CHAPTER I

INTRODUCTION
A variety of theorists, using case studies, experiments and a variety of
research methods, have attempted to better understand the sources of creativity
and innovation in individuals. While these efforts have contributed significantly
to broadening our comprehension of the subject, there is nonetheless disagreement
between theorists and many hypotheses that remain to be fully substantiated. The
challenge lies partially in the nature and definition of creativity itself. Broad,
complex and multi-faceted, creativity can take many forms and can be found
within a variety of contexts. It is embodied by individuals with a broad range of
personal characteristics and backgrounds. It appears that the only rule is that there
are

no

hard

and

fast

rules

concerning

the

sources

of

creativity.

(http://www.fpspi.org/pdf/innovcreativity.pdf )
Creativity is a function of knowledge, curiosity, imagination, and
evaluation. The greater your knowledge base and level of curiosity, the more ideas,
patterns, and combinations you can achieve, which then correlates to creating new
and innovative products and services. But merely having the knowledge does not
guarantee the formation of new patterns. The bits and pieces must be shaken up
and iterated in new ways. Then the embryonic ideas must be evaluated and
developed into usable ideas. In other words, there really is a process. (
http://www.huffingtonpost.com/daniel-burrus/creativity-andinnovation_b_4149993.html )
Studies have confirmed that all businesses want to be more innovative.
One survey identified that almost 90 per cent of businesses believe that innovation
is a priority for them. The conclusion is that the importance of innovation is
increasing, and increasing significantly. In the current day economic scenario,
innovativeness has become a major factor in influencing strategic planning. It has
been

acknowledged

that

innovation

leads

to

wealth

creation.

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(http://www.paggu.com/getting-into-roots/what-is-innovation-why-innovation-isimportant/ )

CHAPTER 2
THEORITICAL VIEW
2.1 Definition
2.1.1 Innovation
Innovation is a new idea, or more-effective device or process. [1] Innovation can be
viewed as the application of better solutions that meet new requirements,
unarticulated needs, or existing market needs.[2] This is accomplished through
more-effective products, processes, services, technologies, or business models that
are readily available tomarkets, governments and society. The term "innovation"
can be defined as something original and more effective and, as a consequence,
new, that "breaks into" the market or society.[3]
1. "Innovation | Definition of Innovation by Merriam-Webster". Merriamwebster.com. Retrieved 2016-03-14.
2. Jump up^ Maryville, S (1992). "Entrepreneurship in the Business
Curriculum". Journal of Education for Business. Vol. 68 No. 1, pp. 27-31.
3. Jump up^ Based on Frankelius, P. (2009). "Questioning two myths in
innovation

literature". Journal

of

High

Technology

Management

Research. Vol. 20, No. 1, pp. 4051.

2.1.2 Creativity
Creativity is a phenomenon whereby something new and somehow valuable is
formed. The created item may be intangible (such as an idea, a scientific theory,
a musical composition or a joke) or a physical object (such as an invention,
a literary work or a painting).

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2.2 How to become more creative and innovative

What you need to do in order to become more creative and
innovative. Here the steps you need to do in order to become more
creative and innovative:
a) Change your routine: Research has shown that fixed routine is a great
creativity killer. In order to become more creative and innovative you need
not to stick to the same routine each day. Change anything you can change
in your daily activities, try to do the same things in a different way or even
try things you never tried before
b) Dedicate free time for creative thinking: Even if you changed your
routine you might still not be that creative because of being bound by
rules. In order to become really creative you need to dedicate some free
time for creative thinking where you are not bound by any rules
c) Get rid of your limiting beliefs: One of the things that kills creatively and
prevents innovation is limiting beliefs. Limiting beliefs prevent you from
seeing possibilities and the result is being stuck in a certain reality without
trying to change it
d) Overcome fear of failure: In order to become more creative and
innovative you need to keep trying and failing. Creativity is all about
doing few wrong things until you come across the right thing. If you fear
failure or if you fear taking risks then you will always be stuck in your
comfort zone and you will never become creative
e) Learn to observe: Sometimes observing other people can inspire you and
lead you to innovate and become creative. Contrary to common beliefs
you wont be stealing people's ideas when you observe them but instead
you will be adding pieces of information from here and there together until
you come up with something totally new

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2.3 Epidemiology
The prevalence of GD is approximately 1/60,000 in the general population
though this may reach 1/1000 in the Ashkenazi Jewish population. Its clinical
expression is extremely variable, ranging from asymptomatic forms to lethal inutero forms.

2.4 Pathophysiology
Gaucher disease (GD) is a lysosomal storage disorder (LSD). These
metabolic disorders are caused by mutations in genes encoding a single lysosomal
enzyme or cofactor, resulting in intracellular accumulation of undegraded
substrates. Most LSDs, including GD, are inherited in an autosomal recessive
fashion. In GD, 200 different mutations have been described in the gene encoding
lysosomal glucocerebrosidase (glucosylceramidase, GlcCerase) , and as a result,
glucosylceramide (GlcCer, glucosylcerebroside) is degraded much more slowly
than in normal cells and accumulates intracellularly, primarily in cells of
mononuclear phagocyte origin. These GlcCer-laden macrophages are known as
Gaucher cells, and are the classical hallmark of the disease. Since GlcCer is an
important constituent of biological membranes and is a key intermediate in the
biosynthetic and degradative pathways of complex glycosphingolipids, its
accumulation in GD is likely to have severe pathological consequences.
The cellular pathology of GD begins in lysosomes, membranebound
organelles that consist of a limiting, external membrane and intra-lysosomal
vesicles. Endogenous and exogenous macromolecules, including GlcCer, are
delivered to lysosomes by processes such as endocytosis, pinocytosis,
phagocytosis and autophagocytosis and the lysosomal proteins themselves, at least
the soluble hydrolases, are targeted to lysosomes mainly via the mannose-6phosphate receptor . Surprisingly, the mechanism by which GlcCerase is targeted
from its site of synthesis in the endoplasmic reticulum to lysosomes is not known.

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In addition, little is known about how GlcCer accumulation in lysosomes

leads to cellular pathology. One vital, but as yet unanswered question, is whether
GlcCer mediates all of its pathological effects from within the lysosome, or
whether some GlcCer can escape the lysosome and thereby interact with
biochemical and cellular pathways located in other organelles. Some evidence
exists to support the latter possibility.

2.5 Diagnosis and Symptom

A. Type 1, non-neuroneopathic GD (95% of cases)
The clinical presentation is very heterogeneous.
Diagnosis may be made at any age (average age of diagnosis: 20 years).
There are asymptomatic forms.
The following signs should be sought during the interview and physical:
1. Asthenia, which is frequently observed and may have a negative impact on
school and socio-professional life;
2. Growth retardation or delayed puberty;
3. Splenomegaly, which is sometimes very severe and observed in 95% of
patients; sometimes painful spleen infarct. Rupture of the spleen is
extremely rare.
4. Bleeding, which is usually only moderate.
Hepatomegaly (more than 80% of cases). Progression to hepatic
fibrosis and then cirrhosis is rare.
Hepatosplenomegaly sometimes causes painful abdominal distension.
5. Bone involvement (80 % of cases)
This impacts the functional prognosis. It may result in:
Crises of disabling hyperalgic pain caused by bone infarcts and
a. aseptic osteonecrosis;
b. Pathological fractures;
c. Vertebral compression;
d. Chronic pain;
e. Deformities.
6. Involvement of other organs with rarely:
a. Pulmonary lesions (lung fibrosis, secondary restrictive syndrome with

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b. deformity of the spine, pulmonary hypertension);

c. Cardiac lesions (interstitial infiltration of the myocardium or
pericardium);
7. Pigmentation of the skin and ocular, gastrointestinal or renal
involvement is very rare.
B. Acute neuronopathic type 2 (1% of cases)
This is the most severe and rarest form. Onset is usually in infants aged from
3 to 6 months (sometimes in utero).
It associates:
1. Systemic involvement with hepatosplenomegaly;
2. An early and severe neurological syndrome;
3. The first signs are oculomotor paralysis or bilateral fixed strabismus
secondarily associated with bulbar signs, in particular severe swallowing
disorders, progressive spasticity and dystonic movements;
4. Convulsions occur later, with the onset of myoclonic epilepsy resistant to
antiepileptic treatments.
The initial neurological workup includes:
1. Clinical examination conducted by a neurologist who, if possible, already
2.

has experience of GD;

Filmed recording by a specialized team of possible oculomotor apraxia.

C. Type 3 (4 % of cases)
This is also called juvenile or subacute neuroneopathic GD. As for type 1, it
comprises a heterogeneous group of patients. Neurological involvement occurs
later and progression is more gradual than in type 2. Certain patients have
moderate systemic involvement and associated ophthalmoplegia is the only
neurological symptom.
Variable neurological signs are seen in the more severe forms: supranuclear
horizontal ophthalmoplegia, progressive myoclonic epilepsy, cerebellar ataxia,
spasticity and dementia.
The initial neurological workup includes:

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1. Clinical examination conducted by a neurologist who, if possible, already

has experience of GD;
2. Filmed recording, by a specialized team, of possible oculomotor apraxia.
Chronic non-neuroneopathic type I: this accounts for 95% of cases.
Diagnosis may be made at any age. The clinical presentation is very
heterogeneous. The main signs and symptoms are hepatosplenomegaly, bone
involvement (pain, bone infarcts, osteonecrosis) and thrombocytopenia. There are
asymptomatic forms. Asthenia is frequent with sometimes a negative impact on
school and socio-professional life. There may be growth retardation or delayed
puberty. Splenomegaly may be complicated by spleen infarcts. Rupture of the
spleen may occur in very rare cases. Progression to hepatic fibrosis and then
cirrhosis rarely occurs. Hepatosplenomegaly sometimes causes painful abdominal
distension which may obstruct breathing.
Acute neuroneopathic type II: this is the most severe and rarest form.
Onset is usually in the infant aged from 3 to 6 months (sometimes, in utero) with
systemic toxicity, hepatosplenomegaly and an early and severe neurological
syndrome. The first signs are oculomotor paralysis or bilateral fixed strabismus
associated secondarily with bulbar signs and in particular, severe swallowing
disorders, gradually worsening spasticity and choreoathetosic movements.
Convulsions occur later and lead to myoclonic epilepsy resistant to antiepileptic
treatments. Death generally occurs before the age of 2 years.
Subacute neuroneopathic type III: like type 1 disease this includes a very
heterogeneous group of patients. Certain patients have moderate systemic
involvement associated with ophthalmoplegia as the only neurological symptom.
Variable neurological signs are seen in more severe forms: Supranuclear
horizontal ophthalmoplegia, progressive myoclonic epilepsy, cerebellar ataxia,
spasticity and dementia.
2.6 Treatment
Enzyme Replacement Therapy

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Soon after the discovery of the enzymatic defect in Gaucher disease, I

began to consider what might be done to help patients with this and other
metabolic storage disorders and postulated that enzyme replacement might be
beneficial. 31 In order to examine this possibility, my colleagues and I undertook
the purification of glucocerebrosidase from human placental tissue to reduce the
possibility of sensitizing recipients to the exogenous protein. When placental
glucocerebrosidase was injected into two patients with this disorder,
glucocerebroside that has accumulated in the liver was reduced significantly in
both patients. In addition, elevated glucocerebroside in the blood of the recipients
returned to normal within 3 days following injection of the enzyme.
The reduction of glucocerebroside in the circulation lasted many months.
Greater quantities of glucocerebrosidase were required to remove the large
amounts of glucocerebroside that accumulated in the organs of many patients with
Gaucher disease. Therefore, my associates and I developed a large-scale
procedure for the purification of placental glucocerebrosidase. The enzyme is a
glycoprotein with four oligosaccharide chains. It was discovered that it was
necessary to modify these oligosaccharide moieties to target glucocerebrosidase to
macrophages, the scavenger cells in the body in which glucocerebroside
accumulates.
Macrophages have a lectin on their surface that interacts avidly with
glycoproteins with terminal molecules of mannose.Targeting glucocerebrosidase
to these cells was accomplished by the removal of oligosaccharides by the
sequential action of three exoglycosidases. Mannose-terminal glucocerebrosidase
that is effectively targeted to macrophages was produced in this fashion.
Dose-response and clinical efficacy trials were undertaken with
macrophage targeted glucocerebrosidase. All of the recipients experienced
dramatic improvement. Their anemia and thrombocytopenia improved greatly.
Splenomegaly and hepatomegaly diminished significantly and skeletal benefit
occurred in all of the patients. Before receiving the enzyme, many of the patients
had severe bouts of pain due to infarctions in their spleens, livers, and bones. They
became completely free from pain. No patient in the trial had an untoward

Page | 8

reaction or became sensitized to the enzyme. Enzyme replacement therapy for

patients with Gaucher disease was approved by the U.S. Food and Drug
Administration in 1991. It was subsequently approved in 50 additional countries.
Macrophage-targeted

glucocerebrosidase

was

later

produced

recombinantly in Chinese hamster ovary cells. Recombinant glucocerebrosidase

was shown to be as effective as the enzyme obtained from placenta, and it was
approved in the U.S. for the treatment of patients with Gaucher disease in 1994.
More than 4500 patients throughout the world are currently receiving this lifesaving therapy. The remarkable benefit of enzyme replacement in Gaucher disease
appeared to indicate the potential of this strategy for the treatment of other human
metabolic storage disorders.

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CHAPTER III
CONCLUSION
Gaucher disease is part of a category of diseases referred to as Lysosomal
Storage Diseases (LSD). As a group, LSDs are relatively common, occurring in
1:7000 births. Similar to most LSDs (Tay-Sachs, Niemann Pick, Battens, Krabbe,
Mannosidosis, Fucosidosis, Sialidosis, Mucolipidosis, etc.), type 2 and type 3
Gaucher disease affects the central nervous system. The impact on the brain is
what makes these diseases terminal for many of the children who are affected and
is also the most difficult part of the disease to understand. Currently, there is no
effective treatment for the neurological symptoms of any LSD. Although each of
these diseases has a different etiology, it is likely that common pathogenic
processes exist. Researchers believe that a better understanding of one of these
neuronopathic LSDs will lend itself to a greater understanding of the others.
Further, and more exciting, researchers believe that a cure for one of these
diseases may help pave the way toward finding a cure for the others.

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REFERENCE
1. Zimran A, Gelbart T, Westwood B, Grabowski GA, Beutler E (1991).
"High frequency of the Gaucher disease mutation at nucleotide 1226
among Ashkenazi Jews". Am. J. Hum. Genet. 49 (4): 855859.
2. HAS. Gaucher Disease: National Diagnosis and Treatment Protocol. 2007
3. Brady RO. The Physician Guide To Gaucher Disease. [cited 2015 Oct 18].
Available from: nordphysicianguides.org/Gaucher-Disease
4. Futerman AH, Zimran A. Gaucher Disease. [cited 2015 oct 18]. Available
from:http://s3.amazonaws.com/academia.edu.documents/34972620/Gauch
er_disease.pdf?
AWSAccessKeyId=AKIAJ56TQJRTWSMTNPEA&Expires=1445354520
&Signature=VZsT042Yts4lT0ubJDDi6986lxE
%3D&responsecontentdisposition=attachment%3B%20filename
%3DGaucher_disease.pdf

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