by an university hospital which has between 240,000 and 260,000 hospitalizations per year. 10These findings were published recently, and the conclusions are consistent both with literature data available in today specialty literature and with personal observations generated during similar studies in our hospital which has 25,000 presentations through the Emergency Department per year.
The efficiency of using presepsin to diagnose cases of sepsis, severe sepsis and septic shock was significantly increased by using MEDS score in evaluating these patients as it will be shown below.It is also worth mentioning that although PCT (procalcitonin) can be used as a biomarker for the diagnosis of sepsis, it increases in other situations, such as: multiple injury, extensive burns, pancreatitis, organ transplantation, major surgery and SIRS -not only in infections, therefore, only the positive and negative predictive values are not enough to exclude or confirm sepsis. 10A recent meta-analysis showed that the diagnostic performance of PCT was reduced, with 71% (95% confidence interval 67-76%) sensitivity and specificity for serum PCT, as a biomarker for sepsis.In conclusion PCT can not clearly differentiate sepsis from other diseases in critic adult patients. 10,14,14,16,17,18Thus, to diagnose sepsis, severe sepsis and septic shock, PSEP proved to be superior to PCT, moreover, PSEP together with the assessment by MEDS score was superior to PSEP taken as sole indicator. 10,19 the 28-day mortality prognosis PSEP was inferior to PCT, but these were lower to the correlated interpretation and MEDS score.For septic patients and prognostication of mortality after 28 days, PSEP, MEDS and APACHE II score proved to be independent predictors unlike PCT which did not have this capacity.The mentioned study showed that plasma levels of PSEP were a parameter closely related to the severity of sepsis. 10,19,20mpared to the PCT, PSEP is a highly specific biomarker for the diagnosis of a bacterial infection because it is produced in conjunction with bacterial phagocytosis.
PSEP was higher than PCT and had greater sensitivity, specificity, positive predictive value, negative predictive value and accuracy of prognosis in early stages of sepsis which is consistent with the data from the updated literature.
The more severe the sepsis was, mortality also increased with over 50%, that is: mortality in severe sepsis.Dellinger et all., in Early-Goal Directed Therapy from 2013 guides of the Surviving Sepsis Campaign, recommends that the potential source of infection should be confirmed as quickly as possible, if possible within 6 hours since presentation and that large spectrum antibiotic therapy should be administered within one hour from the identification of severe sepsis or septic shock.Therefore identifying these patients at risk is very important.Table 1.MEDS Score (Mortality in Emergency Department Sepsis Score) 30,31

Variables for MEDS Score Points
Comorbidity fast terminal -fast terminal associated disease (metastatic cancer or another condition that can cause death in 30 days) 6 Age >65 years 3 Septic shock (PAs<90 mmHg with all volemic repletion) 3 Number of plates <150000/mm 3 3 Leukocytes premature unsegmented -bands (> 5% of total leukocytes) 3 Lower respiratory infection (clinical infiltrated pneumonia or chest RxG) 2 Altered mental status (level of alert or another change in the level of consciousness) 2 Chronic patients treated at home 2

STUDY ON THE IMPORTANCE OF PRESEPSIN IN ASSOCIATION WITH MEDS SCORE, SEPSIS PRECOCIOUS DIAGNOSIS. PRELIMINARY DATA
In the Emergency Department of the Universitary Central Emergency Military Hospital, a study was made during a year, involving 300 patients suspected of sepsis that came to the Emergency Department, patients brought by their relatives or by the ambulances from the national emergency system.
From these, 32 patients were introduced in the study (19 men and 13 women), for which the following inclusion and exclusion criteria were used: Criteria for inclusion in the study: • Age ≥18 years with clinical signs of severe infections requiring blood sampling; • The presence of 2 of 4 SIRS criteria: fever > 38 0 C <36 0 C; heart rate> 90 / min; respiratory rate > 20/min or existence of hyperventilation (PaCO2 <4.3 kPa / 32 mmHg in arterial blood); leukocytosis> 12,000/ml, leukopenia<4000/ml or > 10% premature unsegmented granulocytes (bands); Exclusion criteria: age under 18 and refusal to sign the consent.

All patients were examined by doctors of emergency medicine and ATI employees of the Emergency
Department and after the former signed the informed consent, venous peripheral approach was made, blood was collected for laboratory testing and they were subjected to other paraclinical investigations (abdominal ultrasound, CT in different regions, x-rays) in order to make a diagnosis and start the appropriate treatment immediately.
Analyses were performed in the Central Laboratory of SUUMC, and the Emergency Department's own laboratory, using "Point of care testing -POCT" and PATHFAST® device type.
Evaluation of patients admitted to the Emergency Department was made with the score MEDS -Sepsis Mortality in Emergency Department 19,30,31 .The score was developed to predict mortality for patients with SIRS hospitalized in the Emergency Department.The maximum score is 27 points, score variables and the score awarded to each variable can be found in Table 1.
For all these variables, a score are awarded, score which is summed up for each patient, the sum of the obtained points offers a prognostic for mortality at 28 days.
The determination of presepsin was made using a POCT type device, more precisely PATHFAST ® , and the evaluation of the patient's state according to the values/concentration of presepsin obtained was made using the correlations from Table 3.
Patients were evaluated using MEDS score which varied between 3 -21 points according to the health state of each patient.Some of the laboratory analyses were made in the Central Laboratory, that is the blood cultures and other cultures sampled from 15 patients, out of which only 3 were positive.POCT (Point of Care Testing) devices were used to determine the biomarkers, in the case of PSEP; presepsin had values between 102 -7129 pg/mL, as it can be seen in figure 3.In the case of procalcitonine, the results were negative or they reached the maximum value of >10 ng/mL, and for PCT, the determination method that was used, was a semiquantitative one, THERMO SCIENTIFIC BRAHMS, which has the following intervals as possibilities:< 0,5; ≥0,5-≤2,0; ≥ 2,0-10; >10 ng/mL.Regarding the diagnosis of sepsis in its different stages, there were 13 patients with SIRS, 8 patients with sepsis, 6 patients with severe sepsis and 5 patients with septic shock who also had the highest values of presepsin.
Out of the 32 patients included in the study, 8 died in hospital (25%) who had MEDS with values ranging between 8-21 points, the values obtained for presepsin were between 593-6745 pg/mL.3 cases were diagnosed with sepsis, 2 cases were diagnosed with severe sepsis and 3 cases were diagnosed with septic shock.The affections which were the starting point for the development of sepsis were the following types of infections: respiratory -5 cases, endocarditis -1 case, diabetic ketoacidosis coma -1 case, bowel obstruction -1 case.Patients who died had a number of associated diseases, some of which were extremely serious, namely: neurological diseases -4 cases, malignancies -2 cases, ischemic

Preliminary conclusions of the study
Presepsinul is an important biomarker having a role in rapid diagnosis of sepsis (17 minutes) to 30 minutes for PCT (on the type of test that we had available), it allows the patient evaluation and classification in a risk category, and its association with MEDS score increased the possibility to provide a correct evaluation of the patients.Rapid diagnosis allows to early start any kind of treatment, primarily the antibiotic, right from the Emergency Department, and in the unclear cases, the physician from the Emergency Department requires further investigations to elucidate the diagnosis.
In selected cases -patients with unrecognized sepsis, the determination of PSEP allows the physician from the Emergency Department, to present their situation to the doctors within Universitary Central Emergency Military Hospital and to suggest and if necessary to hospitalize the patient in cases with diagnostic on the edge according to legal provisions. 32In our experience related to the sepsis cases presented to the Emergency Department, PSEP determination had a special importance because we could demonstrate the presence of sepsis and not of SIRS as it would have been diagnosed unless for this biomarker.Diagnosing sepsis favored the decision of hospitalizing the patient, his/her close supervision, the commencement of antibiotic treatment in the Emergency Department, in some cases earlier surgical intervention.All patients hospitalized in the Emergency Department and then in the hospital, were investigated using the imaging tools available in the hospital (ultrasound, X-rays, CT with or without contrast, etc.).
In addition to that, determination of the dynamic values of PSEP in hospitalized patients with sepsis allowed monitoring the effectiveness of the implemented treatment, the cost-effectiveness ratio was very good, given the early start of antibiotic treatment and beyond.
In our study, we used the device type PATHFAST® of the company Mitsubishi Chemical that has all the advantages of POCT, namely: the results are quantitative (using a chemiluminescence method type), fast (between 17 minutes), they can be obtained in our own laboratory at local level -from the Emergency Department, can be printed easily, there is a unit memory to store patient data, it uses whole blood -150 μL (no spin) as sampled from the patient without the need for tube collection.
Moreover, the device is extremely precise (CV <5%), quantitative results are obtained from the blood tests carried out at the same time, because it results in the same test / or up to 6 different assays for six patients at the same time.Such determinations can be made for 1 to 6 patients, making any combination of 1 to 6 tests required.
Presepsin determination by this method allowed risk stratification in criticc patients, monitoring of disease progression and very important, monitoring of the response to drug therapy and other measures (surgery, supportive treatment in the ICU, etc.).

INTRODUCTION
In a normal health care system, the patient must be in the center of all activities and any medical error should be avoided, in order to protect the patient from a fatal result.For this reason, a complex source of knowledge could be of great help for doctors.
Health care delivery involves more than one could know, more than a simple relation between doctor and patient.Health care delivery covers health care professionals like physicians, specialists, nurses, lab technicians, social workers, counselors, etc.Also, it includes further parties like hospital/clinic administrators, managers in finances/accounting/ human resources/drug companies/ health care insurance companies etc.What is more, health care partners are dispersed around many areas, even if they are acting on the same patient.Therefore, it is well understood that the amount of knowledge is extremely relevant and that any data knowledge, created by one of the partners, is of great importance to the others in order to deliver quality care.
The term of "knowledge management" (KM) appeared in the 20 th century, from fields like management, cognitive sciences and psychology.The present activity of KM started in the 1980s along with the wide use of information technologies in enterprises.There, the main focus was on what knowledge represented as an intangible asset.

SYSTEMATIC REVIEW
Basically, the word KM was revealed in the 80s and the academic field was created in 1995 (Stankosky,  2005).

WHAT EXACTLY IS "KNOWLEDGE"?
Basically, there are 3 major elements often used together: data, information and knowledge.Still, there are some differences between them, as specified below:  Data: represents a specific tact or figure, without a specified context.
 Information: represents a data that is organized. Knowledge: built on the information, in order to define a proper context.
The main difference between knowledge and information is that knowledge lets us the power to take action.Therefore, we are able to use it.
According to Bryan Duhon (1998), knowledge management represents a discipline that promotes an integrated approach in order to identify, capture, evaluate, and share the amount of an enterprise's information assets.These assets may include databases, documents, policies, procedures, and previously un-captured expertise and experience in individual workers.
Basically, Knowledge management is essentially especially for getting the right knowledge to the right person at the right time.The main objective is to create value and to leverage, improve, and refine the firm's competences and knowledge assets in order to meet organizational goals and targets.
When we look to implement knowledge management, we have to take into consideration several dimensions like: -KM Strategy: Knowledge management strategy must present a certain dependence on corporate strategy.Its objective is to manage, share, and create relevant knowledge assets that will help meet tactical and strategic requirements -Organizational Culture: The way people interact, the context where knowledge is created, people's resistance towards change and also the way they share (or not) knowledge are easily influenced by the organizational culture.
-Organizational Processes: Are represented by the right processes, environments, and systems that enable knowledge management to be implemented in a certain organization.
-Management & Leadership: KM needs competent and experienced leadership at all levels.There are a wide variety of KM-related roles that an organization may or may not need to implement.
-Technology: Represents by the assembly of systems, tools, and technologies that fit the organization's requirements -properly designed and implemented.
-Politics: The long-term support in order to implement and sustain initiatives that involve virtually all organizational functions, which may require a higher cost for implementation (both from the perspective of time and money), and which often do not have a directly visible return on investment.Knowledge management could be described in 3 ways:  Explicit: represented by the information or knowledge set out in a tangible form.Also, is represented by the information that is easy to capture, to structure or share with other people.For example, in a hospital, an explicit knowledge could be represented by the hospital's documentation, like internal policies and procedures, clinic methodologies etc.
 Implicit: represented by the information or knowledge that is not set out in tangible form but could be made explicit.
 Tacit: represented by the information or knowledge that would have extreme difficulty in an operational process setting out in a tangible form.What is more, this kind of knowledge is composed of the amount of experience and skills that a doctor can acquire overtime and apply to problems.Unlike the explicit knowledge, tacit knowledge is sometimes difficult to capture, to structure and/or transfer to other individuals 5 .

TYPES OF HEALTHCARE KNOWLEDGE
a. Provider knowledge -also called "practitioner knowledge".This type of knowledge is the most obvious one especially due to the fact that medical professionals in this capacity have both explicit and tacit knowledge.
An example is sustained by the fact that doctors have to know standard medical information easily comprehended from different reference materials such as text books.Still, some may consider that one of the most important types of providers' knowledge is of tacit form.
b. Patient knowledge -this type of knowledge consists also in tacit knowledge.Nowadays, patients have complex knowledge in past and current medical conditions that doctors may not know about.However, such knowledge is mandatory for doctors to know.
c. Organizational knowledge -this type of knowledge consists in sum of knowledge elements like medical diagnostic systems, text-based materials, etc.What is more, this field contains medical land treatment that is strongly recommended by an institution or medical society.
Why Romania needs to adopt knowledge management practices in its clinics and hospitals?
According to a report from the World Health Organization in 2014, in Romania there are almost 40,000 doctors with free practice.This number is relatively small, with a position that represents a total of 2,5 physicians reported at 1000 individuals.
As we can observe in the above figure, in 2014 Romania was occupying the last position regarding the number of medical personnel.Countries like United Kingdom, France, Germany and even Bulgaria, were in front of us.
Even if, in Romania there is not a huge number of physicians, the information needs to circulate as well as possible.That is why, every doctor has to have knowledge of every new information that appears regarding a medicine, a treatment, a diagnostic, etc.
Here are several reasons why KM needs to be adopted by the Romanian sanitary system: 1.A significant amount of data is in multiple places.Data collected from healthcare tend to be stored in multiple places-from different systems like HR software, to different departments, like radiology or cardiology.Practically, healthcare data comes from the entire hospital/clinic.
Another example is that healthcare data is under multiple forms (like text, numeric, paper, digital, etc).There are times when the same data exists in What sanitary institution could do, is to aggregate this data into a single and central system, accessible to every physician.
2. Healthcare data could be structured or unstructured.In present, Romanian sanitary system is strong related to the National Healthcare Insurance House (NHIH), which created a software that is able to capture consistent data from patients.This would be helpful, but the software appeared only 3 years ago, and before it, all the information regarding the patients' state were wrote down on a paper folder.This is way, hospitals and clinics need KM -to gather all the structured and unstructured data in the same place.
3. Variable definitions; new research practices are coming out daily.Often, healthcare data have variable definitions (regarding a certain treatment, diagnostic etc).There are cases when there may not be a level of consensus about a particular treatment or definition.What is more, the parts that are conducting a certain discussion about a medicine, treatment, etc. are constantly discovering new data knowledge.4. The complexity of data.Searching for different developing standard processes that are able to improve quality has always been a main objective for health care providers.Still, the number of data variables involved makes this process more challenging.In health care system, doctors are not working with machines or computer; instead, they work with individuals, more precisely, with human body, which is an amalgam of complex information in constant changing.
Seeing these reasons, we can be sure that healthcare data will not get simpler in the future.On the contrary, it will advance; it will need more than simple software and will present challenges that only a complex and well organized sanitary system could cope.

A POSSIBLE EXAMPLE FOR APPLYING KM IN ROMANIAN SANITARY SYSTEM
From the beginning of 2015, in Romania has been implemented the so called "national health care card", which is nominative for each patient.Its role is to show the doctor what medical treatment has the patient followed, what was his diagnostic and at what medical sections the patient went.In this way, if a patient has firstly went to his family doctor, who diagnosed him and gave him a certain treatment, the second doctor (let's say for example, the dermatologist) would be able to see (with the help of this new system by card) the day when the patient was at his family doctor, the medicines prescribed and the exact diagnose.So far, everything is in order.
Issue that needs to be solved through KM: The new system shows the information only beginning with the date that the card was introduced.In other words, if a 40 years old patient comes for 10 years (since 2005) at the same family doctor, and only this year he had the card (2015), that means that the information area from 2005 till 2015 (regarding his treatments, illness, diagnostics, lab tests etc) is missing on the software program (the doctor is able to see the medical history from a patient only starting with 2015).
Practically, this represents a gap both for physician and also for the patient (of course that the information from 2005 exists, written in the patient's medical record -a notebook, in most of the casesbut is not inserted in the medical informatics system).Solution of KM: If KM practices would be applied, the present informatics system could be extended, in a manner that would include the whole patient's history from the beginning.Also, the system could specify, for example, if a patient is allergic to some substances (when the doctor prescribes a medicine, if the patient is allergic to a certain substance from that medicine, the program would alert the doctor and in this way, the doctor would prescribe something else -it is also a way of avoiding medical errors).

MAIN BENEFITS FOR IMPLEMENTING KNOWLEDGE MANAGEMENT
The main advantage of introducing knowledge management in Romanian sanitary system is that the information between doctors is easily shared, and most of all, that information is not lost if one of the doctors is sick or has another reason for leaving the cabinet earlier.
In this way, hospitals could be able to have substantial savings.Doctors are brought up to speed, and valuable knowledge assets are not lost (this translates into fact that the hospital or clinic do not lose time and money when doctors need to learn new information quickly).
In a hospital, knowledge management has the power to increase innovation and also to create better patient relationship.For example, if a certain clinic has a global team, knowledge management can create a more powerful workforce when all cultures are brought together in order to share assets (in Romanian clinics, this example is more suitable for private sanitary system).
Another important advantage is that KM could reduce the medical errors and their cost, by providing a decision support.
Next, we will present another KM advantages for healthcare: -Cooperation between different health care providers; -Innovation; -Quality of care; -Efficiency of work; -Cost reduction.
All in all, knowledge management gives doctors the capacity of knowledge they need to do their jobs better.In this way, they become more productive.

CONCLUSION
The adoption of knowledge management practices into the Romanian sanitary system could become either a success or a failure.Like any other project, just because a system has been put in place, with the help of the appropriate methodologies or practices, this does not mean that it will become successful in terms of adoption and use.Because healthcare data is so complex, it's more than relevant that a traditional approach to manage it will not be able to succeed.This is why, a different approach is needed.The new approach needs to handle multiple sources, structured and unstructured data, variability, the complexity within a constantly changing environment.
The use of KM in sanitary industry promises to enhance the quality of care for patients.Its implementation will allow healthcare partners to conduct evidence based practice, and also to collaborate relying on the best knowledge available.
To sum up, the implementation of knowledge management practices and systems is a topic of great interest for the healthcare community around the world.A complex KM system for health care industry would represent a huge step, both for doctors (preventing medical errors) and for patients.

Spondylodiskitis, etiology, diagnosis and treatment
Cristian Bănică1 , Ion Ştefan 1 Spondylodiskitis is a spinal infection comprising vertebral osteomyelitis and intervertebral disc.Diagnosis can be difficult considering that the symptomatology is not specific, low back pain is common in people over 50 years.
The etiology of the disease includes pyogenic germs, tuberculous, parasitic and fungal etiology.It is known that staphylococcal and tuberculous etiology are responsible for most cases in clinical practice, being the main issue of differential etiological diagnosis.Gram-negative germs are a rarer etiology, being involved in secondary spinal infections as a consequence of dissemination of retroperitoneal or intra-abdominal collections.Other etiologies are very rare: parasitic, fungal or Brucella.
Spinal infection has, in most cases, marrow dissemination as pathogen mechanism; it is recorded in staphylococcal sepsis and secondary determinations of tuberculosis (Pott morbidity).
Contiguous infection from septic foci nearby is a rare complication due to esophageal ruptures or retropharyngeal abscess or aortic vascular prosthesis infections.Iatrogenic, postoperative, postpuncture infection is also recognized.
Due to the particularities of spine vasculature, marrow infection includes intervertebral disc and vertebral body; septic emboli cause infarcts within bones, leading to osteolysis, mechanical deformations, cavitation, mechanical instability.Paravertebral abscesses could occur, the infection can spread into the spinal canal.
The location of these spinal infections is more common in the lower back, however, thoracic and cervical locations are also common.Initial infectious outbreaks are often difficult to identify, less than 50% of cases are recognized as the source of spondylodiskitis, skin and soft tissue infections, genitourinary infections, respiratory infections, endocarditis, ORL infections.Predisposing factors are recognized and represented by comorbidities, diabetes, rheumatic diseases, cirrhosis, malignancy, immunosuppressive treatments.
Staphylococcus aureus is the most common nontuberculous etiology, methicillin-resistant Staphylococcus is more and more common in both community infections and in hospital infections.Staphylococcal spondylodiskitis has as starting point, infections of the soft tissues, infections of intravascular devices, infectious endorcaditis and iatrogenic infections: postpuncture, postoperative.MRSA staphylococcus spectrum of resistance comprises lately, besides penicillin, aminopenicillins, 3rd generation cephalosporins and other classes of antibiotics: macrolides, clindamycin, aminoglycosides, florochinolone rifampicin, moreover, the rate of resistant strains is increasing.
Viridans streptococci represent less than 10% of the etiology of spondylodiskitis, their association with bacterial endocarditis in sepsis is known.

SYSTEMATIC REVIEW
Pneumococcus, anaerobic bacteria represent a rare etiology.
Tuberculosis is a constant presence in the range of spinal infections.As a form of bone tuberculosis, bone cold abscess has a slow, insidious, soundless development and it is sometimes associated with other bacillary determinations: psoas abscess, renal, prostate, lung or even brain abscess.
Gram negative bacteria represent 10-30% of the etiology of spinal infections, the most common germ is Escherichia coli, followed by Proteus, Klebsiella and Enterobater.
Rarely, spondylodiskitis etiology may be represented by other bacteria: Brucella, Bartonella or fungi: candida albicans (more frequently), Cryptococcus, Coccidioides, blastomices.As an exception, cases of spinal infection with Echinococcus granulosus are described.
The difficulty of diagnosis lies in the poor symptoms; lumbar spine pains are common in the general population.Sometimes, the presence of low grade fever or febrile episodes draws attention.Neurologic deficit may occur in complicated cases with radiculopathy and spinal cord compression.During anamnesis, recent history of skin or soft tissue infections, presence of an intravascular device or surgery in the spine is presented.Patients with comorbidities and immunosuppressive treatments are more exposed to the risk of sepsis with secondary determinations.Bacillary etiology is insidious, diagnosis is retroactive.
Laboratory examination raises suspicion of infection when neutrophilic leukocytosis is present, high ESR, CRP is often higher in spondylodiskitis.Alkaline phosphatase may be increased.
Radiological examination and magnetic resonance imaging of the spine brings valuable proofs for diagnosis, showing inflammatory modifications and bone structure modifications of the vertebrae and intervertebral disc, which also appear in degenerative lesions and can therefore be difficult to interpret.Technetium 99 scintigraphy and the one with Gallium 67 can bring sensitive data to support the diagnosis.
Computed tomography has good resolution for changes in bone structure, it highlights destruction of vertebral plateaus, bone formation seizure, but MRI is superior in viewing abscesses and lesions in nervous tissue.From the imaging point of view, RM lesions TB are different because the intervertebral disc is not affected but paravertebral abscesses are present, bone destruction.
Proof of infectious etiology can be obtained by biopsy-puncture and culture for aerobic bacteria, anaerobes, mycobacteria and fungi.Blood cultures can have a positive result in about 50% of cases, infection is frequently marrow.Histopathological examination of biopsies can guide diagnosis in bacillary infections but also the differential diagnosis of vertebral bone tumors and metastases.
Complications of the disease are caused by damage to the spinal architecture and mechanics, with neurologic and infectious complications.
Neurological complications can be significant, from the root syndrome up to paralysis.Infectious complications are: paravertebral abscesses, epidural abscesses, secondary meningitis, but also sepsis complications , in the context of which spondylodiskitis was diagnosed.
Treatment is anti-infective, analgesic, immobilization and surgery.
Antimicrobial treatment is injected on the basis of probability criteria or after the results of biopsy or blood culture.Antistaphylococcal antibiotics with broad-spectrum are used depending on the etiological suspicion.In the context of increasing frequency of MRSA staphylococcus, Vancomycin, Linezolid or Targocid is used for minimum 6 weeks.Injectable antibiotic therapy may be continued orally up to 3 months, depending on the disease evolution.For bacillary etiology, tritherapy for 3 months, in the 4th month, the 4th antituberculosis antibiotic is associated, then, the therapy continues with two antibiotics up to 12 months.The favorable evolution is clinically assessed, especially by clinical evidence of inflammation in normal limits, C-reactive protein and VSH within normal limits, as well as the course of radiologic imaging, magnetic resonance.If paraspinal, epidural abscesses or neurological injuries secondary to compression appear, surgery is required.
The prognosis is favorable by antimicrobial fair treatment and surgery if necessary, spondylodiskitis mortality is less than 5%.Prompt diagnosis and antimicrobial treatment are essential.

Article received on November 15, 2014 and accepted for publishing on December 5, 2014.
A cholestatic syndrome may be a surprising cause of medical error

Keywords: autoimmune cholangitis, primary biliary cirrhosis, hyper IgG4 syndrome.
Cholestatic syndromes are very often encountered in gastroenterology practice.The causes may be quite different but there is a largely accepted consensus of classification into two categories: extrahepatic and intrahepatic, rendering very different treatment and prognosis.A proper diagnosis is mandatory for a proper treatment.Conversely, a failure of a correct diagnosis may result in wrong treatment and medicolegal issues.The subject of malpraxis legal actions is often considered to be associated with an embarrassing professional failure with only punitive results.In fact, the conclusions of malpraxis cases may, as well, give very documented information to healthcare professionals in order to better improve medical care.
The differential diagnosis of the causes of cholestatic syndromes is quite challenging.An extrahepatic cause is an obstructive one, may it be acute (billiary colic) or slowly developing (benign or malign strictures, pancreatic head tumor, ampuloma).The imaging workup (CT scan, cholangioMRI) are sufficiently revealing for an extrahepatic obstructive cause in order to conduct a proper treatment.The intrahepatic cholestatic syndromes are even more challenging as there are a quite large array of very different causes with very different treatment and prognosis spanning from viral hepatitis to primary billiary cirrhosis and primitive sclerosing cholangitis.The rare the cause the frequent misdiagnosis and medico-legal consequences.
Among rare intrahepatic causes, autoimmune cholangitis is a term recently coined for a spectrum of ORIGINAL ARTICLES 1 Carol Davila Central Emergency Military Hospital, Bucharest 2 Carol Davila University of Medicine and Pharmacy, Faculty of Medicine, Bucharest 3 Titu Maiorescu University, Faculty of Medicine, Bucharest cholestatic liver diseases where an immunologic pathological mechanism is highly suspected with regard to the cause of inflammation of bile ducts.This term implies also a fare response to immunosuppressive therapy.There is, though, some confusion in literature regarding this disease as it may refer to several ailments: an overlap syndrome between primary biliary cirrhosis AMA (antimithocondrial antibodies) negative and autoimmune hepatitis, a form of hyper IgG4 syndrome (associated with autoimmune pancreatitis), a separate entity as a transition form in spectrum of cholestatic disorders.This confounding data makes the diagnosis in this cases very difficult and, also, a potential source of medico-legal issues The name autoimmune cholangitis was coined for the first time be Brunner et al 1 to describe the situation of three patients suffering of primary biliary cirrhosis AMA negative; all those patients had antinuclear antibody (ANA) and cholangiopancreatography showed no abnormality.The therapy with prednisolone and azathioprine was successful.
The antigen specificity for AMA was demonstrated to be an inner membrane mithocondrial antigen, a 74 kDa E2 subunit of pyruvate dehidrogenase complex (PDC-E2).The most sensitive lab test to assess the presence of these antibodies is an ELISA using recombinant or purified antigens.5 to 8% of patients suffering of primary biliary cirrhosis lack AMA in spite of having typical clinical and histological features of this disease. 2All of these patients had ANA (antinuclear antibodies), highly suggestive of autoimmune hepatitis.Moreover the level of serum IgM was significantly lower in these patients then AMA positive counterparts.
Considering the fact that AMA may have a role in the pathogenesis of the disease, a study by Kitami et al of patients AMA negative and AMA positive demonstrated that there is not truly AMA negative primary biliary cirrhosis.Kitami performed an exhaustive immunoblotting studies of various inner mithocondrial membrane antigens that are not currently looked for. 3om the pathologist's point of view AMA positive patients have an increased risk of cirrhosis comparing with AMA negative counterparts.Among histological features, the granulomatous destruction of bile ducts is the only histological marker highly specific for primary biliary cirrhosis AMA negative or positive, but this lacks sensitivity.These data further increases the difficulty of diagnosis. 4at about the treatment: ursodeoxycholic acid is the treatment of choice in both forms of primary biliary cirrhosis with equal efficiency.
Autoimmune cholangitis may also be a manifestation of immunoglobulin G4 associated systemic disease, most commonly encountered in patients with autoimmune pancreatitis.Autoimmune pancreatitis (AIP) was first described by Yoshida and colleagues 5 in 1995 referring to a type of chronic pancreatitis with certain histopathologic and imaging features.Early or atypical manifestations of autoimmune cholangitis may not involve the pancreas, thus making the diagnosis even more challenging.There are no definitive diagnosis criteria so far, also some have been proposed like Mayo criteria (HISORt) and Asian Consensus Criteria.Two types of AIP have been described: type I which is a pancreatitis associated with immunoglobulin G4 systemic disease characterized by lymphoplasmocitic infiltration and elevated serum IgG4 levels; type II which is less commonly associated with elevated serum IgG4 levels and involves a granulocytic infiltration.44% of all patients do not have hyper IgG4 serum levels. 6The cholangitis is a sclerosing stricturing inflammation of bile ducts.The occasional absence of pancreatic involvement have been described.The natural course of AIP involves relapses.Low dose steroid treatment is very effective treatment.
Besides those two types of autoimmune cholangitis, the clinical practice may come along different situations where an intrahepatic cholestatic syndrome may not have sufficient diagnostic criteria to render a proper diagnosis also the response to corticosteroids is straight forward.These situations may be prevalent.

CASE PRESENTATION Clinical data
We present the case of a male patient aged 48, living in country area, driver, who is admitted in an emergency department for biliary colic comprising of Charcot triad (colicky pain, fever, jaundice), intense itching, acolic stools and hyperchrome urine.This clinical picture is elicited by a fatty meal.The patient does not smoke cigarettes or drink alcohol and personal as well as family disease history are unremarkable.
Abdominal US indicated an increased common bile duct (8 mm) with normal sized intrahepatic ducts, thickened gall bladder walls (3 mm) with multiple small (less than 1 cm) calculi.The clinical picture subsides progressively due to a treatment with: antispastics, antibiotics and proton pump inhibitors.The itching and jaundice didn't subside, though.The total bilirubine level reaches 5 mg/dL and direct bilirubine 2.7 mg/dL.In this particular moment the patient is referred to our clinic with the diagnosis of remitted biliary colic and with indication of elective endoscopic biliary sphincterotomy.
Clinical exam was remarkable for intense sclerotegumentary jaundice, pruritus, dark urine and white chalky stools.
Otherwise the patients had no complains.

Imaging and and endoscopy data
Abdominal US indicated: normal size and ecogenicity of the liver, normal sized common bile duct (6 mm), normal gall bladder with minimal biliary sludge.We performed superior digestive endoscopy and sideview duodenoscopy which were unremarkable for pathologic changes, but indicated increased amount of intraluminal bile and a normal papilla major.CT scan with radiocontrast media was unremarkable.Colangio MRI was, also, unremarkable.

Immunology data
In the meanwhile the level of total bilirubine continued to increase to 8.5 mg/dL without the sharp predominance of direct fraction.An extended lab workup indicated: normal level of gammaglobulin, AgHBs negative, Ab antiHBc negative, Ab anti HCV negative, Ab anti HAV negative, CA 19-9 negative, alpha fetoprotein normal, CEA negative, AMA negative, Ab anti LKM1 negative, ANA negative, ASMA negative, pANCA negative, cANCA negative, Ab anti Ro negative, Ab anti La negative, Ab anti HIV negative.

Histopathology data
Liver biopsy was performed: liver tissue sample with marked biliary stasis predominantly intraductular, biliary clots, areas of hepatocellular steatosis, chronic inflammatory infiltrate of portal areas and intralobular areas, hepatocellular regeneration, interface hepatitis with bridging necrosis.(Figure 1, Figure 2).This description fits into pathology diagnosis of autoimmune cholangitis.

Diagnosis and differential diagnosis
We agreed upon the final diagnosis: autoimmune cholangitis; remitted biliary colic by passage of microcalculi.Hence, it has been concluded that the patient had two different causes of jaundice (acute extrahepatic cholestasis and chronic intrahepatic cholestasis), segregated by quite different prognosis and treatment.Considering the presence of interface hepatitis with chronic inflammatory infiltrate it had suggested that future evolution of clinical, serological, immunological and histopathology data may be in the direction of an overlap syndrome between AMA negative PBC and autoimmune hepatitis.The differential diagnosis included: primitive and secondary sclerosing cholangitis, primitive biliary cirrhosis, HIV cholangitis, Sjogren syndrome, non Hodgkin lymphoma.
The treatment was highly effective (32 mg of methylprednisolone daily -0.5 mg/kg prednisolon equivalent -with tapering to 8 mg daily in one month and ursodeoxicholic acid 10 mg/kg resulting in disappearance of cholestasis and hepatocitolysis after 2 month.The dosage of Medrol reached 4 mg per day in the 4th month of treatment, the current clinical and biological status of the patient being excellent.

DISCUSSION AND CONCLUSION
Autoimmune cholangitis is a very challenging diagnosis in the face of a lack of international consensus on terminology used in the literature.This very particular confounding situation may come in defense of the practitioner in case of a malpraxis legal action as it may occur.On the other hand should the diagnosis be late the disease may progress to complications such as cirrhosis, liver failure and, even, death.Referral of patient to a tertiary center of hepatology may be a reasonable course of action to fully benefit medical care act.This is not always very handy.
A diagnosis workup involves various differential diagnosis of cholestasis syndrome; among these diagnosis AMA negative primary biliary cirrhosis, primitive sclerosing cholangitis of small ductules and hyperIgG4 cholangitis are the most important.Liver biopsy, high definition imaging workup and immunology panels are mandatory for a proper diagnosis.
The response to corticosteroid treatment is highly suggestive of immunologic process involved in the pathogenesis of liver ailment but it is not, whatsoever, pathognomonic as some are tempted to consider.The diagnostic criteria may uncover progressively in time, endorsing the idea of a continuum in a spectrum of autoimmune cholestatic diseases.

Capsule endoscopy Raluca S. Costache 1,2
We present the case of a 42 years old, female, diagnosed with chronic hepatitis C viral infection treated with peginterferon and ribavirin.
During the treatment she was admitted in the hospital with persistent diarrhoea, weight loss, and anemia.The serologic tests for celiac disease were positive together with upper endoscopy.
We performed small bowel investigation with Endocapsule  in order to determine the extent of disease.
The images (figures 1, 2 and 3) show typical aspects of celiac disease: absence of normal villi, nodularity of the jejunal mucosa with absent folds, fissuring and mild nodularity of the valvulae coniventes.
The gluten free diet was beneficent for the patient which continue the antiviral treatment with sustained viral response.

EDUCATION AND IMAGING INTRODUCTION
Paraneoplastic Cushing syndrome represents 5-10% of all Cushing syndrome and has a severe prognosis due to severe metabolic imbalance, denutrition, associated infections and progression of tumoral underlying pathology.The death is a rule in more than 50% of cases.Some medication used to treat it -Metirapone -is not available in Romania.Ketoconazole was recently approved by CHMP for treatment of paraneoplastic Cushing's only in November 2014.

CLINICAL CASE
A 67 years old woman presented on the 21 st of November with mental confusion, progressive weight loss, severe edema and kypokalemia, without typical features of Cushing or hyperpigmentation.Patient's behavior changed in the last 5 months, she was nasty with her daughter, bickering, while diabetes and hypertension aggravated in the last 3 months.
The electrolytic imbalance was severe at admission K 1.65 mmol/l, in spite of multiple attempts to correct it with 150 mmol/day KCl on peripheral i.v.line, 40 mmol/day of KCl orally and 200 mg/day of Spironolactone, treatment used initially in "C.I. Parhon" National Institute of Endocrinology.Patient was transferred in the I. C. U. of "Dr.Carol Davila" Central Military Emergency Hospital for the weekend, in order to obtain a better control using a central intravenous catheter.
Patient had also left breast tumor, Helicobacter pylori gastritis, polinodular goiter, denutrition and hepatic dysfunction.

CLINICAL PRACTICE
showed uptake at 10 minute in left breast and jejunal loop; upper and lower endoscopy, echo endoscopyrevealed no tumors; bronchoscopy -no visible tumor (after procedure, patient suffered a syncope that lasted 2 minutes); thyroid ultrasound -found nodule of 15/18/22 mm located in the lower part of left lobe -15/18/22 mm, with low peripheral vascularisation, uptakes iodine at CT scan and has a peripheral calcification.

Treatment
We initiated treatment with Ketoconazole 400 mg, 1 day, and then 600 mg, for 2 days, but with inadequate correction of alkalosis and kypokalemia -pH was The adrenal resection was difficult due to diffuse bleeding and lack of tissue elasticity.
Hepatic biopsy showed periportal fibrosis, but no necrosis of hepatocytes, probably due to toxic substances used at work; left adrenal was 7/3/1.5 cm in diameters, with focal hemorrhage.Imunochemistry -Ck7, Ck20, CEA, TF1, ER -negative, MELAN A positive -suggested diffuse hyperplasia of left adrenal gland.

Evolution of patient
One hour after left adrenalectomy -cortisol was 18.2 mcg/dl, ACTH 42.3 pg/ml, patient needed inotrop support with Noradrenaline, hydrocortisone 75 mg 1 day, 50 mg in the second day.
The third day cortisol desupressed to 51.25 mcg/dl, ACTH 43 pg/ml (3-66), K decreased again to 2.9 mmol/l, Hb was 8.4 g/dl.Ketoconazole 600 mg/day was started again.Patient had fever, delirium, pulmonary riles, so Meronem was initiated for 2 days, then Tigecycline 3 days, then 7 days of Klacid at home, also Calcium 1 g/day, 1,000 UI D3, 0.5 mcg of 1 alfa-calcidol/day, hepatic protection, vitamins, basal insulin.10 days after adrenal resection cortisol was 26.6 mcg/dl, K 3.9 mmol/l, calcium was normal, Mg was 1.57 mg/dl, allowing second operation -resection of lung tumor -proved to be typical carcinoid with ki-67 3%, ACTH, synaptophysin and cromogranine positive.We also performed control thoracic CT -revealed left breast tumor of 0.76/1.21cm, right adrenal with stationary aspect; portal vein was enlarged 14.5 mm; patient performed FNAB of left thyroid nodule on 20 April 2015, showing benign adenoma.
Mild kypokaliemia and hypomagnesemia, even with oral supplementation, sartan therapy and normal levels of cortisol and ACTH persisted after surgery, probably due to severe deficit of intracellular compartment, even at 3 months after carcinoid resection.Patient does not remember the 2 months prior to surgery, even if cognitive impairment is mild now.

COMMENTS
This case was difficult due to metabolic challenges, multiple associated pathology, lack of SSTR2 and SSTR5 receptors on lung carcinoid with negative scan, mild elevation of cromogranine A levels despite a typical bronchial carcinoid.Patient's sister was operated for adrenal adenoma confirmed on histology exam, her daughter had papillary thyroid cancer, but no MEN association was proven in this family.Patient needed more than 30 days of hospital admittance in two different hospitals and five clinics in order to obtain a good clinical result.The vital risk was high due to sepsis, denutrition, metabolic and ionic imbalance, hepatic lesions, anesthesia, brain atrophy, relative adrenal insufficiency after surgery.
There are no guidelines that state the adequate cortisol levels to be reached before surgery, nor the duration of Ketoconazole wash-out to prevent adrenal insufficiency.
Recently the patient discovered ductal invasive left breast carcinoma, operated at 6 months after thoracic surgery and will soon start chemotherapy.This rare condition is caused by extrinsic compression, given the low abnormal insertion of median arcuate ligament or fibrous bands and ganglion periaortitis tissue from the celiac plexus.The ligament is composed of tendon medial edges of the two poles of the diaphragm which meet in the median plane to form an arch before the aorta.

CLINICAL PRACTICE
Our patient D.G., male, aged 53, known with hypertension responsive to treatment and diabetes type II non-insulin requiring, with no clinical complaints, came to the Nephrology Department where an abdominal ultrasound was performed and a pancreatic formation was detected.He came to our department for abdominopelvic CT with contrast iv.
During examination, multiple arterial branches arising from the pancreatic duodenal artery and superior mesenteric artery (arch pancreatitis) are observed, which include pancreatic duodenal region; filiform stenosis in the aortic origin of the celiac trunk, through the median arcuate ligament.

Treatment
The goal of the treatment is to decompress and obtain celiac artery revascularization.
Treatment options are quite limited and the revascularization surgery has a risk of morbidity and mortality of 5% to 15%.
As treatment methods may be used: conventional laparotomy, laparoscopy or endovascular methods (percutaneous transluminal angioplasty, stent implantation).
Laparotomy, by retroperitoneal approach via left subcostal incision or by transabdominal approach via midline incision, allows surgical separation of the median arcuate ligament fibers to decompress the celiac artery.Decompression is completed by celiac ganglion resection and evaluation of celiac artery blood flow using a Doppler ultrasound intraoperatively.In case of low blood flow, celiac artery revascularization is performed.Literature studies show that classical laparotomy is no longer prefered, due to an increased risk of morbidity and mortality, especially in patients with associated pathologies.
Laparoscopy is used more frequently compared to laparotomy because it is less invasive presenting a lower risk of morbidity and mortality, with low cost due to short hospitalization.
Laparoscopic intervention also allows decompression of celiac artery, but if the celiac artery requires revascularization, surgical management should be changed and the classic approach should be used (laparotomy).
Percutaneous balloon angioplasty is an attractive method because it is a minimally invasive procedure, ideal for patients with associated comorbidities.This method delivers suboptimal results because most lesions develop in the ostium.Percutaneous balloon angioplasty in ostial lesions is associated with more severe residual stenosis due to intense elastic recoil caused by a large number of circular elastic fibers from the ostium.Because of this, the rate of complications (acute occlusion) and restenosis increases.
Stent implantation offers a metallic support that prevents elastic recoil and thus decreases the complications of this type.The risks of this method include distal embolism with secondary ischemia, fat embolism, aortic dissection.
Percutaneous angioplasty and stent implantation, according to a 2009 study, are complementary methods to laparoscopy after decompression of celiac artery was performed.

DISCUSSION
The peculiarity of this case is that the patient did not present any symptoms.This may be due to the development of a rich collateral blood supply that compensates for celiac artery stenosis.

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Figure 1 .Figure 2 .
Figure 1.The correlation between the number of cases and SIRS criteria

Figure 3 .
Figure 3.The evolution of presepsin values for the patients involved in the study

Figure 4 .
Figure 4. Correlation between the number of cases and the affections which led to sepsis

Figure 1 .
Figure 1.Key elements that constitute the knowledge management infrastructure (from Wickramasinghe and Sharma, 2004)

Figure 2 .
Figure 2. World Health Organization, Medical personnel per 1,000 people

Figure 2 .
Figure 2. Thoracic CT revealed pulmonary tumor located in Fowler segment of left superior lung lobe.

Figure 1 .
Figure 1.Graphic image of the arcuate ligament compressing the celiac trunk Case courtesy of Dr Matt Skalski, Radiopaedia.org,rID: 36837

Figure 2 .
Figure 2. Axial section acquired during early arterial time that highlights arterial type collateral circulation between AMS and the celiac trunk at the level of the pancreatic duodenal arch.

Figure 4 .
Figure 4. 3D VR Image highlighting the filiform stenosis at the origin of the celiac trunk

Figures
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Table 2 .
Correlation between MEDS score and mortality at 28 days as percentage30,31

Table 3 .
Correlation between PSEP values, diagnosis and measures to be taken14,15,16,17,18,19 As for forensic results by POCT, given that the sheets can be printed and attached to Emergency Department presentation sheets and general clinical observation sheets, these are of particular importance.It certifies permanent care of the patient under close monitoring of blood different parameters and not only those.With this type of equipment, we can quickly modify patient treatment in real time to correct the dysfunctions and inadequacies thus arisen.10.Bo Liu, Yun-Xia Chen, Qin Yin, Yun-Zhou Zhao and Chun-Sheng Li: Diagnostic value and prognostic evaluation of Presepsin for sepsis în an emergency department.Critical Care 2013, 17:R244 11.Endo S, Suzuki Y, Takahashi G, Shozushima T, Ishikura H, Murai A, Nishida T, Irie Y, Miura M, Iguchi H, Fukui Y, Spanuth, H.Ebelt, B.Ivandic and K. Werdan.The new Sepsis Marker Presepsin is Superior for Prognosis and Disease Monitoring compared to Procalcitonin.20Th IFCC-EFLM European Congress of Clinical Chemistry and Laboratory Medicine-19-23 May 2013-Milano, Italy 15.E. Spanuth, B. Ivandic, H.Ebelt, K.Werdan.Diagnostic and Prognostic Value of suPAR în Patients with Sepsis în Comparison to Presepsin and Procalcitonin.20Th IFCC-EFLM European Congress of Clinical Chemistry and Laboratory Medicine-19-23 May 2013-Milano, Italy 16.Linas Pieteris, Gieddre Baksyte, Tadas Cesnaitis, Astra Vitkauskiene, Andrius Macas.New strategies în sepsis diagnosis.Acta Medica Lituanica, 2012, vol.19,No.3, P.Jeffrey A. DuBois The role of POCT and rapid testing, September 2013, http://www.mlo-online.com/articles/201309/the role-of-poct-and-rapid-testing.php.23.Sauer-Budge AF, Mirer P, Chatterjee A, Klapperich CM, Chargin D, Sharon A. Low cost and manufacturable complete microTAS for detecting bacteria.Lab Chip.

Article received on October 12, 2014 and accepted for publishing on November 15 2014. Median arcuate ligament syndrome (Dunbar Syndrome) Crina Laslo 1 , Anamaria Puiu 1 , Ștefan Mardale 2 , Iulian Raus 2 , Cosmin Căpușan 2
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