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Section 8. Medical science
Volikova Olga Aleksandrovna, SE «Dnepropetrovsk Medical Academy of Health Ministry of Ukraine», teaching assistant
E-mail: ovolja@ukr.net
Correlation of locus alleles of DRB1 II class of histocompatibility complex with clinical, immunological and virological parameters in HIV infection
Abstract: Associations between the presence in HIV infected patients of different variants of HLA DRB1 locus alleles and the risk of HIV-associated diseases development while receiving HAART are determined. There is a correlation between HLA DRB1 locus alleles of histocompatibility class II and levels of ^2-microglobulin, neopterin, immune cell activation and HIV load in patients receiving HAART.
Keywords: HIV infection, HIV-associated diseases, the system of HLA II class, allele locus DRB1, viral load,
CD4, HAART.
It was shown that the increase in viral load (VL) may promote systemic activation of the immune system in HIV infection, which is a strong predictor of disease progression in HIV infection. It was proved that increased level of ^2-microglobulin (^2-MG) is associated with changes in the immune status and HIV viral load and is connected with HIV progression and survival of patients [2; 3].
There are literary data regarding positive associations of tuberculosis with specific HLA DRB1 locus that indicate susceptibility to tuberculosis [1].
Objective
Identify association between the presence of different variants of locus alleles of DRB1 in patients with HIV infection and the risk of HIV-associated disorders and changes in immunological and virological parameters in patients receiving highly active antiretroviral therapy (HAART).
Materials and methods
The study involved 102 patients with HIV aged 24 to 58 years, the average age of patients was 38 years. The term of infection of examined subjects was in averaged 7.4 ± 0.33 years. According to the clinical course of HIV infection, all patients were divided into three groups. The 1st group included 32 patients (31.4 %) with I and II clinical stages, the 2nd group included 26 (25.5 %) patients with clinical stage III, the 3rd group included 44 (43.1 %) patients with IV clinical stage. All patients were also divided into seven groups by the presence of locus alleles DRB1 of class II histocompatibility complex. Six research groups consisted of patients with alleles of genes that occur most frequently among persons in the Dnepropetrovsk region: HLA DRB1 *01, HLA DRB1 *04, HLA DRB1 *07, HLA DRB1 *11, HLA DRB1 *13, HLA DRB1 *15. The seventh group consisted of patients with alleles locus that is rarely found (HLA DRB1 *03, HLA DRB1 *08, HLA DRB1 *10, HLA DRB1 *12, HLA DRB1 *14, HLA DRB1 *16, HLA DRB1 *17, HLA DRB1 *18). Most examined patients (87.3 %) received HAART for medical reasons, 12.7 % of patients in the study did not receive HAART for any other reason. The control group involved 15 healthy donors.
Specificities of 15 alleles of genes DRB1 were defined with amplified test systems. Determination of levels of neopterin (N) and ^2-MG handled by ELISA with standard test systems (manufacturer Germany).
Statistical analysis of the obtained material used the methods of Fisher criterion and Student’s test. Value of p <0.05 was considered statistically significant. Statistical analysis of the results was performed using the software MathCad and Excel-2010. Considering the large range ofVL data, for statistical analysis a log scale data were calculated.
Results
According to our observations the highest percentage of occurrence of various forms of HIV-associated tuberculosis (TB), including first diagnosed tuberculosis (FDTB) observed in the lungs of patients with locus alleles HLA DRB1 *13 *15 and rarely seen locus alleles. Also various forms of TB in a smaller percentage ofcases developed in patients with locus alleles HLA DRB1 *04 *07 *11. TB never occurred in patients who had gene allele HLA DRB1 *01 (Table 1).
As shown in Table 1, recurrent bacterial infection of the upper respiratory tract (URT) occurred in patients with HIV locus with alleles HLA DRB1 *01, *04, *07, *11 and with rare alleles. Pneumonia developed in patients who have had locus alleles HLA DRB1 * 01, * 11, * 13. Concurrent herpetic infections in HIV-infected patients occurred in the presence of gene alleles HLA DRB1 *04 *07 *11 and rare alleles of locus. In HIV-infected examined patients of all groups regardless of the system of HLA DRB1 HIV-associated oropharyngeal candidiasis developed. Persistent generalized lymphadenopathy (PGL) was seen in HIV infected patients with locus alleles HLA DRB1 *01 *04 *11 *13 and rare alleles.
Chronic viral hepatitis C (CHCV) and chronic hepatitis (CH) unspecified (including toxic hepatitis) as concomitant disease, developed in HIV-infected patients irrespective of HLA class II. Chronic viral hepatitis B (CHBV) occurred in patients with gene alleles HLA DRB1 *01, *04, *11 and rare alleles. CH progressed into cirrhosis in patients with locus alleles HLA DRB1 *04. Anemia I, II, III degree accompanies patients with HIV infection who have locus alleles HLA DRB1 *04, *11, *13 and rare alleles. (Table 2)
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Correlation of locus alleles of DRB1 II class of histocompatibility complex with clinical, immunological...
Table 1. - Dynamics of HIV-associated diseases in patients with different alleles of HLA DRB1 locus in patients receiving HAART
Alleles HLA DRB1 locus PGL, % Oropharyngeal candidiasis, % Recurrent bacterial infection of the URT, % Pneumonia, % FDTB lung Various forms of TB, % Herpetic infection, %
HLA DRB1 *01 31.6 67.7 31.6 31.6 - - -
HLA DRB1 *04 43.6 87.5 37.5 - 31.3 - 37.5
HLA DRB1 *07 - 50 37.5 - - 26.9 34.6
HLA DRB1 *11 30.4 78.3 33.3 33.3 - 33.3 23.3
HLA DRB1 *13 37.5 79.2 - 41.7 37.5 45.8 -
HLA DRB1 *15 - 75 - - 50 50 -
Rare alleles 20 80 30 - 35 40 30
P < 0.004 < 0.003 < 0.004 < 0.005 < 0.003 < 0.004 < 0.005
Table 2. - Dynamics of disease development in HIV-infected patients with different locus alleles of HLA DRB1 in patients receiving HAART
Alleles HLA DRB1 locus CHCV, % CHBV, % CH unspecified (including toxic hepatitis), % Cirrhosis, % Anemia I, II, III degree, %
HLA DRB1 *01 63 42 84 - -
HLA DRB1 *04 68.7 43.8 81.3 31.3 56.3
HLA DRB1 *07 41.7 - 58.3 - -
HLA DRB1 *11 60.8 34.8 78.3 - 52.2
HLA DRB1 *13 62.5 - 79.2 - 33.3
HLA DRB1 *15 50 - 66.7 - -
Rare alleles 52.5 37.5 72.5 - 30
P < 0.004 < 0.003 < 0.005 < 0.004 < 0.003
Table. 3. - Dynamics of biochemical and immunological parameters in HIV-infected patients with different locus alleles DRB1 II class while taking HAART
Alleles of HLA DRB1 locus Groups of patients N, nmol/l Pz-MG, mcg/ml CD4+ T-helper cells P
I 33.444 ± 29.479 6.578 ± 1.676 426 ±185 < 0.003
HLA DRB1 *01 II 53.5 ± 3.536 9.25 ± 0.355 340 ± 4.95 < 0.006
III 56.714 ± 10.847 9.429 ± 1.117 323±200 < 0.004
I 65 ± 42.509 9.2 ± 45.197 428±115 < 0.003
HLA DRB1 *04 II 68.4 ± 1.709 9.44 ± 2.389 422±184 < 0.006
III 77.125 ± 10.062 25.039 ± 1.432 127±123 < 0.004
I 29.125 ± 14.055 7.05 ± 1.623 552±191 < 0.003
HLA DRB1 *07 II 53.333 ± 33.399 8.6 ± 2.245 279 ± 59 < 0.006
III 50 ± 10.583 8.14 ± 0.876 193 ± 89 < 0.004
I 24 ± 9.899 6.45 ± 0.636 468 ±145 < 0.003
HLA DRB1 *11 II 56.222 ± 14.292 9.389 ± 1.013 359 ± 86 < 0.006
III 68.1 ± 30.658 10.06 ± 1.831 130 ± 92 < 0.004
I 46 ± 9.077 8.3 ± 1.011 533±238 < 0.003
HLA DRB1 *13 II 56.333 ± 37.033 8.7 ± 2.573 387±146 < 0.006
III 61.083 ± 24.839 9.042 ± 1.215 171±129 < 0.004
I 31.875 ± 13.943 7.238 ± 1.48 551±172 < 0.003
HLA DRB1 *15 II 79 ± 8.888 9.663 ± 1.212 211 ± 69 < 0.006
III 83 ± 33.141 9.757 ± 1.427 201±201 < 0.004
I 31 ± 12.423 7.757 ± 1.176 447±183 < 0.003
Rare alleles II 50 ± 20.255 8.531 ± 1.284 344±117 < 0.006
III 74.706 ± 32.247 9.641 ± 1.855 162±130 < 0.004
Tables shown in almost all patients in all examined groups cells and increased levels of N and ^2-MG in the development there was an increase in VL, reduced levels of CD4 + T-helper of HIV from I till IV clinical stages in patients receiving HAART.
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Section 8. Medical science
Table. 4. - Dynamics of changes in viral load in HIV-infected patients with different gene alleles DRB1 II class on HAART
Alleles HLA DRB1 locus Groups of patients VL (ln) P
HLA DRB1 *01 I 4.325 ± 3.433 < 0.004
II 3.689 < 0.007
III 2.405 ± 5.753 < 0.005
HLA DRB1 *04 I 3.689 < 0.004
II 4.677 ± 3.047 < 0.007
III 7.461 ± 4.423 < 0.005
HLA DRB1 *07 I 4.359 ± 2.085 < 0.004
II 4.144 ± 1.991 < 0.007
III 5.583 ± 2.81 < 0.005
HLA DRB1 *11 I 3.924 ± 0.332 < 0.004
II 5.661 ± 2.942 < 0.007
III 7.486 ± 4.377 < 0.005
HLA DRB1 *13 I 4.619 ± 2.168 < 0.004
II 7.767 ± 2.857 < 0.007
III 5.292 ± 2.127 < 0.005
HLA DRB1 *15 I 6.216 ± 3.632 < 0.004
II 8.154 < 0.007
III 8.154 ± 4.327 < 0.005
Rare alleles I 5.064 ± 3.074 < 0.004
II 4.008 ± 0.625 < 0.007
III 7.16 ± 4.139 < 0.005
In patients with the allele HLA DRB1 *01 reduction in VL 1.8-fold (between I and III groups) was observed and CD4+ T-helper cells were kept at a high level (up to 323 ± 200) even taking into account the stage of HIV infection that was not observed in other alleles of the HLA DRB1 gene. In all other patients who had the allele HLA DRB1 locus *04, *07, *11, *13, *15 and rare alleles with IV clinical stage CD4+ T-helper cells were decreased to the level of < 200 in 1 mm 3 and VL was increased 1.2-2.1 times. Increased levels of N and ^2-MG were observed in all patients with different alleles of the HLA DRB1 locus. However, the most significant increase in both N and ^2-MG was seen in carriers of alleles of the locus HLA DRB1 *01, *11, *15. Thus, at HLA DRB1 *01 N was increased 1.7 times, ^2-MG by 1.4 times; in HLA DRB1 *11 N was increased 2.8 times, ^2-MG is 1.6; with HLA DRB1 *15 N was increased 2.6 times, |?2-MG 1.4 times. A separate significant 1.7 times increase of N was observed in patients with alleles of the locus HLA DRB1 *07 and in rare alleles 2.4 times. A separate and significant increase of |?2-MG 2.7 times was observed in patients who had the alleles of the locus HLA DRB1 *04.
Conclusions
1. There was a correlation between alleles of DRB1 locus of HLA histocompatibility class II and ^2-MG, N, cellular immune activation and HIV load in patients receiving HAART.
2. In the process of receiving HAART in patients with alleles of the locus HLA DRB1 *01 there was observed the 1.8 times decrease of VL, the content of CD4+ T-helper cells at a sufficiently high level, even taking into account the stage of HIV infection
that was not observed in other alleles of the HLA DRB1 gene. With the alleles of the locus HLA DRB1 *04, *07, *11, *13, *15 and rare alleles even with HAART there was a sharp decrease in CD4+ T-helper cells to the level of < 200 in 1 mm 3 and an increase in VL.
3. Increased levels of N and ^2-MG were observed in all patients with different alleles of the HLA DRB1 locus. However, the most significant increase in both N and P2-MG was seen in alleles of the locus HLA DRB1 *01, *11, *15.
4. The highest percentage of occurrence of HIV-associated TB of various forms, including FDTB lung was observed in patients with alleles of the locus HLA DRB1 *13, *15 and with rare alleles. Also TB of various forms in a smaller percentage of cases developed in patients with alleles of the locus HLA DRB1 *04, *07, *11. In patients who had the allele of gene HLA DRB1 *01 TB did not develop.
5. Pneumonia developed in HIV-infected patients who had alleles of the locus HLA DRB1 *01, *11, *13.
6. The development of herpetic infection in HIV-infected patients occurred in the presence of gene HLA DRB1 alleles *04, *07, *11 and rare alleles.
7. Chronic HCV and chronic hepatitis unspecified (including toxic hepatitis) as a concurrent disease developed in HIV-infected patients regardless of the HLA class II. Chronic HBV was seen in patients with HLA alleles DRB1 *01, *04, *11, and rare alleles. Chronic hepatitis progressed to cirrhosis in patients with alleles of the locus HLA DRB1 *04.
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Ultrasound examination of upper lip in patients with unilateral cheilognathopalatoschisis
References:
1. Stavitsky N. V. The development of genetic factors in children with latent tuberculosis infection.//Fundamental research. -2010. - № 5. - P. 53-59.
2. Leligdowicz Aleksandra, Feldmann Jerome, Jaye Assan et al. Direct Relationship between Virus Load and Systemic Immune Activation in HIV-2 Infection.//J Infect Dis. - 2010. - 201 (l): 114-122.
3. Liu Zhiyuan, Cumberland William G., Hultin Lance E., et al. Elevated CD38 Antigen Expression on CD8+ T Cells Is a Stronger Marker for the Risk of Chronic HIV Disease Progression to AIDS and Death in the Multicenter AIDS Cohort Study Than CD4+ Cell Count, Soluble Immune Activation Markers, or Combinations of HLA-DR and CD38 Expression.// Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology. - October 1, 1997. - Volume 16 -Issue 2 - Р. 83-92.
Vokhidov Utkirbek Nuridinovich, Tashkent State Stomatological Institute, Department of children's maxillofacial surgery E-mail: dr_utkirbek@mail.ru
Ultrasound examination of upper lip in patients with unilateral cheilognathopalatoschisis
Abstract: Congenital cheilognathopalatoschisis is one of the most actual and urgent problems of the stomatology. 205 patients were under supervision, 122 of them were the patients with unilateral bilateral cleft of the lip and palate, 83 of them suffered from unilateral isolated cleft lip. The research showed that the echographic examination which allows a detailed image of the upper lip, alveolar process, hard and soft palate, palatal suture and tongue is highly efficient method of assessment of individual anatomical peculiarities of the building of the upper jaw in children with cheilognathopalatoschisis.
Keywords: congenital cheilognathopalatoschisis, echographic study, children, labioplasty.
The enhancement in the sphere of medical rehabilitation of children with congenital cheilognathopalatoschisis is one of the most actual and urgent problems of the present day. Complete medical, psychological, social adaptation of a child and the formation of the personality depend on the results of elimination of anatomical, functional and cosmetic defects as well as timely conduction of rehabilitation works [1; 4].
In order to provide qualified assistance to this group of difficult patients multi-stage surgery and constant supervision of surgeons, orthodontists, pediatricians, speech therapists and other specialists are required from the birth till an adult age at the specialized centers [2].
Detailed knowledge of individual anatomical peculiarities of children with congenital cheilognathopalatoschisis allows the surgeon to choose the appropriate operative method. Underestimation of the degree of anatomical defect in the patients with congenital cheilognathopalatoschisis hinders the achievement of good post operative results.
Traditionally to examine these type patients ray diagnostics such as radiography, computer tomography, magnetic resonance tomography are used in addition to physical methods. However the usage of ray diagnostics may be maximally limited in patients of an early age. Moreover, in order to examine infants and children of a preschool age, it is important to ensure immobility of them, which requires the condiction of the examination under anesthesia.
Ultrasound examination has become widely used in the practice of maxillofacial surgery in the recent years. The competency of ultrasound is spreading not only on the study of soft tissues of face and neck, which is the traditional variant of using this method, but also it allows to evaluate bone structures-the surface of the bone, its configuration, the degree of mineralization as well as relative positioning of bone fragments. Absolute advantages of this method are its non-invasiveness, safety and the opportunity of using it on patients for many times [5-7].
Ultrasound-based diagnostic imaging can be carried out at a different position of the patient (standing, sitting, lying), which is particularly important in the assessment of functional condition of soft tissues. This method may be applied to the patients of any age including newborns and it does not require special preparation and assistive means.
Informativeness of echographic study gives an opportunity to limit the use of radiological methods, to use invasive diagnostic intervention less frequently, to approach to the usage of expensive examinations as CT and MRI more rationally [3].
Study objective
To improve the quality of examination of patients with congenital cheilognathopalatoschisis on the basis of introduction of improved methods of echographic study to the diagnostic process.
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