Hyperornithinemia-hyperammonemia-homocitrullinuria: a rare neurometabolic disorder in two siblings.

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is an extremely rare disorder of urea cycle, with few patients reported worldwide. Despite hyperammonemia control, the long-term outcome remains poor with progressive neurological deterioration. We report the clinical, biochemical, and molecular features of two Lebanese siblings diagnosed with this disorder and followed for 8 and 15 years, respectively. Variable clinical manifestations and neurological outcome were observed. The patient with earlier onset of symptoms had a severe neurological deterioration while the other developed a milder form of the disease at an older age. Diagnosis was challenging in the absence of the complete biochemical triad and the non-specific clinical presentations. Whole exome sequencing revealed a homozygous variant, p.Phe188del, in the SLC25A15 gene, a French- Canadian founder mutation previously unreported in Arab patients. Hyperammonemia was controlled in both patients but hyperonithinemia persisted. Frequent hyperalaninemia spikes and lactic acidosis occured concomitantly with the onset of seizures in one of the siblings. Variable neurological deterioration and outcome were observed within the same family. This is the first report from the Arab population of the long-term outcome of this devastating neurometabolic disorder.

Genetic literacy among primary care physicians in a resource-constrained setting.

BACKGROUND: Genetic literacy among primary healthcare providers is crucial for appropriate patient care with the advances in genetic and genomic medicine. Studies from high-income countries highlight the lack of knowledge in genetics and the need to develop curricula for continuing professional development of non-geneticists. Scarce data is available from resource-constrained countries in Middle East and North Africa. Lebanon is a small country in this region characterized by high rates of consanguinity and genetic disorders like several surrounding countries, such as Jordan, Syria, and Turkey. METHODS: The primary aim of this study assessed the genetic literacy, self-perceived and actual knowledge as well as practices among primary care providers in Lebanon. The secondary aim identified their educational needs and proposed evidence-based continuing education programs. A cross-sectional survey-based study, using a self-administered questionnaire, was conducted targeting physicians from Family Medicine, Obstetrics and Gynecology, and Pediatrics. The questionnaire was divided into five sections: demographics, familiarity with genetic tests, self-reported and actual knowledge, genetic practices, and educational needs. Statistics were performed using SPSS v24. The Chi-square test was used for independent variables. Differences between mean scores were measured using paired sample t-tests for groups of two levels and one-way ANOVA for more than two. Multiple linear regression was used to study the variables associated with the knowledge score while controlling for other variables. RESULTS: The survey included 123 physicians. They were mostly familiar with karyotype as first-tier genetic test. Although 38% perceived their knowledge as good, only 6% scored as such in knowledge assessment. A better knowledge score was observed in academic institutions as well as in urban settings (p<0.05). One third never ordered any genetic testing, mostly due to poor knowledge. Almost all (98%) were ready to attend continuing professional development sessions in genetics. CONCLUSION: Our findings show the need to improve genetic literacy among healthcare frontliners, focusing on remote regions and nonacademic centers in Lebanon, a model for other resource-constrained country in the Middle East and North Africa region. This study advances recommendations for evidence-based genetic continuing education programs and highlighted the role of that the few genetic specialists can play in their successful implementation.

The effect of preferred music on mental workload and laparoscopic surgical performance in a simulated setting (OPTIMISE): a randomized controlled crossover study.

BACKGROUND: Worldwide, music is commonly played in the operation room. The effect of music on surgical performance reportedly has varying results, while its effect on mental workload and key surgical stressor domains has only sparingly been investigated. Therefore, the aim is to assess the effect of recorded preferred music versus operating room noise on laparoscopic task performance and mental workload in a simulated setting. METHODS: A four-sequence, four-period, two-treatment, randomized controlled crossover study design was used. Medical students, novices to laparoscopy, were eligible for inclusion. Participants were randomly allocated to one of four sequences, which decided the exposure order to music and operation room noise during the four periods. Laparoscopic task performance was assessed through motion analysis with a laparoscopic box simulator. Each period consisted of ten alternating peg transfer tasks. To account for the learning curve, a preparation phase was employed. Mental workload was assessed using the Surgery Task Load Index. This study was registered with the Netherlands Trial Register (NL7961). RESULTS: From October 29, 2019 until March 12, 2020, 107 participants completed the study, with 97 included for analyzation. Laparoscopic task performance increased significantly during the preparation phase. No significant beneficial effect of music versus operating room noise was observed on time to task completion, path length, speed, or motion smoothness. Music significantly decreased mental workload, reflected by a lower score of the total weighted Surgery Task Load Index in all but one of the six workload dimensions. CONCLUSION: Music significantly reduced mental workload overall and of several previously identified key surgical stressor domains, and its use in the operating room is reportedly viewed favorably. Music did not significantly improve laparoscopic task performance of novice laparoscopists in a simulated setting. Although varying results have been reported previously, it seems that surgical experience and task demand are more determinative.

Outcome of Nonketotic Hyperglycinemia in Lebanon: 14-Year Retrospective Review.

Nonketotic hyperglycinemia is a rare inborn error of glycine metabolism characterized by a severe metabolic encephalopathy with drug-resistant seizures. Here, we report the outcome of nonketotic hyperglycinemia in a cohort of patients diagnosed and followed-up at a tertiary care reference center in Lebanon, between 2000 and 2014.Eight out of 12 patients with nonketotic hyperglycinemia were retrospectively reviewed. The remainders were excluded for incomplete data. The majority of cases presented with seizures and hypsarrhythmia or burst suppression patterns. Half of the patients died. Survival varied between 7 days and 18 years. Seizures remained unresponsive with poor outcome, despite standard supportive care and antiepileptic therapy; however, two patients were responsive to ketogenic diet and one of them became seizure-free.Scarce data on the outcome of nonketotic hyperglycinemia patients from the Middle East and North Africa region are available. The ketogenic diet, in combination with standard therapies, appears to be effective in controlling the seizures in this devastating disorder. Larger multicenter studies are still needed to establish the role of the ketogenic diet in nonketotic hyperglycinemia.

Diagnostic challenges and outcome of fatty acid oxidation defects in a tertiary care center in Lebanon.

BACKGROUND: Fatty acid oxidation defects are rare autosomal recessive disorders with variable clinical manifestations and outcome. Early detection by systematic neonatal screening may improve their prognosis. Long-term outcome studies of these disorders in the Middle East and North Africa region are limited. The purpose of this study is to report the diagnostic challenges and outcome of fatty acid oxidation defects in a major tertiary care center in Lebanon, a resource-constrained country in the Middle East. METHODS: A retrospective review of charts of all fatty acid oxidation defects sequential patients diagnosed and followed at our center was conducted. Collected data included: parental consanguinity, age at diagnosis, clinical presentation, biochemical profile, confirmatory diagnosis, treatment and outcome. A genotype-phenotype correlation was also performed, when available. RESULTS: Seven types of fatty acid oxidation defects were identified in a total of 34 patients from 21 families. Most families (79%) were consanguineous (first-degree cousins). The majority were diagnosed when clinically symptomatic (78%), at various ages between 10 days and 19 years (average: 2 years). Follow-up duration spanned between 2 months and 15 years (average: 5 years). The remainder of the patients were detected while still asymptomatic by systematic neonatal screening (9%) or due to positive family history (9%). The most common defect was carnitine transporter deficiency (50%) with an exclusive cardiac presentation related to a founder variant c.981C > T, (p.Arg254*) in the SLC22A5 gene. Medium chain acyl-CoA dehydrogenase deficiency was found in 13% only, which could be explained by the absence of systematic neonatal screening. Rare gene variants were detected in very long chain and multiple acyl-CoA dehydrogenase deficiency. The worse prognosis was observed in very long chain acyl-CoA dehydrogenase deficiency. The overall survival at last follow-up reached 75% with a complete reversal of symptoms with treatment in most patients (63%), despite their late diagnosis. CONCLUSIONS: Our experience highlights the diagnostic challenges and outcome of fatty acid oxidation defects in a resource-constrained country with high consanguinity rates. Physicians' awareness and systematic neonatal screening are key for diagnosis. Larger genotype-phenotype studies are still needed to understand the natural history of these rare diseases and possibly improve their outcome.

Epileptic and electroencephalographic manifestations of guanidinoacetate-methyltransferase deficiency.

AIM: Describe the seizure-related manifestations of guanidinoacetate methyltransferase (GAMT) deficiency in two new cases and compare these to the related literature. METHODS: We reviewed the clinical and electroencephalographic manifestations of two siblings with GAMT deficiency. We also performed a thorough literature review of all cases of GAMT deficiency, using the PubMed database, and compared our findings to those previously reported. RESULTS: One sibling presented with Lennox-Gastaut syndrome while the second had manifestations of late-onset West syndrome. Based on a literature search, we found that the clinical picture of GAMT deficiency has been described in a total of 58 cases, including our two patients, 45 of whom had at least some description of EEG and/or seizure manifestation. Epilepsy was present in 81%, with age at onset usually between 10 months and 3 years. Drug resistance was observed in approximately 45%. Initial seizures were febrile, tonic, or tonic-clonic. Drop attacks and generalised seizures were the most frequent seizure type. Absence and febrile seizures also occurred. Less frequently, focal seizures and late-onset infantile spasms (one prior case) were observed. Multifocal spikes and generalised <3-Hz-spike slow waves were common while only one prior single case report of hypsarrhythmia was described. Lennox-Gastaut syndrome was common, while progressive myoclonic epilepsy was also, less frequently, reported. CONCLUSIONS: To our knowledge, this is the second report of the occurrence of West syndrome in GAMT deficiency. The majority of patients with GAMT deficiency have seizures and approximately half are drug-resistant. Late-onset of hypsarrhythmia and/or epileptic spasms could potentially prove to be a distinctive, albeit infrequent, feature of this treatable metabolic disorder.

Mitochondrial depletion syndrome type 3: the Lebanese variant.

Introduction: Mitochondrial DNA depletion syndrome type 3 is an emerging disorder linked to variants in the deoxyguanosine kinase gene, which encodes for mitochondrial maintenance. This autosomal recessive disorder is frequent in the Middle East and North Africa. Diagnosis is often delayed due to the non-specificity of clinical presentation with cerebro-hepatic deterioration. The only therapeutic option is liver transplantation, although the value of this remains debatable. Methods: We describe the clinical, biochemical, and molecular profiles of Lebanese patients with this rare disorder. We also present a review of all cases from the Middle East and North Africa. Results: All Lebanese patients share a unique mutation, unreported in other populations. Almost half of patients worldwide originate from the Middle East and North Africa, with cases reported from only 7 of the 21 countries in this region. Clinical presentation is heterogeneous, with early-onset neurological and hepatic signs. Liver failure and lactic acidosis are constants. Several variants can be identified in each population; a unique c.235C>T p. (Gln79*) pathogenic variant is found in Lebanese patients. Outcome is poor, with death before 1 year of age. Conclusion: The pathogenic nonsense variant c.235C>T p. (Gln79*) in the deoxyguanosine kinase gene may be considered a founder mutation in Lebanon. Further genotypic delineation of this devastating disorder in populations with high consanguinity rates is needed.

Challenges of genetic diagnosis of inborn errors of metabolism in a major tertiary care center in Lebanon.

Background: Inborn errors of metabolism are rare genetic disorders; however, these are prevalent in countries with high consanguinity rates, like Lebanon. Patients are suspected, based on a combination of clinical and biochemical features; however, the final confirmation relies on genetic testing. Using next generation sequencing, as a new genetic investigational tool, carries several challenges for the physician, the geneticist, and the families. Methods: In this retrospective study, we analyzed the clinical, biochemical, and genetic profile of inborn errors of metabolism suspected patients, seen at a major tertiary care center in Lebanon, between 2015 and 2018. Genetic testing was performed using next generation sequencing. Genotype-phenotype correlation and diagnostic yield of each testing modality were studied. Results: Out of 211 patients genetically tested, 126 were suspected to have an inborn error of metabolism. The diagnostic yield of next generation sequencing reached 64.3%. Single gene testing was requested in 53%, whole exome sequencing in 36% and gene panels in 10%. Aminoacid disorders were mostly diagnosed followed by storage disorders, organic acidemias and mitochondrial diseases. Targeted testing was performed in 77% of aminoacid and organic acid disorders and half of suspected storage disorders. Single gene sequencing was positive in 75%, whereas whole exome sequencing diagnostic yield for complex cases, like mitochondrial disorders, reached 49%. Good clinical and biochemical correlation allowed the interpretation of variants of unknown significance and negative mutations as well as therapeutic management of most patients. Conclusion: Tailoring the choice of test modality, by next generation sequencing, to the category of suspected inborn errors of metabolism may lead to rapid diagnosis, shortcutting the cost of repeated testing. Whole exome sequencing as a first-tier investigation may be considered mainly for suspected mitochondrial diseases, whereas targeted sequencing can be offered upon suspicion of a specific enzyme deficiency. Timing and modality of gene test remain challenging, in view of the cost incurred by families.

Lack of association between IL-1ß, TNF-α, and IL-10 gene polymorphisms and sporadic Parkinson's disease in an Italian cohort.

OBJECTIVE: There is increasing evidence suggesting that neuroinflammation and microglia activation may play important roles in the pathway leading to neuronal cell death in Parkinson's disease (PD). Chronic activation of microglia may cause neuronal damage through the release of potentially cytotoxic molecules, such as pro-inflammatory cytokines. Different functional promoter polymorphisms within genes coding pro- or anti-inflammatory cytokines involved in the immune reactions in the brain might influence the risk of developing PD or the age of disease onset. AIM: To investigate the interleukin (IL)-1ß-511, tumor necrosis factor alpha (TNF-α)-308, and interleukin (IL)-10-1082 gene polymorphisms as susceptibility factors for PD. METHODS: We analyzed genotype and allele distributions of these polymorphisms in 146 Italian patients with PD and 156 healthy controls. RESULTS: None of the polymorphisms we investigated was found to be associated with PD or with age of disease onset. No significant differences between patients with PD and controls were found as regards the concomitant presence of variant alleles in the three polymorphisms studied. We found that only the combined genotype TNF-α-308GG/IL-1ß-511T+ is associated with a decreased risk of PD. CONCLUSION: Our results indicate that the cytokine gene polymorphisms we investigated are not related to the development of PD in the Italian population; further studies are warranted to clarify the role of the TNF-α-308GG/IL-1ß-511T+ combined genotype.

Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review.

Background: Hereditary tyrosinemia type 1 is a rare genetic disorder leading to liver cirrhosis and hepatocellular carcinoma. Few decades ago, dietary measures and ultimately liver transplant constituted the only treatment modalities. Nowadays, early diagnosis and therapy with nitisinone can reverse the clinical picture. In developing countries, diagnostic and therapeutic challenges may affect the outcome of this disease. The choice of the treatment modality may depend on the economic status of each country. Few reports on the long-term outcome of hereditary tyrosinemia type 1 are available from developing and Arab countries. Methods: A retrospective study of charts of Lebanese patients diagnosed with tyrosinemia type 1 and followed, at the American University of Beirut, during a 12-year period was performed. Clinical presentation and liver biochemical profile at diagnosis were analyzed, along with therapeutic modalities and long-term outcome. Results: Twenty-two children were diagnosed and followed during the study period. Median age at diagnosis was 7 months (range: one day to 35 months). Most of the patients presented with hepatomegaly and jaundice. Four patients were referred for atypical presentations with developmental delay and seizures, secondary to undiagnosed hypoglycemia episodes. Around half of the patients presented with failure to thrive. Transaminitis, cholestasis and increased α-fetoprotein level were variably present at diagnosis (36% to 50%). All patients had elevated plasma tyrosine and urinary succinylacetone levels. Genetic testing was performed in 9%. Only one third could be treated with nitisinone. Liver transplant was electively performed in 9% of cases, to overcome the long-term cost of nitisinone. One third of the patients died between the age of 1 month and 11 years. Surviving patients are still candidates for liver transplant. Conclusion: Our experience reflects the challenges of diagnosis and treatment of hereditary tyrosinemia type 1 in a developing country. In the absence of specific neonatal screening, early diagnosis relies mostly on the clinical awareness of the physician. Long-term nitisinone use may be deterred by its high cost and liver transplantation carries risks of surgical complications. New, effective, and less expensive treatments are needed, especially for developing countries.

Metformin turns 62 in pharmacotherapy: Emergence of non-glycaemic effects and potential novel therapeutic applications.

Metformin is the most commonly prescribed oral antidiabetic medication. Direct/indirect activation of Adenosine Monophosphate-activated protein kinase (AMPK) and non-AMPK pathways, amongst others, are deemed to explain the molecular mechanisms of action of metformin. Metformin is an established insulin receptor sensitising antihyperglycemic agent, is highly affordable, and has superior safety and efficacy profiles. Emerging experimental and clinical evidence suggests that metformin has pleiotropic non-glycemic effects. Metformin appears to have weight stabilising, renoprotective, neuroprotective, cardio-vascular protective, and antineoplastic effects and mitigates polycystic ovarian syndrome. Anti-inflammatory and antioxidant effects of metformin seem to qualify it as an adjunct therapy in treating infectious diseases such as tuberculosis, viral hepatitis, and the current novel Covid-19 infections. So far, metformin is the only prescription medicine relevant to the emerging field of senotherapeutics. Non-glycemic effects of metformin favourable to its repurposing in therapeutic use are hereby discussed.

Kidney and Metabolic Phenotypes in Glycogen Storage Disease Type-I Patients.

Patients and Methods: A retrospective chart review of 32 GSD- I patients, followed at the American University of Beirut Medical Center, between 2007 and 2018 was conducted. Diagnosis was confirmed by enzymatic and/or genetic studies. Clinical presentation, growth, and kidney outcome were assessed. All patients were evaluated for body mass index, blood parameters of metabolic control including uric acid, alanine, lactic acid, and triglycerides in blood. Kidney evaluation included creatinine clearance, microalbuminuria, citraturia, and calciuria as well as urine microalbumin/creatinine ratio. Results: Almost one third of GSD-I patients developed microalbuminuria. This was detected below 7 months of age in 36% of patients who required early treatment with ACEI with significant reduction in albuminuria. Kidney stones were present in 6% and were associated with hypercalciuria and hypocitraturia. Poor metabolic control reflected by hyperuricemia, lactic acidosis, and hyperalaninemia were noted only in patients who developed microalbuminuria. Conclusion: Glomerular injury may appear in early infancy in poorly controlled patients. Adequate metabolic control and ACEI therapy may improve kidney outcome in GSD I patients. Plasma alanine appears to be a promising and reliable marker reflecting metabolic control in GSD-I patients.

Diagnosis and management of symptomatic profound biotinidase deficiency in a tertiary care center in Lebanon.

Neonatal screening for biotinidase deficiency is still lacking in several countries worldwide, although this neurocutaneous disorder is treatable and preventable. Therefore, unscreened patients are diagnosed when symptomatic; treatment with Biotin is known to reverse cutaneous symptoms and improve neurological outcome. We describe a series of five symptomatic patients diagnosed with profound biotinidase deficiency and followed at a tertiary care center in Lebanon, for a variable period from 16 months to 11 years. Adjustment of Biotin therapy is correlated to clinical response and biochemical profile including 3-hydroxyisovalerylcarnitine on dried blood spots and urine organic acids. A previously unreported mutation is also reported in a patient who displayed an unusual outcome with reversible hearing loss on Biotin therapy. Clinical responsiveness to Biotin may be related to the underlying genetic mutation, although no clear genotype-phenotype correlation in biotinidase deficiency is proven. Furthermore, in the absence of systematic newborn screening for this disorder in several countries, identification of a reliable blood biomarker of Biotin responsiveness is warranted for better management of late diagnosed symptomatic patients.

Two new familial severe infantile spasm syndromes in males.

We describe two new familial severe infantile spasm syndromes (ISSs) unrelated to Aristaless-related homeobox (ARX) gene mutation. Family A contains two male siblings each with dysmorphism, profound psychomotor delay, gastroesophageal reflux, infantile spasms, hypsarrhythmia, prominent independent central apneas, and early death. Family B contains two male siblings with dysmorphism, profound psychomotor delay, ambiguous genitalia, macular hypoplasia, neurosensory hearing deficit, gastroesophageal reflux, infantile spasms, no hypsarrhythmia, apneas, and early death in one sibling. Etiologic workup and ARX gene sequencing were negative. This indicates that several familial ISSs exist but are not genetically characterized.

Yield of endoscopy of the lower digestive tract in relation to ethnic descent.

BACKGROUND: Not much is known of the yield of endoscopy in relation to ethnic descent. The aim is to study endoscopy of the lower digestive tract in relation to the ethnicity. METHODS: A prospectively collected dataset was used. Presence four endoscopic findings (diverticuli, polyps, colorectal cancer, and signs of inflammation) was studied. The patients were divided in four groups. Group 1 patients of Western descent, group 2 patients of Turkish descent, group 3 patients originating from Morocco, Northern Africa and the Middle East, and, group 4 patients of Asian descent. RESULTS: In group 1, 35,340 procedures were done in 24,223 patients, in group 2 this was 1,776 in 1,338 patients respectively. In groups 3 and 4 this was 465 in 371 patients, and 416 in 305 patients. There was no difference in gender between the four groups, the number of women undergoing endoscopy was higher in all groups. Overall abnormalities in colon and rectum were significantly more often seen in group 1. Colorectal cancer was significantly less often diagnosed in patients of groups 3 and 4. Polyp(s) were significantly less often seen in patients of groups 2 and 3. While diverticulosis of the colon was significantly more often diagnosed in patients of group 1. Signs of inflammation in colon and/or rectum were significantly more often seen in patients of groups 2, 3, and 4. CONCLUSIONS: There are clear differences in presence of colorectal abnormalities in patients from different ethnic descent. The implication of this finding in daily practice is not obvious.

Determination of fermentable sugars in beer wort by gold nanoparticles@polydopamine: A layer-by-layer approach for Localized Surface Plasmon Resonance measurements at fixed wavelength.

Polydopamine decorated in-situ with Localized Surface Plasmon Resonance (LSPR)-active gold nanoparticles (AuNPs) may extend the applicability of nanoplasmonic materials to original and innovative applications in several fields. Here we report the modification of disposable UV-Vis polystyrene cuvettes with AuNPs@PDA for refractive index LSPR-based measurements. An original layer-by-layer deposition method of PDA followed by AuNPs growth is here developed, showing linear correlation between PDA thickness and optical properties. In particular, the modulation from wavelength sensitivity toward absorbance sensitivity is obtained, allowing measurements at fixed wavelength (578 nm). As applicative example of the photonic cuvettes, the measurement of fermentable sugars in beer wort is here reported. The analytical performance of our approach has been directly compared to portable refractometer of reference, displaying excellent results in terms of the precise estimation of sugars in beer wort (expressed in degrees Brix), reproducibility and sensitivity. The approach may be extended to other materials of interest in LSPR based optical sensors, e.g. optical fibers.

The incidence of colorectal cancer in patients with previously removed polyp(s)-a cross-sectional study.

BACKGROUND: Years ago, it was established that removal of adenomas will lead to a lower incidence of colorectal cancer. This study aims to establish the occurrence of colorectal cancer in unselected patients after index colonoscopy with polyp removal. METHODS: A prospectively collected dataset on colonoscopy covering 25 consecutive years was used. Patients in who during the index (first) procedure a polyp(s) was removed were included. Excluded were patients with colorectal cancer and patients belonging to Lynch families. In case of cancer time after the index and previous procedure, tumor stage, histology of earlier removed polyps, localization of the tumor and demographics were noted. RESULTS: In 1,617 patients polyp(s) were removed. Thirty (1.9%) patients developed colorectal cancer. In 18 cases adenomas were removed during prior endoscopies. Five patients only had hyperplastic polyp(s). Nine patients with cancer already were older than 75 years when the previous endoscopy was done. Patients with adenomas prior to the cancer were older compared with patients with hyperplastic polyps [mean (SD): 71.6 (5.8) versus 64.2 (10.5) years, P=0.046]. The majority of cancers were located in the proximal colon (75%). The time between diagnosing cancer and the previous colonoscopy was mean 70.6 months with a median of 60.0 months (range, 12.0-167.0 months). CONCLUSIONS: It is concluded that follow-up after removal of polyps in normal daily practice is associated with a low incidence of developing colorectal cancer.

Pamidronate Rescue Therapy for Hypercalcemia in a Child With Williams Syndrome.

A 15-month-old male infant diagnosed with Williams Syndrome (WS) was admitted with severe hypercalcemia and nephrocalcinosis. Intravenous hydration and furosemide failed to yield an appreciable and sustainable fall in serum calcium, while the injection of pamidronate achieved a significant decrease in serum calcium in a short period of time. This bisphosphonate could be considered as a second-line treatment for refractory hypercalcemia in WS.

Intercepting Parkinson disease non-motor subtypes: A proof-of-principle study in a clinical setting.

The construct of non-motor symptoms (NMS) subtyping in Parkinson Disease (PD) is emerging as a line of research in the light of its potential role in etiopathological interpretation of PD heterogeneity. Different approaches of NMS subtyping have been proposed: an anatomical model suggests that NMS aggregate according to the underpinning pathology; other researchers find aggregation of NMS according to the motor phenotype; the contribution of genetic background to NMS has also been assessed, primarily focusing on cognitive impairment. We have analyzed NMS burden assessed through an extensive clinical and neuropsychological battery in 137 consecutive non-demented PD patients genotyped for MAPT haplotypes (H1/H1 vs H2 carriers) in order to explore the applicability of the "anatomo-clinical", "motor" or "genetic" models for subtyping PD in a clinical setting; a subsequent independent analysis was conducted to verify a possible cluster distribution of NMS. No clear-cut NMS profiles according to the previously described models emerged: in our population, the autonomic dysfunctions and depressive symptoms represent the leading determinant of NMS clusters, which seems to better fit with the hypothesis of a "neurotransmitter-based" model. Selective preferential neurotransmitter network dysfunctions may account for heterogeneity of PD and could address translational research.

The early nucleation stage of gold nanoparticles formation in solution as powerful tool for the colorimetric determination of reducing agents: The case of xylitol and total polyols in oral fluid.

Herein we report a simple non-enzymatic assay for xylitol and total polyols in water and oral fluid based on the time resolved formation of gold NPs in solution, and their colorimetric detection at fixed wavelength (520 nm). The key novelty of the proposed approach relies on the exploitation of information given by the early nucleation step of NPs formation instead of those related to final products at the end point of AuNPs growth, as generally reported in literature. We demonstrate that the nucleation stage is linearly correlated to the concentration of the reducing agent in solution. On the contrary, the optical reading carried out the end point of the reaction shows non-linear correlation and several undesired features. As case study, we applied the proposed method to xylitol and polyols determination, first tested in water and spiked oral fluid samples. The detection limits obtained on xylitol resulted 180 mg L-1 (CV% = 6.9) and 44 mg L-1 (CV% = 6.5) in water and oral fluid, respectively. Afterward, we successfully performed the monitoring of total polyols in oral fluid over time during xylitol-containing gums consumption. Data here reported show high correspondence with available data in literature. The proposed approach is fast, cheap, highly reproducible, and can be extended to other reducing substances of interest for analytical purposes.