I.

Basic Research
A. Depression in young adults

Daniel J. Smith & Douglas H. R. Blackwood

a.)

Affective illnesses may present at any age, but it is becoming clear that patients who suffer from
recurrent and severe forms of mood disorder often experience their first episode of illness early in life.
The clinical presentation of depression at this stage of life can be atypical and is often complicated by
personality difficulties and substance misuse. A significant proportion of young people presenting with
recurrent depression will go on to develop a bipolar disorder, with important implications for future
pharmacological treatment choices.

Problem Investigated

The emergence of gender differences during adolescence

That women are twice as likely as men to have depression is a consistent finding in psychiatric
epidemiology and is not simply a consequence of females being more likely to report, recall or seek help
for depressive symptoms. Before puberty, boys are slightly more likely than girls to be depressed, but
between the ages of 11 and 13 this trend is reversed, with girls outnumbering boys by two to one. This
predominance of females over males persists for the next 35 to 40 years (Cyranowski et al, 2000).

Progression from early-onset unipolar depression to bipolar disorder

Pre-pubertal onset of depression is a strong marker for bipolar disorder, with some studies
finding that at least one-third of depressed children will develop bipolar disorder in adult life (Geller et
al, 2001). In a 7-year prospective study of 28 out-patient adolescents with depression, Rao et al (1995)
detected a rate of bipolar outcome of almost 20%. Rates of switching polarity are higher for those with
more severe episodes of depression. A 15-year follow-up of 74 young adults hospitalised for unipolar
depression found that 27% subsequently developed hypomania, with an additional 19% experiencing at
least one episode of mania (Goldberg et al, 2001).

The role of genetics

Adoption and family studies have established that depression runs in families and that most of
this familiality occurs as a result of genetic rather than environmental influences (Sullivan et al, 2000).
Unipolar depression, as a heterogeneous disorder, is likely to include subgroups that represent more
genetic forms of depressive illness. Recurrent, early onset depression, defined as two or more episodes
before the age of 25, is associated with a strong family history of affective disorder and appears to
follow a particularly malignant course, with frequent recurrence, poor response to treatment and high
psychiatric and physical comorbidity (Zubenko et al, 2001).

Neuroticism

Neuroticism, defined as a general vulnerability to neurotic breakdown under stress, is a

heritable personality trait (Tambs et al, 1991) and has been positively associated with depression
(Duggan et al, 1995; Roberts & Kendler, 1999). In a longitudinal study of 897 young adults followed
between the ages of 18 and 21 years, Krueger et al (1996) found a strong association between high
premorbid neuroticism and the subsequent development of a depressive illness.

Early adversity

Childhood physical, emotional and sexual abuse are established as important risk factors for the
development of a range of psychiatric disorders in adult life and are increasingly recognised as
important in early-adulthood psychopathology. Traumatic experiences can interfere with normal
emotional and psychological development, with the result that abused or neglected individuals often
struggle to negotiate the maturational tasks of adolescence and early adulthood (Brown et al, 1999).

Life events

People with depression are more likely to generate stressful events, and individuals with a
higher genetic loading for affective disorder are more likely to experience depression after a stressful
event than those with low genetic loading (Kendler & Karkowski-Shuman, 1997; Silberg et al, 2001). In
recurrent depressive disorder, the association between life events and depression is strongest for early
episodes and becomes weaker as the number of episodes increases (Ghaziuddin et al, 1990).

Substance misuse

Drug and alcohol use in adolescence are important risk factors for the development of affective
disorders in early adulthood and are likely to complicate the long-term course of depression. In a 5-year
longitudinal study of 155 adolescent females, Rao et al (2000) found that 19% developed a substance
use disorder and that substance use was a marker for the eventual occurrence of depression.
Conversely, when Lewinsohn et al (2000) followed 274 formerly depressed adolescents to age 24, two-
thirds had experienced another depressive episode and, from the remaining third who had not, 77%
were found to have a substance misuse disorder. This suggests that an episode of depression in
adolescence, or a diagnosis of substance misuse, represents an opportunity for early intervention to
prevent recurrence of both disorders in later life.

Type of sample use

Clinical presentation of depression

Depression varies widely in its clinical presentation. This is especially true in adolescence and
young adulthood, when atypical symptoms are more common and the more classic melancholic
presentations are relatively rare (Parker et al, 2003). Younger adults with depression also tend to report
more irritability and anxiety and, as detailed above, there should be a high index of suspicion for the
possibility of an emerging bipolar disorder.

Analytical procedures used is observation

Case 1 Anxious–hostile presentation

A 21-year-old student was assessed on an orthopaedic ward 2 days after a violent suicide
attempt. He had jumped from a height of 60 m, sustaining a broken leg, multiple cuts, severe bruising
and a minor head injury. He had taken the decision to kill himself after 2 weeks of escalating anxiety,
irritability, disturbed sleep and agitation in the lead up to some important exams.
 Case 1 is an example of depression in a young man with prominent anxiety, irritability and
impulsivity. Depressions characterised by irritability and hostility, particularly in young men, frequently
go undiagnosed and are often associated with dangerous impulsive behaviour and potentially lethal acts
of self-harm.

Case 2 Bipolar-spectrum disorder

A 19-year-old undergraduate was referred by her general practitioner because of a failure to

respond adequately to two different classes of antidepressant. She had presented 12 months earlier
with an episode of depression with prominent anxiety symptoms and a recurrence of self-cutting (at age
14 she had cut herself for several months around the time of her parents’ separation).

Case 2 is an example of depression in a young woman who has a first-degree relative with
bipolar disorder. She had been difficult to treat and antidepressants led to fluctuations in her mood with
recurrent, brief periods of hypomania occurring against a background of residual depressive symptoms.

Case 3 Bipolar depression

A 20-year-old woman was referred by her general practitioner because she described mood
swings. She gave a 4-month history of feeling depressed and irritable, with excessive fatigue, overeating,
weight gain and hypersomnia.

This is a case of depression characterised by excessive fatigue, hyperphagia, weight gain and
hypersomnia. These symptoms are typical of the features of bipolar depression. Diagnosing a bipolar-
spectrum disorder in this case rather than unipolar depression has important implications for future
pharmacological treatment choices, particularly because antidepressants can act as mood destabilisers
in patients with a bipolar diathesis, by triggering mania, mixed affective states and rapid-cycling
(Altshuler et al, 1995).

Conclusions

Depression that has its onset in adolescence or young adulthood represents a severe form of
affective disorder associated with a range of poor long-term outcomes. It often arises in families where
multiple firstand second-degree relatives have a mood disorder and is frequently complicated by
substance misuse.

Although we have highlighted the high rate of progression to bipolar disorder in this group, and
ways in which subtle indicators of bipolarity can be used to guide treatment choices, further studies of
the validity of the proposed diagnostic criteria for bipolarspectrum disorder are clearly required.

Genetic, neuroendocrine and brain-imaging studies are unravelling the complex interaction of
constitutional and environmental risk factors in earlyonset depression, but there remains a need for
longterm prospective studies of young people in the early stages of illness. These studies will have to
allow the integration of findings from a diverse range of disciplines, from basic and clinical
neurosciences to social science and epidemiology.

B. Vaccines R&D 2020: Novel nanoparticle based vaccine against respiratory viruses
Mazhar Khan
Lower respiratory tract diseases (LRTIs) comprise a significant general wellbeing trouble around
the world. LRTIs speak to a main source of human mortality and bleakness, causing every year
more than 3 million passings around the world. Among these diseases, about 80% of LRTI cases
are brought about by infections. Much of the time, these pathogens enter the host by means of
airborne transmissions (e.g., beads or mist concentrates), duplicate proficiently in the
respiratory tract and cause clinical indications, going from fever to bronchiolitis and pneumonia.
What's more, LRTIs related with infections speak to a significant wellspring of financial
misfortune for domesticated animals and poultry industry as these diseases incline creatures to
optional bacterial contaminations.

At present, there is a huge assortment of particles assessed as antigen transporters, including

inorganic and polymeric nanoparticles, infection like particles (VLPs), liposomes and self-
collected protein nanoparticles. The upsides of these materials live principally in their size (at
any rate one measurement ought to be at the nano-meter level), since numerous natural
frameworks, for example, infections and proteins are nano-sized. Nanoparticles can be
regulated by means of sub-cutaneous and intramuscular infusions, or can be conveyed through
the mucosal locales (oral and intranasal), and enter vessels just as mucosal surfaces. Ongoing
advances have permitted the arrangement of nanoparticles with one of a kind physicochemical
properties. For example, size, shape, dissolvability, surface science, and hydrophilicity can be
tuned and controlled, which permits the readiness of nanoparticles with customized organic
properties. Also, nanoparticles can be intended to permit the consolidation of a wide scope of
atoms including antigens which makes them profoundly intriguing in vaccinology Nanoparticles
and the Respiratory Tract Immune System.

In the course of the most recent decade, various nanoparticles have been intended to mirror
respiratory infections as far as size, shape and surface property so as to target NALT just as to
raise humoral and cell invulnerable reactions. Initially, adjacent to a nanoparticle size of 20–200
nm in width to coordinate the size of most respiratory infections, nanoparticles ought to be
ideally decidedly charged. Truth be told, emphatically charged polymeric, phospholipidic,
metallic, inorganic, and proteinbased nanoparticles have demonstrated more grounded
insusceptible reactions contrasted with their contrarily charged partners. Second, the
consolidation of antigens/epitopes inside or on the outside of the nanoparticles can be testing
and requires propelled approaches in compound and additionally natural designing. The most
well-known technique is to typify or ensnare antigens/epitopes inside the nanoparticles. For this
situation, nanoparticles are utilized to ensure the antigen/epitopes and convey them to NALT.
Nanoencapsulation can be accomplished by utilizing various systems, remembering
nanoprecipitation and oil for water (o/w) emulsion. On the other hand, antigens can be joined
and uncovered on the nanoparticle surface. This system targets imitating infections. Conjugation
of antigenic epitope can be performed legitimately on the nanoparticles utilizing distinctive
compound responses like the disulfide bond and the thiolategold bond development. Else, it
tends to be accomplished by first setting up an epitope-functionalized self-collecting unit, which
upon self-get together structure nanoparticles enhanced with the antigen. Third, the detailing
and organization methodologies are additionally basic perspectives to consider. Antibodies
managed by means of subcutaneous or intramuscular infusion initiate foundational resistance
and generally, a powerless mucosal reaction is watched. Then again, mucosal inoculation, either
oral or intranasal conveyance, instigates humoral, and cell safe reactions at the foundational
level and the mucosal surfaces, which is progressively viable in the security against respiratory
infections. Studies have exhibited that inoculation by means of the intranasal course gives a
superior security when contrasted with subcutaneous vaccination with regards to respiratory
pathogens and mucosal resistance. Intranasal immunization prompted higher antigenexplicit
lymphocyte expansion, cytokine creation (interferon-γ, interleukins) and acceptance of antigen-
explicit IgA neutralizer. A promising detailing procedure is the intranasal splash, which conveys
advantageously and securely the nanovaccines straightforwardly to the respiratory mucosa. In
any case, the quantity of clinical preliminaries utilizing nanovaccine plans for intranasal
conveyance, including splash dried nanovaccines, is constrained.

This is for the most part connected with the trouble of keeping the nanovaccine trustworthiness
during the whole plan process (76). Besides, the safe reaction is especially touchy to the nature,
size, shape, and surface properties of the nanoparticles just as to the thickness and the power of
the antigens. In this way, it is exceptionally testing to foresee the impact of a given nanovaccine
on the safe framework. What's more, nanoparticles have a few restrictions related with their
union, or readiness, and their properties. These incorporate restricted antigen stacking, low
amalgamation yield, poor focusing on capacity to insusceptible cells, constrained
manufacturability, and, now and again, poisonousness. These downsides can prompt symptoms
and additionally poor immunogenicity, which blocks their clinical use. Furthermore, little is
thought about the communications among nanoparticles and invulnerable cells. Indeed, their
adjuvant impact and their capacity to actuate the resistant framework despite everything stay
muddled and should be better comprehended at the atomic level. In any case, nanoparticle
definitions have as of late uncovered promising outcomes against respiratory infection diseases.

Inorganic Nanoparticles A wide scope of atoms, including adjuvants and antigens can be
conjugated on AuNPs at high thickness, bringing about improved immunogenicity and antigen
introduction. AuNPs can be figured for intranasal organization and can diffuse into the lymph
hubs, activating hearty antigen-explicit cytotoxic Tcell resistant reactions. Tao and associates
have exhibited that the peptide agreement M2e of flu An infections with a nonlocal cysteine
buildup at the C-terminal end could be joined on the AuNPs by means of thiolate–Au science.
The subsequent M2e-AuNPs was managed by the intranasal course to mice with CpG (cytosine-
guanine rich oligonucleotide) adjuvant, setting off a completely defensive insusceptible reaction
against the flu infection PR8 strain. All the more as of late, it was shown that this detailing could
incite lung B cell enactment and hearty serum hostile to M2e IgG reaction, with incitement of
both IgG1 and IgG2a subclasses. Moreover, this immunization procedure prompted security
against contamination by the pandemic flu infection strain, A/California/04/2009 (H1N1pdm)
pandemic strain, flu infection A/Victoria/3/75 (H3N2) strain and the profoundly pathogenic
avian flu infection A/Vietnam/1203/2004 (H5N1) . Albeit gold nanoparticles establish an
appealing stage for antigen conjugation, they can amass in organs, for example, liver and spleen
for a significant stretch, which could be at last connected with poisonousness. Covering with
biocompatible materials decreases their harmfulness, despite the fact that it can prompt
 modifications of the physicochemical and organic properties. In this way, security issues of
AuNPs still should be tended to.

Conclusion

Built nanoparticles have exhibited their potential as immunization conveyance stages. They can
be imagined as both antigen nanocarriers and adjuvants. In all cases, intranasal organization of
nanovaccines permits an advantageous and safe conveyance of the antigen to NALT, initiating mucosal
and fundamental insusceptibility. In any case, extra investigations are as yet required before their
clinical interpretation. While intranasal immunization of nanoparticles produces explicit IgA immunizer
in the URT and prompts high endurance rates in creature models, there are as yet constrained
investigations on non-human primates, in this way making nanoparticle's destiny hard to anticipate in a
human URT. What's more, nanoparticle antibodies are for the most part functionalized with explicit
antigen(s), which bring about a resistant reaction focused against these antigenic determinants. Thinking
about antigenic floats, the developing human populace that should be inoculated and the distinctive
sort of infections, the expense to address every one of these angles would be too restrictive to even
think about producing reasonable immunizations. Therefore, the advancement of expansive range
antibodies establishes a basic need and we consider that nanovaccine building will add to accomplish
this target.