Reviewing the environmental and human health knowledge base of carbon nanotubes

Carbon nanotubes (CNTs) are considered one of the most promising materials in nanotechnology, with attractive properties for many technologic applications. The different synthesis, purification, and postprocessing methods produce CNTs with different physical characteristics, which can be applied in different fields ranging from composite materials, medical applications, and electronics to energy storage. The widespread projected use of CNTs makes it important to understand their potential harmful effects. In this environmental health review we observed a remarkable range of results of some of the toxicology studies. The comparability should be improved by further standardization and introduction of reference materials. However, at present the findings of this review suggest several key points: a) there are different types of CNTs, and therefore they cannot be considered a uniform group of substances; and b) in environmental compartments, CNTs can be bioavailable to organisms. The properties of CNTs suggest a possible accumulation along the food chain and high persistence. In organisms the absorption, distribution, metabolism, excretion, and toxicity of CNTs depend on the inherent physical and chemical characteristics such as CNT functionalization, coating, length, and agglomeration state that are influenced by the external environmental conditions during CNT production, use, and disposal stages. Characterized exposure scenarios could therefore be useful when conducting toxicologic studies. However, CNTs produce a toxic response upon reaching the lungs in sufficient quantity; this reaction is produced in a time-and dose-dependent manner. The identification of possible risks to human health and environment is a prerequisite for a successful introduction of CNTs in future applications.     

Convergent and invariant object representations for sight,sound, and touch

We continuously perceive objects in the world through multiple sensory channels. In this study, we investigated the convergence of information from different sensory streams within the cerebral cortex. We presented volunteers with three common objects via three different modalities—sight, sound, and touch—and used multivariate pattern analysis of functional magnetic resonance imaging data to map the cortical regions containing information about the identity of the objects. We could reliably predict which of the three stimuli a subject had seen, heard, or touched from the pattern of neural activity in the corresponding early sensory cortices. Intramodal classification was also successful in large portions of the cerebral cortex beyond the primary areas, with multiple regions showing convergence of information from two or all three modalities. Using crossmodal classification, we also searched for brain regions that would represent objects in a similar fashion across different modalities of presentation. We trained a classifier to distinguish objects presented in one modality and then tested it on the same objects presented in a different modality. We detected audiovisual invariance in the right temporo‐occipital junction, audiotactile invariance in the left postcentral gyrus and parietal operculum, and visuotactile invariance in the right postcentral and supramarginal gyri. Our maps of multisensory convergence and crossmodal generalization reveal the underlying organization of the association cortices, and may be related to the neural basis for mental concepts. Hum Brain Mapp 36:3629–3640, 2015. © 2015 Wiley Periodicals, Inc.     

Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer

BACKGROUND & AIMS: Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern. The protein encoded by PMS2 is also essential for MMR; however, alterations in this gene have been documented only in extremely rare cases. We addressed this unexpected finding by analyzing a large series of CRCs. METHODS: Expression of MSH2, MSH6, MLH1, and PMS2 was studied by immunohistochemistry in 1048 unselected, consecutive CRCs. Where absence of MMR proteins was detected, microsatellite instability and cytosine methylation of the respective gene promoter were analyzed. The DNA of patients presenting with PMS2-deficient cancers was examined for germline and somatic alterations in the PMS2 gene. RESULTS: An aberrant pattern of MMR protein expression was detected in 13.2% of CRCs. Loss of expression of MSH2, MSH6, or MLH1 was found in 1.4%, 0.5%, and 9.8%, respectively. PMS2 deficiency accompanied by microsatellite instability was found in 16 cases (1.5%) with a weak family history of cancer. The PMS2 promoter was not hypermethylated in these cases. Despite interference of the PMS2 pseudogenes, we identified several heterozygous germline mutations in the PMS2 gene. CONCLUSIONS: PMS2 defects account for a small but significant proportion of CRCs and for a substantial fraction of tumors with microsatellite instability. However, the penetrance of heterozygous germline mutations in PMS2 is considerably lower than that of mutations in other MMR genes. The possible underlying causes of this unorthodox inheritance pattern are discussed.     

Sodium-reduced continuous venovenous hemodiafiltration (CVVHDF) for the prevention of central pontine myelinolysis (CPM) in hyponatremic patients scheduled for orthotopic liver transplantation

Two patients in end-stage hepatic failure presented for orthotopic liver transplantation with longstanding severe hyponatremia (121 and 122 mmol/L). Both patients underwent liver transplantation with the concomitant use of continuous venovenous hemodiafiltration. Replacement and dialysate solutions were prepared individually to contain a sodium level that was individually considered safe with regard to the development of central pontine myelinolysis. The sodium increase in both patients was within the expected and planned limits despite a situation of mass transfusion. Both patients did well postoperatively and neither patient suffered neurological deficits.     

AAV1.NT-3 Gene Therapy for Charcot–Marie–Tooth Neuropathy

Charcot–Marie–Tooth (CMT) neuropathies represent a heterogeneous group of peripheral nerve disorders affecting 1 in 2,500 persons. One variant, CMT1A, is a primary Schwann cell (SC) disorder, and represents the single most common variant. In previous studies, we showed that neurotrophin-3 (NT-3) improved the trembler^J (Tr^J) mouse and also showed efficacy in CMT1A patients. Long-term treatment with NT-3 was not possible related to its short half-life and lack of availability. This led to considerations of NT-3 gene therapy via adenoassociated virus (AAV) delivery to muscle, acting as secretory organ for widespread distribution of this neurotrophic agent. In the Tr^J model of demyelinating CMT, rAAV1.NT-3 therapy resulted in measurable NT-3 secretion levels in blood sufficient to provide improvement in motor function, histopathology, and electrophysiology of peripheral nerves. Furthermore, we showed that the compound muscle action potential amplitude can be used as surrogate for functional improvement and established the therapeutic dose and a preferential muscle-specific promoter to achieve sustained NT-3 levels. These studies of intramuscular (i.m.) delivery of rAAV1.NT-3 serve as a template for future CMT1A clinical trials with a potential to extend treatment to other nerve diseases with impaired nerve regeneration.     

Management of pulmonary tuberculosis in Tajikistan: which factors determine hospitalization?

Objective To assess predictors for tuberculosis hospitalization and treatment outcome in Tajikistan. Methods Stratified, single stage cluster sample survey of 1495 adult patients with pulmonary TB during 2 calendar years (2005–2006) from the registries of 10 TB centres chosen by simple random sampling. The primary outcome was referral to hospital. Logistic regression was conducted to test associations with the study outcome using linearization and a variance formula. Results Prevalence of hospitalization for tuberculosis was 58%. The odds of patients with smear‐positive tuberculosis being referred were three times those of smear‐negative patients [OR 2.99 (95% CI 1.81–4.96)]. Other predictors for hospitalization were the availability of TB hospital beds within the same district [OR 2.15 (95% CI 1.22–3.76)] and male gender [OR 1.46 (95% CI 1.07–2.48)]. The overall treatment success was 80%. Conclusions Hospitalization of patients with pulmonary tuberculosis was determined by positive sputum smear, supply of hospital beds, and gender. Reducing hospitalization with support of national guidelines is not expected to have a negative impact on treatment outcome and spread of disease, but could lead to improved efficiency and effectives of health service delivery for pulmonary tuberculosis in Tajikistan.     

Transverse Coloplasty Pouch After Total Mesorectal Excision: Functional Assessment of Evacuation

PURPOSE Colon pouch reconstruction after total mesorectal excision is functionally superior to straight colorectal/anal anastomosis. In the long-term, stool evacuation difficulties could jeopardize the functional benefit. The transverse coloplasty pouch presents an alternative to the standard J-pouch. This study was designed to analyze functional outcome and defecography findings after total mesorectal excision and transverse coloplasty pouch reconstruction.METHODS Thirty consecutive patients with cancer of the middle and lower third of the rectum underwent a total mesorectal excision and were examined in a prospective study. In all patients, reconstruction was performed with a transverse coloplasty pouch. Pouch and anastomosis were checked by Gastrografin^® enema postoperatively. Patients were examined within eight months by means of defecography, manometry, pouch volumetry, and a standardized continence questionnaire.RESULTS Total mesorectal excision with transverse coloplasty pouch anastomosis was performed successfully in all patients. Symptomatic anastomotic leakage was observed in 2 of 30 patients and the radiologic leak rate was 4 of 30. All patients evacuated the pouch completely; none needed enemas or suppositories to facilitate defecation. Twenty-five of 27 patients had a maximum of three bowel movements per day, and all patients were continent for solid stools. Patients with abnormal findings on defecography proved more likely to have anal dysfunction.CONCLUSIONS Transverse coloplasty pouch reconstruction after total mesorectal excision leads to good functional results and is not associated with stool evacuation problems. Urgency and incontinence correlate rather with impaired pelvic floor movement than with pouch size or anal sphincter tonus.Presented at the Congress: Rectal Cancer Treatment, Heidelberg, Germany, October 9 to 11, 2003.Reprints are not available.     

Accurate and rapid prenatal diagnosis of the most frequent East Mediterranean beta-thalassemia mutations

Beta-thalassemia is the most common genetic disorder in the Lebanese population. Of the 200 different mutations in the beta-globin gene that leads to thalassemia, the IVSI-110 (29.87%), IVSI-6 (20.74%), IVSI-1 (14.07%), IVSII-1 (9.13%), Cd29 (9.13%), and Cd30 (3.95%) mutations are the most frequent among Lebanese thalassemic patients. These mutations are also present at high frequencies in the East Mediterranean region. Due to this high prevalence of certain beta-thalassemia mutations, a rapid technique for the prenatal diagnosis of these mutations was implemented. The technique used is based on Real-Time PCR quantification and melting curve analysis of the amplified fragment using the LightCycler. The DNA samples used for amplification were obtained from CVS or amniotic fluid. Six mutations were easily and efficiently detected using only 3 sets of probes. With this method, mutant genotypes can be easily distinguished from normal alleles. In prenatal diagnosis, the accuracy and the speed of testing are paramount. The method of prenatal beta-thalassemia mutations detection described here is efficient and fast, with the entire procedure including DNA preparation taking less than half a workday. It is safe, does not involve radioactivity, and is accurate showing 100% concordance with conventional DNA sequencing methods.     

Beta-globin gene cluster haplotypes and HbF levels are not the only modulators of sickle cell disease in Lebanon

Sickle cell disease (SCD) is an inherited autosomal recessive disorder of the beta-globin chain. Despite the fact that all subjects with SCD have the same single base pair mutation, the severity of the clinical and hematological manifestations is extremely variable. This study examined for the first time in Lebanon the correlation between the clinical manifestation of SCD and the beta-globin gene haplotypes. The haplotypes of 50 patients diagnosed with SCD were determined using polymerase chain reaction amplification of fragments containing nine polymorphic restriction sites around and within the epsilon-Ggamma-Agamma-psibeta-delta-beta-globin gene complex. Most reported haplotypes were found in our population with the Benin haplotype as the most prevalent one. When the patients were divided according to their HbF levels into three groups (Group A: HbF < 5%, Group B: HbF between 5 and 15%, and Group C: HbF > 15%), surprisingly, the highest levels of HbF were associated with the most severe clinical cases. Our findings suggest that fetal hemoglobin levels are important but not the only parameters that affect the severity of the disease. In addition, the high levels of HbF in patients with CAR haplotypes did not seem to ameliorate the severity of symptoms, suggesting that genetic factors other than haplotypes are the major determinants of increased HbF levels in Lebanon.