A Systematic Review of Symptoms of Pernicious Anemia.

BACKGROUND: Pernicious anemia (PA) is a type of macrocytic anemia caused by autoimmune gastritis. To facilitate timely diagnosis and treatment of PA there is a pressing need for improved understanding among Healthcare providers of the condition's symptoms and diagnostic criteria. OBJECTIVE: This systematic review aims to extend existing clinical knowledge on the presentation of PA by determining which symptoms and clinical complications are reported in published adult case studies. METHODS: Relevant studies were identified through electronic searches of PsycINFO, Embase, and MEDLINE, via OvidSP. During data extraction symptoms were categorized according to the International Classification of Diseases and were grouped based on frequency. RESULTS: Symptoms were documented for 103 adults with a diagnosis of PA; the most frequent symptoms were fatigue (55%), loss of sensation in limbs (32%), excessive weight loss (27%), and a sore tongue (23%). CONCLUSIONS: This review highlights the diverse symptomology of adults who are diagnosed with PA. Most symptoms documented in case studies are consistent with the core signs of B12 and folate deficiencies. Research is needed to identify if there are common clusters of PA symptoms that can be used as prompts for diagnostic testing in patients with suspected B12 deficiency.

Plain language titleA Review of Symptoms of Pernicious AnemiaPlain language summaryThis study reviewed case studies that have been written about adults with pernicious anemia, it has documented the frequency of the core symptoms and the impact these have on health.

Development of a Vitamin B12 Deficiency Patient-Reported Outcome Measure for Clinical Practice and Research.

BACKGROUND: It is difficult to recognize vitamin B12 deficiency and to evaluate the effect of B12 treatment due to a broad range of variable clinical symptoms overlapping with other diseases and diagnostic biomarkers that quickly normalize during treatment. This poses a risk of delay in diagnosis and a challenge to uniformly monitor the effect of B12 treatment. There is a need for a new clinical outcome measure suitable for clinical practice and clinical evaluation studies. OBJECTIVE: To develop a Patient-Reported Outcome Measure (PROM) which measures the severity of vitamin B12 deficiency symptoms. METHODS: The B12 PROM was developed by (1) gathering input from experts and literature review to define a construct and develop a conceptual model, (2) processing input from health care providers, scientists, and patients to develop items and response options, and (3) improving items based on the feedback from laypersons, test interviews, semi-structured cognitive interviews with patients, and forward and backward translation (ENG-NL). RESULTS: The B12 PROM includes 62 items grouped into 8 categories of symptoms related to vitamin B12 deficiency (General, Senses, Thinking, In limbs and/or face, Movement, Emotions, Mouth & Abdomen, Urinary tract & Reproductive organs). Cognitive interviews demonstrated good comprehensibility and comprehensiveness. CONCLUSIONS: This study is the first step in the development of a disease-specific PROM for vitamin B12 deficiency to measure the burden of symptoms. Further validation and reliability testing are necessary before the PROM can be applied in clinical practice and research.

Plain language titleDevelopment of a Vitamin B12 Deficiency Questionnaire for Clinical Practice and ResearchPlain language summaryThis study is the first step in the development of a questionnaire for vitamin B12 deficiency to measure the severity of vitamin B12 deficiency symptoms. The questionnaire includes 62 items grouped into 8 categories of symptoms related to vitamin B12 deficiency (General, Senses, Thinking, In limbs and/or face, Movement, Emotions, Mouth & Abdomen, Urinary tract & Reproductive organs). Interviews with patients demonstrated good comprehensibility and comprehensiveness of the questionnaire. Further testing is necessary before the questionnaire can be applied in clinical practice and research.

Persisting Effects of Ayahuasca on Empathy, Creative Thinking, Decentering, Personality, and Well-Being.

Background: Naturalistic and placebo-controlled studies have suggested that ayahuasca, a traditional Amazonian beverage, could be helpful in the treatment of psychopathologies like depression and anxiety disorders by changing otherwise disturbed cognitive and emotional processes. To better understand its full therapeutic potential, one way is to study the effects on processes like flexible thinking, empathy, and well-being, which are normally compromised in stress-related psychopathologies. Materials and Methods: Volunteers attending ayahuasca ceremonies were asked to complete a test battery at three separate occasions: baseline, the morning after, and 1 week after the ceremony. We included the constructs of creative thinking (measured by Picture Concept Test), empathy (Multifaceted Empathy Test), satisfaction with life (Satisfaction with Life Scale), decentering (Experiences Questionnaire), and personality (Big Five Inventory) into the test battery. Additionally, the psychedelic experience was quantified with the Persisting Effects Questionnaire, the Ego Dissolution Scale, and Visual Analogue Scales. Results: In total, 43 attendees (males = 22; females = 21) completed parts of the baseline assessment, 20 (males = 12; females = 8) completed assessments in the morning after the ceremony, and 19 (males = 14; females = 5) completed assessments at the 1-week follow-up. At one and 7 days post-ceremony, cognitive empathy, satisfaction with life, and decentering increased, while divergent thinking (Fluency corrected for Originality) decreased, when compared to baseline. Implicit emotional empathy increased at 1-week follow-up, whereas ratings of the trait neuroticism decreased. Conclusion: The study suggests that a single ingestion of ayahuasca in a social setting is associated with enhancement of subjective well-being, an enhanced ability to take an objective and non-judging stance towards the self (decentering), and the ability to correctly recognize emotions in others, compared to baseline, lasting up to 1 week post-ceremony. To understand the therapeutic potential related to these effects, further research with clinical populations is needed in which these effects can be assessed, including its link with therapeutic outcomes. Together, this will increase our understanding of the effectiveness and breadth of future therapeutic options.

Voice Characteristics in Patients with Acromegaly during Treatment.

BACKGROUND: Active acromegaly is characterized by Growth Hormone and Insulin-like Growth Factor (IGF)-1 excess. Voice complaints are common in active acromegaly and are suggested to be caused by effects of Growth Hormone or IGF-1 on vocal folds and the surrounding soft tissues. Prospective studies on the course of voice characteristics in acromegaly patients are scarce and results are conflicting. This study investigates objective changes in voice parameters, self-reported perception of voice and laryngostroboscopic features during the first 2.5 years of acromegaly treatment. MATERIAL AND METHOD: In this prospective study, acoustic voice analysis (and videolaryngostroboscopic examination were performed in 27 consecutive treatment-naive acromegaly patients at diagnosis (T0), after 1 year (T1) and after 2.5 years (T2) of treatment. The voice handicap index (VHI-30) questionnaire was taken. RESULTS: During acromegaly treatment, VHI scores decreased, and mucosal edema & hypertrophy diminished. No significant changes in objective voice parameters were detected. The within-subject change in serum IGF-1 levels (97.3 (40.6-208) to 22.4 (10.2-34.1) nmol/L (P < 0.001)) during follow-up correlated positively with the changes in VHI questionnaire scores (R 0.32-0.45; P = 0.002-0.03). CONCLUSIONS: At diagnosis and during acromegaly treatment, mean VHI scores were in the normal range, although they decreased during follow-up. Mucosal edema and hypertrophy largely resolved during treatment. No significant changes in objective voice parameters were observed. Voice characteristics are in the normal range in patients with acromegaly, but may change during treatment. However, voice complaints are important to discuss, since they may influence quality of life.

White matter lesions in multiple sclerosis are enriched for CD20dim CD8+ tissue-resident memory T cells.

Brain CD8+ CD69+ tissue-resident memory T (TRM ) cells comprise a CD20dim subset, which is proportionally larger in CD103-negative TRM cells. In multiple sclerosis (MS) lesions, CD20dim TRM -cell proportions are increased. CD20-expression is associated with higher levels of CXCR6, Ki-67, and granzyme B, supporting CD20dim TRM cells as a relevant subset in MS.

Circulating and Tissue-Resident CD4+ T Cells With Reactivity to Intestinal Microbiota Are Abundant in Healthy Individuals and Function Is Altered During Inflammation.

BACKGROUND & AIMS: Interactions between commensal microbes and the immune system are tightly regulated and maintain intestinal homeostasis, but little is known about these interactions in humans. We investigated responses of human CD4+ T cells to the intestinal microbiota. We measured the abundance of T cells in circulation and intestinal tissues that respond to intestinal microbes and determined their clonal diversity. We also assessed their functional phenotypes and effects on intestinal resident cell populations, and studied alterations in microbe-reactive T cells in patients with chronic intestinal inflammation. METHODS: We collected samples of peripheral blood mononuclear cells and intestinal tissues from healthy individuals (controls, n = 13-30) and patients with inflammatory bowel diseases (n = 119; 59 with ulcerative colitis and 60 with Crohn's disease). We used 2 independent assays (CD154 detection and carboxy-fluorescein succinimidyl ester dilution assays) and 9 intestinal bacterial species (Escherichia coli, Lactobacillus acidophilus, Bifidobacterium animalis subsp lactis, Faecalibacterium prausnitzii, Bacteroides vulgatus, Roseburia intestinalis, Ruminococcus obeum, Salmonella typhimurium, and Clostridium difficile) to quantify, expand, and characterize microbe-reactive CD4+ T cells. We sequenced T-cell receptor Vß genes in expanded microbe-reactive T-cell lines to determine their clonal diversity. We examined the effects of microbe-reactive CD4+ T cells on intestinal stromal and epithelial cell lines. Cytokines, chemokines, and gene expression patterns were measured by flow cytometry and quantitative polymerase chain reaction. RESULTS: Circulating and gut-resident CD4+ T cells from controls responded to bacteria at frequencies of 40-4000 per million for each bacterial species tested. Microbiota-reactive CD4+ T cells were mainly of a memory phenotype, present in peripheral blood mononuclear cells and intestinal tissue, and had a diverse T-cell receptor Vß repertoire. These cells were functionally heterogeneous, produced barrier-protective cytokines, and stimulated intestinal stromal and epithelial cells via interleukin 17A, interferon gamma, and tumor necrosis factor. In patients with inflammatory bowel diseases, microbiota-reactive CD4+ T cells were reduced in the blood compared with intestine; T-cell responses that we detected had an increased frequency of interleukin 17A production compared with responses of T cells from blood or intestinal tissues of controls. CONCLUSIONS: In an analysis of peripheral blood mononuclear cells and intestinal tissues from patients with inflammatory bowel diseases vs controls, we found that reactivity to intestinal bacteria is a normal property of the human CD4+ T-cell repertoire, and does not necessarily indicate disrupted interactions between immune cells and the commensal microbiota. T-cell responses to commensals might support intestinal homeostasis, by producing barrier-protective cytokines and providing a large pool of T cells that react to pathogens.

Clinical Outcome After Arthroscopic Debridement and Microfracture for Osteochondritis Dissecans of the Capitellum.

BACKGROUND: Various surgical treatment techniques have been developed to treat capitellar osteochondritis dissecans; however, the optimal technique remains the subject of ongoing debate. PURPOSE: To evaluate clinical outcomes after arthroscopic debridement and microfracture for advanced capitellar osteochondritis dissecans. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between 2008 and 2015, the authors followed 77 consecutive patients (81 elbows) who underwent arthroscopic debridement and microfracture, and loose body removal if needed, for advanced capitellar osteochondritis dissecans. Seventy-one patients (75 elbows) with a minimum follow-up of 1 year were included. The mean age was 16 years (SD, ±3.3 years; range, 11-26 years) and the mean follow-up length was 3.5 years (SD, ±1.9 years; range, 1-8.2 years). Based on CT and/or MRI results, 71 lesions were classified as unstable and 4 as stable. Clinical elbow outcome (pain, function, and social-psychological effect) was assessed using the Oxford Elbow Score (OES) at final follow-up (OES range, 0-48). Range of motion and return to sports were recorded. Multivariable linear regression analysis was performed to determine predictors of postoperative OES. RESULTS: Intraoperatively, there were 3 grade 1 lesions, 2 grade 2 lesions, 10 grade 3 lesions, 1 grade 4 lesion, and 59 grade 5 lesions. The mean postoperative OES was 40.8 (SD, ±8.0). An open capitellar physis was a predictor of better elbow outcome (5.8-point increase; P = .025), as well as loose body removal/grade 4-5 lesions (6.9-point increase; P = .0020) and shorter duration of preoperative symptoms (1.4-point increase per year; P = .029). Flexion slightly improved from 134° to 139° ( P < .001); extension deficit slightly improved from 8° to 3° ( P < .001). Pronation ( P = .47) and supination did not improve ( P = .065). Thirty-seven patients (55%) returned to their primary sport at the same level, and 5 patients (7%) returned to a lower level. Seventeen patients (25%) did not return to sport due to elbow-related symptoms, and 10 patients (13%) did not return due to non-elbow-related reasons. No complications were recorded. CONCLUSION: Arthroscopic debridement and microfracture for advanced capitellar osteochondritis dissecans provide good clinical results, especially in patients with open growth plate, loose body removal, and shorter duration of symptoms. However, only 62% of patients in this study returned to sports.

Separate and combined effects of dehydration and thirst sensation on exercise performance in the heat.

Using intravenous infusion, we separated the physiologic consequences of 3% body mass dehydration from the conscious awareness of fluid replacement on time trial (TT) performance in the heat. Eleven trained cyclists performed 90 min of steady-state (50% V ˙ O 2 peak ) cycling followed by a self-paced 20-km TT in a hot-dry (35 °C, 10% relative humidity, wind speed 3.0 m/s) environment while euhydrated-not thirsty (EU-NT), euhydrated-thirsty (EU-T), dehydrated-not thirsty (DH-NT), or dehydrated-thirsty (DH-T). Thirst was manipulated by providing (NT) or withholding (T) ad libitum 35 °C water oral rinse. Distinct hydration states existed, with 0.4 ± 0.5% dehydration following the 20-km TT (EU) compared with 3.2 ± 0.6% in DH (P < 0.001). Greater perceived thirst existed in T (7 ± 2 on a 1-9 scale) than NT (4 ± 2, P < 0.001) after the TT. No significant differences in power output existed during the TT between hydration (EU 202.9 ± 36.5 W vs DH 207.0 ± 35.9 W, P = 0.362) and thirst conditions (NT 203.3 ± 35.6 W vs T 206.6 ± 36.8 W, P = 0.548), nor were there differences in completion time (P = 0.832) or pacing profile (P = 0.690). Within the range of up to 3% body mass loss, neither the physiologic effects from lowered hydration status nor the perception of thirst, separately or combined, affected sustained submaximal exercise performance in the heat for a healthy and fit population.

Let's use those tests! Evaluations of crime-related amnesia claims.

Suspects awaiting trial often claim that they cannot remember important parts of their violent crimes. It is not unusual that forensic experts readily accept such claims and interpret them in terms of dissociative amnesia or, more specifically, a "red-out". This interpretation hinges on the assumption that heightened levels of stress implicated in violent crimes interfere with memory. We argue that the notion of red-out is a priori not plausible and that alternative interpretations-primarily malingering and substance-induced organic amnesia-should be considered and ruled out first before concluding that memory loss is dissociative in nature. We illustrate our point with four cases that superficially have the contours of red-out tragedies. We believe that, in such cases, neuropsychological tests and/or psychopharmacological information on dose-response relationships can assist forensic experts to exclude malingering or substance-induced amnesia. There is no reason for not using tests and tools from neuropsychology and psychopharmacology.

Prediction of BRCA2-association in hereditary breast carcinomas using array-CGH.

Germline mutations in BRCA1/2 increase the lifetime risk for breast and ovarian cancer dramatically. Identification of such mutations is important for optimal treatment decisions and pre-symptomatic mutation screening in family members. Although current DNA diagnostics is able to identify many different mutations, it remains unclear, how many BRCA2-associated breast cancer cases remain unidentified as such. In addition, mutation scanning detects many unclassified variants (UV) for which the clinical relevance is uncertain. Therefore, our aim was to develop a test to identify BRCA2-association in breast tumors based on the genomic signature. A BRCA2-classifier was built using array-CGH profiles of 28 BRCA2-mutated and 28 sporadic breast tumors. The classifier was validated on an independent group of 19 BRCA2-mutated and 19 sporadic breast tumors. Subsequently, we tested 89 breast tumors from suspected hereditary breast (and ovarian) cancer (HBOC) families, in which either no BRCA1/2 mutation or an UV had been found by routine diagnostics. The classifier showed a sensitivity of 89% and specificity of 84% on the validation set of known BRCA2-mutation carriers and sporadic tumor cases. Of the 89 HBOC cases, 17 presented a BRCA2-like profile. In three of these cases additional indications for BRCA2-deficiency were found. Chromosomal aberrations that were specific for BRCA2-mutated tumors included loss on chromosome arm 13q and 14q, and gain on 17q. Since we could separate BRCA1-like, BRCA2-like, and sporadic-like tumors, using our current BRCA2- and previous BRCA1-classifier, this method of breast tumor classification could be applied as additional test for current diagnostics to help clinicians in decision making and classifying sequence variants of unknown significance.

Genomic signature of BRCA1 deficiency in sporadic basal-like breast tumors.

About 10-20% of all breast carcinomas show a basal-like phenotype, while ∼ 90% of breast tumors from BRCA1-mutation carriers are of this subtype. There is growing evidence that BRCA1-mutated tumors are not just a specific subset of the basal-like tumors, but that (the majority of) basal-like tumors show a dysfunctional BRCA1 pathway. This has major treatment implications, because emerging regimens specifically targeting DNA repair mechanisms would then be most effective against these tumors. To further understand the involvement of BRCA1 deficiency in sporadic basal-like tumors, we investigated 41 basal-like tumors for BRCA1 mRNA expression by quantitative real-time polymerase chain reaction, BRCA1 promoter methylation, their genomic profile by array-CGH, and gene expression levels by whole genome expression arrays. Array-CGH results were compared to those of 34 proven BRCA1-mutated tumors. Basal-like tumors were subdivided into two equal groups: deficient and proficient in BRCA1 gene expression. The chromosomal makeup of BRCA1 deficient sporadic basal-like tumors was similar to that of BRCA1-mutated tumors. BRCA1 proficient sporadic basal-like tumors were more similar to nonbasal-like tumors. Only half of the basal-like breast tumors are actually deficient in BRCA1 expression. Gain of chromosome arm 3q is a marker for BRCA1 deficiency in hereditary and sporadic breast tumors.

Generalized priority-queue network dynamics: impact of team and hierarchy.

We study the effect of team and hierarchy on the waiting-time dynamics of priority-queue networks. To this end, we introduce generalized priority-queue network models incorporating interaction rules based on team-execution and hierarchy in decision making, respectively. It is numerically found that the waiting-time distribution exhibits a power law for long waiting times in both cases, yet with different exponents depending on the team size and the position of queue nodes in the hierarchy, respectively. The observed power-law behaviors have in many cases a corresponding single or pairwise-interacting queue dynamics, suggesting that the pairwise interaction may constitute a major dynamic consequence in the priority-queue networks. It is also found that the reciprocity of influence is a relevant factor for the priority-queue network dynamics.

Waiting time dynamics of priority-queue networks.

We study the dynamics of priority-queue networks, generalizations of the binary interacting priority-queue model introduced by Oliveira and Vazquez [Physica A 388, 187 (2009)]. We found that the original AND-type protocol for interacting tasks is not scalable for the queue networks with loops because the dynamics becomes frozen due to the priority conflicts. We then consider a scalable interaction protocol, an OR-type one, and examine the effects of the network topology and the number of queues on the waiting time distributions of the priority-queue networks, finding that they exhibit power-law tails in all cases considered, yet with model-dependent power-law exponents. We also show that the synchronicity in task executions, giving rise to priority conflicts in the priority-queue networks, is a relevant factor in the queue dynamics that can change the power-law exponent of the waiting time distribution.

Reducing discomfort while measuring crown-heel length in neonates.

AIM: To assess the degree of discomfort caused by length measurement in neonates, performed with one or both lower limbs extended, on the first and second day after birth, with either one or both lower limbs extended. METHODS: Healthy full-term neonates were systematically sampled during the months of February and March 2004. Crown-heel length was measured, using a 1-mm precision neonatometer, at approximately 8 h and 32 h after birth, with one and both lower limbs extended. The Neonatal Facial Coding System was used to assess discomfort during measurements. Data were analysed by parametric and non-parametric tests as appropriate. RESULTS: Whatever the measurement technique, discomfort scores are significantly higher during the length measurement than at baseline. Whenever length measurements are performed, discomfort scores are significantly higher when extending both lower limbs rather than one lower limb (p < 0.006). The measured length is greater with one lower limb extended; however, the difference decreases over time, being 0.19 cm (95% CI 0.1-0.3; p < 0.001) at approximately 32 h of age. No significant differences in length were found between measurements at approximately 8 or 32 h, regardless of the technique used. The best correlation between length measurements with one or both lower limbs extended was observed at approximately 32 h after birth (r = 0.98). CONCLUSION: Measuring crown-heel length is a distressful procedure for the neonate. Measurements with one lower limb extended result in less discomfort than when both lower limbs are extended, without decreasing the accuracy.

Vestibular schwannoma with malignant transformation: a case report.

We describe a rare case of malignant transformation in a vestibular schwannoma in a 33-yr-old woman. She presented herself with headache, tinnitus, and hearing loss and underwent posterior fossa explorations three times during the short period of 3 months. The clinicopathological features of the original tumor were typical of benign vestibular schwannoma. Despite a complete microsurgical excision, two months later, the tumor recurred locally with a rapid increase in size causing a progressive worsening of neurological symptoms. A diagnosis of malignant schwannoma was made for the recurrent tumor on the basis of the microscopic findings of high cellularity, moderate pleomorphism, and the presence of mitotic cells. Repeat magnetic resonance imaging performed a month after the second surgery unexpectedly showed definite tumor enlargement. She remained clinically stable following the third debulking of the tumor and adjuvant radiotherapy. We propose that this recurrent tumor represent malignant transformation from a benign vestibular schwannoma which was an unusual occurrence in a patient without neurofibromatosis.

Binary spreading process with parity conservation.

Recently there has been a debate concerning the universal properties of the phase transition in the pair contact process with diffusion (PCPD) 2A-->3A, 2A-->0. Although some of the critical exponents seem to coincide with those of the so-called parity-conserving universality class, it was suggested that the PCPD might represent an independent class of phase transitions. This point of view is motivated by the argument that the PCPD does not conserve parity of the particle number. In the present work we question what happens if the parity conservation law is restored. To this end, we consider the reaction-diffusion process 2A-->4A, 2A-->0. Surprisingly, this process displays the same type of critical behavior, leading to the conclusion that the most important characteristics of the PCPD is the use of binary reactions for spreading, regardless of whether parity is conserved or not.

Self-organized growth model for a driven interface in random media.

We introduce a simple self-organized growth model in the quenched Edwards-Wilkinson universality class. The roughness and growth exponents are obtained for the model as alpha approximately 1.15 and beta approximately 0.89, respectively. These values of exponents are in good agreement with previous results obtained from numerical integrations or discretized model simulations of the quenched Edwards-Wilkinson equation. The velocity of a driven interface is found to be independent of the slope of the tilted substrate.

A new endemic focus of Heterophyes nocens, Pygidiopsis summa, and other intestinal flukes in a coastal area of Muan-gun, Chollanam-do.

A small coastal village of Muan-gun, Chollanam-do, was surveyed for intestinal fluke infections, especially heterophyids such as Heterophyes nocens and Pygidiopsis summa by fecal examination on 108 inhabitants. The egg positive rate of heterophyids was very high, 75.0%, and that of other parasites was comparatively low, 0.9-3.7% by parasite species. After treatment of 20 patients showing high E.P.G. with praziquantel and purging with MgSO4, total 3,864 specimens of H. nocens were collected from the diarrheic stools of all the patients treated (3-1,338 individually) and total 703 P. summa were harvested from 18 patients (1-170 individually), together with several other species of flukes. Other flukes included Stictodora fuscata (164 specimens from 4 patients), Heterophyopsis continua (2 from 2 patients), and Gymnophalloides seoi (4 from 3 patients). From this study, the surveyed coastal area of Muan-gun, Chollanam-do was proven to be a new endemic focus of H. nocens and P. summa. The occurrence of a few infected cases suggests that this area should also be a low-grade endemic area of S. fuscata, H. continua, and G. seoi.