GENOME

New Test in NOÛS Catalog

Test Code: 9960

Sample:	Biological Sample
Conservation:	Refrigerated
Method:	Next Generation Sequencing (NGS)
Set Up Days:	Daily
Delivery term:	42 days
Information:

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CARTILAGE OLIGOMERIC MATRIX PROTEIN (COMP), SERUM

New Test in NOÛS Catalog

Test Code: 9959

Sample:	Serum (1 ml)
Conservation:	Refrigerated
Method:	Enzyme Immunoassay
Set Up Days:	Daily
Delivery term:	6 days

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Haemophilia A (inv(intron 22A)-F8) screening, whole blood

Description and Delivery Time Modification

Test code: 3611

Mnemonic code: G04052

Effective update from 08/01/2024

PREVIOUS	NEW
Description: Haemophilia A (inv(intron 22A)-F8) screening, whole blood       Delivery time: 25 days                   Version of Test: 1	Description:  HAEMOPHILIA A · F8 (INTRON 22 INVERSION) · RT-PCR       Delivery time: 27 days                        Version of Test: 2

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ALBENDAZOLE SULFOXIDE, SERUM

New Test in NOÛS Catalog

Test Code: 9958

Sample:	Serum (1 ml)
Conservation:	Frozen
Method:	High Performance Liquid Chromatography
Set Up Days:	Daily
Delivery term:	6 days

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ACID PHOSPHATASE TARTRATE RESISTANT, SERUM

Correction of Units

Test code: 2186

Mnemonic code: FATR

Effective update from 27/12/2023

Correction of units regarding the update made on 27/12/2023. The current units are UI/L, not UI/mL as published on 14/12/2023."

PREVIOUS	NEW
Units: UI/mL                   Version of Test: 5	Units: UI/L                                    Version of Test: 6

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MOLECULAR STUDY GENOTYPE MHC-C (LOW RESOLUTION), WHOLE BLOOD

Reference values and Delivery Time Modification

Test Previous code: 4475

Test New code: 9955

Effective update from 27/12/2023

PREVIOUS	NEW
Results Format:       R1: See attached report	Result Format:       R1: KIR ligand genotype (HLA-C group)       R2: LOCUS C (Class I)       (a*) Interpretative text of the study

(a*) MOLECULAR STUDY HLA-C GENOTYPE (LOW RESOLUTION), WHOLE BLOOD

DETERMINATION

Molecular typing of human leukocyte antigen (HLA -C class I) alleles at the allele group level (low resolution).

TEST PRINCIPLE

The technique is based on the reverse hybridization principle. A P CR-SSO is carried out after DNA isolation.

At the PCR, amplification of exons 2 and 3 of the HLA-C locus occurs and PCR products are biotinylated. Then, amplification products are subsequently hybridized using a typing strip. This test is designed to give the best possible resolution at the allele group level (this means the first two digits after the asterisk in an allele name following standard HLA nomenclature, ex. Cw*07Cw*08), although resolution to the allelic level may be possible for the most allele combinations.

Interpretation of the results is based on the allele population frequency.

ALLELE GROUPS:

C1: C*01, C*03 (except C*03:07), C*07 (except C*07:07, C*07:09), C *08, C*12 (except C*12:04, C*12:05), C*14,C*15:07, C*16 (except C*16:02),C2: C*02, C*03:07, C*04, C*05, C*06, C*07:07, C*07:09, C*12:04, C *12:05, C*15 (except C*15:07), C*16:02, C*17, C*18

APPLICATION IN HUMAN REPRODUCTION

At a pregnancy, maternal uterine natural killer cells (UNKs) are the dominant immune cells in the uterine mucosa and there are multiple studies that support their important role in establishing normal early placentation (1, 2, 3, 4, 5, 6). There are also evidences of a dir ect ligand-receptor interaction between trophoblastic cells (which show HLA -C class I molecules) and UNKs KIR receptors. This interaction seems to

condition the process of placentation. HLA genotypes are organized into two groups (HLA -C1 and HLA-C2), and although both HLA-C1 and HLA-C2 bind to KIR receptors, the strength of the downstream UNKs response is str ongly influenced by C1 and C2 zygosity of

the new pregnancy. The extreme variability in both the maternal KI R and fetal HLA -C ligands means that each pregnancy will feature a range of different combinations. Therefor e, the balance of KIR genotypes in a given patient and the HLA-C exposure in a given pregnancy may influence the initiation of normal placentation (7).

 REFERENCES

(

1). Trundley A., Moffett A. Human Uterine Leukocytes and pregnancy. Tissue Antigens 2004; 63: 1-12.
(2). Caligiuri MA. Human natural killer cells. Blood 2008; 112: 461-9.
(3). Moffett A., Shreeve N. First do no harm: uterine natural kill er (NK) cells in assisted reproduction. Human
Reproduction 2015; 30: 1519-25.
(4). Pace D., Morrison L., Bulmer JN. Proliferative activity in en dometrial stromal granulocytes throughout
menstrual cycle and early pregnancy. J Clin Pathol 1989; 42: 35-9.
(5). Xiong S., Sharkey AM. Kennedy PR, Gardner L, Farrell LE, Cha zara O, et al. Maternal uterine NK cell -
activating receptor KIR2DS1 enhances placentation. J Clin Invest 2013; 123: 4264-72.
(6). Robson A. Harris LK, Innes BA, Lash GE, Aljunaidy MM, Aplin JD, et al. Uterine natural killer cells
initiate spiral artery remodeling in human pregnancy. FASEB J 2012; 26: 4876-85.
(7). Scott J. Morin, Nathan R. Treff, Xin Tao, et al. Combination of uterine natural killer cell immunoglobulin
receptor haplotype and trophoblastic HLA -C ligand influences the risk of pregnancy loss: a retrospective co hort
analysis of direct embryo genotyping data from euploid transfers.

 

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KIR GENOTYPE + HLA-C TYPE I, WHOLE BLOOD

Test code, Description and Result Format Modification

Test code Previous: 7772

Test code New: 9954

Effective update from 27/12/2023

PREVIOUS

NEW

Results Format:      R1: See attached report

Results Format:   R1:   2DL1 GENOTYPE        RV: Absence   R2:   2DL2 GENOTYPE        RV: Absence   R3:   2DL3 GENOTYPE        RV: Absence   R4:   2DL4 GENOTYPE        RV: Absence   R5:   2DL5 GENOTYPE        RV: Absence   R6:   2DP1 GENOTYPE        RV: Absence   R7:   2DS1 GENOTYPE        RV: Absence   R8:   2DS2 GENOTYPE        RV: Absence   R9:   2DS3 GENOTYPE        RV: Absence   R10:  2DS4 GENOTYPE        RV: Absence   R11:  2DS5 GENOTYPE        RV: Absence   R12:  3DL1 GENOTYPE        RV: Absence   R13:  3DL2 GENOTYPE        RV: Absence   R14:  3DL3 GENOTYPE        RV: Absence   R15:  3DP1 GENOTYPE        RV: Absence   R16:  3DS1 GENOTYPE        RV: Absence   R17: KIR HAPLOTYPE   R18: KIR ligand genotype (HLA-C group)   R19: Locus c (Class I)   (b*) Interpretative text of the study

 (b*) KIR GENOTYPE + HLA-C Class I, WHOLE BLOOD

GEKIR – KIR GENOTYPE, WHOLE BLOOD

TECHNIQUE:

KIR Genotyping (killer immunoglobulin -like receptor) from genomic DNA by PCR technology (Polymerase Chai n Reaction), using sequence -specific primers (SSPs) designed for the detection of the 16 human KIR gene:

2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DP1, 2DS1,2DS2,2DS3,2DS4, 2DS5, 3DL1, 3DL2, 3DL3, 3DP1, 3DS1.

 

INTERACTIONS BETWEEN HLA-C - KIR AND ITS ROLE IN THE EVOLUTION OF A PREGNANCY

During the first trimester of pregnancy, infiltration into the decidua of maternal uterus occurs by trophoblastic cells of the blast ocyst. The trophoblast will give place to the placenta, organ which will provide the fetal blood supply. A defect in this process of placentation, produces multiple disorders such as premature births, pre-eclampsia, low fetal growth or spontaneous miscarriage (1).

Studies have shown that part of the regulation of placentation, is produced under the influence of local immunological recognition (2).

The trophoblast cells express high levels of HLA -C which are recognized by the KIR (Killer immunoglobulin-like receptors) of the uNK (Natural Killer cells uterine) (3).

KIRs are expressed from a highly polymorphic family of genes, and the HLA-C of the trophoblast is encoded in an equally polymorphic gene set, derived 50% from the father and 50% from the mother (4, 9). This fact gives rise to a different embryonic HLA-C genotype in each pregnancy, even in the case of same parents (5).

The maternal KIR haplotype can be AA, AB or BB (6). Haplotype A co ntains mainly genes for inhibitory KIRs and haplotypes B have addi tional genes that encode activating KIRs (3). The presence of activating KIRs (haplotype B) confers protection against disorders in pregnancy (7) and their absence (haplotype A), increases the risk of complications ( 5). The balance between activation - inhibition, results in the release of cytokines that favor placental trophoblastic infiltration (8).

The HLA-C ligands for the KIR belong to two allelic groups, C1 and C2. It has been observed that the risk of recurrent miscarriages, pree clampsia, or low fetal growth is increased when mothers own KIR AA haplotype

and the fetus expresses more HLA-C2 genes than maternal cells; moreover when these additional HLA-C2 are inherited from the father (7). This situation takes another outlook in assisted pregnancies, wher e patients often are receptors of more than one embryo and adition ally, those could be the result of a fertilization with an sperm or oocyte donors or both. In these cases, HLA -C molecules expressed by the trophoblast would behave as if they were of paternal origin (3).

With this information we can reach the following conclusion (appli ed to the field of reproductive medicine):

Consideration to take into account in cases where it is necessary sperm or oocytes donors, or both:

- If the receiving woman has a KIR AA haplotype, the better choice for a more efficient and safe implantation of the embryo, seems to be the selection of a semen and egg donors with HLA-C1/C1 haplotype.

 REFERENCES

 (1) Brosens et al. The `Great Obstetrical Syndromes´ are associated wi th disorders of deep placentation. Am. J. Obstet. Gynecol.(2011);204:193-201.
(2) A. Moffett et al. Variation of maternal KIR and fetal HLA -C genes in reproductive failure: too early for clinical interventi on. Reproductive BioMedicine Online (2016); 33:763-769.
(3) D. Alecsandru et al. Why natural killer cells are not enough: a fu rther understanding of killer immunoglobulin -like receptor and human
leukocyte antigen. Fertility and Sterility (2017) Vol.107 no. 6, 0015-0282.
(4) D. Torres -García et al. Receptores de células NK (KIR): Estructura, función y relevancia en la susceptibilidad de enfermedades. Revista
Instituto Nacional de Enfermedades Respiratorios Ismael Cosío Vill egas (2008), vol.21 No.1
(5) Moffett A. et al. Uterine NK cells: active regulators at the mater nal-fetal interface. J Clinic Invest (2014);124:1872-9.
(6) Uhrberg M. et al. Human diversity in killer cell inhibitory receptor genes. Immunity (1997); 7:753-63.
(7) Hiby SE. et al. Maternal activating KIRs protect against human rep roductive failure mediated by fetal HLA-C2. J Clin Invest (2010); 120:4102-10.
(8) Kennedy PR. et al. Activating KIR2DS4 is expressed by uterine NK c ells and contributes to successful pregnancy. J Immunol (2016);
197:4292-300.
(9) Midleton D. et al. The extensive polymorphism of KIR genes. J Immu nol (2009); 129:8-19.

 

MOLECULAR STUDY HLA-C GENOTYPE (LOW RESOLUTION), WHOLE BLOOD

DETERMINATION

Molecular typing of human leukocyte antigen (HLA -C class I) alleles at the allele group level (low resolution).

TEST PRINCIPLE

The technique is based on the reverse hybridization principle. A P CR-SSO is carried out after DNA isolation.

At the PCR, amplification of exons 2 and 3 of the HLA-C locus occurs and PCR products are biotinylated. Then, amplification products are subsequently hybridized using a typing strip. This test is designed to give the best possible resolution at the allele group level (this means the first two digits after the asterisk in an allele name following standard HLA nomenclature, ex. Cw*07Cw*08), although resolution to the allelic level may be possible for the most allele combinations.

Interpretation of the results is based on the allele population frequency.

ALLELE GROUPS:

C1: C*01, C*03 (except C*03:07), C*07 (except C*07:07, C*07:09), C *08, C*12 (except C*12:04, C*12:05), C*14,C*15:07, C*16 (except C*16:02),C2: C*02, C*03:07, C*04, C*05, C*06, C*07:07, C*07:09, C*12:04, C *12:05, C*15 (except C*15:07), C*16:02, C*17, C*18

APPLICATION IN HUMAN REPRODUCTION

At a pregnancy, maternal uterine natural killer cells (UNKs) are the dominant immune cells in the uterine mucosa and there are multiple studies that support their important role in establishing normal early placentation (1, 2, 3, 4, 5, 6). There are also evidences of a dir ect ligand-receptor interaction between trophoblastic cells (which show HLA -C class I molecules) and UNKs KIR receptors. This interaction seems to

condition the process of placentation. HLA genotypes are organized into two groups (HLA -C1 and HLA-C2), and although both HLA-C1 and HLA-C2 bind to KIR receptors, the strength of the downstream UNKs response is str ongly influenced by C1 and C2 zygosity of

the new pregnancy. The extreme variability in both the maternal KI R and fetal HLA -C ligands means that each pregnancy will feature a range of different combinations. Therefor e, the balance of KIR genotypes in a given patient and the HLA-C exposure in a given pregnancy may influence the initiation of normal placentation (7).

 REFERENCES

(

1). Trundley A., Moffett A. Human Uterine Leukocytes and pregnancy. Tissue Antigens 2004; 63: 1-12.
(2). Caligiuri MA. Human natural killer cells. Blood 2008; 112: 461-9.
(3). Moffett A., Shreeve N. First do no harm: uterine natural kill er (NK) cells in assisted reproduction. Human
Reproduction 2015; 30: 1519-25.
(4). Pace D., Morrison L., Bulmer JN. Proliferative activity in en dometrial stromal granulocytes throughout
menstrual cycle and early pregnancy. J Clin Pathol 1989; 42: 35-9.
(5). Xiong S., Sharkey AM. Kennedy PR, Gardner L, Farrell LE, Cha zara O, et al. Maternal uterine NK cell -
activating receptor KIR2DS1 enhances placentation. J Clin Invest 2013; 123: 4264-72.
(6). Robson A. Harris LK, Innes BA, Lash GE, Aljunaidy MM, Aplin JD, et al. Uterine natural killer cells
initiate spiral artery remodeling in human pregnancy. FASEB J 2012; 26: 4876-85.
(7). Scott J. Morin, Nathan R. Treff, Xin Tao, et al. Combination of uterine natural killer cell immunoglobulin
receptor haplotype and trophoblastic HLA -C ligand influences the risk of pregnancy loss: a retrospective co hort
analysis of direct embryo genotyping data from euploid transfers.

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VASOPRESSIN - ANTIDIURETIC HORMONE (ADH), PLASMA

Units and Reference values Modification

Test code: 415

Mnemonic code: VASO

Effective update from 02/01/2024

PREVIOUS	NEW
Units: pg/mL Reference values:1. 0 - 3.6 pg/mL        * Fuente: PNT, Insert       Version of Test: 17	Units: pmol/l Reference values: Less than or equal to 13 pmol/l           * Fuente: PNT, Insert                Version of Test: 18

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ALUMINIUM, SERUM/PLASMA - MANGANESIUM, SERUM

Sample Modification

Test code: 275, 380

Mnemonic code: ALU, MN

Effective update from 27/12/2023

PREVIOUS	NEW
Heparin Li Plasma Trace Metal-Free	Serum Trace Metal-Free

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INHIBIN B , SERUM

Reference values Modification

Test code: 2518

Mnemonic code: INHI

Effective update from 02/01/2024

PREVIOUS	NEW
Little girls: Less than 83 pg/mL Little boys: 4 - 352 pg/mL Men: 25 - 325 pg/mL Women: Less than 341 pg/mL Women (3rd day of cycle): Less than 273 pg/mL Women (post-menopause): Less than 5.79 pg/mL             Version of Test: 16	Little girls: Less than 83 pg/mL Little boys: Less than 352 pg/mL Men: 25 - 325 pg/mL Women: Less than 341 pg/mL Women (3rd day of cycle): Less than 273 pg/mL Women (post-menopause): Less than 5.8 pg/mL                              Version of Test: 17

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PARATHYROID GLAND ANTIBODIES, SERUM

New Test in NOÛS Catalog

Test Code: 9942

Sample:	Serum (2 ml)
Conservation:	Refrigerated
Method:	Indirect fluorescent antibody
Set Up Days:	Daily
Delivery term:	7 days

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BICTEGRAVIR, SERUM

New Test in NOÛS Catalog

Test Code: 9953

Sample:	Serum (3 ml)
Conservation:	Frozen
Method:	Liquid Chromatography/Tandem Mass Spectrometry
Set Up Days:	Daily
Delivery term:	21 days

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CYTOKINE ASSAY PANEL FOR IMMUNE PROFILE

Delivery Time Modification

Test code: 8953

Mnemonic code: PIPC

Effective update from 27/12/2023

PREVIOUS	NEW
Delivery term: 15 days	Delivery term: 25 days

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Chromosome Y microdeletions (AZFa, AZFb, AZFc, DAZ) screening, total blood

Description, Method and Reference values Modification

Test code: 2674

Mnemonic code: Does not apply

Effective update from 02/01/2023

PREVIOUS	NEW
Description: Chromosome Y microdeletions (AZFa, AZFb, AZFc, DAZ) screening, total blood       Method: Multiplex PCR       Reference Values:       Not detected.                                  Version of Test: 3	Description: AZOOSPERMIA/SEVERE OLIGOZOOSPERMIA · Y CHROMOSOME (AZFa, AZFb, AZFc MICRODELETIONS) · FRAGMENTS A.      Method: Multiplex Fluorescent PCR - Fragment Analysis        Reference Values:      See in attached report                   Version of Test: 4

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