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Biomedical subjects

J Rastad

Publications and source records attributed to J Rastad.

At least 37 records · Page 2Linked to original sources

Circulating ionized calcium and parathyroid hormone levels following coronary artery by-pass surgery.

In critically ill patients, hypocalcaemia is a common finding. Also variable derangements in the normally tight Ca2+-mediated control of the parathyroid hormone (PTH) secretion have been found. Utilizing coronary artery by-pass grafting (CABG) as a standardized model of severe trauma, 18 patients underwent determinations of blood levels of calcium, magnesium (Mg), ionized calcium (Ca2+), serum levels of intact PTH, procalcitonin (PCT) and the proinflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). Samples were collected before, directly after, the morning after and 5 days after surgery. A significant, but minor, decrease in blood Ca2+ levels (mean 0.04 mmol/L, p<0.05) was seen shortly after CABG, not accompanied by any significant change of serum PTH levels. This alteration of the Ca2+ control of the steady-state PTH levels contrasted with the maintenance of the PTH secretory response to a sequential citrate and calcium infusion (CiCa clamp), which was normal in two patients evaluated in the morning following surgery. Serum Mg levels were transiently increased after operation (+0.25 mmol/L, p<0.001) and correlated to the TNF-alpha (r=0.62, p <0.01) and PCT (r=0.67, p < 0.006) levels in the morning after surgery. Serum levels of IL-6 and TNF-alpha were significantly (p < 0.0001) increased immediately after surgery, while the peak in serum PCT levels (p < 0.001) occurred in the morning after CABG. Serum PTH levels correlated positively with IL-6 (r=0.68, p<0.008) 5 days after surgery. In conclusion, CABG caused a decrease in ionized calcium levels without a rise in steady-state PTH levels, but rapid changes in Ca2+ during CiCa clamping revealed a normal PTH secretory response. These findings might relate to elevated serum Mg levels, while a direct action of TNF-alpha or IL-6 on the PTH release seem less possible.

Aged↗

Abdominal US for diagnosis of pancreatic tumor: prospective cohort analysis.

PURPOSE: To elucidate the accuracy of abdominal ultrasonography (US) in the diagnosis of pancreatic tumors. MATERIALS AND METHODS: In all patients referred for pancreatic US during 1988-1990, data on malignant disease and survival were analyzed by using the Swedish Death and Cancer Registries. Nine hundred nineteen patients were entered into the analysis. In 140 of them, a clinical diagnosis of tumor in the pancreatic area was confirmed within 1 year after US. These tumors were primary pancreatic tumors (n = 102), common bile duct and duodenal cancers (n = 17), and metastases in the pancreatic area (n = 21). RESULTS: The sensitivity of US in the detection of all tumors in the pancreatic area was 88.6% (124 of 140 patients), which was similar to that for the detection of exocrine pancreatic cancer, 90% (79 of 88 patients). There were nine false-positive US examinations, for a specificity of 98.8% (770 of 779 patients). Systematic sampling of 94 investigations confirmed an association between US accuracy and presence of clinical symptoms of pancreatic cancer. Significant differences in the sensitivity (P < .05) and accuracy (P < .01) of diagnosis were observed between three experienced investigators. CONCLUSION: Study results support the use of US as a first-line diagnostic examination in patients suspected of having pancreatic tumor. Dependency on the investigator's experience with US mandates continuous evaluation of its performance.

Abdomen↗

The vitamin D receptor (VDR) start codon polymorphism in primary hyperparathyroidism and parathyroid VDR messenger ribonucleic acid levels.

Vitamin D regulates parathyroid cell proliferation and secretion of PTH. Increased prevalence of the polymorphic vitamin D receptor (VDR) alleles b, a, and T has been reported in sporadic primary hyperparathyroidism (PHPT), suggesting that these genetic variants may predispose to the disease. Recently, another polymorphism in the VDR gene was related to bone mineral density, and this VDR-FokI polymorphism causes different lengths of the VDR, implying possible functional consequences. The VDR-FokI polymorphism was studied in 182 postmenopausal women with sporadic PHPT and in matched controls. No significant differences in distribution of the VDR-FokI genotypes could be detected between the groups, although there was a tendency toward overrepresentation of the F allele in the PHPT patients (P = 0.05). There were no significant associations with age, serum calcium, serum PTH, bone mineral density, or parathyroid tumor weight. The VDR genotypes were unrelated to VDR and PTH messenger ribonucleic acid levels in the parathyroid adenomas of 42 PHPT patients. In 23 PHPT patients, the Ca2+-PTH set-points were determined in vivo and were unrelated to the VDR alleles. We suggest that the VDR-FokI polymorphism has at most a minor pathogenic importance in the development of PHPT.

Adult↗

Population based case-control study of sick leave in postmenopausal women before diagnosis of hyperparathyroidism.

OBJECTIVE: To analyse sick leave in women at risk of primary hyperparathyroidism before its diagnosis. DESIGN: Case-control study nested within a screened cohort of postmenopausal women. Cases were women with hyperparathyroidism without prior knowledge of their disease and no traditional symptoms or complications. Controls were women from the screened population without hyperparathyroidism. SETTING: Population based screening within a Swedish community. SUBJECT: 48 case-control pairs of women aged 55-70 years. MAIN OUTCOME MEASURE: Sick leave during the 5 years before diagnosis. RESULTS: Total duration of sickness benefits was longer in the cases than controls, and this discrepancy included sick leave on full time or half time and for periods of longer than a week. Cases had an increased risk of sick leave more than half of the investigated time compared with controls (odds ratio 12). Doctors' certificates showed that the overrepresented sick leave in the cases related mainly to cardiovascular diseases. CONCLUSION: Asymptomatic mild primary hyperparathyroidism in postmenopausal women is accompanied by a previously unrecognised morbidity, which has consequences for clinical management of the disorder and its impact on the health economy.

Aged↗

Mutation of the multiple endocrine neoplasia type 1 gene in nonfamilial, malignant tumors of the endocrine pancreas.

Endocrine pancreatic tumors are rare neoplasms that occur sporadically or as part of a multiple endocrine neoplasia type 1 (MEN1) syndrome. Germ-line mutations of the MEN1 gene, located at 11q13, have been demonstrated in MEN1 kindreds, and loss of heterozygosity (LOH) on 11q13 together with somatic MEN1 mutations have been detected in 20% of nonfamilial parathyroid tumors. Here, we examine 11 non-MEN1 malignant tumors of the endocrine pancreas, 9 nonfunctioning tumors, and 2 glucagonomas. LOH of at least one informative locus on 11q13 was found in 70% of the tumors. Three tumors displayed somatic mutations of the MEN1 gene together with LOH on 11q13, whereas the corresponding germ-line DNA was normal. These findings support the hypothesis that MEN1 gene mutations contribute to the tumorigenesis of nonfamilial, malignant endocrine pancreatic tumors.

Adult↗

Prospective study of calcium homeostasis after renal transplantation.

Nineteen consecutive patients receiving renal transplants underwent prospective evaluation of their calcium homeostasis for 1 year after transplantation to characterize indices of hyperparathyroidism (HPT) amelioration. All but one underwent dialysis, and six had vitamin D supplementation before grafting. The rapid falls in serum creatinine concentrations and increased creatinine clearances the first weeks after grafting were accompanied by rapidly reversed hypercalcemia and hypermagnesemia, induced hypophosphatemia, maintained parathyroid hormone (PTH) excess and calcitriol deficiency, and decreased alkaline phosphatases. At 3 months when the serum calcitriol had started to rise, serum PTH levels were the lowest and parathyroid responses to induced hypocalcemia the least abnormal. This was coupled to peaks in serum calcium, 24-hour urine calcium excretions, and serum alkaline phosphatase levels. All patients had subnormal creatinine clearances at the study end, and normal serum PTH occurred in only seven of them. Arbitrary subgrouping of the material was performed according to posttransplant creatinine clearance and serum PTH levels. More satisfactory graft function related to lower serum PTH values and less abnormal parathyroid responses to induced hypocalcemia, earlier and higher rises in serum calcitriol, and higher urine calcium excretion. Patients with mild HPT at the study end generally had higher creatinine clearance, lower serum PTH, calcium, and alkaline phosphatase values, and lower urine calcium excretion. Moreover, they had fewer prevalent signs of radiologic bone involvement before grafting. These temporal diversities in conjunction with the variable graft function and intensity of immunosuppression provide a complex interaction in renal transplant recipients, which should be considered in the light of improved function of the PTH/PTHrP receptor in bone and kidney and cation receptors in the parathyroid and kidney.

Adult↗

Limited tumor involvement found at multiple endocrine neoplasia type I pancreatic exploration: can it be predicted by preoperative tumor localization?

Radiologically demonstrable pancreatic endocrine tumors are a frequent requirement for exploration in patients with multiple endocrine neoplasia type I (MEN-I). Such delayed intervention is accompanied by a 30% to 50% incidence of pancreatic endocrine metastases. This study explores biochemical tumor markers and operative findings in relation to preoperative pancreatic radiology in 25 MEN-I patients. They underwent pancreatic surgery with (n = 19) or without (n = 6) radiologic signs of primary tumor and absence of metastases upon conventional examination, including OctreoScan testing (n = 10). Biochemical diagnosis required an increasing elevation of at least two independent pancreatic tumor markers. Tumor diameters averaged 1.1 cm (0-5 cm) and 0.9 cm (0.2-1.5 cm) in the patients with and without positive preoperative radiology, respectively. These investigations never displayed more than one of the consistently multiple tumors, and the results were falsely positive in 26%. Preoperatively unidentified regional or hepatic metastases were found at surgical exploration in 26% of patients with radiologic localization and in none of the others. Limited pancreatic tumor involvement necessitated intraoperative absence of metastases and pancreatic lesions </= 1 cm in diameter on palpation, intraoperative ultrasonography, and microscopy. It occurred in 37% and 50% of the patients with and without radiologic tumor localization, respectively. The number of positive tumor markers was similar for patients with limited and major disease (2.3 vs. 2.7), whereas four or more such markers were found in all those with malignancies. The mean marker level was higher in patients with radiologically demonstrable tumors and lower in those with limited disease, but with a substantial overlap. OctreoScan testing was negative in all cases with limited disease and was the single most sensitive method (75%) in the others. Limited pancreatic disease could not be identified preoperatively, and the present means of biochemical pancreatic tumor identification invariably involved the presence of at least one lesion >/= 7 mm in diameter. Conventional pancreatic imaging is insensitive and nonspecific for recognizing even substantial pancreatic tumors associated with MEN-I.

Adult↗

Vitamin D receptor gene polymorphism and parathyroid calcium sensor protein (CAS/gp330) expression in primary hyperparathyroidism.

Calcitriol, via its receptor (VDR), inhibits parathyroid hormone (PTH) secretion and cell proliferation. Physically linked polymorphic VDR alleles denoted b,a, and T, comprise a novel risk factor for postmenopausal primary hyperparathyroidism (pHPT) by their presumed coupling to reduced VDR expression. This study examines VDR gene polymorphisms, parathyroid calcium-regulated cytoplasmic calcium concentrations ([Ca2+]i) and parathyroid expression of a calcium sensor protein (CAS/gp330). Genomic DNA was obtained from 66 postmenopausal women with pHPT and 66 age-matched female controls. Polymorphic VDR alleles were detected after polymerase chain reaction (PCR) and restriction digestion. Cryosections of pathologic parathyroid glands from 41 of the patients were immunostained with a monoclonal anti-CAS/gp330 antibody. Homozygosity for the VDR alleles b, a, and T was overrepresented in pHPT (p < 0.01-0.05) but did not couple to ED50 for calcium-regulated [Ca2+]i. The enlarged parathyroid glands possessed heterogeneous down-regulation of CAS/gp330. This down-regulation was the least conspicuous in the BBgenotype, and these few patients generally had larger parathyroid lesions (p < 0. 05). The VDR haplotype baTis a risk factor for pHPT possibly by hampering the regulatory actions of calcitriol. In contrast the BAt haplotype seems to be underrepresented in pHPT and to couple to larger parathyroid lesions as well as less deranged CAS/gp330 expression and parathyroid cell function. HPT in these individuals may relate to genetic events principally altering the regulation of cell proliferation, rather than calcium sensing of the parathyroid cells.

Aged↗

Double parathyroid adenoma, a clinically nondistinct entity of primary hyperparathyroidism.

Double parathyroid adenoma (DA) has been suggested to be a clinically distinct entity of primary hyperparathyroidism (HPT). Altogether 659 patients with sporadic primary HPT were analyzed retrospectively by evaluating consecutive primary operations for more than three decades. Patients with postoperatively persistent HPT and those with incomplete medical, operative, or histologic records were disregarded. The mean age (+/- SD) at surgery was 60.9 +/- 12.7 years; 78% of the patients were female; and the duration of postoperative follow-up averaged 7.8 +/- 7.2 years. DA, defined as two enlarged parathyroid glands, was found in 77 patients (12%). Enlargement of a single gland (SA) or three or more glands (MA) occurred in 80% and 8%, respectively. DAs were bilateral in 72% of patients, and the weight of the two glands differed by 317 +/- 407 mg. The three histologic subgroups of patients exhibited no significant discrepancy with respect to age, classic symptoms of HPT, proportion of overtly asymptomatic individuals, or parathyroid tissue weight. A lower female predominance and extent of hypercalcemia and higher preoperative serum creatinine level occurred with DA and MA compared to SA. SA and DA differed from MA with respect to variably strong trends to lower postoperative incidences of recurrent HPT and hypoparathyroidism. DA seems to comprise an underrated histologic cause of HPT, which is eligible for a conservative operative approach. Clinical characteristics consistent with a distinct entity of sporadic primary HPT were not seen.

Adenoma↗

Regulation of gp330/megalin expression by vitamins A and D.

BACKGROUND: A membrane-bound 550-kD Ca2+-binding glycoprotein belonging to the low-density lipoprotein (LDL) receptor superfamily has recently been identified as a putative calcium-sensing molecule. This molecule, known as gp330/megalin, is among several tissues present in the proximal tubule, parathyroid and placental cytotrophoblasts, in which a Ca2+-sensing function has been demonstrated. METHODS: Regulation of mRNA and protein expression of gp330/megalin were studied in a recently established cell line derived from rat kidney proximal tubule cells (IRPTCs), in human JEG-3 cells and in the mouse embryonal carcinoma cell line F9. RESULTS: In IRPTCs, quantification of mRNA and protein expression demonstrated two- to five-fold increases after addition of 10(-6) mol L(-1) all-trans-retinoic acid, 9-cis-retinoic acid or 1,25-dihydroxyvitamin D3, alone or in combination. Similarly, an increase in gp330/megalin mRNA expression was seen in JEG-3 cells cultured with vitamin D and retinoids, as well as when F9 cells were differentiated by incubation with retinoic acid and cAMP. The IRPTCs were immortalized by viral infection with the SV40 genome preceded by a temperature-sensitive promoter. Thus, by culture of the cells at 41 degrees C, SV40 genome transcription is inhibited and the IRPTC phenotype is reversed towards non-infected proximal tubule cells. At 41 degrees C, gp330/megalin mRNA expression was significantly increased compared with cells incubated at 34 degrees C. CONCLUSION: The results indicate a correlation between exposure to retinoic acid or vitamin D or induction of cell differentiation (by retinoic acid/cAMP in F9 cells or inhibition of SV40 transcription in IRPTCs) and an increase in gp330/megalin protein and mRNA expression.

Animals↗

Parathyroid hormone and ionized calcium levels are related to the severity of illness and survival in critically ill patients.

BACKGROUND: The present study explores serum parathyroid hormone (PTH) and blood ionized calcium (Ca2+) levels in relation to the severity of disease and mortality in the intensive care unit (ICU). METHODS: In a pilot study, 37 consecutive critically ill patients admitted to the ICU were studied with determinations of serum PTH and total serum calcium within the first 24 h. In a following prospective study, patients suffering from sepsis (n = 13) or subjected to major surgery (n = 13) were investigated daily for 1 week with determinations of serum PTH and ionized calcium (Ca2+). Severity of disease was assessed by the APACHE II score and hospital mortality was recorded. RESULTS: In the pilot study, serum PTH levels were elevated (> 55 ng L-1) in 38% of the patients and were not related to serum calcium but showed a significant relationship to the APACHE II score (r = 0.39, P < 0.05). In the prospective study, serum PTH was elevated in 69% of the patients in both groups at inclusion, and 6 days later 87% of the septic and 37% of the surgery patients still showed elevated levels. Hypocalcaemia was more commonly seen in the septic patients [mean Ca2+ 1.03 +/- 0.08 (SD) mmol L-1] than in the surgical patients (1.14 +/- 0.06 mmol L-1) at inclusion. Both PTH and Ca2+ levels were significantly related to the APACHE II score (r = 0.46, P < 0.03, and r = -0.54, P < 0.009, respectively). Furthermore, PTH levels were significantly increased in non-survivors (n = 5) compared with survivors (mean 161 +/- 51 vs. 79 +/- 51 ng L-1, P < 0.005). CONCLUSION: Hypocalcaemia and increased levels of PTH were common findings in critically ill patients. These alterations in calcium homeostasis were related to the severity of disease and increased PTH levels were associated with a poor outcome.

APACHE↗

Vitamin D receptor (VDR) and parathyroid hormone messenger ribonucleic acid levels correspond to polymorphic VDR alleles in human parathyroid tumors.

Calcitriol, via its receptor (VDR) is a main regulator of PTH secretion and parathyroid cell proliferation. Recently, marked overrepresentation of the polymorphic VDR alleles b, a, and T was found in patients with primary hyperparathyroidism (pHPT), which suggests pathogenic importance in the disease. Using the ribonuclease protection assay, relative VDR and PTH messenger ribonucleic acid (mRNA) levels of parathyroid adenomas from 42 patients with sporadic pHPT were related to these VDR polymorphisms. The tumors of patients homozygous for the b, a, or T alleles demonstrated significantly lower VDR and higher PTH mRNA levels than those exhibiting the BB, AA, or tt genotypes (P < 0.0001-0.02), whereas heterozygotes had intermediate values. A similar discrepancy was found when comparing the baT and non-baT haplotypes (0.042 +/- 0.005 vs. 0.064 +/- 0.004 for VDR; 34.4 +/- 3.7 vs. 21.6 +/- 2.2 for PTH; both P < 0.005). The lower VDR mRNA levels associated with the b, a, and T alleles may affect the calcitriol-mediated control of parathyroid function and thereby contribute to the development of sporadic pHPT.

Adenoma↗

Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism.

Biochemical signs and severity of symptoms of primary hyperparathyroidism (pHPT) differ among patients, and little is known of any coupling of clinical characteristics of nonfamilial pHPT to genetic abnormalities in the parathyroid tumors. Mutations in the recently identified MEN1 gene at chromosome 11q13 have been found in parathyroid tumors of nonfamilial pHPT. Using microsatellite analysis for loss of heterozygosity (LOH) at 11q13 and DNA sequencing of coding exons, the MEN1 gene was studied in 49 parathyroid lesions of patients with divergent symptoms, operative findings, histopathological diagnosis, and biochemical signs of nonfamilial pHPT. Allelic loss at 11q13 was detected in 13 tumors, and 6 of them demonstrated previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of the detected mutations would most likely result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and biochemical characteristics of HPT were apparently unrelated to the presence or absence of LOH and the MEN1 gene mutations. However, the demonstration of LOH at 11q13 and MEN1 gene mutations in small parathyroid adenomas of patients with slight hypercalcemia and normal serum PTH levels suggest that altered MEN1 gene function may also be important for the development of mild sporadic pHPT.

Adenoma↗

Major histocompatibility complex class II expression and parathyroid autoantibodies in primary hyperparathyroidism.

BACKGROUND: Autoimmune diseases are characterized by induced parenchymal expression of major histocompatibility complex (MHC) class II antigens and circulating autoantibodies directed toward surface structures on the target cells. MHC class II expressions can be modified by viral infections of potential pathogenic importance in autoimmune reactions. Primary hyperparathyroidism exhibits incompletely clarified cause. METHODS: With cryosections, human parathyroid glands were stained with monoclonal antibodies to MHC class II antigens according to a peroxidase-antiperoxidase technique. Human parathyroid adenoma tissue transplanted to nude mice and rat parathyroid glands was tested with serum from patients with hyperparathyroidism and control subjects. RESULTS: Induced MHC class II expression was demonstrated on parathyroid parenchymal cells in 13 of 54 adenomatous and eight of 23 hyperplastic glands of patients with primary hyperparathyroidism. This reactivity was absent in 12 normal glands, nine normal-sized glands associated with the adenomas, and 17 enlarged glands of patients with hyperparathyroidism caused by uremia. Staining of parathyroid tissue was found with serum from 27 of 38 patients with primary hyperparathyroidism, whereas this reactivity was absent on rat thyroid and pancreatic tissue, as well as with control sera. CONCLUSION: The concurrent induction of MHC class II antigen expression and c circulating antiparathyroid autoantibodies in 16 or 38 patients with primary hyperparathyroidism suggests hitherto unrecognized immunologic involvement in this disease.

Adenoma↗

[Differential diagnosis in adrenal gland tumors using PET and 11C-metomidate].

We have investigated 13 patients with incidentaloma using PET with 11C-metomidate. The patients included six adrenocortical adenomas, one adrenal cancer, two pheochromocytomas, one myelolipoma, one benign cyst and two metastases. A very high tracer uptake was observed in all tumors originating from the adrenal cortex, allowing excellent visualisation, whereas all other processes were negative. PET with 11C-metomidate is a very promising method for the characterisation of incidentalomas and is suggested to be included very early in the evaluation of these patients.

Adrenal Cortex Neoplasms↗

Case-control study on symptoms and signs of "asymptomatic" primary hyperparathyroidism.

BACKGROUND: Symptoms, signs, and treatment of mild primary hyperparathyroidism (HPT) are controversial. METHODS: One hundred two patients with HPT and matched controls were recruited from 5202 females attending population-based mammography screening at age 55 to 75 years. Patients' total serum calcium averaged 10.40 +/- 0.564 mg/dL and intact serum parathyroid hormone 58 +/- 33 ng/L. All patients lacked knowledge of their disease. Questions revealed traditional symptoms of HPT in 24% of cases and 43% of controls (P = .01). All individuals underwent the same biochemical analyses, bone mass determination, and questionnaires on symptoms, illnesses, medications, and background variables. RESULTS: Patients with HPT had more psychic complaints (P = .03 to .007) of lassitude, fatigue, irritability, and lack of sexual and emotional interests. They had lower bone density in total body, spine, and hip (P = .008 to .0004) and higher serum alkaline phosphatase, cholesterol (very-low-density lipoprotein), triglycerides (total, very-low-density lipoprotein), glucose, urate, and hemoglobin values (P = .02 to .0001). Patients visited physicians more often (P = .008) and had more antihypertensive therapy (P = .02). CONCLUSIONS: Mild, "asymptomatic" HPT in patients unaware of their disorder displays significant psychic symptoms, bone loss, and risk factors of cardiovascular disease.

Aged↗

Primary and reoperative parathyroid operations in hyperparathyroidism of multiple endocrine neoplasia type 1.

BACKGROUND: Operation and reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is controversial regarding surgical strategy, preoperative localization, and biochemical indexes of recurrence. METHODS: Fifty patients with MEN 1 with hyperparathyroidism were followed up 2 to 27 years after subtotal (SPX; n = 35) or total parathyroidectomy with forearm autografiing (TPX; n = 15), including 24 who underwent 28 reoperations because of persistent or recurrent hyperparathyroidism. RESULTS: Persistent or recurrent hyperparathyroidism was seen in 66% and 20% of patients after SPX involving extirpation of at least 3 glands and TPX, respectively, and 100% after single-gland excision as a primary procedure. After reoperation, hypercalcemia was reversed in 33% of patients by SPX and 61% by intended TPX procedures. All patients received vitamin D substitution after TPX, but restricted thyroid function allowed withdrawal in all but 10 patients (36%). Intact serum parathyroid hormone levels in nongrafted and grafted arms rose with time, but only exceptional ratios localized graft recurrence. Localization of recurrent hyperparathyroidism was achieved with 11C-labeled methionine positron emission tomography. CONCLUSION: MEN 1 hyperparathyroidism has a high risk of recurrence, and operation may include primarily SPX of at least 3 glands or TPX, although the latter includes a higher risk of long-term hypoparathyroidism. Reoperation should involve TPX with recognition of the enhanced recurrence rate in individuals with postoperative hyperparathyroidism.

Adolescent↗