Updated evidence of the safety and efficacy of the miniaturized percutaneous nephrolithotomy with holmium laser lithotripsy for the treatment of recurrent nephrolithiasis.

OBJECTIVE: The objective of the present communication is to report the safety and efficacy of applying miniaturized percutaneous nephrolithotomy (mini-PCNL) in Vietnamese patients with recurrent kidney stones using a miniature nephroscope through a 18F metal access sheath. PATIENTS AND METHODS: We performed a retrospective cohort study of patients who were diagnosed with recurrent nephrolithiasis and underwent mini-PCNL after previous treatments between 2017 and 2020. Clinical profile, preoperative characteristics, intraoperative events, and postoperative outcomes were obtained from the hospital database. Descriptive statistics were used for the whole analysis. RESULTS: Of 89 eligible patients, 54 were male. The mean age was 53.4 years. Mean stone size was 24.9 mm. 37 patients had right side stone, 39 had left side stone, and 13 had stone on both sides. Pain in the flanks and back was the most symptom in our patients (n = 87, 97.8%), followed by hematuria (n = 13, 14.6%), dysuria (n = 8, 8.9%), fever (n = 7, 7.9%), acute renal colic (n = 5, 5.6%), and pyuria in 2 patients. 27 had complex stones, and the remaining stone position included renal pelvis (21, 23.6%), upper calyx (15, 16.9%), lower calyx (14, 15.7%), and middle calyx (12, 13.5%). 35 of them had grade I, 27 grade II, 8 grade III and 2 grade IV of hydronephrosis. Renal failure was documented in 12 patients (13.5%). 18 patients were performed with 2-times punctures (20.2%) and 13 with 3-times punctures (14.6%). We used one percutaneous tract in 79 patients and the remaining 10 were performed with two tracts. The upper, middle, and lower calyx was the site of puncture access in 6 (6.7%), 73 (82.0%), and 10 (11.3%) cases, respectively. 3 patients had bleeding requiring intraoperative blood transfusion and 2 were converted to open surgery. Intraoperative parameters recorded percutaneous puncture duration of 20.9 minutes (5-50), and total operative duration of 112.9 minutes (40-240). 7 patients developed secondary bleeding after surgery, besides 5 cases of fever, 2 cases of septic shock and one case of drainage failure. Early stone-free rate was 89.9% and this rate was 94.4% for patients after one month of mini-PCNL. Mean duration of ureteral catheter circulation was 2.7 days (2-20), mean length of postoperative hospitalization was 6.6 days (4-25) and mean total hospital stay was 12.9 days (7-28). CONCLUSIONS: Present results show the safety of mini-PCNL with respect to recurrent nephrolithiasis. Our updated evidence may provide appropriate modified approaches that aim at reducing the risk of recurrent kidney stone development.

Consumption of freshwater fish: A variable but significant risk factor for PFOS exposure.

PFOS, PFOA, PFNA and PFHxS are the PFAS substances that currently contribute most to human exposure, and in 2020 the European Food Safety Authority (EFSA) presented a draft opinion on a tolerable intake of 8 ng/kg/week for the sum of these four substances (equaling 0.42 µg/kg if expressed as an annual dose). Diet is usually the dominating exposure pathway, and in particular the intake of PFOS has been shown to be strongly related to the consumption of fish and seafood. Those who eat freshwater fish may be especially at risk since freshwater and its biota typically display higher PFOS concentrations than marine systems. In this study, we estimated the range in PFOS intake among average Swedish "normal" and "high" consumers of freshwater fish. By average we mean persons of average weight who eat average-sized portions. The "normal consumers" were assumed to eat freshwater fish 3 times per year, and the "high consumers" once a week. Under these assumptions, the yearly tolerable intake for "normal" and "high" consumers is reached when the PFOS concentrations in fish equals 59 and 3.4 µg per kg fish meat. For this study, PFOS concentrations in the muscle tissue of edible-sized perch, pike and pikeperch were retrieved from three different Swedish datasets, covering both rural and urban regions and a total of 78 different inland waters. Mean PFOS concentrations in fish from these sites varied from 0.3 to 750 µg/kg. From the available data, the annual min-max dietary PFOS intake for male "normal consumers" was found to be in the range 0.0021-5.4 µg/kg/yr for the evaluated scenarios, with median values of 0.02-0.16 µg/kg/yr. For male "high consumers", the total intake range was estimated to be 0.04-93 µg/kg/yr, with median values being 0.27-1.6 µg/kg/yr. For women, the exposure estimates were slightly lower, about 79% of the exposure in men. Despite highly variable PFOS concentrations in fish from different sites, we conclude that the three most commonly consumed freshwater species in Sweden constitute an important source for the total annual intake even for people who eat this kind of fish only a few times per year. The analyses of PFOA, PFNA and PFHxS showed values which were all below detection limit, and their contribution to the total PFAS intake via freshwater fish consumption is negligible in comparison to PFOS.

A survey on IVIVC/IVIVR development in the pharmaceutical industry - Past experience and current perspectives.

The present work aimed to describe the current status of IVIVC/IVIVR development in the pharmaceutical industry, focusing on the use and perception of specific approaches as well as successful and failed case studies. Two questionnaires have been distributed to 13 EFPIA partners of the Oral Biopharmaceutics Tools Initiative and to the Pharmacokinetics Working Party of the European Medicines Agency in order to capture the perspectives and experiences of industry scientists and agency members, respectively. Responses from ten companies and three European Agencies were received between May 21st 2014 and January 19th 2016. The majority of the companies acknowledged the importance of IVIVC/IVIVR throughout the drug development stages and a well-balanced rate of return on investment. However, the IVIVC/IVIVR approach seemed to be underutilized in regulatory submissions. Four of the ten companies stated to have an internal guidance related to IVIVC/IVIVR modelling, whereas three felt that an overall strategy is not necessary. Successful models mainly served to support formulation development and to provide a better mechanistic understanding. There was not yet much experience with safe-space IVIVRs as well as the use of physiologically based modelling in the field of IVIVC. At the same time, the responses from both industry and agencies indicated that there might be a need for a regulatory framework to guide the application of these novel approaches. The relevance of IVIVC/IVIVR for oral IR drug products was recognized by most of the companies. For IR formulations, relationships other than Level A correlation were more common outcomes among the provided case studies, such as multiple Level C correlation or safe-space IVIVR, which could be successfully used for requesting regulatory flexibility. Compared to the responses from industry scientists, there was a trend towards a higher appreciation of the BCS among the regulators, but a less positive attitude towards the utility of non-compendial dissolution methods for establishing a successful IVIVC/IVIVR. The lack of appropriate in vivo data and regulatory uncertainty were considered the major difficulties in IVIVC/IVIVR development. The results of this survey provide unique insights into current IVIVC/IVIVR practices in the pharmaceutical industry. Pursuing an IVIVC/IVIVR should be generally encouraged, considering its high value from both industry and regulators' perspective.

Chronic Diarrhea in L-Amino Acid Decarboxylase (AADC) Deficiency: A Prominent Clinical Finding Among a Series of Ten French Patients.

Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive inborn error of metabolism, affecting catecholamines and serotonin biosynthesis. Cardinal signs consist in psychomotor delay, hypotonia, oculogyric crises, dystonia, and extraneurological symptoms. PATIENTS AND METHODS: We present a retrospective descriptive multicentric study concerning ten French children with a biochemical and molecular confirmed diagnosis of AADC deficiency. RESULTS: Clinical presentation of most of our patients was consistent with the previous descriptions from the literature (hypotonia (nine children), autonomic signs (nine children), sleep disorders (eight children), oculogyric crises (eight children), motor disorders like hypertonia and involuntary movements (seven children)). We described however some phenotypic particularities. Two patients exhibited normal intellectual abilities (patients already described in the literature). We also underlined the importance of digestive symptoms like diarrhea, which occurred in five among the ten patients. We report in particular two children with chronic diarrhea, complicated by severe failure to thrive. Vanillactic acid (VLA) elevation in urines of one of these two patients led to suspect the diagnosis of AADC deficiency, as in two other patients from our population. CONCLUSION: Some symptoms like chronic diarrhea were atypical and have been poorly described in the literature up to now. Diagnosis of the AADC deficiency is sometimes difficult because of the phenotypic heterogeneity of the disease and VLA elevation in urines should suggest the diagnosis.

High-dose short-term administration of naringin did not alter talinolol pharmacokinetics in humans.

Naringin is considered the major causative ingredient of the inhibition of intestinal drug uptake by grapefruit juice. Moreover, it is contained in highly dosed nutraceuticals available on the market. A controlled, open, randomized, crossover study was performed in 10 healthy volunteers to investigate the effect of high-dose naringin on the bioavailability of talinolol, a substrate of intestinal organic anion-transporting polypeptide (OATP)-mediated uptake. Following 6-day supplementation with 3 capsules of 350 mg naringin daily, 100mg talinolol were administered orally with 3 capsules of the same dietary supplement (1050 mg naringin) on the seventh day. This test treatment was compared to 100mg talinolol only (control). The results showed that short-term high-dose naringin supplementation did not significantly affect talinolol pharmacokinetics. Geometric mean ratios of test versus control ranged between 0.90 and 0.98 for talinolol c(max), AUC(0-48 h), AUC(0-∞), t(1/2) and A(e(0-48 h)). The high dose may provoke inhibition of the efflux transporter P-glycoprotein (P-gp) which counteracts the uptake inhibition. As disintegration and dissolution processes are required for the solid dosage form, dissolved naringin may arrive at the site of interaction after talinolol is already absorbed. In conclusion, the effect of nutraceuticals on drug pharmacokinetics can deviate from that observed when administered as food component due to the different dose and dosage form.

New first order Raman-active modes in few layered transition metal dichalcogenides.

Although the main Raman features of semiconducting transition metal dichalcogenides are well known for the monolayer and bulk, there are important differences exhibited by few layered systems which have not been fully addressed. WSe2 samples were synthesized and ab-initio calculations carried out. We calculated phonon dispersions and Raman-active modes in layered systems: WSe2, MoSe2, WS2 and MoS2 ranging from monolayers to five-layers and the bulk. First, we confirmed that as the number of layers increase, the E', E″ and E2g modes shift to lower frequencies, and the A'1 and A1g modes shift to higher frequencies. Second, new high frequency first order A'1 and A1g modes appear, explaining recently reported experimental data for WSe2, MoSe2 and MoS2. Third, splitting of modes around A'1 and A1g is found which explains those observed in MoSe2. Finally, exterior and interior layers possess different vibrational frequencies. Therefore, it is now possible to precisely identify few-layered STMD.

Effect of single-dose and short-term administration of quercetin on the pharmacokinetics of talinolol in humans - Implications for the evaluation of transporter-mediated flavonoid-drug interactions.

Quercetin has been shown to inhibit intestinal P-glycoprotein-mediated drug efflux. A crossover clinical study was performed in 10 healthy volunteers to assess the effect of single-dose and repeated quercetin intake on the pharmacokinetics of talinolol, a substrate of intestinal P-glycoprotein. Unexpectedly, mean area under the plasma concentration-time curve (AUC0-48h) and maximal plasma concentration (cmax) were slightly decreased following concomitant and short-term quercetin administration (3186.0 versus 2468.3 and 2527.7 ng h/ml, p>0.05; 309.7 versus 212.0 and 280.6 ng/ml, p>0.05). Individual analysis revealed that talinolol AUC0-48h was lowered by 23.9% up to 60.6% in 5 subjects and cmax was decreased by 29.2% up to 78.7% in 7 subjects after quercetin co-administration. These effects were less pronounced following repeated quercetin intake. Overlapping modification of efflux and uptake transport involving carrier proteins of the OATP superfamily as well as site-dependent interaction are possible explanations for these observations. In conclusion, clinically relevant quercetin-drug interaction cannot be ruled out.

[A child with sepsis-associated encephalopathy]. / Encéphalopathie associée au sepsis (EAS), un cas pédiatrique.

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction due to a systemic response to infection. We report the case of a 4-year-old girl with fever and vomiting for 48h, brought to the university hospital of Grenoble because of vigilance disorders, loss of verbal fluency, and a cerebellar syndrome. She had a biological infectious syndrome. Infectious encephalitis was suggested first, but the cerebral scan and the lumbar punction were normal. Magnetic resonance imaging (MRI) showed a diffuse brain edema with extended involvement of cortical and basal ganglia. The electroencephalogram was globally slow. The infectious syndrome was explained by perforated appendicitis with peritonitis, treated by surgery and antibiotic therapy. Other infectious explorations were negative. No metabolic or autoimmune diseases were found. Hence, our final diagnosis was sepsis-associated encephalopathy. After 1 year of follow-up care, her clinical exam, MRI, and EEG were normal. Sepsis-associated encephalopathy has been increasingly described in the adult population, but until today only three pediatric cases have been published. It is diagnosed when the patient has a severe infectious syndrome associated with neurologic symptoms, mostly vigilance or consciousness disorders, no signs of shock, and only when other potential reasons have been ruled out. The MRI shows non-specific diffuse lesions with vasogenic edema on the subcortical substance or on the basal ganglia and the thalami. The electroencephalogram is slowed down on the whole. The main differential diagnoses are infectious encephalitis, acute disseminated encephalomyelitis, and cerebral vasculitis. Posterior reversible encephalopathy syndrome is an MRI diagnosis that presents characteristics similar to SAE. In the future, it could be discovered that it is the same physiopathology. At the moment, we only treat the symptoms and the causative infection. Most of the time, patients have neurologic sequelae that affect their verbal fluency. It can persist from a few months up to 6yrs. Although quite slow, the neurologic progression is good. The mechanisms are studied and there are hopes for specific treatments. The main explanation seems to be immune with alterations of the blood-brain barrier. Cytokines and activated leukocytes may attack the cerebral substance.

[Acrodermatitis enteropathica-like syndrome secondary to branched-chain amino acid deficiency during treatment of maple syrup urine disease]. / Pseudo-acrodermatite entéropathique secondaire à un déficit en acides aminés ramifiés au cours du traitement d'une leucinose.

INTRODUCTION: Clinical pictures resembling acrodermatitis enteropathica have been described in acquired zinc deficiency and deficiencies of other nutrients such as biotin, essential fatty acids and amino acids as well as biotin metabolism disorders. We describe the case of an infant with maple syrup urine disease who developed an acrodermatitis-like syndrome due to iatrogenic valine and isoleucine deficiency. CASE-REPORT: A diagnosis of maple syrup urine disease was made in a 5-month-old infant girl with severe neurologic disorders with extremely high levels of the three branched-chain amino acids (leucine, valine and isoleucine) in plasma and urine. Seven days after the start of therapy with a diet excluding these branched-chain amino acids, plasma isoleucine and valine concentrations were low while plasma leucine remained elevated. At the same time, a periorificial and acral dermatitis appeared together with diarrhea. Serum zinc concentrations were normal. A diagnosis of acrodermatitis enteropathica-like syndrome secondary to isoleucine and valine deficiency was suspected. Valine and isoleucine supplementation resulted in rapid resolution of the eruption. DISCUSSION: Several cases of acrodermatitis enteropathica-like eruptions resulting from therapeutic protein restriction diets have been described in infants with different aminoacidopathies. The accompanying dermatosis was associated with a raised plasma leucine/isoleucine ratio and/or isoleucine deficiency, or valine deficiency. While the exact pathogenesis of the skin lesions has not been established, these observations show that branched-chain amino acids are essential for normal growth and differentiation of keratinocytes. The essential role of isoleucine is further substantiated by the fact that its presence is critical in keratinocyte culture media, with growth arrest occurring upon its depletion.

Organochlorine pesticides and PCBs along the coast of north Vietnam.

Organochlorine pesticides and polychlorinated biphenyls (PCBs) were determined in sediments and clams collected from the coast of the north of Vietnam during the rainy season (August-September 1997). Results show that the organochlorine pesticides of major concern are HCHs (1.2-33.7 ng g-1 dry wt.), DDTs (6.2-10.4 ng g-1 dry wt.) and HCB (0.1-6.5 ng g-1 dry wt.). PCBs, in aroclor 1254 equivalents, were also generally present in concentrations ranging from 0.47 to 28.1 ng g-1 sediment dry wt. Concentrations measured in the soft tissues of clams (Meretrix meretrix) generally reflect the level of contamination at the sampling sites. In the clams, the concentrations of DDTs (12.0-23.3 ng g-1 dry wt.) and PCBs (5.1-25.3 ng g-1 dry wt.) were generally higher than those of other chlorinated hydrocarbons. These results underscore the need to improved environmental protection measures in order to reduce the exposure of the population to these persistent and bioaccumulative compounds through food ingestion.

A profile of the behavioral changes produced by facilitation of AMPA-type glutamate receptors.

A newly developed group of benzoylpiperidine drugs that enhance AMPA-receptor-gated currents ("ampakines") has been shown to improve memory encoding in rats across a variety of experimental paradigms. The present experiments were intended to i) provide a partial profile of the behavioral changes produced by ampakines, ii) test if two ampakines (BDP-12 and BDP-20) that differ significantly in their effects on AMPA receptor kinetics produce similar behavioral profiles, and iii) determine if physiological potency is reflected in behavioral potency. BDP-20 reduced two measures of exploratory activity in aged rats but increased speed of performance in a radial maze; the drug also caused substantially improved retention of spatial information. These results are similar to those obtained with BDP-12, an analog that differs from BDP-20 in its effects on ligand binding to the AMPA receptor and on the physiological responses of the receptors to glutamate. BDP-20 was approximately ten-fold more potent in behavioral effects than BDP-12, which agrees with the relative potencies of the two drugs as assessed with excised patches and excitatory synaptic responses. These findings indicate that ampakines, though differing in their effects on AMPA-receptor-mediated responses, have similar effects at the behavioral level.

A comparative study of the biologic and immunologic response to medical devices derived from dermal collagen.

We examined collagen materials for soft tissue augmentation [Zyderm Collagen Implant (ZCI), glutaraldehyde cross-linked (GAX) collagen, and Koken Atelocollagen (Atelocollagen)]; hemostatic collagens [Gelfoam Gelatin Powder (Gelfoam), Avitene Microfibrillar Collagen Hemostat (Avitene), and Collastat Collagen Hemostat (Collastat)]; and reconstituted, intact fibrillar collagen from bovine skin in a subcutaneous guinea pig model. After 11, 25, and 39 days in situ, explants from animals injected with GAX collagen demonstrated greater wet-weight persistence than all other materials. Conversely, at all time points, the explants of Atelocollagen were the least persistent. Following 25 days in vivo, explants were examined using differential scanning calorimetry; ZCI and Atelocollagen displayed thermal transition temperatures of 58 degrees C. Avitene and Gelfoam explants displayed transition points of 30 degrees C and 32 degrees C, indicating denatured or cleaved collagen. By contrast, GAX collagen explants had a high (68 degrees C) transition temperature, reflecting its cross-linking. With respect to immunogenicity, day 39 sera from ZCI treated animals showed significantly lower titers in the ELISA to their respective implant collagen than all other groups examined, while antibody activity in the GAX collagen, Gelfoam, Atelocollagen, and intact collagen groups were not significantly different. Collastat elicited antibodies with a greater affinity than observed in these previous groups. Sera from Avitene treated animals demonstrated the highest antibody levels and were the only sera which reacted with bovine serum albumin. Thus, Avitene was the most immunogenic of the collagen materials examined, while GAX collagen demonstrated the greatest persistence and minimal immunogenicity, and ZCI was the least immunogenic.