Aromatase inhibitors as a therapeutic strategy for male prolactinoma resistant to dopamine agonists: a retrospective cohort study and literature review.

PURPOSE: To assess the effect of letrozole, an aromatase inhibitor (AI), in patients with resistant prolactinoma that presented an increase in serum prolactin (PRL) levels during testosterone replacement therapy (TRT). METHODS: A retrospective cohort study in a single tertiary care center. From March 2012 to July 2023, 53 male patients over 18 years with prolactinoma were followed in our Neuroendocrine Unit. Of those, 90.6% presented macroadenomas, 41% of them were resistant to cabergoline and 25% presented persistent hypogonadism to whom TRT was indicated. Among them, five presented a significant increase in PRL levels and AI was initiated. All five patients had resistant prolactinomas. One of them was excluded due to tumor aggressiveness and concomitant use of temozolomide during AI therapy. RESULTS: Four patients were included in the analysis, with a mean age of 28.5 (± 7.5) years, median prolactin of 1060 (600 to 6700) ng/mL and median of the largest tumor diameter of 3.6 (1.5 to 5) cm at the time of prolactinoma diagnosis. On TRT, all presented an increase in serum PRL levels (231 to 396%), with a subsequent decrease (61 to 93%) after adding AI. During AI treatment for a median time of 60.5 (21 to 120) months, tumor shrinkage was observed in two cases (-8 and -3 mm in the maximum diameter) and tumor stability in the other two. No major side effects occurred and AI was well tolerated. CONCLUSION: AI might be an option for men with resistant prolactinoma who have an increase in PRL levels on TRT. Nevertheless, prospective randomized clinical trials are needed to ensure efficacy and security for this approach.

Preoperative factors correlated with post-bariatric surgery weight loss.

Whether preoperative parameters can predict weight loss following bariatric surgery is a matter of debate. We conducted a longitudinal and prospective pilot study on 35 patients that underwent bariatric surgery, with a 12-month follow-up. In the preoperative period, a high HOMA-beta index, lower fasting blood glucose, and lower HbA1c were correlated with a lower BMI at 12 months. Traditional preoperative factors, such as weight and BMI, were correlated with the postoperative BMI values. The presence of well-controlled diabetes may influence weight loss after surgery.

Phylodynamics for cell biologists.

Multicellular organisms are composed of cells connected by ancestry and descent from progenitor cells. The dynamics of cell birth, death, and inheritance within an organism give rise to the fundamental processes of development, differentiation, and cancer. Technical advances in molecular biology now allow us to study cellular composition, ancestry, and evolution at the resolution of individual cells within an organism or tissue. Here, we take a phylogenetic and phylodynamic approach to single-cell biology. We explain how "tree thinking" is important to the interpretation of the growing body of cell-level data and how ecological null models can benefit statistical hypothesis testing. Experimental progress in cell biology should be accompanied by theoretical developments if we are to exploit fully the dynamical information in single-cell data.

METHIMAZOLE-INDUCED AGRANULOCYTOSIS AND SEPSIS: WAS THYROID STORM PRESENT OR JUST BEING MIMICKED?

INTRODUCTION: Agranulocytosis induced by thioamides is rare, occurring only in 0.2-0.5% of cases. CASE PRESENTATION: We present the case of a 45-year-old woman previously diagnosed with Graves' disease that discontinued the use of methimazole on her own. She attended the Emergency Department presenting fever (40.5¯C), agitation and diaphoresis. A thyroid storm diagnosis was initially thought, but after laboratory results showing neutrophil count near 0.06x109/L, sepsis due to neutropenia seemed the most logical hypothesis. Cephepime was promptly initiated. For thyrotoxicosis management, cholestyramine and atenolol were prescribed. In her second day of hospitalization, subcutaneous granulocyte colony-stimulating factor was started for an earlier medullar response. The patient was discharged after 7 days with atenolol 50mg/day and instructed to have a definite treatment for Graves disease as soon as possible. CONCLUSION: Such case purpose is to remember clinicians that sepsis diagnosis can be challenged, especially when a thyroid storm is a possible diagnosis as well. In this particular case, both conditions should be treated, but life-threatening sepsis should have the focus for a quick therapeutic approach.

Construction of quasipotentials for stochastic dynamical systems: An optimization approach.

The construction of effective and informative landscapes for stochastic dynamical systems has proven a long-standing and complex problem. In many situations, the dynamics may be described by a Langevin equation while constructing a landscape comes down to obtaining the quasipotential, a scalar function that quantifies the likelihood of reaching each point in the state space. In this work we provide a novel method for constructing such landscapes by extending a tool from control theory: the sum-of-squares method for generating Lyapunov functions. Applicable to any system described by polynomials, this method provides an analytical polynomial expression for the potential landscape, in which the coefficients of the polynomial are obtained via a convex optimization problem. The resulting landscapes are based on a decomposition of the deterministic dynamics of the original system, formed in terms of the gradient of the potential and a remaining "curl" component. By satisfying the condition that the inner product of the gradient of the potential and the remaining dynamics is everywhere negative, our derived landscapes provide both upper and lower bounds on the true quasipotential; these bounds becoming tight if the decomposition is orthogonal. The method is demonstrated to correctly compute the quasipotential for high-dimensional linear systems and also for a number of nonlinear examples.

Dairy cows change locomotion score and sensitivity to pain with trimming and infectious or non-infectious lesions.

Lameness can negatively affect production, but there is still controversy about the perception of pain in dairy cows. This study aimed to verify the effects of hoof affections in dairy cows on locomotion score, physiological attributes, pressure nociceptive threshold, and thermographic variables, as well as assess improvement on these variables after corrective trimming and treatment. Thirty-four lame lactating cows were gait-scored, and all cows with locomotion score ≥4 were retained for this study 1 day before trimming. Lame cows were diagnosed, pressure nociceptive threshold at sound, and affected hooves were measured, thermographic images were recorded, and physiological attributes were evaluated. Hooves with lesions were trimmed and treated and cows were re-evaluated 1 week after such procedures. The experimental design was a completely randomized design. Each cow was considered an experimental unit and traits were analyzed using paired t test, linear correlation, and linear regression. Digital and interdigital dermatitis were classified as infectious diseases while laminitis sequels, sole ulcers, and white line were classified as non-infectious diseases. After 1 week, the locomotion score was reduced on average in 1.5 points. Trimming increased the pressure nociceptive threshold for cows with non-infectious affections while tended to increase the pressure nociceptive threshold for cows with infectious affections. Physiological attributes and thermographic values did not change with trimming. Trimming and treatment have benefic effects on animal welfare as gait is improved and sensitivity to pain is reduced.

Access to shade changes behavioral and physiological attributes of dairy cows during the hot season in the subtropics.

The effect of shade on behavior and physiological attributes of grazing cows in a high altitude subtropical zone is not well established. This work aimed to investigate how social and ingestive behaviors, as well as physiological and other attributes of dairy cows such as milk production, change in a subtropical environment during the hot season either with or without free access to shade. Fourteen lactating cows were kept on pasture either with no shade or with free access to shade for 5 days and their behavior was recorded with instantaneous scan sampled every 10 min, from sunrise, 0530 h (Greenwich mean time, GMT-0200 h) to sunset, 2100 h (GMT-0200 h). Behavior traits included (1) time spent in activities such as grazing, ruminating, resting, lying, standing, walking, seeking shade and staying in the proximity to the water trough and (2) number of events such as water ingestion, aggressive interactions, as well as competition for shade and water. Physiological attributes such as heart and respiratory rates, rectal temperature, number of rumen movements, panting score, as well as milk yield, were evaluated. Time spent in behavioral activities, number of behavioral events and physiological attributes varied between groups (with and without access to shade). Cows with no shade showed increased respiratory and heart rates and panting score at 1300 h, higher values for time of permanence near the water trough, number of competition and aggression events for shade. On the other hand, they showed lower values for time spent resting while lying, ruminating while standing, seeking shade. Access to shade did not change time spent lying, standing, walking with the head up, ruminating while lying, resting while standing, as well as milk yield and number of ruminal movements. Significant interactions between access to shade and days of measurements were detected for time spent walking, ruminating, grazing, resting, number of water ingestion events, competition events near the water trough and for shade, as well as for rectal temperature and panting score measured at 1700 h. In the high altitude subtropical region, access to shade minimizes negative heat stress effects on behavior and physiological aspects of dairy cows.

[Stabilization of the pelvic ring with photodynamic bone stabilization (IlluminOss™)]. / Stabilisierung einer Beckeninsuffizienzfraktur mit einem photosensiblen Kunststoff (IlluminOss™).

We describe the case of an 88-year-old woman who presented with painful symptoms of the pelvis after low-energy trauma. Conservative treatment with pain therapy and pain-adapted mobilization was unsuccessful. Diagnostics showed a fragility fracture of the pelvic ring; therefore, we performed photodynamic bone stabilization (IlluminOss™) of the pubic bone and percutaneous cement-augmented fixation of the iliosacral joint assisted by computed tomography (CT) fluoroscopy. Imaging showed a stable healed fracture 4 months after surgery.

Suture-free and mesh reinforced small intestinal anstomoses: a feasibility study in rabbits.

INTRODUCTION: Anastomotic leakage still remains a major complication in general surgery. Beside general risk factors, the ideal method of anastomotic technique has not been found until now. The aim of the present study was to analyze wound healing in suture-free small intestine anastomoses using fibrin glue with and without mesh-reinforcement. METHODS: Laparotomy and four different types of small bowel anastomoses were performed in 32 chinchilla rabbits. Standard hand-sewn anastomoses (CG), suture-free glued anastomoses (FG) with and without mesh reinforcement using two different types of meshes [Vicryl-mesh (VM) and Surgisis (SM)]. Animals were sacrificed after 5 and 21 days. Bursting pressure, collagen type I/III ratio, and matrix-metalloproteinase 2, 9, and 13 were analyzed. RESULTS: None of the animals died due to an anastomotic leakage. All animals in the long term group with Surgisis mesh died due to a mechanical bowel obstruction based on a distinctive stenosis of the anastomosis. The bursting pressures did significantly differed in animals with fibrin glue alone compared to animals with Vicryl-mesh reinforcement (p < 0.05). Histological examination revealed statistically significant differences (p < 0.05) in the values for MMP-2 (VM < SM), MMP-9 (VM < CG), and MMP-13 (CG < SM, VM < FG, and VM < SM). However, collagen type I/III ratios were not significantly different between groups. CONCLUSIONS: Our results suggest that a mesh reinforced glued anastomosis is technically feasible. Furthermore, mesh-reinforcement using VM increased the integrity and simplified the technique of suture-free anastomoses.

[Understand the neurodevelopment of language: a necessity to prevent learning disabilities in children]. / Comprendre le neurodéveloppement du langage, une nécessité pour prévenir les troubles des apprentissages de l'enfant ?

Clinical and radiological knowledge of language development in the former premature infant compared to the newborn allows us to argue for exploration of the sensorimotor co-factors required for proper language development. There are early representations of the maternal language in the infant's visual, auditory, and sensorimotor areas, activated or stabilized by orofacial and articulatory movements. The functional architecture of language is different for vulnerable children such as premature infants. We have already mentioned the impact of early dysfunction of the facial praxis fine motor skills in this population presenting comprehension disorders. A recent meta-analysis confirms the increasing difficulty of understanding between 3 and 12 years, questioning the quality of the initial linguistic processes. A precise analysis of language, referenced from 3 years of age, should be completed by sensorimotor tests to assess possible constraints in automating neurolinguistic foundations. The usual assessment at this age can exclude sensory disturbances and communication and offers guidance and socialization. However, a recent study shows the ineffectiveness of "language-reinforced immersion" at 2 and 3 years in a population of vulnerable children. The LAMOPRESCO study of language and motor skills in the premature infant (National PHRC 2010) has assessed language and sensorimotor skills of preterm-born (<33 weeks) 3.5-year-old children without cerebral palsy. Fragile children were randomized into 2 groups, 1 stimulated by a specific individual protocol, the other given guidance. The primary endpoint was phonology, assuming that it is composed of very early good-quality sensorimotor integration stabilized by the child's oral facial motor skills before 5 years of age. This developmental integrative dynamic validates the "motor theory of speech perception." Early and accurate assessment of language and the patient's constraints should differentiate and specify management strategies for all children, whatever their background and pathologies.

Severe feed restriction increases permeability of mammary gland cell tight junctions and reduces ethanol stability of milk.

A total of twelve lactating Jersey cows were used in a 5-week experiment to determine the effects of severe feed restriction on the permeability of mammary gland cell tight junctions (TJs) and its effects on milk stability to the alcohol test. During the first 2 weeks, cows were managed and fed together and received the same diet according to their nutritional requirements (full diet: 15 kg of sugar cane silage; 5.8 kg of alfalfa hay; 0.16 kg of mineral salt and 6.2 kg of concentrate). In the 3rd week, animals were distributed into two groups of six cows each. One group received the full diet and the other a restricted diet (50% of the full diet). In the 4th and 5th weeks, all animals received the full diet again. Milk composition and other attributes, such as titratable acidity, ethanol stability, pH, density and somatic cell count (SCC) were evaluated. Cortisol levels indicated the stress condition of the cows. Plasma lactose and milk sodium were measured to assess mammary TJ leakiness. Principal factor analysis (PFA) showed that the first two principal factors (PFs) contributed with 44.47% and 20.57% of the total variance in the experiment and, as feeding levels increased, milk stability to the ethanol test became higher and plasma lactose levels decreased, which indicates lower permeability of the mammary gland cell TJ. Correspondence analyses were consistent with PFA and also showed that lower feeding levels were related to reduced milk stability, high plasma lactose, high sodium in milk, low milk lactose (another parameter used to assess TJ permeability) and higher cortisol levels, indicating the stress to which animals were submitted. All observations were grouped in three clusters, with some of the above-mentioned patterns. Feeding restriction was associated with higher permeability of TJ, decreasing milk stability to the ethanol test.

Effect of the carrier-envelope-offset dynamics on the stabilization of a diode-pumped solid-state frequency comb.

We investigate the dynamics of the carrier-envelope-offset (CEO) frequency, f(CEO), controlled by a pump current on the self-referencing of an optical frequency comb generated from a diode-pumped solid-state laser at 1.56 µm. We observe a reversal point in the tuning of f(CEO) with the pump current. Between the low- and high-frequency region in the dynamic response of f(CEO) to pump current modulation, we observe a significant phase shift of ≈180 deg in the transfer function. As a result, it is impossible to stabilize f(CEO) at a pump current above the reversal point, although the free-running CEO beat at this point has a higher signal-to-noise ratio than underneath the reversal point at which the locking is straightforward. Our results indicate that a high signal-to-noise ratio and a low-noise CEO beat are not sufficient indicators for the feasibility of comb self-referencing in cases for which CEO dynamics play a dominant role.

Assessing coverage of protein interaction data using capture-recapture models.

Protein interaction networks comprise thousands of individual binary links between distinct proteins. Whilst these data have attracted considerable attention and been the focus of many different studies, the networks, their structure, function, and how they change over time are still not fully known. More importantly, there is still considerable uncertainty regarding their size, and the quality of the available data continues to be questioned. Here, we employ statistical models of the experimental sampling process, in particular capture-recapture methods, in order to assess the false discovery rate and size of protein interaction networks. We uses these methods to gauge the ability of different experimental systems to find the true binary interactome. Our model allows us to obtain estimates for the size and false-discovery rate from simple considerations regarding the number of repeatedly interactions, and provides suggestions as to how we can exploit this information in order to reduce the effects of noise in such data. In particular our approach does not require a reference dataset. We estimate that approximately more than half of the true physical interactome has now been sampled in yeast.

The evolution of the phage shock protein response system: interplay between protein function, genomic organization, and system function.

Sensing the environment and responding appropriately to it are key capabilities for the survival of an organism. All extant organisms must have evolved suitable sensors, signaling systems, and response mechanisms allowing them to survive under the conditions they are likely to encounter. Here, we investigate in detail the evolutionary history of one such system: The phage shock protein (Psp) stress response system is an important part of the stress response machinery in many bacteria, including Escherichia coli K12. Here, we use a systematic analysis of the genes that make up and regulate the Psp system in E. coli in order to elucidate the evolutionary history of the system. We compare gene sharing, sequence evolution, and conservation of protein-coding as well as noncoding DNA sequences and link these to comparative analyses of genome/operon organization across 698 bacterial genomes. Finally, we evaluate experimentally the biological advantage/disadvantage of a simplified version of the Psp system under different oxygen-related environments. Our results suggest that the Psp system evolved around a core response mechanism by gradually co-opting genes into the system to provide more nuanced sensory, signaling, and effector functionalities. We find that recruitment of new genes into the response machinery is closely linked to incorporation of these genes into a psp operon as is seen in E. coli, which contains the bulk of genes involved in the response. The organization of this operon allows for surprising levels of additional transcriptional control and flexibility. The results discussed here suggest that the components of such signaling systems will only be evolutionarily conserved if the overall functionality of the system can be maintained.

[Evaluation of language at 6 years in children born prematurely without cerebral palsy: prospective study of 55 children]. / Évaluation à 6 ans du langage de l'enfant né grand prématuré sans paralysie cérébrale : étude prospective de 55 enfants.

OBJECTIVES: Very premature birth carries a high risk of neurocognitive disabilities and learning disorders. Acquiring sufficient speech skills is crucial to good school performance. METHODS: A prospective study was conducted in 2006 to evaluate speech development in 55 children born very prematurely in 2000 at the Rouen Teaching Hospital (Rouen, France), free of cerebral palsy, compared to 6-year-old born at full term. A computerized speech assessment tool was used (Bilan Informatisé du Langage Oral, BILO II). RESULTS: In the premature-birth group, 49 % of 6-year-old had at least 1 score below the 25th percentile on 1 of the 8 BILO II tests. Significant speech impairments were noted for 2 components of speech, namely, comprehension and phonology. Oral comprehension scores no higher than the 10th percentile were obtained by 23 % of prematurely born children (P<0.02 vs controls). On word repetition tasks used to test phonology, 21 % of prematurely born children obtained scores no higher than the 10th percentile (P<0.01 vs controls). An evaluation of sensorimotor language prerequisites (constraints) in 30 of the 55 prematurely born children showed significant differences with the controls for word memory, visual attention, and buccofacial praxis. CONCLUSION: The speech development impairments found in 6-year-old born very prematurely suggest a distinctive pattern of neurodevelopmental dysfunction that is consistent with the motor theory of speech perception.

[Realistic surgical training. The Aachen model]. / Praxisnahe Weiterbildung: Das Aachener Modell.

The Aachen model is a practical mode in teaching and advanced training, which is closely geared to the areas of academic acquisition and training. During medical education optional student courses with constitutive curricula offer practical points of contact to the surgical department at all times. Besides improvement of manual training the aims are enhancing interests and acquisition of talents. This guided structure will be intensified with progression into advanced education. Next to the formal guidelines of the curriculum, education logbook and progression conversations, quality, transparency and reliability are particularly emphasized. An evaluation of both the reforms and the surgical trainers is still to be made. In addition procurement of an affirmative occupational image is essential.

Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes.

BACKGROUND: The aim of this study was to investigate the prognostic effect of tumour-infiltrating lymphocytes (TILs) in serous stage III ovarian carcinoma to determine TIL clonality and to correlate this to Her2/neu expression. METHODS: Formalin-fixed and paraffin-embedded ovarian carcinomas were examined for CD20-, CD3-, CD4- and CD8-positive lymphocytes (n=100), and for Her2/neu-positive tumour cells (n=55/100) by immunohistochemistry. Clonality analysis was carried out by T-cell receptor gamma (TCRgamma) gene rearrangements (n=93/100). Statistical analyses included experimental and clinico-pathological variables, as well as disease-free (DFS) and overall (OS) survival. RESULTS: CD20-positive B lymphocytes were present in 57.7% (stromal)/33.0% (intraepithelial) and CD3-positive T lymphocytes in 99.0% (stromal)/90.2% (intraepithelial) of ovarian carcinomas. Intraepithelial CD3-positive T lymphocytes were correlated with improved DFS in optimally debulked patients (P=0.0402). Intraepithelial CD8-positive T lymphocytes were correlated with improved OS in all optimally debulked patients (P=0.0201) and in those undergoing paclitaxel/carboplatin therapy (P=0.0092). Finally, rarified and clonal TCRgamma gene rearrangements were detected in 37 out of 93 (39.8%) and 15 out of 93 (16.1%) cases, respectively. This was marginally associated with improved DFS (P=0.0873). Despite a significant correlation of HER2/neu status and intraepithelial CD8-positive lymphocytes (P=0.0264), this was non-directional (R=-0.257; P=0.0626). CONCLUSION: Improved survival of ovarian cancer patients is related to the infiltration, clonal selection and intraepithelial persistence of T lymphocytes.