Transition paths of marine debris and the stability of the garbage patches.

We used transition path theory (TPT) to infer "reactive" pathways of floating marine debris trajectories. The TPT analysis was applied on a pollution-aware time-homogeneous Markov chain model constructed from trajectories produced by satellite-tracked undrogued buoys from the National Oceanic and Atmospheric Administration's Global Drifter Program. The latter involved coping with the openness of the system in physical space, which further required an adaptation of the standard TPT setting. Directly connecting pollution sources along coastlines with garbage patches of varied strengths, the unveiled reactive pollution routes represent alternative targets for ocean cleanup efforts. Among our specific findings we highlight: constraining a highly probable pollution source for the Great Pacific garbage patch; characterizing the weakness of the Indian Ocean gyre as a trap for plastic waste; and unveiling a tendency of the subtropical gyres to export garbage toward the coastlines rather than to other gyres in the event of anomalously intense winds.

Markov-chain-inspired search for MH370.

Markov-chain models are constructed for the probabilistic description of the drift of marine debris from Malaysian Airlines flight MH370. En route from Kuala Lumpur to Beijing, MH370 mysteriously disappeared in the southeastern Indian Ocean on 8 March 2014, somewhere along the arc of the 7th ping ring around the Inmarsat-3F1 satellite position when the airplane lost contact. The models are obtained by discretizing the motion of undrogued satellite-tracked surface drifting buoys from the global historical data bank. A spectral analysis, Bayesian estimation, and the computation of most probable paths between the Inmarsat arc and confirmed airplane debris beaching sites are shown to constrain the crash site, near 25°S on the Inmarsat arc.

Successful in vitro maturation of oocytes in a woman with gonadotropin-resistant ovary syndrome associated with a novel combination of FSH receptor gene variants: a case report.

Infertility due to Gonadotropin-Resistant Ovary Syndrome (GROS) is a rare type of hypergonadotropic hypogonadism. Here, we report an original case of GROS, associated with compound heterozygous follicle-stimulating hormone receptor (FSHR) variants, in a woman who achieved a live birth by in vitro maturation (IVM) of her oocytes. This 31-year-old woman consulted our assisted reproduction center for a second opinion after having been advised, because of pervasive high serum follicle-stimulating hormone (FSH) levels, to pursue in vitro fertilization (IVF) with donor oocytes. She presented with primary infertility and progressively prolonged menstrual cycles. Her serum FSH levels were indeed found to be high, but in discordance with a normal anti-Müllerian hormone (AMH) level and antral follicle count. Genetic investigation found the patient to be compound heterozygous for two FSHR variants: I160T, a known pathologic variant, and N558H, which has never been previously reported. As there was no ovarian response to high daily doses of exogenous gonadotropins, IVM was proposed to the patient with success and she finally delivered at term a healthy boy. Effects of the receptor variants were analyzed in heterologous cells. Whereas the I160T mutation blocked FSHR membrane trafficking and FSH-stimulated cAMP-dependent signaling in transfected CHO cells, the novel variant, N558H, functioned equivalently to wild-type FSHR in the assays employed. In conclusion, IVM should always be offered as a first-line therapy to infertile women presenting with GROS. The N558H variant discovered in FSHR is novel, but its functional significance, if any, is unresolved and merits further investigation as it may be associated with a recessive FSHR-related disorder.

Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers.

BACKGROUND: Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. METHOD: To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. RESULTS: No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. CONCLUSION: Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.

Evaluation of the laryngoscopy view using the modified Cormack-Lehane scale during tracheal intubation in an intensive care unit. A prospective observational study. / Evaluación de la escala modificada de Cormack-Lehane para visión laringoscópica durante la intubación orotraqueal en una unidad de cuidados críticos. Estudio prospectivo observacional.

BACKGROUND AND OBJECTVIES: Tracheal intubation in the Intensive Care Unit is associated with a high incidence of difficult intubation and complications. This may be due to a poor view of the glottis during direct laryngoscopy. The aim of this study is to determine if there is a relationship between laryngoscopy view using the modified Cormack-Lehane scale with the incidence of difficult intubation and complications. METHODS: All patients who were subjected to tracheal intubated with direct laryngoscopy in the Intensive Care Unit over a 45 month period were included in the study. In all patients, an evaluation was made of the laryngoscopy view using the modified Cormack-Lehane scale, as well as the technical difficulty (number of intubations at first attempt, operator-reported difficulty, need for a Frova introducer), and the incidence of complications (hypotension, hypoxia, oesophageal intubation). RESULTS: A total of 360 patients were included. When the grade of the modified Cormack-Lehane scale was increased from 1 to 4, the incidence of first success rate intubation decreased (1: 97%, 2a: 94%, 2b: 80%, 3: 60%, 4: 0%, p<.001), the incidence of moderate and severe difficulty intubation increased (1: 2%, 2a: 4%, 2b: 36%, 3: 77%, 4: 100%, p<.001.), as well as the need for a Frova guide (1: 7%, 2a: 8%, 2b: 45%, 3: 60%, 4: 100%, p<.001). When the grade of the modified Cormack-Lehane scale increased from 1 to 4, the incidence of hypoxia<90% increased (1: 20%, 2a: 20%, 2b: 28%, 3: 47%, 4: 100%, p=.0073), as well as hypoxia<80% (1: 11%, 2a: 10%, 2b: 12%, 3: 27%, 4: 100%, p=.00398). No relationship was observed between the incidence of hypotension and the grade of the modified Cormack-Lehane scale (p=ns). CONCLUSIONS: During tracheal intubation in the Intensive Care Unit a close relationship was found between a poor laryngoscopy view using the modified Cormack-Lehane scale and a higher difficulty technique of intubation. A relationship was found between the incidence of hypoxia with a higher grade in the modified Cormack-Lehane scale. No relationship was found between hypotension and the modified Cormack-Lehane scale.

Germline E-cadherin mutations in familial lobular breast cancer.

BACKGROUND: The cell surface glycoprotein E-cadherin (CDH1) is a key regulator of adhesive properties in epithelial cells. Germline mutations in CDH1 are well established as the defects underlying hereditary diffuse gastric cancer (HDGC) syndrome, and an increased risk of lobular breast cancer (LBC) has been described in HDGC kindreds. However, germline CDH1 mutations have not been described in patients with LBC in non-HDGC families. This study aimed to investigate the frequency of germline CDH1 mutations in patients with LBC with early onset disease or family histories of breast cancer without DGC. METHODS: Germline DNA was analysed in 23 women with invasive lobular or mixed ductal and lobular breast cancers who had at least one close relative with breast cancer or had themselves been diagnosed before the age of 45 years, had tested negative for a germline BRCA1 or BRCA2 mutation, and reported no personal or family history of diffuse gastric cancer. The full coding sequence of CDH1 including splice junctions was amplified using PCR and screened for mutations using DHPLC and sequencing. RESULTS: A novel germline CDH1 truncating mutation in the extracellular portion of the protein (517insA) was identified in one woman who had LBC at the age of 42 years and a first degree relative with invasive LBC. CONCLUSIONS: Germline CDH1 mutations can be associated with invasive LBC in the absence of diffuse gastric cancer. The finding, if confirmed, may have implications for management of individuals at risk for this breast cancer subtype. Clarification of the cancer risks in the syndrome is essential.

Lagrangian dynamical geography of the Gulf of Mexico.

We construct a Markov-chain representation of the surface-ocean Lagrangian dynamics in a region occupied by the Gulf of Mexico (GoM) and adjacent portions of the Caribbean Sea and North Atlantic using satellite-tracked drifter trajectory data, the largest collection so far considered. From the analysis of the eigenvectors of the transition matrix associated with the chain, we identify almost-invariant attracting sets and their basins of attraction. With this information we decompose the GoM's geography into weakly dynamically interacting provinces, which constrain the connectivity between distant locations within the GoM. Offshore oil exploration, oil spill contingency planning, and fish larval connectivity assessment are among the many activities that can benefit from the dynamical information carried in the geography constructed here.

Shock séptico secundario a fascitis necrotizante abdominal tras drenaje de absceso interesfintérico perianal / Septic shock secondary to abdominal necrotizing fascitis after drainage of perianal intersphyteric abscess

Resumen Objetivo: El objetivo de este manuscrito es presentar el caso de un varón de 41 años que debuta con shock séptico y fascitis necrotizante abdominal en el posoperatorio del desbridamiento de un absceso perianal para focalizar la atención del lector en la posible evolución clínica hacia gangrena de Fournier. Materiales y Método: Tras la intervención, el paciente refiere aumento de temperatura y sensación de crepitación subcutánea a nivel abdominal, junto con empeoramiento clínico y hemodinámico, evidenciándose evolución tórpida hacia gangrena de Fournier extendida a región abdominal. Resultados: Tras la reintervención, el paciente presentó una evolución favorable aunque requirió sucesivas curas y desbridamientos quirúrgicos. Conclusiones y Discusión: Cabe destacar la importancia de una exploración clínica completa y detallada previa a cualquier intervención quirúrgica, así como el diagnóstico temprano en situaciones de shock séptico que permitan inicio de antibioterapia precoz y control del foco eficaz.

Aim: The objective of this manuscript is to present the case of a 41-year-old man with septic shock and abdominal necrotizing fasciitis after drainage of an interesphinteric perianal abscess to focus the reader's attention on the possible clinical evolution towards Fournier's gangrene. Materials and Method: After the intervention, the patient reported an increase in temperature and a sensation of subcutaneous crepitus at the abdominal level, with clinical and hemodynamic worsening, showing a torpid evolution towards Fournier's gangrene extended to the abdominal area. Results: After the reoperation, the patient presented a favorable evolution, although he required successive cures and surgical debridements. Conclusions and Discussion: It is worth highlighting the importance of a complete and detailed clinical examination prior to any surgical intervention, as well as the early diagnosis in situations of septic shock that allow early initiation of antibiotic therapy and effective control of the focus.

Platelet-activating factor acetylhydrolase activity in peritoneal fluids of women with endometriosis.

OBJECTIVE: To investigate whether platelet-activating factor acetylhydrolase may play a role in the pathophysiology of endometriosis. METHODS: Peritoneal fluids were obtained at laparoscopy from eight fertile women without endometriosis and 12 women with mild endometriosis. Platelet-activating factor acetylhydrolase activity was assayed in serum and peritoneal fluid by the release of 3H-acetate from [3H]-platelet-activating factor during a 15-minute incubation. RESULTS: Platelet-activating factor acetylhydrolase activity (mean +/- standard error of the mean) was significantly lower (P < .01) in peritoneal fluids from women with mild endometriosis (29.5 +/- 2.7%) than in controls (39.9 +/- 3.4%). The platelet-activating factor acetylhydrolase-cholesterol and -albumin ratios were also significantly lower in peritoneal fluids of women with endometriosis compared with controls (P < .006 and P < .012, respectively). CONCLUSION: These data suggest that mild endometriosis is associated with decreased platelet-activating factor acetylhydrolase activity in peritoneal fluid.

The effect of antisperm autoantibodies in male or female partners undergoing in vitro fertilization-embryo transfer.

OBJECTIVE: To evaluate the effects of sperm bound autoantibodies on the outcome of IVF-ET. DESIGN: Couples with positive antisperm autoantibodies as determined by the immunobead test were retrospectively classified into two groups: group A, consisting of 15 couples with positive antisperm antibodies in the female sera; and group B, consisting of 16 couples with sperm antibodies bound to motile spermatozoa from the male partner. Both groups were subclassified according to pregnancy outcome, i.e., pregnant and nonpregnant cycles. PATIENTS: Thirty-one couples with positive antisperm autoantibodies were compared with 312 couples with tubal infertility undergoing IVF-ET. RESULTS: No significant correlation could be shown between the mean percent binding of any specific immunoglobulin (Ig) class (G, A, and M) nor localization of sperm binding with regard to fertilization and embryonic development among pregnant and nonpregnant cycles within groups A and B. The mean fertilization rate was 59% in the control group, compared with 62% in group A and 52% in group B. Overall, the pregnancy rate (PR) in IVF-ET cycles with positive sperm autoantibodies did not demonstrate a decreasing trend compared with controls. The PR per cycle, per oocyte retrieval, and per ET was higher in group A (47%, 50%, and 53%, respectively) compared with group B (32%, 33%, and 37%) and to controls (27%, 31%, and 34%). The implantation rate was lowest in the control group (10%) compared with the study groups (group A, 20% and group B, 14%). CONCLUSION: In vitro fertilization-embryo transfer is not significantly affected by the presence of sperm autoantibodies in female sera used to supplement the culture media or antibodies bound to inseminated sperm.

Comparison of reoperation for moderate (stage III) and severe (stage IV) endometriosis-related infertility with in vitro fertilization-embryo transfer.

OBJECTIVE: To evaluate the efficacy of reoperation for stage III or IV endometriosis-related infertility versus IVF-ET. DESIGN: Retrospective analysis. SETTING: In vitro fertilization-embryo transfer unit and tertiary infertility clinic. PATIENTS: Twenty-three couples with stage III or IV endometriosis-related infertility undergoing IVF-ET and 18 women undergoing reoperation for stage III or IV disease, both groups undergoing treatment after failed initial surgery to restore fertility. RESULTS: The cumulative pregnancy rate (CPR) after reoperation for stage III or IV endometriosis-related infertility after 3, 7, and 9 months was 5.9 percent, 18.1 percent and 24.4 percent, respectively. The cumulative PR after one and two cycles of IVF-ET with stage III or IV endometriosis was 33.3 percent and 69.6 percent, respectively. The cumulative PR after one cycle of IVF-ET was higher than with reoperation 33.3 percent versus 24.4 percent. After two cycles the cumulative PR was significantly higher than reoperation 69.6 percent versus 24.4 percent. The mean number of oocytes retrieved was 8.5 +/- 4.6, the mean number of embryos was 4.8 +/- 2.9, and the fertilization rate was 64 percent +/- 21.8 percent. The PR per cycle, per oocyte retrieval and per ET was 38 percent, 42 percent, and 44 percent, respectively, with the implantation rate being 16 percent. The live birth rate per oocyte retrieval and per ET was 29.7 percent and 34.4 percent, respectively. No statistically significant difference could be demonstrated with regard to the fertilization, implantation, nor pregnancy or live birth rates, as compared with IVF-ET outcome with tubal infertility. CONCLUSION: If initial surgery fails to restore fertility in patients with moderate (stage III) or severe (stage IV) endometriosis-related infertility, IVF-ET is an effective alternative; reoperation for asymptomatic patients offers little added benefit.

Platelet-activating factor acetylhydrolase in human seminal plasma.

OBJECTIVE: To search for the presence of platelet-activating factor (PAF) acetylhydrolase activity in human seminal plasma. DESIGN: Experimental. SETTING: Reproductive laboratory in a university-affiliated hospital research center. PARTICIPANTS: Human male volunteers were selected on the basis of apparent normal health. RESULTS: Human seminal plasma contained significant levels of PAF-acetylhydrolase activity. Enzymatic hydrolysis of PAF displayed typical kinetics and was a calcium-independent process. Platelet-activating factor acetylhydrolase in seminal plasma was associated with a very high-density lipoprotein fraction. Enzymatic activity was independent of sperm count and motility. CONCLUSION: Human seminal plasma contains significant levels of PAF acetylhydrolase. This enzyme may be an important factor in the regulation of PAF concentration and activity.

Effect of follicular fluid supplementation on the in vitro development of human pre-embryos.

OBJECTIVE: To evaluate the value of supplementing a standard culture medium with 10% heat-inactivated mature follicular fluid (FF). DESIGN: Prospective randomized study evaluating the in vitro development of nontransferred, nonfrozen human pre-embryos in three culture conditions from day 3 to day 8 postfertilization. Preliminary evaluation by RIA and electrophoresis of factors responsible for these results. RESULTS: Ten percent mature FF supplementation of Inra Menezo (B2 medium) was associated with a significantly higher proportion of human pre-embryos reaching the morula (95% versus 72% with 10% maternal serum, P = 0.04) and the blastocyst stage (50% versus 11% with B2 alone, P = 0.02). The concentration of insulin-like growth factors I and II did not differ significantly between serum and mature FF-supplemented medium. Protein electrophoresis showed a difference of two bands corresponding to a molecular weight of 17,000 present in the serum and not in the FF-supplemented medium. CONCLUSION: Culture medium supplementation with 10% mature FF is associated with a significantly higher proportion of pre-embryos reaching the morula and blastocyst stage. The observed difference could be explained by the presence of a low molecular weight (17,000) embryotoxic factor contained in the serum-supplemented medium.

Effect of lysoplatelet-activating factor on human sperm fertilizing ability.

OBJECTIVE: To evaluate the penetration rates in the hamster zona-free oocyte sperm penetration assay (SPA) after exposure of spermatozoa to lysoplatelet-activating factor (LPAF) and lysophosphatidyl choline (LPC). DESIGN: Washed human spermatozoa were exposed to 100 microM of LPAF or LPC, followed by the assessment of their fertilizing ability using the SPA. The percentage of penetration, the sperm binding in the SPA, the percentage of motile spermatozoa, and the acrosome reaction rates were quantified. SETTING: Private research and university laboratories. PATIENTS, PARTICIPANTS: Fresh and frozen semen samples from fertile donors with proven fertility were used as well as fresh semen from infertile patients attending a fertility clinic. All the infertile patients had abnormal semen analysis. INTERVENTIONS: Human spermatozoa were incubated for 90 minutes in the presence or absence of LPAF or LPC at 100 microM with 0.3% albumin in Ham's F-10 (GIBCO, Dorval, Quebec, Canada), and their fertilizing ability was evaluated using the SPA. The effect of these lysophospholipids on the percentage of acrosome reaction was evaluated with a fluorescent microscopy technique. RESULTS: The penetration rates of the SPA in male factor increased significantly from 3% +/- 6% with controls to 19% +/- 9% and 34% +/- 22% after incubation with LPC and LPAF, respectively. Sperm-oocyte binding was not significantly increased in this group. Sperm penetration assay penetration rates were also increased in fertile cryopreserved spermatozoa with LPC and LPAF. In this group, the acrosome reaction was significantly increased from 2% +/- 1% in controls to 10% +/- 6% and 8% +/- 3% after incubation with LPC and LPAF, respectively. CONCLUSION: Lysoplatelet-activating factor and LPC independently increased the penetration rate of spermatozoa and the percentage of acrosome reaction. Lysophosphatidylcholine and LPAF may be beneficial in the treatment of spermatozoa with male factor infertility and may increase fertilization rates in IVF.

Human embryos produce transforming growth factors alpha activity and insulin-like growth factors II.

OBJECTIVE: To assess whether growth factors are produced by early human embryos in culture. DESIGN: We studied various growth factors in the culture media of human embryos (n = 6) cultured from days 3 to 8 after fertilization. MAIN OUTCOME MEASURES: Four growth factors were measured: Insulin growth factors I and II (IGF-I and IGF-II), epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) activity. RESULTS: Nonconditioned INRA Menezo B2 (Biomerieux, S.A., Paris, France) culture medium contained significant levels of TGF alpha activity (5.2 ng/mL) and low levels of IGF-I (1.02 ng/mL) and IGF-II (2.8 ng/mL), whereas EGF was below detection of our assay. With human embryo, the culture media contained lower TGF alpha activity on days 3 and 4 after fertilization (2.5 ng/mL and 2.8 ng/mL, P less than 0.05). From days 5 to 8 after fertilization, a significant increase in TGF alpha activity and IGF-II was detected (TGF alpha activity: day 5: 3.7 ng/mL; day 6: 4.4 ng/mL; day 7: 6.4 ng/mL; day 8: 8.4 ng/mL) (IGF-II: day 5: 3.4 ng/mL; day 6: 3.1 ng/mL; day 7: 4.1 ng/mL; day 8: 4.2 ng/mL). Epidermal growth factor was undetectable, and IGF-I did not vary significantly. CONCLUSION: Transforming growth factor alpha activity and IGF-II are produced by human embryos in culture at a time when they could play a role in morula to blastocyst transformation.

Midcycle changes of 17-OH-progesterone levels in women superovulated with clomiphene citrate and human menopausal gonadotropin for in vitro fertilization.

The dynamics of 17-alpha-hydroxy-progesterone (17-OHP) production during the onset of the luteinizing hormone (LH) surge were evaluated at 8-hour intervals and correlated with plasma estradiol (E2), LH, and progesterone (P) in 22 women superovulated for in vitro fertilization. Plasma 17-OHP levels rose 8 to 16 hours before the earliest rise in LH and P in 18% of patients, but had risen significantly in 82% of patients by the onset of the LH surge. In the late follicular phase, 17-OHP levels correlated significantly with E2 and LH levels, and the number of follicles greater than 10 mm. Because rising 17-OHP levels preceded the LH surge in only a few patients, it has no clinical value as a marker for human chorionic gonadotropin administration for timed oocyte recovery. Plasma 17-OHP levels, however, may complement LH levels better than P levels in determining the most appropriate stage for surge-timed oocyte retrieval.

Flow cytometric evaluation of leukocyte subpopulations in the follicular fluids of infertile patients.

OBJECTIVES: To evaluate the leukocyte subpopulations present in follicular fluid (FF) of infertile patients undergoing IVF-ET for tubal factor, idiopathic infertility, and endometriosis. PATIENTS: Sixty patients undergoing IVF-ET with a tubal factor diagnosis (n = 35), idiopathic infertility (n = 13), and endometriosis (n = 12) had their subpopulations of FF leukocytes analyzed by flow cytometry. MAIN OUTCOME MEASURE: Nonblood-contaminated samples of FF were collected under sterile conditions and centrifuged. Cells were labeled with a panel of monoclonal antibodies: anti-CD3, -CD4, -CD8, -CD14, -CD20, -CD45, and -CD56, and analyzed by cytofluorometry. RESULTS: Follicular fluid leukocytes from patients with idiopathic infertility had a significantly higher proportion of T lymphocytes than tubal factor and endometriosis patients. Endometriosis patients had significantly higher proportions of natural killer (NK) cells, B lymphocytes, and monocytes compared with groups of idiopathic infertility and tubal factor. CONCLUSIONS: The differences observed in the leukocyte subpopulations from FF of patients with idiopathic infertility and endometriosis may affect folliculogenesis and oocyte maturation. Moreover, these modifications could be one of the factors altering their fertility.

In-vitro maturation of oocytes: biological aspects.

Natural cycle and in-vitro maturation (IVM) of oocytes are becoming interesting alternatives to classical assisted reproduction technology approaches for patients, especially in those at high risk for ovarian hyperstimulation syndrome or with poor ovarian reserve. More than for their clinical and biological indications, natural cycle and IVM of oocytes can also be considered as good social and economic alternatives to the classical IVF treatment, based on their financial cost-effectiveness with exclusion of expensive medications. To be successful, IVM must entail both nuclear and cytoplasmic maturation, and its maturation and success rates are affected by the number of collected cumulus layers, the degree of atresia and the maturation rate between 24 and 48 h. Endogenous regulation of oocyte maturation is a complex sequence of events regulated by endocrine parameters, oocyte/follicular cross-talk, and intra-oocyte kinase/phosphatase interactions. This complex process requires a better definition of each contributing factor affecting oocyte development and the resulting embryo quality. The clinical aspects of IVM have been documented earlier; the present paper will mainly focus on the biological aspect of oocyte maturation in vitro and the quality of derived embryos.

Scanning electron microscopy of euthyroid goiter and Graves's disease.

The scanning electron microscopy of 5 euthyroid polynodular goiters and 5 cases of Grave's disease was studied. In the polynodular goiter most of the follicular cells were flattened. Small, coarse, irregular microvilli were noticed. In the Grave's disease cases the follicular cells were columnar, covered with long microvilli. Marked epithelial infoldings were found. Thick bundles of collagen surrounded the follicles, especially in the polynodular goiter.