Relationship of Vitamin-D Deficiency with Kidney Disease in Patients with Type-2 Diabetes Mellitus (T2DM) in the Makkah Region: A Cross-Sectional Study.

Aim: Vitamin D deficiency is linked with type 2 diabetes mellitus (T2DM) and the occurrence of complications in patients with type 2 diabetes mellitus. None of the studies have focused on the association between vitamin D levels in patients with type 2 diabetes mellitus and diabetic nephropathy (DN) in the Makkah region, Saudi Arabia. Hence, the purpose of this study is to investigate the relationship of vitamin D with kidney disease in patients with T2DM in the Makkah region, of Saudi Arabia. Materials and Methods: This descriptive cross-sectional study was conducted at different hospitals in the Makkah region on T2DM patients from 2021 to 2022. In total, 328 patients with confirmed diabetes were enrolled in this study. T2DM patients over the aged>18 to 92 years were included in the study. General laboratory characteristics of the study population were measured, including fasting blood sugar, HbA1C (Glycated hemoglobin), vitamin D, kidney function (BUN-Blood urea nitrogen and creatinine), and lipid profiles (cholesterol, triglycerides, LDL-Low density lipoprotein, and HDL-High density lipoprotein). Results: 46.6% (n=153) of participants had normal serum vitamin D levels. Insufficient and deficient serum vitamin D level were observed in 43.9% (n=144) and 9.5% (n=31) of participants, respectively. Of the participants, 25.9% (n=85) had good glycemic control (<7.0%). Moderate and poor glycemic control were observed in 39.9% (n=131) and 34.1% (n=112) of the participants, respectively. A significant negative correlation (p<0.5) was found between vitamin D levels and kidney function test results (blood urea nitrogen and serum creatinine levels). An inverse relationship was observed between HbA1c levels and vitamin D deficiency. Conclusion: Nephropathy is more likely to develop in people with type 2 diabetes mellitus and vitamin D deficiency.

Cardiovascular and mortality outcomes with GLP-1 receptor agonists vs other glucose-lowering drugs in individuals with NAFLD and type 2 diabetes: a large population-based matched cohort study.

AIMS/HYPOTHESIS: We aimed to determine whether the use of glucagon-like peptide-1 receptor agonists (GLP-1RA) in individuals with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus decreases the risk of new-onset adverse cardiovascular events (CVEs) and mortality rate compared with other glucose-lowering drugs in a real setting at a population level. METHODS: We conducted a population-based propensity-matched retrospective cohort study using TriNetX. The cohort comprised patients over 20 years old who were newly treated with glucose-lowering drugs between 1 January 2013 and 31 December 2021, and followed until 30 September 2022. New users of GLP-1RAs were matched based on age, demographics, comorbidities and medication use by using 1:1 propensity matching with other glucose-lowering drugs. The primary outcome was the new onset of adverse CVEs, including heart failure, composite incidence of major adverse cardiovascular events (MACE; defined as unstable angina, myocardial infarction, or coronary artery procedures or surgeries) and composite cerebrovascular events (defined as the first occurrence of stroke, transient ischaemic attack, cerebral infarction, carotid intervention or surgery), and the secondary outcome was all-cause mortality. Cox proportional hazards models were used to estimate HRs. RESULTS: The study involved 2,835,398 patients with both NAFLD and type 2 diabetes. When compared with the sodium-glucose cotransporter 2 (SGLT2) inhibitors group, the GLP-1RAs group showed no evidence of a difference in terms of new-onset heart failure (HR 0.97; 95% CI 0.93, 1.01), MACE (HR 0.95; 95% CI 0.90, 1.01) and cerebrovascular events (HR 0.99; 95% CI 0.94, 1.03). Furthermore, the two groups had no evidence of a difference in mortality rate (HR 1.06; 95% CI 0.97, 1.15). Similar results were observed across sensitivity analyses. Compared with other second- or third-line glucose-lowering medications, the GLP-1RAs demonstrated a lower rate of adverse CVEs, including heart failure (HR 0.88; 95% CI 0.85, 0.92), MACE (HR 0.89; 95% CI 0.85, 0.94), cerebrovascular events (HR 0.93; 95% CI 0.89, 0.96) and all-cause mortality rate (HR 0.70; 95% CI 0.66, 0.75). CONCLUSIONS/INTERPRETATION: In individuals with NAFLD and type 2 diabetes, GLP-1RAs are associated with lower incidences of adverse CVEs and all-cause mortality compared with metformin or other second- and third-line glucose-lowering medications. However, there was no significant difference in adverse CVEs or all-cause mortality when compared with those taking SGLT2 inhibitors.

Identification of a de novo LRP1 mutation in a Saudi family with Tetralogy of Fallot.

BACKGROUND: Tetralogy of Fallot (TOF) is a rare, complex congenital heart defect caused by genetic and environmental interactions that results in abnormal heart development during the early stages of pregnancy. Genetic basis of TOF in Saudi populations is not yet studied. Therefore, the objective of this study is to screen for the molecular defects causing TOF in Saudi patients. METHODS: A family with non-syndromic TOF was recruited from the Western region of Saudi Arabia. Whole exome sequencing (WES) was performed on the proband and her parents. The identified candidate variant was verified by sanger sequencing. Also, different computational biology tools were used to figure out how candidate variants affect the structure and function of candidate protein involved in TOF. RESULTS: A novel heterozygous de novo mutation in LRP1 (p. G3311D) gene was identified in the index case. Also, this variant was absent in the in-house exome sequencing data of 80 healthy Saudi individuals. This variant was predicted to be likely pathogenic, as it negatively affects the biophysical chemical properties and stability of the protein. Furthermore, functional biology data from knock out mouse models confirms that molecular defects in LRP1 gene leads to cardiac defects and lethality. This variant was not previously reported in both Arab and global population genetic databases. CONCLUSION: The findings in this study postulate that the LRP1 variant has a role in TOF pathogenesis and facilitate accurate diagnosis as well as the understanding of underlying molecular mechanisms and pathophysiology of the disease.

Bioprospection of Antiviral and Antitumor Compounds from Some Marine Algae from Egyptian Shores.

BACKGROUND: The marine algae are considered a diverse source of bioactive compounds. Many active compounds have been isolated from algae and show good biological activities. MATERIALS AND METHODS: The aim of this study is to detect the antiviral and anticancer activities in some extracts of marine algae. Extraction, purification and identification of some marine algae common in Egypt were conducted. Extraction of Ulva lactuca, Sargassum dentifolium, and Cystoseiara myrica was conducted. A sequence of extractions, including extraction by ethanol, boiling water, hydrochloric acid and sodium hydroxide were carried out. The obtained extracts were evaluated for their antitumour and antiviral activities against liver tumour cells, brain tumour cell lines, measles virus, mumps virus and hepatitis B virus (HBV). The extracts of the best activities were subjected for purification by size exclusion chromatography and anion exchange chromatography for ethanolic extracts or precipitation by cetylpyridinium chloride (CPC) then by size exclusion chromatography and anion exchange chromatography for aqueous extracts. Separation by GLS/MS was performed. The structures of the active compounds have been identified through different chemical analyses, including sugar analysis, configurational analysis, High-Performance Liquid Chromatography (HPLC), infrared spectroscopy (IR), Gas-Liquid Chromatography-Mass Spectroscopy (GLC-MS) and 1H,13C nuclear magnetic resonance (NMR) at ZV. RESULTS: The active compounds from the water extracts have been identified mainly as polysaccharides and sulphated polysaccharides. The antitumour and the antiviral activities of ethanolic extracts are attributable to compound identified as Ethyl Palmitate. These natural compounds did not show cytotoxic effect. CONCLUSION: These outputs could be preliminary for further biological studies aiming to therapeutic application.

Nanoplatform for the Delivery of Topotecan in the Cancer Milieu: An Appraisal of its Therapeutic Efficacy.

Chemotherapy has been the predominant treatment modality for cancer patients, but its overall performance is still modest. Difficulty in penetration of tumor tissues, a toxic profile in high doses, multidrug resistance in an array of tumor types, and the differential architecture of tumor cells as they grow are some of the bottlenecks associated with the clinical usage of chemotherapeutics. Recent advances in tumor biology understanding and the emergence of novel targeted drug delivery tools leveraging various nanosystems offer hope for developing effective cancer treatments. Topotecan is a topoisomerase I inhibitor that stabilizes the transient TOPO I-DNA cleavable complex, leading to single-stranded breaks in DNA. Due to its novel mechanism of action, TOPO is reported to be active against various carcinomas, namely small cell lung cancer, cervical cancer, breast cancer, and ovarian cancer. Issues of cross-resistance with numerous drugs, rapid conversion to its inactive form in biological systems, appended adverse effects, and higher water solubility limit its therapeutic efficacy in clinical settings. Topotecan nanoformulations offer several benefits for enhancing the therapeutic action of this significant class of chemotherapeutics. The likelihood that the target cancer cells will be exposed to the chemotherapeutic drug while in the drug-sensitive s-phase is increased due to the slow and sustained release of the chemotherapeutic, which could provide for a sustained duration of exposure of the target cancer cells to the bioavailable drug and result in the desired therapeutic outcome. This article explores nanoenabled active and passive targeting strategies and combinatorial therapy employing topotecan to ameliorate various cancers, along with a glimpse of the clinical studies utilizing the said molecule.

Cardiac anomalies associated with Escobar syndrome: A case report and a review of the literature.

RATIONALE: Escobar syndrome (ES) is an autosomal recessive disorder. It is highly characterized by facial abnormalities, congenital diaphragmatic muscle weakness, myasthenic-like features, and skin pterygiums on multiple body legions. ES is a rare condition associated with many external and internal abnormalities. The internal malformations described in ES affect many organs including the heart, lungs, esophagus, liver, spleen, and intestine. The purpose of this paper is to explore the cardiac manifestations associated with ES. PATIENT CONCERNS: A 3.5-year-old girl, who was born for double first cousins, was admitted to the hospital for neuromuscular evaluation of multiple congenital contractures. DIAGNOSIS: The girl was diagnosed with ES and isolated dextrocardia which is a rare cardiac manifestation. However, to the best of our knowledge, no similar cases have been reported to date, and this case is thus believed to be very rare. INTERVENTIONS: The patient underwent an operative intervention to correct the bilateral fixed flexion deformity at her knees which was related to the posterior bilateral fibrotic bands/pterygia. OUTCOMES: Post-operatively, complete knee extension was obtained, the patient was fitted with a cast and extension night splint. She was discharged alive and had no complications. The patient was followed regularly in the orthopedic clinic and had periodic physiotherapy sessions. CONCLUSIONS: ES and isolated dextrocardia concurrence in the presented case resulted from different pathogenic mechanisms. Our findings suggest that ES might be caused by dysfunction in the acetylcholine receptor throughout fetal life, which may have affected muscle strength and movement. Other cardiac conditions include hypoplastic left-sided heart, Hypertrophic cardiomyopathy, patent ductus arteriosus, and heterotaxia.

Incidence and profile of acute intoxication among adult population in Najran, Saudi Arabia: A retrospective study.

Acute poisoning is considered one of the most important medical emergencies, resulting in severe morbidity and mortality, and is an economic burden on governments. This study aimed to determine the extent of acute adult intoxication among the population located in the Najran area, Saudi Arabia, over the last 3 years (from January 2017 to December 2019). The study is a hospital-based retrospective observational study. The data of all acutely intoxicated adult patients were collected from patients' files of King Khalid Hospital, the main hospital in the Najran area. In this study, the total number of intoxicated patients was 852. Patients were divided into three groups according to their age: 15-25 years, 26-35 years and >35 years. Accidental intoxication was predominant (64.6%), especially with therapeutic drugs (60.2%), predominantly acetaminophen and amphetamine, which intoxicated 24.5% and 23.4% of the patients, respectively. Moreover, this study showed that 10.6% of patients were intoxicated with overdoses of alcohol, mostly among patients aged over 35 years. Furthermore, the present study revealed that 23.9% of patients were intoxicated with household chemicals, especially Clorox bleach or Flash. Patients presented with a wide range of symptoms; some were even asymptomatic. Overall, patients' outcomes were good; mortalities were few (1.2%), and most fatalities were found in patients aged over 35 years (60%). The present study showed that pharmaceutical drugs constituted the most common causative agents in acute intoxication. Household chemicals, especially Clorox bleach, Flash and pesticides, are highly implicated in the acute toxicity problem. Drug abuse, especially amphetamine and alcohol, still represents a great threat facing people from the Najran region. It is crucial to deliver effective public health education programmes to increase community awareness about the predisposing risk factors of acute toxicity, whether as overdoses or suicide attempts.

Effect of COVID-19 Pandemic on the Cardiac Outpatients' Perception of Seeking Medical Advice.

OBJECTIVES: During this unprecedented time of COVID-19 pandemic, it was noticed a decline in cardiovascular cases presentation to the Emergency rooms in many countries, raising many speculations about the reasons and its ramifications. 1 - Identify the reasons during this pandemic that refrain patients from seeking medical care and its impact on stress level and medication adherence. 2 - Emphasize the new role of virtual medicine. METHODS: A quantitative descriptive cross-section survey study of 388 patients. It has been done in the cardiac outpatient department and conducted virtually through telemedicine. RESULTS: Despite this pandemic and its consensuses, the majority of cardiac outpatients will still seek medical advice in case of experiencing symptoms. Nevertheless, the fear of contracting COVID-19 infection, which can alter patient's decisions from visiting the emergency room and the increase in stress level during these challenging times, is genuine and no more an element of guessing. CONCLUSION: The majority of cardiac outpatients will wisely seek medical advice in case of serious cardiac symptoms and are adherent to their medications during this pandemic. Nevertheless, they face many concerns which need to implement a preventive and helping measures to fight the consensuses of COVID-19 such as, patient educations, establishing a hotline to all patients, telemedicine, new phone applications, and delivering medications to patients are essential in such circumstances to ensure continuity of care.

Multistage Segmentation of Prostate Cancer Tissues Using Sample Entropy Texture Analysis.

In this study, a multistage segmentation technique is proposed that identifies cancerous cells in prostate tissue samples. The benign areas of the tissue are distinguished from the cancerous regions using the texture of glands. The texture is modeled based on wavelet packet features along with sample entropy values. In a multistage segmentation process, the mean-shift algorithm is applied on the pre-processed images to perform a coarse segmentation of the tissue. Wavelet packets are employed in the second stage to obtain fine details of the structured shape of glands. Finally, the texture of the gland is modeled by the sample entropy values, which identifies epithelial regions from stroma patches. Although there are three stages of the proposed algorithm, the computation is fast as wavelet packet features and sample entropy values perform robust modeling for the required regions of interest. A comparative analysis with other state-of-the-art texture segmentation techniques is presented and dice ratios are computed for the comparison. It has been observed that our algorithm not only outperforms other techniques, but, by introducing sample entropy features, identification of cancerous regions of tissues is achieved with 90% classification accuracy, which shows the robustness of the proposed algorithm.

Trends in the incidence of oral cancer in Saudi Arabia from 1994 to 2015.

BACKGROUND: Oral cancer is one of the most common non-communicable diseases worldwide. This paper presents an evaluation of the trends and geographical distributions of oral cancers in the Saudi Arabian population. METHODS: Data from Saudi Cancer Registry reports were used in this analysis, which assessed the period between 1994 and 2015. All cancer cases are recorded in these reports, as well as the age, gender, region and histological cancer sites for each patient. Age-standardised and age-specific incidence rates were calculated in these reports. For the purposes of this paper, only cancers of the lips, tongue and mouth were considered oral cancers. RESULTS: Between 1994 and 2015, the Saudi Cancer Registry identified 172,424 cancer cases in total. Of these, 3184 were oral cancer. The mean age-standardised rate of oral cancer for the study period was 2.9 per 100,000 people; for females, it was 1.5, and for males, it was 1.4. The incidence of oral cancer varied by region, with Jazan displaying the highest age-standardised rate and Hail displaying the lowest. A positive correlation was observed between oral cancer incidence and age. CONCLUSION: The overall trend of the age-standardised rate for both sexes remained constant from 1994 to 2015. However, the oral cancer incidence in Saudi Arabia varies by region. Studying this variation in more detail will help to guide awareness programmes in the regions that are most in need.

The Role of Transthyretin in Oligodendrocyte Development.

Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs) in blood and cerebrospinal fluid. Previously, two reports identified TTR null mice as hypothyroid in the central nervous system (CNS). This prompted our investigations into developmentally regulated TH-dependent processes in brains of wildtype and TTR null mice. Despite logical expectations of a hypomyelinating phenotype in the CNS of TTR null mice, we observed a hypermyelination phenotype, synchronous with an increase in the density of oligodendrocytes in the corpus callosum and anterior commissure of TTR null mice during postnatal development. Furthermore, absence of TTR enhanced proliferation and migration of OPCs with decreased apoptosis. Neural stem cells (NSCs) isolated from the subventricular zone of TTR null mice at P21 revealed that the absence of TTR promoted NSC differentiation toward a glial lineage. Importantly, we identified TTR synthesis in OPCs, suggestive of an alternate biological function in these cells that may extend beyond an extracellular TH-distributor protein. The hypermyelination mechanism may involve increased pAKT (involved in oligodendrocyte maturation) in TTR null mice. Elucidating the regulatory role of TTR in NSC and OPC biology could lead to potential therapeutic strategies for the treatment of acquired demyelinating diseases.

The prevalence of APOL1 gene variants in a cohort of renal disease patients in Western Saudi Arabia.

Two variants for APOL1; the gastrointestinal (G1) variant (S342G and 1384M substitutions) and the G2 variant (N388 and Y389 deletions) have been previously described to be associated with renal disease. The prevalence of APOL1 variants in Saudi Arabia is unknown. We aimed to determine the prevalence of APOL1 variants in a cohort of patients with renal disease in Saudi Arabia. Patients with renal disease followed up at King Abdulaziz University Hospital were approached consecutively at the out patient clinic, and unaffected controls were approached at the blood donation area. Clinical and laboratory data were collected from electronic medical records. Laboratory variables in controls were obtained on enrollment. This is a cross-sectional, cohort study. One hundred and one patients with a mean age of 54.5 (±19) years, and 119 unaffected controls with a mean age of 31.9 (±7.89) years, were enrolled. Seventy-four patients (68.5%) had hypertension and 62 (57.4%) had diabetes. The mean estimated glomerular filtration rate was 22.47 (± 27.6) mL/min. Two patients were heterozygous for G1 allele. Among the control group, two were heterozygous for G1 allele, and three were heterozygous for G2. All five controls had no evidence of renal disease and no family history of renal disease. The prevalence of APOL1 genetic risk variants in the study cohort was very low. Larger studies are needed to determine the prevalence among renal disease patients in Saudi Arabia.

Ultra-low loss ridge waveguides on lithium niobate via argon ion milling and gas clustered ion beam smoothening.

Lithium niobate's use in integrated optics is somewhat hampered by the lack of a capability to create low loss waveguides with strong lateral index confinement. Thin film single crystal lithium niobate is a promising platform for future applications in integrated optics due to the availability of a strong electro-optic effect in this material coupled with the possibility of strong vertical index confinement. However, sidewalls of etched waveguides are typically rough in most etching procedures, exacerbating propagation losses. In this paper, we propose a fabrication method that creates significantly smoother ridge waveguides. This involves argon ion milling and subsequent gas clustered ion beam smoothening. We have fabricated and characterized ultra-low loss waveguides with this technique, with propagation losses as low as 0.3 dB/cm at 1.55 µm.

Autosomal recessive long QT syndrome, type 1 in eight families from Saudi Arabia.

BACKGROUND: One of the most common primary cardiac arrhythmia syndromes is autosomal dominant long QT syndrome, type 1 (LQT1), chiefly caused by mono-allelic mutations in the KCNQ1 gene. Bi-allelic mutations in the KCNQ1 gene are causal to Jervell and Lange-Nielsen syndrome (JLNS), characterized by severe and early-onset arrhythmias with prolonged QTc interval on surface ECG and sensorineural deafness. Occasionally, bi-allelic mutations in KCNQ1 are also found in patients without any deafness, referred to as autosomal recessive long QT syndrome, type 1 (AR LQT1). METHODS: We used Sanger sequencing to detect the pathogenic mutations in KCNQ1 gene in eight families from Saudi Arabia with autosomal recessive LQT1. RESULTS: We have detected pathogenic mutations in all eight families, two of the mutations are founder mutations, which are c.387-5T>A and p.Val172Met/p.Arg293Cys (in cis). QTc and cardiac phenotype was found to be pronounced in all the probands comparable to the cardiac phenotype in JLNS patients. Heterozygous carriers for these mutations did not exhibit any clinical phenotype, but a significant number of them have sinus bradycardia. CONCLUSION: To the best of our knowledge, this is the first description of a large series of patients with familial autosomal recessive LQT, type 1. These mutations could be used for targeted screening in cardiac arrhythmia patients in Saudi Arabia and in people of Arabic ancestry.

Descriptive Epidemiological Analysis of Thyroid Cancer in the Saudi Population (2001-2013)

Objective: Thyroid cancer has one of the highest frequency rates among thyroid diseases, and ranks second for neoplasia in the Saudi female population. This paper concerns a comprehensive evaluation of increasing incidence trends and geographical distribution of different patterns of thyroid cancer among the Saudi Arabian population using the latest Saudi Cancer Registry (SCR) reports. Methods: The analysis included a total of 7,670 thyroid cancer cases (1604 male and 6066 female) which were recorded in the SCR files for the period between January 2001 and December 2013. Results: The overall incidence of thyroid cancer increased during the period from 2001 to 2013. The most common age group affected was 35­39 years in both sexes. Najran recorded the highest differences in thyroid cancer rates with increase between 2001 and 2013. Controversially, other regions like Tabuk and the Northern provinces recorded obvious decreases in rates of thyroid cancer among females. Conclusion: Thyroid cancer is the second most common cancer among females in Saudi Arabia with incidence peaks in both genders aged 35­39 years and increase overtall in the country from 2001 to 2013. The specific causes of this upward trend are unknown. Further clinical and epidemiological research must be conducted for clarification, with an emphasis of causes of the variation in thyroid cancer prevalence between regions in Saudi Arabia.

A systematic review examining the effects of therapeutic radioactive iodine on ovarian function and future pregnancy in female thyroid cancer survivors.

BACKGROUND: For women with differentiated thyroid carcinoma (DTC), the effect of radioactive iodine (RAI) therapy on gonadal and reproductive function is an important consideration. OBJECTIVE AND METHODS: We systematically reviewed controlled studies examining the gonadal and reproductive effects of RAI therapy in women and adolescents surviving DTC. We searched nine electronic databases. All abstracts and papers were independently reviewed by two reviewers. RESULTS: After reviewing 349 unique citations and 61 full-text papers, 16 papers including data from 3023 women or adolescents with DTC were included. All studies were observational, with no long-term randomized control trial data. The age at first RAI treatment varied from 8 to 50 years and the cumulative activities of RAI administered for treatment varied from 30 to 1099 mCi. Transient absence of menstrual periods occurred in 8-27% of women within the first year after RAI, particularly in older women. In addition, RAI-treated women experienced menopause at a slightly younger age than women not treated with RAI. In the first year after RAI therapy, several studies reported increased rates of spontaneous and induced abortions. However, RAI treatment for DTC was generally not associated with a significantly increased risk of long-term infertility, miscarriage, induced abortions, stillbirths, or offspring neonatal mortality or congenital defects. CONCLUSIONS: In female survivors of DTC, there is little observational evidence to suggest important adverse effects of RAI treatment on gonadal function, fertility or pregnancy outcomes beyond 12 months, with the exception of a possible slightly earlier age of menopause.

A systematic review of the gonadal effects of therapeutic radioactive iodine in male thyroid cancer survivors.

BACKGROUND: For patients with well-differentiated thyroid carcinoma (WDTC), the gonadal effects of radioactive iodine (RAI) therapy is an important consideration. OBJECTIVE AND METHODS: We systematically reviewed the controlled studies examining the gonadal effects of RAI therapy in male WDTC survivors. We searched in nine electronic databases. All abstracts and papers were independently reviewed by two reviewers. RESULTS: After reviewing 334 abstracts and 59 full-text papers, seven papers were included. In longitudinal studies examining the effect of single primary RAI dose activities of 594 mCi. Cumulative RAI dose correlated with FSH measurements at long-term follow-up. In one study, approximately one in eight men experienced oligospermia 1 year after RAI therapy. Rates of infertility, pregnancy loss and offspring congenital malformation were not elevated, but studies were limited by small size and self-reported outcomes. CONCLUSIONS: Abnormalities in testicular function are common within several months of a single therapeutic dose of RAI for WDTC. Biochemical abnormalities usually resolve within 18 months after administration of a single activity of < 150 mCi of RAI. The risk of persistent gonadal dysfunction is increased after repeated or high cumulative RAI activities. Controlled, prospective studies, with long-term follow-up, examining male gonadal and offspring effects of RAI therapy are needed.