Safe cigerette !!!

All of you may be awwstruck with this  term(safe cigerette). !! Can any one tell me how and Why ?

Novel approaches in hair cuticle research

Info is under processing

Role of Nitric oxide in ageing process

First of all, I want to put front a statement that ageing and process of ageing will be a very challenging part in research which would be very synergic aspect in research on diseases, and common disorders like erectile dysfunction.

Nitric oxide and aging of LHRH and oxytocin systems

While the involvement of NO in hypothalamic regulation of LHRH and oxytocin release is becoming accepted, the putative role of NO as a potential proapoptotic factor for LHRH and oxytocin neurons has not been extensively studied until recently. Vernet et al. suggested that increased expression of iNOS may lead to neurotoxicity, which can be involved in impaired pulsatile LHRH secretion, as well as acts as a possible inducer of age-associated neuronal loss. Recent findings of aging-related iNOS induction in LHRH and oxytocinergic neurons  support the view that iNOS expression is associated with the previously observed decrease in the number of LHRH] and oxytocin cells. This suggests an additional, possibly destructive action of NO on the hypothalamic neuroendocrine pathways. The endogenous factors that induce iNOS expression in aging LHRH and oxytocinergic hypothalamic neurons are unknown. Nevertheless, indirect observations seem to indicate cytokines as potential regulators of the age-related iNOS induction. Earlier studies revealed that TNF-γ in the cerebrospinal fluid and peripheral circulation and IL-1β and interferon-γ were increased in monocytes by aging. Cytokines were found to be synthesized in the hypothalamus. Accordingly, observation that the exogenous administration of interleukin 1-α can block the nitrergic control of LHRH release both in vivo and in vitro  through iNOS induction, additionally implicates cytokines in aging-related control of iNOS expression in the hypothalamic neurons.

Bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause inducible (i) NO synthase (NOS) synthesis, which in turn produces massive amounts of nitric oxide (NO). NO, by inactivating enzymes and leading to cell death, is toxic not only to invading viruses and bacteria, but also to host cells. Injection of LPS induces interleukin (IL)-1beta, IL-1alpha, and iNOS synthesis in the anterior pituitary and pineal glands, meninges, and choroid plexus, regions outside the blood-brain barrier. Thereafter, this induction occurs in the hypothalamic regions (such as the temperature-regulating centers), paraventricular nucleus (releasing and inhibiting hormone neurons), and the arcuate nucleus (a region containing these neurons and axons bound for the median eminence). Aging of the anterior pituitary and pineal with resultant decreased secretion of pituitary hormones and the pineal hormone melatonin, respectively, may be caused by NO. The induction of iNOS in the temperature-regulating centers by infections may cause the decreased febrile response in the aged by loss of thermosensitive neurons. NO may play a role in the progression of Alzheimer's disease and parkinsonism. LPS similarly activates cytokine and iNOS production in the cardiovascular system leading to coronary heart disease. Fat is a major source of NO stimulated by leptin. As fat stores increase, leptin and NO release increases in parallel in a circadian rhythm with maxima at night. NO could be responsible for increased coronary heart disease as obesity supervenes. Antioxidants, such as melatonin, vitamin C, and vitamin E, probably play important roles in reducing or eliminating the oxidant damage produced by NO.

Over the past ten years despite a slight increase in life expectancy and a decrease in all causes of deaths, the percent of the US population with heart disease, cancer, diabetes, hypertension and obesity have all increased.  According to the 2010 National Center for Health Statistics Report life expectancy has increased 1.1 years over the past decade going from 76.8 to 77.9.  All causes of death adjusted for age have decreased by 12.5% from 2000 to 2008.  However, the percent of the population 18 years and over with heart disease has risen from 10.9% to 11.8% and the population 65 and over has risen from 29.6% to 31.7% over the same 8 years.  Diabetes has gone from 8.5% of the population 20 years and older to 11.9% in just 8 years.  The percent of people with hypertension has risen from 28.9% to 32.6%.  Cancer has followed a similar trend going from 4.9% to 6.1% in patients 18 years old and over.  These data suggests that although people are living longer, they are not living better or they are living with a chronic disease that requires care and treatment.  It is the care and treatment of these chronic patients that causes the enormous economic burden on the health care system and on the patients.  In fact from 2000 to 2008, total healthcare expenditures increased from $1.1 to $2.0 trillion dollars or from $4,032 to $6,411 per capita. 

This trend is also reflective of the global population where 17.3 million people died from cardiovascular disease in 2008 and an estimated 23.6 million expect to die in 2030.  Whereas access to medical care and better management of certain diseases have improved, it is clear that the incidence and treatment of chronic disease is not improving.  The discovery of nitric oxide (NO) production in the human body is a relatively new advancement of modern medicine.  Unfortunately is still not at the forefront of modern medicine.  There are no standard laboratory measurements of NO in the clinical setting and no prescription therapies to safely and effectively restore NO homeostasis despite being recognized as the earliest indicator of a number of different chronic diseases.  We also now know that modern medical practices and western lifestyles actually lead to a decrease in NO homeostasis in the patients from pediatrics to geriatrics.   

The discovery of nitric oxide (NO) in the 1980s as a vasodilator and signaling molecule in the cardiovascular system, immune system and nervous system marked a point of inflexion in medicine.  The discovery that a simple molecule produced as a gas could perform so many essential and critical biological and physiological functions established a new paradigm in cell signaling.  Now almost 30 years later, endothelial dysfunction or insufficient NO production is recognized as the earliest event in the onset and progression of a number of chronic diseases.  Loss of endothelial NO function is associated with several cardiovascular disorders, including atherosclerosis, which is due either to decreased production or to increased degradation of NO.  A number of studies provide evidence that endothelial NO dysfunction is not only associated with all major cardiovascular risk factors, such as hyperlipidemia, diabetes, hypertension, smoking and severity of atherosclerosis, but also has a profound predictive value for the future atherosclerotic disease progression.  There is becoming a clear and convincing association with Alzheimers disease (AD) and NO.  Decreased levels of nitrite and nitrate (NOx) has been detected in patients with different forms of dementia especially AD.  The exact etiology of sporadic AD is unclear, but it is interesting that cardiovascular risk factors including hypertension, hypercholesterolemia, diabetes mellitus, aging, and sedentary lifestyle are associated with higher incidence of AD (all conditions associated with NO insufficiency).  The link between cardiovascular risk factors and AD has yet to be identified; however, a common feature is endothelial dysfunction, specifically, decreased bioavailability of NO.  Insulin has vasodilator actions that depend on endothelium-derived NO.  Type 2 diabetes mellitus accounts for 80-90% of diabetes cases in the US and is associated with an increased risk for a number of life-threatening complications.  These include heart disease and stroke, high blood pressure, blindness, kidney disease, nervous system disease, amputation, and complications of pregnancy and surgery.  Probably not coincidental, all of the above complications are associated with insufficient NO production. Endothelial dysfunction with reduced NO generation and bioavailability plays a key role in the pathogenesis of diabetic vascular disease and complications and likely serves as the key link between metabolic disorders and cardiovascular disease (CVD). 

While the medical literature is rich with clear association and almost causal relationships between NO and the onset and progression of chronic disease, it is not commonly considered in the treatment or management of patients.  In fact, some prescription medications will reduce NO availability, many lifestyle and dietary habits that lead to chronic disease are linked to insufficient NO production or availability and the standard of care for patients in intensive care units or hemodialysis patients leads to a complete removal of NO functionality in the patients.  

Despite NO being recognized by the scientific and medical community as one of the most important molecules produced within the body and being named “Molecule of the Year” by Science in 1992 and a Nobel Prize in Physiology or Medicine awarded for its discovery, there are currently only 3 FDA approved products on the market directly related to NO: 1) organic nitrates, such as nitroglycerin for the treatment of acute angina (these have been used for centuries long before the discovery of NO); 2) inhaled NO therapy for neonates for treatment of pulmonary hypertension due to underdeveloped lungs; and 3) phosphodiesterase inhibitors, such as sildenafil, which do not directly affect NO production but act through affecting the downstream second messenger of NO, cyclic guanosine monophosphate (cGMP).  With the knowledge gained in the physiology and pharmacology of NO, better and new drugs are being designed not only for cardiovascular diseases but for neurological and several other disorders as well. 

One of the most predictive indicators for insufficient NO production is age.  As we age we lose our ability to produce NO through the L-arginine pathway.  Aging and hypertension are well-documented cardiovascular risk factors.  Most of the functional and structural vascular alterations that lead to cardiovascular complications are similar in aging and hypertension [20].  Moreover, these vascular changes associated with essential hypertension are generally considered to be an accelerated form of the changes seen with aging.  When we are young and healthy, the endothelial production of NO through L-arginine is efficient and sufficient to produce NO; however, as we age we lose our ability to synthesize endothelial derived NO.  Most of the works on the activity of NO in cells and tissues agree that the bioavailability or the generation of NO decreases with aging.  It has been proposed that superoxide can scavenge NO to form peroxynitrite and thereby reduce its effective concentrations in cells.  It has also been reported that there is decreased nitric oxide synthase (NOS) expression with aging both in constitutive and inducible isoforms.  Berkowitz et al.  observed the upregulation of arginase (an enzyme that degrades the natural substrate for NOS, L-arginine) in aged blood vessels and the corresponding modulation of NOS activity.  Taddei et al.  have shown that there is a gradual decline in endothelial function due to aging with greater than 50% loss in endothelial function in the oldest age group tested as measured by forearm blood flow assays.  Egashira et al.  reported more dramatic findings in the coronary circulation of aging adults whereby there was a loss of 75% of endothelium-derived nitric oxide in 70-80 year old patients compared to young, healthy 20 year olds.  Vita and colleagues demonstrated that increasing age was one predictor of abnormal endothelium-dependent vasodilation in atherosclerotic human epicardial coronary arteries. Gerhard et al., concluded from their 1996 study that age was the most significant predictor of endothelium-dependent vasodilator responses by multiple stepwise regression analysis.  Collectively, these important findings illustrate that endothelium-dependent vasodilation in resistance vessels declines progressively with increasing age.  This abnormality is present in healthy adults who have no other cardiovascular risk factors, such as diabetes, hypertension, or hypercholesterolemia. Most of these studies found that impairment of endothelium-dependent vasodilation was clearly evident by the fourth decade. In contrast, endothelium-independent vasodilation does not change significantly with aging, demonstrating that the responsiveness to NO does not change only the ability to generate it.  These observations enable us to conclude that reduced availability of endothelium-derived NO occurs as we age.  Being able to diagnose and intervene early on is the key to optimal health and disease prevention. 

 

What is Pharmacology? And How is it related to daily life?

The Mystery Disease !!!

Mystery disease !!!! The name itself has the meaning,"mystery" that means neither any one does know the cause, nor even the name of the disease. Many diseases are throwing a challenge for researchers and doctors all around the world. Most of these diseases are so exotic and dangerous that we doesnt' even know the root cause. Such diseases when hit the humans, will cause a serious nebulic situation where we cant proceed with the treatment.

Can any one dare to imagine? , A small cute little girl who is always indulged in fun and laughter, who doesnt' know anything other than love and affection is now prone to such a condition where she has left nothning to her parents except agony.

Brianna Skriver was a bouncy, blond "wild child" who loved playing dress-up and jumping rope with her fellow 5-year-olds, according to her mom. But a mysterious illness swiftly stole her ability to walk and talk, leaving her family desperate for answers.
It all started at a soccer game.
"I noticed she was running differently and falling a lot," said Skriver's mom, Tammy Skriver, a single mother of two in Central Florida. "When we got home I said, 'Show mommy how you skip' -- she loved to skip -- and she couldn't do it."
Skriver became increasingly lethargic, and soon began drooling and wetting the bed. Within a year, she could no longer walk. And by age 9, she needed a feeding tube. But countless blood tests, biopsies, brain scans and spinal taps have failed to uncover the cause of her ever-worsening condition.
"Doctors say it's a neurodegenerative disorder, but they don't know what it is or why it's happening," said Tammy Skriver, talking through tears. "It's excruciating. I get down on my knees all the time and just pray this is a dream."
 Now doctors arent' able to judge what is the root cause of this condition.
This is high-time for researchers to take a forward step in research and i strongly urge that governments all around the world should endorse the research firms and encourage in research.

Ebola !! The Lethal Ailment with 90% mortality rate

Ebola virus disease (EVD) or Ebola hemorrhagic fever (EHF) is the human disease which may be caused by any of four of the five known ebola viruses. These four viruses are: Bundibugyo virus (BDBV), Ebola virus (EBOV), Sudan virus (SUDV), and Taï Forest virus (TAFV, formerly and more commonly Côte d'Ivoire Ebola virus (Ivory Coast Ebolavirus, CIEBOV)). EVD is a viral hemorrhagic fever (VHF), and is clinically nearly indistinguishable from Marburg virus disease (MVD).

Symptoms :
EVD/EHF is clinically indistinguishable from Marburg virus disease (MVD), and it can also easily be confused with many other diseases prevalent in Equatorial Africa, such as other viral hemorrhagic fevers, falciparum malaria, typhoid fever, shigellosis, rickettsial diseases, cholera, gram-negative septicemia or EHEC enteritis. The most detailed studies on the frequency, onset, and duration of EVD clinical signs and symptoms were performed during the 1995 outbreak in Kikwit, Zaire (EBOV) and the 2007–2008 outbreak in Bundibugyo, Uganda (BDBV). The mean incubation period, best calculated currently for EVD outbreaks due to EBOV infection, is 12.7 days (standard deviation = 4.3 days), but can be as long as 25 days. EVD begins with a sudden onset of an influenza-like stage characterized by general malaise, fever with chills, arthralgia and myalgia, and chest pain. Nausea is accompanied by abdominal pain, anorexia, diarrhea, and vomiting. Respiratory tract involvement is characterized by pharyngitis with sore throat, cough, dyspnea, and hiccups. The central nervous system is affected as judged by the development of severe headaches, agitation, confusion, fatigue, depression, seizures, and sometimes coma.
Cutaneous presentation may include: maculopapular rash, petechiae, purpura, ecchymoses, and hematomas (especially around needle injection sites). Development of hemorrhagic symptoms is generally indicative of a negative prognosis. However, contrary to popular belief, hemorrhage does not lead to hypovolemia and is not the cause of death (total blood loss is low except during labor). Instead, death occurs due to multiple organ dysfunction syndrome (MODS) due to fluid redistribution, hypotension, disseminated intravascular coagulation, and focal tissue necroses.

Treatment:
There is currently no FDA-approved ebolavirus-specific therapy for EVD. Treatment is primarily supportive in nature and includes minimizing invasive procedures, balancing fluids and electrolytes to counter dehydration, administration of anticoagulants early in infection to prevent or control disseminated intravascular coagulation, administration of procoagulants late in infection to control hemorrhaging, maintaining oxygen levels, pain management, and administration of antibiotics or antimycotics to treat secondary infections. Hyperimmune equine immunoglobulin raised against EBOV has been used in Russia to treat a laboratory worker who accidentally infected herself with EBOV—but the patient died anyway. Experimentally, recombinant vesicular stomatitis Indiana virus (VSIV) expressing the glycoprotein of EBOV or SUDV has been used successfully in nonhuman primate models as post-exposure prophylaxis. Such a recombinant post-exposure vaccine was also used to treat a German researcher who accidentally pricked herself with a possibly EBOV-contaminated needle. Treatment might have been successful as she survived. However, actual EBOV infection could never be demonstrated without a doubt. Novel, very promising, experimental therapeutic regimens rely on antisense technology. Both small interfering RNAs (siRNAs) and phosphorodiamidate morpholino oligomers (PMOs) targeting the EBOV genome could prevent disease in nonhuman primates.

Referal sources and evidences of this disease:

The above video is about ebola virus outbreak .

Case studies

Unrecognized Ebola Hemorrhagic Fever at

Mosango Hospital during the 1995

Epidemic in Kikwit, Democratic Republic

of the Congo:

On April 20, 1995, a 70-year-old nun, working

as a nurse in Kikwit General Hospital, was

admitted to Mosango General Hospital with a 5-

day history of fever, despite antimalarial

treatment. The day before hospitalization she

had profuse diarrhea, vomiting, high fever, and

severe agitation with delirium. On arrival, quiet

and apyretic, she complained of headache, loss of

appetite, and severe asthenia, but she walked to

her room without help. On examination, the only

abnormalities recorded were severe dehydration

and oral thrush-like lesions, raising a suspicion of

candidiasis. Pulse rate was 80/min and blood

pressure 120/80. Medical history included an

amebiasis liver abscess 15 years ago and chronic

coronaritis since 1990.

Electrocardiogram (ECG) abnormalities were

consistent with chronic diffuse ischemia. Laboratory

investigations showed the following values:

few trophozoites on a thick film; erythrocyte

sedimentation rate (ESR) 15 mm/h; bleeding time

(BT) 7½ min; coagulation time (CT) 9 min; and

white blood cells (WBC) 8.4x10

9/L (73% neutrophils,

23% lymphocytes, 2% eosinophils, 1%

basophils, 1% mastocytes). Urinalysis showed

proteinuria (++), hyaline cylinders (+++), 50

white cells per field, and hematuria (+). The

patient was perfused with 4L/day of glucose and

1.5 g of quinine. She was kept in a private room in

the nearby nuns’ convent.

Later during the day, high fever (40°C) and

severe diarrhea with melena developed; the pulse

rate was normal (80/min). Typhoid fever was

suspected despite the lack of hepatosplenomegaly;

Widal test was not available for

confirmation. Treatment was started with

intravenous (i.v.) amoxicillin (1g/6h during the

first 24 h and then 1g/4h) and i.v. chloramphenicol

(2g/24h). Subsequently, coagulation abnormalities

developed in addition to the melena;

vitamin K and epsilon amino caproic acid were

added to i.v. therapy. Watery vomits remained

frequent and abundant, and the patient’s

condition was unresponsive to treatment.

On hospitalization day 2, the clinical picture

remained the same, with severe asthenia,

anorexia, abundant blackish diarrhea, and

watery vomits. An intractable hiccup developed.

The fever remained in plateau around 40°C with

spikes. Obnubilation occurred during episodes of

high fever. Pulse and blood pressure remained

stable. ECG showed no modifications. Cutaneous

examination detected for the first time a

maculopapular rash and petechiae on flanks and

limbs, and the patient complained of gastric pain

for which the neurologic examination was

normal. Urine was abundant and clear.

On hospitalization day 3, high fever

continued, with some defervescence during

which the patient regained lucidity, although she

responded

only with monosyllables because of the

extreme asthenia and somnolence; diarrhea

persisted but without hemorrhage. The patient

had less vomiting. Laboratory data showed ESR

35 mm/h; BT 10 min; CT 12 min; WBC 12.6x10

9/L

(70% neutrophils, 24% lymphocytes, 2% eosinophils,

1% basophils, 3% mastocytes). During the

night, the patient maintained a high temperature,

still with temperature-pulse disparity. The

diagnosis of typhoid fever was questioned, and

other diagnostic possibilities were reconsidered

(shigellosis, mononucleosis); leukocytosis was

considered against the possibility of Ebola

hemorrhagic fever. Chloramphenicol was switched

to rifampicin (1,200 mg/24h).

On April 23, the patient’s status was

unchanged with fever, asthenia, and diarrhea.

Later in the day, her condition deteriorated:

petechiae could be seen on the entire body, and

for the first time, bruises and bleeding at

injection sites were observed and precluded

intramuscular injections. The patient had

bleeding cracks on the lips and diffuse bleeding in

the oral cavity (i.e., gums, tongue). The volume of

urine was low, and antibiotic therapy was

changed to cephalosporin.

On hospitalization day 5, hemorrhages increased,

and fever remained high until the end of

the day, when it started to normalize. Urine volume

was still low (verified by vesical catheter) despite

the i.v. rehydration of 4 L/day. Fresh blood

transfusion (300 ml) did not slow the hemorrhaging;

disseminated intravascular coagulation was

suspected, and heparin treatment was started.

The patient became comatose. The laboratory

results showed ESR 55mm/h and WBC 30.2x10

9/

L with an unchanged formula. No coagulation

was observed on BT and CT. Blood pressure fell

(80/50); the clinical status remained unchanged

until the patient’s death on April 25 at 10:00 a.m.

No special nursing precautions were taken

either during the hospitalization or after the

death, and the body was transferred to Kikwit to

be buried. On April 30, another nun who took care of

the index patient during the night of April 23

became ill with fever, headache, and myalgia. Over

the next few days, the second patient had a clinical

picture identical to that of the index patient,

including high fever, severe asthenia, vomiting,

hiccups, and diarrhea. On May 5, epistaxis and

coagulation abnormalities developed, followed by

other clinical signs of the hemorrhagic syndrome.

The second patient was transferred to Kikwit

General Hospital, where she died 6 days later. A

laboratory confirmation of Ebola hemorrhagic fever

was made on a blood specimen collected on May 5

and sent to Special Pathogens Branch (Centers for

Disease Control and Prevention, Atlanta, GA).

These cases of unrecognized Ebola hemorrhagic

fever were part of the hospital outbreak

that precipitated and mobilized international

community efforts (2). Retrospectively, the

clinical symptoms observed were typical of Ebola

hemorrhagic fever (3,4) and were described again

in subsequent patients during this outbreak (5).

In tropical Africa, the presence of hemorrhagic

symptoms in the course of a febrile illness should

raise the possibility of one of the viral hemorrhagic

fever diseases. In viral hemorrhagic fevers,

maculopapular rash is constantly observed only in

filovirus disease. Typically, the clinical laboratory

findings include an early lymphopenia and marked

thrombocytopenia. Containment and barrier nursing

procedures should be initiated until the

diagnosis of viral hemorrhagic fever can be ruled

out. The index patient described here was the third

patient transferred from Kikwit General Hospital

in less than 1 month to die of a hemorrhagic

illness after a few days of an unexplained febrile

syndrome. Two patients were health-care

workers in Kikwit General Hospital. This cluster

of hemorrhagic illness and possible human-tohuman

transmission, particularly among hospital

staff, was (and should always be) sufficient to

suspect a viral hemorrhagic fever. The laboratory

confirmation of this presumptive diagnosis was

the clenching factor in

he multinational effort in
Kikwit.

Virology

Main article: Ebola virus

Genome

Electron micrograph of an Ebola virus virion

Like all mononegaviruses, ebolavirions contain linear nonsegmented, single-stranded, non-infectious RNA genomes of negative polarity that possesses inverse-complementary 3' and 5' termini, do not possess a 5' cap, are not polyadenylated, and are not covalently linked to a protein. Ebolavirus genomes are approximately 19 kilobase pairs long and contain seven genes in the order 3'-UTR-NP-VP35-VP40-GP-VP30-VP24-L-5'-UTR.The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV, and TAFV) differ in sequence and the number and location of gene overlaps.

Structure

Like all filoviruses, ebolavirions are filamentous particles that may appear in the shape of a shepherd's crook or in the shape of a "U" or a "6", and they may be coiled, toroid, or branched. Ebolavirions are generally 80 nm in width, but vary somewhat in length. In general, the median particle length of ebolaviruses ranges from 974–1,086 nm (in contrast to marburgvirions, whose median particle length was measured to be 795–828 nm), but particles as long as 14,000 nm have been detected in tissue culture. Ebolavirions consist of seven structural proteins. At the center is the helical ribonucleocapsid, which consists of the genomic RNA wrapped around a polymer of nucleoproteins (NP). Associated with the ribonucleoprotein is the RNA-dependent RNA polymerase (L) with the polymerase cofactor (VP35) and a transcription activator (VP30). The ribonucleoprotein is embedded in a matrix, formed by the major (VP40) and minor (VP24) matrix proteins. These particles are surrounded by a lipid membrane derived from the host cell membrane. The membrane anchors a glycoprotein (GP) that projects 7 to 10 nm spikes away from its surface. While nearly identical to marburgvirions in structure, ebolavirions are antigenically distinct.

Replication

The ebolavirus life cycle begins with virion attachment to specific cell-surface receptors, followed by fusion of the virion envelope with cellular membranes and the concomitant release of the virus nucleocapsid into the cytosol. The viral RNA polymerase, encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive-stranded mRNAs, which are then translated into structural and nonstructural proteins. Ebolavirus RNA polymerase (L) binds to a single promoter located at the 3' end of the genome. Transcription either terminates after a gene or continues to the next gene downstream. This means that genes close to the 3' end of the genome are transcribed in the greatest abundance, whereas those toward the 5' end are least likely to be transcribed. The gene order is therefore a simple but effective form of transcriptional regulation. The most abundant protein produced is the nucleoprotein, whose concentration in the cell determines when L switches from gene transcription to genome replication. Replication results in full-length, positive-stranded antigenomes that are in turn transcribed into negative-stranded virus progeny genome copy. Newly synthesized structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane. Virions bud off from the cell, gaining their envelopes from the cellular membrane they bud from. The mature progeny particles then infect other cells to repeat the cycle.

Pathophysiology

Pathogenesis schematic

Endothelial cells, mononuclear phagocyte, and hepatocytes are the main targets of infection. After infection, in a secreted glycoprotein (sGP) the Ebola virus glycoprotein (GP) is synthesized. Ebola replication overwhelms protein synthesis of infected cells and host immune defenses. The GP forms a trimeric complex, which binds the virus to the endothelial cells lining the interior surface of blood vessels. The sGP forms a dimeric protein which interferes with the signaling of neutrophils, a type of white blood cell, which allows the virus to evade the immune system by inhibiting early steps of neutrophil activation. These white blood cells also serve as carriers to transport the virus throughout the entire body to places such as the lymph nodes, liver, lungs, and spleen. The presence of viral particles and cell damage resulting from budding causes the release of cytokines (specifically TNF-α, IL-6, IL-8, etc.), which are the signaling molecules for fever and inflammation. The cytopathic effect, from infection in the endothelial cells, results in a loss of vascular integrity. This loss in vascular integrity is furthered with synthesis of GP, which reduces specific integrins responsible for cell adhesion to the inter-cellular structure, and damage to the liver, which leads to coagulopathy.

Diagnosis

EVD is clinically indistinguishable from Marburg virus disease (MVD), and it can also easily be confused with many other diseases prevalent in Equatorial Africa, such as other viral hemorrhagic fevers, falciparum malaria, typhoid fever, shigellosis, rickettsial diseases such as typhus, cholera, gram-negative septicemia, borreliosis such as relapsing fever or EHEC enteritis. Other infectious diseases that ought to be included in the differential diagnosis include leptospirosis, scrub typhus, plague, Q fever, candidiasis, histoplasmosis, trypanosomiasis, visceral leishmaniasis, hemorrhagic smallpox, measles, and fulminant viral hepatitis. Non-infectious diseases that can be confused with EVD are acute promyelocytic leukemia, hemolytic uremic syndrome, snake envenomation, clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura, hereditary hemorrhagic telangiectasia, Kawasaki disease, and even warfarin intoxication.
The most important indicator that may lead to the suspicion of EVD at clinical examination is the medical history of the patient, in particular the travel and occupational history (which countries were visited?) and the patient's exposure to wildlife (exposure to bats, bat excrement, nonhuman primates?). EVD can be confirmed by isolation of ebolaviruses from or by detection of ebolavirus antigen or genomic or subgenomic RNAs in patient blood or serum samples during the acute phase of EVD. Ebolavirus isolation is usually performed by inoculation of grivet kidney epithelial Vero E6 or MA-104 cell cultures or by inoculation of human adrenal carcinoma SW-13 cells, all of which react to infection with characteristic cytopathic effects. Filovirions can easily be visualized and identified in cell culture by electron microscopy due to their unique filamentous shapes, but electron microscopy cannot differentiate the various filoviruses alone despite some overall length differences.Immunofluorescence assays are used to confirm ebolavirus presence in cell cultures. During an outbreak, virus isolation and electron microscopy are most often not feasible options. The most common diagnostic methods are therefore RT-PCR in conjunction with antigen-capture ELISA which can be performed in field or mobile hospitals and laboratories. Indirect immunofluorescence assays (IFAs) are not used for diagnosis of EVD in the field anymore.

Prevention

A researcher working with the Ebola virus while wearing a BSL-4 positive pressure suit to avoid infection

Ebola viruses are highly infectious as well as contagious.
As an outbreak of ebola progresses, bodily fluids from diarrhea, vomiting, and bleeding represent a hazard. Due to lack of proper equipment and hygienic practices, large-scale epidemics occur mostly in poor, isolated areas without modern hospitals or well-educated medical staff. Many areas where the infectious reservoir exists have just these characteristics. In such environments, all that can be done is to immediately cease all needle-sharing or use without adequate sterilization procedures, isolate patients, and observe strict barrier nursing procedures with the use of a medical-rated disposable face mask, gloves, goggles, and a gown at all times, strictly enforced for all medical personnel and visitors. The aim of all of these techniques is to avoid any person’s contact with the blood or secretions of any patient, including those who are deceased.
Vaccines have successfully protected nonhuman primates; however, the six months needed to complete immunization made it impractical in an epidemic. To resolve this, in 2003, a vaccine using an adenoviral (ADV) vector carrying the Ebola spike protein was tested on crab-eating macaques. The monkeys were challenged with the virus 28 days later, and remained resistant.In 2005, a vaccine based on attenuated recombinant vesicular stomatitis virus (VSV) vector carrying either the Ebola glycoprotein or Marburg glycoprotein successfully protected nonhuman primates, opening clinical trials in humans. By October, the study completed the first human trial; giving three vaccinations over three months showing capability of safely inducing an immune response. Individuals were followed for a year, and, in 2006, a study testing a faster-acting, single-shot vaccine began. This study was completed in 2008. The next step is to try the vaccine on a strain of Ebola that is closer to the one that infects humans.
There are currently no Food and Drug Administration-approved vaccines for the prevention of EVD. Many candidate vaccines have been developed and tested in various animal models. Of those, the most promising ones are DNA vaccines or are based on adenoviruses,vesicular stomatitis Indiana virus (VSIV)or filovirus-like particles (VLPs) as all of these candidates could protect nonhuman primates from ebolavirus-induced disease. DNA vaccines, adenovirus-based vaccines, and VSIV-based vaccines have entered clinical trials.
Contrary to popular belief, ebolaviruses are not transmitted by aerosol during natural EVD outbreaks. Due to the absence of an approved vaccine, prevention of EVD therefore relies predominantly on behavior modification, proper personal protective equipment, and sterilization/disinfection.
On 6 December 2011, the development of a successful vaccine against Ebola for mice was reported. Unlike the predecessors, it can be freeze-dried and thus stored for long periods in wait for an outbreak. The research will be presented in Proceedings of National Academy of Sciences.

In endemic zones

The natural maintenance hosts of ebolaviruses remain to be identified. This means that primary infection cannot necessarily be prevented in nature. The avoidance of EVD risk factors, such as contact with nonhuman primates or bats, is highly recommended, but may not be possible for inhabitants of tropical forests or people dependent on nonhuman primates as a food source.

During outbreaks

Since ebola viruses do not spread via aerosol, the most straightforward prevention method during EVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their excretions and body fluids, or possibly contaminated materials and utensils. Patients should be isolated and medical staff should be trained and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional burial rituals, especially those requiring embalming of bodies, should be discouraged or modified, ideally with the help of local traditional healers.

In the laboratory

Ebolaviruses are World Health Organization Risk Group 4 Pathogens, requiring Biosafety Level 4-equivalent containment. Laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment.

Orphan diseases !! All the diseases need attention.

Source: http://www.orpha.net/consor4.01/www/cgi-bin/Disease_Search_List.php?lng=EN


The above link has the source of orphan diseases. Browse it and i bet you will find information about all the orphan diseases.