WORLD'S MOST EXPENSIVE DRUG

 OPENSIVE MIND// THE KB

Invention:- Zolgensma was developed by AveXis, a Chicago-headquartered biotech that Novartis bought in 2018 for $8.7bn. It had been manufactured in Maryland.

Zolgensma (onasemnogene abeparvovec-xioi), marketed by Novartis Gene Therapies, is an FDA-approved therapy to treat SMA. It is a type of treatment referred to as gene therapy or gene replacement therapy. More than 20 private health-insurance plans and four Medicaid plans have set up coverage policies for Zolgensma since the FDA approval, according to Novartis.

How it works ?

As a gene therapy, ZOLGENSMA^® (onasemnogene abeparvovec-xioi) is designed to target the genetic root cause of spinal muscular atrophy (SMA) by replacing the function of the missing or nonworking SMN1 gene with a new, working copy of a human SMN gene. ZOLGENSMA does not change or become a part of the child's DNA.

Pathophysiology:- Survival motor neuron (SMN) proteins facilitate proper signaling between CNS motor neurons and muscles in the body § SMA is an autosomal recessive condition caused by deletions or mutations in the SMN1 gene, resulting in a shortage of SMN protein o SMN2 gene produces a small amount of functional length SMN protein, and an increase in copy number may decrease severity of disease but cannot fully compensate for the loss-of-function of SMN1.

 

Why is it so expensive?

The reason Zolgensma is so expensive is because that is the price Novartis has decided it is worth because it “dramatically transforms the lives of families affected by this devastating disease” and the claimed cost of bringing new drugs to market. But this price is not without controversy. While a genetic test for SMA costs just under $500, more than 12,500 women would have to be screened to prevent one case of SMA, which affects only about 1 in 10,000 newborns.

Result of application

Zolgensma® data shows rapid, significant, clinically meaningful benefit in SMA including prolonged event-free survival, motor milestone achievement and durability now up to 5 years post-dosing.

Dosage:- Monitor troponin-I before ZOLGENSMA infusion and on a regular basis for at least 3 months afterwards (weekly for the first month, and then monthly for the second and third months until troponin-I level returns to baseline). Now that Zolgensma is finally approved in Europe, though, Novartis has an opportunity to steal market share from Biogen's SMA drug Spinraza. That's because the European approval allows the Zolgensma to be used in children weighing up to 21 kilograms, which basically covers any child under the age of 5.

Comparison of Zolgensma and Spinraza:-

An indirect comparison of the two treatments indicates that Zolgensma may be more effective than Spinraza among infants with symptomatic SMA type 1 in terms of overall survival, independence from permanent assisted ventilation, motor function and motor milestones.

Availability:-

Novartis Gene Therapies' Zolgensma (onasemnogene abeparvovec) will be available for use in the UK's National Health Service (NHS) following recommendations by regulators in England and Wales, as well as Scotland. Zolgensma is deemed to be the most expensive drug in the world with a list price of £1.79m per dose.

THE HEADLESS CHICKEN

 OPENSIVE MIND// THE KB

Mike the Headless Chicken (April 20, 1945 – March 17, 1947) was a Wyandotte’s chicken that lived for 18 months after his head had been cut off. After the loss of his head, Mike achieved national fame until his death in March 1947. In Fruita, Colorado, an annual "Mike the Headless Chicken Day" is held every May.

Beheading:- On September 10, 1945, farmer Lloyd Olsen of Fruita, Colorado, was planning to eat supper with his mother-in-law and was sent out to the yard by his wife to bring back a chicken. Olsen chose a five-and-a-half-month-old Wyandotte chicken named Mike. The axe removed the bulk of the head, but missed the jugular vein, leaving one ear and most of the brain stem intact.

Due to Olsen's failed attempt to behead Mike, the chicken was still able to balance on a perch and walk clumsily. He attempted to preen, peck for food, and crow, though with limited success; his "crowing" consisted of a gurgling sound made in his throat. When Mike did not die, Olsen instead decided to care for the bird. He fed it a mixture of milk and water via an eyedropper, and gave it small grains of corn and worms.

Death:- In March 1947, at a motel in Phoenix on a stopover while traveling back from tour, Mike started choking in the middle of the night. He had managed to get a kernel of corn in his throat. The Olsens had inadvertently left their feeding and cleaning syringes at the sideshow the day before, and so were unable to save Mike. Olsen claimed that he had sold the bird off, resulting in stories of Mike still touring the country as late as 1949. Other sources say that the chicken's severed trachea could not properly take in enough air to be able to breathe, and it therefore choked to death in the motel.

Explanation of death: - 

• It was determined that the axe had missed the jugular vein and a clot had prevented Mike from bleeding to death. Although most of his head was severed, most of his brain stem and one ear were left on his body. Since basic functions (breathing, heart rate, etc.) as well as most of a chicken's reflex actions are controlled by the brain stem, Mike was able to remain quite healthy. 
• This is a good example of central motor generators enabling basic homeostatic functions to be carried out in the absence of higher brain centers. 
• In addition, birds possess a secondary balance organ in the pelvic region, the lumbosacral organ, which controls walking locomotion virtually independently from the vestibular organ involved in flight. This has been used to explain how a headless chicken can walk and balance, despite the destruction of much of the cranial vestibular system.

 

Fame:- Once his fame had been established, Mike began a career of touring sideshows in the company of such other anomalies as a two-headed baby. He was also photographed for dozens of magazines and papers, and was featured in Time and Life magazines.  

Legacy:- Mike the Headless Chicken is now a cultural institution in Fruita, Colorado, with an annual "Mike the Headless Chicken Day", the third weekend of May, starting in 1999. Events held include the "5K Run Like a Headless Chicken Race", egg toss, "Pin the Head on the Chicken", the "Chicken Cluck-Off", and "Chicken Bingo", in which chicken droppings on a numbered grid choose the numbers.

Mike the Headless Chicken was an inspiration for the poultry-themed comedy punk band The Radioactive Chicken Heads, serving as the subject of their 2008 song "Headless Mike", for which a music video was filmed. The band also features a Headless Mike puppet which is frequently used in their live shows.

References:-  

BBC NEWS ONLINE

CLINICAL NEUROSCIENCE

Amy Reiter (1999). "Mike the Headless Chicken more popular than Clinton".

FAMOUS HIPPO FROM PROTEAN LAND

 HUBERT OR HUBERTA?                                                                       THE KB // OPENSIVE MIND

Huberta (initially named Hubert; the gender was discovered after death) was a hippopotamus and one of the most famous animals in South African history.

In November 1928, Huberta left her waterhole in the St. Lucia Estuary in Zululand and set off on the 1,600-kilometre (1,000 mi) journey to the Eastern Cape, a journey which took her three years. 

In that time, Huberta became a minor celebrity in South Africa and attracted crowds wherever she went. She was initially thought to be a male and was nicknamed Hubert by the press. The first report in the press was on 23 November 1928 in the Natal Mercury and reported the appearance of a hippo in Natal. The report was accompanied by the only photograph of Huberta in life.

Huberta stopped for a while at the mouth of the Mhlanga River about 15 kilometers (9 mi) north of Durban and a failed attempt was made to capture her and put her in Johannesburg Zoo. After this, she headed south to Durban where she visited a beach and a country club. Moving on to the Umgeni River, she became revered by Zulus and Xhosas alike.

Finally, Huberta arrived in East London in March 1931. Despite her having been declared royal game (and thus protected) by the Natal Provincial Council, she was shot by farmers a month later. After a public outcry, the farmers were arrested and fined £25. Huberta's body was recovered and sent to a taxidermist in London. Upon her return to South Africa in 1932, she was greeted by 20,000 people and was displayed at the Amatole Museum (previously known as the Kaffrarian Museum) in King William's Town.

Huberta is the subject of the children's book Hubert The Traveling Hippopotamus by Edmund Lindo and illustrated by Jane Carlson. The book was published in 1961 by Little, Brown and Company.

REFERENCES:- 

Witz, Leslie (2004). "The making of an animal biography: Huberta's journey into South African natural history, 1928-1932". Kronos. 30: 138–166.

Lindop, Edmund; Carlson, Jane (1961). Hubert, the Traveling Hippopotamus. Little, Brown.

FOXP2 : A master gene for language?

 

Perhaps the greatest insight into the evolution of language has come from work on the FOXP2 gene. This gene plays a key role in language and vocalization and allows us to explore the changes underpinning the evolution of complex language.
The FOXP2 gene was first discovered by Simon Fisher, Anthony Monaco and colleagues at the University of Oxford in 2001. They came across the gene through their studies of DNA samples from a family with distinctive speech and language difficulties. Around 15 members of the family, across three generations, were able to understand spoken words perfectly, but struggled to string words together in order to form a response. The pattern in which this condition was inherited, suggested that it was a dominant single-gene condition (one copy of the altered gene was enough to disrupt their overall language abilities). The researchers identified the area of the genome likely to contain the affected gene but were unable to identify the specific gene mutation within this region.
They then had a stroke of luck, in the form of another unrelated child with very similar symptoms. Looking at this child’s DNA they identified a chromosome rearrangement that sliced through a gene in the region of DNA where they suspected the mutated gene was. This gene was FOXP2.  After sequencing the FOXP2 gene in the family they found a specific mutation in the gene that was shared by all the affected family members. This confirmed the importance of FOXP2 in human language.
Simon and his colleagues went on to characterize FOXP2 as a ‘master controller’, regulating the activity of many different genes in several areas of the brain. One key role is in the growth of nerve cells and the connections they make with other nerve cells during learning and development. Mutations in the FOXP2 gene interfere with the part of the brain responsible for language development, leading to the language problems seen in this family.

The evolution of FOXP2 

The FOXP2 gene is highly conserved between species. This  means that the gene has a very similar DNA sequence in different species, suggesting it has not evolved much over time. The FOXP2 protein in the mouse only differs from the human version by three amino acids. The chimpanzee version only differs from the human version by two amino acids. These two changes in amino acids may be key steps in the evolution of language in humans.  What difference do these small changes in sequence make to the functionality of the FOXP2 protein? Studies with mice show that changing the mouse version of the FOXP2 gene to be the same sequence as the human version only has subtle effects. Remarkably, the resulting mouse pups are essentially normal but show subtle changes in the frequency of their high-pitched vocalizations. They also show distinctive changes to wiring in certain parts of their brain. From these studies scientists have concluded that FOXP2 is involved in the brain’s ability to learn sequences of movements. In humans this has translated into the complex muscle movements needed to produce the sounds for speech, whereas in other species it may have a different role, coordinating other movements.FOXP2 regulates many other genes in the body and evolution seems to have favored a subset of these as well, particularly in Europeans. FOXP2 regulated genes are important not only in brain development, but they also play important roles in human reproduction and immunity.

FOXP2 and the Neanderthals

Neanderthals have generally been characterized as a large, brutish species with little or no intellectual, social or cultural development. However, the fact that they had the same FOXP2 gene as modern humans suggests that Neanderthals may have had some capacity for speech and communication. Various strands of evidence have helped to establish a picture of how Neanderthals might have lived and communicated. Archaeological records suggest that they probably lived in small groups and due to their high energy needs, spent most of their time hunting. Neanderthals are unlikely to have developed social groups bound together by effective communication. This is probably because they lacked the key mental abilities needed to establish and maintain social groups. Recursive thinking (thinking about thinking), theory of mind (appreciating what is going on in someone else’s head) and inhibition of impulsive reactions (being able to control impulses) are all important elements to successful social interactions. Interestingly brain injury and developmental disorders, such as autism, can interfere with these abilities and social skills in humans. This evidence suggests that the Neanderthal brain may not have been wired to support effective communication and diplomatic skills. They would have been extremely difficult to get along with! The Neanderthal brain was probably better adapted to maximize their visual abilities. They would have used their oversized eyes and large brains to survive and hunt in the lower-light levels in Europe. This would limit the space available in the brain to develop the systems needed for communication and social interactions. However, their smaller social brain regions could have enabled them to establish smaller social networks which may have improved their chances of survival in the harsh European environment. 

BRRS : A BRIEF OVERVIEW

 Banyan–Riley–Ruvalcaba syndrome (BRRS)

It is a rare overgrowth syndrome and hamartomata's disorder with occurrence of multiple subcutaneous lipomas, macrocephaly and hemangiomas. The disease is inherited in an autosomal dominant manner.

Banyan–Riley–Ruvalcaba syndrome is associated with enlarged head and benign mesodermal hamartomas (multiple hemangiomas, and intestinal polyps). 

Dysmorphia as well as delayed neuro psychomotor development can also be present. The head enlargement does not cause widening of the ventricles or raised intracranial pressure; these individuals have a higher risk of developing tumors, as the gene involved in BRRs is phosphatase and tensin homologue. 

Some individuals have thyroid issues consistent with multinodular goiter, thyroid adenoma, differentiated non-medullary thyroid cancer, most lesions are slowly growing. Visceral as well as intracranial involvement may occur in some cases, and can cause bleeding and symptomatic mechanical compression.

GENETICS IN BEHIND:- 

• The genetics of the Banyan–Riley–Ruvalcaba syndrome is determined, in the majority of cases, via the PTEN gene which presents about 30 mutations in this condition. 
• This gene which regulates cell growth, when not working properly can lead to hamartomas.
• PTEN chromosomal location is 10q23.31, while the molecular location is 87,863,438 to 87,971,930 There are many syndromes that are linked to PTEN aside from Banyan–Riley–Ruvalcaba Syndrome.

The syndrome combines Banyan–Zonana syndrome, Riley–Smith syndrome, and Ruvalcaba–Myhre–Smith syndrome. Banyan–Zonana syndrome is named for George A. Banyan and Jonathan Zonana.

In terms of diagnosing Banyan–Riley–Ruvalcaba syndrome there is no current method outside the physical characteristics that may be present as signs/symptoms. There are, however, multiple molecular genetics tests (and cytogenetic test) to determine Banyan–Riley–Ruvalcaba syndrome.

SOURCES:- 

OMIM

NORD GUIDE

Hobert, Judith A; Eng, Charis (6 August 2009). "PTEN hamartoma tumor syndrome: An overview". Genetics in Medicine. 11 (10): 687–694. 

ALCOHOL SUPERVISOR

 ALCOHOL; NOT TO ADDICTION 

Alcohol is a widely consumed drug in western societies that can lead to addiction. A small shift in consumption can have dramatic consequences on public health. 

It is found that a locus in the gene encoding β-Klotho is associated with alcohol consumption. Β-Klotho is an essential receptor component for the endocrine FGFs, FGF19 and FGF21. 

Using mouse models and pharmacologic administration of FGF21, it is shown that β-Klotho in the brain controls alcohol drinking. These findings reveal a mechanism regulating alcohol consumption in humans that may be pharmacologically tractable for reducing alcohol intake.

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. Meta-analysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10⁻¹²). Β-Klotho is an obligate co receptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. Brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver–brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

The UTSW team worked with other research teams across the U.S., Europe and in China to see if there is a gene for controlled drinking. They did what’s called a genome-wide association study, screening all the genes in people to see if they could associate it with behavior.

They think they found such a link with beta-Klotho. Like so many genes, it doesn’t act by itself but works with genes called FGF21 and FGF19. These two genes control hormones with the same names that are associated with alcohol preferences, as well as for craving sweet foods.

Tests in mice showed that when they did not have beta-Klotho, they strongly preferred water laced with alcohol to plain water, even when dosed with FGF21 hormone. Monkeys given FGF21 hormone crave sweet drinks less.

WORLD'S RAREST DISEASE

 RPI Deficiency: A brief overview

• RPI deficiency. Ribose-5-phosphate isomerase deficiency is a human disorder caused by mutations in the pentose phosphate pathway enzyme ribose-5-phosphate isomerase. 
• With only three diagnosed patients over a 27-year period, RPI deficiency is currently the rarest disease in the world. 
• In the case of this disorder, RPI functions partially in tissues, because if the gene was simply non-functional, it would likely be lethal. This means that a specific type of mutation needs to occur for this disorder to occur. 
• Symptoms:- optic atrophy, nystagmus, cerebellar ataxia, seizures, spasticity, psychomotor retardation, leukoencephalopathy and global developmental delay.

FURTHER ANALYSIS:-

The present article describes the first patient with a deficiency of ribose-5-phosphate isomerase (RPI) (Enzyme Commission number 5.3.1.6) who presented with leukoencephalopathy and peripheral neuropathy. Proton magnetic resonance spectroscopy of the brain revealed highly elevated levels of the polyols ribitol and D-arabitol, which were subsequently also found in high concentrations in body fluids. Deficient activity of RPI, one of the pentose-phosphate-pathway (PPP) enzymes, was demonstrated in fibroblasts. RPI gene–sequence analysis revealed a frame shift and a missense mutation. Recently, we described a patient with liver cirrhosis and abnormal polyol levels in body fluids, related to a deficiency of transaldolase, another enzyme in the PPP. RPI is the second known inborn error in the reversible phase of the PPP, confirming that defects in pentose and polyol metabolism constitute a new area of inborn metabolic disorders.

Because of the biochemical findings, we decided to sequence the gene RPI. cDNA was synthesized from total RNA derived from lymphoblast’s of the patient by Omni script Transcriptase (RT) (Qiagen).

TREATMENT:- No such particular type of treatment method is discovered yet but the disease can be detected by some medicinal tests like MRI and further medications has been done by the concerned specialist.

                                RPI ( Ribulose 5 phosphate isomerase molecular structure)

                                                           Condition of RPI deficiency
(Source: NCBI. NORD, OMIM)