Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction.

Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by LMNA mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient's neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies.

Feasibility, Safety, and Satisfaction of Combined Hysterectomy with Bilateral Salpingo-Oophorectomy and Chest Surgery in Transgender and Gender Non-Conforming Individuals.

The demand for masculinizing breast surgery and hysterectomy with bilateral salpingo-oophorectomy (HBSO) from transmen has increased. With a multidisciplinary approach, these surgeries can be performed in a single session. The objective of this study was to retrospectively evaluate the feasibility, safety, and satisfaction of HBSO and chest surgery in transmen. A cohort of 142 subjects who underwent HBSO alone or combined with chest surgery at Sant'Orsola Hospital was analyzed. Intra and post operation events were evaluated. Subjective post-intervention satisfaction, acceptability, and impact of intervention were assessed via a semi-structured interview. Nineteen transmen underwent HBSO alone and 123 underwent combined surgery. HBSO was performed laparoscopically in 96.5% of transmen (137/142). As expected, length of hospital stay and blood loss were significantly higher in the combined surgery group. A total of 13 intra or post-operative complications occurred in the combined surgery group (10.5%) with thoracic hematoma being the most frequent complication (7.6%). Only one rare complication occurred in the HBSO group (omental herniation through a laparoscopic breach). The overall subjective satisfaction score was 9.9 out of 10 for both groups. Positive changes in all areas of life were reported, with no significant differences. We found that the combined surgery appears to be well tolerated, safe, and feasible in transmen and satisfaction with the combined procedure was high in all subjects.

Autologous platelet-rich fibrin: a novel method for tracheoesophageal puncture site closure: a case report.

Closure of a tracheoesophageal puncture site performed during voice prosthesis implantation may sometimes be required. Besides local techniques, more elaborate procedures, such as closure by means of free microvascular flaps, have been advocated. In this report, we describe a case of local treatment of a hard-to-heal fistula with local application of autologous platelet-rich fibrin matrix in a 77-year-old male patient. At one-week follow-up, the size of the fistula had decreased dramatically but some leakage remained when drinking. After one month, the patient was able to drink and eat normally without any leakage. There was no recurrence of the leakage at two years' follow-up. In summary, local application of platelet-rich fibrin seems to be a simple, safe and effective procedure for tracheoesophageal fistula closure.

A Randomized Double-Blind Placebo-Controlled Pilot Trial on the Effects of Testosterone Undecanoate Plus Dutasteride or Placebo on Muscle Strength, Body Composition, and Metabolic Profile in Transmen.

BACKGROUND: While the effects of androgens on muscle are well described in hypogonadal men, literature is still scarce on muscular strength or size variations in transmen; in this population there are no data regarding the relative effect of testosterone (T) and its metabolite dihydrotestosterone on muscle. AIM: Our primary objective was to compare the effects on muscle strength of 54-week administration of testosterone undecanoate (TU) combined with the 5α-reductase inhibitor dutasteride (DT) or placebo (PL). Secondary outcomes included evaluation of body composition, bone, cutaneous androgenic effects, and metabolic variations. METHODS: In this randomized, double-blind PL-controlled pilot trial, 16 ovariectomized transmen were randomized to receive TU 1,000 mg IM at week 0, 6, 18, 30, 42 plus a PL pill orally daily (TU + PL, n = 7) or plus DT 5 mg/d (TU + DT, n = 7). OUTCOMES: At week 0 and 54 the following parameters were evaluated: isokinetic knee extension and flexion peak torque and handgrip strength, body composition, and bone mineral density, biochemical, hematological, and hormonal parameters. RESULTS: Handgrip and lower limb strength increased significantly in both groups with no differences between the 2 groups. Fat mass decreased and lean mass increased significantly similarly in both groups. Metabolic parameters remained stable in the 2 groups except for high-density lipoprotein cholesterol that was reduced in both groups. Hepatic and renal function remained normal in both groups and no major adverse effects were registered in either group. CLINICAL IMPLICATIONS: These results may be particularly relevant for transmen experiencing cutaneous androgenic adverse events such as acne and androgenetic alopecia and in light of the development of non-5α-reduced androgens. STRENGTHS & LIMITATIONS: The strength of this study was the randomized, double-blind PL-controlled design, while the small number of subjects was definitely the biggest limitation. CONCLUSION: For the first time we demonstrated that the addition of DT does not impair the anabolic effects of T on muscles in transmen previously exposed to T, supporting the hypothesis that the conversion in dihydrotestosterone is not essential for this role. Gava G, Armillotta F, Pillastrini P, et al. A Randomized Double-Blind Placebo-Controlled Pilot Trial on the Effects of Testosterone Undecanoate Plus Dutasteride or Placebo on Muscle Strength, Body Composition, and Metabolic Profile in Transmen. J Sex Med 2021;18:646-655.

A brief very-low oxygen tension regimen is sufficient for the early chondrogenic commitment of human adipose-derived mesenchymal stem cells.

PURPOSE: The aim of this study was to evaluate the effects exerted over chondrogenic commitment of human adipose-derived mesenchymal stem cells (ADSCs) by a very low oxygen tension (<1% pO2). MATERIALS/METHODS: Cell morphology, mRNA levels of chondrocyte-specific marker genes and the involvement of p38 MAPK signalling were monitored in human ADSCs under a very low oxygen tension. RESULTS: Cell morphology was significantly changed after two days of hypoxic preconditioning when they featured as elongated spindle-shaped cells. SRY-box containing gene 9, aggrecan and collagen type II mRNA levels were enhanced under severe hypoxic culture conditions. Moreover, the inhibition of p38 MAPK resulted in a substantial reduction in transcription of the above-mentioned specific genes, proving the pivotal role of this pathway in the transcriptional regulation of chondrogenesis. CONCLUSIONS: Here, we propose a protocol showing the early commitment of stem cells towards the chondrogenic phenotype in only 2 days of culture via a very low hypoxic environment, in the absence of growth factors added in the culture medium.

Sub-muscular Reconstruction after NAC Sparing Mastectomy: Direct to Implant Breast Reconstruction with Human ADM Versus Tissue Expander.

BACKGROUND: Nipple areola complex (NAC) sparing mastectomy allows good oncological and aesthetic results. The study compares the results, in terms of self-evaluated satisfaction and symmetry, of direct to implant (DTI) sub-muscular breast reconstruction, with the aid of human acellular dermal matrix (ADM) versus two-stage reconstruction with sub-muscular tissue expander, followed by implant. MATERIALS AND METHODS: This is a retrospective, observational, single-center, non-randomized, case-control study. Inclusion criteria were: unilateral NAC sparing mastectomy at Forlì Hospital between 2014 and 2018; sub-muscular reconstruction; minimum follow-up of 12 months from the reconstructive stage; no history of radiotherapy. Patients were divided into two groups: group A included patients who underwent DTI breast reconstruction with the aid of human ADM; group B were those who underwent a two-stage reconstruction with tissue expander then implant. We collected data on: (1) Self-evaluated satisfaction by Breast Q questionnaire (scores from 0 to 100). (2) Observer-evaluated symmetry. Bi-dimensional photographs were collected and evaluated by 11 breast surgeons blinded to each other, who assigned a score for symmetry (from 0 to 10). (3) Symmetry of anthropometric measures collected by hand and volume estimated by Breast V application. RESULTS: Group A included 28 patients; group included B 26 patients. Breast-Q questionnaires reported the following results: satisfaction with breasts in group A 65 ± 12 versus group B 68 ± 14; satisfaction with outcome in group A 88 ± 16 versus group B 93 ± 11; psychosocial well-being in group A 71 ± 20 versus group B 76 ± 17; sexual well-being in group A 63 ± 26 versus group B 60 ± 13; physical well-being in group A 68 ± 15 versus group B 60 ± 12. The average symmetry breast score assigned to group A was 6.9, versus group B 7.2. Regarding the anthropometric measures in group A, the differences between right and left were major to those in group B. Regarding breast volume, the mean difference between right and left in group A was 31.89 cc ± 24.97, whereas in group B was 25.46 cc ± 23.59. CONCLUSION: Our data show better symmetry and better psychosocial well-being in the two-stage reconstruction, and higher satisfaction with sexual and physical well-being in DTI reconstructions. These aspects should be discussed with the patient while collecting the informed consent. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The Enzymatic Debridement for the Treatment of Burns of Indeterminate Depth.

The rapid eschar removal by surgical debridement is currently considered the standard of care for the treatment of burned patients. However, the excision of viable dermal residues can frequently occur when this procedure is applied affecting, in turn, the possible spontaneous re-epithelialization of the lesion area and increasing the amount of autologous skin grafts required for its treatment. To overcome these problems, the use of enzymatic debridement by proteolytic enzymes enriched in Bromelain has aroused great interest in the clinical field as a valid alternative to surgical procedure for the treatment of burns when they appear of indeterminate depth. With the aim to evaluate the effectiveness of this new approach in comparison with a surgical procedure for the treatment of these types of burns we performed a retrospective data analysis taking into account patients hospitalized in our Burn Center from 2014 to 2017. The results obtained show a significant reduction in the time frame to perform debridement when an enzymatic approach is chosen, with the maintenance of viable dermal tissue on the superficial areas of the wounds, their spontaneous re-epithelialization, and a reduction of the bleeding time in the treated patients. A reduced amount of autologous skin grafts is also used when enzymatic treatment is applied. The length of stay of the patients treated with enzymatic debridement did not show significant differences compared to that treated with surgery, with excellent aesthetic results after 1 to 3 years.

NAM Therapy-Evidence-Based Results.

Many orthodontists working on patients with cleft lip and palate (CLP) have shown great enthusiasm for presurgical infant orthopedics (PSIO) to improve surgical outcomes with minimal intervention. Even though every clinician aims to use the best treatment modality for their patients, PSIO effects can be confounded by surgical type and timing of the primary repair, as is discussed in many studies. In such cases, one should be cautious when evaluating the particular outcomes for patients with CLP since it is difficult to differentiate the sole effect of an individual surgical or orthodontic intervention. As with any treatment methodology, nasoalveolar molding (NAM) has both benefits and limitations. Commonly cited concerns with NAM, and PSIO in general, include increased cost, increased burden of care, and a negative impact on maxillary growth. However, NAM cannot be deemed as having apparent long-term negative or positive effects on skeletal or soft tissue facial growth, based on previous studies. A review of the literature suggests that NAM does not alter skeletal facial growth when compared with the samples that did not receive PSIO. Nevertheless, the published studies on NAM show evidence of benefits to the patient, caregivers, the surgeon, and society. These benefits include documented reduction in severity of the cleft deformity prior to surgery and as a consequence improved surgical outcomes, reduced burden of care on the care givers, reduction in the need for revision surgery, and consequent reduced overall cost of care to the patient and society.

ROCK1 is associated with non-syndromic cleft palate.

BACKGROUND: Craniofacial morphogenesis is the result of an intricate multistep network of tightly controlled spatial and temporal signalling that involves several molecules and transcription factors organized into highly coordinated pathways. Any alteration in even one step of this delicate process can lead to congenital malformations such as cleft palate. One of the first steps in embryonal orofacial development is the migration of cells from the neural crests to the branchial arches. Next, the cells have to proliferate, differentiate, move and connect to each other in order to correctly form the palate. Cell contraction, promoted by the interaction of non-muscle myosin II and actin A, is a crucial step in morphogenesis and is regulated by ROCK1 protein. METHODS: A family-based association study was carried out in order to verify whether or not genetic variants of ROCK1 were associated with non-syndromic cleft palate (nsCP). Two cohorts from Italy and Iran, a total of 189 nsCP cases and their parents were enrolled. RESULTS: The rs35996865-G allele was under-transmitted in cases of nsCP [P = .006, odds ratio (OR) = 0.63 (95% CI 0.45-0.88)]. CONCLUSION: This investigation reveals for the first time data supporting a role for ROCK1 in nsCP aetiology.

Deferoxamine Protects Stromal/Stem Cells of "Lull pgm System"-Processed Lipoaspirates Against Damages Induced by Mitochondrial Respiration Inhibition.

BACKGROUND: The ischemic environment of the receiving area compromises the outcome of autologous fat grafts. The aim of this study was to isolate and expand the stromal vascular fraction from patient lipoaspirates and investigate the gain in cell viability exerted by some protective agents against the blockage of mitochondrial respiration. METHODS: The aspirates were (1) washed, using the "Lull pgm system," (2) centrifuged and (3) decanted. The corresponding stromal vascular fractions were isolated, and after cell adherence selection, the stromal/stem cell subpopulations were exposed to Antimycin A for 1 h. Then, the protection induced by cell pretreatment with deferoxamine, diazoxide and IGF-1 was evaluated. RESULTS: The residual cell viability of the "Lull pgm system"-washed samples was greater than that of the centrifuged samples (p < 0.05), and this advantage was maintained during the following 12 days of culture. The administration of 400 µM deferoxamine before Antimycin A treatment increased the number of viable cells from 56.5 to 80.8% (p < 0.05). On the contrary, the pretreatment with 250 µM diazoxide or 0.1 µg/ml IGF-1 did not exert any significant pro-survival action. Echinomycin abolished the positive effect of deferoxamine, suggesting that its protection involved HIF-1α. CONCLUSIONS: Adipose-derived stromal-stem cells survive the inhibition of mitochondrial respiration better if the lipoaspirate is washed using the "Lull pgm system" rather than centrifuged. Moreover, a significant contribution to cell survival can be obtained by preconditioning stromal-stem cells with deferoxamine. In a clinical perspective, this drug could be safely administered before surgery to patients undergoing autologous fat transfer. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Deep Inferior Epigastric Perforator Breast Reconstruction With Computer-Aided Design/Computer-Aided Manufacturing Sizers.

BACKGROUND: The goal of microsurgical breast reconstruction is to return to the precancer state, maximizing symmetry with less morbidity. This requires a long learning curve, in particular where modeling is concerned. In this context, reverse engineering technologies found an application, allowing the creation of molds that can be used during the surgery. METHOD: We created 10 molds named DIEP sizers, which help to simplify deep inferior epigastric perforator (DIEP) flap insetting. For this, we designed a virtual model using Geomagic X software to construct the sizers. Our model has a thorax circumference, breast projection, and footprint correspondent to an average of the measurements we collected from 15 patients undergoing such surgery. We made a comparative study between 2 groups each of 24 patients, using as comparison criteria surgical times in patients undergoing breast microsurgical reconstruction with or without DIEP sizers. In both groups, we included immediate and delayed reconstructions as well as monolateral, bilateral and monolateral with contralateral symmetrization. RESULT: In all the cases we performed with DIEP sizers, we achieved an average time saving of 105 minutes in monolateral reconstruction, 80 minutes in monolateral reconstruction with contralateral symmetrization, and 120 minutes in bilateral reconstruction (P < 0.001). No major complications occurred. CONCLUSIONS: We performed 24 breast reconstructions with preformed molds, obtaining a proper "library" with different DIEP sizers that can be used both in preoperative planning and in intraoperative modeling. We recommend the use of a preformed mold in microsurgical breast reconstruction to improve symmetry, to shorten the learning curve and to save time.

Chest Wall Masculinization in Female-to-Male Transsexuals: Our Treatment Algorithm and Life Satisfaction Questionnaire.

Esthetic masculinization of the chest wall is one of the first surgical steps in female-to-male transsexual (FTMTS) reassignment.This surgical procedure is not a simple mastectomy: it is required for removal of breast tissue with glandular resection and skin excess revision, to reduce and replace the nipple-areola complex in the right location, minimizing chest wall scars. The creation of an esthetically pleasing male chest allows the patient to live at ease in the male gender role.In this article, we present our series of 68 FTMTSs who underwent bilateral mastectomies for surgical sexual reassignment (a total of 136 mastectomies) according to our algorithm, in the period between January 2010 and December 2017. We selected 4 different operative procedures, classified as subcutaneous ("pull-through" and "concentric circular" techniques) and skin extended ("ultrathin vertical bipedicle" and free nipple graft).We achieved a total complication rate of 6.6%, less than that reported in the literature; additional procedures for esthetic improvements were performed in 14.7% of cases. The mean patient satisfaction was approximately 4.57% of a maximal value of 5 (excellent).To help surgeons in choosing the most appropriate FTMTS surgical technique and to reduce unfavorable results, we propose the use of our treatment algorithm in preoperative evaluation of the chest wall according to the breast volume, degree of glandular ptosis, and skin elasticity.

Non-syndromic cleft palate: Association analysis on three gene polymorphisms of the folate pathway in Asian and Italian populations.

Periconceptional folic acid supplementation can reduce the risk of inborn malformations, including orofacial clefts. Polymorphisms of MTHFR, TCN2, and CBS folate-related genes seem to modulate the risk of cleft lip with or without cleft palate (CL/P) in some populations. CL/P and cleft palate only (CPO) are different malformations that share several features and possibly etiological causes. In the present investigation, we conducted a family-based, candidate gene association study of non-syndromic CPO. Three single nucleotide polymorphisms, namely, rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS, were investigated in a sample that included 129 Italian and 65 Asian families. No evidence of association between the three genotyped polymorphisms and CPO was found in the Italian and Asian cases, indeed the transmission disequilibrium test did not detect any asymmetry of transmission of alleles. This investigation, although with some limitation, further supports that CL/P and CPO diverge in their genetic background.

Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning.

Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease.

Informed consent in plastic surgery, evaluation of its effectiveness for mutual satisfaction of patient and doctor: Comparison of methods.

BACKGROUND: The acquisition of signed informed consent is not always enough to ensure adequate medical protection. Particularly, in plastic surgery, improving the doctor-patient relationship by understanding the patient's emotions and expectations becomes a determining factor when choosing the best therapeutic strategy for the subject in question, which may also include nonsurgical eligibility. METHODS: Ninety patients with various plastic surgery disabilities were recruited and randomly divided into three groups: Patients in the first group underwent the ``traditional'' clinical interview, those in the second underwent the clinical approach called Shared Decision Making (SDM), and those in the third group received both the SDM and a questionnaire evaluating patient expectations (Expectation Questionnaire-Pgm). At the end of each interview, a specialist physician in Plastic, Reconstructive and Aesthetic Surgery was asked to fill in a questionnaire regarding his/her satisfaction with the method used. Likewise, the patient filled in a questionnaire on his/her satisfaction with the interview. RESULTS: For the doctors, the third method was superior in investigating patient expectations, emotions, and personal preferences. For the patients, the third method scored significantly higher than the first one for overall satisfaction and ability to evaluate personal preferences and needs and higher than the first and second methods in assessing expectations. CONCLUSIONS: For doctors, the SDM coupled with the Expectation Questionnaire-Pgm proved to be the most useful tool to understand patient expectations and emotions and thus improve the medical-patient relationship through shared decision-making. The third method therefore aims for better patient coverage and improved informed consent, thereby reducing the likelihood of litigation and better assessing nonfitness for operation.