Mechanical Cardiac Tamponade as an Initial Presentation of Malignant Lymphoma: Case Report - Juniper Publishers

 Cardiology & Cardiovascular Therapy - Juniper Publishers

Abstract

Cardiac tamponade results from an accumulation of pericardial fluid under pressure, leading to impaired cardiac filling and haemodynamic compromise. In malignant lymphoma, cardiac and pericardial involvement, even though relatively uncommon, can be one early manifestations of this neoplastic disease. We describe a case of a 21 year old female with no medical history, whose first presentation for mediastinal lymphoma was a mechanical cardiac tamponade.

Keywords: Mechanical cardiac tamponade; Mediastianl lymphoma; Diagnosis

Introduction

Cardiac tamponade is a life-threatening setting due to slow or rapid pericardial build-up of fluid with subsequent compression of the heart. One of the many causes of it is neoplastic diseases, such as lymphomas.

There are several explanations regarding pericardial effusion in lymphoma. It may be due to lymphatic and blood spread. Effusion may be caused by an obstacle of the lymphatic and venous drainage of pericardial fluid. It may also not involve the pericardium. The lymphatic channels from visceral pericardium have drainage at the aortic root. This drainage spot can be blocked either by malignant deposits or via compression due to enlarged lymph nodes [1].

Malignant lymphoma can arise in or spread to the mediastinum. Mediastinal lymphadenopathy due to lymphoma may present early due to rapid growth of the tumor and compression caused by it [1].

The objective of this observation is to report the case of a mechanical tamponade caused by a compression of the right heart chambers by a probable mediastinal lymphoma.

Case Report

We report the case of a 21-year-old female patient, without any known medical history, who was admitted to the emergency department for a stage III to IV dyspnea of NYHA and right chest pain that had been progressing for 3 weeks. On clinical examination, her blood pressure was 100/60 mmhg, heart rate was 96 beats/minute, with muffled heart sounds, elevated jugular veins pressure, signs of right pleural effusion and a supraclavicular lymphadenopathy. The electrocardiogram revealed a sinus tachycardia, a decreased electrocardiographic voltage without electrical alternans. The chest X-ray showed total opacification of the right hemithorax with an enlarged cardiac silhouette (Figure 1). A thoracic CT scan was performed showing a large right mediastinal mass measuring 174x40x86 mm, causing an upper right segmental collapse and significant compression of the cardiac chambers, as well as a moderate pleural effusion (Figure 2 & 3). The transthoracic echocardiography objectified a 35mm pericardial effusion over the right heart chambers, with a preserved LV function (Figure 4).

Routine blood tests showed a hypochromic microcytic anemia (Hemoglobin at 9.7g/dl), normal white blood cell count (9800), elevated platelets (578000), normal prothrombin levels at 82%, and elevated fibrinogen at 6.4g/l; and abnormal hepatic enzymes with ALT at 110 IU/l and AST at 60 IU/l. Serological tests for hepatitis, HIV and syphilis were negative. A thoracentesis was done revealing an exudate pleural fluid. A bone marrow biopsy was also performed objectifying a lymphoid infiltration and overactive bone marrow. Multiple transparietal pleural biopsies and a biopsy of the supraclavicular lymphadenopathy were non- conclusive (inflammation, necrosis and lymphadenitis). After discussing the patient’s case by a multidisciplinary team, lymphoma was considered the most likely diagnosis and chemotherapy wasn’t possible in her case. A trial of corticosteroid therapy was started, with a twice daily 120mg dose of methylprednisolone, allowing a relative decompression of the heart chambers. The patient was referred for surgical pericardiectomy and diagnostic mediastinoscopy.

Discussion

All diseases that can involve the pericardium can cause a pericardial effusion. Therefore, idiopathic pericarditis and numerous infections, neoplasms, autoimmune diseases, radiation, post-ST segment elevation myocardial infarction (STEMI) pericarditis, and noxious substances, for example, blood, may be responsible. Some studies have suggested that as many as 20% of pericardial effusions without an obvious cause after routine evaluation constitute the initial manifestation of a cancer [2]. Indeed, Perek B et al concluded in their study of 81 previously healthy patients, which cardiac tamponade was the main symptom of cancer, especially of the lungs [3]. Mediastinal masses are rare and are often found incidentally; however, finding the exact etiology of the tumor is relatively difficult. The most common tumors are: small cell carcinoma (40%), lymphoma (20%), thymomas (16%). The definitive diagnosis is histological [4].

Cardiac presentaions from lymphomas can be primary or secondary. Primary cardiac lymphoma concerns the heart or pericardium and is considered a rare presentation of lympohmas, accounting for less than 1% of all extranodal localization of these tumors. However, masses involving other sites, such as mediastinal lymphadenopathy or disease below the diaphragm, most likely represent secondary cardiac lymphomatous involvement. In some studies, secondary heart involvement by lymphoma was identified at postmortem in 10% to 30% of the cases. Lymphomas represented more than 9% of the total metastases to the heart, and up to 20% of patients with lymphoma are found, at autopsy, to have cardiac involvement [5].

There are three main entities of mediastinal lymphomas: T lymphoblastic lymphoma, mediastinal (thymic) diffuse large B cell lymphoma, and classical Hodgkin lymphoma [6]. Cardiac involvement of a malignant lymphoma is usually a late manifestation of the disease; it is difficult to make a definite diagnosis in some cases. Therefore, treatment may be started before histological confirmation. In our case, the definitive diagnosis of lymphoma wasn’t possible after many transparietal pleural biopsies and the biopsy of the supraclavicular lymphadenopathy, so after a multidisciplinary discussion, it was decided to start a trial corticosteroid therapy Ischiwata et al. [7] described a rare case of malignant lymphoma with diffuse cardiac and pericardium involvement that initially presented as congestive cardiac failure. A tissue diagnosis of the mediastinal mass could not be performed due to the patient’s generally poor condition. The patient received corticosteroid therapy, but died 42 days after her admission.

Conclusion

Mechanical cardiac tamponade is both a medical and surgical emergency that can complicate mediastinal tumors, and may in some cases of hemodynamically unstable patients, delay the management of the underlying etiology. For histologically unconfirmed compressive mediastinal lymphomas, trial corticosteroid therapy may be considered. 

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Ruptured Giant Leiomyoma of the Appendix: A Case Report - Juniper Publishers

 Gastroenterology & Hepatology - Juniper Publishers

Abstract

We present a case of a 79-year-old female who was admitted with acute abdominal pain and haemoperitoneum. Pathological findings demonstrated a spindled-cell lesion arising from the appendix. The lesion consisted of smooth muscle bundles arranged in fascicles with a whorled appearance. Appendicular leiomyoma is a rare lesion with only a few case reports previously described. We discuss the possible pathological differential diagnosis of such lesions, including GIST, leiomyosarcoma and schwannoma. We present a discussion of the utility of immunohistochemistry in such cases in order to diagnose such tumours.

Keywords: Appendix; Leiomyoma; Tumour; Immunohistochemistry

Introduction

Leiomyomas are rare soft-tissue tumours of the appendix. A review of soft-tissue tumours of the large bowel found a total of 23 appendiceal leiomyomas published in the literature between 1875-1996¹. A single-centre case series of 101 appendiceal tumours between 1949 and 1972 included only two leiomyomas². The most common presenting symptoms include pain, palpable abdominal mass and haemorrhage. Appendiceal leiomyosarcomas are rarer than leiomyomas and more commonly present with haemorrhage. There was no significant difference between the size of leiomyomas and leiomyosarcomas reported, with the majority of appendiceal lesions measuring less than 5cm maximal length [1]. Case reports demonstrate these lesions can be very large, with previously reported giant leiomyomas weighing up to 500 grams and 15cm maximal length [2-4].

Case Presentation

A 79-year-old female presented to Queen’s Medical Centre Emergency Department, Nottingham, UK with severe sudden onset right-sided flank pain. This pain had started suddenly the previous day and worsened overnight with one episode of vomiting. Whilst the patient described that she had generally been feeling well previously, she noted abdominal bloating in the previous two weeks. She was otherwise of minimal co-morbidity and able to live alone independently. She had a past medical history of hypertension, previous ectopic pregnancy, and previous hysterectomy. She did not take any regular medications. Blood tests demonstrated: Hb 109, from baseline of 135 in the previous year; Lactate was 1.6; WCC 7.61; Neutrophils 5.86; CRP 7. The patient was apyrexic, haemodynamically stable and observations were normal.

CT abdomen-pelvis with contrast demonstrated a 95mm rounded mixed density mass within the lower abdomen and pelvis to the right of the midline and contiguous with the appendix. Free fluid was present in the abdomen with predominantly high-density fluid in the pelvis consistent with haemoperitoneum. The radiological differential diagnosis was of a ruptured Gastrointestinal Stromal Tumour or torted fibroid (Figure 1).

The patient underwent laparotomy and appendicectomy the day after admission. Management options of angio-embolization and open surgery were considered. The patient was a Jehovah’s Witness and refused to receive exogenous blood products. This, along with the radiological suspicion of active bleeding, resulted in the decision to proceed to emergency surgery to achieve a definitive solution as promptly as possible. Although the patient had agreed to receive cell-saver autologous transfusion, the surgical team were hesitant to use this owing to the perceived risk of tumour seeding by recycling blood arising from the tumour bed. At laparotomy there was haemoperitoneum and active bleeding from the lesion. The patient had an uneventful recovery and was discharged day 5 after surgery.

The resected specimen demonstrated a well-circumscribed lesion measuring 110 x 105 x 85mm arising in the distal appendix. Its gross weight was 450 grams. On grossing, the cut surface had a whorled appearance with focal yellow degenerate areas. Histopathological examination demonstrated a spindled-cell lesion arising from the body and distal portion of the appendix. The lesion consisted of smooth muscle bundles arranged in fascicles with a whorled appearance. The stroma of the tumour showed collections of lymphoid aggregate with focal areas of necrosis. However, cytologically the lesion was bland with mild pleomorphism and mitotic activity was very low with 1 mitosis per 50 high-power fields (Figure 2A). At the periphery of the lesion there are large ectatic vessels lying close to the subserosa. In one of the sections there was evidence of bleeding into the subserosa, probably representing the site of haemorrhage. Immunohistochemical staining revealed: Desmin (+), SMA (+), Caldesmon (+), DOG1 (-), CD34 (-), CD117 (-), S100 (-). Ki67 staining was very low. The above histological and immunohistochemical features confirmed a diagnosis of appendiceal leiomyoma (Figure 3).

Discussion

A PubMed (1950-2020) search was conducted using the following keywords: appendiceal leiomyoma OR appendix + leiomyoma OR appendicular leiomyoma OR veriform leiomyoma OR appendix + fibroid OR appendiceal fibroid OR vermiform fibroid. Six English-language case reports were found in this search [3-8]. A review of 50,000 appendicies included 830 leiomyomas, accounting for 1.66% of the tumours identified in the case series, and 632 malignant tumours [9]. The rarity of leiomyomas of the appendix compared to the rest of the large bowel is largely accounted for by the small volume of the appendix, reducing the probability of neoplastic mutation within this structure. Appendectomies, often as a consequence of acute appendicitis, decrease the percentage of the adult population with an intact appendix, thus further decreasing the incidence of neoplasms arising from this structure in the adult population. Whilst appendicular leiomyomas presenting with haemoperitoneum have been reported, such a presentation is uncommon and many leiomyomas are often asymptomatic¹. As previous reports have shown^3,4, these leiomyomas can reach a very large size. In the present case, this caused mechanical compression and dilatation of the overlying subserosal vessels, leading to haemorrhage (Figure 2B).

To our knowledge, no previous reports discuss the utility of immunohistochemistry in such cases. Indeed, many of the published cases precede the widespread availability of this technique¹. However, immunohistochemistry is of use in such rare cases to exclude other tumours (Table 1). The main differentials in this case are leiomyosarcoma, gastrointestinal stromal tumour (GIST) and schwannoma. Leiomyosarcoma of the appendix is less common than leiomyoma but carries a far worse prognosis¹. Criteria to distinguish these tumours include degree of nuclear atypia and mitotic count. As such, ki67 may help illustrate regions of proliferation and help determine the malignant potential of the tumour. Both leiomyosarcoma and leiomyoma are positive for the smooth muscle markers SMA, desmin and caldesmon. Gastrointestinal stromal tumour (GIST) is the most common malignant mesenchymal tumour of the gastrointestinal tract [10]. Cytologically they demonstrate spindle or epithelioid cells arranged in a fascicular pattern. They characteristically express CD117, DOG1 and CD34. S100 and SMA are typically negative. Schwannomas of the appendix are very rare, with only a handful of cases reported in the literature [11]. Microscopic appearances are of interlaced spindle cells and with features of nuclear palisading, hylanised vessels and Verocay bodies. S100 staining is positive on immunohistochemistry with CD34, CD117, DOG1 and desmin typically negative.

In conclusion, we present a case of appendiceal leiomyoma presenting with acute haemorrhage. This case illustrates the need to consider soft tissue tumours of the appendix in the differential diagnosis of acute abdomen pain. Furthermore, we demonstrate the importance of immunohistochemistry in subtyping soft-tissue tumours of the appendix, as within this group of tumours there are considerably different prognoses.

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Six Years After the Closure of the OPGs and the Establishment of REMS: Considerations and Future Perspectives - Juniper Publishers

 Psychology and Behavioral Science - Juniper Publishers

Editorial

The law of 30 May 2014, n. 81 represents the point of arrival of an important reform of the Italian psychiatric forensic system. With it, in fact, Italy passed from a forensic psychiatric model based on OPGs to one based on REMS. The first OPG (Ospedale Psichiatrico Giudiziario, High Security Hospital), was established in Italy in 1872 in Aversa, in Southern Italy to place those offenders recognized as “not guilty by reason of insanity” at the time of committing the crime [1]. At that time, the OPGs were still called MG (Manicomio Giudiziario) and only with the law n. 354/1975 their name was changed. The OPGs were basically Italy’s maximum security hospitals and their model of care remained unchanged until the DPCM (Decree of the President of the Council of Ministers) of April 1, 2008, when the responsibility for treating OPG inpatients and mentally ill prisoners was transferred from the Department of Justice to the Department of Health. With the same decree, the government recommended for the first time in more than a century the overcoming of the OPGs, finally implemented seven years later with the aforementioned law 81 of 2014.

After that law, the six existing OPGs have been closed and substituted by an alternative network of residential care facilities called REMS - Residencies for Execution of Security Measures. During their closing, while inpatients were progressively transferred to the REMS, the OPGs continued to operate but they have not accepted any new patients since their final closure was set for April 1, 2015. The total number of patients confined in the OPGs by June 30, 2010 amounted to 1,457 men and 95 women (Ministry of Health); at the end of 2014 there were 672 inpatients in the 6 OPGs. It took almost two years to complete the discharge of all the remaining patients from OPGs [2]. The structural and functional characteristics of the REMS are aimed at assuring general security, individual care, rehabilitation programs in community environment and small scale dimensions [3]. In fact, the law established that each REMS consists of residential structures capable of accommodating a maximum of 20 patients assisted by health professionals 24 hours a day. The law also wanted to ensure that the presence of these structures covered the entire national territory, providing that each of the 20 Italian regions had at least one REMS. To date, thirty one REMSs are active in Italy, for a total of up to 600 beds reserved only to the offenders whose criminal responsibility is totally excluded or reduced due to a serious mental illness at the time of the crime, socially dangerous, according to the Italian legislation (art. 203 Penal Code). Internment in REMS is designed as a custodial security measure which is “extreme and exceptional” and in any case Law 81 of 2014 limits the maximum duration of internment in REMS to the maximum time of imprisonment had the offender been found guilty of the crime and sentenced.

The exceptional nature of the REMS security measure derives from the intention of the Italian legislator to balance two different principles of equal dignity. On the one hand, in fact, there is the principle of patient consent which consists in the voluntary nature of the medical treatment already recognized for non-forensic patiens by Law 180 of 1978. On the other hand, there is the need to contain patients who have committed offenses with restrictive measures because of their recognized social dangerousness. By balancing the two colliding requirements, the legislator intended to give the REMS internment the character of “last resort”. In fact, with Law 81 of 2014, it was established that the judge will have to opt for lighter security measures (such as “libertà vigilata, sort of probation) whenever the social dangerousness of the patient who is the offender can be managed and contained in general community facility.

A study by Catanesi and colleagues [4] on REMSs conducted in 2019 showed that the 89% of the patients were male and the most frequently diagnosed psychiatric disorder in REMS patients was schizophrenia (33.0%), followed by personality (32.0%) and substance-related disorders (21.4%). The same study reported that most of the patients (81,2%) are involved in rehabilitation programs; almost a quarter of patients (23,3%) receive more than one type of psychotherapy and almost a fifth (19.3%), psychoeducational programs. The most frequent drug therapies prescribed are oral antipsychotics (79% of total sample); acting injectable (LAI) preparation (47% of total sample); mood stabilizers (47.5%), such as carbamazepine, lithium carbonate, or sodium valproate, were co-administered to patients receiving a LAI or with oral antipsychotics too. Observing the main characteristics of the REMS, it appears more clearly that they were designed to overcome the problems that affected the previous OPG system: inadequate treatment provided, the presence of police officers and the possibility of indefinite hospitalization, due to prison buildings characterized by a restrictive architecture.

Although many of these critical issues have been addressed by the reform that led to the establishment of REMS, six years after their introduction, new problems can also be highlighted. Some critical issues that emerged are due to the absence of specific regulations set ad hoc on the equally specific area of intervention affected by the law. The definitive overcoming of the OPGs by the Law n. 81 of 2014 took place, in fact, completely unrelated to the Criminal Code, the Criminal Procedure Code and the Penitentiary Law, which remained unchanged [5]. The consequent birth of the REMS has entailed many problems of interpretation given that the REMS differ from the OPG for the presence of an almost full sanitization of these structures. The management of the REMS, in fact has been entrusted exclusively to health professionals, while in the OPGs the custodial management belonged to the penitentiary administration. In this way, a distinction has been made by law between the health aspect and the prison aspect. At the moment, however, due to a lack of coordination of the REMS instituting law with the other areas of the aforementioned legal system, it is not clear whether and to what extent the custodial management and application of the penitentiary system in REMS falls on psychiatrists.

Other issues emerged referring to the need for greater homogeneity. In Italy, each region decides autonomously on health matters and this has led to a great heterogeneity in the practices adopted in the individual regional realities. This can cause problems with the compliance of the principle of territoriality according to which people must be hosted in the forensic facilities present in the regions of origin. For last, the saturation of the structures, considering that the approximately 600 beds made available by all the REMSs represent less than half of the total beds of the six OPGs before their closure. A limited availability of places in REMSs has led, in fact, to the creation of a “waiting list” for admissions. In addition to this and the already difficult management of waiting lists, there is an increasing risk of the measure in REMS being ineffective due to the large presence in it of people subjected to temporary security measures. Despite the legislator’s intentions to use REMS only as a last resort and to privilege the “libertà vigilata”, where possible, many prosecutors continue to apply internment in REMS as a provisional security measure, with a consequent detriment of the therapeutic potential of the same, both against subjects who at the end of the process may be subjected to an ordinary prison sentence outside the forensic structures, both of patients already present in REMS in a definitive manner, given the greater number of subjects in need of treatment at the same time.

An important point is that these lists are managed directly by the Ministry of Justice without the use of admission priority criteria based on clinical risk assessments [6] and doubts were raised regarding the criteria that it must consider ascertaining the dangerousness of the perpetrator, suffering from a mental illness, in order to decide whether to apply, or even just continue, the security measure. If, on the one hand, the introduction of the maximum duration of the security measure of detention is in line with the principles of legal civilization, on the other hand, it should be counterbalanced in light of the absence of certainty criteria in the psychiatric-forensic assessment of the social dangerousness. Overall, REMS structures appear undersized not only for the capacity of beds but also for the number of staff who often find themselves having to deal with aggressive patients, difficult to treat and complicated in their management, also in terms of safety and security. For these reasons, the closure of OPGs has created a duty to adopt evidence-based strategies for assessing the risk of violence that are functional to the development of risk management and treatment strategies [3].

Once again, it is right to specify that the Italian psychiatric system has always been in many ways very peculiar at an international level. With the law 833 of 1978, Italy decree for the first time the closure of the OPs (Psychiatric Hospitals) and provided for the transition to a community treatment model. Later on, as we saw, Italy closed also the OPGs in 2014. During the years following these important changes in the psychiatric patient care system, Italian psychiatrists have acquired specialized skills that characterize the operational practices to which they apply, often different from other European countries. Some of the strengths of the current Italian mental health care model include the widespread public outpatient psychiatric services throughout the country, interventions by the family and social environment and attention to other protective prognostic factors [7].

After the closure of OP, however, Italian general psychiatrists did not manage the violent and criminal behavior of their patients, which had previously been the responsibility of the Judicial System and its OPGs, so the National Health System psychiatrists gradually came to completely neglect these issues. Therefore, clinical psychiatrists, after OPGs closure, have to manage the risk of violence. It is the authors’ opinion that the use in Italian psychiatrist’s clinical practice of use of assessment and management tools, including those for the risk of violent acts is desirable in the near future for different reasons. At first, begin to use them habitually and regularly, as it should be, especially in our REMSs, in our forensic but in non-forensic facilities too would have the undoubted advantage of allowing us to compare ourselves with the models of other countries. Our forensic model of treatment is very unusual indeed, so the use of such tools would provide more objective data with which to support statements that today may appear self-referential. Hopefully, in few years, maybe, we will be able to demonstrate that our approach to the care of mentally ill patients it is no less effective than those chosen from countries other than ours and surely more ethical. From a practical perspective, these instruments can also guide the decision makers with the choice of priority criteria in accessing the waiting lists for admission to REMS. Finally, we think that the clinical and professional experience remains fundamental, but the use of these tools can be of valid comfort to the diagnostic and clinical reasoning both in the practice of general psychiatry and in forensic psychiatry evaluation as it can provide a unique, easyto- share clinical-anamnestic and historical information base that functions as a common source of reflection for all.

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Anti-Viral Vaccine Activity of Zinc(Ⅱ) for Viral Prevention, Entry, Replication, and Spreading During Pathogenesis Process - Juniper Publishers

 Biomedical Engineering & Biosciences - Juniper Publishers

Abstract

Anti-viral vaccine activity of Zn2+ ions for viral prevention, pathogenesis processes, and ROS generation causing to oxidative stress have been investigated. AZP is efficient for viral prevention by inhibitions of BSCTV and DNA virus replications. The AZP phenotypes show strongly resistant to virus infection and viral DNA replication could be applied to the prevention of virus infections in humans. ZnOTs exhibit the ability to neutralize HSV-2 virions and blocking HSV-2 attachment activity. Zinc salts can mediate antiviral activity on RSV by altering the ability of the cell to support RSV replication. The effect of zinc sulfate on seroconversion after a simple method vaccination had been identified that accelerated HB vaccination can shorten duration of immunization of this clinical trial for showing its effectiveness. The inhibition of zinc binding activity of hMPV M2-1 protein can lead to the development of novel, live attenuated vaccines as well as antiviral drugs for pneumoviruses. The CCHH zinc finger motif provides potential vaccine candidates for the development of live species-specific attenuated influenza virus vaccines. Chelates zinc ions inhibit HIV-1 replication. The LAIVs are attracting attention as several advantages over inactivated vaccines. Zinc finger reactive compounds also inactivate retroviruses. ZOTEN promoted the presentation of bound HSV-2 virions.

The regulated ZFNs in the presence of HIV-1 Tat may provide a safer and novel genome-editing technology for eradicating HIV-1 proviral DNA from infected host cells. Zinc ions inhibit vaccine virus growth. The ZAP inhibits HIV-1 infection by viral mRNAs degradation. ZAP also inhibits the spreading against XMRV. The treatment of viral infections with viral spreading will be achieved and improved the therapeutic effects by using zinc oxide nanoparticles. ROS and RNS within viruses of viral entry, viral replication, and viral spread are generated in all situations. ROS in virus pathogenesis play an important role in cell signaling and regulate hormone action, growth factors, cytokines, transcription, apoptosis, immunomodulation, and neuromodulation, leading to chronic oxidative stress. Oxidative stress has been occurred in various viral infections. The antioxidant components lead to an excess storage of H2O2, which further increases the hydroxyl radicals and lipid peroxide that signal the cell to undergo a programmed cell death. Thus, zinc-associated vaccine activity mechanism against viruses is indicated that the anti-viral vaccine activity of released Zn2+ ions from zinc solutions and ZnO NPs, may be enhanced by Zn2+ ion-induced Zn2+ ions-coordinated adapted immunity, viral growth regulation, and viral apoptosis and death.

Keywords: AZP/ZOTEN/ZAP/ZFN; Zinc salts and zinc sulfate; ROS; Oxidative stress; HIV/hMPV/ LAV/RSV/XMRV

Abbreviations: APCs: Antigen Presenting Cell; AZP: Artificial Zinc Finger Protein; BSCTV: Beet Severe Curly Top Virus; HIV: Human Immunodeficiency Virus; hMPV: Human Metapneumovirus; HBV: Hepatitis B Virus; HEV: Hepatitis E Virus; HSV2: Herpes Simplex Virus Type-2; IRF3: Interferon Regulatory Factor 3; ISREs: Interferon Stimulated Response Elements; LAIVs: Live Attenuated Influenza Vaccines; LAV: Live Attenuated Virus; NKT: Natural Killer T; PLZF: Promyelocytic Leukemia Zinc Finger; RdRp: RNA-Dependent RNA Polymerase; RNS: Reactive Nitrogen Species; ROS: Reactive Oxygen Species; RSV: Respiratory Syncytial Virus, SSP: Stable Signal Peptide; TALENs: Transcription Activator-Like Effector Nucleases; XMRV: Xenotropic Murine Leukemia Virus related Virus; ZBD: Zinc-Binding Domain; ZAP: Zinc-Finger Antiviral Protein; ZFN: Zinc Finger Nuclease; ZnOTs: ZINC OXIDE TETRAPODS; ZOTENs: Zinc Oxide Tetrapod Nanoparticles

Introduction

Viruses are small protein capsid that harbor genetic information. In the case of enveloped viruses, an additional lipid bilayer surrounds the capsid that enveloped viruses can spread via two distinct routes, either through the cell-free aqueous environment or, alternatively, by remaining cell associated and being passed on by direct cell-cell contact [1].

The other, zinc is the second most abundant trace metal with human body 2-3g, 90% in muscle and bone, and 10% other organs include prostate, liver, the gastrointestinal tract, kidney, skin, lung brain, heart, and pancreas in humans which cellular zinc underlies an efficient homeostatic control that avoids accumulation of zinc in excess [2]. The role of zinc in cell death has apoptosis that the influence of zinc on apoptosis is tissue/ cell type, zinc concentration, and expression of zinc transporters and zinc-binding proteins [2]. Zinc has a rather low toxicity and influences apoptosis by acting on several molecular regulators of programmed cell death, including caspases and proteins from the Bcl and Bax families.

Zinc induced anti-virus activity may be enhanced for Tcell division, maturation and differentiation, lymphocyte response to mitogens, programmed cell death of lymphoid and myeloid origins, gene transcription, and biomembrane function [3]. Nonstructure NS5A is a zinc metalloprotein and zinc coordination is likely required for NS5A function in the hepatitis C replicase that reduced NS5A zinc coordination and zinc binding motif were tolerated for replication [4]. The zinc-finger antiviral protein (ZAP) induced virus during viral infection little is known, however, mutational analysis of the human ZAP promoter revealed that multiple interferon stimulated response elements (ISREs) distal to the transcription start site serve redundantly to control interferon regulatory factor 3 (IRF3)-dependent induction of ZAP trancription [5].

Anti-virus vaccine principle is to viral prevention and devoid serious diseases that live attenuated virus (LAV) vaccines have provided ideal protection from several major diseases. The ability to create a zinc finger nuclease (ZFN) vaccine that can prevent and eliminate persistent viral infections is a long way from being realized, in which the efficacies by available LAV, live attenuated rotavirus, influenza, and varicella zoster vaccines are strong incentive to redouble efforts to improve the safety characteristics of this type of vaccine [6]. Vaccines for numerous infectious diseases have been developed using whole inactivated virions that live attenuated influenza vaccines (LAIVs) are particularly attracting attention as effective strategy due to several advantages over inactivated vaccines [7].

Zinc-binding activity of human metapneumovirus (M21) protein was found to incorporate zinc ions, although the specific roles of the zinc binding activity in viral replication and pathogenesis remains unclear [8]. The pathogenic process, namely viral pathogenesis is the process by which an infection leads to disease that pathogenic mechanisms of viral disease include viral entry, local replication, and spread to organs and shedding of disease site [9]. Accordingly, the zinc induced Zn2+ ion coordinated activity results in regulation of viral growth and may lead to virus death in host cell-virus interaction during pathogenesis process.

In this review, zinc-mediated anti-viral vaccine activities have been investigated for viral prevention, viral entry, replication/ DNA/RNA virus, and spreading to organs during pathogenesis process. Lastly, ROS productions and leading to oxidative stress and virus death are discussed.

Viral prevention

Viral prevention is a major objective in human health. One attractive approach to the prevention is inhibition of virus replication. Artificial zinc finger proteins (AZP) have been targeted to the replication origin of the Beet severe curly top virus (BSCTV), a model DNA virus that the AZP efficiently blocked binding of the viral replication protein, which initiates virus replication, to the replication origin. These results showing to the AZP phenotypes strongly resistant to virus infection and viral DNA replication could be applied to the prevention of virus infections in humans [10]. Inhibition of virus DNA replication by AZP is comparable to viral prevention. Zinc oxide tetrapods (ZnOTs) exhibit the ability to neutralize herpes simplex virus type-2 (HSV-2) virions and blocking HSV-2 attachment activity by ZnOTs can have prophylactic as well as therapeutic applications [11].

Viral entry and replication

Zinc salts was examined in the presence of zinc during preincubation, adsorption, or penetration by the degree of inhibition of respiratory syncytial virus (RSV) replication, the resulting that zinc can mediate antiviral activity on RSV by altering the ability of the cell to support RSV replication [12]. Further, zinc salts did not show any effect on the entry of g-1 hepatitis E virus (HEV) into the host cell, directly inhibit the activity of the viral RNA-dependent RNA polymerase (RdRp), leading to inhibition of viral replication, suggesting their possible therapeutic value in controlling HEV infection [13]. The other, Zinc sulfate has no effect in level of immunity among elderly and zinc may stimulate antibody response in the nonresponders to recombinant hepatitis B vaccine. The effect of zinc sulfate on seroconversion after a simple method vaccination had been identified that accelerated hepatitis B vaccination can shorten duration of immunization of this clinical trial for showing its effectiveness [14]. The inhibition of zinc binding activity of human metapneumovirus (hMPV) M2-1 protein can lead to the development of novel, live attenuated vaccines as well as antiviral drugs for pneumoviruses [8].

The CCHH zinc finger motif provides a critical determinant for virulence in mouse and mutations in the CCHH motif yield potential vaccine candidates for the development of live speciesspecific attenuated influenza virus vaccines [15]. Chelates zinc ions (a bisthiadiazolbenzene-1,2-diamine) from retroviral nucleocapsid zinc fingers inhibit HIV-1 replication [16]. This compound thus acts via a different mechanism than the previously reported zinc ejectors, as its structural features do not allow an acyl transfer to Cys or a thioldisulfide interchange. The cleaved stable signal peptide (SSP) is retained in GPC through interaction with a zincbinding domain (ZBD) in the cytoplasmic tail of G2 [17]. The live attenuated influenza vaccines (LAIVs) are attracting attention as an effective strategy due to several advantages over inactivated vaccines [18]. Zinc finger reactive compounds also inactivate retroviruses by targeting the zinc finger motif in their nucleocapsid proteins. These compounds are effective against respiratory syncytial virus (RSV) that AT- 2-inactivated RSV vaccine may not be enough to produce a highly efficacious inactivated virus vaccine which does not lead to an atypical disease [19]. Intravaginal zinc oxide tetrapod nanoparticles (ZOTEN) promoted the presentation of bound HSV-2 virions to mucosal APCs, enhancing T cell-mediated and Ab-mediated responses to the infection, and thereby suppressing a reinfection [20].

DNA/RNA virus inhibitors

A human papillomavirus type 16 E7 DNA vaccine indicated a significantly stronger E7-specific cytotoxic T-lymphocyte induction and better antitumor protection [21]. Zinc finger nucleases (ZFNs) can specifically and efficiently excise HIV-1 proviral DNA from latently infected human T cells, the resulting from HIV-1infected human primary T cells and latently infected T cells treated with the inducible ZFNs validated that proviral DNA can be excised [22]. The regulated ZFNs in the presence of HIV-1 Tat may provide a safer and novel genome-editing technology for eradicating HIV-1 proviral DNA from infected host cells. ZFNs and transcription activator-like effector nucleases (TALENs) bear sequence-specific DNA-binding modules that recognize HIV DNA sequences [23]. Therapeutic potential of ZFNs and zinc finger arrays (ZFAs) is confirmed with unique specificity to HSV-2 the genome which ZFNs with specificity to HSV-2 genomic DNA are precursors of novel host genome expressed HSV-2 gene-therapeutics or vaccines [24]. Zinc supplementation in cultured HeLa cells inhibits DNA laddering & caspase-3 activity, and inhibitory effect on influenza virus induced apoptotic death can be determined at an early stage of the infection by zinc treatment [25]. Further, zinc ions inhibit vaccine virus growth, and a fraction of RNA which is normally synthesized infected cells, was missing from a proper part of the gradient if the cell were treated with zinc ions within 1 h post infection that a transcriptional step is involved in zinc-caused inhibition of vaccinia virus growth [26]. The zinc-finger antiviral protein (ZAP) inhibits HIV-1 infection by viral mRNAs degradation that ZAP inhibits HIV-1 by recruiting both the 5’ and 3’ mRNA degradation to specifically promote the degradation of multiply spliced HIV-1 mRNA [27].

Higher levels of dietary zinc oxide (ZnO) levels could not provide enhanced protection against porcine reproductive and respiratory syndrome virus (PRRSV) vaccine and infection that have the potential to stimulate or modulate systemic immune responses after vaccination [28]. In the synthesized ZnO tetrapod nanoparticles (ZOTENs), ZOTENs prevent HSV-2 infection and disease that ZOTEN provides a platform for virus capture and presentation of neutralized virions to mucosal antigen presenting cell (APCs), for initiating and boosting adaptive immunity which provides the novel evidence for the protective efficacy of an intravaginal microbicide/vaccine or microbivac platform against primary and secondary female genital herpes infection [29].

Viral spread inhibitor

ZAP inhibits the spreading of replication-competent xenotropic murine leukemia virus-related virus (XMRV) which ZAP inhibits viral infection [30]. The treatment of viral infections with viral spreading will be achieved and improved the therapeutic effects by using zinc oxide nanoparticles [31].

ROS Generation in Host Cell-Virus Interaction and Leading to Virus Growth Regulation and Virus Death

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) within viruses of viral entry, viral replication, and viral spread are generated in all situations. ROS induce several cellular effects, including cell cycle progression, apoptosis, DNA damage, senescence, and neurodegeneration. ROS in virus pathogenesis play an important role in cell signaling and regulate hormone action, growth factors, cytokines, transcription, apoptosis, immunomodulation, and neuromodulation, leading to chronic oxidative stress [32]. Oxidative stress has been occurred in various viral infections. For human immunodeficiency virus (HIV), the body antioxidant system becomes weaker as HIV progresses that the imbalances inside and outside the cell influence the cell to undergo a programmed cell death [32]. The antioxidant components lead to an excess storage of H2O2, which further increases the hydroxyl radicals and lipid peroxide that signal the cell to undergo a programmed cell death [32]. The influenza virus induces ROS production in host cells that can damage the virus genome which ROS enhance the pathogenesis ability of infectious influenza that leads to the thymus specific elevation of the mitochondrial superoxide, which interferes with the normal functioning of T-cells lymphocyte damage in influenza A virus infections [32]. Influenza A virus infection causes a rapid influx of inflammatory cells, resulting in increased ROS production, cytokine expression, and acute lung injury which inhibition of this activity would restore host cytokine homeostasis following avian influenza virus infection [33]. Promyelocytic leukemia zinc finger (PLZF) controls the ROS levels that in turn PLZF governs the inflammatory function of natural killer T (NKT) cells, in which ROS regulate homeostasis and effector function of NKT cells, both of which are regulated by PLZF [34]. As mentioned above, anti-viral vaccine activities of Zn2+ ions for viral prevention, entry, replication, and spreading with pathogenesis process are exhibited in Table 1. Zinc-associated vaccine activity mechanism against viruses is indicated that the vaccine activity of released Zn2+ ions from zinc solutions and ZnO NPs, may be enhanced by zinc(Ⅱ)-induced Zn2+ coordinated adapted immunity, viral growth regulation, and viral apoptosis and death

Conclusion

AZP can efficiently block binding of the viral replication protein, which initiates virus replication, to the replication origin against BSCTV, DNA virus. The AZP phenotypes show strongly resistant to virus infection and viral DNA replication could be applied to the prevention of virus infections in humans. ZnOTs exhibit the ability to neutralize herpes simplex virus type-2 (HSV-2) virions and blocking HSV-2 attachment activity by ZnOTs can have prophylactic as well as therapeutic applications. Zinc salts can mediate antiviral activity on RSV by altering the ability of the cell to support RSV replication. The effect of zinc sulfate on seroconversion after a simple method vaccination had been identified that accelerated HB vaccination can shorten duration of immunization of this clinical trial for showing its effectiveness. The inhibition of zinc binding activity of hMPV M2-1 protein can lead to the development of novel, live attenuated vaccines as well as antiviral drugs for pneumoviruses. The CCHH zinc finger motif provides a critical determinant for virulence in mouse and mutations in the CCHH motif yield potential vaccine candidates for the development of live species-specific attenuated influenza virus vaccines. Chelates zinc ions also inhibit HIV-1 replication. The LAIVs are attracting attention as an effective strategy due to several advantages over inactivated vaccines. Zinc finger reactive compounds also inactivate retroviruses. ZOTEN promoted the presentation of bound HSV-2 virions to mucosal APCs, enhancing T cell-mediated and Ab-mediated responses to the infection, and thereby suppressing a reinfection.

ZFNs can specifically and efficiently excise HIV-1 proviral DNA from latently infected human T cells, the resulting from HIV-1-infected human primary T cells and latently infected T cells treated with the inducible ZFNs validated that proviral DNA can be excised. The regulated ZFNs in the presence of HIV-1 Tat may provide a safer and novel genome-editing technology for eradicating HIV-1 proviral DNA from infected host cells. Zinc supplementation in cultured HeLa cells inhibits DNA laddering & caspase-3 activity, and inhibitory effect on influenza virus induced apoptotic death can be determined at an early stage of the infection by zinc treatment. Further, zinc ions inhibit vaccine virus growth, and are involved in zinc-caused inhibition of vaccinia virus growth. The ZAP inhibits HIV-1 infection by viral mRNAs degradation that ZAP inhibits HIV-1 by recruiting both the 5’ and 3’ mRNA degradation to specifically promote the degradation of multiply spliced HIV-1 mRNA. Higher levels of dietary ZnO could not provide enhanced protection against PRRSV vaccine that higher levels of dietary ZnO have the potential to stimulate or modulate systemic immune responses after vaccination against PRRSV. ZOTEN provides a platform for virus capture and presentation of neutralized virions to mucosal APCs.

ZAP inhibits the spreading against XMRV which ZAP inhibits viral infection. The treatment of viral infections with viral spreading will be achieved and improved the therapeutic effects by using zinc oxide nanoparticles. ROS and RNS within viruses of viral entry, viral replication, and viral spread are generated in all situations. ROS induce several cellular effects, including cell cycle progression, apoptosis, DNA damage, senescence, and neurodegeneration. ROS in virus pathogenesis play an important role in cell signaling and regulate hormone action, growth factors, cytokines, transcription, apoptosis, immunomodulation, and neuromodulation, leading to chronic oxidative stress. Oxidative stress has been occurred in various viral infections. The body antioxidant system becomes weaker as HIV progresses that the imbalances inside and outside the cell influence the cell to undergo a programmed cell death. The antioxidant components lead to an excess storage of H2O2, which further increases the hydroxyl radicals and lipid peroxide that signal the cell to undergo a programmed cell death. The influenza virus induces ROS production in host cells that can damage the virus genome which ROS enhance the pathogenesis ability of infectious influenza that leads to the thymus-specific elevation of the mitochondrial superoxide, which interferes with the normal functioning of T-cells lymphocyte damage in influenza A virus infections. Zinc-associated vaccine activity mechanism against viruses is indicated that the anti-viral vaccine activity of released Zn2+ ions from zinc solutions and ZnO NPs, may be enhanced by Zn2+ ion-induced Zn2+ ions-coordinated adapted immunity, viral growth regulation, and viral apoptosis and death.

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Blistering Distal Dactylitis: A Narrative Review - Juniper Publishers

 Orthopedics and Rheumatology - Juniper Publishers

Abstract

Blistering distal dactylitis (BDD) is a localized bacterial infection of fingers characterized by tense fluid-filled bullae. It is mostly found in children. The pathogenesis of BBD is still not clearly elucidated and seems to be multifactorial. The most predominant bacterial agents are Staphylococcus aureus and Group A Streptococcus. The diagnosis is generally based on clinical findings alone but may be confirmed with further testing. Its potential incidence in any age group as well as the presence of multiple differential diagnosis make the diagnostic process more challenging. A review of the literature was conducted to gain a better understanding of this disease and to reduce the discrepancies that surround its diagnosis and management.

Keywords: Blistering distal dactylitis; BDD; Streptococcal infections; Staphylococcal infections

Introduction

Blistering distal dactylitis (BDD) is a localized bacterial infection of the finger that was first described by Hays & Mullard [1]. This rare dermatological disease involves the volar fat pad of the distal phalanx of digits with fingers being more commonly affected than toes. It usually presents as non-tender fluid-filled lesions [2] (Figure 1). The most frequent etiologic agent is Staphylococcus aureus [3]. BDD is a diagnosis that relies on clinical reasoning. Its potential incidence in any age group as well as the presence of multiple differential diagnosis make the diagnostic process more challenging. A review of the literature was conducted to gain a better understanding of this disease and to reduce the discrepancies that surround its diagnosis and management.

Epidemiology

Blistering distal dactylitis (BDD) is commonly seen in children of 2 through 16 years of age [4]. It is of rare occurrence in adults regardless of their immune status and even more so in the elderly population [5]. However, physicians should be vigilant about this disease no matter the age group [6]. Rare cases of BDD have also been seen in children under 24 months of age [7].

Etiology

The pathogenesis of BBD is still not clearly elucidated. When seen in children [8], BDD is primarily caused by group A beta-hemolytic Streptococci [5]. Also, group B beta-hemolytic Streptococci are a possible etiologic factor in this age group [9]. Due to the major burden of group A Streptococcal disease worldwide, it was critical to detect changes in disease distribution using epidemiological surveillance methods. Among several available methods for defining strains, the typing of the M cell surface protein, a major virulence and immunological determinant of group A streptococci, is a universally used method. Interestingly, there were contrasting differences in the M protein gene typing profile known as emm sequencing between low and high-income countries as well as different clinical presentations of group A Streptococcal disease. For instance, emm 1 and 12 have been the most encountered types in invasive infections or scarlet fever occurring in high-income countries [10,11].

Furthermore, Staphylococcus aureus is becoming an increasingly incriminated agent in BBD³ with methicillin resistant strains described in one of the reported cases [12]. While Streptococcus and Staphylococcus-BDD are clinically indistinguishable, Staphylococcus is mostly detected in adults⁸ and may be associated with multiple blisters and a more extensive disease. In some cases, two different microorganisms may be isolated simultaneously. The most frequent associations include beta-hemolytic Streptococcus with Staphylococcus aureus [13,14], beta-hemolytic Streptococcus with Staphylococcus epidermidis [15] and Staphylococcus aureus with Herpes simplex virus [16]. BDD occurs more commonly in the fingers than in the toes [11,17] with the index and the thumb being the most frequently concerned digits [12]. The predilection for fingers may be partly explained by the theories behind the development of the disease such as the autoinoculation of the fingers due to nose-picking [6], finger sucking (especially in children aged 1 to 3 years old), exploring the mouths of adults, animal bites [14] and anthropophilic transmission [18,19], traumas like abrasions, finger pricks, and burns [5,7], abnormal skin appendages [20], and iatrogenic causes of intravascular inoculation such as forearm injections [21]. BDD may also be caused by undetectable infections of the anus, conjunctiva or the nasopharynx [8].

Clinical Presentation

Patients with BDD usually present with small (10-30mm in diameter), tense and oval bullae on an erythematous base at the level of the fingers or toes. Most patients report trauma or lesions disrupting the skin of the affected digits, such as insect bites, burns, needle pricks or abrasions. These bullae mostly affect the index fingers and thumbs and tend to occur on the volar fat pads of the distal phalanges but may extend dorsally toward the free edge of the nail, or proximally toward the palm of the hand. These lesions are generally non-tender but may progress into erosive lesions. Multiple lesions occur more frequently with Staphylococcus aureus infections. Upon closer examination, a blood-tinged or purulent liquid is generally found. As is the norm with superficial infections of the digits, systemic symptoms such as fever, chills, and weight loss are rarely reported [5,6,8,12,22,23]. When systemic symptoms do occur, a concomitant infection must be eliminated [12].

Even though herpetic whitlow is considered as a differential diagnosis, these two entities have been reported to coexist, potentially complicating the clinical picture [8]. Moreover, one study suggested screening all patients with BDD for perianal streptococcal dermatitis, however this claim was not backed by any reported cases in the literature [8].

The diagnosis is generally based on clinical findings alone but may be confirmed with further testing [5,8,12]. In the case of ruptured bullae, the enclosed liquid may be collected by swabs previously soaked in sterile normal saline. If no liquid is readily available, collection may be obtained by puncture with a needle and syringe. Direct microscopy and gram staining generally reveal polymorphonuclear leukocytes [23] and gram-positive cocci that are either in chains in the case of Streptococcus pyogenes, or in clusters in the case Staphylococcus aureus. If cultures are taken, they should be performed for both Streptococcus pyogenes and Staphylococcus aureus and are considered as the gold standard method.

Recently, group A streptococcus rapid antigen testing has been shown to be an effective testing method, with a sensitivity of 93.5%, specificity of 89.7%, and positive and negative predictive values of 84.1% and 86% respectively when compared to bacterial cultures. The study also argued that, when compared to PCR testing, the specificity of rapid testing would increase, since cultures of cases where Staphylococcus aureus and Streptococcus pyogenes coinfection had occurred showed negative Streptococcus pyogenes growth probably due to the inhibitive properties of Staphylococcus aureus on the growth of other bacteria in the culture medium. However, caution should be taken when utilizing rapid testing in the setting of BDD, as use of these testing methods outside of pharyngitis remains off-label [11,17,24]. Blood works are generally not performed in cases without systemic symptoms, and when carried out, they tend to come back normal in cases of uncomplicated BDD.

Differential Diagnosis

Differential diagnosis for blistering distal dactylitis is relatively broad (Table 1). It mainly includes chemical, thermal or traumatic burns, Herpes Simplex Virus (HSV) infections, Staphylococcal bullous impetigo [4,15] (Figure 2) as well as acral psoriasis, insect bites, dyshidrotic eczema (pompholyx) (Figure 3), allergic contact and irritant dermatitis, foreign body reactions and pustular dermatosis of the hands [8]. Vasculitis, cellulitis, osteomyelitis, peripheral neuropathy (with or without thermal injury), peripheral arterial disease and thromboembolism were also mentioned [6]. While both are caused by the same bacteria, bullous impetigo is very superficial in comparison with BDD [25]. HSV infections are characterized by their recurrence [26] and their non-response to antibiotics since they are of viral nature [5]. Both herpetic whitlow and staphylococcal bullous impetigo can be distinguishable by appropriate cultures and smears [15]. In addition, epidermolysis bullosa simplex type Weber-Cockayne should also be considered as a differential diagnosis [15]. While BDD is localized on the distal volar fat pad of fingers and toes and can also extend dorsally to the nail folds [14] it is different from paronychia, which generally involves the skin at the edge of the nail [8,11].

Complications

BDD is rarely complicated and is generally known to subside with proper treatment [22]. Cases of recurrent BDD have been described, and this is especially encountered when the greater toe is affected along with an ingrown nail [25]. A solitary case of osteitis and auto-amputation of the distal phalanx has been reported in a 9-month-old girl with HIV who had not received proper treatment until 2 months after the onset of symptoms [26]. One case of recurrent BDD in an immunocompetent elderly woman was found in the literature and was associated to the concomitant initiation of treatment by amiodarone, an antiarrhythmic drug known to be associated to cutaneous vasculitis. After discontinuation of amiodarone for a period of 2-weeks, the blisters had resolved and treatment with amiodarone reinstated⁶. No cases of post-streptococcic glomerulonephritis have been reported in the literature [23].

Treatment and follow-up

BDD is classified as an uncomplicated superficial skin and soft tissue infection (SSTI), and if adequately treated, carries a low risk for limb amputation and bacteremia [27]. Choosing an adequate treatment plan depends on the severity of the local infection, the existence of systemic signs and the presence of comorbidities. Treatment of BDD should start with incision and drainage or deflation with a sterile needle of the bullae followed by the application of wet to dry clean gauze on draining wounds and erosions [8]. In most cases, the diagnosis of BBD is solely clinical and does not require extensive tests. Moreover, with the increasingly poignant universal threat of antibiotic resistance and with Staphylococcus aureus becoming the leading bacterial pathogen worldwide [28], a course of empiric B-lactamase-resistant antibiotic should be initiated to cover both Gram-positive causative agents of BBD, according to local resistance patterns. In the absence of systemic signs, treatment can be carried out in the outpatient setting [27,29,30]. Topical antibiotics can be used in very mild cases but are often not sufficient alone. The mainstay of treatment is a systemic course of antibiotics.

Patients should start improving 24 to 48 hours after the initiation of antibiotics and treatment is continued for 7 to 14 days depending on the clinical response. However, patients who do not improve after 48 hours, develop systemic signs or have worsening local symptoms, need to be re-evaluated by sending specimens for culture and susceptibility testing to tailor the antibiotic treatment and assess for potential admittance to the hospital to avoid worrisome outcomes. In most cases, a multidisciplinary approach improves the management of these patients [31].

Healthy outpatients do not need systematic empirical coverage for methicillin resistant Staphylococcus Aureus (MRSA) in the absence of risk factors (Table 2) [29]. Oral agents effective against MRSA in adult patients in the absence of signs of severity include Linezolid, trimethoprim-sulfamethoxazole (TMP-SMX), and tetracycline (doxycycline or minocycline) among other antibiotics [27]. If coverage of both Streptococci and MRSA is desired in adults for uncomplicated SSTI, oral treatment options include the combination of either TMP-SMX or doxycycline with a B-lactam, clindamycin monotherapy or linezolid as a single agent. Rifampin monotherapy or add-on is not recommended.

In children, tetracyclines are not recommended below eight-years old and Linezolid can be considered starting 12 years of age [30]. In most cases, there were no recurrences [5,7,8] and follow-up was not needed.

Conclusion

BDD is a blistering acral skin and soft tissue infection mostly found in children. The pathogenesis is unclear and seems to be multifactorial. The most frequently isolated pathogens are Streptococcus pyogenes and Staphylococcus Aureus. The diagnosis is mainly clinical and does not allow to differentiate between the two pathogens in most cases. Diagnostic tests are not required initially as they have low yield in uncomplicated cases. They are most effective in non-responding or severe cases where they play an important role in tailoring the antibiotic treatment. Patients are treated with incision and drainage of the bullae followed by an empiric antibiotic treatment. Follow-up is not required as most cases are mild and resolve completely after treatment.

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Persistent Thrombocytosis in a Case of Pseudomyxoma Peritonea Post CRS and HIPEC -A Case Report - Juniper Publishers

 Cancer Therapy & Oncology - Juniper Publishers

Abstract

Background: Cytoreductive surgery (CRS) followed by hyper thermic intraperitoneal chemotherapy (HIPEC) is an evolving treatment for peritoneal carcinomatosis (PC). Mitomycin C (MMC), an alkylating agent, is presently the most commonly used chemotherapeutic agent for hyper thermic intraperitoneal treatment. The spleen has a role in the hematologic response after HIPEC and that splenectomy may enhance hematologic toxicity profiles of MMC. We are presenting a case who developed persistent thrombocytosis After Cytoreductive surgery followed by HIPEC.

Case presentation: A 48-year-old lady was referred to hematology OPD for first time with findings of persistent thrombocytosis on routine CBC follow-up. She underwent Cytoreductive surgery which include left and right parietal peritonectomy, pelvic peritonectomy, TAH+BSO, small bowel resection, right hemicolectomy, splenectomy plus heated intra operative peritoneal chemotherapy for a low-grade mucinous adenocarcinoma. Her initial platelet count was 1520x10^9/L for which she was on aspirin .Follow-up CBC showed a platelet count of 1609x10^9/L. She was investigated further and there was absence of any cause of essential thrombocytosis.

Conclusion: This article to emphasize that Persistent reactive thrombocytosis can occur in a case of peritoneal carcinomatosis after CRS followed by HIPEC.

Keywords: Peritoneal carcinomatosis; Cytoreductive surgery; HIPEC

Introduction

Cytoreductive surgery (CRS) followed by hyper thermic intraperitoneal chemotherapy (HIPEC) is an evolving treatment for peritoneal carcinomatosis (PC). Mitomycin C (MMC), an alkylating agent, is presently the most commonly used chemotherapeutic agent for hyper thermic intraperitoneal treatment. This may cause a fluctuation in platelet level postoperatively, but persistent reactive thrombocytosis is rare and very few articles are available on this topic. We are presenting a case where there is persistent reactive thrombocytosis followed by CRS and HIPEC.

Case Presentation

This A 48-year-old lady, With past medical history of diabetes mellites, cholecystectomy and previous ectopic pregnancy. was referred to hematology OPD for first time with findings of persistent thrombocytosis on routine CBC follow-up. March 2013: She underwent Cytoreductive surgery which include left and right parietal peritonectomy, pelvic peritonectomy, TAH+BSO, small bowel resection, right hemicolectomy, splenectomy plus heated intra operative peritoneal chemotherapy for a low-grade mucinous adenocarcinoma. Her case was further complicated by wound infection and dehiscence that was managed by antibiotic and dressing. She remained under annual follow up with oncology center. Her initial platelet count was 1520x10^9/L for which she was on aspirin 81 mg post splenectomy and sepsis induced reactive thrombocytosis was suspected ,Follow-up CBC showed a platelet count of 1609x10^9/L, She had an added thrombocytosis 18.0x10^9/L. At this stage essential thrombocytosis was suspected. She underwent Bone marrow study in June 2014 which showed no features of essential Thrombocytosis, in addition to a negative JAK2 mutation screen. In view that the patient has persistent thrombocytosis in absence of features of essential thrombocytosis in bone marrow study it was considered to be reactive and advised for further genetic screening to include CALR and MPL which came also negative so she was advised to continue aspirin prophylaxis. she had completed 5 years follow up for her malignancy without recurrence.

Discussion

Pseudomyxoma peritonea (PMP) are rare tumors characterized by large volume, ascites. These tumors are most commonly caused by epithelial neoplasm of the appendix however can also originate from mucinous tumors of the colon, rectum, or ovaries. Unfortunately, patients are often asymptomatic in the initial stage, but vague symptoms can occur [1,2]. Initial treatment of PMP is complete Cytoreductive surgery (CRS) combined with HIPEC. HIPEC consists typically of Mitomycin C however dose and timing differ between centers. Thrombocytosis can be classified into two types: essential thrombocytosis, a myeloproliferative disorder of the bone marrow, and reactive thrombocytosis, also called secondary thrombocytosis. This latter is the most common type and appears after acute inflammatory, infectious, neoplastic and stress processes. In these scenarios the levels of thrombopoietin, interleukin-6 and catecholamines are very high, and are thought to be responsible for the increased number of platelets. Signs and symptoms of the underlying disease usually accompany reactive thrombocytosis. In lung cancer patients, reactive thrombocytosis has a prevalence as high as 30% and has been linked with tumor extension or metastatic disease, and therefore with a poor prognosis. Reactive thrombocytosis may also appear with incidences of iron deficiency (6-12%), autoimmune disease (4- 11%), cancer (1-3%) or drug-induced problems. The reactive thrombocytosis found in patients with systemic inflammatory diseases is not the product of the isolated action of thrombopoietin, but its interaction with other plasma cytokines such as interleukin-6 [3]. Although the diagnostic tests to differentiate essential and reactive thrombocytosis are not easy to perform, laboratory tests that show increased acute phase reactants such as C-reactive protein, fibrinogen, erythrocyte sedimentation rate and interleukin-6 may be useful in the diagnosis of reactive thrombocytosis [4]. It is accepted that lower levels of platelets 1.000.000. μL-1 are a benign condition, although it remains unclear if these findings are associated with an increased post-operative thromboembolic or hemorrhagic risk. Prophylactic treatment with platelet inhibitors in these situations is controversial, although some authors do consider management of low-dose acetylsalicylic acid [5,6]. A study by Carlos parez et al. showed that increasing the initial drug concentration in the peritoneum and/or extending the HIPEC duration leads to a greater fluctuation in platelet counts. Reactive thrombocytosis can occur post splenectomy but usually transient. Some Case reports and Studies have shown that post CRS and HIPEC, there is fluctuation in Platelet level temporarily but Persistent thrombocytosis in a case of PMP post Cytoreductive surgery and HIPEC is rare.

Conclusion

Reactive thrombocytosis can occur post splenectomy but usually transient. Many case reports and studies have shown that post CRS and HIPEC, there is fluctuation in Platelet level temporarily but Persistent thrombocytosis in a case of PMP post Cytoreductive surgery and HIPEC is rare. So we should exclude the essential thrombocytosis but at same time can keep in mind that persistent thrombocytosis can occur in cases of PMS who are undergoing CRS and HIPEC.

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Applying Linear Elastic Glucose Behavior Theory and AI Auto-Correction to Predict A1C Variances Over the Ninth Period Using GH-Method: Math-Physical Medicine (No. 354) - Juniper Publishers

 Gynecology and Womens Health - Juniper Publishers

Summary

In this case study, the author analyzed, predicted, and interpreted a type 2 diabetes (T2D) patient’s hemoglobin A1C variance or A1C value based on nine time periods, ~5 months each, utilizing the GH-Method: math-physical medicine (MPM) approach. He utilized the same method and calculation formulas since 1/1/2014. This particular article emphasizes the ninth period (Period I) ranging from 5/20/2019 to 10/21/2020. Unlike the previous eight periods, in the ninth period, he used the continuous glucose monitor (CGM) sensor collected glucose data, which he implemented with the recently developed linear elastic glucose behavior theory (Reference 7, No. 352) to calculate his postprandial plasma glucose (PPG) difference.

Utilizing an auto-learning and auto-correction technique of artificial intelligence (AI), his software system would learn from lab-tested A1C values and then make necessary corrections. Therefore, in Period I, he utilized a higher conversion factor of 17.13 from glucose to HbA1C instead of 12.5 in the previous seven periods (Period A throughout Period G). He wrote two articles for the eighth period (Period H) using 12.5 (No. 329) and 17.13 (No. 329B), respectively. The difference on the final HbA1C results is a mere 0.01% which increased his predicted HbA1C from 6.31% to 6.39%, while the lab-tested HbA1C was 6.4% [1-6].

There are 10 hemoglobin A1C lab-tested results, with his 10 predicted HbA1C values using his developed methods:

a)6.7% on 4/9/2017 (predict 6.7%)

b)6.1% on 9/12/2017 (predict 6.1%)

c)6.9% on 1/26/2018 (predict 6.9%)

d)6.5% on 6/29/2018 (predict 6.5%)

e)6.6% on 10/22/2018 (predict 6.6%)

f)6.8% on 4/4/2019 (predict 6.8%)

g)6.6% on 9/25/2019 (predict 6.6%)

h)6.6% on 12/20/2019 (predict 6.6%)

i)6.4% on 5/20/2019 (predict 6.4%)

j)6.2% on 10/21/2020 (predict 6.2%)

It should be pointed out that all of his 10 predicted HbA1C values match 100% with his lab-tested HbA1C values. The author focused on nine periods over 1,299 days. It contains 3,897 meal data, including key contribution factors such as carbs/sugar intake, post-meal exercise, weather, and more. This study demonstrated a high degree of accuracy for the calculation and prediction of the patient’s forthcoming HbA1C value by using the GH-Method: math-physical medicine approach. In this article, the author also utilized CGM sensor glucose data with AI-tuned conversion factor between glucose and HbA1C. Furthermore, he also implemented his developed linear elastic glucose behavior theory [7] for his PPG calculation in order to obtain a better estimation for the final HbA1C value. Once the healthcare professionals and T2D patients understand the HbA1C mathematical prediction method, then the overall diabetes condition for the patient can be easier to control. The purpose for this research paper is to help people with T2D by preventing further damage to their internal organs caused by elevated A1C values, before taking the laboratory test [1,2].

If healthcare professionals and diabetes patients have an interest to delve deeper regarding the formation of tested glucose and mathematical predicted A1C, they should focus on the influential factors and their respective weighted contribution percentages described in the author’s previous papers.

Here is the summary:

a)The most important month which contributes to the A1C is the month prior to the lab test.

b)PPG contribute > 2/3 of HbA1C.

c)Body weight controls ~77% or more of the fasting plasma glucose (FPG) which contributes <1/3 of HbA1C; therefore, it is important to keep BMI below 25.

d)Carbs/sugar amount contributes ~39% to PPG. For T2D patients, it is safe to keep carbs/sugar intake amount below 15 grams per meal.

e)Post-meal walking steps contributes ~41% to PPG. It is recommended to maintain post-meal walking exercise around 4,000 steps after each meal.

f)A combined effort of diet and exercise controls ~80% to PPG formation [3,4].

Introduction

In this case study, the author analyzed, predicted, and interpreted a type 2 diabetes (T2D) patient’s hemoglobin A1C variance or A1C value based on nine time periods, ~5 months each, utilizing the GH-Method: math-physical medicine (MPM) approach. He utilized the same method and calculation formulas since 1/1/2014. This particular article emphasizes the ninth period (Period I) ranging from 5/20/2019 to 10/21/2020. Unlike the previous eight periods, in the ninth period, he used the continuous glucose monitor (CGM) sensor collected glucose data, which he implemented with the recently developed linear elastic glucose behavior theory (Reference 7, No. 352) to calculate his postprandial plasma glucose (PPG) difference. Utilizing an auto-learning and auto-correction technique of artificial intelligence (AI), his software system would learn from lab-tested A1C values and then make necessary corrections. Therefore, in Period I, he utilized a higher conversion factor of 17.13 from glucose to HbA1C instead of 12.5 in the previous seven periods (Period A throughout Period G). He wrote two articles for the eighth period (Period H) using 12.5 (No. 329) and 17.13 (No. 329B), respectively. The difference on the final HbA1C results is a mere 0.01% which increased his predicted HbA1C from 6.31% to 6.39%, while the lab tested HbA1C was 6.4% [5,6].

Material and Methods

As shown in Figure 1, there are 10 hemoglobin A1C labcheckup results, with his 10 predicted HbA1C values using his developed methods:

a) 6.7% on 4/9/2017 (predict 6.7%)

b) 6.1% on 9/12/2017 (predict 6.1%)

c) 6.9% on 1/26/2018 (predict 6.9%)

d) 6.5% on 6/29/2018 (predict 6.5%)

e) 6.6% on 10/22/2018 (predict 6.6%)

f) 6.8% on 4/4/2019 (predict 6.8%)

g) 6.6% on 9/25/2019 (predict 6.6%)

h) 6.6% on 12/20/2019 (predict 6.6%)

i) 6.4% on 5/20/2019 (predict 6.4%)

j) 6.2% on 10/21/2020 (predict 6.2%)

It should be pointed out that all of his 10 predicted HbA1C values match 100% with his lab-tested HbA1C values.

The author selected nine periods of almost equal length with ~5 months each, then observed their measured A1C changes (variances) against the previous period as follows:

a. Period A (4/1/2017 - 8/31/2017): -0.6%

b. Period B (9/1/2017 - 1/31/2018): +0.8%

c. Period C (2/1/2018 - 6/30/2018): -0.4%

d. Period D (6/29/2018 - 10/22/2018): +0.1%

e. Period E (10/22/2018 - 4/4/2019): +0.2%

f. Period F (4/4/2019 - 9/25/2019): -0.2%

g. Period G (9/25/2019 - 12/20/2019): +0.0%

h. Period H (12/20/2019 - 5/20/2020): -0.2%

i. Period I (5/20/2020 - 10/21/2020): -0.2%

He applied his developed GH-Method: math-physical medicine approach along with the following seven contribution factors of HbA1C:

(1) A1C variances contributed by FPG between 15% to 35%, where he used 25% in his calculation for this article.

(2) FPG variance due to weight change with ~77% contribution.

(3) Colder weather impact on FPG with a decrease of each Fahrenheit degree caused 0.3 mg/dL decrease of FPG.

(4) A1C variances contributed by PPG between 65% to 85%, where he used 75% in his calculation for this article.

(5) PPG variance due to carbs/sugar intake with ~39% weighted contribution on PPG.

(6) PPG variance due to post-meal walking with ~41% weighted contribution on PPG.

(7) Warm weather impact on PPG with an increase of each Fahrenheit degree caused 0.9 mg/dL increase of PPG [7].

It should be noted that his developed mathematical HbA1C prediction model is based on different weighted ratio for the previous 4-month glucose data, instead of the standard concept of the three-month average glucose for A1C with equal weighting factors. He chose 120 days for his HbA1C calculation which is based on the fact that the average human red blood cells (RBC), after differentiating from erythroblasts in the bone marrow, are released into the blood and survive in circulation for approximately 115 days.

In 2019, he developed the following simple linear equation for PPG prediction:

Predicted PPG = (measured FPG * 0.97) + (carbs/sugar intake amount * GH-modulus) - (post-meal walking K-steps * 5) Where 97% of FPG can be served as the baseline PPG. In 2010, after re-arranging the above equation into the following two new terms with a newly defined coefficient, the “GH-modulus”:

X = carbs/sugar amount

Y = measured PPG - (FPG * 0.97) + (post-meal walking k-steps * 5)

where X functions as the input, stress, or stimulator on the liver, and Y functions as the output, strain, or consequence from the liver. Both X input and Y output are related to each other through the coefficient of GH-modulus, as shown below:

GH-modulus = (Y output) / (X input) in endocrinology of biomedical science and

Young’s modulus (E) = stress / strain in linear elasticity of engineering strength of materials The author has applied this linear elastic glucose theory in his PPG calculation for estimating his HbA1C value in the ninth period. Please note that other than his acquired biomedical knowledge and his findings from previous research work, there are no other complicated or sophisticated mathematical tools being used in this analysis.

Result

Based on the author’s numerous publications of HbA1C contributions by FPG and PPG, along with the prediction models of these two glucoses and HbA1C, a summarized chart of these HbA1C values over nine periods from 4/1/2017 to 10/21/2020 are observed in Figure 1. This long period of ~3.5 years, ~43 months, 1,299 days are divided into nine periods of almost equal length of 4.6 months. Although his calculated daily A1C data and curves are fluctuating, the 10 lab-checkup dates with two sets of A1C values (predicted A1C and lab-tested A1C) are identical to each other.

Figure 2 shows the step-by-step background data table of Period I. During this time, his primary input data for the “linear elastic glucose equation” are:

Average FPG = 100.84 mg/dL

Average carbs = 12.24 grams

GH-modulus = 3.9 [7]

Averaged walking = 4.122 k-steps

Predicted PPG = (measured FPG * 0.97) + (carbs/sugar intake amount * GH-modulus) - (post-meal walking K-steps * 5)

Therefore,

Predicted average PPG in Period I

= (100.84*0.97)+(12.24*3.9)-(4.122*5)

= 125mg/dL

This value has been used in the calculation of obtaining the 6.2% HbA1C value in the ninth period. Figure 3 depicts his weight, carbs/sugar intake, post-meal walking, sensor FPG, and sensor PPG in Period I from 5/20/2020 to 10/21/2020.

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Conclusion

The author focused on nine periods over 1,299 days. It contains 3,897 meal data, including key contribution factors such as carbs/sugar intake, post-meal exercise, weather, and more. This study demonstrated a high degree of accuracy for the calculation and prediction of the patient’s forthcoming HbA1C value by using the GH-Method: math-physical medicine approach. In this article, the author also utilized CGM sensor glucose data with AI-tuned conversion factor between glucose and HbA1C. Furthermore, he also implemented his developed linear elastic glucose behavior theory [7] for his PPG calculation in order to obtain a better estimation for the final HbA1C value.

Once the healthcare professionals and T2D patients understand the HbA1C mathematical prediction method, then the overall diabetes condition for the patient can be easier to control. The purose for this research paper is to help people with T2D by preventing further damage to their internal organs caused by elevated A1C values, before taking the laboratory test. If healthcare professionals and diabetes patients have an interest to delve deeper regarding the formation of tested glucose and mathematical predicted A1C, they should focus on the influential factors and their respective weighted contribution percentages described in the author’s previous papers.

Here is the summary:

a) The most important month which contributes to the A1C is the month prior to the lab test.

b) PPG contribute > 2/3 of HbA1C.

c) Body weight controls ~77% or more of the fasting plasma glucose (FPG) which contributes <1/3 of HbA1C; therefore, it is important to keep BMI below 25.

d) Carbs/sugar amount contributes ~39% to PPG. For T2D patients, it is safe to keep carbs/sugar intake amount below 15 grams per meal.

e) Post-meal walking steps contributes ~41% to PPG. It is recommended to maintain post-meal walking exercise around 4,000 steps after each meal.

f) A combined effort of diet and exercise controls ~80% to PPG formation.

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