When can we reconstruct the ancestral state? Beyond Brownian motion.

Reconstructing the ancestral state of a group of species helps answer many important questions in evolutionary biology. Therefore, it is crucial to understand when we can estimate the ancestral state accurately. Previous works provide a necessary and sufficient condition, called the big bang condition, for the existence of an accurate reconstruction method under discrete trait evolution models and the Brownian motion model. In this paper, we extend this result to a wide range of continuous trait evolution models. In particular, we consider a general setting where continuous traits evolve along the tree according to stochastic processes that satisfy some regularity conditions. We verify these conditions for popular continuous trait evolution models including Ornstein-Uhlenbeck, reflected Brownian Motion, bounded Brownian Motion, and Cox-Ingersoll-Ross.

Highly unstable heterogeneous representations in VIP interneurons of the anterior cingulate cortex.

A hallmark of the anterior cingulate cortex (ACC) is its functional heterogeneity. Functional and imaging studies revealed its importance in the encoding of anxiety-related and social stimuli, but it is unknown how microcircuits within the ACC encode these distinct stimuli. One type of inhibitory interneuron, which is positive for vasoactive intestinal peptide (VIP), is known to modulate the activity of pyramidal cells in local microcircuits, but it is unknown whether VIP cells in the ACC (VIPACC) are engaged by particular contexts or stimuli. Additionally, recent studies demonstrated that neuronal representations in other cortical areas can change over time at the level of the individual neuron. However, it is not known whether stimulus representations in the ACC remain stable over time. Using in vivo Ca2+ imaging and miniscopes in freely behaving mice to monitor neuronal activity with cellular resolution, we identified individual VIPACC that preferentially activated to distinct stimuli across diverse tasks. Importantly, although the population-level activity of the VIPACC remained stable across trials, the stimulus-selectivity of individual interneurons changed rapidly. These findings demonstrate marked functional heterogeneity and instability within interneuron populations in the ACC. This work contributes to our understanding of how the cortex encodes information across diverse contexts and provides insight into the complexity of neural processes involved in anxiety and social behavior.

Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction.

Schizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is not known whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia patients. We find evidence that microglia-mediated synaptic engulfment is enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile and adult mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in juvenile and adult social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis.

The Effect of Parenting Style on Social Smiling in Infants at High and Low Risk for ASD.

This study examined how parenting style at 9 months predicts growth in infant social engagement (i.e., social smiling) between 9 and 18 months during a free-play interaction in infants at high (HR-infants) and low (LR-infants) familial risk for autism spectrum disorder (ASD). Results indicated that across all infants, higher levels of maternal responsiveness were concurrently associated with higher levels of social smiling, while higher levels of maternal directiveness predicted slower growth in social smiling. When accounting for maternal directiveness, which was higher in mothers of HR-infants, HR-infants exhibited greater growth in social smiling than LR-infants. Overall, each parenting style appears to make a unique contribution to the development of social engagement in infants at high- and low-risk for ASD.

Postoperative vocal fold palsy in patients undergoing thyroid surgery with continuous or intermittent nerve monitoring.

BACKGROUND: Continuous monitoring of electromyographic (EMG) amplitudes of the vocal muscles detects impending injury of the recurrent laryngeal nerve (RLN) during thyroid operations earlier than intermittent EMG monitoring. This may alert the surgeon to stop a manoeuvre causing stretching or pressure on the RLN, with better recovery of nerve function. METHODS: Patients with intact preoperative RLN function who underwent thyroid surgery for benign disease between January 2011 and September 2014 under continuous intraoperative nerve monitoring (CIONM) or intermittent intraoperative nerve monitoring (IIONM) were included in this observational study conducted at a tertiary surgical centre. For CIONM, combined EMG events indicative of imminent nerve injury were defined as an EMG amplitude decrease of 50 per cent or more and a latency increase of 10 per cent relative to baseline values. The rates of early and permanent palsy for the two groups of patients were compared. RESULTS: There were 1526 patients, 788 of whom (1314 nerves at risk) underwent thyroid surgery using CIONM and 738 (965 nerves at risk) had IIONM. With the use of CIONM, 63 (82 per cent) of 77 combined events were reversible during the operation. No permanent vocal fold palsy occurred with CIONM, whereas four unilateral permanent vocal fold palsies (0·4 per cent) were diagnosed after IIONM (P = 0·019). CONCLUSION: Operation with CIONM resulted in fewer permanent vocal fold palsies compared with IIONM after thyroid surgery in patients with benign disease.

[Surgical strategy during intended total thyroidectomy after loss of EMG signal on the first side of resection]. / Operative Strategie bei geplanter totaler Thyreoidektomie und Verlust des Neuromonitoring-Signals auf der erstoperierten Seite.

BACKGROUND: Unambiguous identification of the recurrent laryngeal nerve with detection of nerve dysfunction giving rise to postoperative vocal cord palsy (VCP) is the principal objective of intraoperative neuromonitoring (IONM) in thyroid surgery. Because intraoperative loss of the electromyographic (EMG) signal (LOS) does not result in VCP in one third of patients, controversy surrounds the issue of whether a change in strategy is needed in planned total thyroidectomy after LOS on the first side of resection. PATIENTS AND METHODS: This was a retrospective institutional study of 1,049 consecutive patients (2,086 nerves at risk) with intended bilateral thyroid surgery who were operated on between April 2010 and July 2012 with the use of IONM. The rates of temporary and permanent VCP were analyzed on the basis of the IONM results of the first side of resection and the extent of contralateral resection for completion: resection without LOS (group 1); resection with LOS and contralateral thyroidectomy (group 2); resection with LOS and contralateral subtotal resection (group 3); resection with LOS without any contralateral resection (group 4). RESULTS: LOS on the first side of resection was noted in 27 patients (2.6 %). All VCPs were unilateral. The rates of temporary and permanent VCP were 2.5 and 0.4 %, respectively, overall; specifically: group 1: 0.5 and 0 %; group 2: 64 and 9.1 %; group 3: 100 and 50 %; group 4: 83 and 8.3 %, respectively. CONCLUSION: Because an abnormal intraoperative electromyogram carries an 80 % risk for early postoperative VCP, the initial plan of bilateral surgery needs to be critically reviewed after LOS has occurred on the first side of resection, taking into account the underlying thyroid disease of the patient and surgeon expertise. Since more than 80 % of affected nerves will fully recover after the operation, staged completion thyroidectomy is recommended.

[Total thyroidectomy with lymph node dissection of the central compartment for node-positive, capsular invasive papillary thyroid cancer: video contribution]. / Totale Thyreoidektomie mit Lymphknotendissektion des zentralen Kompartments beim nodal-positiven, organkapselinvasiven papillären Schilddrüsenkarzinom: Videobeitrag.

The aim of radical oncological surgery for nodal metastasized papillary thyroid cancer is, as for other oncological interventions in visceral surgery, the anatomy-related implementation of the concept of en bloc (no touch) resection of the organ bearing the primary tumor together with the first lymph node station, while the structures of the aerodigestive tract, the recurrent laryngeal nerves and parathyroid glands are preserved. The surgical technique is demonstrated in detail with the help of a video of the operation and which is available on-line, the advantages and disadvantages of the technique are discussed.

[Endocrine surgery for neck paraganglioma: operation, radiation therapy or wait and scan?]. / Endokrine Chirurgie zervikaler Paragangliome: Operation, Strahlentherapie oder "wait and scan"?

BACKGROUND: Head and neck paraganglioma (HNP) represent rare endocrine tumors. Therapy is decided on genetic findings, tumor characteristics (e.g. tumor size, localization and dignity), age of patient and symptoms. In terms of local control radiation therapy is as equally effective as surgery but surgical morbidity rates secondary to cranial nerve injuries remain high. PATIENTS: Based on 6 patients with 11 solitary (4 patients) and multiple (2 patients) HNP (8 carotid body tumors, 1 vagal, 1 jugular and 1 jugulotympanic paraganglioma) the specific characteristics of the need for surgery as well as correct choice of treatment in cases of sporadic succinate dehydrogenase (SDH) negative and hereditary SDH positive HNP will be exemplarily demonstrated. RESULTS: A total of 6 carotid body tumors (four sporadic, two hereditary) were resected in 4 patients, five as primary surgery and one as a revision procedure. In one case a preoperative embolization was performed 24 h before surgery. Malignancy could not be proven in any patient. The 30-day mortality was zero. In the patient with bilateral hereditary carotid body tumors, unilateral local recurrent disease occurred. After resection of the recurrent tumor permanent unilateral paralysis of the laryngeal nerve, glossopharyngeal nerve and hypoglossal nerve occurred. All patients were followed-up postoperatively for a mean of 64 months (range 23-78 months) with a local tumor control rate of 100%. The overall survival rate after 5 years was 100%. CONCLUSIONS: Given a very strict indication with awareness of surgical risks selective surgery has a key position with low postoperative morbidity in the treatment of HNPs. We prefer surgery for small unilateral paraganglioma, malignant or functioning tumors.

Loss of the nerve monitoring signal during bilateral thyroid surgery.

BACKGROUND: This study aimed to assess current use of recurrent laryngeal nerve monitoring (RLNM) for bilateral thyroid surgery in Germany. It explored the willingness of surgeons to change strategy after loss of signal (LOS) on the first side of resection. METHODS: Surgical departments in Germany equipped with nerve monitors were asked to complete a structured questionnaire, specifying the number of thyroidectomies done in 2010, and the frequencies of RLNM, vagal stimulation, and electromyographic (EMG) recording before and after thyroidectomy. They were also asked about the surgical plan for bilateral goitre after LOS on the first side of resection. RESULTS: Based on manufacturers' sales data, 1119 (89·1 per cent) of 1256 surgical departments in Germany were equipped with nerve monitors in 2010. A total of 595 departments (53·2 per cent), accounting for approximately 75 per cent of all thyroidectomies in Germany during that year, returned a completed questionnaire. RLNM was used in 91·7-93·5 per cent of thyroidectomies, with the addition of routine vagal stimulation in 49·3 per cent before, and 73·8 per cent after resection. EMG responses to vagal stimulation were recorded in 54·8 per cent before, and 72·5 per cent after resection. Some 93·5 per cent of surgeons changed the resection plan for the other side in bilateral thyroid surgery after LOS had occurred on the first side. CONCLUSION: RLNM is now the standard of care during thyroidectomy in Germany. After LOS on the first side of resection in bilateral goitre, more than 90 per cent of respondents declared their willingness to change the resection plan for the contralateral side to avoid the risk of bilateral recurrent laryngeal nerve palsy.

[Thyroid carcinoma found incidentally after thyroidectomy: postoperative strategy]. / Postoperativer Zufallsbefund Schilddrüsenkarzinom: chirurgisches Konzept.

Completion operations after thyroid surgery due to incidental postoperative diagnosis of thyroid cancer are indicated in differentiated thyroid cancer with tumor size > 1 cm, extrathyroidal invasion, multifocality, angioinvasion or metastases. By thorough preoperative clinical work-up of nodular goiter (ultrasonography, fine needle aspiration cytology the frequency of completion thyroidectomies are aimed to be less than 10% of all thyroid cancer operations. To facilitate postoperative radioiodine ablation prophylactic completion operations can be postponed to 3 months postoperatively to minimize surgical morbidity, if not performed during the early postoperative period. Prophylactic central node dissection as part of the completion operation is reserved for papillary (PTC) and medullary carcinomas (MTC) but not for follicular cancer. Lateral node dissection is recommended in nodal-positive MTC and in PTC with more than 5 lymph node metastases in the central compartment.

[Prophylactic parathyroidectomy for familial parathyroid carcinoma]. / Das familiäre Nebenschilddrüsenkarzinom Indikation zur prophylaktischen Parathyreoidektomie?

In contrast to primary hyperparathyroidism, parathyroid carcinoma is a rare disease. In patients with hyperparathyroidism jaw tumor (HPT-JT) syndrome, caused by germline mutations in HRPT2, the development of parathyroid carcinoma is estimated to be 10-15%. This review summarizes the clinical and molecular genetic data of about 100 patients in the literature and three of our own cases. Unfortunately, osteofibromas, which might enable timely diagnosis of HPT-JT syndrome, occur in only about 30% of patients; about 80% have uniglandular disease. Based on the current data, a general recommendation to perform prophylactic parathyroidectomy cannot be given. However, thorough screening of patients at risk is mandatory. Of note in patients thought to have sporadic parathyroid carcinoma, germline HRPT2 mutations are found in up to 20%. Hence, any patient with parathyroid carcinoma should undergo HRPT2 mutation analysis.

[Subtotal bilateral adrenalectomy preserving adrenocortical function]. / Subtotale bilaterale Adrenalektomie mit adrenokortikalem Funktionserhalt.

This study analyzed the frequency of recurrence and postoperative adrenocortical function in 16 patients who had been operated on by bilateral subtotal adrenalectomy since 1995. Bilateral pheochromocytoma was found in 13 patients, bilateral adrenal metastases in 2 patients, and bilateral micronodular adrenocortical hyperplasia with primary aldosteronism in 1 patient. An endoscopic approach was performed in four patients. The remaining 12 patients were operated on by an open approach. In ten patients, unilateral subtotal adrenalectomy with contralateral total adrenalectomy (synchronous or metachronous) was performed. Six patients underwent bilateral subtotal adrenalectomy. In all patients, a total of residual adrenal tissue of at least 1/3 of a normal adrenal gland was left in situ. 15 patients were successfully weaned from exogenous steroid substitution. During a mean follow-up period of 24 months, no recurrences were observed. Three patients died without local recurrence. The present study provided evidence for the safety and benefit of subtotal bilateral adrenalectomy, which could guarantee sufficient adrenocortical function in adrenal remnant volume of more than one-third of one adrenal gland even after dividing the main adrenal vein. At our institution, particularly in patients with inherited pheochromocytoma, subtotal adrenalectomy has become a common surgical strategy.

Unilateral open and minimally invasive procedures for primary hyperparathyroidism: a review of selective approaches.

The currently established procedure for surgical treatment of primary hyperparathyroidism is bilateral exploration and visualization of all four glands to identify an adenoma and exclude multiglandular disease. With the development of improved preoperative localization imaging of the parathyroids using high-resolution ultrasonography and sestamibi scintigraphy, on the one hand, and perioperative control of surgical success with a rapid parathyroid hormone assay on the other, unilateral and minimally invasive techniques have become feasible. For patients with unequivocal localization in preoperative sestamibi scintigraphy and high-resolution ultrasonography of the parathyroid adenoma in probable single-gland disease, the unilateral and minimally invasive parathyroidectomy present a therapeutic option. Perioperative rapid parathyroid hormone assays, although costly, offer immediate supervision of adenoma extirpation and differentiation of single- and multiglandular disease. These methods demonstrate advantages with favorable cosmetic results and lower reported rate of postoperative hypoparathyroidism. These methods are already being practiced in some places under local anesthesia and in an ambulatory setting. This contribution provides an introduction and overview of the currently practiced unilateral and minimally invasive techniques of parathyroidectomy for primary hyperparathyroidism, discussing indications, advantages and disadvantages, and technical differences in the practiced methods.

[Use of the heart-lung machine in extra-cardial carcinoma surgery]. / Einsatz der Herz-Lungen-Maschine in der extrakardialen Carcinomchirurgie.

The employment of the heart-lung machine to assisting the circulatory system for the resection of extracardial tumors is increasing because of their location, growth and infiltration. We report on three patients in whom the resection of the tumor was only possible with extracorporeal circulation (ECC). In the first patient sarcoma of the pulmonary artery and valve was resected under ECC. Artery and valve were replaced with a cryo-preserved valved bifurcation homograft. In the other patients ECC was used on the basis of tumorinfiltration of the inferior vena cava and tumor embolus of the pulmonary artery in a case of primary renal cell carcinoma, and tumor infiltration of the superior vena cava and right atrium in a case of follicular thyroid carcinoma. All patients had a good postoperative course and excellent long term survival.

Minimally invasive video-assisted parathyroidectomy--selective approach to localized single gland adenoma.

BACKGROUND: The valid operative standard for primary hyperparathyroidism (pHPT) consists of cervicotomy and presentation of all parathyroid glands. This operative technique features the macroscopic identification of the responsible adenoma. It also has the advantage of detecting multiglandular disease. The increasing sensitivity of preoperative localization methods and the possibility of intra-operative measurement of parathyroid hormone prepared the way for minimally invasive procedures. METHODS: All patients with pHPT were examined by cervical sonography and sestamibi scintigraphy of the parathyroid glands. Patients eligible for the described procedure had to comply to the following inclusion criteria: biochemical evidence of pHPT, localization of one unequivocally enlarged parathyroid gland on two corresponding imaging results; no former surgery or radiation to the neck; no multinodular goiter; no suspected carcinoma of the thyroid; and no secondary or recurrent hyperparathyroidism. We used an operative technique first described by Miccoli in 1997. Before preparation and at 2, 10 and 15 min after exstirpation of the parathyroid adenoma, peripheral blood was drawn. The operation was terminated when a 50% decrease of preoperative PTH levels was reached. RESULTS: During a 12-month period (1 December 1997 to 30 November 1998), 13 patients with pHPT of a total of 59 patients (22%) with hyperparathyroidism (pHPT and sHPT) were operated on employing this minimally invasive procedure. In three patients, the operative technique had to be converted to the conventional procedure due to superior adenomas in two cases and a dorsoesophageal adenoma in one case. The procedure could thus be successfully completed in ten patients. The overall failure rate was zero in all patients with regard to the underlying disease. There was one temporary, recurrent laryngeal-nerve palsy. The mean overall length of the hospital stay was 3 days. CONCLUSION: The minimally invasive video-assisted parathyroidectomy for localized single-gland adenoma is a new and attractive surgical therapy option for primary hyperparathyroidism due to improved patient comfort, shortened length of hospital stay and favorable cosmetic results. This may lead to one-day surgery and, therefore, to a reduction of overall costs.