The earliest events in BRAF-mutant colorectal cancer: exome sequencing of sessile serrated lesions with a tiny focus dysplasia or cancer reveals recurring mutations in two distinct progression pathways.

Around 15-30% of colorectal cancers (CRC) develop from sessile serrated lesions (SSLs). After many years of indolent growth, SSLs can develop dysplasia and rapidly progress to CRC through events that are only partially understood. We studied molecular events at the very early stages of progression of SSLs via the MLH1-proficient and deficient pathways to CRC. We collected a cohort of rare SSLs with a small focus (<10 mm) of dysplasia or cancer from the pathology archives of three hospitals. Whole-exome sequencing was performed on DNA from nonprogressed and progressed components of each SSL. Putative somatic driver mutations were identified in known cancer genes that were differentially mutated in the progressed component. All analyses were stratified by MLH1 proficiency. Forty-five lesions with a focus dysplasia or cancer were included, of which 22 (49%) were MLH1-deficient. Lesions had a median diameter of 10 mm (interquartile range [IQR] 8-15), while the progressed component had a median diameter of 3.5 mm (IQR 1.75-4.75). Tumor mutational burden (TMB) was high in MLH1-deficient lesions (23.9 mutations per MB) as compared to MLH1-proficient lesions (6.3 mutations per MB). We identified 34 recurrently mutated genes in MLH1-deficient lesions. Most prominently, ACVR2A and RNF43 were affected in 18/22 lesions, with mutations clustered in three hotspots. Most lesions with RNF43 mutations had concurrent mutations in ZNRF3. In MLH1-proficient lesions APC (10/23 lesions) and TP53 (6/23 lesions) were recurrently mutated. Our results show that the mutational burden is exceptionally high even in the earliest MLH1-deficient lesions. We demonstrate that hotspot mutations in ACVR2A and in the RNF43/ZNRF3 complex are extremely common in the early progression of SSLs along the MLH1-deficient serrated pathway, while APC and TP53 mutations are early events in the the MLH1-proficient pathway. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

[Cutaneous granulomatous reactions at botulinum neurotoxin A injection sites: First manifestation of systemic sarcoidosis]. / Granulomatöse Hautveränderungen an Botulinumtoxin-A-Injektionsstellen : Erstmanifestation einer systemischen Sarkoidose.

CASE REPORT: We report a case of granulomatous skin reaction after injection of an unknown botulinum neurotoxin (BoNT) A preparation. Four years after occurrence of skin lesions, systemic sarcoidosis became manifest. CONCLUSION: In addition to injection trauma, the BoNT A preparation may have acted as an immunogenic stimulus leading to cutaneous manifestation of sarcoidosis.

[Psoriasis-associated keratitis: case report]. / Psoriasisassoziierte Keratitis : Eine Fallvorstellung.

Psoriasis is a common skin disease, which is associated with multiple extracutaneous manifestations. This article presents a case report of a rare ocular manifestation of psoriasis; psoriasis-associated keratitis. In a 37-year-old man we could show that systemic immunomodulatory therapy led to a rapid improvement of the ocular symptoms.

Assessment of vision-related quality of life in patients with central retinal artery occlusion.

BACKGROUND: Central retinal artery occlusion (CRAO) is a major cause for severe visual impairment. Its effect on vision-related quality of life has not yet been determined. The purpose of the present study was thus to assess vision-related quality of life in patients with CRAO using the 39-item National Eye Institute Visual Function Questionnaire. METHODS: The case-control study comprised 26 patients with unilateral CRAO and a control group consisting of 26 control subjects, matched for age and sex. Vision-related quality of life was measured using the 39-item National Eye Institute Visual Function Questionnaire. RESULTS: After Bonferroni correction, the median 39-item National Eye Institute Visual Function Questionnaire composite score was significantly lower in patients with CRAO than in those in the control group (P(corr) < 0.001). Patients with CRAO showed significantly lower median scores in 9 of 12 subscales: general vision (P(corr) < 0.001), peripheral vision (P(corr) < 0.001), difficulties with near-vision activities (P(corr) < 0.001), difficulties with distance-vision activities (P(corr) < 0.001), role difficulties as a result of vision problems (P(corr) < 0.001), dependency on others because of vision problems (P(corr) < 0.001), limitations in social functioning because of vision problems (P(corr) < 0.001), mental health symptoms because of vision problems (P(corr) < 0.001), and general health (P(corr) = 0.008). CONCLUSION: Our data suggest that vision-related quality of life is reduced in patients with CRAO.

Appendiceal spirochaetosis in children.

BACKGROUND: Acute appendicitis is a surgical emergency in which the appendix is surgically removed to prevent peritonitis due to perforation of the appendix. Depending on age and gender, up to 17% of removed appendices do not show the histopathological changes pathognomonic for acute appendicitis and are called 'pseudo-appendicitis'. Intestinal spirochaetes have been reported in up to 12.3% of these non-inflamed appendices obtained from adults. Although children carry the highest risk for acute appendicitis, not much is known on the prevalence of intestinal spirochaetes in children. The aim of this study was to determine whether there is an association between pseudo-appendicitis and appendiceal spirochaetosis in children. METHODS: Archival appendix specimens from paediatric patients (less than 18 years old) were obtained from two Dutch hospitals (acute appendicitis, n = 63; pseudo-appendicitis, n = 55; control appendices, n = 33) and microscopically analysed by H&E staining and spirochaete-specific immunohistochemistry and Brachyspira species specific real-time PCR. RESULTS: Five out of 142 appendices were found to be positive, all in male patients: one in the acute appendicitis group, two in the pseudo-appendicitis group and two in the control group. CONCLUSION: The results obtained do not provide evidence for a role of Brachyspira species infection in the aetiology of acute appendicitis in children.

Expression of matrix metalloproteinases in human growth plate chondrocytes is enhanced at high levels of mechanical loading: A possible explanation for overuse injuries in children.

Matrix metalloproteinases (MMPs), responsible for extracellular matrix remodelling and angiogenesis, might play a major role in the response of the growth plate to detrimental loads that lead to overuse injuries in young athletes. In order to test this hypothesis, human growth plate chondrocytes were subjected to mechanical forces equal to either physiological loads, near detrimental or detrimental loads for two hours. In addition, these cells were exposed to physiological loads for up to 24 hours. Changes in the expression of MMPs -2, -3 and -13 were investigated. We found that expression of MMPs in cultured human growth plate chondrocytes increases in a linear manner with increased duration and intensity of loading. We also showed for the first time that physiological loads have the same effect on growth plate chondrocytes over a long period of time as detrimental loads applied for a short period. These findings confirm the involvement of MMPs in overuse injuries in children. We suggest that training programmes for immature athletes should be reconsidered in order to avoid detrimental stresses and over-expression of MMPs in the growth plate, and especially to avoid physiological loads becoming detrimental.

Bioassay-guided investigation of the Tanzanian plant Pyrenacantha kaurabassana for potential anti-HIV-active compounds.

Two new anti-HIV xanthones, 6,7,11-trihydroxy-10-methoxy-9-(7-methoxy-3-methyl-1-oxoisochroman-5-yl)-2-methyl-12-oxo-12H-benzo[b]xanthene-4-carboxylic acid (1) and 6,7-dihydroxy-10,11-dimethoxy-9-(7-methoxy-3-methyl-1-oxoisochroman-5-yl)-2-methyl-12-oxo-12H-benzo[b]xanthene-4-carboxylic acid (2), and a new hexadecahydrochrysen-3-ol (3) were isolated from the tubers of Pyrenacantha kaurabassana. Compounds 1 and 2 showed moderate anti-HIV activity when tested in the deCIPhR assay on HIV virus type NL4-3, with IC50 values of 21 and 2 µg/mL, respectively.

Observer variation in the histopathologic assessment of extranodal tumor spread in lymph node metastases in the neck.

BACKGROUND: Extranodal spread (ENS) of tumors is widely used as a prognosticator for patients with head and neck cancer and is used as an indicator for postoperative treatment. However, the histopathologic agreement among pathologists on the assessment of the presence or absence of this criterion has never been studied. METHODS: The interobserver and intraobserver agreement among 10 pathologists on the diagnosis of ENS in 41 tumor-positive lymph nodes was evaluated. RESULTS: The kappa value of the interobserver agreement among pathologists varied between 0.14 and 0.75, the overall kappa value was 0.42 and 0.49 in the 2 scoring sessions. The intraobserver kappa value varied between 0.49 and 0.95. CONCLUSION: The intraobserver and interobserver agreement among pathologists in the assessment of the presence of ENS was low in metastatic lymph nodes in the neck. Because of the widely accepted prognostic significance and therapeutic consequences of ENS, there is a need for internationally accepted reproducible criterion for the histopathologic assessment of ENS in metastatic lymph nodes in the neck.

A uterine leiomyoma in which a leiomyosarcoma with osteoclast-like giant cells and a metastasis of a ductal breast carcinoma are present.

Leiomyosarcoma of the uterus is a rare tumor, and the presence of osteoclast-like giant cells in this tumor is even rarer. A leiomyosarcoma arising in a leiomyoma is also quite unique. Breast cancer metastasizing to the uterus is seldom seen as well. A 70-year-old woman presented with metastasized breast cancer to the bones. An evaluation of the computed tomographic scan was made, which showed an enlarged uterus with a tumor. The tumor was a leiomyoma in which a leiomyosarcoma with osteoclast-like giant cells as well as a metastasis of a ductal breast carcinoma was present. To our knowledge, this is the first report of a leiomyosarcoma containing osteoclast-like giant cells, present in a leiomyoma, in a uterus also containing a ductal breast cancer metastasis present in the leiomyoma and myometrium.

Development of a real-time PCR for identification of brachyspira species in human colonic biopsies.

BACKGROUND: Brachyspira species are fastidious anaerobic microorganisms, that infect the colon of various animals. The genus contains both important pathogens of livestock as well as commensals. Two species are known to infect humans: B. aalborgi and B. pilosicoli. There is some evidence suggesting that the veterinary pathogenic B. pilosicoli is a potential zoonotic agent, however, since diagnosis in humans is based on histopathology of colon biopsies, species identification is not routinely performed in human materials. METHODS: The study population comprised 57 patients with microscopic evidence of Brachyspira infection and 26 patients with no histopathological evidence of Brachyspira infection. Concomitant faecal samples were available from three infected patients. Based on publically available 16S rDNA gene sequences of all Brachyspira species, species-specific primer sets were designed. DNA was extracted and tested by real-time PCR and 16S rDNA was sequenced. RESULTS: Sensitivity and specificity for identification of Brachyspira species in colon biopsies was 100% and 87.7% respectively. Sequencing revealed B. pilosicoli in 15.4% of patients, B. aalborgi in 76.9% and a third species, tentatively named "Brachyspira hominis", in 26.2%. Ten patients (12.3%) had a double and two (3.1%) a triple infection. The presence of Brachyspira pilosicoli was significantly associated with inflammatory changes in the colon-biopsy (p=0.028). CONCLUSIONS: This newly designed PCR allows for sub-differentiation of Brachyspira species in patient material and thus allows large-scaled surveillance studies to elucidate the pathogenicity of human Brachyspira infections. One-third of affected patients appeared to be infected with a novel species.

Use of traditional medicines in the management of HIV/AIDS opportunistic infections in Tanzania: a case in the Bukoba rural district.

BACKGROUND: Ethnobotanical surveys were carried out to document herbal remedies used in the management of HIV/AIDS opportunistic infections in Bukoba Rural district, Tanzania. The district is currently an epicenter of HIV/AIDS and although over 90% of the population in the district relies on traditional medicines to manage the disease, this knowledge is impressionistic and not well documented. The HIV/AIDS opportunistic conditions considered during the study were Tuberculosis (TB), Herpes zoster (Shingles), Herpes simplex (Genital herpes), Oral candidiasis and Cryptococcal meningitis. Other symptomatic but undefined conditions considered were skin rashes and chronic diarrhea. METHODS: An open-ended semi-structured questionnaire was used in collecting field information. Descriptive statistics were used to analyze the ethnobotanical data collected. Factor of informant consensus (Fic) was used to analyze the ethnobotanical importance of the plants. RESULTS: In the present study, 75 plant species belonging to 66 genera and 41 families were found to be used to treat one or more HIV/AIDS related infections in the district. The study revealed that TB and oral candidiasis were the most common manifestations of HIV/AIDS opportunistic infections affecting most of the population in the area. It unveils the first detailed account of ethnomedical documentation of plants focusing the management of HIV/AIDS related infections in the district. CONCLUSION: It is concluded that the ethnopharmacological information reported forms a basis for further research to identify and isolate bioactive constituents that can be developed to drugs for the management of the HIV/AIDS opportunistic infections.

Long-term effects of rainforest disturbance on the nutrient composition of throughfall, organic layer percolate and soil solution at Mt. Kilimanjaro.

At the lower parts of the forest belt at Mt. Kilimanjaro, selective logging has led to a mosaic of mature forest, old secondary forests ( approximately 60 years), and old clearings ( approximately 10 years) covered by shrub vegetation. These variations in the vegetation are reflected by differences in nutrient leaching from the canopy and in both amount and quality of litter reaching the ground, thereby also influencing mineralization rates and the composition of seepage water in litter percolate and soil solution. The aim of this study was to investigate how above- and belowground nutrient dynamics vary between regeneration stages, and if forest regeneration at the clearings is hampered by a deterioration of abiotic site conditions. K, Mg, Ca, Na and N compounds were analysed in rainfall, throughfall, organic layer percolate and the soil solution to a depth of 1.00 m at three clearings, three secondary forest and four mature forest sites. Element fluxes via throughfall showed only small variations among regeneration stages except for K and NO(3)-N. With 57-83 kg ha(-1) a(-1)and 2.6-4.1 kg ha(-1) a(-1) respectively, K and NO(3)-N fluxes via throughfall were significantly higher at the clearings than at the mature forest sites (32-37 and 0.7-1.0 kg ha(-1) a(-1) for K and NO(3)-N). In organic layer percolate and in soil solution at 0.15-m soil depth, concentrations of K, Mg, Ca and N were highest at the clearings. In the organic layer percolate, median K concentrations were e.g. 7.4 mg l(-1) for the clearings but only 1.4 mg l(-1) for the mature forests, and for NO(3)-N, median concentrations were 3.1 mg l(-1) for the clearings but only 0.92 mg l(-1) for the mature forest sites. Still, differences in annual means between clearings and mature forests were not always significant due to a high variability within the clearings. With the exception of NO(3)-N, belowground nutrient concentrations in secondary forests ranged between concentrations in mature forests and clearings. Vegetation type-specific differences decreased with increasing soil depths in the soil solution. Overall, the opening of the forest led to a higher spatial and seasonal variation of nutrient concentrations in the seepage water. These results suggest differences in both mineralization rates and in nutrient budgeting at different regeneration stages. Since nutrient availability was highest at the clearings and no compaction of the soil was observed, deterioration of soil properties did not seem to be the main reason for the impeded regeneration on the clearings.

Key science questions from the second conference on early Mars: geologic, hydrologic, and climatic evolution and the implications for life.

In October 2004, more than 130 terrestrial and planetary scientists met in Jackson Hole, WY, to discuss early Mars. The first billion years of martian geologic history is of particular interest because it is a period during which the planet was most active, after which a less dynamic period ensued that extends to the present day. The early activity left a fascinating geological record, which we are only beginning to unravel through direct observation and modeling. In considering this time period, questions outnumber answers, and one of the purposes of the meeting was to gather some of the best experts in the field to consider the current state of knowledge, ascertain which questions remain to be addressed, and identify the most promising approaches to addressing those questions. The purpose of this report is to document that discussion. Throughout the planet's first billion years, planetary-scale processes-including differentiation, hydrodynamic escape, volcanism, large impacts, erosion, and sedimentation-rapidly modified the atmosphere and crust. How did these processes operate, and what were their rates and interdependencies? The early environment was also characterized by both abundant liquid water and plentiful sources of energy, two of the most important conditions considered necessary for the origin of life. Where and when did the most habitable environments occur? Did life actually occupy them, and if so, has life persisted on Mars to the present? Our understanding of early Mars is critical to understanding how the planet we see today came to be.

Procalcitonin and C-reactive protein levels in HIV-positive subjects with tuberculosis and pneumonia.

Pulmonary tuberculosis (PTB) and pneumococcal community-acquired pneumonia (PCAP) are common causes of lower respiratory tract infections in HIV-seropositive patients and may have similar clinical and radiological features. This study aimed to assess the value of serum procalcitonin (PCT) and C-reactive protein (CRP) levels in HIV-seropositive patients with pneumonia, and to investigate their potential role in differentiating pneumococcal from mycobacterial infections. HIV-seropositive patients admitted with pneumonia were evaluated prospectively, 34 with PTB and 33 with PCAP. All 33 patients in the PCAP group and 20 of 34 patients in the PTB group had elevated PCT levels (>0.1 ng x mL(-1)). All patients in both groups had elevated CRP levels (>10 mg x L(-1)). The PTB group had significantly lower CD4 T-lymphocyte counts, lower CRP levels, lower white cell counts, and lower PCT levels than the PCAP group. Receiver operating characteristic analysis showed that optimal discrimination between PTB and PCAP could be performed at a cut-off point of 3 ng x mL(-1) for PCT (sensitivity 81.8%; specificity 82.35%) and 246 mg x L(-1) for CRP (sensitivity 78.8%; specificity 82.3%). In conclusion, HIV-seropositive patients with pneumococcal community-acquired pneumonia had significantly higher procalcitonin and C-reactive protein levels than those with pulmonary tuberculosis. A procalcitonin level >3 ng x mL(-1) and a C-reactive protein level >246 mg x L(-1) were both highly predictive of pneumococcal infection.

New perspectives on ancient Mars.

Mars was most active during its first billion years. The core, mantle, and crust formed within approximately 50 million years of solar system formation. A magnetic dynamo in a convecting fluid core magnetized the crust, and the global field shielded a more massive early atmosphere against solar wind stripping. The Tharsis province became a focus for volcanism, deformation, and outgassing of water and carbon dioxide in quantities possibly sufficient to induce episodes of climate warming. Surficial and near-surface water contributed to regionally extensive erosion, sediment transport, and chemical alteration. Deep hydrothermal circulation accelerated crustal cooling, preserved variations in crustal thickness, and modified patterns of crustal magnetization.

Levels of plasma homocysteine in persons with spinal cord injury.

BACKGROUND: Premature coronary vascular disease is a leading cause of morbidity and mortality in persons with chronic spinal cord injury (SCI). Evidence indicates that an elevated plasma homocysteine level is an independent risk factor for vascular disease. METHODS: Plasma homocysteine levels were collected in 845 subjects with SCI and compared to those in a reference population. Differences in plasma homocysteine were determined for sex, race/ethnicity, neurological deficit, and age, as well as for serum creatinine concentration. RESULTS: Plasma homocysteine was significantly higher in men than in women. Men were more likely to have moderately or severely elevated plasma homocysteine levels. Stratifying by male sex, greater percentages of whites and African Americans had severely elevated plasma homocysteine levels (>20 micromol/L) compared with Latinos (12% and 14% versus 8%; P > .01). For the total group with SCI, plasma homocysteine levels were not significantly different by race/ethnicity or neurological deficit subgroup. For the total group (P < .05) and within each sex (men, P < .05; women, P < .01), the older age group with SCI (>50 years) had significantly higher mean plasma homocysteine levels than the younger age group. Age was positively related to plasma homocysteine levels in men (P < .05) and women (P < .01). Plasma homocysteine levels were higher among men for any given age than among women (P < .0001) by an average of 3.19 +/- 0.51 micromol/L. Regardless of age or sex, persons with SCI tended to have higher levels of plasma homocysteine than able-bodied persons matched for age and sex. CONCLUSION: Because the risk of a vascular event increases with age, elevated levels of plasma homocysteine place older persons with SCI at further increased risk for a vaso-occlusive event. Of note, there was a stepwise increase in plasma homocysteine concentration for each quartile of higher serum creatinine concentration. Patients who have elevated levels of plasma homocysteine should receive a trial course of daily supplementation with oral folic acid and vitamin B12. If that is ineffective, they should receive vitamin B6 supplementation to lower their plasma homocysteine levels.