Exome sequencing identifies compound heterozygous PKHD1 mutations as a cause of autosomal recessive polycystic kidney disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disease, which is a disorder with multiple organ involvement, mainly the kidney and liver. It is caused by mutations in the PKHD1 gene. Here, we reported the clinical characteristics of a case with ARPKD and analyze the genetic features of this patient as well as of his father using targeted exome sequencing and Sanger sequencing.</p><p><b>METHODS</b>Genomic DNA was extracted from peripheral blood leukocytes obtained from a patient with ARPKD. The mutations were identified using exome sequencing and confirmed by Sanger sequencing.</p><p><b>RESULTS</b>The patient was diagnosed as ARPKD based on ultrasonography and abdominal computed tomography which showed polycystic changes, multiple calcinosis of both kidneys, and multiple dilated bile ducts of the liver. Compound heterozygous PKHD1 gene mutations A979G and G5935A, which lead to substitution of an asparagine for an aspartate at amino acid 327 (N327D) and a glycine for an arginine at amino acid 1979 (G1979R) respectively, were identified using targeted exome sequencing and confirmed by Sanger sequencing for the patient. In addition, the father of the patient was identified to be a carrier of heterozygous A979G mutation of this gene.</p><p><b>CONCLUSIONS</b>We identified that the compound heterozygous PKHD1 gene mutations are the molecular basis of the patient with ARPKD. Targeted exome sequencing is suitable for genetic diagnosis of single-gene inherited diseases like ARPKD in which the pathogenic gene is a large.</p>

Clinical and pathological features of Riedel's thyroiditis / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To evaluate the clinical and pathological features of Riedel's thyroiditis (RT), and current diagnostic and treatment methods for that disease.</p><p><b>METHODS</b>Five RT cases identified by surgery and pathological examinations at Peking Union Medical College Hospital from 1985 to 2009 were analyzed and compared with the cases reported in the literature in terms of clinical and pathological features. Immunohistochemical staining of kappa and lambda light chains was carried out for RT tissues from all the five patients.</p><p><b>RESULTS</b>All the five cases were females, aged 45-55 years. Elevation of serum thyroid autoantibodies was found in only one patient, who had longer disease duration than the others. Pathological examination revealed invasive fibrosclerosis of the thyroid follicles, thyroid capsule, and the surrounding tissues. In RT tissues, the number of cells containing lambda chains was a little higher than those containing kappa chains.</p><p><b>CONCLUSIONS</b>RT is a rare disease which might be more common in middle-aged females than in other populations. Pathological features include the destruction of thyroid follicle, extension into surrounding tissues by inflammatory cells and fibrous tissues. Immunohistochemical staining of kappa and lambda chains could help diagnose RT.</p>

Bilateral pheochromocytoma as first presentation of von Hippel-Lindau disease in a Chinese family / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To investigate the clinical and genetic features of a Chinese family with von Hippel-Lindau (VHL) disease revealed by bilateral pheochromocytoma.</p><p><b>METHODS</b>The proband and other members in a Chinese family with familial pheochromocytoma were clinically evaluated and followed up. Genomic DNA extracted from the peripheral blood of 8 family members (including 3 patients) was amplified by polymerase chain reaction (PCR) and the PCR products were directly sequenced.</p><p><b>RESULTS</b>The first presentation in the proband, his mother, and his sister was bilateral pheochromocytoma, and the missense mutation of 695G-A (Arg161Gln) in exon 3 of VHL gene was detected in the three patients. In the follow-up study, the proband and his mother were found to have other VHL tumors, induding retinal and cerebellar hemangioblastomas and pancreatic tumor. Neither clinical presentation of VHL disease nor gene mutation was found in other family members.</p><p><b>CONCLUSION</b>VHL disease should be suspected in some patients with familial pheochromocytoma, and VHL gene screening helps to achieve early diagnosis of the disease.</p>

Retroperitoneal laparoscopic resection for pheochromocytoma (experience of 107 cases) / 中华外科杂志

<p><b>OBJECTIVE</b>To evaluate the safety and efficacy of retroperitoneal laparoscopic resection for pheochromocytoma.</p><p><b>METHODS</b>The clinical data of 107 cases of pheochromocytoma in PUMCH from 2003 to 2008 were analyzed retrospectively. There were 58 males and 49 females with an age range from 8 to 77 years (mean 44 years) in this cohort. One hundred and two cases were intra-adrenal and 5 extra-adrenal. Of the 102 intra-adrenal tumors, 43 tumors were located in left adrenal, 51 in right adrenal and 8 in both sides. All of the 5 extra-adrenal tumors were at para-abdominal aorta. Retroperitoneal laparoscopic resection was performed for the 107 cases. This period was separated to 3 stages based on the degrees of the practical ability for retroperitoneal laparoscopic resection, such as tentative and exploratory stage, accumulative stage, and mature stage.</p><p><b>RESULTS</b>At tentative and exploratory stage from June 2003 to December 2003, 10 cases underwent retroperitoneal laparoscopic surgery, of which 3 cases were converted to open surgery. The mean diameter was 4.2 cm (range in diameter from 2.5 cm to 6.0 cm). The mean operation time was 105 min (range from 60 min to 230 min). The mean volume of blood loss during operation was 620 ml (range from 150 ml to 1800 ml). At accumulative stage from January 2004 to December 2006, 66 cases underwent retroperitoneal laparoscopic surgery with none converted to open surgery. The mean diameter was 5.7 cm (range in diameter from 2.1 cm to 8.7 cm), and the diameter was above 6.0 cm in 19 cases. The mean operation time was 95 min (range from 40 min to 210 min). The mean volume of blood loss during operation was 350 ml (range from 50 ml to 1800 ml). At mature stage from January 2007 to June 2008, 31 cases, including 5 extra-adrenal pheochromocytomas, underwent retroperitoneal laparoscopic surgery. The mean diameter was 6.5 (range in diameter from 1.5 cm to 12.3 cm). The mean operation time was 75 min (range from 40 min to 160 min). The mean volume of blood loss during operation was 180 ml (range from 50 ml to 800 ml). No peri-operative death occurred. Follow up period was ranging from 1 to 62 months (the mean was 34 months), and 7 failed to be followed up, 3 cases recurred. And there was no distant metastases and death case.</p><p><b>CONCLUSIONS</b>Retroperitoneal laparoscopic surgery for pheochromocytoma is feasible and safe. This procedure will be more and more performed as the advancement of the skill and accumulation of experience. The dimension, recurrence and location of tumor are not the absolute contraindication of retroperitoneal laparoscopic surgery for pheochromocytoma.</p>

Effect of hypokalemia on glucose metabolism in primary hyperaldosteronism / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the effect of potassium deficiency on glucose and insulin metabolism in primary hyperaldosteronism, including aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA).</p><p><b>METHODS</b>Totally 178 patients who were diagnosed as primary hyperaldosteronism (103 patients with APA and 75 with IHA) were divided into hypokalemia group and normal potassium group according to their serum potassium levels. All patients received 3 hours of oral glucose tolerance test and aldosterone test to observe the relationship among glucose, insulin and serum potassium.</p><p><b>RESULTS</b>Area under curve of serum potassium, area under curve of plasma insulin, and fasting serum insulin were significantly lower in the hypokalemia group than in the normal potassium group (P <0. 05, P <0. 01); area under curve of glucose and aldosterone level were significantly higher in the hypokalemia group than in the normal potassium group ( P < 0. 05 ) . The prevalence of metabolic syndrome was significantly higher in IHA than in APA (57. 3% vs 38. 8% ; P < 0. 05).</p><p><b>CONCLUSION</b>Hypokalemia may play an important role in inhibiting insulin secretion in primary hyperaldosteronism.</p>

Expression of renin-angiotensin-aldosterone system in human adipose tissues / 中国医学科学院学报

<p><b>OBJECTIVE</b>To compare the mRNA expression of renin-angiotensin-aldosterone system in human subcutaneous and visceral adipose tissues.</p><p><b>METHODS</b>Total RNA was extracted from 12 human subcutaneous adipose tissues, 12 perirenal adipose tissue and 9 periadrenal adipose tissues. The expressions of angiotensinogen ( AGT) , renin, angiotensin converting enzyme ( ACE) , angiotensin converting enzyme 2 (ACE2), angiotensin I1 receptor type 1 (AT1), angiotensin II receptor type 2 (AT2 ), CYP11 B2, and their internal reference glyceraldehyde phosphate (GAPDH) were studied by reverse transcription-polymerase chain reaction. The ratios of each target genes were used to evaluate the expression levels of AGT, renin, ACE, ACE2, AT1, AT2, and CYP11B2 in different adipose tissues.</p><p><b>RESULTS</b>The mRNA expressions of AGT, ACE, ACE2, AT1, and AT2 were detected in human subcutaneous, perirenal, and periadrenal adipose tissues. However, CYPI B2 mRNA expression was not found in these three adipose tissues. The mRNA expressions of renin was only detected in perirenal and periadrenal adipose tissues, which was significantly higher in perirenal adipose tissues than in periadrenal adipose tissues ( P < 0. 05 ). The mRNA expressions of ACE and ACE2 in perirenal adipose tissues were significantly higher than that in subcutaneous adipose tissues ( P < 0. 05). The mRNA expressions of ACE were significantly higher than that of ACE2 in subcutaneous, perirenal, and periadrenal adipose tissues (P <0. 05). The mRNA expressions of AT1 were significantly lower than that of AT2 in periadrenal adipose tissues (P < 0. 05).</p><p><b>CONCLUSION</b>Local renin-angiotensin system exists in the adipose tissues; however, aldosterone is not synthesized in the adipose tissues.</p>

RET gene cys 634 trp mutation in a multiple endocrine neoplasia type 2A kindred / 中国医学科学院学报

<p><b>OBJECTIVE</b>To identify the genotype of RET gene in one multiple endocrine neoplasia type 2A (MEN2A) kindred.</p><p><b>METHODS</b>Genome DNA was extracted from peripheral blood leucocytes. The DNA sequence of gel-purified polymerase chain reaction (PCR) products was determined with the previously reported 6 pairs of primers of PCR amplification of 10, 11, 13, 14, 15, and 16 exons of RETgene.</p><p><b>RESULTS</b>No abnormalities were found in exon 10, 13, 14, 15, and 16. C to G replacement in nucleotide 14 996 of exon 11 was identified in DNA samples obtained from both peripheral blood of 2 affected brothers. This missense point mutation arisen in heterozygosity and caused a substitution of Cys to Trp residue at codon 634 ( Cys 634 Trp) in RET protein.</p><p><b>CONCLUSION</b>The genotype of the family is identified as Cys 634 Trp substitution of RET gene.</p>

Vasoactive polypeptides and cardiovascular endocrine diseases / 中国医学科学院学报

Cardiovascular bioactive peptides constitute life activity of human beings. They play important roles in regulating the development of cardiovascular system, and controlling disease progression. Recently, interests have arised on the adjusting effects of cardiovascular bioactive peptides on endocrine metabolism, its changes during disease course, influence on disease pathogenesis, as well as its effects on the diagnosis, treatment, and early interventions. New advances have been increasingly achieved in basic and clinical researches. It has become one of the most active areas in life sciences.

Expression of adrenomedullin and its receptor mRNA in the tissues of normal adrenal medulla and pheochromocytoma / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the expression of human adrenomedullin (ADM) and its receptor-receptor activity modifying protein 2/calcitonin receptor-like receptor (RAMP2/CRLR) mRNA in the tissues of normal adrenal medulla and pheochromocytoma.</p><p><b>METHODS</b>Total RNA was extracted from normal adrenal medulla and pheochromocytomas. The expression of ADM and RAMP2/CRLR mRNA were studied by reverse transcription-polymerase chain reaction. The ratios of ADM/GAPDH, RAMP2/ GAPDH, CRLR/GAPDH were used to evaluate the expression levels of ADM, RAMP2 and CRLR mRNA.</p><p><b>RESULTS</b>Expressions of ADM and its receptor- RAMP2/CRLR mRNA were detected in normal adrenal medulla and pheochromocytoma tissues. ADM/GAPDH were 0.48+/-0.09 and 0.75+/-0.24, RAMP2/ GAPDH 0.79+/-0.12 and 1.29+/-0.30, CRLR/GAPDH 0.40+/-0.08 and 0.87+/-0.22 in normal adrenal medulla and pheochromocytomas, respectively (P < 0.05).</p><p><b>CONCLUSION</b>ADM exerts a possible autocrine or paracrine effect in the adrenal. ADM may be involved in the pathogenesis of pheochromocytoma.</p>

Expression of urotensin II and G-protein coupled receptor 14 mRNA in human pheochromocytoma tissues / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the expression of urotensin II (U II) and G-protein coupled receptor 14 (GPR14) mRNA in human pheochromocytoma tissues.</p><p><b>METHODS</b>Total RNA from normal adrenal and pheochromocytoma tissues was extracted. The reverse transcription-polymerase chain reaction method was used to evaluate the levels of U II and GPR14 mRNA expression in human pheochromocytoma tissues.</p><p><b>RESULTS</b>There was no significant difference of U II and GPR14 mRNA expression between normal adrenal cortex and medulla. The expression of U II and GPR14 mRNA in pheochromocytoma was significantly lower than that in normal adrenal cortex and medulla (P < 0.05). The expression of GPR14 mRNA in adrenal pheochromocytomas was significantly lower than that of extra-adrenal pheochromocytomas (P < 0.05).</p><p><b>CONCLUSION</b>U II and GPR14 may play a role in the pathogenesis and hypertension regulating of pheochromocytoma.</p>

A vasoactive peptide: urotensin II / 中国医学科学院学报

Urotensin II (U II ) is currently the most potent vasoconstrictor. G-protein coupled receptor 14 ( GPR-14) is its specific receptor. This review mainly discribes the structure and distribution of U II and GPR14, the activities that U II and GPR14 stimulates proliferation of vascular smooth muscle cells and vasoconstriction, as well as its mechanism.

Clinical diagnosis and treatment of nonfunctioning pheochromocytomas in 14 patients / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To analyze the clinical characteristics of nonfunctioning pheochromocytoma, and to evaluate the efficacy of 131I-metaiodobenzylguanidine (MIBG) scan in the diagnosis and perioperative treatment of nonfunctioning pheochromocytoma.</p><p><b>METHODS</b>The clinical data of 14 patients with nonfunctioning pheochromocytoma were analyzed retrospectively. Plasma free corticoid, renin, aldosterone, and urine catecholamines levels were estimated. B-mode ultrasonography, computed tomography scan, thoracic X-ray and 131I-MIBG were used.</p><p><b>RESULTS</b>All patients with nonfunctioning pheochromocytoma had no hypertension and the tumors were found incidentally. The 24 hours urine catecholamines levels in 80% (8/10) patients were normal. The positive rate of 131-MIBG was 80% (8/10) and the specificity was 100%. All patients underwent surgical operation of tumor resection. No preoperative volume expansion was given to all patients. All tumors were resected completely, and no death accident happened. There was no recurrence and metastasis after operation by long-term follow-up.</p><p><b>CONCLUSION</b>131I-MIBG scan is the first choice technique for the diagnosis of nonfunctioning pheochromocytoma. Blood volume expansion is unnecessary before resection of pheochromocytoma.</p>

The discussion of standards for clinical functional gradation and preoperative preparation of pheochromocytoma / 中华外科杂志

<p><b>OBJECTIVE</b>To discuss the standards for clinical functional gradation and preoperative preparation of pheochromocytoma.</p><p><b>METHODS</b>According to the preoperative clinical manifestations and 24 hr urine catecholamine, 172 cases of pheochromocytomas were divided into 4 grades. Functionary grade 0 including 22 patients was given no volume expansion. Functionary Grade 1 consisted of 17 cases, 10 of which were given phenoxybenzamine orally 5 - 10 mg/d for 1 week (therapeutic group), the rest were control group; the results were analyzed by the chi(2) test. Functionary Grade 2 including 120 patients had phenoxybenzamine orally 30 - 240 mg/d for 4 weeks, hemodynamics and microcirculation image were standards for evaluating volume expansion. Functionary Grade 3 consisted of 13 patients including 1 with acute heart failure, 2 and 10 patients with past history of cerebral hemorrhage and hypertensive crisis respectively, they were treated with enough phenoxybenzamine and other emergent measures.</p><p><b>RESULTS</b>The perioperative blood pressure of Functionary Grade 0 had no fluctuation. The blood pressure of therapeutic group of Functionary Grade 1 had small range fluctuation (< 20 mm Hg), that of the control group was large (> 40 mm Hg). Chi(2) = 13.12, P < 0.01. The hemodynamics of Functionary Grade 2 and Grade 3 recovered within 24 hours postoperatively and no complications occurred.</p><p><b>CONCLUSION</b>According to the function of pheochromocytoma, it is safe and efficient to use different preoperative preparations. Hemodynamics and microcirculation image are golden standards for evaluating preoperative preparations.</p>

Expression of transforming growth factor alpha, tumor necrosis factor alpha, and vascular endothelial growth factor of human pheochromocytoma tissues / 中国医学科学院学报

<p><b>OBJECTIVE</b>To compare the expressions of transforming growth factor alpha (TGFalpha), tumor necrosis factor alpha (TNFalpha), and vascular endothelial growth factor (VEGF) between pheochromocytoma (PHEO) tissues and normal adrenal medulla tissues.</p><p><b>METHODS</b>The mRNA expressions of TGFalpha, TNFalpha, and VEGF detected by RT-PCR, were compared between 22 PHEO tissues and 18 normal adrenal medulla tissues (according with the principle of medical ethnics). Immunohistochemistry staining was performed on 27 PHEO tissues and 14 normal adrenal medulla tissues. The comparisons of the protein expression of TGFalpha, TNFalpha, and VEGF were analyzed in both of PHEO tissues and normal adrenal medulla tissues.</p><p><b>RESULTS</b>Compared with normal adrenal medulla tissues, the expressions of TGFalpha and TNFalpha mRNA and protein were higher in PHEO tissues, and VEGF145 mRNA expression was also higher in PHEO tissues, while there was no significant difference of the mRNA expression of VEGF121 and VEGF165 between these two tissues. Positive staining rates for VEGF of endothelial cells and tumor cells were higher in PHEO tissues than in normal adrenal medulla tissues. Expressions of the TGFalpha, TNFalpha, and VEGF protein were higher in extra-adrenal PHEO than in adrenal PHEO. The TNFalpha immunohistochemistry staining rate was higher in the malignant or multiple PHEO than in the benign or single PHEO.</p><p><b>CONCLUSIONS</b>The mRNA and protein expressions of TGFalpha, TNFalpha, and VEGF are higher in PHEO tissues than those in normal adrenal medulla tissues. Expressions of these cytokines vary in PHEO with different characteristic.</p>

Reevaluation of the hypothalamic-pituitary-adrenal axis function in patients with severe sepsis or septic shock / 中华内分泌代谢杂志

Serum cortisol and plasma ACTH were determined in 10 patients with severe sepsis and 12 with septic shock on day 1,3,5 after diagnosis were made,and the data were compared with 12 control patients. To evaluate the hypothalamic-pituitary-adrenal(HPA)axis function in patients with severe sepsis and septic shock,1?g ACTH stimulation test was applied after hormone concentrations were obtained on day 1.Compared with the control patients,ACTH level was significantly higher in patients with severe sepsis and lower in septic shock(P

Insulin resistance and abnormal glucose metabolism in patients with primary aldosteronism / 中华内分泌代谢杂志

Objective To analysis the relationship of primary aldosteronism to insulin resistance and abnormal glucose metabolism in patients with primary aldosteronism.Methods One hundred and three patients were diagnosed as aldosterone-producing adenoma(APA),75 cases as idiopathic hyperaldosterenism(IHA),56 patients as metabolic syndrome(MS)in Peking Union Medical College Hospital from September 2003 to December 2005.All patients were accepted 3 h oral glucose tolerance test and calculated HOMA-insulin resistance index (HOMA-IR)by Homeostasis Model.Results The Insulin area under curve[INS_(AUC) 270.8(192.7,370.4)mU?L~(-1)?h~(-1)]、HOMA-IR[3.2(2.4,4.7)]and prevalence of insulin resistance(64.3%)were significantly higher in patients with MS as compared with APA[113.2(81.5,193.6)mU?L~(-1)?h~(-1),1.4(1.0,2.2),16.5%]and IHA[186.9(116.6,243.3)mU?L~(-1)?h~(-1),2.0(1.4,3.1),32.0%]groups (all P＜0.01);The INS_(AUC), HOMA-IR and prevalence of insulin resistance were significantly higher in patients with IHA than those with APA (P＜0.05 or P＜0.01).There was no difference between the prevalence of impaired glucose regulation(41.7%, 34.7%),diabetes mellitus(15.5%,16.0%)in patients with APA,IHA and those with MS(41.1%, 26.8%).Conclusion Insulin resistance is present in primary aldosteronism patients,and the prevalence of insulin resistance is higher in patients with IHA.