New evidence from magnetic resonance imaging of brain changes after climbs at extreme altitude

The aim of the present study was to look for anatomical changes in climbers' brains, using magnetic resonance imaging (MRI), after extremely high-altitude climbs and to relate them to possible associated risk factors. Clinical history, neurological examinations and MRI were carried out on a group of nine climbers before and after climbing to over 7500 m without the use of supplementary oxygen. None of the subjects showed any neurological dysfunctions. In five climbers MRI abnormalities (high signal areas, cortical atrophy) were observed before the expedition. After the descent, two of them showed new high intensity signal areas recorded by MRI. Both subjects suffered severe neurological symptoms during the climb. The present study suggested that the brain changes observed by MRI could be related to the severity of clinical events at high altitude. However, we do not know the exact meaning of such MRI findings or the reason for their location, predominantly in posterior regions of the brain. The new evidence that a high percentage of climbers show MRI brain abnormalities, and especially the appearance of changes after the ascent, reinforces the possibility of a potential neurological risk in high-altitude climbing.     

Metabolic polymorphisms and the micronucleus frequency in buccal epithelium of adolescents living in an urban environment

Micronuclei and other biomarkers were evaluated in oral cells from 11- to 16-year-old girls living in a foster home in the central area of México City. Variables analyzed for possible association with these biomarkers include smoking habits, body mass index, metabolic polymorphisms for NAT1 and GSTM1 and whether the cells were obtained from the cheek or pharynx. The results indicated that individuals having the NAT1*10 homozygous genotype showed a significant increase in chromatin buds and binucleated cells. When the damage in the cheek was compared with damage in the pharynx, a significant increase in micronuclei and binucleated cells was found for the latter tissue in all the individuals analyzed.     

Interphase fluorescence in situ hybridization analysis of del(11)(q23) and del(17)(p13) in chronic lymphocytic leukemia. a study of 40 early-onset patients

Although B-cell chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia in Western countries, little is known about its underlying molecular abnormalities and their prognostic significance, particularly for use in early therapeutic interventions in young patients. As TP53 tumor suppressor gene abnormalities and 11q23 deletions are reported to be prognostically adverse in hematologic malignancies, we used interphase fluorescence in situ hybridization to analyze their incidence and prognostic significance in young B-CLL patients. Bone marrow samples from 40 untreated B-CLL patients at diagnosis were studied using five yeast artificial chromosome clones from the 11q23.1 approximately q23.3 chromosomal region and a probe specific for the 17p13.1 locus. Twenty-three patients (58%) carried 11q deletions. Interestingly, 16 of 17 patients (94%) who showed early disease progression exhibited this chromosomal abnormality, suggesting that 11q deletions may help to identify more aggressive disease in early stage patients. In contrast, monoallelic TP53 deletions were found in all of the patients. The TP53 and 11q deletions were only present in a proportion of the clonal B-cells, which suggests that they are secondary events in B-CLL.     

Esophageal adenocarcinoma after sleeve gastrectomy: actual or potential threat? Italian series and literature review

BackgroundSleeve gastrectomy (SG) leads to esophageal mucosal damage in an elevated percentage of cases, configuring a clinical condition of Barrett’s esophagus (BE) in a proportion as high as 15–18.8%. BE may rarely evolve into esophageal adenocarcinoma (EAC).ObjectivesTo raise awareness of BE as a precancerous lesion which may progress toward malignancy after this popular bariatric procedure.SettingBariatric referral centers, Italy.MethodsAll patients referred to our bariatric center who developed an EAC after SG between 2012 and 2019 were reviewed and consecutively included in this study. The available scientific literature regarding this complication is additionally reviewed.ResultsThe 3 male patients comprised in this case series underwent laparoscopic SG between 2012 and 2015 in different bariatric referral centers. Age and body mass index at baseline ranged from 21–54 years and 43.1–75.6 kg/m², respectively. All patients were lost to follow-up early after surgery (3.7 ± 1.4 months), and were diagnosed with EAC at a mean of 27.3 ± 7.6 months after SG. The 4 reported cases in the scientific literature developed an EAC at a mean of 32.5 ± 23 months from SG. Overall, a diagnosis of EAC was made approximately 30.3 ± 17.1 months postoperatively, which seems relatively and worryingly early after surgery.ConclusionAlthough the rate and probability of progression from BE to EAC is still not well defined, assuming that the rising popularity and execution of SG leads to a growth in the BE incidence, then the preoperative identification and stratification of cancer risk factors in this subset of patients is strongly encouraged. Clinical and endoscopic follow-ups are essential to allow for prevention and early diagnosis and for epidemiologic data collection purposes.     

Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251)

BackgroundThis is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations.MethodsSafety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI_2.5). Secondary endpoints included %predicted FEV₁ and sweat chloride level.ResultsClass IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV₁ increased by 6.46%, LCI_2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del.ConclusionsIcenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations.ClinicalTrials.gov: NCT02190604     

Pharmacological characterization of mediators and vagal influence in the acute allergic bronchoconstriction in guinea pigs

Summary The allergic bronchoconstriction in guinea pigs has been attributed mainly to the release of mast cell mediators. Histamine has been involved in the first minutes of the anaphylactic reaction and new-formed compounds in the subsequent response. In this asthma model the vagal influence has been sparsely investigated. In the present work we evaluated the pharmacological modification of the acute allergic bronchoconstrictor response in guinea pigs sensitized to ovalbumin through aerosol exposure. Pyrilamine (20 g/kg), diethylcarbamazine (a lipoxygenase inhibitor, 10 mg/kg) and dexamethasone (4 mg/kg) each reduced the antigen-induced bronchoconstriction throughout the 30 min studied. Indomethacin (3.1 mg/kg) did not modify the response to the antigen. Atropine (2 mg/kg) plus bilateral vagotomy also diminished this response from 5 min onward. On the other hand, from 5 min ahead pyrilamine-resistant bronchoconstriction was partially inhibited by dexamethasone, and it was almost completely blocked during all of the response when atropine plus bilateral vagotomy were added to dexamethasone. Dipyridamole (an inhibitor of the adenosine uptake, 0.4 mg/kg) enhanced the bronchoconstriction, though this was significant only in the 2–5 min time-interval of the response. These results suggest that histamine and vagal influence play an important role in the whole response to antigen, that other mediators, probably leukotrienes, participate in this response from 5 min onward, and that adenosine could exert a potentiation effect on this response. Send offprint requests to L. M. Montaño at the Instituto Nacional de Enfermedades Respiratorias     

Selective incorporation of111In-labeled PHOTOFRIN™ by glioma tissuein vivo

The use of PHOTOFRIN for photodynamic therapy of human gliomas has been studied by i.v. administration and laser photosensitization. Defining the uptake of PHOTOFRIN in the patient's tumor in comparison with the surrounding normal brain tissue is highly desirable for patient selection and study ofin vivo kinetics. We utilized a non-invasive approach to the detection of PHOTOFRIN uptake in brain tumors with¹¹¹In-oxine radiolabeled PHOTOFRIN and external imaging and quantitation using a gamma camera. Biodistribution of¹¹¹In-labeled PHOTOFRIN in 13 organs was determined in four dogs and 15 mice with gliomas.^99mTc-DTPA was used as a control for nonspecific uptake. The greatest concentration of¹¹¹In-PHOTOFRIN in the brain tumor occurred at 24 hours post i.v. administration. The brain tumor PHOTOFRIN uptake was seven times greater than that of normal brain. The decreased blood background at 72 hours made this the optimum time for imaging. Specific tumor tissue uptake of¹¹¹In-PHOTOFRIN occurred, well beyond that resulting from blood-brain-barrier (BBB) breakdown.     

Age at starting smoking and number of cigarettes smoked in Catalonia, Spain

BACKGROUND: Few studies have investigated the association between age at starting smoking and the average number of cigarettes smoked per day in adulthood. To provide further evidence on this issue, we analyzed data from the Catalan Health Interview Survey (CHIS). METHODS: The CHIS was conducted in 1994 on a randomly selected sample (N = 15,000) of the population of Catalonia, Spain. A total of 4,897 current or exsmokers (3,276 males and 1,621 females) were included for analysis. Age-standardized proportions of subjects smoking <15, 15-24, and >/=25 cigarettes/day, age-standardized mean number of cigarettes smoked per day, and multivariate odds ratios (OR) of being a heavy smoker (>/=25 cigarettes/day) according to age at starting smoking (<15, 15-17, 18-19, >/=20 years) were computed. RESULTS: Men who started smoking before the age of 15 smoked on average 5.5 cigarettes more than those who started at age 19 or over. Women who started smoking early in life smoked, on average, 6.8 cigarettes/day more than women who started later. The proportion of smokers of <15 cigarettes/day was higher among subjects who started smoking later. Both for males and for females, the OR of being a heavy smoker significantly increased with decreasing age at starting smoking (OR = 2.4 for males and 4.5 for females who started at age <15 versus >/=20 years). The level of education did not modify the relationship in males, whereas the association with age at starting was only apparent for more educated women. CONCLUSIONS: This study confirms that age at starting smoking is inversely and strongly associated to the number of cigarettes smoked per day. Thus, actions aimed at the prevention or delay of smoking onset among adolescents would have an important beneficial effect.