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Biomedical subjects

A Giwercman

Publications and source records attributed to A Giwercman.

At least 73 records · Page 4Linked to original sources

Endocrine and reproductive health status of men who had experienced short-term radiation exposure at Chernobyl.

Hormonal and semen parameters in 416 men aged 25-45 years were examined: 328 were men who cleaned the territory around the Chernobyl nuclear reactor (called 'liquidators') and 88 were healthy age-matched controls. The dose of radiation received by the liquidators was 0.16 +/- 0.08 Gy. LH, FSH, prolactin, testosterone and cortisol levels were assayed using WHO-matched reagents. Semen analyses were performed according to the WHO Manual (1992). The mean concentration of all hormones in liquidators and controls were within the WHO-defined normal range. The mean levels of LH and cortisol in liquidators were significantly lower (p = 0.013 and p < 0.001, respectively) and testosterone significantly higher (p = 0.023) than in controls. The variations in hormone levels in liquidators were not correlated with the acquired doses of radiation as measured by personal dosimeters (film badges). Semen parameters in a subgroup of 70 liquidators were within the normal WHO-defined range. The percentage of normal forms of spermatozoa in liquidators (35.0 +/- 13.1%) was significantly lower (p < 0.015) than in a control group (42.8 +/- 8.9%). The study has shown that exposure of men to relatively short-term radiation did not cause long-lasting disruption of their endocrine status and spermatogenesis. The study was 7-9 years retrospective and it is therefore impossible to infer what the immediate effects of the radiation exposure were on these parameters.

Adult↗

The applicability of the flow cytometric sperm chromatin structure assay in epidemiological studies. Asclepios.

The impact of demographic, lifestyle, and seminal factors on the sperm chromatin structure assay (SCSA) parameters was evaluated in a population of 277 healthy Danish men. This cohort was established within the framework of a European Concerted Action on occupational hazards to male reproductive capability in order to examine the possible reproductive effects of exposure to styrene or pesticides. The SCSA measures the susceptibility of sperm DNA to in-situ acid-induced denaturation, by multiparameter flow cytometric analysis after staining with the DNA-specific fluorescent dye acridine orange. The green versus red bivariate cytogram patterns were quite variable among donors, showing a wide heterogeneity of sperm DNA denaturability. Nevertheless, in those cases where we had the possibility to measure two semen samples from the same donor, the cytogram pattern remained stable over time (0.64 < r < 0.78). Analysis of variance demonstrated that the SCSA results can be influenced by the age of the donor (P < 0.0001), smoking habits (P < 0.05), the presence of leukocytes and immature germ forms in the ejaculate (P < 0.0001), and the duration of sexual abstinence (P < 0.0001). Furthermore, the relationship between the SCSA data and sperm concentration, morphology, and vitality was weak (-0.22 < r < -0.46). Therefore, the SCSA provides independent and complementary measurements of semen quality and is thus a useful tool for epidemiological studies, but the effects of some confounders should be accounted for in the survey design and analysis.

Adolescent↗

Germ cell cancer and disorders of spermatogenesis: an environmental connection?

Why is there a small peak of germ cell tumours in the postnatal period and a major peak in young age, starting at puberty? And, paradoxically, small risk in old age, although spermatogenesis is a lifelong process? Why is this type of cancer more common in individuals with maldeveloped gonads, including undescended testis, gonadal dysgenesis and androgen insensitivity syndrome? Why has there, during the past 50 years, been a quite dramatic increase in testicular cancer in many developed countries? These are just a few of many questions concerning testicular cancer. However, the recent progress in research in the early stages of testicular cancer (carcinoma in situ testis (CIS)) allows us to begin to answer some of these questions. There is more and more evidence that the CIS cell is a gonocyte with stem cell potential, which explains why an adult man can develop a non-seminoma, which is a neoplastic caricature of embryonic growth. We consider the possibility that CIS cells may loose their stem cell potential with ageing. Along these lines, a seminoma is regarded a gonocytoma where the single gonocytes have little or no stem cell potential. The Sertoli and Leydig cells, which are activated postnatally and during and after puberty, may play a crucial role for both the development of the CIS gonocyte and progression of the neoplasm to invasiveness. The reported increase in testicular cancer is not the only sign that male reproductive health is at risk. There are reports that undescended testis and hypospadias have become more common. Also semen quality has deteriorated, at least in some countries. The epidemiological evidence suggests that environmental factors may play a role. Are the environmental hormone disrupters (e.g. DDT, PCB, nonylphenol, bisphenol A) to be blamed for the apparently synchronised deterioration in these aspects of male reproductive health?

Adult↗

Gonadal function in men with testicular cancer: biological and clinical aspects.

This paper reviews current knowledge about the effect of testicular germ cell cancer (TGCC) on gonadal function and of cancer treatment on spermatogenesis and Leydig cell function. It is well documented that testicular cancer is associated with impaired spermatogenic function and some patients already have impairment of Leydig cell function before orchidectomy. The degree of spermatogenic dysfunction is higher than what can be explained by local tumour effect and by a general cancer effect, since patients with other malignant diseases have normal, or only slightly decreased, semen quality. Furthermore, sperm counts after orchidectomy are further reduced to less than half of the values in healthy men, even in patients cured from the cancer disease after orchidectomy alone. These observations are supported by histological investigations which have shown a high prevalence of abnormalities of spermatogenesis in the contralateral testis in patients with unilateral TGCC. The association between testicular cancer and poor gonadal function is very interesting both from a biological and from a therapeutic point of view. Firstly, the increase in incidence of testicular cancer has been suggested to be associated with a general decline in male reproductive health and it seems likely that the development of TGCC shares common aetiologic factors with development of other types of testicular dysfunction. This suggestion is supported by the observation that men with various types of gonadal dysfunction such as testicular dysgenesis, androgen insensitivity syndrome, and cryptorchidism have increased risk of testicular cancer. Secondly, the general cure rate in patients with testicular cancer exceeds 90% and the quality of life, including fertility aspects, is therefore important in the management of these patients. Spermatogenesis is already so severely impaired before treatment that fertility is lower than in healthy men. Moreover, radiotherapy and chemotherapy both induce dose-dependent impairment of spermatogenesis and recovery of spermatogenesis after treatment may be long lasting even more than five years in some patients. Sufficient androgen production is seen in the majority of the patients, but some patients suffer from testosterone deficiency. The effect of chemotherapy on Leydig cell function also seems to be dose-dependent. In conclusion there is no doubt that testicular cancer is associated with poor gonadal function even before treatment. Furthermore, the treatment of testicular cancer may have a serious impact on the gonadal function in these patients, most of whom are in the reproductive age. Moreover, the epidemiological and clinical data indicate a common aetiology between testicular germ cell cancer and other abnormalities in male reproductive health (such as infertility and cryptorchidism). These observations are in agreement with the suggestions of hormonal involvement in the aetiology of testicular cancer. Generally, men with TGCC need counselling about their reproductive function with respect to semen cryopreservation, chance of recovery of spermatogenesis, fertility, and the possible need for androgen replacement.

Antineoplastic Combined Chemotherapy Protocols↗

Job strain and time to pregnancy.

OBJECTIVES: The association between fertility and job strain defined as high job demands and low job control has not previously been studied. A follow-up study was conducted with prospective collection of information on job strain among women, achievement of pregnancy, and potential confounding variables. METHODS: A total of 297 Danish couples without previous reproductive experience was followed for a maximum of 6 menstrual cycles from termination of birth control until pregnancy. Job demand and job control were measured by a questionnaire developed by Karasek and his co-workers. RESULTS: The odds ratio and 95% confidence interval (95% CI) for conception per menstrual cycle for women with high job strain was 0.9 (95% CI 0.5-1.5) when compared with that of women in low-strain jobs. Only in secondary analyses restricted to couples with no suspected competitive causes of reduced fertility was a statistically significant reduced odds found for women with high-strain jobs compared with all other jobs. CONCLUSIONS: The main finding of this study did not corroborate a hypothesis of a substantial detrimental effect of job strain on fecundability.

Adult↗

Year of birth and sperm count in 10 Danish occupational studies.

OBJECTIVES: Several reports indicate a secular decline of human sperm counts. It is still not known if these findings are artifacts related to shortcomings in the data and applied methodologies. Even less is known about possible mechanisms, but it has been proposed that potential changes may be related to disruption of the hormonal regulation of testicular development in prenatal life. The objective of this study was to examine whether sperm count was related to year of birth. METHODS: An analysis was made of the sperm count of 1196 men participating in 10 cross-sectional occupational sperm studies in 3 regions of Denmark from 1986 through 1995. RESULTS: The median sperm concentration was 63 million per milliliter for men born in 1937-1949 and 52 million per milliliter for men born in 1970 or later, and the median total sperm was 206 million and 117 million, respectively. The inverse relationship between sperm concentration and year of birth was statistically significant even after adjustment for duration of sexual abstinence, season of the year, and study population. However, bias because of differential participation related to age and fertility or lack of comparability across the populations cannot be ruled out. CONCLUSIONS: The apparent decline of sperm count with increasing year of birth is compatible with the hypothesis of a common risk factor for male reproductive health operating in prenatal life or early childhood, but the evidence is circumstantial. Age-related selection bias is an alternative and perhaps not a less likely explanation.

Adult↗

Gonadal function in men with testicular cancer.

This article reviews current knowledge on the effect of testicular germ cell cancer (TGCC) on gonadal function and of the cancer treatment on spermatogenesis and Leydig cell function. It seems likely that development of TGCC shares common etiological factors with development other types of testicular dysfunction. This suggestion is supported by the observation that men with various types of gonadal dysfunction such as testicular dysgenesis, androgen insensitivity syndrome, and cryptorchidism have increased risk of testicular cancer. Epidemiological and clinical data indicate common etiology between testicular germ cell cancer and other abnormalities in male reproductive health such as infertility and cryptorchidism. These observations are in agreement with the suggestions of hormonal involvement in the etiology of testicular cancer. It is well documented that testicular cancer is associated with impaired spermatogenic function and some patients have impairment of Leydig's cell function already before orchidectomy. The degree of spermatogenic dysfunction is higher than what can be explained by local tumor effect and by a general cancer effect. These observations are supported by histological investigations, which have shown a high prevalence of abnormalities of spermatogenesis in the contralateral testis in patients with unilateral TGCC. The spermatogenetic function is still severely impaired after orchidectomy and radiotherapy as well as chemotherapy induce further dose-dependent impairment of spermatogenesis. Recovery of spermatogenesis after treatment may be long, in some patients lasting more than 5 years. Sufficient androgen production is seen in the majority of the patients but some patients do suffer from testosterone deficiency. The effect of chemotherapy on Leydig's cell function seems to be dose dependent. Trials on protection of spermatogenetic function against the harmful effects of radiotherapy and chemotherapy by suppression of spermatogenesis has not been successful. The only way to maintain fertility is to limit gonadal exposure to harmful agents. Moreover cryopreservation of semen should be done before treatment. The optimal time for cryopreservation is before orchiectomy at least in some patients. Generally men with TGCC need counselling about their reproductive function, with respect to semen cryopreservation, chance for recovery of spermatogenesis, fertility, and the possibility of need for androgen replacement.

Antineoplastic Combined Chemotherapy Protocols↗

Prevalence of carcinoma in situ of the testis in 207 oligozoospermic men from infertile couples: prospective study of testicular biopsies.

OBJECTIVE: To investigate the prevalence of carcinoma in situ of the testis in a group of oligozoospermic men from infertile couples. DESIGN: A consecutive group of oligozoospermic men from infertile couples were offered bilateral testicular biopsy. The observed prevalence of carcinoma in situ was compared with the expected prevalence of testicular cancer in a corresponding age matched population of Danish men, assuming all untreated cases of carcinoma in situ progress to tumour stage. This calculation was based on data from the Danish Cancer Registry. SUBJECTS: 207 men aged 18-50 years who had sperm density below 10 million/ml in two samples within the previous 2 years or sperm density below 20 million/ml in two samples within the previous 2 years and a history of cryptorchidism or one or two atrophic testicles (orchidometer volume less than 15 cm3), or both. INTERVENTIONS: Bilateral testicular biopsies. MAIN OUTCOME MEASURES: Carcinoma in situ in the biopsy specimen. RESULTS: No case of carcinoma in situ was found among the 207 men. The expected number in a normal age matched population of corresponding size was 0.8. CONCLUSIONS: There is no increase in risk of carcinoma in situ of the testis in moderately oligozoospermic men of couples referred because of infertility.

Adolescent↗

Semen analysis performed by different laboratory teams: an intervariation study.

Some recent studies have indicated that sperm concentration has decreased during the last 50 years. However, comparisons between laboratories have revealed that geographical differences seem to exist and that any decrease may not be global. One point of criticism concerning comparison of results from different laboratories has been that some of the discrepancies detected could reflect the lack of standardized methods used in the different laboratories. Four teams, each consisting of one physician and one technician from groups which have recently published data on semen quality, met in order to evaluate the variability between their laboratories on semen analysis. Twenty-six fresh semen samples from unselected men were analysed. The groups analysed the samples according to the normal practice in their laboratories, using their own equipment. The variation between laboratories was estimated through a random effects model. For sperm concentration and semen volume assessment a remarkable consistency between laboratories was detected, in contrast to the very considerable inter-individual variation. For sperm motility and morphology assessments interlaboratory consistency was much poorer. In conclusion, evaluation of sperm motility and morphology characteristics requires further standardization in order to achieve comparable data from different laboratories. However, semen volume and sperm concentration are characteristics which can be compared reliably between laboratories, when similar methodologies are used.

Adolescent↗

Inhibin B as a serum marker of spermatogenesis: correlation to differences in sperm concentration and follicle-stimulating hormone levels. A study of 349 Danish men.

Recent studies have focused on reproductive health of men in the general population. However, semen samples are difficult to obtain within sampling frames that allow comparisons. Blood samples are easier to obtain than ejaculates. Therefore, serum biomarkers of spermatogenesis are of major interest for population studies. FSH has previously been used as a marker of spermatogenesis, although it is also influenced by the hypothalamus. Serum inhibin B was recently suggested as a possible, more direct serum marker of spermatogenesis in men with testicular disorders. In a Danish nationwide collaborative study, we found an unexpected difference in semen concentration between two groups of men recruited from two different centres. We, therefore, analyzed reproductive hormones in blood, including inhibin B, to test whether the observed difference in semen concentration was reflected in the reproductive hormones. From 1992 to 1995, a total of 430 men, 20-35 yr old, who lived with a partner and who had not previously attempted to achieve a pregnancy, were recruited. The couples were enrolled into the study in one of two centres (centre A, n = 231; and centre B, n = 199) when they discontinued birth control. At enrollment, they provided a semen sample (n = 419), and a blood sample was drawn (n = 349). The semen analysis was performed in accordance with the WHO 1992 guidelines, and interlaboratory differences were tested. Inhibin B was measured in an enzyme immunometric assay, which has previously been described. All blood samples were analyzed in the same laboratory. Median sperm concentration and the percentage of morphologically normal spermatozoa were significantly higher among men from centre A (56.0 mill/mL and 42.5%), compared with men from centre B (44.8 mill/mL and 39%). Men from centre B had a significantly higher median FSH (3.42 IU/L) and a lower inhibin B (186 pg/mL) than men from centre A (3.21 IU/L and 209 pg/mL). The differences persisted after control for potentially confounding variables. A significant correlation was found between the cubic root-transformed serum FSH and inhibin B levels (r = -0.61, P < 0.001), between the cubic root-transformed serum FSH and sperm concentration (r = -0.40, P < 0.001), and between the cubic root-transformed inhibin B and sperm concentration (r = 0.38, P < 0.001). The predictive power of detecting sperm counts below 20 mill/mL among men who's inhibin B and FSH both were below 80 pg/mL and above 10 IU/L, respectively, was 100%. The unexpected significant difference in semen concentration between two groups of normal Danish men was probably caused by differences in sampling procedures in the two centres where the men were recruited, rather than geographical differences. However, similar differences in serum levels of inhibin B and FSH between centres were found. These findings suggest that a real difference in spermatogenic potential between the two groups of men existed. We suggest that serum inhibin B, in future population studies on male reproductive health, may serve as a new marker of spermatogenesis, in addition to sperm concentration and serum FSH.

Adult↗

Craniofacial morphology in patients with Kallmann's syndrome with and without cleft lip and palate.

OBJECTIVE: Kallmann's syndrome is characterized by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. The principal endocrine defect of hypogonadotropic hypogonadism is a failure to secrete luteinizing hormone-releasing hormone (LHRH), resulting in underdevelopment of the pituitary gonadotropes and an inability to synthesize and release luteinizing hormone and follicle-stimulating hormone. The purpose of the present investigation was to describe the dentition and the craniofacial morphology in patients diagnosed with Kallmann's syndrome. DESIGN: The sample consisted of 11 patients, 2 of whom also had bilateral cleft lip and palate. Radiographic investigations, including cephalometry, were performed. Comparisons were made to normal individuals and to cleft lip individuals without Kallmann's syndrome. RESULTS: Dentition: tooth agenesis occurred more frequently in patients with Kallmann's syndrome. Craniofacial morphology: Increased mandibular inclination and mandibular angulation were seen in Kallmann patients. When clefting also occurred, extreme retrognathism of both maxilla and mandible was seen, a deviation which seemingly worsened during growth. The anterior cranial base and the sphenoid bone showed an altered morphology in one of the patients with Kallman's syndrome. CONCLUSIONS: An early diagnosis of Kallmann's syndrome is very important because the prognosis for endocrine treatment thereby improves, and therefore, it is recommended that the sense of smell be evaluated in patients with the craniofacial morphology described.

Adolescent↗

Comparative analysis of cell surface antigens expressed by cell lines derived from human germ cell tumours.

The pattern of cell surface antigen expression of a set of cell lines derived from human germ cell tumours and corresponding to various cell phenotypes found within these tumours was studied using immunofluorescence. Twenty-two different antibodies were used. Many of these antibodies have been noted to recognise epitopes that are either preferentially expressed by embryonal carcinoma (EC) cells, or by more differentiated cell types. Using scatter plots and rank correlations, 6 groups of antibodies were distinguished with respect to their staining patterns on the cell lines tested. Several antibodies showed a specific staining pattern in relation to the differentiation state of the cells. Two groups of antibodies included those recognising high m.w. glycoproteins (antibodies TRA-1-60, TRA-1-81, GCTM2, 3-177, K4 and K21) and the ganglioseries glycolipid antigens SSEA-3 and -4 (antibodies MC631 and MC813-70). These antibodies mostly stained EC cells but not other cell types, confirming previously published data. However, one of these groups, comprising antibodies K4 and MC631, was more exclusively associated with the EC cell phenotype than was the other group. Antibodies recognising the liver isozyme of alkaline phosphatase (TRA-2-49 and TRA-2-54) also reacted strongly with most EC cell lines, although they reacted significantly with a number of other cell lines as well, whereas antibodies to the placental isozyme tended to react only weakly with EC cells. The antibodies recognising the ganglioseries glycolipids GD2 and GD3 (VIN2PB22 and VINIS56) preferentially stained cells with neuroectodermal characteristics. Other antibodies showed a heterogeneous staining pattern for the cell lines with different phenotypes. The data obtained from the cell lines were, in general, similar to data obtained from immunohistochemical studies on tissue sections of primary germ cell tumours of the adult testis, including carcinoma in situ.

Adult↗

Investigation of carcinoma in situ cells of testis by quantification of argyrophilic nucleolar organizer region associated proteins (AgNORs).

The silver staining which specifically stains argyrophilic proteins (AgNORs) in interphase nuclei was applied to paraffin sections of 24 testicular specimens with carcinoma in situ (CIS). AgNOR area per nucleus was quantified by a computerized image analyser. Significant quantitative differences were found between CIS, Sertoli cells, and spermatogonia (P = 0.0001), with median values of 10.3, 2.8, and 1.4 microns2 in the three cell types, respectively. A Sertoli cell index (SCI), defined as the ratio between AgNORs in CIS or spermatogonia and Sertoli cells, was shown to be significant in the differential diagnosis of CIS cells from spermatogonia when 1.0 was used as the cut-off value (CIS > 1; spermatogonia < 1). Furthermore, CIS associated with non-seminoma was found to have a significantly higher level of AgNORs than CIS associated with pure seminoma (P < 0.01), indicating that subclonal variation in transformation potential might be present within morphologically identical CIS of the testis. It remains to be seen whether quantification of AgNORs in isolated CIS could be used to predict transformation of CIS into seminoma or non-seminoma.

Carcinoma in Situ↗

Quality of semen obtained by penile vibratory stimulation in men with spinal cord injuries: observations and predictors.

OBJECTIVES: To study the semen quality and to examine prognostic factors that may affect semen quality in men with spinal cord injuries (SCI) who respond to penile vibratory stimulation (PVS). METHODS: Fifty-one PVS responders were prospectively examined. Penile vibratory stimulation was induced with optimized vibration parameters. Semen quality was characterized by semen analysis. The gel agglutination test for the presence of antisperm antibodies and serum hormone assays were performed. Characteristics of the spinal lesions, type of bladder management, and hormone assays were compared to semen quality and incidence of azoospermia or total lack of motility. RESULTS: The mean semen parameters were: volume-1.9 mL (range 0.2 to 7.0); total sperm-457 million (range 0 to 10,900); motility-12.6% (range 0% to 55%); total motile sperm-39.3 million (range 0 to 401); normal morphology-50.1% (range 0% to 90%). Better sperm motility was seen in men with cervical lesions versus those with thoracic lesions (16% versus 7%) and incomplete versus complete lesions (19% versus 10%). There was a higher incidence of azoospermic specimens in men with thoracic lesions versus cervical level (26% versus 3%) and a lower incidence of finding any motile sperm in the specimen (47% versus 81%). Men voiding without catheters had a lower incidence of azoospermia (3% versus 28%). Abnormalities of hormone and antibody tests were rare. CONCLUSIONS: Better sperm specimens from PVS of men with SCI may be expected from men with higher neurologic level, incomplete lesions, and those voiding without the use of a catheter. Hormonal abnormalities and immunologic causes do not explain the poor sperm quality seen in men with SCI.

Adult↗

Neuropeptide Y in the human prenatal and mature gonads.

In the present paper we have examined the distribution and identity of neuropeptide Y (NPY) immunoreactivity in the prenatal and mature human gonads. Tissue specimens were obtained from prenatal gonads (gestational age < 42 weeks) of induced abortions, premature birth and stillbirths. Specimens were also taken from infants who died aged less than 4 days. Tissue from mature gonads was obtained during surgery. The distribution and concentration in tissue extracts were determined by immunohistochemistry and radioimmunoassay. NPY-immunoreactivity (NPY-IR) was demonstrated in both the prenatal and mature human gonads. In the gonads from fetuses at 16-25 weeks the NPY-IR was scarce and could only be demonstrated by radioimmunoassay. In the female gonads from fetuses at 40 weeks of gestation, distinct nerve fibres were detected in relation to blood vessels and primordial follicles. In the prenatal male gonads at the same gestational length as well as in the mature testis, the NPY-IR nerves were detected in relation to blood vessels and seminiferous tubules. The gel filtration profile from the prenatal gonads and from the mature ovary revealed a single peak corresponding to the elution position of bioactive synthetic human NPY. The gel filtration profile from the mature testis demonstrated an additional peak at Kd of 0.17. The presence of NPY-IR in relation to the developing and mature gonads suggests that NPY participates in gonadal functions from an early point in life.

Chromatography, Gel↗

Detection and enrichment of carcinoma-in-situ cells in semen by an immunomagnetic method using monoclonal antibody M2A.

Carcinoma-in-situ (CIS) is a precursor of germ cell cancers in the testis. Early detection and treatment of CIS can prevent the development of invasive cancer. We have developed an immunomagnetic approach for enrichment of CIS cells from semen. Immunomagnetic beads were coated with monoclonal antibody (mAb) M2A, which is specific for seminoma and CIS. In preliminary mixing experiments, cultured human HEY cells, which express the M2A surface antigen, were added to semen samples and recovered selectively by incubation with M2A-coated immunomagnetic beads followed by magnetic activated cell sorting (MACS). Application of this procedure to ejaculates from five subjects with CIS and 22 control subjects with no evidence of testicular neoplasia resulted in the preferential recovery of a population of large round cells from a 0.5 ml semen sample obtained from CIS subjects (median 1 x 10(4), range 2 x 10(3) to 2 x 10(4)) relative to controls (median 2 x 10(2); range 0 to 10(3)), with no overlap between the two groups (p < 0.001). These results suggest that a subpopulation of large round cells recovered from the semen of CIS patients by incubation with M2A-coated immunomagnetic beads and MACS are CIS cells. Immunomagnetic enrichment of CIS cells in semen will facilitate the definitive identification of exfoliated CIS cells in ejaculates and could be an important first step in a non-invasive screening procedure for testicular CIS.

Antibodies, Monoclonal↗