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P3
1. PSP 3 Placement Presentation
Amelia Edmondson
Biomedical Science BSc
University of Sheffield
Academic Unit Of Bone Metabolism
2. Placement
• Based at Northern General Metabolic
Bone Centre.
• Employed with the University of Sheffield
& NHS.
• 8:30 – 16:00 from June 2017- June 2018
• Recruiting patients onto various studies
run by the department.
4. Hypophosphatasia (HPP) Study
• Mutation in the TNSALP leading to
low alkaline phosphatase activity
(ALP).
• Causes defective mineralisation.
• Several variants based on the level
of ALP activity, mainly looked at
adult/delayed diagnosis cases.
• Diagnosis rarely suspected from a
routine blood test.
• Mutations in the gene leads to
accumulation of pyridoxal 5’-
phosphate (PLP) and inorganic
pyrophosphate (lead to
hypercalcemia).
5. Case Example
• Female 54yrs old.
• Alkaline Phosphatase (Low Normal)
• Pyridoxal 5’ phosphate (High)
• Lost majority of adult teeth at age 21.
• Foot pain – due to 4th metatarsal stress
fracture.
• Mother also had stress fractures.
• Took Alendronate for 6 years for
osteopenia.
6. HPP Recruitment
• Collected under the South Yorkshire &
North Derbyshire Musculoskeletal BioBank.
• Initially approached to see if they were
interested, given a participant information
sheet (PIS) to read.
• Consented onto the project & give a unique
study ID.
• Ask about bone history,
supplement/medication use & general
health background.
• Blood taken with a routine blood test or
alone.
7. Sample Handling
• Transferred in a sealed envelope to
avoid UV damage.
• Aliquotted into Serum and Plasma
apart from 1 Whole Blood.
• Labelled Anonymously & frozen at
-80°C
• Transferred weekly to Medical
School.
• Abnormal biochemistry results
went forward to SHADES/BOHO
study.
Serum
Gel
Matrix
Plasma
Platelets/
WBC
Erythrocytes
Erythrocytes
8. SHADES/BOHO
• Understand more about
Hypophosphatasia symptoms &
improve diagnosis.
• Patients where invited back for
SHADES visit with abnormal
biochemistry & healthy matched
controls.
• If they were BOHO then the
doctor was informed with a
clinical interview
taking place.
• Whole Blood had genetic
analysis to confirm if the
mutation was present.
9. Other
Studies Opportunities
• 100,000 Genome Project.
• IDS
• Selenium Study
• Pycnodysostosis
• Mellanby Research Day
• Medical School Research Day.
• Bone Biology Course.
• microRNA in Bone Course.
• Journal Club & AUBM Teaching
Sessions.
• Guest Lectures.
• Clinic Observations
10. Pros & Cons
• Taught me to be more independent.
• Organise my time better.
• Rewarding, helping the patients.
• Unpaid – despite having student
finance
• Only so much you can do.
• Stressfully at times
Apply for Placements
Pros Cons
- Only picture from our department (was at the Christmas party)
- Also taking the blood samples for the study, processing & aliquoting them before transporting them to the medical school.
Prevalence is estimated at 1:538,000 worldwide, higher in the Manitoba Mennonite Community 1:100,000 due to consanguinity.
Under reported due to 1:1,544 suspected to have a low ALP
Loss of function mutation in the ALPL gene than encodes for the TNSALP.
ALP itself is non-specific so the bones specific for bALP is used specifically for this disease.
ALP 30-130 IU/L
bALP 4.2 – 23/8 ug/l
Defective mineralization means the bones are more prone to fracturing & deformities – as well as tooth loss.
Skeletal, dental are the main charcteritsics but others inc, muscular, renal, respiritory, rheumalogical or neurological.
Childhood, Infantile (both fatal), Prenatal Begin (non-fatal), odontohyphosphatasia (just teeth) & Pseudohyphosphatasia.
Other causes of low ALP, Wilson’s decease (copper deficiency), the most frequent being cardiac surgery and cardiopulmonary bypass (26.5%), malnutrition (celiac/thyroid) (12.0%), magnesium deficiency (4.8%), hypothyroidism (2.4%), and severe anaemia (1.2%).
Genetic conformation of the mutation is needed.
Lead to hypocalcemia
PLP also the bioactive form of vitamin B6 – can cause a false positive diagnosis.
- Total ALP 42 IU/L Bone ALP 12IU/L
- PLP 190 nmol/L (40-100)
- High dose vitamin D, calcium supplements & bisphosphonates are given as the treatment for osteopenia/low BMD.
- Around age 50.
- Exacerbate the symptoms of HPP and increase the risk of an AFF (within a shorter time frame half or even quarter– usually after 10yr+ )
- Fall causing an AFF (in the middle of the femur shaft on both sides).
Collected as a Sub-Study recruiting 1000 patients to screen for abnormal HPP biochemistry.
Patients came from from consultants clinics, post-DXA scan work-ups & day case, all needing blood tests or interested in research.
2 x 8.5ml SST (Gold) & 2 x 4ml EDTA (Purple) - Sometimes not all blood could be obtained.
2x SST & 1 x EDTA - Centrifige (3,000 rpm, 4°C, 10/15 minutes).
1 Whole blood.
Usually got approximately 15 serum & 4 plasma.
SHADES = Suspected hypophosphatasia in Adults Evaluation Study
BOHO = Burden of health on hyphophosphatasia
Consented before taking ‘fasted’ blood or urine. Medical history & SPPB muscle function test (Chair stand test, 8ft walk test & Tandem balance test).
BOHO = Confirmed diagnosis of HPP.
Sometimes the whole blood analysis came back with negative results – fed onto the 100,000 Genomes Project.
