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THIS MONTH: Cleaning surgical instruments after use in a procedure involving chemotherapeutic medications Key words: deactivation, decontamination, cleaning, disinfection, chemotherapeutic medication. Paper count sheets sterilized inside instrument sets Key words: count sheets, instrument sets, printer ink, toner, toxicity. Off‐label use of dental devices during direct laryngoscopy Key words: mouth guard, dental injury, direct laryngoscopy, anesthesia, intubation. Using intermittent pneumatic compression devices on patients in lithotomy position Key words: mechanical compression devices, compartment syndrome, lithotomy, venous thromboembolism, thromboprophylaxis. [ABSTRACT FROM AUTHOR]

THIS MONTH: Securing sterile drapes with skin staples Key words: sterile drapes, manufacturer's instructions for use, skin stapler, skin integrity, puncture wound. Sterility of rubber stoppers on medication vials Key words: rubber stopper, medication vial, alcohol swab, dust cover, contamination. Social media use in the OR Key words: social media, distractions, personal electronic device, Health Insurance Portability and Accountability Act (HIPAA), liability. Staffing for local‐only anesthesia procedures Key words: staffing, RN circulator, patient acuity, monitoring, local anesthetic systemic toxicity (LAST). [ABSTRACT FROM AUTHOR]

THIS MONTH: Flying insects in the OR Key words: fly, pest control, infestation, surgical wound classification, sterile field. Reprocessing and reusing single‐use devices Key words: US Food and Drug Administration (FDA), reprocessing, manufacturer, single‐use devices (SUDs), adverse event. Using instrument‐marking tape Key words: instrument tape, sterile processing, manufacturer's instructions for use (IFU), inspection, unintentionally retained surgical item. Epinephrine in orthopedic irrigation Key words: epinephrine, irrigation, vasoconstrictor, arthroscopic procedures, visual field. [ABSTRACT FROM AUTHOR]

THIS MONTH: Debris in sterilized instrument sets Key words: organicdebris, inorganic debris, instrument sets,sterile processing, sterilizing agent. Preventingdebris in sterilized instrument sets Key words: debris, instrument sets,sterile processing equipment, instructions for use (IFU), quality assurance. Bonecement precautions during pregnancy Key words: bone cement, exposure, methyl methacrylate (MMA), pregnant. Usinga bed sheet or blanket for positioning Key words: patient positioning devices, improvised positioning device, pressure distribution, skin shear, pressure injury. Launderingof cloth head coverings Key words: laundering, head covering, reusable cloth hat, surgical attire, disposable bouffant. [ABSTRACT FROM AUTHOR]

Background: Black‐White disparities in cognitive test scores are well documented. Studies suggest that structural racism‐related factors like quality of education and cumulative stress exposure may contribute to disparities in inflammation and cardiometabolic health that undergird racial disparities in Alzheimer's disease and cognitive health. Method: We used MESA data from (N = 1,839) participants that self‐report being racialized as Black or White. We used path analyses to examine the association between racialized group and age‐ and education‐adjusted cognitive scores from the Cognitive Ability Screening Test (CASI) at Exam 5 (2010‐12) and Exam 6 (2016‐18). We examined the relationship between discrimination using the Everyday Discrimination Scale at Exam 1 (2000‐02) and physiological dysregulation at Exam 5 (using a cardiometabolic index = waist‐to‐hip ratio, triglycerides, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, glucose, systolic blood pressure, resting heart rate, and pulse pressure). All models were adjusted for Exam 5 age, sex, site, depression, general stress, socioeconomic stress, and APOE‐e4. Result: Mean age was 69.6 years (SD = 9.3) at Exam 5. Participants racialized as Black had significantly lower CASI scores at Exam 5 (b = ‐0.26) and Exam 6 (b = ‐0.29) than counterparts. Physiological dysregulation was directly associated with lower CASI scores at both exams (Table 1). Discrimination and physiological dysregulation had a significant indirect association with racialized group‐cognition at both exams (Figure 1). Physiological dysfunction was associated with lower CASI scores for participants racialized as Black compared to White at Exam 5 (b = ‐0.004, 95% CI: ‐0.010, ‐0.001) and Exam 6 (b = ‐0.005, 95% CI: ‐0.011, ‐0.002). Higher discrimination was associated with higher CASI scores for participants racialized as Black compared to White at Exam 5 (b = 0.013, 95% CI: 0.001, 0.024) and Exam 6 (b = 0.012, 95% CI: 0.001, 0.024). There was no racialized difference in decline from Exam 5 to Exam 6. Conclusion: Physiological dysregulation may be a mechanism to partially explain the Black‐White disparity in cognitive test scores among middle‐aged and older adults. Endorsing more everyday discrimination was associated with a significantly higher cognitive test scores, though further research is needed to determine if this is due to coping‐related resilience. [ABSTRACT FROM AUTHOR]

Background and purpose: Charcot–Marie–Tooth disease type 1 (CMT1) is a group of autosomal dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the first to second decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication of PMP22 whilst point mutations in PMP22 and other genes are rare causes. Recently, FBLN5 mutations have been reported in CMT1 families. Methods: Individuals with FBLN5‐associated CMT1 were compiled from clinical and research genetic testing laboratories. Clinical data were extracted from medical records or obtained during patients' visits at our centres or primary care sites. Results: Nineteen CMT1 families containing 38 carriers of three different FBLN5 missense variants were identified and a mutational hotspot at c.1117C>T (p.Arg373Cys) was confirmed. Compared to patients with the common PMP22 duplication, individuals with FBLN5 variants had a later age of diagnosis (third to fifth decade) and less severely reduced motor median nerve conduction velocities (around 31 m/s). The most frequent clinical presentations were prominent sensory disturbances and painful sensations, often as initial symptom and pronounced in the upper limbs, contrasting with rather mild to moderate motor deficits. Conclusions: Our study confirms the relevance of FBLN5 mutations in CMT1. It is proposed to include FBLN5 in the genetic work‐up of individuals suspected with CMT1, particularly when diagnosis is established beyond the first and second decade and comparably moderate motor deficits contrast with early and marked sensory involvement. FBLN5‐associated CMT1 has a recognizable clinical phenotype and should be referred to as CMT1H according to the current classification scheme. [ABSTRACT FROM AUTHOR]

THIS MONTH: Using adhesive tape for patient positioning Key words: adhesive tape, surgical tape, patient positioning, pressure injury, contamination. Border sterility of open sterile wrappers Key words: wrapped sterile item, unsterile border, wrapper flap, contaminated, aseptic technique. Cost per minute of OR time Key words: cost comparison, direct costs, cost savings, perioperative efficiency, product evaluation. Packages containing an incorrect number of suture needles Key words: multipack, retained surgical item (RSI), counting, needle, package. [ABSTRACT FROM AUTHOR]

THIS MONTH: Ensuring patient safety under time pressure Key words: on‐time starts, turnover time, briefing, team communication, delays. Holes in the outer layer of sterilization wraps Key words: package integrity, defects, sterilization wrap, contaminated item, sterile field. Changing surgical attire after smoking outside Key words: surgical attire, cigarette smoke, tobacco smoke, third‐hand smoke, wound healing. Methemoglobinemia after local anesthesia Key words: methemoglobinemia, methemoglobin (MetHb), lidocaine‐prilocaine, methylene blue, cyanosis. [ABSTRACT FROM AUTHOR]

Biallelic SBF2 mutations cause Charcot‐Marie‐Tooth disease type 4B2 (CMT4B2), a sensorimotor neuropathy with autosomal recessive inheritance and association with glaucoma. Since the discovery of the gene mutation, only few additional patients have been reported. We identified seven CMT4B2 families with nine different SBF2 mutations. Revisiting genetic and clinical data from our cohort and the literature, SBF2 variants were private mutations, including exon‐deletion and de novo variants. The neuropathy typically started in the first decade after normal early motor development, was predominantly motor and had a rather moderate course. Electrophysiology and nerve biopsies indicated demyelination and excess myelin outfoldings constituted a characteristic feature. While neuropathy was >90% penetrant at age 10 years, glaucoma was absent in ~40% of cases but sometimes developed with age. Consequently, SBF2 mutation analysis should not be restricted to individuals with coincident neuropathy and glaucoma, and CMT4B2 patients without glaucoma should be followed for increased intraocular pressure. The presence of exon‐deletion and de novo mutations demands comprehensive mutation scanning and family studies to ensure appropriate diagnostic approaches and genetic counseling. [ABSTRACT FROM AUTHOR]

Background: Early‐life disadvantage may increase the risk for later cognitive decline. Recently, other aspects of early‐life adversity (ELA) have received attention but their associations with cognitive decline in later life has not been widely studied. Due to the sensitivity of such questions and the potential for systematic bias, we examined (1) predictors of response patterns to ELA questions, and (2) among those who completed ELA questions, we examined whether responses were associated with cognitive decline in the Multi‐Ethnic Study of Atherosclerosis (MESA). Method: ELA was self‐reported via a 7‐item telephone assessment of socioemotional and physical threat or deprivation at MESA annual follow‐up call in 2019. Descriptive statistics were grouped by completion status: not completed, partially completed, and fully completed. Continuous variables were compared across groups with t‐tests; categorical variables were compared with chi‐square tests. Cognitive function was measured using the Cognitive Abilities Screening Instrument (CASI) at MESA Exams 5 (2010‐2012) and 6 (2016‐2018). Multinomial logistic regression was used to determine predictors of completion group membership. Cognitive decline from Exam 5 to 6 by completion group was assessed using multivariable linear regression. Result: Of the 3,990 participants interviewed, the mean age was 59.2y (SD = 8.8), 55% were female, and 40% were White (n = 1,604), 13% Chinese (n = 508), 26% Black (n = 1,036), and 21% Hispanic/Latino (n = 842). The odds of partial response was higher for those born outside of the U.S. (2.17, CI 95%: 1.53‐3.09), and among participants who spoke Spanish (2.82, CI 95%: 1.74‐4.58) or Chinese (2.04, CI 95%: 1.08‐3.88) at baseline. Among participants with completed ELA (n = 3,173), one component of childhood adversity: how often was your household well‐organized/managed, was associated with better Exam 6 CASI score (β = 0.80, SE = 0.33; p = 0.015) adjusting for age, race, education, gender, language, years in the U.S., socio‐economic status (SES), and parental birthplace. There was no significant association between cognitive change from Exam 5 to Exam 6 and ELA completion. Conclusion: Factors associated with acculturation including country of participant's birth and language preference predicted completion status on questions of ELA. Future studies should be mindful of the potentially differential response patterns and the implications for interpretation when analyzing ELA data. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic has had disproportionate effects on the health and well‐being of older adults. Little is known about the effects of isolation and social distancing measures on the mental health of older adults with cognitive impairment. Method: 194 participants from the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core cohort adjudicated as cognitively normal (CN, n = 129), and mild cognitive impairment (MCI, n = 65) were given questionnaires cross‐sectionally measuring loneliness, perceived stress, well‐being, and coping style. We created multivariable regression models (adjusted for age, sex, race, and education) to assess relationships among dependent variables, loneliness and perceived stress, and independent variables of interest, well‐being and coping style (Table 2). Result: Overall, the mean age was 72±8 years. Table 1 lists baseline demographic and study measures for CN and MCI groups. Table 2 shows associations between dependent variables (perceived stress, loneliness) and independent variables of interest. Participants with MCI had significantly higher levels of loneliness (B = 3.30; p = 0.03) than CN participants. Participants who reported lower eudaimonic and hedonic well‐being had higher levels of perceived stress and loneliness (p < 0.01), and those who endorsed using self‐blame and behavioral disengagement to cope with stress had higher perceived stress (B = 3.06, = < 0.01) and loneliness (B = 7.84, p < 0.01). There was no interaction by cognitive diagnosis. Conclusion: Participants with MCI had higher levels of loneliness, but not perceived stress, than those with normal cognition. We found that participants expressing high feelings of well‐being had significantly lower, and participants reporting a coping style with self‐blame and behavioral disengagement had significantly higher perceived stress and loneliness. Next steps involve exploring associations of neuroimaging and Alzheimer's disease biomarkers with perceived stress and loneliness and evaluating transcriptional measures of stress measured concurrently. [ABSTRACT FROM AUTHOR]

Hereditary motor and sensory neuropathy type Russe ( HMSNR), also called CMT4G, is an autosomal recessive inherited peripheral neuropathy ( IPN) caused by a founder mutation in the HK1 gene. HMSNR affects only patients with Roma origin, similar to the better known HMSN type Lom clarified earlier. By testing IPN patients with Roma origin, we realized that HMSNR affects surprisingly many patients in the Czech Republic. HMSNR is one of the most frequent types of IPN in this country and appears to be twice more frequent than HMSNL. Pronounced lower limb atrophies and severe deformities often lead to walking inability in even young patients, but hands are usually only mildly affected even after many years of disease duration. The group of 20 patients with HMSNR presented here is the first report about the prevalence of HMSNR from central Europe. [ABSTRACT FROM AUTHOR]

Introduction There is a substantial interest in identifying interventions that can protect and buffer older adults from atrophy in the cortex and particularly, the hippocampus, a region important to memory. We report the 2-year effects of a randomized controlled trial of an intergenerational social health promotion program on older men's and women's brain volumes. Methods The Brain Health Study simultaneously enrolled, evaluated, and randomized 111 men and women (58 interventions; 53 controls) within the Baltimore Experience Corps Trial to evaluate the intervention impact on biomarkers of brain health at baseline and annual follow-ups during the 2-year trial exposure. Results Intention-to-treat analyses on cortical and hippocampal volumes for full and sex-stratified samples revealed program-specific increases in volumes that reached significance in men only ( P 's ≤ .04). Although men in the control arm exhibited age-related declines for 2 years, men in the Experience Corps arm showed a 0.7% to 1.6% increase in brain volumes. Women also exhibited modest intervention-specific gains of 0.3% to 0.54% by the second year of exposure that contrasted with declines of about 1% among women in the control group. Discussion These findings showed that purposeful activity embedded within a social health promotion program halted and, in men, reversed declines in brain volume in regions vulnerable to dementia. Clinical Trial Registration: NCT0038 . [ABSTRACT FROM AUTHOR]

Alteration of the prairie pothole ecosystem through installation of subsurface tile drains has enabled the U.S. Corn Belt to become one of the most agriculturally productive areas in the world but has also led to increased nitrogen losses to surface water. The literature contains numerous field plot studies but few in-depth studies of nitrate exports from small, tile-drained catchments representative of agricultural drainage districts. The objectives of this study were to quantify hydrology and nitrate-nitrogen (NO3-N) export patterns from three tile-drained catchments and the downstream river over a 5-yr period, compare results to prior plot-, field-, and watershed-scale studies, and discuss implications for water quality improvement in these landscapes. The tile-drained catchments had an annual average water yield of 247 mm yr-1, a flow-weighted NO3-N concentration of 17.1 mg L-1, and an average NO3-N loss of nearly 40 kg ha-1 yr-1. Overall, water yields were consistent with prior tile drainage studies in Iowa and the upper Midwest, but associated NO3-N concentrations and losses were among the highest reported for plot studies and higher than those found in small watersheds. More than 97% of the nitrate export occurs during the highest 50% of flows, at both the small catchment and river basin scale. Findings solidified the importance of working at the drainage district scale to achieve nitrate reductions necessary to meet water quality goals. They also point to the need for implementing strategies that address both hydrology and nitrogen supply in tile-drained landscapes. [ABSTRACT FROM AUTHOR]

Quantifying the effectiveness of perceived best management practices (BMPs) at the field and landscape-scale is difficult, so paired watershed studies are used to detect water quality improvements. We evaluated concentrations of NO3-N discharged from three tiled Iowa watersheds during a 4-yr period to assess their suitability for a paired watershed approach. Our objectives were to evaluate similarities in physical characteristics, concentration patterns, and correlation among the three paired sites and perform a minimum detectable change (MDC) analysis on paired site configurations. The study results demonstrate that concentration variability within and between sample sites affected correlation among the paired basins, even though the physical characteristics of the basins are quite similar. Restricting comparisons to the active tile drainage period (March-July) improved correlations. The lack of a suitable correlation will impair the ability to detect changes expected to result from BMP implementation. The MDC for NO3-N concentration change detection varied from 6.9 to 12.9% and averaged 8% for the best control-treatment pair. To ensure that conservation resources are being used effectively, implemented BMPs should focus on practices capable of achieving at least this magnitude of change. These practices may include reduced fertilizer applications, adoption of cover crops, and land use change. [ABSTRACT FROM AUTHOR]

Šafka Brožková D, Laštůvková J, Štěpánková H, Krůtová M, Trková M, Myška P, Seeman P. DFNB49 is an important cause of non-syndromic deafness in Czech Roma patients but not in the general Czech population. Due to endogamy, the Roma have a higher risk for autosomal recessive (AR) disorders. We used homozygosity mapping on single-nucleotide polymorphism chips in one Czech Roma consanguineous family with non-syndromic hearing loss (NSHL). The second largest homozygous region in a deaf patient was mapped to the previously reported DFNB49 region. The MARVELD2 gene was recently reported as a causal gene for NSHL DFNB49. Sequencing of the MARVELD2 gene revealed a previously reported homozygous mutation c.1331+2 T>C (IVS4 + 2 T>C) in the deaf child. Subsequently, the same mutation was found in two more Roma families from an additional 19 unrelated Czech Roma patients with deafness tested for the MARVELD2 gene. To explore the importance of MARVELD2 mutations and DFNB49 for the general Czech and Central European population with early hearing loss we also tested 40 unrelated Czech patients with AR NSHL. No pathogenic mutation in the MARVELD2 gene was found in a group of 40 Czech non-Roma patients. Mutations in the MARVELD2 gene seem to be a significant cause of early NSHL in Czech Roma and this gene should be tested in this group of patients after GJB2. [ABSTRACT FROM AUTHOR]

Laššuthová P, Mazanec R, Vondráček P, Šišková D, Haberlová J, Sabová J, Seeman P. High frequency of SH3TC2 mutations in Czech HMSN I patients. Charcot-Marie-Tooth (CMT) neuropathy type 4C (CMT4C) is an autosomal recessive (AR), demyelinating neuropathy with early spine deformities caused by mutations in the SH3TC2 gene. To determine the spectrum of SH3TC2 mutations in the Czech population, the entire coding region of SH3TC2 was sequenced in 60 unrelated Czech patients. The prevalent mutation was shown to be the p.Arg954Stop. Therefore, 412 additional patients referred for CMT testing were tested for the presence of p.Arg954Stop only. Of 60 patients in whom the SH3TC2 gene was sequenced, at least one mutation was detected in 13 (21.7%) patients and biallelic pathogenic mutations were detected in 7 (11.6%) patients. Of the 412 patients tested for p.Arg954Stop, the mutation was found in 8 patients (1.94%), 6 were homozygous and 2 were heterozygous. The second causative mutation was detected by sequencing in one of the patients but not in the other. Nine novel sequence variants were detected. Their pathogenicity was further tested in silico and in control samples. Mutations in the SH3TC2 gene are a frequent cause of demyelinating hereditary neuropathy among Czech patients. In total, at least one mutation was found in 21 unrelated patients. CMT4C seems to be the most frequent type of AR CMT and one of the most frequent of all CMT types. Mutation p.Arg954Stop is highly prevalent in the Czech population. Patients with demyelinating neuropathy along with non-dominant mode of inheritance and negative for CMT1A/hereditary neuropathy with liability to pressure palsy should be tested for the presence of the p.Arg954Stop mutation or other mutations in the SH3TC2 gene. [ABSTRACT FROM AUTHOR]

Significant advances have been made in understanding the role of disrupted-in-schizophrenia-1 (DISC1) in the brain and accumulating findings suggest the possible implication of DISC1 in the regulation of dopamine (DA) function. A mutation in the second exon of DISC1 at L100P leads to the development of schizophrenia-related behavior in mutant mice (DISC1-L100P). We investigated here the role of DA in the expression of schizophrenia-related endophenotypes in the DISC1-L100P genetic mouse model. The mutated DISC1 resulted in facilitation of the psychostimulant effect of amphetamine in DISC1-L100P mutant mice assessed in the open field and prepulse inhibition (PPI) tests. Biochemical studies detected a 2.1-fold increase in the proportion of striatal D receptors without significant changes in DA release in vivo in the striatum of DISC1-L100P mutants in response to the low dose of amphetamine. The D2 receptor antagonist haloperidol reversed the hyperactivity, PPI and latent inhibition (LI) deficits and blocked the psychostimulant effect of amphetamine in DISC1-L100P mutants. Taken together, our findings show the role of DISC1 in D2-related pathophysiological mechanism of schizophrenia, linking DISC1 with well-established DA hypothesis of schizophrenia. [ABSTRACT FROM AUTHOR]

Brožková D, Mazanec R, Haberlová J, Sakmaryová I, Seeman P. Clinical and in silico evidence for and against pathogenicity of 11 new mutations in the MPZ gene. Mutations in the myelin protein zero ( MPZ) gene are one of the frequent causes of Charcot-Marie-Tooth (CMT) hereditary neuropathies. Because the mutation rate of MPZ gene is rather high and some mutations are reported as polymorphisms, the proper clinical, electrophysiological examination and the segregation of the new mutation in larger families are crucial for the correct interpretation of the pathogenic or non-pathogenic character of each novel mutation. We examined 11 families with novel MPZ mutations. Eight of the mutations (L48Q, T65N, E97fs, G103W, P132T, T143R, V146G, c.645+1G>T) seem to be pathogenic on the basis of perfect segregation with the CMT phenotype and two (G213R and D246N), on the contrary, seem to be non-pathogenic/rare polymorphisms because they are present in healthy relatives. The character of the V46M mutation is difficult to interpret definitely; it may cause a sensory neuropathy or may also be a rare polymorphism. Phenotypes associated with each of the new mutations include severe hereditary motor and sensory neuropathy type III (HMSN III), and mild phenotype CMT1B presented mostly with only decreased or absent reflexes, foot deformities and mild or even absent atrophies in the lower limbs. Our report and careful family investigations with genotype–phenotype correlations should help to improve genetic counselling and correct interpretation of DNA testing results in further isolated patients or smaller families worldwide where these novel mutations might be found. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on the impact of COX6A1 mutation on axonal hereditary motor and sensory neuropathy.

Primary congenital glaucoma (PCG) is a genetically heterogeneous disorder of autosomal recessive inheritance, with mutations in the cytochrome P450 1B1 ( CYP1B1) gene detected in an average of ∼50% of cases worldwide. The Roma/Gypsies are considered to be a rare example of a single founder CYP1B1 mutation, E387K (identified in the Slovak Roma), accounting for 100% of disease alleles. Contrary to this concept, unusual genetic heterogeneity was revealed in this study of 21 Gypsy PCG patients from Bulgaria and 715 controls from the general Gypsy population. In our small sample of affected subjects, we identified five different CYP1B1 mutations – four known (E229K, R368H, E387K and R390C) and one novel and potentially pathogenic (F445I), which together accounted for ∼30% of disease alleles. E387K was rare in both the patient and the control group, indicating that its high frequency in the Slovak Roma is the product of local founder effect not representative of the overall molecular pattern of PCG in the Gypsy population. Data on other Mendelian disorders and on the population genetics of the Gypsies suggest that a true founder mutation is likely to exist and has remained undetected. Our analysis of another candidate gene, MYOC, and the GLC3B and GLC3C loci did not provide support for their involvement. The molecular basis of PCG in the Gypsies is thus unresolved, and diagnostic analyses should be extended beyond the E387K mutation. [ABSTRACT FROM AUTHOR]

Background: Mutations in the periaxin ( PRX) gene cause autosomal recessive demyelinating neuropathy Charcot–Marie–Tooth (CMT) type 4F. To date, 10 non-sense or frameshift PRX mutations have been reported in patients with early-onset neuropathy and further disease course consistent with either Dejerine–Sottas neuropathy or slow-progressive demyelinating CMT. Methods: We sequenced 59 patients from 55 Czech families including four unrelated patients of Romani (Gypsy) origin with early-onset CMT displaying decreased nerve conduction velocities. Results: We identified a novel homozygous mutation c.3286_3356del71 (K1095fsX18) in one Romani patient showing very slow disease progression. Amongst non-Romani Czech CMT patients, PRX mutations have been proven to be very rare. [ABSTRACT FROM AUTHOR]

Trace amines have been implicated in a number of neuropsychiatric disorders including depression and schizophrenia. Although long known to modulate neurotransmission indirectly through the release of catecholamines, the identification of the Trace Amine 1 receptor (TA1) offers a mechanism by which trace amines can influence synaptic activity directly. TA1 binds and is activated by trace amines such as β-phenylethylamine and tyramine. Our pharmacological characterization of mouse TA1 showed that, as in rat and primate, amphetamine is an agonist at this receptor but with surprisingly high potency. Without selective ligands for TA1 that do not also possess catecholamine-releasing properties, however, it has not been possible to study its physiological role in the central nervous system. To that end, a line of mice lacking the TA1 receptor was generated to characterize its contribution to the regulation of behavior. Compared with wild-type littermates, TA1 knockout (KO) mice displayed a deficit in prepulse inhibition. Knockout animals, in which the TA1-agonist influence of amphetamine was absent, showed enhanced sensitivity to the psychomotor-stimulating effect of this drug, which was temporally correlated with significantly larger increases in the release of both dopamine and norepinephrine in the dorsal striatum and associated with a 262% increase in the proportion of striatal high-affinity D2 receptors. TA1 therefore appears to play a modulatory role in catecholaminergic function and represents a potentially novel mechanism for the treatment of neuropsychiatric disorders. Furthermore, the TA1 KO mouse may provide a useful model for the development of treatments for some positive symptoms of schizophrenia. [ABSTRACT FROM AUTHOR]

We report a 24-year-old male with an unusual combination of two inherited neuromuscular disorders – Charcot-Marie-Tooth (CMT) disease type 1A and Duchenne muscular dystrophy (DMD). A phenotypic presentation of this patient included features of both these disorders. Nerve conduction studies revealed demyelinating peripheral neuropathy. Electromyography showed a profound myogenic pattern. The serum creatine kinase level was highly elevated. Muscle biopsy revealed a dystrophic picture with deficient dystrophin immunostaining. CMT1A duplication on chromosome 17p11.2 was found. The frame-shift mutation c.3609–3612delTAAAinsCTT (p.K1204LfsX11) was detected in the dystrophin gene by analysing mRNA isolated from the muscle tissue. The patient inherited both these mutations from his mother. The combination of CMT1A and DMD has not been reported as yet. [ABSTRACT FROM AUTHOR]

Biallelic pathogenic GJB2 gene mutations cause pre-lingual genetic hearing loss in up to 50% of individuals with bilateral sensorineural hearing loss worldwide. Sequencing of the entire GJB2 gene-coding region in Czech patients with pre-lingual bilateral hearing loss revealed that 10.3% of Czech patients carry only one monoallelic pathogenic mutation in the coding region of the GJB2 gene, which is significantly more than the population frequency of 3.4%. The 309-kb GJB6 deletion, frequent in Spain and France, is very rare in the Czech population. In order to evaluate the impact of the IVS1 + 1 G to A splice site mutation in the non-coding part of the GJB2 gene among Czech patients, we tested all available patients with pre-lingual hearing loss with only one monoallelic mutation in the coding part of GJB2. By sequencing of the exon 1 region of the GJB2 gene and HphI restriction analysis in 20 Czech patients we identified nine patients carrying IVS1 + 1 G to A. Testing for this mutation explained deafness in 45% of Czech GJB2 monoallelic patients. This mutation represents now 4% of GJB2 pathogenic mutations in Czech patients and is the third most common GJB2 mutation found in our cohort of 242 unrelated Czech patients with prelingual hearing loss. A similar frequency may also be expected in other Central European or Slavic populations. [ABSTRACT FROM AUTHOR]

In searching for genes dysregulated in schizophrenia, we measured the expression of the two splice variants of calcium/calmodulin-dependent protein kinase II (CaMKIIα and CaMKIIβ) in postmortem frontal cerebral cortex tissues from patients who had died with schizophrenia, bipolar disorder, or severe depression. The mRNA levels of expression of these two splice variants were measured by real-time Quantitative PCR, using an Mx4000 instrument. The values for the expression of CaMKIIα and CaMKIIβ were normalized by the expression of β-glucuronidase in the tissues. The expression of CaMKIIα was significantly elevated in the depression tissues by 29%. The expression of CaMKIIβ was significantly elevated in the schizophrenia tissues by 27%, and in the depression tissues by 36%. Because CaMKIIβ influences the expression of many neuroreceptors and influences neural outgrowth and pruning, its altered expression in the cerebral cortex in schizophrenia or depression may contribute to these diseases. Synapse 59:61-68, 2006. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Mutations in theGJB2gene are the most common cause of prelingual, autosomal recessive, sensorineural hearing loss worldwide. Nevertheless, 10% to 50% of patients with prelingual nonsyndromic deafness only carry one mutation in theGJB2gene. Recently a large 342 kb deletion namedΔ(GJB6-D13S1830) involving theGJB6gene was reported in Spanish and French deafness patients, either in a homozygous state or in combination with a monoallelicGJB2mutation. No data have been reported about the frequency of this mutation in central Europe.Thirteen Czech patients with prelingual nonsyndromic sensorineural deafness carrying only one pathogenic mutation in theGJB2gene were tested for the presence of theΔ(GJB6-D13S1830) mutation. One patient with aGJB2mutation (313del14) also carried theΔ(GJB6-D13S1830). This is the first reported Czech case, and probably also the first central European case, of prelingual deafness due to mutations involving both theGJB2andGJB6genes. In addition, theΔ(GJB6-D13S1830) was not detected in 600 control chromosomes from Czech individuals with normal hearing. We show that in the Czech Republic theΔ(GJB6-D13S1830) is not the second most common causal factor in deafness patients heterozygous for a singleGJB2mutation, and thatΔ(GJB6-D13S1830) is very rare in central Europe compared to reports from Spain, France and Israel. [ABSTRACT FROM AUTHOR]

Seeman P, Malíková M, Rašková D, Bendová O, Groh D, Kubálková M, Sakmaryová I, Seemanová E, Kabelka Z. Spectrum and frequencies of mutations in the GJB2 ( Cx26) gene among 156 Czech patients with pre-lingual deafness. Mutations in the gene gap junction beta 2 ( GJB2), the gene for the connexin 26, are the most common cause of pre-lingual deafness worldwide. The mutation 35delG within GJB2 is prevalent in Europe. To date, there are no data about GJB2 mutation spectrum and frequencies from the Czech population. We investigated and report here the spectrum and frequencies of mutations in the GJB2 gene among 156 unrelated, congenital deafness Czech patients. Allele-specific polymerase chain reaction, together with fluorescent fragment analysis, were used for the detection of the 35delG mutation. The entire coding region of the GJB2 was directly sequenced in all patients who were not homozygous for the 35delG. No pathogenic mutation was detected in 51.9% of patients. At least one pathogenic mutation was found in 48.1% of patients, and both pathogenic mutations were detected in 37.8% of patients. Single mutations in a heterozygous state were detected in 10.3% of patients. The mutation 35delG accounts for 82.8% of detected disease mutations, Trp24stop accounts for 9.7% of pathogenic alleles and was found in patients with gypsy heritage. Mutation 313del14 accounts for 3.7% of pathogenic alleles. The frequency of 35delG heterozygotes in the Czech Republic is 1 : 29.6. Testing for only the three most common mutations would detect over 96% of all pathogenic alleles in the Czech Republic. [ABSTRACT FROM AUTHOR]

Discusses the psychic process by which children develop its pictorial aptitude. Steps by which the young child learns to handle a drawing implement; Recessions in the learning process at the point in the unfolding of pictorial aptitude; Variation in the drawing-expression of the sexes.

Presents a research focusing on the self-expression of identical twins in handwriting and drawing. Influence of the environment on identical twins; Explanation of the main principles on which the psychological interpretation of handwriting is based; Role of imitation in the formation of an individual handwriting.

A letter to the editor is presented in response to issues raised by B. E. Christopher Nordin and his colleagues on the inappropriate prescribing for osteoporosis.

Variants in the ATL1 gene have been repeatedly described as the second most frequent cause of hereditary spastic paraplegia (HSP), a motor neuron disease manifested by progressive lower limb spasticity and weakness. Variants in ATL1 have been described mainly in patients with early onset HSP. We performed Sanger sequencing of all coding exons and adjacent intron regions of the ALT1 gene in 111 Czech patients with pure form of HSP and additional Multiplex-Ligation Probe Analysis (MLPA) testing targeting the ATL1 gene in 56 of them. All patients except seven were previously tested by Sanger sequencing of the SPAST gene with negative results. ATL1 diagnostic testing revealed only five missense variants in the ATL1 gene. Four of them are novel, but we suppose only two of them to be pathogenic and causal. The remaining variants are assumed to be benign. MLPA testing in 56 of sequence variant negative patients revealed no gross deletion in the ATL1 gene. Variants in the ATL1 gene are more frequent in patients with early onset HSP, but in general the occurrence of pathogenic variants in the ATL1 gene is low in our cohort, less than 4.5% and less than 11.1% in patients with onset before the age of ten. Variants in the ATL1 gene are a less frequent cause of HSP among Czech patients than has been previously reported among other populations., (© 2017 John Wiley & Sons Ltd/University College London.)

We describe a patient with early onset severe axonal Charcot-Marie-Tooth disease (CMT2) with dominant inheritance, in whom Sanger sequencing failed to detect a mutation in the mitofusin 2 (MFN2) gene because of a single nucleotide polymorphism (rs2236057) under the PCR primer sequence. The severe early onset phenotype and the family history with severely affected mother (died after delivery) was very suggestive of CMT2A and this suspicion was finally confirmed by a MFN2 mutation. The mutation p.His361Tyr was later detected in the patient by massively parallel sequencing with a gene panel for hereditary neuropathies. According to this information, new primers for amplification and sequencing were designed which bind away from the polymorphic sites of the patient's DNA. Sanger sequencing with these new primers then confirmed the heterozygous mutation in the MFN2 gene in this patient. This case report shows that massively parallel sequencing may in some rare cases be more sensitive than Sanger sequencing and highlights the importance of accurate primer design which requires special attention., (© 2016 John Wiley & Sons Ltd/University College London.)

Objectives: To evaluate lower urinary tract (LUT), bowel, and sexual dysfunctions in a series of patients with Charcot-Marie-Tooth disease (CMT)., Materials and Methods: A cohort of 58 patients and 54 healthy controls filled out the International Prostate Symptoms Score (IPSS) and the International Consultation on Incontinence Modular (ICIQ) Questionnaires to assess their symptoms and their impact on the patient's quality of life., Results: On the IPSS questionnaire, CMT patients reported a significantly higher score compared with the healthy controls in 7 of 8 questions. The ICIQ-male LUT symptoms questionnaire revealed a significantly higher score in 7 of 26 questions. In the ICIQ-female LUT questionnaire, a significantly higher score was observed in 13 of 24 questions. When assessing the bowel function in CMT patients using the ICIQ-bowel questionnaire, a significantly higher score in 30 of 40 questions was noted. No differences in sexual function were found in either group., Conclusions: The occurrence of the LUT symptoms and bowel dysfunctions in CMT patients was significantly higher when compared with an age-matched control group. The symptoms were more frequent in female patients. The findings suggest that autonomic dysfunction should be evaluated and included in the diagnostic approach and care of CMT patients., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The dopamine D2 receptor is the common target for antipsychotics, and the antipsychotic clinical doses correlate with their affinities for this receptor. Antipsychotics quickly enter the brain to occupy 60-80% of brain D2 receptors in patients (the agonist aripiprazole occupies up to 90%), with most clinical improvement occurring within a few days. The D2 receptor can exist in a state of high-affinity (D2(High) ) or in a state of low-affinity for dopamine (D2Low)., Aim: The present aim is to review why individuals with schizophrenia are generally supersensitive to dopamine-like drugs such as amphetamine or methyphenidate, and whether the D2(High) state is a common basis for dopamine supersensitivity in the animal models of schizophrenia., Results: All animal models of schizophrenia reveal elevations in D2(High) receptors. These models include brain lesions, sensitization by drugs (amphetamine, phencyclidine, cocaine, corticosterone), birth injury, social isolation, and gene deletions in pathways for NMDA, dopamine, GABA, acetylcholine, and norepinephrine., Conclusions: These multiple abnormal pathways converge to a final common pathway of dopamine supersensitivity and elevated D2(High) receptors, presumably responsible for psychotic symptoms. Although antipsychotics alleviate psychosis and reverse the elevation of D2(High) receptors, long-term antipsychotics can further enhance dopamine supersensitivity in patients. Therefore, switching from a traditional antipsychotic to an agonist antipsychotic (aripiprazole) can result in psychotic signs and symptoms. Clozapine and quetiapine do not elicit parkinsonism or tardive dyskinesia because they are released from D2 within 12 to 24 h. Traditional antipsychotics remain attached to D2 receptors for days, preventing relapse, but allowing accumulation that can lead to tardive dyskinesia. Future goals include imaging D2(High) receptors and desensitizing them in early-stage psychosis.

Mutations in SLC26A4 cause Pendred syndrome (PS) - hearing loss with goitre - or DFNB4 - non-syndromic hearing loss (NSHL) with inner ear abnormalities such as Enlarged Vestibular Aqueduct (EVA) or Mondini Dysplasia (MD). We tested 303 unrelated Czech patients with early hearing loss (298 with NSHL and 5 with PS), all GJB2-negative, for SLC26A4 mutations and evaluated their clinical and radiological phenotype. Among 115 available HRCT/MRI scans we detected three MD (2.6%), three Mondini-like affections (2.6%), 16 EVA (13 bilateral - 19.2% and 15.6% respectively) and 61 EVA/MD-negative scans (73.4%). We found mutation(s) in 26 patients (8.6%) and biallelic mutations in eight patients (2.7%) out of 303 tested. In 18 of 26 (69%) patients, no second mutation could be detected even using MLPA. The spectrum of SLC26A4 mutations in Czech patients is broad without any prevalent mutation. We detected 21 different mutations (four novel). The most frequent mutations were p.Val138Phe and p.Leu445Trp (18% and 8.9% of pathogenic alleles respectively). Among 13 patients with bilateral EVA, six patients (50%) carry biallelic mutations. In EVA -negative patients no biallelic mutations were found but 4.9% had monoallelic mutations. SLC26A4 mutations are present mostly in patients with EVA/MD and/or progressive HL and those with affected siblings.

Repeated administration of psychostimulants produces a behavioural sensitization. Amphetamine-sensitized animals are known to have a higher proportion of high-affinity states of dopamine D2 receptors (D2(High) receptors) in the striatum. We recently reported that repeated administration of a dopamine D1 receptor agonist, R-(+)-SKF38393, reverses the established behavioural sensitization to methamphetamine (MAP). To investigate the mechanisms for reversal of behavioural sensitization, we examined the effect of repeated administration of the dopamine D1 receptor agonist on the proportions of D2(High) receptors and the high-affinity states of dopamine D1 receptors (D1(High) receptors) in the striatum. In the striatum from the MAP-sensitized rats, the proportions of D1(High) and D2(High) receptors (28.5 +/- 1.96 and 57.5 +/- 3.58%) were higher than those in the saline-control rats (12.0 +/- 1.01 and 21.9 +/- 1.60%, respectively). Repeated administration of R-(+)-SKF38393 to the MAP-sensitized rats reduced the increased proportions of D1(High) and D2(High) receptors to 12.4 +/- 1.57 and 31.0 +/- 2.14%, respectively, which were similar to the proportions in the saline-control rats. The total densities of dopamine D1 and D2 receptors were not altered in each treatment condition. The results demonstrate that the proportions of D1(High) and D2(High) receptors in the striatum are elevated in MAP-sensitized rats, and that repeated administration of the dopamine D1 receptor agonist to the MAP-sensitized rats reverses the increased proportions of D1(High) and D2(High) receptors. The findings reveal postsynaptic mechanisms for the development of behavioural sensitization to MAP and the reversal of established sensitization by repeated administration of the dopamine D1 receptor agonist.

Objective: Nicotine has a powerful preventive effect on neuroleptic-induced dopamine D2 receptor upregulation in the rat. The aim of this human positron emission tomography (PET) study was to compare upregulation in a smoker and a non-smoker, both of whom had received haloperidol for the same duration of time., Method: Two subjects who had been treated for 16 years with a constant dose of haloperidol were scanned after temporary haloperidol withdrawal, using [11C]-raclopride., Results: The non-smoker, who had received a dose of 10 mg/day, showed a D2 upregulation of 98% and developed severe and persistent symptoms of tardive dyskinesia (TD) upon withdrawal. The chronic smoker, who had been treated with 40 mg/day, displayed a D2 upregulation of 71% and did not develop TD., Conclusion: These human observations agree with animal data which showed that nicotine can decrease neuroleptic-induced D2 receptor upregulation. This property of nicotine may play a protective role in movement disorders whose pathophysiology involves D2 receptor hypersensitivity.

A variety of biological factors may account for the atypical lack of parkinsonism that is a characteristic of the administration of the many 'atypical' neuroleptics. Although dopamine D2 receptor blockade continues to be a dominant feature of successful neuroleptics, the concomitant blockade of muscarinic or serotonergic S2 receptors helps to prevent neuroleptic-induced parkinsonism for some atypical neuroleptics (clozapine, thioridazine, risperidone). The D2-selective benzamides, however, do not block other known receptors (with the possible exception of sigma sites). Therefore, the atypical nature of the benzamides may be based on their sensitivity to the level of endogenous dopamine released in the different regions of the brain. Finally, atypical neuroleptic action may possibly stem from direct linkage between different receptors coupled through components of the G protein system.