Nivaldo Alonso

Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development.

Remarkable gains have been made in global health in the past 25 years, but progress has not been uniform. Mortality and morbidity from common conditions needing surgery have grown in the world’s poorest regions, both in real terms and relative to other health gains. At the same time, development of safe, essential, life-saving surgical and anesthesia care in low- and middleincome countries (LMICs) has stagnated or regressed. In the absence of surgical care, case-fatality rates are high for common, easily treatable conditions including appendicitis, hernia, fractures, obstructed labor, congenital anomalies, and breast and cervical cancer. Although the term, low- and middleincome countries (LMICs), has been used throughout the report for brevity, the Commission realizes that tremendous income diversity exists between and within this group of countries. In 2015, many LMICs are facing a multifaceted burden of infectious disease, maternal disease, neonatal disease, noncommunicable diseases, and injuries. Surgical and anesthesia care are essential for the treatment of many of these conditions and represent an integral component of a functional, responsive, and resilient health system. In view of the large projected increase in the incidence of cancer, road traffic injuries, and cardiovascular and metabolic diseases in LMICs, the need for surgical services in these regions will continue to rise substantially from now until 2030. Reduction of death and disability hinges on access to surgical and anesthesiacare,whichshouldbeavailable, affordable,timely,andsafetoensuregood coverage, uptake, and outcomes. Despite a growing need, the develop

High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes

Twenty‐eight families with a clinical diagnosis of Treacher Collins syndrome were screened for mutations in the 25 coding exons of TCOF1 and their adjacent splice junctions through SSCP and direct sequencing. Pathogenic mutations were detected in 26 patients, yielding the highest detection rate reported so far for this disease (93%) and bringing the number of known disease‐causing mutations from 35 to 51. This is the first report to describe clustering of pathogenic mutations. Thirteen novel polymorphic alterations were characterized, confirming previous reports that TCOF1 has an unusually high rate of single‐nucleotide polymorphisms (SNPs) within its coding region. We suggest a possible different mechanism leading to TCS or genetic heterogeneity for this condition, as we identified two families with no apparent pathogenic mutation in the gene. Furthermore, our data confirm the absence of genotype–phenotype correlation and reinforce that the apparent anticipation often observed in TCS families is due to ascertainment bias. Hum Mutat 16:315–322, 2000.

New Source of Muscle-Derived Stem Cells with Potential for Alveolar Bone Reconstruction in Cleft Lip and/or Palate Patients

Cleft lip and palate (CLP), one of the most frequent congenital malformations, affects the alveolar bone in the great majority of the cases, and the reconstruction of this defect still represents a challenge in the rehabilitation of these patients. One of the current most promising strategy to achieve this goal is the use of bone marrow stem cells (BMSC); however, isolation of BMSC or iliac bone, which is still the mostly used graft in the surgical repair of these patients, confers site morbidity to the donor. Therefore, in order to identify a new alternative source of stem cells with osteogenic potential without conferring morbidity to the donor, we have used orbicular oris muscle (OOM) fragments, which are regularly discarded during surgery repair (cheiloplasty) of CLP patients. We obtained cells from OOM fragments of four unrelated CLP patients (CLPMDSC) using previously described preplating technique. These cells, through flow cytometry analysis, were mainly positively marked for five mesenchymal stem cell antigens (CD29, CD90, CD105, SH3, and SH4), while negative for hematopoietic cell markers, CD14, CD34, CD45, and CD117, and for endothelial cell marker, CD31. After induction under appropriate cell culture conditions, these cells were capable to undergo chondrogenic, adipogenic, osteogenic, and skeletal muscle cell differentiation, as evidenced by immunohistochemistry. We also demonstrated that these cells together with a collagen membrane lead to bone tissue reconstruction in a critical-size cranial defects previously induced in nonimmunocompromised rats. The presence of human DNA in the new bone was confirmed by PCR with human-specific primers and immunohistochemistry with human nuclei antibodies. In conclusion, we showed that cells from OOM have phenotypic and behavior characteristics similar to other adult stem cells, both in vitro and in vivo. Our findings suggest that these cells represent a promising source of stem cells for alveolar bone grafting treatment, particularly in young CLP patients.

Fat grafts supplemented with adipose-derived stromal cells in the rehabilitation of patients with craniofacial microsomia.

Background: Although first reports of the clinical use of adipose-derived stromal cells suggest that this approach may be feasible and effective for soft-tissue augmentation, there is a lack of randomized, controlled clinical trials in the literature. Thus, this study aimed to investigate whether a faster protocol for isolation of adipose-derived stromal cells and their use in combination with fat tissue improve the long-term retention of the grafts in patients with craniofacial microsomia. Methods: Patients with craniofacial microsomia (n = 14) were grafted either with supplementation of adipose-derived stromal cells (experimental group) or without supplementation of adipose-derived stromal cells (control group). The number of viable cells isolated before and after the supplementation of the grafts was calculated, and these cells were examined for mesenchymal cell surface markers using flow cytometry. Computed tomography was performed to assess both hemifaces preoperatively and at 6 months postoperatively. Results: The average number of viable cells isolated before and after the supplementation of the grafts was 5.6 × 105 and 9.9 × 105 cells/ml of fat tissue (p = 0.015). Flow cytometric analysis revealed that the adipose-derived stromal cells were positive for mesenchymal cell markers (>95 percent for CD73 and CD105). Surviving fat volume at 6 months was 88 percent for the experimental group and 54 percent for the control group (p = 0.003). Conclusion: These results suggest that this strategy for isolation and supplementation of adipose-derived stromal cells is effective, safe, and superior to conventional lipoinjection for facial recontouring in patients with craniofacial microsomia. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Maternal MTHFR interacts with the offspring's BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate

The 677 C → T polymorphism in the 5-10 methylenetetrahydrofolate reductase (MTHFR) gene has been associated with nonsyndromic cleft lip with or without cleft palate (CL/P) in some populations, but not others. Previous studies (ie, case–control and transmission disequilibrium tests (TDT)) in Brazilian families with CL/P have been unable to replicate this putative association. However, our group observed a lower proportion of CT heterozygotes among the mothers of CL/P probands, suggesting that the maternal genotype for this polymorphism might influence predisposition to CL/P. In order to further examine this issue, we performed a case–control study of the 677 C → T/MTHFR polymorphism in families with CL/P ascertained in two regions of Brazil: 172 from São Paulo (SP) and 252 from Ceará (CE). The control samples included 243 individuals from SP and 401 from CE. TDT was carried out in 102 patients with CL/P and their parents. No evidence of an association was observed between the 677 C → T/MTHFR polymorphism and CL/P using the case–control design, while borderline significance was obtained with the TDT (P=0.055). We have also looked for an interaction between maternal MTHFR genotypes and the propositi offsprings genotypes at two candidate susceptibility loci for CL/P, TGFA and BCL3. Interestingly, we observed an interaction between the maternal MTHFR and offsprings BCL3 genotypes (OR: 2.3; 95% CI: 1.1–4.8; P=0.03) but not with the offsprings TGFA genotypes. Therefore, our results reinforce the idea that the maternal MTHFR genotype plays a significant role in susceptibility to CL/P, but its teratogenic effect depends on the genotype of the offspring.

Description of a new mutation and characterization of FGFR1, FGFR2, and FGFR3 mutations among Brazilian patients with syndromic craniosynostoses

Dominant mutations in three fibroblast growth factor receptor genes (FGFRs1-3) cause Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. In the present study, 50 Brazilian patients with these four syndromes (27 Apert, 17 Crouzon, 5 Pfeiffer, and 1 Jackson-Weiss patients) were screened for mutations in the FGFR1-3 genes. Except for one, all the Apert patients had either S252W (n = 16) or P253R (n = 10) mutations. The remaining Apert case is atypical with a mutation altering the splice site of FGFR2 exon IIIc. The Pfeiffer patients had mutations in one of the FGFR genes: three in FGFR2, one in FGFR1, and one in FGFR3. In contrast, only 8 of the 17 Crouzon patients studied had a mutation in either FGFR2 (n = 7) or FGFR3 locus (n = 1). Mutations in the FGFR2 locus account for most (93%) of our syndromic craniosynostotic cases, whereas 5% had mutations in the FGFR3 locus and only 2% had mutations in the FGFR1 gene. Except for one, all the other mutations were reported previously in craniosynostotic patients from other populations. Interestingly, the mutation C278F, previously described in Crouzon and Pfeiffer cases, was here identified in a familial case with Jackson-Weiss. Also, unexpectedly, a common mutation altering the splice site of the FGFR2 exon IIIc was found in one Apert and two Pfeiffer patients. In addition, we identified a new mutation (A337P) in the FGFR2 exon IIIc associated with Crouzon phenotype.

Global Surgery 2030: Evidence and solutions for achieving health, welfare, and economic development

John G Meara*, Andrew J M Leather*, Lars Hagander*, Blake C Alkire, Nivaldo Alonso, Emmanuel A Ameh, Stephen W Bickler, Lesong Conteh, Anna J Dare, Justine Davies, Eunice Dérivois Mérisier, Shenaaz El-Halabi, Paul E Farmer, Atul Gawande, Rowan Gillies, Sarah L M Greenberg, Caris E Grimes, Russell L Gruen, Edna Adan Ismail, Thaim Buya Kamara, Chris Lavy, Ganbold Lundeg, Nyengo C Mkandawire, Nakul P Raykar, Johanna N Riesel, Edgar Rodas‡, John Rose, Nobhojit Roy, Mark G Shrime, Richard Sullivan, Stéphane Verguet, David Watters, Thomas G Weiser, Iain H Wilson, Gavin Yamey, Winnie Yip

Using computed tomography to evaluate maxillary changes after surgically assisted rapid palatal expansion.

Surgically assisted rapid palatal expansion (SARPE) is the procedure of choice for treating transverse maxillary deficiency in adult patients. The use of computed tomography (CT) as a method of evaluating the efficiency of this procedure has not been yet reported. Consequently, few landmarks for use in evaluating maxillary expansion have been defined. The goals of the present study were to define parameters to assess skeletal changes after SARPE and to use CT to evaluate those parameters. From June of 2004 to May of 2005, 15 patients underwent SARPE (a modified Le Fort I maxillary osteotomy without pterygomaxillary separation, together with a sagittal palatal osteotomy) according to a defined protocol. To determine the pattern of transversal expansion, linear and angular measurements of the anterior, intermediate, and posterior portions of the maxilla were evaluated in axial and coronal views. The cross-sectional area of the maxilla was calculated to obtain general information about maxillary expansion. The reliability of the method was confirmed. Significant overall expansion was observed. However, different patterns of expansion were seen in the three regions analyzed. In the anterior and intermediate portions of the maxilla, the increase in maxillary width was greater than that observed in the posterior portion. The transverse expansion of the maxilla achieved through SARPE without pterygoid plate separation was less than uniform. The accurate evaluation of the postoperative changes was heavily dependent upon images acquired through CT.

Myotomy of the Levator Labii Superioris Muscle and Lip Repositioning: A Combined Approach for the Correction of Gummy Smile

Background: Treatment of excessive gingival display usually involves procedures such as Le Fort impaction or maxillary gingivectomies. The authors propose an alternative technique that reduces the muscular function of the elevator of the upper lip muscle and repositioning of the upper lip. Methods: Fourteen female patients with excessive gingival exposure were operated on between February of 2008 and March of 2009. They were filmed before and at least 6 months after the procedure. They were asked to perform their fullest smile, and the maximum gingival exposures were measured and analyzed using ImageJ software. Patients were operated on under local anesthesia. Their gingival mucosa was freed from the maxilla using a periosteum elevator. Skin and subcutaneous tissue were dissected bluntly from the underlying musculature of the upper lip. A frenuloplasty was performed to lengthen the upper lip. Both levator labii superioris muscles were dissected and divided. Results: The postoperative course was uneventful in all of the patients. The mean gingival exposure before surgery was 5.22 ± 1.48 mm; 6 months after surgery, it was 1.91 ± 1.50 mm. The mean gingival exposure reduction was 3.31 ± 1.05 mm (p < 0.001), ranging from 1.59 to 4.83 mm. Conclusion: This study shows that the proposed technique was efficient in reducing the amount of exposed gum during smile in all patients in this series.

Region 8q24 is a susceptibility locus for nonsyndromic oral clefting in Brazil

BACKGROUND Nonsyndromic cleft lip with or without cleft palate is a relatively common craniofacial defect with multifactorial inheritance. The association of the rs987525 single nucleotide variant, located in a gene desert at 8q24.21 region, has been consistently replicated in European populations. We performed a structured association approach combined with transcriptional analysis of the MYC gene to dissect the role of rs987525 in oral clefting susceptibility in the ethnically admixed Brazilian population. METHODS We performed the association study conditioned on the individual ancestry proportions in a sample of 563 patients and 336 controls, and in an independent sample of 221 patients and 261 controls. The correlation between rs987525 genotypes and MYC transcriptional levels in orbicularis oris muscle mesenchymal stem cells was also investigated in 42 patients and 4 controls. RESULTS We found a significant association in the larger sample (p = 0.0016; OR = 1.80 [95% confidence interval {CI}, 1.21-2.69], for heterozygous genotype, and 2.71 [95% CI, 1.47-4.96] for homozygous genotype). We did not find a significant correlation between rs987525 genotypes and MYC transcriptional levels (p = 0.14; r = -0.22, Spearman Correlation). CONCLUSIONS We present a positive association of rs987525 in the Brazilian population for the first time, and it is likely that the European contribution to our population is driving this association. We also cannot discard a role of rs987515 in MYC regulation, because this locus behaves as an expression quantitative locus of MYC in another tissue.