SIR Model of Spread of Zika Virus Infections: ZIKV Linked to Microcephaly Simulations

An SIR model of Zika virus (ZIKV) spread is formulated that includes ZIKV infections to newborns. Analytically, the model has one disease free and one endemic equilibrium point. The free one is stable for some conditions when R0 and unstable when R0>1. In Brazil, when R0≈2>1 ZIKV infections expand and for R0 = 0.875R0) of the model. There are parameters for human-mosquito transmission and some for sexual-transmission factor. It appears that controlling spread of ZIKV infections by human-mosquito transmission may greatly reduce the value of R0.

Does Zika Really Have the Capacity to Affect the Nervous System and Cause Microcephaly or Intracranial Calcifications?

Although the Centers for Disease Control and Prevention (CDC) reports that brain abnormalities in infants with laboratory-confirmed Zika infection include microcephaly, disrupted brain growth, intracranial calcifications, and abnormal eye findings—it is not known presently if the Zika virus itself causes any of these. In a recent 2016 review of Zika dealing with possible brain abnormalities appearing with Zika, Melo et al. mention that among the Flaviviruses, which Zika is, such brain insults and pathologic findings are practically unheard of. Melo et al. conclude that until more cases are diagnosed and more histopathological proofs are obtained, the possibility of other causes besides Zika cannot be ruled out. This paper considers just such other possible causes that have, to this point, escaped general notice. The Aedes aegypti and other Aedes species can transmit tiny viral-like, cell-wall-deficient mycobacterial forms, independent of viruses, yet prevalent in the very same Rhesus Monkey used in the original 1952 Zika communication—which spoke of “A filterable transmissible agent”. In addition, the universal fetal prenatal vaccination of Brazilian neonates is considered, strongly discouraged by The Royal Children’s Hospital in Melbourne, which forbids BCG vaccination of pregnant women and those immunosuppressed or already having tuberculosis (TB) or AIDS. And finally thought is focused on the prime candidate itself, towards explaining what an alternative cause for “Zika” might look like—an infectious agent with transmissible, filterable, viral-like forms. One which can be transmitted by the very same Aedes mosquitoes that carry Zika—one that is neurotrophic, and extremely prevalent in Brazil—and that can disrupt brain growth, cause microcephalus, cause a fever, is sexually transmissible, instigates Guillain-Barré syndrome and causes cranial calcifications—the Mycobacterium tuberculosis complex, which includes the Mycobacterium africanum prevalent, yet completely ignored, in the Rhesus monkeys used in the original Zika study.

Development of Psychic Pain in the Context of Microcephaly and Abortion: Systematic Review and Meta-Analysis

Background: In the year of 2015, evidence of a relation between Zika virus and the development of microcephaly in pregnant women who acquired the infection started to come up. Thus, it is extremely necessary that the analysis of the affliction affects these women in a biopsychosocial context, in order to discuss and comprehend in a more reliable manner the affection from the perception of the disease, origin, and psychic pain mechanisms. Methods: Systematic review with meta-analysis, using the PRISMA protocol. The study period was 2016 and the keywords included “microcephaly” and “abortion”, one at a time and then combined with the Boolean operator “AND.” The statistical analysis was done using the BioEstat 5.0 program. Calculation was based on an adjustment of Mantel-Haenszel random effect. Results: 41,046 registrations were found. Of this total, 40,992 articles were excluded because they only mentioned the fact or referred to spontaneous abortion, did not analyze abortion on the eyes of microcephaly, only treated with Zika virus, or were repeated. Limitations: Psychic pain and suffering need studies in the mother/son/disease relation, which were not found in the databases. The article was based on other sources. Conclusions: The pains vary in different areas of the female life, since internal conflicts, gender violence, stress, fear, insecurity, psychologic torture, grieve, loneliness, among other kinds of psychic suffering. More studies on psycho-emotional themes need to be promoted to discuss the female suffering on a wider vision, closer to the reality faced by these women.

Research progress of the causal link between Zika virus and microcephaly

Zika virus (ZIKV) was an emergent flavivirus transmitted by Aedes genus mosquitoes and made an explosive outbreak in Latin America in 2015. A few months later, an obvious increase in the number of microcephaly neonates has been observed, which might be related to ZIKV infection during the mothers’ pregnancy. Since then, researchers in many countries and territories have been working on the causal link between ZIKV and microcephaly and have made a number of achievements. To summarize the most recent evidence and the contribution of Chinese researchers on this issue, and to provide perspectives and challenges for future studies, we reviewed the literature of both microcephaly and ZIKV. Based on previous research results, ZIKV has been preliminarily proved to be the direct cause of microcephaly in newborns and Chinese researchers have made many important discoveries in the pathogenesis of microcephaly. Even so, future researches should also further investigate the mechanism of ZIKVrelated microcephaly to advance the development of therapeutic and preventive strategies.

A Model for the Risk of Microcephaly Induced by the Zika Virus (ZIKV)

It has been introduced and analyzed a mathematical model based on integral equations, which turns into a dynamical system of non-linear differential equations to account for the risk of microcephaly incidence caused by the Zika virus. A specific pregnant women susceptible group has been accounted for. The epidemic threshold (basic reproduction number) has been obtained by implementing the next generation matrix method. A sensitivity analysis with respect to each parameter has been applied to that threshold. Finally, the incidence to the exposure is obtained by performing several system simulations.

WDR62-deficiency Causes Autism-like Behaviors Independent of Microcephaly in Mice

Brain size abnormality is correlated with an increased frequency of autism spectrum disorder(ASD)in offspring.Genetic analysis indicates that heterozygous mutations of the WD repeat domain 62(WDR62)are associated with ASD.However,biological evidence is still lacking.Our study showed that Wdr62 knockout(KO)led to reduced brain size with impaired learning and memory,as well as ASD-like behaviors in mice.Interestingly,Wdr62 Nex-cKO mice(depletion of WDR62 in differentiated neurons)had a largely normal brain size but with aberrant social interactions and repetitive behaviors.WDR62 regulated dendritic spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons.Finally,we revealed that retinoic acid gavages significantly alleviated ASD-like behaviors in mice with WDR62 haploinsufficiency,probably by complementing the expression of ASD and synapse-related genes.Our findings provide a new perspective on the relationship between the microcephaly gene WDR62 and ASD etiology that will benefit clinical diagnosis and intervention of ASD.

Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like （ASPM related primary） microcephaly disease

The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial （RG） and outer radial glial （oRG） cells in the ventrJcular zone （VZ） and subventricular zone （SVZ） of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in culture dishes successfully, however we demonstrate a new paradigm that recapitulates neocortical development process with VZ, OSVZ formation and the lamination organization of cortical layer structure. In addition, using patient.specific induced pluripotent stem cells （iPSCs） with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.

Available Evidence of Association between Zika Virus and Microcephaly

Objective：To clarify the possible association between the Zika virus （ZIKV） and microcephaly and understand where we are in terms of research and the debate on the causation between mild maternal clinical features and severe fetal microcephaly.Data Sources：We did a comprehensive literature review with the keywords ＂zika＂ and/or ＂microcephaly＂ from inception to May 27,2016,with PubMed.Study Selection：Studies were included and analyzed if they met all of the following criteria：＂probable or confirmed infant microcephaly＂ and ＂probable or confirmed ZIKV infection among mothers or infants＂.Results：We emphasize the diagnosis of ZIKV infection,including maternal clinical manifestations,maternal and fetal laboratory confirmation,and possible autopsy if need.Other confounders that may lead to microcephaly should be excluded from the study.We presented the results from clinical manifestations of ZIKV infection,testing methods evolving but the mechanism of microcephaly uncertain,flexible definition challenging the diagnosis ofmicrocephaly,and limited causal reference on pregnant women.We made analog comparison of severe acute respiratory syndrome and chikungunya virus in terms of DNA mutation and global movement to provide further research recommendation.The chance of catch-up growth may decrease the number of pervious ＂diagnosed＂ microcephaly.Conclusions：There are some evidence available through mice models and direct isolation of ZIKV in affected pregnancies on kindly causal relationship but not convincible enough.We analyzed and presented the weakness or limitation of published reports with the desire to shed light to further study directions.

A case report of microcephaly and refractory West syndrome associated with WDR62 mutation

The autosomal recessive form of primary microcephaly(MCPH)is a rare disorder characterized by microcephaly with variable degree of intellectual disability.WDR62 has been reported as the second causative gene of MCPH2.West syndrome is a severe epilepsy syndrome composed of the triad of spasms,hypsarrhythmia,and mental retardation.There are limited clinical reports regarding WDR62 mutation and West syndrome.Here we report a boy who was identified with WDR62 mutation and was followed up from age 3 months to 5 months and 14 days.He had the first seizure as the classic epileptic spasm at the age of 3 months.Psychomotor retardation was noted before the seizure occurred.The head circumference was 38.5 cm(SD 2.6)when he was 4 months old,no dysmorphic facial features were observed.He couldn’t support his head steadily or turn over.He was able to laugh when tricked by the parents,but couldn’t track the sound and light.At the early stage,the electroencephalogram showed multifocal discharges,which evolved into hypsarrhythmia one month later,and brain MRI showed developmental malformation of cerebral gyrus.Two heterozygous mutations were identified in WDR62 by whole exome sequencing c.1535G>A,p.R512Q and c.2618dupT,p.K874Qfs40.The patient was administrated with oral sodium valproate,nitrazepam,intramuscular adrenocorticotropic hormone for 2 weeks,and followed by prednisone,levetiracetam,topiramate and vigabatrin.However,there was no significant improvement on the seizure control after these treatments.According to the genetic report and clinical manifestation,we speculated that the WDR62 compound heterozygous mutation is responsible for the serious clinical phenotype.

Different Gene Networks Are Disturbed by Zika Virus Infection in A Mouse Microcephaly Model

The association of Zika virus(ZIKV)infection with microcephaly has raised alarm worldwide.Their causal link has been confirmed in different animal models infected by ZIKV.However,the molecular mechanisms underlying ZIKV pathogenesis are far from clear.Hence,we performed global gene expression analysis of ZIKV-infected mouse brains to unveil the biological and molecular networks underpinning microcephaly.We found significant dysregulation of the sub-networks associated with brain development,immune response,cell death,microglial cell activation,and autophagy amongst others.We provided detailed analysis of the related complicated gene networks and the links between them.Additionally,we analyzed the signaling pathways that were likely to be involved.This report provides systemic insights into not only the pathogenesis,but also a path to the development of prophylactic and therapeutic strategies against ZIKV infection.

Microcephaly prevalence after the 2015 to 2016 Zika outbreak in Tangará da Serra, Brazil: a population-based study

Objective::Prenatal infection with the Zika virus (ZIKV) can lead to congenital Zika syndrome (CZS), characterized by microcephaly and brain injury. However, there are questions regarding the prevalence of microcephaly/CZS after the ZIKV outbreak in defined geographic areas. This study aimed to identify adverse outcomes in live births of fetuses exposed in utero to the ZIKV, compared to unexposed births, as well as maternal sociodemographic, delivery, and birth characteristics.Methods::Here, we conducted a cross-sectional observational study to investigate the characteristics of all live births in the city of Tangará da Serra, Mato Grosso, Brazil, in 2016, after the outbreak of ZIKV infection in late 2015. All live births of children to women residing in the municipality of Tangará da Serra between January 1 and December 31, 2016, were evaluated, and head circumference was measured at birth and after 24 hours. Children born with microcephaly or a maternal history of confirmed or suspected prenatal ZIKV infection were evaluated by a multidisciplinary team. The outcomes of the exposed and non-exposed children were compared. Prevalence ratios and their respective 95% confidence intervals were calculated for sociodemographic, delivery, and live birth characteristics.Results::Of 1,441 live births, 106 (7.3%) were from mothers with confirmed or highly probable exposure to ZIKV. The prevalence of severe congenital microcephaly (41.7/10,000) in Tangará da Serra in 2016 was ten-fold higher than that in Latin America before 2015.Conclusion::This study may serve as a model to investigate possible outbreaks of infections in a defined geographical space in the future.

Epigenetic and transcriptional landscapes during cerebral cortex development in a microcephaly mouse model

The cerebral cortex is a pivotal structure integral to advanced brain functions within the mammalian central nervous system.DNA methylation and hydroxymethylation play important roles in regulating cerebral cortex development.However,it remains unclear whether abnormal cerebral cortex development,such as microcephaly,could rescale the epigenetic landscape,potentially contributing to dysregulated gene expression during brain development.In this study,we characterize and compare the DNA methylome/hydroxymethylome and transcriptome profiles of the cerebral cortex across several developmental stages in wild-type(WT)mice and Mcph1 knockout(Mcph1-del)mice with severe microcephaly.Intriguingly,we discover a global reduction of 5′-hydroxymethylcytosine(5hmC)level,primarily in TET1-binding regions,in Mcph1-del mice compared to WT mice during juvenile and adult stages.Notably,genes exhibiting diminished 5hmC levels and concurrently decreased expression are essential for neurodevelopment and brain functions.Additionally,genes displaying a delayed accumulation of 5hmC in Mcph1-del mice are significantly associated with the establishment and maintenance of the nervous system during the adult stage.These findings reveal that aberrant cerebral cortex development in the early stages profoundly alters the epigenetic regulation program,which provides unique insights into the molecular mechanisms underpinning diseases related to cerebral cortex development.

Zika virus,a pathway to new challenges

The current Zika outbreak is largest of its kind with 1.4 million cases in Brazil alone.World Health Organization declared the current outbreak as the public health emergency of international concerns.The major route of Zika virus transmission is mosquito bites.Sexual transmission and monkey bites are also observed in few cases.There is dire need to evaluate the other routes of transmission like blood transfusion,lactation and contact with body fluids.Zika virus is infecting infants,not only causing microcephaly but also creating number of complications resulting in bad outcomes of pregnancy.In Brazil alone,4 000 cases of microcephaly have observed during the current outbreak.The incidence of Guillian-Barre(GB) syndrome is also observed during the current Zika virus outbreak.GB syndrome is acute medical condition leading the patients to death due to weakness of respiratory muscles or can cause the life time disability.There is no anti-viral drug or vaccine available for Zika virus.Zika infection can be prevented by using mosquito repellents,mosquito nets,cooling rooms by air conditions and wearing full sleeves or permethrin treated clothes.The current outbreak of Zika has not only affected the health care but also caused great economic loss.Estimated loss in Latin America and Caribbean is US$3.5 billion.United Nation's sustainable development goal 3.d stresses the strengthening of early warning,risk reduction and management of national and global health risks.The world will keep on facing new challenges in the form of Ebola or Zika;there is strong need to prepare ourselves for any disease outbreak.

Zika virus infection, transmission, associated neurological disorders and birth abnormalities: A review of progress in research, priorities and knowledge gaps

On February 1, 2016, the World Health Organization declared that the cluster of microcephaly cases and other neurological disorders constitute public health emergency of international concern. Furthermore, few studies demonstrated that there was an increased evidence of causal relationship of Zika virus(ZIKAV) infection and microcephaly, birth abnormalities and neurological disorders such as Guillain–Barre′ syndrome.ZIKAV transmission occurs mainly by the bite of infected mosquitos(Aedes species), but there are also reports that infections could occur via the placenta, breast milk, saliva,blood transfusion and sex. This article reviews the global efforts, progress in scientific research to understand the pathogenesis of ZIKAV infection & disease, clinical presentations, congenital transmission and autoimmune neurological disorders. The paper further explores the knowledge gaps, future priority research agenda for strategic response including vector control and prevention. We conducted a systematic literature review to synthesise available evidence on ZIKAV infection and its vector and host interaction from electronic databases.

Zika virus infection and its emerging trends in Southeast Asia

Zika virus is a mosquito-borne flavivirus that represents a public health emergency at the ongoing epidemic.Previously,this rare virus was limited to sporadic cases in Africa and Asia until its emergence in Brazil,South America in 2015,where it rapidly spread throughout the world.Recently,a high number of cases were reported in Singapore and other Southeast Asia countries.A combination of factors explains the current Zika virus outbreak although it is highly likely that the changes in the climate and high frequency of travelling contribute to the spread of Aedes vector carrying the Zika virus mainly to the tropical climate countries such as the Southeast Asia.The Zika virus is known to cause mild clinical symptoms similar to those of dengue and chikungunya and transmitted by different species of Aedes mosquitoes.However,neurological complications such as Guillain-Barrésyndrome in adults,and congenital anomalies,including microcephaly in babies born to infected mothers,raised a serious concern.Currently,there is no specific antiviral treatment or vaccine available for Zika virus infection.Therefore,international public health response is primarily focused on preventing infection,particularly in pregnant women,and on providing up-to-date recommendations to reduce the risk of non-vector transmission of Zika virus.

Biological and historical overview of Zika virus

The recent outbreak of the Zika virus attracts worldwide attention probably because the most recently affected country(Brazil) will host the 2016 Olympic Game. Zika virus infected cases are now spreading to many other countries and its infection might be linked to some severe medical sequelae. Since its first isolation from the infected monkey in 1947 in Uganda, only a few studies had been taken until recent outbreak. According to the history of referenced publications, there is a 19-year gap from 1989 to 2007. This might be because only mild diseases were diagnosed from Zika virus infected populations. Obviously, the recent reports that Zika virus infection is probably associated with microcephaly of the neonates makes us reevaluate the medical significance of the viral pathogen. It can be transmitted sexually or by mosquito biting. Sexual transmission of the Zika virus distinguishes it from other members of the Genus Flavivirus. Detailed information of the Zika virus is needed through a thorough investigation covering basic, epidemical, subclinical and clinical studies. Here, we reviewed the published information of Zika virus.

The Global Impact of the Zika Virus Pandemic: The Importance of Emergency Preparedness

The 2015 outbreak of Zika virus in Brazil led to a significant increase of neonatal microcephaly. While Zika virus was identified in Africa in the 1940s and was noted to be present in Asia, it was not until 2007 that there was a significant shift in the behavior of the virus. Reasons for this change in Zika virus behavior and pathogenesis could be due to a change in the virulence of the virus, and a new ability to infect the human host. Additionally, the changing habitat of mosquitoes along with increasing urbanization and changes of human habitats has increased the risk of Zika virus exposure. This review summarizes the response to the Zika pandemic and recommendations for interventions through the lens of the Sendai Framework for disaster risk reduction. Emergency preparedness focuses on lessening the likelihood and the impact of disasters. Preparedness encompasses the actions of mitigation, prevention, response, and recovery.

A Case of Complete Neu-Laxova Syndrome: Report and Literature Review

Neu-Laxova syndrome (NLS) is a rare autosomal recessive and early fatal disease. It is a complex entity that includes intrauterine growth retardation, abnormal facial structure, limb and skeletal abnormalities, and ichthyosis and severe malformations of the central nervous system. We report a rare case of recurrence of Neu-Laxova syndrome in a 32-year-old pauciparous woman, which occurred after a first cousin’s consanguineous marriage. Typical ultrasound findings included hydramnios, severe intrauterine growth restriction, craniofacial and central nervous system abnormalities such as ventriculomegaly. The newborn shows a terrible face with a usual craniofacial aspect, eyeball proptosis, puffy hands and feet, large bilateral cleft lip/palate, severe hall body ichthyosis. The overcome was fatal, the death occurred in less than one hour after birth. Consanguinity remains the most implicated cause which is high in developing countries. Prenatal serial ultrasound examinations with genetic counselling should be performed on high-risk pregnant women to terminate affected pregnancies.

Neurological manifestations of Zika virus infection

Zika virus(ZIKV) is a flavivirus(Flaviviridae family) transmitted mainly by Aedes mosquitoes. The virus was restricted to the African continent until its spread to south-east Asia in the 1980's, the Micronesia in 2007, the French Polynesia in 2013 and, more recently in the Americas in 2015, where, up to date, the World Health Organization(WHO) has estimated about 3-4 million total cases of ZIKV infection. During outbreaks in the French Polynesia and Brazil in 2013 and 2015, respectively, national health authorities reported potential neurological complications of ZIKV disease, chiefly an upsurge in Guillain-Barré syndrome, which coincided with ZIKV outbreaks. On the other hand, the emergence of ZIKV in Brazil has been associated with a striking increase in the number of reported cases of microcephaly in fetus and newborns, twenty times higher than in that reported in previous years. While investigations are currently assessing whether there is an actual association between neurological complications and ZIKV infections, the evidence was enough worrisome for WHO to declare a public health emergency of international concern. Here we present an updated review addressing what is currently known about the possible association between ZIKV infection and the development of severe neurological disorders.

Zika virus infections:an overview of current scenario

Zika virus(ZIKV) was discovered more than half a century ago,recently it has gained unprecedented attention by the global health community.Until 2007,only 14 cases of human ZIKV infections were reported around the globe,while during the current outbreak,estimated cases mounted to approximately 1.5 million in Brazil alone,the virus was disseminated to wider South-American territories and travel-associated ZIKV infections were reported in USA,Europe and recently in China.ZIKV infections remain asymptomatic in approximately 80% of the individuals,and no anti-viral treatments were recommended.Yet,neurological complications associated with the infections,such as infant microcephaly and Guillain-Barré syndrome are major cause of the concern.Although,based on small numbers of cases,existing evidence strongly supports an exclusive link of viral infection and observed neurological complications.However,much work remains to assign exact numbers of complications caused by ZIKV.Regarding its structural attributes ZIKV shows remarkable resemblance with dengue virus and West-Nile virus.Despite,genomes of different ZIKV strains have already been decoded;role of the viral components in infection process and particularly pathogenesis of the disease remain widely unclear.In vulnerable areas,most viable strategy to ensure public health safety is vector control and enhanced public awareness about the transmission of the disease.