Cannabinoid Analgesia in Postoperative Pain Management: From Molecular Mechanisms to Clinical Reality.

Postoperative pain (POP) is a challenging clinical phenomenon that affects the majority of surgical patients and demands effective management to mitigate adverse outcomes such as persistent pain. The primary goal of POP management is to alleviate suffering and facilitate a seamless return to normal function for the patient. Despite compelling evidence of its drawbacks, opioid analgesia remains the basis of POP treatment. Novel therapeutic approaches rely on multimodal analgesia, integrating different pharmacological strategies to optimize efficacy while minimizing adverse effects. The recognition of the imperative role of the endocannabinoid system in pain regulation has prompted the investigation of cannabinoid compounds as a new therapeutic avenue. Cannabinoids may serve as adjuvants, enhancing the analgesic effects of other drugs and potentially replacing or at least reducing the dependence on other long-term analgesics in pain management. This narrative review succinctly summarizes pertinent information on the molecular mechanisms, clinical therapeutic benefits, and considerations associated with the plausible use of various cannabinoid compounds in treating POP. According to the available evidence, cannabinoid compounds modulate specific molecular mechanisms intimately involved in POP. However, only two of the eleven clinical trials that evaluated the efficacy of different cannabinoid interventions showed positive results.

Additive antinociceptive action of intrathecal anandamide reuptake inhibitor and morphine in the management of post-incisional pain in rats.

Spinal opioids have mixed efficacy and their adverse effects force treatment cessation of postoperative pain. Consequently, there is an ongoing search for new therapeutic strategies. Here, we evaluated the analgesic efficacy of intrathecal UCM707, an anandamide reuptake inhibitor, and morphine combination. Firstly, we assessed the effects of morphine (1, 5 and 10 µg), UCM707 (75 µg) and its combination in the hot plate. Then, morphine + UCM707 at sub-effective doses was evaluated in a rat post-incisional pain model. In addition, µ-, CB1r-, CB2r- and TRPV1-antagonists were pre-administered before the combination. Activation of µ-opioid and CB1r, and Cnr1, Cnr2, Oprm1 and TRPV1 expressions were evaluated in the lumbar sacra and periaqueductal grey by [35 S]-GTPγS binding autoradiography and qPCR studies. In the hot plate, morphine (1 µg) and UCM707 (75 µg) induced a more robust analgesic effect than each drug alone. Morphine plus UCM707 did not modify µ-opioid nor CB1 receptor function in the PAG or LS. Cnr1 and TRPV1 expression increased in the lumbar sacra (LS). Morphine plus UCM707 significantly reduced post-incisional pain at 1 and 4 days after surgery. Cnr1, Cnr2 and TRPV1 expressions increased in the LS. Blockade of µ-opioid receptor reduced combination effects on days 1 and 4. CB1r- and CB2r-antagonism reduced morphine + UCM707 effects on days 1 and 4, respectively. CB1r and TRPV1-antagonism improved their antinociceptive effects on day 4. These results revealed a synergistic/additive analgesic effect of UCM707 and morphine combination controlling postincisional pain. CB1r, CB2r and TRPV1 contribute differently as central sensitization occurs.

[Diagnostic accuracy of the tri-ponderal mass index in identifying the unhealthy metabolic obese phenotype in obese patients]. / Precisión diagnóstica del índice de masa triponderal (kg/m3) para identificar el fenotipo de riesgo metabólico en pacientes obesos.

INTRODUCTION: The metabolically healthy obese (MHO) phenotype defines obese patients who have preserved insulin sensitivity and absence of metabolic complications. This phenotype is associated with a lower risk of cardiovascular disease and type2 diabetes in adulthood. OBJECTIVES: To determine the prevalence of MHO and the metabolically unhealthy obesity (MUO) phenotype in a cohort of obese children and adolescents and to establish the predictive capacity of the tri-ponderal mass index (TMI) and other anthropometric parameters in order to identify these patients. PATIENTS AND METHODS: A cross-sectional study was conducted on 239 obese patients (125males) from 8 to 18years of age. Grade3 obesity was present in 45.9% of the patients. ROC curves were used to find the best cut-off point for: TMI, body mass index (BMI), BMI z-score (BMIzs), and waist/height index (WHI). MHO components: plasma blood glucose, plasma triglycerides, HDL-cholesterol, and blood pressure. RESULTS: The prevalence of MUO in the study cohort was 62.4%. No differences between genders were observed, and it was increasing with the age and obesity degree. The TMI has a sensitivity of 75.8 and a specificity of 42.2 to identify the MUO patients. The best cut-off point for TMI is 18.7kg/m3, for BMI it was 30.4kg/m2, for BMIzs +3.5SD, and 0.62 for WHI. CONCLUSIONS: The diagnostic accuracy of TMI in identifying obese adolescents with metabolic risk was similar to BMI and WHI. However, the TMI is much simpler to use and simplifies the categorization of the obesity in both genders.

Measurement of the soliton number in guiding media through continuum generation.

No general approach is available yet to measure directly the ratio between chromatic dispersion and the nonlinear coefficient, and hence the soliton number for a given optical pulse, in an arbitrary guiding medium. Here we solve this problem using continuum generation. We experimentally demonstrate our method in polarization-maintaining and single-mode fibers with positive and negative chromatic dispersion. Our technique also offers new opportunities to determine the chromatic dispersion of guiding media over a broad spectral range while pumping at a fixed wavelength.

A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness.

CONTEXT: Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness. OBJECTIVE: To identify genetic variants associated with GH responsiveness. DESIGN: Genome-wide association study (GWAS). SETTING: Cohorts from multiple academic centers and a clinical trial. PATIENTS: A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age. INTERVENTION: Association of more than 2 million variants was tested. MAIN OUTCOME MEASURES: Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness. RESULTS: No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score. CONCLUSIONS: We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height.

Isolated pulmonary interstitial glycogenosis associated with alveolar growth abnormalities: A long-term follow-up study.

INTRODUCTION: Pulmonary interstitial glycogenosis (PIG) is a rare infant interstitial lung disease characterized by an increase in the number of interstitial mesenchymal cells, presenting as enhanced cytoplasmic glycogen, and is considered to represent the expression of an underlying lung development disorder. METHODS: This study describes the clinical, radiological, and functional characteristics and long-term outcomes (median 12 years) of nine infants diagnosed with isolated PIG associated with alveolar simplification in the absence of other diseases. RESULTS: All patients presented with tachypnea. Additionally, seven patients had breathing difficulties and hypoxemia. Abnormalities in chest-computerized tomography (CT) with a pattern of ground-glass opacity, septal thickening, and air trapping were observed in all individuals, with images suggesting abnormal alveolar growth (parenchymal bands and architectural distortion). All lung biopsies showed alveolar simplification associated with an increased number of interstitial cells, which appeared as accumulated cytoplasmic glycogen. In the follow-up, all patients were asymptomatic. The respiratory function test was normal in only two patients. Five children showed an obstructive pattern, and two children showed a restrictive pattern. Chest-CT, performed after an average of 6.5 years since the initial investigation, revealed a partial improvement of the ground-glass opacity pattern; however, relevant alterations persisted. CONCLUSION: Although the patients with PIG in the absence of other associated pathologies had a good clinical outcome, significant radiographic alterations and sequelae in lung function were still observed after a median follow-up of 12 years, suggesting that PIG is a marker of some other persistent abnormalities in lung growth, which have effects beyond the symptomatic period.

[Body mass index and tri-ponderal mass index of 1,453 healthy non-obese, non-undernourished millennial children. The Barcelona longitudinal growth study]. / Índice de masa corporal e índice de masa triponderal de 1.453 niños no obesos ni malnutridos de la generación del milenio. Estudio longitudinal de Barcelona.

INTRODUCTION: Body mass index-for age (BMI) and tri-ponderal mass index-for-age (TMI) values of healthy non-underweight, non-obese millennial children have not been reported until now. We aimed to obtain these values. SUBJECTS AND METHODS: Longitudinal growth study (1995-2017) of 1,453 healthy non-underweight, non-obese millennial children, from birth (n = 477) or from 4 years of age (n = 976) to 18 years in girls and 19 years in boys (25,851 anthropometric measurements). RESULTS: In each sex, mean BMI-for-age values increased from birth to one year, declined until 5and increased from then onwards. Mean TMI-for-age values decreased abruptly during the first 6years of age and slowly thereafter, in both sexes. Although, at some ages, mean BMI-for age values differed statistically between sexes, differences were scant and of poor clinical significance. The same occurred for TMI-for-age values. BMI-for-age cut-off values to define underweight status (-2 SD) were similar to those proposed by Cole and the WHO for both sexes. However, BMI-for-age cut-off values to define obesity (+2 SD) were lower in both sexes (1.0-5.3) than those proposed by Cole and similar to those proposed by the WHO until 12 in girls and 14 in boys and lower (1.0-4.8) from these ages onwards. CONCLUSIONS: BMI-for-age and TMI-for-age values of healthy non-underweight, non-obese millennial children are provided. No clinically relevant differences were observed between sexes. These values may be used to measure underweight status and obesity in present pediatric populations and to evaluate the relationship between BMI-for-age and TMI-for-age in a clinical setting.

[Pubertal growth of 1,453 healthy children according to age at pubertal growth spurt onset. The Barcelona longitudinal growth study]. / Crecimiento puberal de 1.453 niños sanos según la edad de inicio de la pubertad. Estudio longitudinal de Barcelona.

INTRODUCTION: Pubertal growth pattern differs according to age at pubertal growth spurt onset which occurs over a five years period (girls: 8-13 years, boys: 10-15 years). The need for more than one pubertal reference pattern has been proposed. We aimed to obtain five 1-year-age-interval pubertal patterns. SUBJECTS AND METHODS: Longitudinal (6 years of age-adult height) growth study of 1,453 healthy children to evaluate height-for-age, growth velocity-for-age and weight-for-age values. According to age at pubertal growth spurt onset girls were considered: very-early matures (8-9 years, n=119), early matures (9-10 years, n=157), intermediate matures (10-11 years, n=238), late matures (11-12 years, n=127) and very-late matures (12-13 years, n=102), and boys: very-early matures (10-11 years, n=110), early matures (11-12 years, n=139), intermediate matures (12-13 years, n=225), late matures (13-14 years, n=133) and very-late matures (14-15 years, n=103). Age at menarche and growth up to adult height were recorded. RESULTS: In both sexes, statistically-significant (P<.0001) and clinically-pertinent differences in pubertal growth pattern (mean height-for-age, mean growth velocity-for-age and mean pubertal height gain, values) were found among the five pubertal maturity groups and between each group and the whole population, despite similar adult height values. The same occurred for age at menarche and growth from menarche to adult height (P<.05). CONCLUSIONS: In both sexes, pubertal growth spurt onset is a critical milestone determining pubertal growth and sexual development. The contribution of our data to better clinical evaluation of growth according to the pubertal maturity tempo of each child will obviate the mistakes made when only one pubertal growth reference is used.

Impact of Empathy in the Patient-Doctor Relationship on Chronic Pain Relief and Quality of Life: A Prospective Study in Spanish Pain Clinics.

Objective: To assess the impact of the empathy of physicians, perceived by patients with chronic pain, regarding pain relief and health-related quality of life (HR-QoL). Methods: A prospective noninterventional study was conducted in 2,898 patients with moderate to severe chronic pain who were referred to pain clinics. The same physician visited each patient at baseline and after one and three months. Study questionnaires included the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE), the Life Orientation Test-Revised (LOT-R), the Pain Coping Questionnaire (CAD-R), the Brief Pain Inventory Short Form (BPI-SF), and the EuroQol-5D (EQ-5D). Regression analyses were used to evaluate the independent contribution of the changes in perceived empathy over pain intensity and improvement of HR-QoL. Results: BPI-SF scores for pain intensity, rated as worst, least, average, and current pain, decreased significantly (P < 0.001) from baseline to month 3, with reductions of 33.7%, 42.5%, 40.0%, and 46.9%, respectively. Pain intensity decreased from 6.3 ± 1.5 at baseline to 4.7 ± 1.8 at one month and 3.8 ± 1.9 at three months (P < 0.050). Significant (P < 0.001) improvements in the EQ-5D tariff (+37.1%) and EQ-5D VAS (+26.7%) were also recorded. In the linear regression analysis, JSPPPE and LOT-R, but not CAD-R, were significantly associated with pain relief and HR-QoL. Conclusions: Physicians' empathy and patients' dispositional optimism have a role in determining positive outcomes in patients with chronic pain. Physicians' empathy may therefore be a suitable, yet relatively unexplored, target for intervention.

Microcephaly with simplified gyral pattern, epilepsy and permanent neonatal diabetes syndrome (MEDS). A new patient and review of the literature.

Microcephaly with simplified gyration, epilepsy and permanent neonatal diabetes syndrome (MEDS) is a recently described, autosomal recessive-inherited syndrome. We report the case of an infant presenting with lethargy at age five weeks and clinical findings of persistent hyperglycaemia and microcephaly with simplified gyration, suggestive of MEDS. The diagnosis was confirmed by the detection of a known c.233 T > C mutation in the IER3IP1 gene. Only eight cases of MEDS have been reported in the literature. We reviewed these with the aim of better delineating their clinical manifestations, which should allow earlier and more accurate diagnosis and genetic counseling.

Discordant Genotypic Sex and Phenotype Variations in Two Spanish Siblings with 17α-Hydroxylase/17,20-Lyase Deficiency Carrying the Most Prevalent Mutated CYP17A1 Alleles of Brazilian Patients.

17α-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia caused by mutations in CYP17A1. Two phenotypic female sisters, aged 17 and 15 years and with 46,XY and 46,XX karyotypes, respectively, presented with primary amenorrhea and absent secondary sexual characteristics. The elder sib also presented with high blood pressure. Both patients had elevated levels of ACTH, gonadotropins, progesterone, corticosterone, and deoxycorticosterone, and reduced levels of estradiol, testosterone, androstenedione, 17-OH-P, DHEA-S, cortisol, aldosterone, and renin activity. The CYP17A1 gene was sequenced, and polymorphic haplotypes were further analyzed in the Spanish family and in Brazilian patients. The 2 sisters were compound heterozygous for p.Arg362Cys and p.Trp406Arg mutations, previously described as the most prevalent mutations in Brazilian families of Spanish (p.Trp406Arg) or Portuguese (p.Arg362Cys) origin. Analysis of polymorphisms in CYP17A1 suggested that the paternal allele with p.Arg362Cys may share a common origin with the Brazilian carriers, while the maternal allele with p.Trp406Arg did not. Hydrocortisone and sex hormone replacement therapy was initiated in both patients. In conclusion, one CYP17A1 mutation (p.Arg362Cys) may share a common ancestry in Brazilian and our present Spanish patients, while p.Trp406Arg may have arisen separately. The elder patient (46,XY) developed a more severe phenotype and a poorer response to estradiol replacement therapy.

Adiponectin, Leptin and Inflammatory Markers in HIV-associated Metabolic Syndrome in Children and Adolescents.

BACKGROUND: Metabolic syndrome (MetS) is more common in HIV-infected adults and children than in the general population. Adipocytokines and inflammatory markers may contribute to the pathophysiology of this condition and could be useful indices for monitoring MetS. The objective of this study was to provide information on the prevalence of MetS and investigate the role of adipocytokines and other biomarkers in this syndrome in HIV-infected pediatric patients. METHODS: A cross-sectional study was conducted between October 2013 and March 2014 in the outpatient clinics of 2 tertiary pediatric referral hospitals. Fifty-four HIV-infected children and adolescents were included. MetS was defined according to the International Diabetes Federation and modified National Cholesterol Education Program Adult Treatment Panel III criteria. Measurements included anthropometry, waist circumference, blood pressure, fasting lipids, glucose and insulin, adiponectin, leptin, interleukin-6, vitamin D and C-reactive protein and clinical lipodystrophy assessment. RESULTS: Among the total, 3.7% of patients met the International Diabetes Federation criteria for MetS and 7.4% met the National Cholesterol Education Program Adult Treatment Panel III criteria. C-reactive protein and leptin levels were significantly higher and adiponectin level significantly lower in patients with MetS, regardless of the criteria used. Insulin resistance was observed in 40.7% of patients; abnormal quantitative insulin sensitivity check index values were found in 88.9%. Eighteen patients (33.3%) had vitamin D deficiency. CONCLUSIONS: The prevalence of MetS was similar to that observed in larger cohorts of HIV-infected patients in our setting. Adipocytokine dysregulation seems to be related to MetS in HIV-infected children. A high percentage of patients showed insulin resistance, which should be strictly monitored.

Hysteroscopic myomectomy outcomes after 3-month treatment with either Ulipristal Acetate or GnRH analogues: a retrospective comparative study.

Ulipristal Acetate (UPA) modifies the endometrium, as well as fibroids, and therefore it might make hysteroscopic surgery more difficult. To confirm that pre-treatment with UPA is as safe and effective an option as pre-treatment with GnRH analogues, considered the gold standard. We present the first series of 26 hysteroscopic myomectomies after 3 months treatment with UPA and we compare the results with a series of 24 cases pretreated with GnRH analogues. This was a retrospective cohort study between July 2013 and May 2015. We analyszed patients with submucous myomas >2.5 in diameter. Hysteroscopic myomectomy was performed after 3 months of treatment with either UPA (5mg daily) or the GnRH agonist (3.75mg/month). Both groups were similar in age, myoma initial size and classification. There were no significant differences between UPA and GnRHa treated groups in terms of percentage of myomas resected (93% vs 98%), duration of surgery (38 vs 37min), fluid deficit (200 vs 350ml) and complications. In the surgeon's subjective opinion, UPA treatment was associated with an easier resection. Based on our experience, previous treatment with UPA does not difficult Hhysteroscopic myomectomy. Endometrial changes have no impact on surgery. Safety and feasibility are comparable to hysteroscopic myomectomies with previous treatment with GnRH analogues. This allows us to take advantage of the reduction in size of fibroids before surgery with less side effects.

Metabolic Syndrome in Children and Adolescents Living with HIV.

BACKGROUND: Metabolic syndrome (MetS) is considered an independent risk factor for developing cardiovascular disease. It is well known that the prevalence of metabolic disorders have increased in pediatric HIV-infected children. The objective of this study is to assess the prevalence and characteristics of MetS in HIV-infected children and adolescents in Spain. METHODS: A cross-sectional multicenter study in 152 patients from the pediatric cohort of the Spanish AIDS Research Network (CoRISpe) was performed. MetS was defined according to the new International Diabetes Federation (IDF) diagnostic criteria and the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria. Measurements included anthropometry, waist circumference, blood pressure, fasting lipids, glucose and insulin and lipodystrophy assessment. Demographic, clinical, immunological, virological and antiretroviral therapy data were obtained from the Network database. RESULTS: An abnormally low high-density lipoprotein-cholesterol level was the most prevalent disturbance (21.05%) found. Three patients met IDF criteria for MetS (1.97%), and MetS was significantly associated with lipohypertrophy (P=0.029) in the analysis. When the modified NCEP-ATP III criteria were used, the prevalence of MetS was 5.92% (9 patients), and MetS was significantly associated with Tanner stage ≥2 (P=0.041), lipohypertrophy (P=0.001) and higher Z scores for weight and body mass index (P=0.002 and P<0.001). Insulin resistance was observed in 17 patients (11.18%) and was associated with MetS (as per the modified NCEP-ATP III criteria) (P=0.03) and lower high-density lipoprotein-cholesterol values (P=0.036). CONCLUSIONS: The prevalence of MetS in our cohort was 1.97% or 5.92%, depending on the diagnostic criteria used. MetS should be actively assessed, particularly in children who show lipohypertrophy.

LRH-1 May Rescue SF-1 Deficiency for Steroidogenesis: An in vitro and in vivo Study.

Steroidogenic factor 1 (NR5A1/SF-1) mutations usually manifest in 46,XY individuals with variable degrees of disordered sex development and in 46,XX women with ovarian insufficiency. So far, there is no genotype-phenotype correlation. The broad spectrum of phenotype with NR5A1 mutations may be due to a second hit in a gene with similar function to NR5A1/SF-1. Liver receptor homologue-1 (LRH-1/NR5A2) might be a good candidate. We performed in vitro studies for the interplay between SF-1, LRH-1 and DAX-1, expression profiles in human steroidogenic tissues, and NR5A2 genetic studies in a cohort (11 patients, 8 relatives, 11 families) harboring heterozygote NR5A1/SF-1 mutations. LRH-1 isoforms transactivate the CYP17A1 and HSD3B2 promoters similarly to SF-1 and compensate for SF-1 deficiency. DAX-1 inhibits SF-1- and LRH-1-mediated transactivation. LRH-1 is found expressed in human adult and fetal adrenals and testes. However, no NR5A2/LRH-1 mutations were detected in 14 individuals with heterozygote NR5A1/SF-1 mutations. These findings demonstrate that in vitro LRH-1 can act like SF-1 and compensate for its deficiency. Expression of LRH-1 in fetal testis suggests a role in male gonadal development. However, as we found no NR5A2/LRH-1 mutations, the 'second genetic hit' in SF-1 patients explaining the broad phenotypic variability remains elusive.

Clinical challenges in the management of isolated GH deficiency type IA in adulthood.

UNLABELLED: Isolated GH deficiency type IA (IGHDIA) is an infrequent cause of severe congenital GHD, often managed by pediatric endocrinologists, and hence few cases in adulthood have been reported. Herein, we describe the clinical status of a 56-year-old male with IGHDIA due to a 6.7 kb deletion in GH1 gene that encodes GH, located on chromosome 17. We also describe phenotypic and biochemical parameters, as well as characterization of anti-GH antibodies after a new attempt made to treat with GH. The height of the adult patient was 123 cm. He presented with type 2 diabetes mellitus, dyslipidemia, osteoporosis, and low physical and psychological performance, compatible with GHD symptomatology. Anti-GH antibodies in high titers and with binding activity (>101 IU/ml) were found 50 years after exposure to exogenous GH, and their levels increased significantly (>200 U/ml) after a 3-month course of 0.2 mg/day recombinant human GH (rhGH) treatment. Higher doses of rhGH (1 mg daily) did not overcome the blockade, and no change in undetectable IGF1 levels was observed (<25 ng/ml). IGHDIA patients need lifelong medical surveillance, focusing mainly on metabolic disturbances, bone status, cardiovascular disease, and psychological support. Multifactorial conventional therapy focusing on each issue is recommended, as anti-GH antibodies may inactivate specific treatment with exogenous GH. After consideration of potential adverse effects, rhIGF1 treatment, even theoretically indicated, has not been considered in our patient yet. LEARNING POINTS: Severe isolated GHD may be caused by mutations in GH1 gene, mainly a 6.7 kb deletion.Appearance of neutralizing anti-GH antibodies upon recombinant GH treatment is a characteristic feature of IGHDIA.Recombinant human IGF1 treatment has been tested in children with IGHDIA with variable results in height and secondary adverse effects, but any occurrence in adult patients has not been reported yet.Metabolic disturbances (diabetes and hyperlipidemia) and osteoporosis should be monitored and properly treated to minimize cardiovascular disease and fracture risk.Cerebral magnetic resonance imaging should be repeated in adulthood to detect morphological abnormalities that may have developed with time, as well as pituitary hormones periodically assessed.