Human epidermal growth receptor polymorphisms (HER1-rs11543848 and HER2-rs1136201) exhibited significant association with breast cancer risk in Pashtun population of Khyber Pakhtunkhwa, Pakistan.

Background and Aims: Breast cancer is the most common type of cancer in women. The genetic polymorphism in HER (HER1-rs11543848 and HER2-rs1136201) were found to be associated with breast cancer risk in different ethnicities worldwide with inconsistent results. The aim of this research study was to evaluate the association of HER1-rs11543848 and HER2-rs1136201 polymorphisms as a risk of breast cancer in Pashtun population of Khyber Pakhtunkhwa, Pakistan. Methods: A total of 314 women including 164 breast cancer patients and 150 age and gender-matched healthy controls were enrolled from June 2021 to May 2022. All the samples were subjected to DNA extraction followed by Tetra-ARMS-PCR for genotyping and gel electrophoresis. Results: Our results indicated that HER1-rs11543848 risk allele A (p = 0.0001) and heterozygous genotype GA (p = 0.0001) displayed highly significant association with breast cancer, while the homozygous mutant genotype AA indicated association but nonsignificant results (odds ratio [OR] = 2.637, 95% confidence interval [CI] = 1.2258-5.6756, p = 0.0833). Similarly, the HER2-rs1136201 risk allele G (p = 0.0023), the heterozygous genotype AG (p = 0.0530) and homozygous mutant genotype GG showed significant association (OR = 2.5946, 95% CI = 0.9876-6.8165, p = 0.0530) with breast cancer risk. Both the SNPs presented a higher but nonsignificant risk of breast cancer in postmenopausal women (OR = 2.242, p = 0.08 and OR = 2.009, p = 0.06). However, both the SNPs showed significant association (p < 0.005) with family history, metastasis, stage, luminal B, and TNBC. Conclusion: In conclusion, HER1-rs11543848 and HER2-rs1136201 polymorphisms are significantly associated with the higher risk of breast cancer in Pashtun population of Khyber Pakhtunkhwa, Pakistan. These findings advocate for further exploration with larger datasets, offering promising avenues for personalized approaches in breast cancer research and potentially enhancing clinical practices for better risk assessment and targeted management strategies.

Assessment of HER1 (rs11543848) and HER2 (rs1136201) polymorphism and their association with colorectal cancer susceptibility in Khyber Pakhtunkhwa, Pakistan.

BACKGROUND: Colorectal cancer (CRC) is a widespread malignancy characterized by uncontrolled growth in the colon or rectum and remains a leading cause of cancer-related mortality globally. Various genes polymorphisms have been linked with the risk of CRC, but our study aimed to investigate the association between HER1 (rs11543848) and HER2 (rs1136201) polymorphisms with the risk of CRC in the Khyber Pakhtunkhwa (KPK) population of Pakistan. The association of the selected polymorphisms (rs11543848 and rs1136201) with CRC risk has been investigated in various ethnic groups, but their impact remains unexplored in Pakistan, particularly within the KPK population, highlighting the need of the study in this region. METHODS: In this study 120 CRC patients and 120 healthy controls were enrolled. The DNA was extracted from the blood by salting-out method and genotyping was done using ARMS-PCR. RESULTS: Our investigations provided convincing evidence of a strong association between HER1 (rs11543848) and the risk of CRC. Both the genotypes heterozygous GA (OR = 2.07, CI = 1.18 to 3.64, P = 0.01) and homozygous AA (OR = 6.22, CI = 2.56 to 15.08, P = 0.0001) showed higher risk and significant association with the CRC risk. Similarly, heterozygous genotype AG of HER2 (rs1136201) was significantly associated (OR = 3.16, 95% CI = 1.78 to 5.58, P = 0.0001) while mutant genotype GG showed higher risk but non-significant association (OR = 3.23, 95% CI = 0.84 to 12.43, P = 0.08) with CRC patients. HER1 (rs11543848) demonstrated a significant association (P = 0.003) with the age at diagnosis in CRC patients, while HER2 (rs1136201) showed a non-significant association (P = 0.434). Both the SNPs were non-significantly associated with gender (P = 0.793 and 0.117), metastasis (P = 0.582 and 0.129), location of the tumor (P = 0.555 and 0.993), tumor grade (P = 0.290 and 0.920), tumor size (P = 0.535 and 0.289) and stages of cancer (P = 0.892 and 0.352). CONCLUSION: In conclusion, both the polymorphisms rs11543848 and rs1136201 displayed susceptibility with CRC in the KPK population. However, further investigations are recommended while using whole exome sequencing on a larger sample size for more precise results.

The cross-talk between macrophages and tumor cells as a target for cancer treatment.

Macrophages represent an important component of the innate immune system. Under physiological conditions, macrophages, which are essential phagocytes, maintain a proinflammatory response and repair damaged tissue. However, these processes are often impaired upon tumorigenesis, in which tumor-associated macrophages (TAMs) protect and support the growth, proliferation, and invasion of tumor cells and promote suppression of antitumor immunity. TAM abundance is closely associated with poor outcome of cancer, with impediment of chemotherapy effectiveness and ultimately a dismal therapy response and inferior overall survival. Thus, cross-talk between cancer cells and TAMs is an important target for immune checkpoint therapies and metabolic interventions, spurring interest in it as a therapeutic vulnerability for both hematological cancers and solid tumors. Furthermore, targeting of this cross-talk has emerged as a promising strategy for cancer treatment with the antibody against CD47 protein, a critical macrophage checkpoint recognized as the "don't eat me" signal, as well as other metabolism-focused strategies. Therapies targeting CD47 constitute an important milestone in the advancement of anticancer research and have had promising effects on not only phagocytosis activation but also innate and adaptive immune system activation, effectively counteracting tumor cells' evasion of therapy as shown in the context of myeloid cancers. Targeting of CD47 signaling is only one of several possibilities to reverse the immunosuppressive and tumor-protective tumor environment with the aim of enhancing the antitumor response. Several preclinical studies identified signaling pathways that regulate the recruitment, polarization, or metabolism of TAMs. In this review, we summarize the current understanding of the role of macrophages in cancer progression and the mechanisms by which they communicate with tumor cells. Additionally, we dissect various therapeutic strategies developed to target macrophage-tumor cell cross-talk, including modulation of macrophage polarization, blockade of signaling pathways, and disruption of physical interactions between leukemia cells and macrophages. Finally, we highlight the challenges associated with tumor hypoxia and acidosis as barriers to effective cancer therapy and discuss opportunities for future research in this field.

Adeno-Associated Virus-Mediated Gene Therapy.

Choice of vector is the most critical step in gene therapy. Adeno-associated viruses (AAV); third generation vectors, are getting much attention of scientists to be used as vehicles due to their non-pathogenicity, excellent safety profile, low immune responses, great efficiency to transduce non-dividing cells, large capacity to transfer genetic material and long-term expression of genetic payload. AAVs have multiple serotypes and each serotype shows tropism for a specific cell. Different serotypes are used to target liver, lungs, muscles, retina, heart, CNS, kidneys, etc. Furthermore, AAV based gene therapies have tremendous marketing applications that can be perfectly incorporated in the anticipated sites of the host target genome resulting in life long expression of transgenes. Some therapeutic products use AAV vectors that are used to treat lipoprotein lipase deficiency (LPLD) and it is injected intramuscularly, to treat mutated retinal pigment epithelium RPE65 (RPE65) that is introduced to subretinal space, an intravenous infusion to treat spinal muscular atrophy and rAAV2-CFTR vector is introduced into nasal epithelial cells to treat cystic fibrosis. AAV therapies and other such interdisciplinary methodologies can create the miracles for the generation of precision gene therapies for the treatment of most serious and sometimes fatal disorders.

Significant association of BRCA1 (rs1799950), BRCA2 (rs144848) and TP53 (rs1042522) polymorphism with breast cancer risk in Pashtun population of Khyber Pakhtunkhwa, Pakistan.

BACKGROUND: Single nucleotide polymorphism (SNPs) in BRCA1, BRCA2 and TP53 has been widely associated with breast cancer risk in different ethnicities with inconsistent results. There is no such study conducted so far in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. Therefore, this study was conducted to check BRCA1 (rs1799950), BRCA2 (rs144848) and TP53 (rs1042522) polymorphism with breast cancer risk in Pashtun population of Khyber Pakhtunkhwa, Pakistan. METHODS: This study, consisting 140 breast cancer patients and 80 gender and age matched healthy controls were subjected to confirm BRCA1, BRCA2 and TP53 polymorphism. Clinicopathological data and blood samples were taken from all the participants. DNA was extracted and SNPs were confirmed using T-ARMS-PCR protocol. RESULTS: Our data indicated that BRCA1, BRCA2, and TP53 selected SNPs risk allele and risk allele containing genotypes displayed significant association (p < 0.05) with breast cancer risk in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. CONCLUSION: All the three selected SNPs of BRCA1, BRCA2 and TP53 showed significant association with breast cancer risk in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. However, more investigation will be required on large data sets to confirm the selected SNPs and other SNPs in the selected and other related genes with the risk of breast cancer.

Estrogen receptor alpha (ESR1) gene polymorphism (rs2234693 and rs2046210) with breast cancer risk in pashtun population of Khyber Pakhtunkhwa.

BACKGROUND: Breast cancer susceptibility is greatly influenced by single nucleotide polymorphisms (SNPs) both in penetrance and non-penetrance genes. The Estrogen Receptor Alfa (ESR1- rs2234693 and rs2046210) have been reported as risk factor of breast cancer in different ethnic groups with inconsistent results. In this study the association of ESR1 (rs2234693 and rs2046210) with breast cancer risk was investigated in patients of Khyber Pakhtunkhwa. METHODS: A total of 312 females including 162 breast cancer patients and 150 healthy controls were enrolled in this study. The polymorphism was confirmed using T-ARMS-PCR. RESULTS: Our results revealed that ESR1-rs2234693 risk allele (C) (P = 0.21, OR = 1.27, CI = 0.87 to 1.87) and containing genotypes CC (P = 0.68, OR = 1.24, CI = 0.42 to 3.68) and TC (P = 0.23, OR = 1.32, CI = 0.83 to 2.13) were not associated with the risk of breast cancer. In case of rs2046210, the risk allele A (P < 0.0001, OR = 2.42, CI = 1.74 to 3.38) and corresponding genotypes GA (P = 0.0001, OR = 2.55, CI = 1.62 to 4.03) and AA (P = 0.02, OR = 2.20, CI = 1.12 to 4.34) were significantly associated with higher risk of breast cancer. Moreover, ESR1-rs2234693 was significantly (P < 0.05) associated with family history, stages, PR status, ER status and luminal B. The ESR1-rs2046210 showed significant (P ≤ 0.05) association with menstrual status, tumor grade and TNBC. Both the SNPs showed non-significant (P > 0.05) association with nulliparity, nodal status, HER2 status, metastasis, HER2 enriched subtype and luminal A. CONCLUSION: It is concluded that ESR1-rs2234693 is not associated with breast cancer, while rs2046210 is significantly associated with the risk of breast cancer in Khyber Pakhtunkhwa population. Further, to confirm the exact situation of ESR1 polymorphism, ESR1 existing and other SNPs need to be investigated in diverse data sets.

Primary Ovarian Burkitts Lymphoma.

Primary ovarian Burkitt lymphoma (BL) is a very rare and aggressive malignancy. We report an 18-year-old female patient who presented with a large, tender abdomen, and highly de-ranged renal and liver functions. Ultrasonography showed hepatosplenomegaly, mild ascites, dilated biliary channels and a heterogeneous pelvic mass of size ~15106.4 cm. Immunohistochemical (IHC) staining of the biopsy sample excised from the left ovary demonstrated reactivity for CD20 and CD10, and negativity for CD3, Bcl-2 and TdT. The C-myc translocation was positive in 60% of tumour cells. Moreover, the proliferation index was ~90%. These features were consistent with BL. After haemodialysis, the patient was planned for multiagent chemotherapy, including cyclophosphamide, doxorubicin, vincristine and prednisone. This case supports the hypothesis that primary ovarian BL is an aggressive malignancy that appears to respond promisingly to multi-agent chemotherapy.

Risk association of RANKL and OPG gene polymorphism with breast cancer to bone metastasis in Pashtun population of Khyber Pakhtunkhwa, Pakistan.

INTRODUCTION: The receptor activator NF-κB ligand (RANKL) and Osteoprotegrin (OPG) single nucleotide polymorphisms (SNPs) have been associated with the risk of breast cancer to bone metastasis. This study was designed to investigate the association of RANKL and OPG gene polymorphisms with breast to bone metastasis in Pashtun population of Khyber Pakhtunkhwa, Pakistan. MATERIALS AND METHODS: A total of 215 participants were enrolled containing 106 breast cancer patients, 58 breast to bone metastasis and 51 age and gender matched healthy controls. RANKL (rs9533156) and OPG (rs2073618, rs3102735) polymorphisms were genotyped in genomic DNA, using Tetra-ARMS PCR protocol. The results were analyzed among the three groups and P-value less then 0.05 were considered statistically significant. RESULTS: Our results displayed significant association of OPG (rs3102735) risk allele and corresponding genotypes in breast cancer vs healthy controls, bone metastasis vs healthy controls and breast cancer vs breast to bone metastasis as a disease risk. However, there was no association observed for OPG (rs2073618) risk allele and corresponding genotypes with the diseases risk. Similarly, RANKL (rs9533156) risk allele and corresponding genotypes in breast cancer vs healthy controls, bone metastasis vs healthy controls and breast cancer vs breast to bone metastasis exhibited significant association except for the risk allele carrying genotypes in breast to bone metastasis. CONCLUSION: OPG (rs3102735) and RANKL (rs9533156) exhibited significant association with breast to bone metastasis while OPG (rs2073618) didn't show significant association with breast to bone metastasis in Pashtun population of Pakistan. However, this study unlocks more questions to investigate the exact scenario of genetic predisposition of breast to bone metastasis.

Low-level laser therapy for the treatment of early stage cutaneous leishmaniasis: A pilot study.

Low-Level Laser Therapy (LLLT) has been investigated for the treatment of various dermatological disorders. Here, we investigate the efficacy of LLLT for the treatment of cutaneous leishmaniasis (CL). This study comprised of 53 patients (total 123 lesions) with a confirmed diagnosis of CL via positive smear of LD-bodies. The CL lesions were classified in Grade I (ie, papule of size ≤1 cm) to Grade V (ie, vesicle formation, ulceration, and superadded infection of size >4 cm). All the patients were divided into group 1 with low grade (ie, Grade I and II) CL lesions and group 2 with high-grade disease (ie, Grade III-V). Red laser light (wavelength = 635 nm) was used for the lesion irradiation, with a light dose of 75 J/cm2 and at a low power of 300 mW. The treatment was divided into four sessions, one session per week. Disease assessment at 10 months follow-up revealed complete response in 91% and partial response in 9% patients of group 1, while no response was observed in patients of group 2. LLLT offers a promising treatment modality for patients presenting with early-stage (ie, Grade I and II) CL lesions.

Fractionated illumination improves the treatment outcomes of photodynamic therapy for high grade cutaneous leishmaniasis.

Photodynamic therapy (PDT) has been widely used in dermatology to treat different skin diseases. Here, we aim to compare the efficacy of single versus multiple fraction light illumination PDT for high grade lesions of cutaneous leishmaniasis (CL). In particular, 60 patients (104 CL lesions) were randomly divided into two groups; 30 patients (46 CL lesions) in group I were treated with methylaminolevulinate (MAL)-based PDT in three sessions, with a light dose of 90 J/cm2 delivered in a single fraction in each session. The 30 patients (58 CL lesions) in group II received the same treatment, except the light dose in each session was delivered in three fractions. Patient assessment at nine months follow-up revealed complete response at 35 (76 %) for group I, compared to 53 (91.4 %) for group II. Moreover, partial response was observed in 11 (24 %) CL lesions for group I, as compared with 5 (8.6 %) CL lesions in group II. Pain and burning sensation in patients from group II was markedly less than patient from group I. In conclusion, fractionated illumination improves the treatment efficacy of PDT for high grade CL lesions.

(99m)Tc-phytate trans-splenic portal scintigraphy in the diagnosis of cirrhotic portal hypertension and compensatory circulation.

BACKGROUND AND AIM: The trans-splenic portal scintigraphy (TPS) was evaluated as a diagnostic tool in the post viral hepatitis cirrhotic patients of various classes of Child Pugh's (CP) classification. The main aim was to determine the portosystemic shunt index (PSSI) and to compare the results with various clinical grades of disease severity in liver cirrhosis. METHODS: TPS was performed on 72 patients and 10 controls and PSSI was derived. All the 72 patients were categorized according to CP classification into three classes. The cirrhotic patients were categorized as CP A (n = 24),CP B (n = 22), and CP C (n = 26)according to CP criteria. PSSI was compared with different CP classes. RESULTS: In the controlled population, the splenic vein was normal in shape and the mean PSSI was calculated to be 0.178 ± 0.031 (n = 10). For CP classes A, B, and C, the mean PSSI was 0.36 ± 0.04, 0.45 ± 0.05, and 0.54 ± 0.04 (n = 26), respectively. There was statistical significance among groups (p ≤ 0.01).The collateral vessels were mostly uphill or complex. The PSSI index increased as the CP score worsened from A to C. CONCLUSION: PSSI is a useful and minimally invasive tool to detect and quantify the shunt severity, which correlates well with different clinical grades of disease severity.

(99m)Tc(CO)(3)-Ibritumomab tiuxetan; a novel radioimmunoimaging (RII) agent of B cell non-Hodgkin's lymphoma (NHL).

To exploit the B-lymphocyte antigen-CD20 binding capacity of the Ibritumomab tiuxetan (IBTN) monoclonal antibody (mAb) for imaging, the over-expression of B cells in non-Hodgkin's lymphoma (NHL) (a myeloproliferative disorder of the lymphatic system) was investigated. In the current investigation, we present the labeling of the IBTN with technetium-99m ((99m)Tc) through [(99m)Tc(CO)(3)](+) precursor for radioimmunoimaging (RII) of the tumor prior to its treatment with (90)Y labeled IBTN. Labeled IBTN was radiobiologically characterized in terms of radiochemical purity, in vitro stability in human plasma, immunoreactivity, binding with Raji and Ramos cells and biodistribution in a female nude mouse (FNM) model. It was observed that the reduced IBTN (rIBTN) showed more promising radiobiologic characteristics than the nonreduced IBTN. Significantly higher transchelation was seen in excess cysteine compared with histidine. The radioconjugate showed higher saturated binding affinity with CD20 antigen. Significantly higher target (tumor) to background ratios were observed 1 h post-injection (p.i.). Based on radiochemical purity, in vitro stability, immunoreactivity, binding and biodistrubtion in the FNM model, we recommend the radiolabeling of the rIBTN using tricarbonyl technique as a potential RII agent.

Extrathyroidal uptake from thyroid carcinoma on 99mTc-pertechnetate scintigraphy.

Three cases of imaging with 99mTc-pertechnetate (99mTcO4) and unusual positive lymph node uptake in the neck are reported hereby. Two cases were later diagnosed to be well-differentiated thyroid carcinoma, (DTC) with nodal metastasis. The third was a confirmed case of carcinoma thyroid that had presented with mass in the neck soon after surgery, being prepared for ablative dose of radioactive iodine (131I). All three were young females under 40 years of age. These 3 cases signify that extra thyroidal areas of uptake on a routine thyroid scan with 99mTcO4 can some time be due to thyroid carcinoma with regional metastases. Foci of metastasis in patients with DTC may be incidentlly detected with 99mTcO4 scan. Multinodular goiter with palpable lymph node should always be investigated for exclusion of malignancy. The patients underwent near total thyroidectomy and radical neck dissection; histopathology confirmed the scan findings.

Radiosynthesis and biodistribution of (99m)Tc-rifampicin: a novel radiotracer for in-vivo infection imaging.

(99m)Tc-rifampicin ((99m)Tc-RMP) a new radioantibiotic complex was synthesized specifically for the infection localization caused by methicillin-resistant Staphylococcus aureus (MRSA). The in-vitro radiochemical purity (RCP) yield, in-vivo biodistribution behavior in artificially infected rats (AIT) and scintigraphic accuracy in artificially infected rabbit (AIB) of the (99m)Tc-RMP complex was investigated using different concentration of the RMP, sodium pertechnetate (Na(99m)TcO(4)), stannous chloride dihydrate (SnCl(2) x 2H(2)O) at different pH ranges 5-6. The best RCP yield observed at 30, 60, 90 and 120 min after labeling was; 98.95+/-0.20, 98.15+/-0.24, 96.50+/-0.27 and 91.55+/-0.22%, respectively, using 1.5 mg RMP, 175 microL of SnCl(2) x 2H(2)O (1 microg/microL in 0.01 N HCl), 3 mCi of Na(99m)TcO(4), at pH 5.6. Initially in the infected muscle (INM) of the AIT the activity was lower but after 90 min it went up to 18.35+/-0.20% from 5.95+/-0.25%. The activity in the inflamed muscle (IMM), normal (NM) muscle, blood, liver and spleen was initially high that decreased with time. The ratios of the INM/NM and IMM/NM were 7.34+/-0.74 and 1.20+/-0.85, respectively. The whole body static (WBS) imaging of the MRSA infected rabbit confirmed the usefulness of the (99m)Tc-RMP as a precise radiotracer for MRSA infection imaging. On the basis of in-vitro RCP, in-vivo biodistribution and scintigraphic precision, we recommend the (99m)Tc-RMP complex prepared aseptically for in-vivo assessment of MRSA infection.

Clinical presentation of non-HIV Kaposi Sarcoma.

Kaposi Sarcoma (KS) is a rare entity. In the north west of Pakistan and Afghanistan, we mostly come across non-HIV related Kaposi sarcoma as Human Immunodeficiency Virus (HIV). Infections are rare in this part of the world. Here, we present a case of a non-auto Immunodeficiency Disease (AIDS) related KS. A 45-year-old male, Afghan patient presented to our oncology outpatient's unit with multiple subcutaneous nodules. The sites of involvement were the periorbital region, retro-auricular region, forearms, legs, chest and back. Oral mucosa was spared at the nodules. The patient had no visceromegaly at the time of presentation. A biopsy specimen from the retro-auricular region revealed a KS with dermal lymphatic involvement. His serum was negative for the common types of viral infections including Human Immunodeficiency Virus (HIV) on routine serology. His total B-lymphocytes (CD 19+), total T-lymphocyte (CD3+), total CD4+ lymphocyte (CD3+, CD4+) and total CD8+ (CD3+, CD8+) counts were all normal or borderline high. The patient was under treatment with 3 weekly chemotherapeutic regimens of Adriamycin, Bleomycin, Vincristine (ABV) keeping in view socioeconomical constrains, logistical difficulties in getting proper medical care and side effects of other options like radiotherapy for extended surface areas.

Thyroid dyshormonogenesis detected through a modified perchlorate discharge test using a gamma-camera.

OBJECTIVE: To find an easy tool to detect dyshormonogenesis. METHODS: In this study, the standard perchlorate discharge test was modified by using a gamma-camera instead of a gamma-probe to detect this rare abnormality. RESULTS: By using this technique two cases of dyshormonogenesis were identified. CONCLUSION: The gamma-camera-based perchlorate discharge test is an easy, reliable, convenient, and feasible procedure where thyroid uptake probe is not available.

Quantitative evaluation of salivary gland dysfunction after radioiodine therapy using salivary gland scintigraphy.

AIM: The most frequent non-thyroidal complication of high-dose (131)I therapy for thyroid carcinoma is salivary gland dysfunction, which may be transient or permanent. In this study, we assessed radioiodine-induced permanent salivary gland dysfunction using quantitative salivary gland scintigraphy. METHODS: Salivary scintigraphy was performed with (99m)Tc-pertechnetate on 50 thyroid carcinoma patients who had been given radioiodine for thyroid ablation; 20 normal subjects were imaged as the control population. Dynamic scintigraphy was performed and time-activity curves for four major salivary glands were generated. The glandular functional parameters maximum secretion, time at maximum count and uptake ratio of the parotid and submandibular glands were calculated. Correlation of the administered dose and subjective symptoms with findings of salivary gland scintigraphy was evaluated. RESULTS: The maximum secretion and uptake ratio were decreased in 46% and 42% of patients who received radioiodine therapy, respectively. Salivary gland dysfunction correlated well with the administered dose. The parotid glands were more affected than the submandibular glands. Fifty-two per cent of patients were symptomatic, 69.23% of whom showed salivary gland dysfunction. CONCLUSION: Parenchymal damage to the salivary glands induced by radioactive iodine treatment can be evaluated by salivary gland scintigraphy. The impairment was worse in parotid glands and increased with the total dose. The maximum secretion and uptake ratio were found to be sufficiently sensitive to distinguish the severity of the damage.