[Modified Harrington Procedure in the Treatment of Extensive Tumor Defects of the Acetabulum]. / Modifikovaná Harringtonova operace v terapii rozsáhlých nádorových defektu acetabula.

PURPOSE OF THE STUDY The increasing prevalance of patients with metastatic bone cancer and their improved survival puts more emphasis on the quality of treatment of bone metastases. Although most pelvic lesions are treated non-operatively, extensive destruction of the acetabular segment poses a therapeutic challenge. A potential treatment option may be the modified Harrington procedure. MATERIAL AND METHODS At our department, this surgical procedure has been opted for in 14 patients (5 men and 9 women) since 2018. The mean age at the time of surgery was 59 years (range 42 to 73). Twelve patients suffered from metastatic cancer, one patient had a fibrosarcoma metastasis and one female patient presented with aggressive pseudotumor. Radiological and clinical followup of the patients was performed. Pain was assessed using the Visual Analogue Scale, and the Harris Hip Score and the MSTS score were used to evaluate the functional outcome. The paired samples Wilcoxon test was used to analyze the statistical significance of the difference. RESULTS The mean follow-up period was 25 months. At the time of assessment, ten patients were alive with the mean follow-up of 29 months (range 2 to 54 months) and four patients had died of cancer progression, with the mean follow-up being 16 months. No perioperative death or mechanical failure were reported. One female patient developed a hematogenous infection during febrile neutropenia, which was successfully managed with early revision and implant preservation. Statistically, a significant improvement in the MSTS (median 23) and HHS (median 86) functional scores compared to the preoperative values (MSTS median 2, p<0.01, r-effect size = 0.6; HHS preop median 0, p<0.005, r-effect size = -0.7) was observed. There was also a statistically significant reduction in pain (VAS postoperative median 1, VAS preoperative median 8, p<0.01, r-effect size = -0.6). All patients were capable of independent ambulation after the surgery, nine patients walked without support. DISCUSSION There are not many alternatives to this surgical procedure. Apart from non-operative palliative treatment, the options include ice cream cone prostheses or customized 3D implants which are, impractical in terms of time and cost. Our results are comparable to other studies, confirming the reproducibility and reliability of the method. CONCLUSIONS The Harrington procedure is an efective method for management of large acetabular tumor defects with good functional outcomes, an acceptable perioperative risk and a low risk of failure in the medium term, thus suitable also for patients with good cancer prognosis. Key words: umor, metastasis, acetabulum, pelvis, Harrington, reconstruction.

[Surgical Treatment of Tuberculous Spondylodiscitis]. / Operacní lécba tuberkulózní spondylodiscitidy.

PURPOSE OF THE STUDY The paper presents a monocentric retrospective study of patients treated surgically for spinal tuberculosis. Clinical and radiological results are analysed, early and late complications are recorded. The study aims to answer the following questions. 1. Can we use instrumentation to restore the stability and alignment in the infected spinal focus? 2. Should we always perform radical anterior resection of TBC lesions? 3. What is the prognosis of surgical treatment of TBC patients with neurological deficit manifestation? MATERIAL AND METHODS Between 2010 and 2020, a total of 12 patients were treated for spinal tuberculosis at our department, of whom 9 patients (5 men, 4 women) with the mean age of 47.3 years (range 29 to 83 years) underwent a surgery. A total of three patients were operated on before the final confirmation of the TBC and treatment with antituberculosis medication, four patients in the initial therapy phase and two patients in the continuous phase. Two patients only underwent a non-instrumented decompression surgery followed by external support fixation. In the other seven patients, always with spinal deformity, instrumentation was used (3 cases of isolated posterior decompression, transpedicular fixation, posterior fusion, 4 cases of anteroposterior instrumented reconstruction). In 2 cases a structural bone graft and in 2 cases an expandable titanium cage were used for anterior column reconstruction. RESULTS Of the total number of patients, altogether eight patients were assessed at 1 year after surgery (one 83-year-old patient died from heart failure 4 months after surgery). Of the remaining eight patients, three patients exhibited a neurological deficit and postoperative regression of the finding. The McCormick score improved from the preoperative mean score of 3.25 to 1.62 at 1 year after surgery (p < 0.001). The clinical VAS score regressed from 5.75 to 1.63 at 1 year after surgery (p < 0.001). Radiographic healing of the anterior fusion was achieved in all patients, both after decompression and instrumented surgery. The initial mean kyphosis of 20.36 degrees of the operated segment measured by the mCobb angle was corrected to 14.6 degrees postoperatively, with a subsequent slight deterioration to 14.86 degrees (p < 0.05). The greatest correction was achieved in patients who had undergone a two-stage surgery with anterior resection and AP reconstruction. DISCUSSION In our cohort, titanium instrumentation was used in seven of nine patients. One patient only manifested persistent tuberculosis with nonspecific bacterial flora superinfection. Revision surgery with anterior radical debridement and subsequent treatment with antituberculotic drugs healed the patient. There were four patients with major preoperative neurological deficit persisting more than 2 weeks before the final treatment with subsequent improvement in all cases. These patients were treated with anteroposterior reconstruction and anterior radical debridement. CONCLUSIONS No increased risk of recurrent infection associated with the use of spinal instrumentation was found in the study. Anterior radical debridement is performed in patients with manifested kyphotic deformity and spinal canal compression, followed by reconstruction with a structural bone graft or a titanium cage. The other patients are treated based on the principle of "optimal" debridement with or without the use of transpedicular instrumentation. If adequate spinal canal decompression and stability are achieved, neurological improvement can be anticipated even in case of a major neurological deficit. Key words: spine tuberculosis, tuberculous spondylitis, Pott's disease, anterior debridement, spine instrumentation.

[Surgical Treatment of Sacral Chordoma]. / Operacní lécba chordomu sakra.

PURPOSE OF THE STUDY The retrospective study of patients treated for sacral chordoma with respect of complications, clinical outcomes and longterm survival is presented. Three main hypotheses have been formulated. Hypothesis 1: survival of patients with respect to generalization of the disease, manifestation of local recurrence and metastases with a R0 resection margin achieved is longer than survival of patients with a R1 or R2 resection margin. Hypothesis 2: survival of patients with the tumor resected from low endplate of S2 distally is longer than in tumors with resection above this level. Hypothesis 3: resection of large tumors with tumor volume greater than 800 cm³ is associated with a significantly shorter survival than resection of tumors with tumor volume less than 800 cm³. MATERIAL AND METHODS A total of 12 patients (7 women, 5 men), with the mean age of 54.3 years, underwent surgical treatment at our department in 1998-2018. Sacral chordoma proximally achieved S1 level in three cases, S2 level in four cases and S3 level in five cases with volume less than 800 cm³ in eight and greater in four patients. In nine patients sacrectomy using isolated posterior approach was performed and in three patients antero-posterior approach was applied. The Kaplan-Meier survival curve was calculated to estimate the survival of patients. The patients were divided into groups and subsequently compared with respect of achieved radicality of surgical resection, i.e. R0 vs. R1 or R2 resection, secondly of the proximal margin of the tumor/resection, i.e. S1 or S2 vs. S3 distally, and thirdly of the volume of the tumor, i.e. less than 800 cm³ vs. more than 800 cm³. RESULTS At the time of evaluation, a total of seven patients were alive (58.3%), with the mean survival of 9.5 years. One patient died from complications associated with the treatment of obstructive ileus manifested 10 months after primary surgery. The remaining four patients died in relation to the generalization of the disease 14.8 years after primary surgery on average. All the patients, in whom R0 resection was achieved, at the average time of evaluation of 7.3 years (range 2.8-15.8 years) showed no signs of local recurrence or generalization of the disease, whereas in group with R1, R2 resection at the time of evaluation only two patients were still alive, both 16.8 years on average (range 15.2-18.4 years) after surgery with repeatedly treated recurrencies. Frequent postoperative complications were observed in a total of five patients (41.7%). DISCUSSION The study did not confirm any difference in patient's survival with respect of the proximal margin affection of sacrum or tumor size. The decisive factor for survival of patients with sacral chordoma is achieving the R0 resection. The size of the chordoma and proximal achievement increase the complexity of surgery, manifestation of early perioperative and subsequently postoperative complications. CONCLUSIONS In primary surgical treatment of sacral chordoma, we always try to achieve R0 resection. In the case of low-volume tumors from S3 distally, we resect the tumor using the isolated posterior approach. The anterior-posterior approach is preferred in the case of large tumors presenting in the S1/2 region. Key words: sacral chordoma, sacral cancer, wide resection, sacrectomy, vertical rectus abdominus myocutaneous (VRAM) flap.

[Surgical Treatment of Cervical Spondylodiscitis]. / Operacní lécba krcní spondylodiscitidy.

PURPOSE OF THE STUDY The purpose of the retrospective study is to analyse a group of patients surgically treated for cervical spondylodiscitis. The first hypothesis states that the removal of infected intervertebral disc without its anterior column reconstruction in the acute phase of infection results in worse clinical and radiological evaluation of the patient. The second hypothesis defines that the use of titanium implant in anterior column reconstruction in the chronic phase of infection increases the risk of recurrent infection. MATERIAL AND METHODS The evaluated group of patients who underwent surgery includes a total of 21 patients (8 females, 13 males) with the mean age of 57.6 years. 12 patients in the acute phase of infection were treated by anterior debridement without disc space reconstruction, of whom four patients were completed by posterior instrumented fusion in the second stage. In 9 patients in the chronic phase of infection radical anterior debridement was completed by anterior titanium implant reconstruction, of whom in five patients posterior instrumented fusion was performed in the second stage. All patients were clinically evaluated by mJOA, VAS and Frankel score preoperatively, at 6 months and at 1 year postoperatively. The radiologic evaluation assessed the instrumentation failure, spinal fusion and kyphosis progression measured by sagittal Cobb angle. RESULTS The mJOA values improved from the mean preoperative value of 1.6 to 13.15 (6M) and 13.3 (1Y) postoperatively (p = 0.055). The VAS score increased from the mean value of 8.5 preoperatively to 2.15 (6M) and 1.35 (1Y) postoperatively (p < 0.001). No patient reported worse neurological finding postoperatively. The kyphosis progression measured by sagittal Cobb angle from the preoperative +6.7 decreased to +3.2 degrees at 1 year after surgery. The group of 12 patients treated in the acute phase of infection by anterior debridement without anterior column reconstruction showed worsening of kyphosis from +1.1 before surgery to +1.6 degrees at 1 year after surgery. The group of eight patients treated in the chronic phase by anterior debridement and reconstruction of the anterior column by implant changed from +15.9 before surgery to +6.1 degrees at 1 year after surgery. In two out of 12 patients with neurological deficit, the T2-weighted MRI finding of signal hyperintensity showed no improvement of the neurological deficit. DISCUSSION In the group of all operated patients, neither the worsening in the clinical evaluation using the mJOA or VAS score, nor kyphosis progression measured by Cobb angle in the sagittal plane, or failure of instrumentation in the anteroposterior procedure were reported postoperatively. In a total of nine patients operated on during the chronic phase of infection, in whom titanium implant was used to reconstruct the anterior column defect, no recurrent deep infection was observed. CONCLUSIONS In the acute phase we prefer anterior debridement with epidural abscess evacuation without anterior column reconstruction and posterior instrumented fusion in case of kyphosis progression in the second stage. In the chronic phase, radical anterior debridement with titanium implant reconstruction, eventually with posterior instrumented fusion is preferred. Key words: cervical spondylodiscitis, epidural abscess, anterior debridement, bacterial biofilm.

[Two-Stage Revision for Periprosthetic Infection of the Total Hip Arthroplasty: a Comparison of Two Methods]. / Srovnání klinických výsledku skupiny pacientu neartikulovaného a artikulovaného spaceru pri dvoudobé reimplantaci TEP kycelního kloubu pro periprotetický infekt.

PURPOSE OF THE STUDY The purpose of the study is a retrospective comparison of results of the two-stage revision total hip arthroplasty using a non-articulating and an articulating spacer to treat periprosthetic joint infection (PJI). Two basic hypotheses are evaluated: (1) the clinical outcomes of the patients treated with "hand made" articulating cement spacer are better than in non-articulating patient's group in two-stage revision for PJI of the total hip arthroplasty and (2) PJI recurrence is higher in the group of patients treated with an articulating spacer group. MATERIAL AND METHODS The evaluated group consists of a total of 57 patients (23 women, 34 men) with the mean age of 61.2 years. Group A of 39 patients were treated by two-stage revision using the "hand-made" articulating cement spacer and Group B of 18 patients were treated using the non-articulating spacer. Both the groups were evaluated retrospectively in the reference period: preoperatively and two years after the surgery using the Harris Hip Score (HHS) clinical assessment. The revision surgery for acute and chronic complications of treatment, length of hospitalization, and the PJI recurrence were evaluated for both the groups. RESULTS The resulting HHS clinical reviews were pre-operatively 43.59 points in both the groups with postoperative improvement up to 81.74 points. The mean preoperative HHS scores were 41.67 points (Group A) and 47.77 points (Group B) and two years after the surgery they were 83.43 points (Group A) and 78.08 points (Group B) (two-tailed t-test, p-value = 0.042). In Group A a total of seven revisions were performed in the interval between the two-stage revision (4x recurrent dislocation, 2x persistent infection, 1x spacer fracture). In Group B one patient was revised for persistent infection. In the two-year period after the operation, a relapse of PJI was recorded in 5 patients in Group A (12.8%) and in 1 patient in Group B (5.6%) (Chi-square test, p-value = 0.41). The average time of hospitalization was 51.58 days, whereby 49.72 days and 55.61 days on average for Group A and B respectively (p-value = 0.53). DISCUSSION According to recent studies, the advantage of motion preservation in articulating cement spacers can be complicated by recurrent dislocations, implant migration, periprosthetic fractures or recurrent joint replacement infections, which can further prolong the treatment and worsen the final clinical results. An alternative treatment option is the application of a nonarticulating spacer maintaining the advantage of local administration of antibiotics and reducing the dead space formed by the infected implant removal. Discussed is mainly the choice of the method in case of muscle disorder or presence of segmental bone defects. CONCLUSIONS The results demonstrate the better clinical outcomes and the higher revision rate of patients with an articulating cement spacer in two stage revision. We didn't find any differences between the risk of PJI recurrence in both groups. Key words:periprosthetic infection, total hip replacement, cement spacer, two stage revision, articulating spacer, nonarticulating spacer.

[Anterior Cruciate Ligament Tears - Influence on Terminal Extension]. / Ruptury predního zkrízeného vazu ­ vliv na terminální extenzi.

PURPOSE OF THE STUDY The aim of this paper was to compare terminal extension in normal and anterior cruciate ligament (ACL) deficient knees, and therefore to determine the role of the ACL during this motion. MATERIAL AND METHODS Ten knees with ACL tears (7 knees with recent ACL tears, 3 knees with long-standing tears) and 10 normal contralateral knees have been examined using MRI in passive hyperextension, 20° flexion and 20° flexion with a 9 kg posteriorly directed load on the femur. Movements of the femoral condyles on the tibia were calculated using previously described methods. RESULTS 1. Under the load at 20° flexion, knees with ACL tear showed posterior femoral subluxation (equivalent to a Lachman test), chronic tears being more unstable. Contralateral normal knees were antero-posteriorly stable. In hyperextension, both femoral condyles subluxed posteriorly in ACL tears but not in normal knees. 2. In all knees with ACL tear, the lateral femoral condyle moved posteriorly from hyperextension to 20°, equating to femoral external rotation. 3. The longitudinal rotation axis during terminal extension in normal knees was medial but in ACL tears it was central causing the medial femoral condyle to move forward from hyperextension to 20°. In normal knees, the medial femoral condyle did not move antero-posteriorly from hyperextension to 20° flexion. DISCUSSION Internal rotation of the femur during terminal extension has been recognized for 150 years. The question remains: what causes the usual combination of longitudinal rotation and extension? In the current literature ACL is considered to be responsible for internal rotation of the femur during terminal extension of the knee. So far, as we are aware, the kinematics of terminal extension, including hyperextension, have not been reported after ACL tear in the living knee. CONCLUSIONS Results of this study imply that: 1. The ACL prevents anterior tibial subluxation in hyperextension. 2. The ACL does not cause rotation in terminal extension. 3. The ACL locates the axis of longitudinal rotation in terminal extension. We hope that by studying living knees with and without ACL tear we may not only clarify the nature and mechanism of rotation in terminal extension, and hence the role of the ACL, but do so in a context of direct clinical relevance. Key words: knee, terminal extension, ACL tear, axis of longitudinal rotation, antero-posterior instability, MRI.

Associations of polymorphisms in the candidate genes for Alzheimer's disease BIN1, CLU, CR1 and PICALM with gestational diabetes and impaired glucose tolerance.

Alzheimer's disease (AD) is the most common type of dementia, with a prevalence that is rising every year. AD is associated with type 2 diabetes mellitus (T2DM) and insulin resistance, and is therefore sometimes called "type 3 diabetes mellitus". The aim of this study was to examine whether the variants of some candidate genes involved in the development of AD, namely BIN1 (rs744373), CLU (rs11136000), CR1 (rs3818361), and PICALM (rs3851179), are related to several disorders of glucose metabolism-gestational diabetes (GDM), T2DM and impaired glucose tolerance (IGT). Our study included 550 women with former GDM and 717 control women, 392 patients with T2DM and 180 non-diabetic controls, and 117 patients with IGT and 630 controls with normal glucose tolerance. Genotyping analysis was performed using specially-designed TaqMan assays. No significant associations of the genetic variants rs744373 in BIN1, rs11136000 in CLU, or rs3818361 in CR1 were found with GDM, T2DM or IGT, but rs3851179 in PICALM was associated with an increased risk of GDM. The frequency of the AD risk-associated C allele was significantly higher in the GDM group compared to controls: OR 1.21; 95% CI (1.03-1.44). This finding was not apparent in T2DM and IGT; conversely, the C allele of the PICALM SNP was protective for IGT: OR 0.67; 95% CI (0.51-0.89). This study demonstrates an association between PICALM rs3851179 and GDM as well as IGT. However, elucidation of the possible role of this gene in the pathogenesis of GDM requires further independent studies.

[Periprosthetic Infection of the Knee Megaprosthesis following a Resection of Malignant Tumours around the Knee]. / Periprotetické infekce megaprotéz po resekcích kostních nádoru oblasti kolene.

PURPOSE OF THE STUDY The study presents the monocentric retrospective study of a group of patients with malignant tumours around the knee, treated by a wide resection and a reconstruction with megaprosthesis due to infectious complications. Provided is a detailed analysis of each operative treatment due to the manifestation and process of periprostethic infection of the knee megaprosthesis and the use of external fixator during a two-stage revision. MATERIAL AND METHODS Between 01/1993 and 12/2013, a total of 67 cemented megaprostheses were assessed, with a detailed analysis of 12 patients with periprosthetic infection. The Kaplan-Meier method and MSTS for lower extremity clinical assessment were used and a range of motion was evaluated. RESULTS The endoprosthesis failed due to all kinds of complications (mechanical, biological, infection) in 27 (40.3%) patients. The estimated one-year survival rate from the surgery was 94%, the five-year survival rate was 72%, and the ten-year survival rate was 46%. Based on the statistical analysis of the implant survival due to infection, the one-year survival rate was 94%, the five-year survival rate was 75%, and the ten-year survival rate was 57%. Three patients were treated with radical surgical debridement. Five patients were treated with a two-stage revision with a cement spacer and external fixator, and three patients underwent nail fixation. Clinical values before and two years after the revision surgery for periprosthetic infection using MSTS were assessed. The mean of the difference of clinical values was 1.91 and the p value of paired t-test was 0.24, therefore there was no prove of the clinical result difference using MSTS before and after the revision surgery. DISCUSSION The acute radical debridement and lavage is preferred, if the surgery can be done up to three weeks after the first clinical signs of infection under the condition of good retention of the implant. In case of extensive infectious damage, when abscess, fistula and loosening of the implant are present and when the patient has a good oncological prognosis, we prefer a twostage revision with a cement spacer stabilized by an external fixator. In patients with mitigated infection or uncertain oncological prognosis we prefer a two-stage revision with the combination of a cement spacer and intramedullary nail fixation. CONCLUSIONS The study presents the results of operative treatment of periprosthetic infection of megaprosthesis and the modification of the two-stage replantation of infected MP with the use of external fixation for stabilisation of a non-articulated cement spacer allowing the patient to remain active during the time before the second stage. Key words: periprosthetic infection, megaprosthesis, bone tumour, external fixator, two-stage revision.

X-Chromosome Inactivation Analysis in Different Cell Types and Induced Pluripotent Stem Cells Elucidates the Disease Mechanism in a Rare Case of Mucopolysaccharidosis Type II in a Female.

Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder resulting from deficiency of iduronate-2-sulphatase activity. The disease manifests almost exclusively in males; only 16 symptomatic heterozygote girls have been reported so far. We describe the results of X-chromosome inactivation analysis in a 5-year-old girl with clinically severe disease and heterozygous mutation p.Arg468Gln in the IDS gene. X inactivation analysed at three X-chromosome loci showed extreme skewing (96/4 to 99/1) in two patient's cell types. This finding correlated with exclusive expression of the mutated allele. Induced pluripotent stem cells (iPSC) generated from the patient's peripheral blood demonstrated characteristic pluripotency markers, deficiency of enzyme activity, and mutation in the IDS gene. These cells were capable of differentiation into other cell types (cardiomyocytes, neurons). In MPS II iPSC clones, the X inactivation ratio remained highly skewed in culture conditions that led to partial X inactivation reset in Fabry disease iPSC clones. Our data, in accordance with the literature, suggest that extremely skewed X inactivation favouring the mutated allele is a crucial condition for manifestation of MPS II in females. This suggests that the X inactivation status and enzyme activity have a prognostic value and should be used to evaluate MPS II in females. For the first time, we show generation of iPSC from a symptomatic MPS II female patient that can serve as a cellular model for further research of the pathogenesis and treatment of this disease.

[Pyoderma Gangrenosum Mimicking Necrotising Fasciitis after Rotator Cuff Reconstruction]. / Gangrenózní pyodermie po rekonstrukci rotátorové manzety ramena pripomínající nekrotizující fasciitidu.

UNLABELLED: Gangrenous pyoderma is a rare complication of surgical treatment mimicking bacterial necrotizing fasciitis. The characteristic symptoms include a pre-existing immune disorder, negative results of the relevant microbiological examinations, no response to any antibiotic therapy, and deteriorating of the condition after radical debridement. Another typical feature is a discrepancy between an ominous appearance of the wound accompanied by leucocytosis and an elevated CRP level, and the patient s good general condition with low-grade fever and no signs of sepsis. The case of a 68-year-old man who underwent an elective open reconstruction of rotator cuff tears of the left shoulder is presented. The surgery was complicated with pyoderma gangrenosum that was first treated unsuccessfully by repeated revision surgery and broad-spectrum antibiotic therapy. The patient was ultimately cured with corticosteroids. The sequellae included limited motion of the shoulder joint and extensive destruction and scarring of the adjacent soft tissue. KEY WORDS: gangrenous pyoderma, necrotizing fasciitis, corticosteroids.

Association of obesity susceptibility gene variants with metabolic syndrome and related traits in 1,443 Czech adolescents.

Genome-wide association studies have revealed several gene variants associated with obesity; however, only a few studies have further investigated their association with metabolic syndrome. We performed a study of eleven variants in/near genes TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R, and FTO in Czech adolescents and analysed their association with obesity, metabolic syndrome and related traits. Genotyping was performed in 1,443 adolescents aged 13.0-17.9 years. Anthropometric parameters, biochemical parameters and blood pressure were assessed. Metabolic syndrome was defined according to the International Diabetes Federation. The FTO rs9939609 variant was associated with overweight/obesity (OR 1.40, 95% CI 1.21-1.63, P < 0.001). The minor allele of TMEM18 rs7561317 was related to underweight (OR 1.78, 95% CI 1.14-2.79, P = 0.015). BDNF rs925946 and MC4R rs17782313 were associated with metabolic syndrome (OR 1.53, 95% CI 1.14-2.04, P = 0.005; 1.51, 95% CI 1.12-2.04, P = 0.009). The PCSK1 rs6235 variant was negatively related to increased blood glucose (OR 0.69, 95% CI 0.49-0.97, P = 0.040). In conclusion, the FTO variant was associated with overweight/obesity in Czech adolescents. Moreover, MC4R and BDNF variants increased the risk of metabolic syndrome, probably through their effect on abdominal obesity. The PCSK1 variant may have a protective role in the development of type 2 diabetes.

Molecular Genetic Aspects of Sporadic Multiglandular Primary Hyperparathyroidism.

Multiglandular primary hyperparathyroidism (MGD) represents a rare form of primary hyperparathyroidism (PHPT). MGD is associated with hereditary PHPT, but the sporadic MGD is more common and affects a similar patient profile as single gland parathyroid disease (SGD). The distinction between SGD and MGD is of great clinical importance, especially for the strategy of parathyroidectomy. Based on the limited knowledge available, MGD is likely to be a genetically heterogeneous disease resulting from the interaction of germline and somatic DNA mutations together with epigenetic alterations. Furthermore, these events may combine and occur independently in parathyroid tumors within the same individual with MGD. Gene expression profiling has shown that SGD and MGD may represent distinct entities in parathyroid tumorigenesis. We are waiting for studies to analyze exactly which genes are different in SGD and MGD in order to identify potential biomarkers that can distinguish between the two forms of the disease.

Age-Related Changes in Proinsulin Processing in Normoglycemic Individuals.

In order to understand the pathological changes associated with glucose homeostasis in old age, it is necessary to know the natural changes in the processing of proinsulin to mature insulin. While there is abundant information about insulin production and function in diabetics, the situation in healthy adults and the elderly has surprisingly rarely been investigated. The aim of the study was to determine how proinsulin secretion changes in individuals with normal glucose tolerance during the process of natural aging. A total of 761 individuals (539 women, 222 men) aged 18-90 years with normal fasting glycemia (less than 5.6 mmol/l) were divided into five groups according to age. Body composition and levels of fasting blood glucose, proinsulin, insulin, and C-peptide were determined, and the ratios of proinsulin to both insulin and C-peptide were calculated. The homeostasis model of ?-cell function (HOMA F) and peripheral insulin resistance (HOMA R) were calculated. The effect of age was assessed using an ANOVA model consisting of the factors sex, age, and sex × age interaction. Statgraphics Centurion v. XVIII statistical software was used. Glycemia, insulin, C-peptide and HOMA R increased in both sexes up to 75 years. On the contrary, proinsulin levels as well as proinsulin/insulin and proinsulin/C-peptide ratios decreased with age up to 75 years. In normoglycemic and normotolerant people, both women and men, the aging process is associated with decreased insulin sensitivity compensated by potentiation of insulin production. In older age, there is also a gradual decrease in circulating proinsulin, which can be explained by its more efficient processing into active insulin by matured healthy beta cells.

Recurrent Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 1 Syndrome.

Primary hyperparathyroidism is a common endocrinopathy. Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare autosomal dominantly inherited endocrine tumor predisposition syndrome, with one of main manifestations being primary hyperparathyroidism. We retrospectively evaluated a set of 1011 patients who underwent surgery for primary hyperparathyroidism between the years 2018-2022, and found 78 (8 %) patients who underwent reoperations and 27 patients with MEN1 syndrome. In the group of patients with MEN1 syndrome, 7 (35 %) needed reoperations. Patients with multiple endocrine neoplasia syndrome have a higher risk of needing reoperation. Genetic testing can help identify MEN1 syndrome preoperatively and to better evaluate the approach to surgery.

Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: FTO gene single nucleotide polymorphisms (SNPs) have been shown to be associated with obesity-related traits and type 2 diabetes. Several small studies have suggested a greater than expected effect of the FTO rs9939609 SNP on weight in polycystic ovary syndrome (PCOS). We therefore aimed to examine the impact of FTO genotype on BMI and weight in PCOS. METHODS: A systematic search of medical databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted up to the end of April 2011. Seven studies describing eight distinct PCOS cohorts were retrieved; seven were genotyped for SNP rs9939609 and one for SNP rs1421085. The per allele effect on BMI and body weight increase was calculated and subjected to meta-analysis. RESULTS: A total of 2,548 women with PCOS were included in the study; 762 were TT homozygotes, 1,253 had an AT/CT genotype, and 533 were AA/CC homozygotes. Each additional copy of the effect allele (A/C) increased the BMI by a mean of 0.19 z score units (95% CI 0.13, 0.24; p = 2.26 × 10(-11)) and body weight by a mean of 0.20 z score units (95% CI 0.14, 0.26; p = 1.02 × 10(-10)). This translated into an approximately 3.3 kg/m(2) increase in BMI and an approximately 9.6 kg gain in body weight between TT and AA/CC homozygotes. The association between FTO genotypes and BMI was stronger in the cohorts with PCOS than in the general female populations from large genome-wide association studies. Deviation from an additive genetic model was observed in heavier populations. CONCLUSIONS/INTERPRETATION: The effect of FTO SNPs on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between FTO and the metabolic context or polygenic background of PCOS.

Multiglandular Parathyroid Disease in Primary Hyperparathyroidism With Inconclusive Conventional Imaging.

Inconclusive preoperative imaging is a strong predictor of multiglandular parathyroid disease (MGD) in patients with primary hyperparathyroidism (PHPT). MGD was investigated in a cohort of 17 patients with PHPT (mean age 64.9 years, total calcium 2.75 mmol/l and parathyroid hormone (PTH) 113.3 ng/l) who underwent 18F-fluorocholine PET/CT (FCH) imaging before surgery. The initial MIBI SPECT scintigraphy (MIBI) and/or neck ultrasound were not conclusive or did not localize all pathological parathyroid glands, and PHPT persisted after surgery. Sporadic MGD was present in 4 of 17 patients with PHPT (24 %). In 3 of 4 patients with MGD, FCH correctly localized 6 pathological parathyroid glands and surgery was successful. Excised parathyroid glands were smaller (p <0.02) and often hyperplastic in MGD than in single gland disease. In two individuals with MGD, excision of a hyperplastic parathyroid gland led to a false positive decline in intraoperative PTH and/or postoperative serum calcium. Although in one patient it was associated with partial false negativity, parathyroid imaging with FCH seemed to be superior to neck ultrasound and/or MIBI scintigraphy in MGD.

BRAFV600E mutation in the pathogenesis of a large series of papillary thyroid carcinoma in Czech Republic.

BACKGROUND: Activating point mutation of the BRAF gene, the most common genetic alteration reported in papillary thyroid carcinomas (PTC), has been associated with poor prognostic characteristics. AIM: Our objective was to determine the frequency of BRAFV600E mutation in PTC tumor tissues from the period 1960-2007 and to correlate it with clinicopathological parameters. SUBJECTS AND METHODS: DNAs were extracted from 242 PTCs, 23 sporadic medullary carcinomas, one anaplastic carcinoma and 6 poorly differentiated carcinomas. The presence of BRAFV600E mutation was determined using single strand conformation polymorphism method and verified by direct sequencing. RESULTS: BRAFV600E mutation was detected in 81 of 242 PTCs (33.5%), in one of 6 poorly differentiated carcinomas (16.7%) and in anaplastic carcinoma. BRAFV600E mutation was much less frequent in the follicular variant compared to classical variant and mixed follicular- classical variant of PTCs (p=0.001). BRAFV600E mutation was significantly associated with presence of nodal metastasis (p=0.029), more advanced TNM stage (p=0.014) and recurrence of disease (p=0.008). The mutation correlated with a higher age at diagnosis (p=0.049) and with a greater tumor size (p=0.041). Multivariate analysis confirmed these findings. The prevalence of BRAFV600E mutation before 1986 was significantly lower than after it (p=0.008). CONCLUSIONS: Our data suggest that BRAFV600E mutation is associated with high-risk clinicopathological characteristics of PTC and worse prognosis of patients. The frequency of the mutation significantly varied during the observed period but rather because of the different age distribution of patients in particular periods than as a consequence of Chernobyl accident.

[Extremely low SHBG level in consequence of Pro156Leu SHBG polymorphism--case reports of two women with polycystic ovary syndrome]. / Extrémne nízké hladiny SHBG jako dusledek polymorfizmu Pro156Leu v genu pro SHBG-- kazuistiky dvou zen se syndromem polycystických ovarií.

Presented case reports illustrate clinical manifestations of two women with polycystic ovary syndrome who had extremely low serum SHBG levels (Sex Hormone Binding Globulin) due to homozygote carriership of the rare Pro156Leu SHBG polymorphism.

[Birth weight and genetic risk of type 2 diabetes in Czech population]. / Porodní hmotnost a genetické pozadí rizika diabetes mellitus 2. typu u ceské populace.

INTRODUCTION: Birth weight is associated with type 2 diabetes mellitus and other late-onset metabolic diseases. Reduced birth weight is associated with an increased risk of insulin resistance, type 2 diabetes, and atherosclerosis. Also high birth weight represents risk factor for development of type 2 diabetes later in life. In this study, we investigate whether type 2 diabetes risk-confering alleles and biochemical as well as anthropometrical type 2 diabetes risk markers associate with birth weight in our Czech cohort. RESULTS: Association between high birth weight and higher BMI in adulthood was found. Low birth weight was associated with higher glycaemia and insulinaemia as well as lower peripheral insulin sensitivity during oGTT. The examination of candidate genes provides evidence that Ngn3 and PPARalpha are involved in final birth weight regulation. CONCLUSION: According to our results, we suggest that birth weight should be an integral part of medical history record.

Insights into the physiology of C-peptide.

Current knowledge suggests a complex role of C-peptide in human physiology, but its mechanism of action is only partially understood. The effects of C-peptide appear to be variable depending on the target tissue, physiological environment, its combination with other bioactive molecules such as insulin, or depending on its concentration. It is apparent that C-peptide has therapeutic potential for the treatment of vascular and nervous damage caused by type 1 or late type 2 diabetes mellitus. The question remains whether the effect is mediated by the receptor, the existence of which is still uncertain, or whether an alternative non-receptor-mediated mechanism is responsible. The Institute of Endocrinology in Prague has been paying much attention to the issue of C-peptide and its metabolic effect since the 1980s. The RIA methodology of human C-peptide determination was introduced here and transferred to commercial production. By long-term monitoring of C-peptide oGTT-derived indices, the Institute has contributed to elucidating the pathophysiology of glucose tolerance disorders. This review summarizes the current knowledge of C-peptide physiology and highlights the contributions of the Institute of Endocrinology to this issue.